A Selected Chronological Bibliography of Biology and Medicine

 

Part 7B

 

1992 — 2022

 

 

Compiled by James Southworth Steen, Ph.D.

Delta State University

 

Dedicated to my loving family

 

This document celebrates those secondary authors and laboratory technicians without whom most of this great labor of discovery would have proved impossible.

 

Please forward any editorial comments to: James S. Steen, Ph.D., Professor Emeritus, jsteen08@bellsouth.net

 

1992

“One reason why medical history is not much taught in medical schools is that so much of it is an embarrassment.” Lewis Thomas (1451).

 

Edmond H. Fischer (US) and Edwin Gerhard Krebs (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism.

 

Eric Betzig (US) and Jay K. Trautman (US) produced a near-field super-resolution image of a biological sample for the first time (123). Note: Near-field scanning optical microscopy overcomes the diffraction limit by removing the lenses and thus eliminates the need for focusing. Instead, the light passes through a small aperture that is positioned close to the sample (in the near-field zone), such that light cannot substantially diffract. The lateral resolution, determined by the diameter of the aperture, is typically 20-120 nm.

 

Kenneth R. Ludwig (US), Kathleen R. Simmons (US), Barney J. Szabo (US), Isaac J. Winograd (US), Jurate M. Landwehr (US), Alan C. Riggs (US), and Ray J. Hoffman (US) were among the first to use mass spectrometric uranium series dating of calcite (MS/U-series). The technique is typically applied to calcite or tooth materials intercalated into archaeological or paleoanthropological sites and works well for samples between 1,000 and 400,000 years old (909).

 

Uwe Maskos (GB) and Edwin Mellor Southern (GB) described a novel linker for the synthesis of oligonucleotides on a glass support. Oligonucleotides synthesized on the support remain tethered to the support after ammonia treatment and are shown to take part in sequence specific hybridization reactions. These hybridizations were carried out with oligonucleotides synthesized on 'ballotini' solid sphere glass beads and microscope slides. The linker has a hexaethylene glycol spacer, bound to the glass via a glycidoxypropyl silane, terminating in a primary hydroxyl group that serves as starting point for automated or manual oligonucleotide synthesis (950).

 

Douglas C. Prasher (US), Virginia K. Eckenrode (US), Franklyn G. Pendergast (US), and Milton J. Cormier (US) described the cloning and sequencing of both cDNA and genomic clones of green fluorescent protein (GFP) from the cnidarian, Aequorea victoria. The GFP gene encoded by the lambda GFP-2 genomic clone is comprised of at least three exons spread over 2.6 kb (1179).

Martin Chalfie (US), Yuan Tu (US), Ghia Euskirchen (US), William W. Ward (US), and Douglas C. Prather (US) showed that a complementary DNA for the Aequorea victoria green fluorescent protein (GFP) produces a fluorescent product when expressed in prokaryotic (Escherichia coli) or eukaryotic (Caenorhabditis elegans) cells. Because exogenous substrates and cofactors are not required for this fluorescence, GFP expression can be used to monitor gene expression and protein localization in living organisms (224).

 

Mark D. Adams (US), Mark Dubnick (US), Anthony R. Kerlavage (US), Ruben Moreno (US), Jenny M. Kelley (US), Teresa R. Utterback (US), James W. Nagle (US), Chris Fields (US), and John Craig Venter (US) partially sequenced 2,672 new, independent cDNA clones isolated from four human brain cDNA libraries to generate 2,375 expressed sequence tags to nuclear-encoded genes (16).

 

Kimiko Murakami-Murofushi (JP), Masaki Shioda (JP), Kazuhiko Kaji (JP), Shonen Yoshida (JP), and Hiromu A. Murofushi (JP) were the first to describe the parent compound, cyclic phosphatidic acid, which they found in myxoamoebae of a true slime mold, Physarum polycephalum (1037).

Tetsuyuki Kobayashi (JP), Rieko Tanaka-Ishii (JP), Ryo Taguchi (JP), Hiroh Ikezawa (JP), and Kimiko Murakami-Murofushi (JP) found cyclic phosphatidic acid later in the human serum albumin fraction where it may have biological activities related to the inhibition of cell proliferation (782).

 

Gifford H. Miller (US), Peter B. Beaumont (ZA), Anthony J.T. Jull (CA), and Beverly J. Johnson (US) discovered that degradation of polypeptides, including hydrolysis to smaller peptide fragments and eventual release of free amino acids, decomposition, and racemization and epimerization occur at regular, predictable rates dependent on ambient temperature. This provided a method of dating materials of biological origin (996). The method is accurate from 500 to 300,000 years ago.

Gifford H. Miller (US), John W. Magee (AU), Beverly J. Johnson (US), Marilyn L. Fogel (US), Nigel A. Spooner (AU), Malcolm T. McCulloch (AU), and Linda K. Ayliffe (AU) used this dating technique to determine that the large flightless bird Genyornis newtoni became extinct in the late Pleistocene, some 50,00 years ago. They reasoned that extinction was the result of human impact (997).

 

Seunghyon Choe (Korean-US), Melanie J. Bennett (US), Gary Fujii (US), Paul M.G. Curmi (AU), Katherine A. Kantardjieff (US), R. John Collier (US), and David Eisenberg (US) solved the three dimensional structure of diphtheria toxin (247).

 

J. Fernando Bazan (US) determined the tertiary structure of interleukin-2 (IL-2) (103).

 

Yan Luo (US), Hiroshi Fujii (US), Thomas Gerster (CH), and Robert Gayle Roeder (US) demonstrated that coactivators can be ubiquitous, monitoring many genes in a variety of cells, or specific to one particular cell type. They introduced the concept of cell specificity after they demonstrated that the coactivator OCA-B, the first cell-specific coactivator, discovered by Roeder in 1992, is unique to immune system B cells (912).

 

Paul S. Meltzer (US), Xin-Yuan Guan (US), Ann Burgess (US), and Jeffrey M. Trent (US) used microdissection and in vitro amplification of specific chromosomal regions, followed by labelling for fluorescent in situ hybridization (FISH) to normal metaphase chromosomes (Micro-FISH). These Micro-FISH probes could successfully determine the derivation of chromosome segments unidentifiable by standard chromosome banding analysis (987).

 

Anne Kallioniemi (FI), Olli P. Kallioniemi (FI), Damir Sudar (US), Denis Rutovitz (GB), Joe W. Gray (US), Frederic Waldman (US), and Dan Pinkel (US) introduced "comparative genome hybridization" (CGH). This is a form of reverse chromosome painting used to detect chromosome deletions and duplications from a patient's total genomic DNA rather than from his or her karyotype. The patient's DNA is labeled in one color and mixed with control DNA labeled in another color. Both are mixed and hybridized to normal metaphases and the ratio of the two colors determined along the length of each chromosome. Duplications are recognized by the predominance of the subject DNA color, whereas deletions are revealed by the predominance of the control DNA color. CGH has been useful both in screening for small constitutional chromosome aberrations in patients and in detecting aberrations in cancer cells (730).

Sabina Solinas-Toldo (DE), Stefan Lampel (DE), Stephan Stilgenbauer (DE), Jeremy E. Nickolenko (DE), Axel Benner (DE), Hartmut Dohner (DE), Thomas Cremer (DE), Peter Lichter (DE) developed a protocol that allows comparative genomic hybridization (CGH) to chips consisting of glass slides with immobilized target DNAs arrayed in small spots. High-copy-number amplifications contained in tumor cells were rapidly scored by use of target DNAs as small as a cosmid. Low-copy-number gains and losses were identified reliably by their ratios by use of chromosome-specific DNA libraries or genomic fragments as small as 75 kb cloned in PI or PAC vectors as targets, thus greatly improving the resolution achievable by chromosomal CGH (1375).

Donald Pinkel (US), Richard Segraves (US), Damir Sudar (US), Steven Clark (US), Ian Poole (US), David Kowbel (US), Colin Collins (US), Wen-Lin Kuo (US), Chira Chen (US), Ye Zhai (US), Shanaz H. Dairkee (US), Britt-marie Ljung (US), Joe W. Gray (US), Donna G. Albertson (US) developed a high resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays (1168). Note: Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes.

 

Håkan Telenius (CA), Bruce A.J. Ponder (GB), Alan Tunnacliffe (GB), Adèle H. Pelmear (GB), Nigel P. Carter (GB), Malcolm Andrew Ferguson-Smith (GB), Annemarie Behmel (AT), Magnus Nordenskjöld (SE), and Roswitha Pfragner (AT) showed that flow sorting of aberrant chromosomes and chromosome painting can be used as a rapid aid to cytogenetic analysis, particularly in cases of difficult karyotypes, such as tumors. Furthermore, the DOP-PCR technique they described will have applications to other areas of genome analysis, such as cloning of new markers; its design will allow a general and representative amplification to occur from any starting DNA in any species (1446).

 

 Karin G. Au (US), Katherine Welsh (US), and Paul L. Modrich (US) revealed the events involved in the initiation of the E. coli methyl-directed mismatch repair pathway. Using purified Mut proteins, they found that MutL, MutS, and ATP activate the MutH- associated endonuclease, that activation was dependent on ATP hydrolysis, and that the incised d(GATC) sequence could lie either 3' or 5' to the mismatch on the unmethylated strand. From these results they concluded that “MutH activation represents the initiation stage of methyl-directed repair and that interaction of a mismatch and a d(GATC) site is provoked by MutS binding to a mispair, with subsequent ATP-dependent translocation of one or more Mut proteins along the helix leading to cleavage at a d(GATC) sequence on either side of the mismatch" (65).

Michelle Grilley (US), Jack Griffith (US), and Paul L. Modrich (US) suggested that the methyl-directed mismatch repair system is capable of bidirectional excision. To this end they described the nature of the excision tracts produced by the bidirectional repair system in E. coli (542).

Woei-horng Fang (US) and Paul L. Modrich (US) found that the human mismatch repair system not only displays a mismatch specificity similar to that of the bacterial reaction but also shares a bidirectional excision mechanism with properties that are essentially identical with those described for the bacterial pathway (390). Note: This reaction is defective in tumors from patients with hereditary nonpolyposis colon cancer.

 

Hermann Bujard (DE) and Manfred Gossen (DE) developed the "Tet-Off" system for controlling expression of genes of interest in mammalian cells. Control elements of the tetracycline-resistance operon encoded in Tn10 of Escherichia coli were utilized to establish a highly efficient regulatory system in mammalian cells. By fusing the tet repressor with the activating domain of virion protein 16 of Herpes simplex virus, a tetracycline-controlled transactivator (tTA) was generated that is constitutively expressed in HeLa cells. This transactivator stimulates transcription from a minimal promoter sequence derived from the human cytomegalovirus promoter IE combined with tet operator sequences. Upon integration of a luciferase gene controlled by a tTA-dependent promoter into a tTA-producing HeLa cell line, high levels of luciferase expression were monitored. These activities are sensitive to tetracycline. Depending on the concentration of the antibiotic in the culture medium (0-1 microgram/ml), the luciferase activity can be regulated over up to five orders of magnitude. Thus, the system not only allows differential control of the activity of an individual gene in mammalian cells but also is suitable for creation of "on/off" situations for such genes in a reversible way (181).

Florence Paillard (US) described "Tet-on": a gene switch for the exogenous regulation of transgene expression (1119).

The difference between "Tet-On" and "Tet-Off" is not whether the transactivator turns a gene on or off, as the name might suggest; rather, both proteins activate expression. The difference relates to their respective response to doxycycline (Dox, a more stable tetracycline analogue); "Tet-Off" activates expression in the absence of Dox, whereas "Tet-On" activates in the presence of Dox.

 

Nigel P. Carter (GB), Malcolm Andrew Ferguson-Smith (GB), Marian T. Perryman (GB), Hakan Telenius (GB), Adele H. Pelmear (GB), Margaret A. Leversha (GB), Mary T. Glancy (GB), Stephan L. Wood (GB), Kern Cook (GB), and Harold M. Dyson (GB) described a method, termed reverse chromosome painting, which allows the rapid analysis of the content and breakpoints of aberrant chromosomes. The method involves the sorting of small numbers of the aberrant chromosome from short term blood culture preparations or cell lines by using bivariate flow karyotype analysis. Reverse chromosome painting is useful for routine clinical cytogenetics when analyzing cases involving an insertion, a deletion, a translocation, and the origin of de novo unbalanced chromosome duplications (208).

 

Carlos J. Gimeno (US), Per O. Ljungdahl (US), Cora A. Styles (US), and Gerald R. Fink (US) rediscovered that yeast cells, and the colonies that they produced, can adopt a mode of growth different from the vegetative style familiar to yeast researches. Instead of forming ovoid buds that separate cleanly from the mother cell, under conditions of nutrient limitation, yeast cells grew as filaments in which the daughter cells remain adhered to the mother cell. They carefully described the physiological events that characterize the phenomenon and investigated the underlying molecular mechanisms (500). See, Guilliermond, 1920.

 

Brian J. Stevenson (US), Nelson Rhodes (US), Beverly Errede (US), and George F. Sprague, Jr. (US) recognized a protein kinase cascade in Saccharomyces cerevisiae that appears to be an essential feature of the pheromone response pathway and probably connects the receptor/G protein to an identified transcription factor, Ste12. STE12 is a gene that encodes a protein kinase activity essential for mating (1403).

Kang-Yell Choi (KR), Brett Satterberg (US), David M. Lyons (US), and Elaine A. Elion (US) produced results using Saccharomyces cerevisiae to substantiate a novel signal transduction component, Ste5 that physically links multiple kinases within a single cascade (248).

 

Yasumasa Ishida (JP), Yasutoshi Agata (JP), Keiichi Shibahara (JP), and Tasuku Honjo (JP) provided evidence to suggest that activation of the PD-1 gene (a member of the immunoglobulin gene superfamily) might be involved in the classical type of programmed cell death (686).

 

Pauline Johnson (GB-CA), Hanne L. Ostergaard (CA), Chris Wasden (US), and Ian S. Trowbridge (US) Johnson helped to established the function of CD45 as a critical protein tyrosine phosphatase in T cell activation (710)

 

Seth Lederman (US), Michael J. Yellin (US), Alexander Krichevsky (US), John Belko (US), Julie J. Le (US), and Leonard Chess (US) discovered 5c8 Ag, a novel, activation-induced surface T cell protein that is involved in mediating a contact dependent element of the helper effector function of CD4+ T lymphocytes (840). Note: CD4+ T lymphocytes provide contact-dependent stimuli to B cells that are critical for the generation of specific antibody responses in a process termed T helper function.

(738)

Robert H. Carter (US) and Douglas T. Fearon (US) noted that lymphocytes must proliferate and differentiate in response to low concentrations of a vast array of antigens. The requirements of broad specificity and sensitivity conflict because the former is met by low-affinity antigen receptors, which precludes achieving the latter with high-affinity receptors. They found that the B cell resolves its dilemma by having an accessory protein (CD19) that enables activation when few antigen receptors are occupied (209).

 

Daisuke Kitamura (DE), Akira Kudo (CH), Stefan Schaal (DE), Werner Muller (DE), Fritz Melchers (CH), and Klaus Rajewsky (DE) generated mice in which the lambda 5 gene is inactivated by targeted gene disruption in embryonic stem cells. In these mice, B cell development in the bone marrow is blocked at the pre-B cell stage. However, the blockade is leaky, allowing B cells to populate the peripheral immune system at a low rate. These cells are allelically excluded and able to respond to antigen (772).

 

Donald F. Hunt (US), Robert A. Henderson (US), Jeffrey Shabanowitz (US), Kazuyasu Sakaguchi (US), Hanspeter Michel (US), Noelle Sevilir (US), Andrea L. Cox (US), Ettore Appella (US), and Victor H. Engelhard (US) described the characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry (666).

 

Franz M. Karlhofer (US), Randall K. Ribaudo (US), and Wayne M. Yokoyama (US) described MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells (738).

 

Rie Watanabe-Fukunaga (JP), Camilynn I. Brannan (US), Neal G. Copeland (US), Nancy A. Jenkins (US), and Shigekazu Nagata (JP) explained a lymphoproliferation disorder in mice by defects in Fas antigen that mediates apoptosis (1544).

 

Murry R. Badger (AU) and G. Dean Price (AU) first suggested the function of the pyrenoid (found in many algae and the hornworts) to be analogous to that of the carboxysome in cyanobacteria, in being associated with carbon-concentrating mechanism activity (72).

 

Toshikazu Takeshita (JP), Kiyoshi Ohtani (JP), Hironobu Asao (JP), Satoru Kumaki (JP), Masataka Nakamura (JP), and Kazuo Sugamura (JP) produced results which suggested the possibility that p64 (a membrane molecule) associates with IL-2R beta and has an important role in formation of the functional IL-2R complex (1435).

 

Laura Velazquez (FR), Marc Fellous (FR), George R. Stark (FR), and Sandra Pellegrini (FR) showed that tyrosine kinase 2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes (1507).

 

Richard O. Williams (GB), Marc Feldmann (GB), and Ravinder Nath Maini (GB) showed that anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis (1575). Note: This research was in response to the considerable evidence implicating tumor necrosis factor (TNF-a) in the pathogenesis of rheumatoid arthritis.

 

Joseph G. Naglich (US), James E. Metherall (US), David W. Russell (US), Leon Eidels (US) determined that the receptor for diphtheria toxin is a membrane bound growth factor precursor that the toxin exploits as a receptor (1050).

 

Simon McQueen-Mason (GB), Lian-Chao Li (US), Daniel M. Durachko (US), and Daniel J. Cosgrove (US) discovered the expansin gene family, which produces expansins; proteins that allow plant cell walls to grow while maintaining their rigidity (866; 978).

 

Harry F. Noller, Jr. (US), Vernita Hoffarth (US), and Ludwika Zimniak (US) confirmed that the ability to catalyze the formation of a covalent bond between adjacent amino acids—the peptidyl bond—lies in rRNA and not in proteins associated with the ribosome (1085).

Poul Nissen (DK), Jeffrey L. Hansen (US), Nenad Ban (Crotian-US-CH), Peter B. Moore (US), and Thomas A. Steitz (US) used the atomic structures of the large ribosomal subunit from Haloarcula marismortui (Archaea) and its complexes with two substrate analogs, to establish that the ribosome is a ribozyme and explored the catalytic properties of its all-RNA active site (1081).

 

Swapan K. Datta (PH), Karabi Datta (PH), Nouchine Soltanifar (CH), Günter Donn (DE), and Ingo Potrykus (CH) produced herbicide resistant rice plants through polyethylene glycol (PEG) mediated transformation of protoplasts (317).

 

Edward F. DeLong (US), Jed A. Fuhrman (US), Kirk McCallum (US), Alison A. Davis (US), Tohru Ueda (JP), Yuko Suga (JP), and Tatsuhiko Matsuguchi (JP) discovered numerous crenarchaeal ribosomal RNA (rRNA) genes in low-temperature marine and terrestrial environments. This destroyed the notion that all Crenarchaeota (a major subdivision of the Archaea) were from high-temperature geothermal environments (329; 445; 1493).

 

Susan K. McLaughlin (US), Peter J. McKinnon (US), and Robert F. Margolskee (US) discovered gustducin, a taste cell expressed G protein (976). Note: Their subsequent work has demonstrated that gustducin is critical to the transduction of compounds that humans consider bitter or sweet.

 

Siegfried Burggraf (DE), Gary J. Olsen (US), Karl O. Stetter (DE), Carl R. Woese (US), Gertrud Huber (DE), Elisabeth Drobner (DE), Harald Huber (DE), Robert Huber (DE), Thomas Wilharm (DE), Antonio Trincone (IT), Helmut König (DE), Reinhard Rachel (DE), Ingrid Rockinger (DE), and Hans Fricke (DE) discovered and characterized Aquifex pyrophilus as a deeply branching, eubacterial (Bacteria) hyperthermophile whose optimum environment is marine and near 85˚C, where it uses small amounts of oxygen to oxidize hydrogen (183; 662; 663).

 

Stephen George Oliver (GB), Quirina J.M. van der Aart (NL), Maria Luisa Agostoni-Carbone (IT), Michel Aigle (FR), Lilia Alberghina (IT), Despina Alexandraki (GR), G. Antoine (FR), R. Anwar (GB), Juan P. Garcia Ballesta (ES), P. Benit (FR), G. Berben (BE), E. Bergantino (IT), N. Biteau (IT), A. Bolle (BE), Monique Bolotin-Fukuhara (FR), Jean-Marie Buhler (FR), C. Carcano (IT), Giovanna Carignani (Italy), H. Cederberg (DE), R. Chanet (FR), Roland Contreras (BE), M. Crouzet (FR), Bertrand Daignan-Fornier (FR), E. Defoor (BE), M. Delgado (ES), J. Demolder (BE), C. Doira (FR), Edu Dubois (BE), Bernard Dujon (FR), A. Dusterhof (DE), D. Erdmann (DE), M. Esteban (ES), F. Fabre (FR), Cecile Fairhead (FR), G. Faye (FR), Horst Feldmann (DE), W. Fiers (BE), M.C. Francingues-Gaillard (FR), L. Franco (ES), L. Frontali (IT), Hiroshi Fukuhara (FR), L.J. Fuller (GB), P. Galland (GR), M.E. Gent (GB), D. Gigot (BE), V. Giliquet (BE), Nicolas Glansdorff (BE), Andre Goffeau (BE), M. Grenson (BE), P. Grisanti (IT), Les A. Grivell (NL), M. de Haan (NL), M. Haasemann (DE), D. Hatat (FR), J. Hoenicka (ES), J. Hegemann (DE), G.J. Herbert (FR), Francois Hilger (BE), S. Hohmann (DE), Cornelis P. Hollenberg (DE), K. Huse (DE), F. Iorra (FR), K.J. Indge (GB), K. Isono (Japan), Claude Jacq (FR), Michel Jacquet (FR), C.M. James (GB), Jean-Claude Jauniaux (BE), Y. Jia (FR), Antonio Jimenez (ES), A. Kelly (GB), U. Kleinhans (DE), P. Kreisl (DE), G. Lanfranchi (IT), C. Lewis (GB), C.G. van der Linden (NL), Giovanna Lucchini (IT), K. Lutzenkirchen (DE), M.J. Maat (NL), Laurent Mallet (FR), G. Mannhaupt (DE), E. Martegani (IT), A. Mathieu (FR), C.T.C. Maurer (NL), M. Muzi-Falconi (IT), David McConnell (GB), Andrew McKee (GB), Francine Messenguy (BE), H.W. Mewes (DE), F. Molemans (BE), M.A. Montague (GB), L. Navas (ES), Carol S. Newlon (US), D. Noone (GB), C. Pallier (FR), L. Panzeri (IT), B.M. Pearson (GB), J. Perea (FR), Peter Philippsen (DE), Andre Pierard (BE), Rudi J. Planta (NL), Paolo Plevani (IT), B. Poetsch (DE), F. Pohl (DE), Benedicte Purnelle (BE), Massoud Ramezani-Rad (DE), Soren W. Rasmussen (DK), A. Raynal (FR), M. Remacha (ES), P. Richterich (DE), A.B. Roberts (GB), F. Rodriguez (IT), E. Sanz (ES), I. Schaaff-Gerstenschlager (DE), B. Scherens (BE), B. Schweitzer (DE), Y. Shu (FR), J. Skala (BE), Piotr P. Slonimski (FR), Frederic Sor (FR), C. Soustelle (FR), R. Spiegelberg (DE), L.I. Stateva (GB), H. Yde Steensma (NL), S. Steiner (DE), A. Thierry (FR), Georges Thireos (GR), M. Tzermia (GR), L. Antonio Urrestarazu (BE), G. Valle (Italy), I. Vetter (DE), J.C. van Vliet-Reedij (NL), M. Voet (BE), Guido Volckaert (BE), P. Vreken (NL), H. Wang (GB), J.R. Warmington (GB), Dietter von Wettstein (DK), B.L. Wicksteed (GB), C. Wilson (IT), H. Wurst (DE), G. Xu (DE), A. Yoshikawa (JP), F.K. Zimmermann (DE), and John G. Sgouros (DE) determined the entire DNA sequence of chromosome III of the yeast Saccharomyces cerevisiae. This was the first complete sequence analysis of an entire chromosome from any organism (1106).

 

Xing-Wang Deng (CN-US), Minami Matsui (JP), Ning Wei (US), Daniel S. Wagner (US), Angela M. Chu (US), Kenneth A. Feldmann (US), Peter H. Quail (US), and Brian P. Dilkes (US) pioneered the development of T-DNA-tagged Arabidopsis mutant populations (331; 339). Note: This resource led to many important discoveries such as cloning of the first Arabidopsis homeotic gene (AG), important in flower development, and the first photomorphogenetic gene (COP1).

 

Francois Rousset (FR), Didier Bouchon (FR), Bernard Pintureau (FR), Pierre Juchault (FR), and Michel Solignac (FR) found that the pill bug, Armadillidium vulgare, frequently associates with bacteria of the genus Wolbachia as a symbiont. These bacterial symbionts convert all hosts to females if they are not already females. The bacterium is passed from one generation of pill bug to the next by the transovarian route (1260).

 

Duncan A. Veal (AU), Joseph E. Trimble (AU), and Andrew J. Beattie (AU) discovered that bull ants, Myrmecia gulosa, possess a gland on the dorsal aspect of the thorax, which contains potent antibiotics (1506).

 

Hugh S. Mason (US), Dominic M. Lam (US), and Charles J. Arntzen (US) genetically transformed tobacco plants with the gene encoding hepatitis B surface antigen (HBsAg) and concluded that transgenic plants hold promise as low-cost vaccine production systems (951).

Tariq A. Haq (US), Hugh S. Mason (US), John D. Clements (US), and Charles J. Arntzen (US) orally immunized mice with potato tubers transgenic for Escherichia coli heat-labile enterotoxin (LT-B) (595).

Carol O. Tacket (US), Hugh S. Mason (US), Genevieve Losonsky (US), John D. Clements (US), Myron M. Levine (US), and Charles J. Arntzen (US) demonstrated immunogenicity in humans for a recombinant bacterial antigen delivered orally in a transgenic potato (1431).

 

Gregory M. Preston (US), Tiziana Piazza Carroll (US), William B. Guggino (US), and Peter Agre (US) developed a striking assay for a water channel gene. They prepared synthetic mRNA from the previously unknown cDNA, injected it into Xenopus laevis oocytes, and then watched them swell and rupture (1182).

 

A new species of the cholera bacteria (O139) was discovered in Bangladesh. It has since been detected in 11 countries raising the possibility of future pandemics (250).

 

Steven D. Norton (US), Linda Zuckerman (US), Kevin B. Urdahl (US), Rachel Shefner (US), Jim Miller (US), and Marc K. Jenkins (US) discovered the first co-stimulating pathway (CD28/B7) for T cell activation (1090).

 

Richard J. Armitage (US), William C. Fanslow (US), Laura Strockbine (US), Timothy A. Sato (US), Ky N. Clifford (US), Brian M. Macduff (US), Dirk M. Anderson (US), Steven D. Gimpel (US), Terri Davis-Smith (US), Charles R. Maliszewski (US), Edward A. Clark (US), Craig A. Smith (US), Kenneth H. Grabstein (US), David Cosman (US), and Melanie K. Spriggs (US) reported the cloning of a ligand for CD40 that is expressed on the cell surface of activated T cells and mediates B-cell proliferation in the absence of co-stimulus, as well as IgE production in the presence of interIeukin-4 (48).

 

Melanie K. Spriggs (US), Richard J. Armitage (US), Laura D. Strockbine (US), Ky N. Clifford (US), Brian M. Macduff (US), Timothy A. Sato (US), Charles R. Maliszewski (US), and William Christian Fanslow (US) identified and cloned a cDNA encoding a murine ligand for the CD40 molecule (mCD40-L) and showed that it has biological activity in vitro. The predicted amino acid sequence indicates that this human ligand for CD40 (hCD40-L) is a 261 amino acid type II membrane protein that exhibits 78% amino acid identity with its murine counterpart. Cells transfected with hCD40-L caused the proliferation of human tonsil B cells in the absence of costimuli and, in the presence of interleukin 4, induced immunoglobulin E secretion from purified human B cells (1387).

 

Randolph J. Noelle (US), Meenakshi Roy (US), David M. Shepherd (US), Ivan Stamenkovic (US), Jeffrey A. Ledbetter (US), and Alejandro Aruffo (US) showed that triggering via CD40 is essential for the activation of resting B cells by helper T cells (Th). The ligand for CD40 was identified as a 39-kDa membrane protein that was selectively expressed on activated Th. The 39-kDa membrane protein expressed on activated Th is a binding protein for CD40 and functions to transduce the signal for Th-dependent B-cell activation (1082).

 

Tsutomu Ogata (GB), Peter Goodfellow (GB), Christine Petit (GB), Mabrouki Aya (GB), and Nobutake Matsuo (GB) proposed that in humans a growth gene(s) is present in the distal part of the pseudoautosomal region of the X chromosomal (1101).

 

Walter Rosenthal (US), Anita Seibold (US), Anaid Antaramian (US), Michèle Lonergan (CA), Marie-Francoise Arthus (CA), Geoffrey N. Hendy (CA), Mariel Birnbaumer (US), and Daniel G. Bichet (CA) discovered the gene for a form of congenital X-linked nephrogenic diabetes insipidus (NDI) —it encoded arginine vasopressin receptor 2 (AVPR2), normally expressed on the plasma membrane of collecting ducts (1254).

 

Jeff M. Hall (US), Lori S. Friedman (US), C. Guenther (US), Ming K. Lee (US), James L. Weber (US), Donald M. Black (GB), and Mary-Claire King (US) found linkage of early-onset familial breast and ovarian cancer to 11 markers on chromosome 17q12-q21 which defines an 8-cM region which is very likely to include the disease gene BRCA-1 (580).

 

Douglas R. Lowy (US), John T. Schiller (US), Reinhard Kirnbauer (AT), Frank P. Booy (GB), Naiqian Cheng (US), Janet Taub (US), Heather L. Greenstone (US), Richard B.S. Roden (US), Matthias Dürst (DE), Lutz Gissmann (DE), Francoise K.R. Breitburd (FR), Nancy L. Hubbert (US), Bernadete Nonnemacher (BR), Trin-Dinh-Desmarquet Carole (FR), and Gérard Orth (FR) devised a blueprint for several safe and effective vaccines that promise to slash the incidence of cervical cancer and mortality, the fourth most common cancer among women worldwide, as well as other malignancies and disorders that arise from human papillomaviruses (159; 767; 768).

 

Wilfred Niels Arnold (US) presented evidence that Vincent van Gogh, the great Dutch painter, suffered from acute intermittent porphyria. This disease makes sufferers more sensitive to the neurotoxicity of absinthe (the active ingredient of absinthe is alpha-thujone) (49).

 

David C. Bellinger (US), Karen M. Stiles (US), Herbert L. Needleman (US) reported that among children exposed to lead early in life, serum lead levels at 24 months of age were significantly associated with decreased cognitive performance on measures of intelligence and educational achievement at 10 years old. Each 0.48 μmol/L (10 μg/dL) increase in serum lead at 24 months of age was associated with a 5.8 point decline in a measure of intelligence quotient and an 8.9 point decline in educational achievement score during cognitive testing at 10 years of age (108).

 

Michael M. Davis (US), Philip M. McCabe (US), Neil Schneiderman (US), Theodore W. Jarrell (US), Christopher G. Gentile (US). Alan H. Teich (US), Ray W. Winters (US), and David R. Liskowsky (US) determined that the neural pathways involved in fear conditioning include sensory pathways transmitting the signal to the amygdala where specific internal connections ultimately project to motor systems. The amygdala is involved in fear conditioning regardless of the sensory modality of the conditioned stimulus and independent of which motor response is used (320; 966).

 

Marc Alan Pfeffer (US), Eugene Braunwald (US), Lemuel A. Moyé (US), Lofty Basta (US), Edward J. Brown, Jr. (US), Thomas E. Cuddy (US), Barry R. Davis (US), Edward M. Geltman (US), Steven Goldman (US), Greg C. Flaker (US), Marc Klein (US), Gervasio A. Lamas (US), Milton Packer (US), Jacques Rouleau (US), Jean L. Rouleau (US), John Rutherford (US), John H. Wertheimer (US), and C. Morton Hawkins (US) found that treating patients with captopril after acute myocardial infarction (MI) with asymptomatic left ventricular dysfunction reduces mortality from cardiovascular causes (i.e., atherosclerotic heart disease, progressive heart failure). The captopril group experienced lower rates of hospitalization due to heart failure and recurrent (MI) (1156).

 

Andrew E. Czeizel (HU) and István Dudás (HU) found that periconceptional vitamin use decreases the incidence of a first occurrence of neural tube defects (307).

 

Olivier J. Goulet (FR), Yann Revillon (FR), Nicole Brousse (FR), Dominique Jan (FR), Danielle Canion (FR), Caroline Rambaud (FR), Nadine Cerf-Bensussan (FR), Christianne Buisson (FR), Philippe Hubert (FR), Sophie de Potter (FR), Jean-Francois Mougenot (FR), Alain Fischer (FR), and Claude Ricour (FR) performed the first successful small bowel transplantation in humans (521).

 

Michel Gagner (CA), Andre Lacroix (CA), and Edouard Bolté (CA) reported the successful use of a laparoscopic approach to adrenalectomy in three patients for Cushing's disease/syndrome and a right-sided phaeochromocytoma (level 4 evidence). They concluded that laparoscopic adrenalectomy is safe, effective, and associated with a rapid recovery and low complication rate. Venous thromboprophylaxis was strongly recommended to avoid potential post-operative morbidity (457).

 

Mehernoor F. Watcha (US) and Paul F. White (US) reported that newer anesthetic drugs (e.g. propofol) appear to have contributed to a recent decline in the incidence of postoperative emesis. Factors associated with an increased risk of postoperative emesis include: age, gender (menses), obesity, previous history of motion sickness or postoperative vomiting, anxiety, gastroparesis, and type and duration of the surgical procedure (e.g., laparoscopy, strabismus, middle ear procedures). Anesthesiologists have control over many factors that influence postoperative emesis (e.g., preanesthetic medication, anesthetic drugs and techniques, and postoperative pain management). Patients at high risk for postoperative emesis should receive special considerations with respect to the prophylactic use of antiemetic drugs. Potent nonopioid analgesics (e.g., ketorolac) can be used to control pain while avoiding some of the opioid-related side effects. Gentle handling in the immediate postoperative period is also essential. If emesis does occur, aggressive intravenous hydration and pain management are important along with antiemetic drugs. If one antiemetic does not appear to be effective, another drug with a different site of action should be considered. New antiserotonin drugs, should reduce the incidence of recurrent (intractable) emesis (1545).

 

John M. Epley (US) described the Canalith Repositioning Procedure (CRP) and its rationale, and reported the results in 30 patients who exhibited the classic nystagmus of benign paroxysmal positional vertigo (BPPV) with Hallpike maneuvers. CRP obtained timely resolution of the nystagmus and positional vertigo in 100%. These results also support an alternative theory that the densities that impart gravity-sensitivity to a semicircular canal in BPPV are free in the canal, rather than attached to the cupula. CRP offers significant advantages over invasive and other noninvasive treatment modalities in current use (377).

 

Gary S. Hoffman (US), Gail S. Kerr (US), Randi Y. Leavitt (US), Claire W. Hallahan (US), Robert S. Lebovics (US), William D. Travis (US), Menachem Rottem (US), and Anthony S. Fauci (US) noted that the course of Wegener granulomatosis has been dramatically improved by daily treatment with cyclophosphamide and glucocorticoids. Nonetheless, disease- and treatment-related morbidity is often profound. A long-term follow-up of patients with Wegener granulomatosis has led to increasing concerns about toxicity resulting from prolonged cyclophosphamide therapy and has encouraged investigation of other therapeutic regimens (636).

 

Frederick A. Moore (US), David V. Feliciano (US), Richard J. Andrassy (US), Allan H. McArdle (US), Frank McL. Booth (US), Tina B. Morgenstein-Wagner (US), John M. Kellum, Jr. (US), Richard E. Welling (US), and Ernest E. Moore (US) showed that in high-risk surgical patients early nutrition reduces post-operative septic complications and where possible the GI tract should be preferred as a route of delivery (1011).

 

Marie-José Ramond (FR), Thierry Poynard (FR), Bernard Rueff (FR), Philippe Mathurin (FR), Christian Théodore (FR), Jean-Claude Chaput (FR), and Jean-Pierre Benhamou (FR) found that compared to placebo, treating patients with severe alcoholic hepatitis with 28 days of prednisolone significantly improved the short-term survival up to 6 months.

There remains significant controversy surrounding the use of glucocorticoids in managing severe alcoholic hepatitis, as numerous other trials have demonstrated no mortality benefit, but significantly higher risk of infection with glucocorticoid therapy (1206).

 

Michael R. Ransom (US) and C. Arden Pope, III (US) took advantage of an industrial quirk to more directly document the health effects of air contaminants in an area of Utah where particulate air pollution was historically dominated by emissions from a steel mill. Owing to a labor dispute, that mill was shut for 13 months, thus providing a “control” period to which pre- and post-closure public health measures could be compared. A significant and robust association was found between PM10 levels and absence rates in local schools, which persisted at levels below current air quality standards. The relative simplicity of this study and its intuitively reasonable findings had major influence on subsequent air pollution policies (1208).

 

The CDC introduced “Public Health Focus: Effectiveness of Disease and Injury Prevention” published monthly in the MMWR (1).

 

Tsu-Ming Han (US) and Bruce N. Runnegar (AU-US) found fossils of the multicellular Grypania spiralis (probably an alga) in the 2.1 Ga Negaunee Iron Formation in Michigan, U.S.A (591). Malcom R. Walter (US), Du Rulin (US), and Robert Joseph Horodyski (US) had previously discovered multicellular fossil (c.1.4 Ga) in old Greyson Shale, lower Belt Supergroup, in Montana, US, and from the similarly aged Gaoyuzhuang Formation, upper Changcheng Group, in the Jixian section, Northern China. The organism was identified as Grypania spiralis, a coiled ribbon-like creature. It was judged to most likely have been a multicellular eukaryotic alga (1530). Shale is rock formed by condensation of layers of clay or mud, along with phytoplankton and other debris, sedimented at the bottoms of lakes or ocean basins.

 

1993

"Humans are here today because our particular line never fractured—never once at any of the billion points that could have erased us from history." Stephen Jay Gould (US) (520)

 

"Living organisms preserve their internal order by taking from their surroundings free energy, in the form of nutrients or sunlight, and returning to their surroundings an equal amount of energy as heat and entropy." Albert Lester Lehninger (US), David L. Nelson (US), and Michael M. Cox (US) (850). This concept was first articulated by Ludwig Boltzmann (DE) (149), then refined by Erwin Schrödinger (DE) (1303).

 

“Very difficult decisions will have to be made if we are to have a sustainable human society in a sustainable environment. Many of those decisions will require extensive knowledge of biology. We have reached the point in history, therefore, when biological knowledge is the sine qua non for a viable human future.” John Alexander Moore (US) (1012).

 

“To discover nature’s true order, the mind must be purified of all its internal obstacles, purged of its habitual tendencies to produce rational or imaginary wish fulfillments in advance of empirical investigation.” Richard TheodoreTarnas (CH) (1440).

 

"In science and elsewhere there are two types of truth: (1) The truth everybody already knows, and (2) the truth that is not yet discovered…The second type of truth is different. At first it looks too bizarre to be true, and it may be as dangerous as fire. If you are not clever it may destroy you." Benno Müller-Hill (DE) (1034).

 

"I have recently been reassured that this formulation of sodium ion-coupled glucose transport in the intestine was the basis for the development by others of the simple glucose-sodium chloride solution taken by mouth that is used world-wide to treat victims of life-threatening diarrhea as in cholera. A practical development based on my little piece of basic research has saved thousands upon thousands of lives." Robert Kellogg Crane (1134). See, Crane, 1961

 

All is Fair in Love and Warts

 

 “He proclaimed she had given him warts

 Of the most ignominious sorts

 Said that her papilloma

 Had entered his soma

 And the issue was clearer than quartz

 

 She denies having given him warts

 Says that, his allegation distorts.

 It's incredibly plain

 That they differ by strain

 As shown in my doctor's reports.

 

And despite his assertion of torts

On the issue of giving him warts,

She was quickly acquitted

Of having transmitted

(And upheld in the lowest of courts).” Robert D. Siegel, November 16, 1993

 

Kary Banks Mullis (US) for his invention of the polymerase chain reaction (PCR) method and Michael Smith (GB-CA) for his fundamental contributions to the establishment of oligonucleotide-based, site-directed mutagenesis and its development for protein studies shared the Nobel Prize in Chemistry.

 

Richard John Roberts (GB) and Phillip Allen Sharp (GB-US) were awarded the Nobel Prize in Physiology or Medicine for their independent discoveries of split genes.

 

David C. Schwatz (US), Xiao Jun Li (US), Luis I. Hernandez (US), Satyadarshan P. Ramnarain (US), Edward J. Huff (US), and Yu-ker Wang (US) developed a method for creating a “visual physical map” along large DNA molecules (similar in principle to a restriction enzyme map), by which one can correlate DNA sequence with physical location (1305). Note: Optical mapping is useful for completing large genome projects (chromosome sized-contigs) and other applications, such as the identification of rearrangements in genomes. It can be used to assist in genome assembly, compare genomic structures, and correct genome assembly errors. It can also be used for comparing strain differences, for instance in medical microbiology applications. A major advantage of this method is that it avoids cloning or PCR artifacts and analyzes a single molecule at a time.

 

Elias James Corey (US) and Yong-Jin Wu (US) carried out the total synthesis of paeoniflorigenin and paeoniflorin (282).

 

Kai Chen (CN-US) and Frances Hamilton Arnold (US) applied directed evolution to engineer a version of the enzyme subtilisin E that was active in a highly unnatural environment, namely in the organic solvent dimethylformamide (DMF). They carried out the work using four sequential rounds of mutagenesis of the enzyme's gene, expressed by bacteria, through error-prone polymerase chain reaction. After each round they screened the enzymes for their ability to hydrolyze the milk protein casein in the presence of DMF by growing the bacteria on agar plates containing casein and DMF. The bacteria secreted the enzyme and, if it were functional, it would hydrolyze the casein and produce a visible halo. They selected the bacteria that had the biggest halos and isolated their DNA for further rounds of mutagenesis. Using this method, she designed an enzyme that had 256 times more activity in DMF than the original (232). Note: Barry G. Hall (US), in 1978, was the first person to use directed evolution for optimizing enzyme activity.

 

Emmanuel Delhaise (AU), Peter R. Ryan (AU), and Peter J. Randall (AU) showed that aluminum tolerance in plants is accomplished by organic acid (e.g. malate or citrate) secretion from roots. The secreted organic acids chelate aluminum extracellularly, inhibiting aluminum uptake and thus avoiding subsequent toxicity to plants (328).

 

Bertil Pettersson (SE), Mathias Uhlen (SE), and Pål Nyren (SE) described the principle of "pyrosequencing" by combining the solid phase sequencing method using streptavidin coated magnetic beads with recombinant DNA polymerase lacking 3´to 5´exonuclease activity (proof-reading) and luminescence detection using the firefly luciferase enzyme (1152).

Marcel Margulies (US), Michael Egholm (US), William E. Altman (US), Said Attiya (US), Joel S. Bader (US), Lisa A. Bemben (US), Jan Berka (US), Michael S. Braverman (US), Yi-Ju Chen (US), Zhoutao Chen (US), Scott B. Dewell (US), Lei Du (US), Joseph M. Fierro (US), Xavier V. Gomes (US), Brian C. Godwin (US), Wen He (US),Scott Helgesen (US), Chun Heen Ho (US), Gerard P. Irzyk (US), Szilveszter C. Jando (US), Maria L. I. Alenquer (US), Thomas P. Jarvie (US), Kshama B. Jirage (US), Jong-Bum Kim (US), James R. Knight (US), Janna R. Lanza (US), John H. Leamon (US), Steven M. Lefkowitz (US), Ming Lei (US), Jing Li (US), Kenton L. Lohman (US), Hong Lu (US), Vinod B. Makhijani (US), Keith E. McDade (US), Michael P. McKenna (US), Eugene W. Myers (US), Elizabeth Nickerson (US), John R. Nobile (US), Ramona Plant (US), Bernard P. Puc (US), Michael T. Ronan (US), George T. Roth (US), Gary J. Sarkis (US), Jan Fredrik Simons (US), John W. Simpson (US), Maithreyan Srinivasan (US), Karrie R. Tartaro (US), Alexander Tomasz (US), Kari A. Vogt (US) , Greg A. Volkmer (US), Shally H. Wang (US), Yong Wang (US), Michael P. Weiner (US), Pengguang Yu (US), Richard F. Begley (US), and Jonathan M. Rothberg (US) described a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, they have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. They showed the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembly of the Mycoplasma genitalium genome with 96% coverage at 99.96% accuracy in one run of the machine (941).

 

Nikolai Lisitsyn (RU-US), Natalya Lisitsyn (RU-US), and Michael Wigler (US) developed a system in which subtractive and kinetic enrichment was used to purify restriction endonuclease fragments present in one population of DNA fragments but not in another. Application of this method to DNA populations of reduced complexity ("representations") resulted in the isolation of probes to viral genomes present as single copies in human DNA, and probes that detect polymorphisms between two individuals (884).

 

Michael R.K. "Dickon" Alley (US), Janine Maddock (US), and Lucy Shapiro (US) were able to show that chemoreceptor proteins occupy specific areas within the bacterial cell (34; 923).

Christine Jacobs (US), Ibrahim J. Domian (US), Janine R.Maddock (US), and Lucy Shapiro (US) discovered that the master CtrA response regulator functions in Caulobacter to repress replication initiation in different phases of the cell cycle. Here, they identify an essential histidine kinase, CckA, that is responsible for CtrA activation by phosphorylation. Although CckA is present throughout the cell cycle, it moves to a cell pole in S phase, and upon cell division it disperses (699).

Lucy Shapiro (US), Michael T. Laub (US), Harley H. McAdams (US), Tamara Feldblyum (US), Claire M. Fraser (US), Swaine L. Chen (US), Christine Jacobs (US), Nora Ausmees (US), and Stuart J. Cordwell (US) were the first to show that bacterial DNA replication occurs in a spatially organized way and that cell division is dependent on this spatial organization. They discovered the genetic basis of cell cycle progression and consequently the identification of three regulatory proteins, DnaA, GcrA, and CtrA, which controlled complex temporal and spatial behaviors affecting large numbers of genes (698; 831; 832).

Patrick H. Viollier (US), Martin Thanbichler (US), Patrick T. McGrath (US), Lisandra West (US), Maliwan Meewan (US), Harley H. McAdams (US), and Lucy Shapiro (US) using time-lapse microscopy and fluorescent tags, were able to demonstrate that chromosomal regions are duplicated in both an orderly and a location-specific manner, involving "a much higher degree of spatial organization than previously thought" (1520).

Erin D. Goley (US), Luis R. Comolli (US), Katherine E. Fero (US), Kenneth H. Downing (US), Lucy Shapiro (US), Andrea Möll (DE), Susan Schlimpert (DE), Ariane Briegel (DE), Grant J. Jensen (DE), Martin Thanbichler (DE), Sebastian Poggio (US), Constantin N. Takacs (US), Waldemar Vollmer (US), and Christine Jacobs-Wagner (US) describe a novel protein, called DipM for Division Involved Protein with LysM domains, that is required for cell division in Caulobacter crescentus. DipM localizes to the mid-cell during cell division, where it is necessary for the hydrolysis of the septal peptidoglycan to remodel the cell wall. DipM is essential for reorganizing the cell wall at the division site, for envelope invagination and cell separation in Caulobacter (508; 1008; 1172). Note: LysM is a protein domain which binds peptidoglycan

Jason Hocking (US), Richa Priyadarshini (US), Constantin N. Takacs (US), Teresa Costa (US), Natalie A. Dye (US), Lucy Shapiro (US), Waldemar Vollmer (US), and Christine Jacobs-Wagner (US) showed that spatial distributions of specific cell wall proteins in Caulobacter crescentus are sensitive to small external osmotic upshifts. An essential cell elongation-specific transpeptidase, switches its localization from a dispersed, patchy pattern to an accumulation at the FtsZ ring location. This osmolality-dependent relocation to the division apparatus is initiated within less than a minute (634).

 

Edward J. Weinman (US), Deborah Steplock (US), Shirish Shenolikar (US), and Yu Wang (US) discovered, purified, and characterized a molecule called sodium-hydrogen exchanger regulatory factor (NHERF) that binds to adrenergic receptors to begin the internal fight-or-flight signaling process (1559; 1560). Note: Prior to this finding G-protein was the only molecule known to have this binding property. This is an entirely new signaling model for the cell's internal machinery.

 

Hua Gu (DE), Yong-Rui Zou (DE), and Klaus Rajewsky (DE) employed a method based on the Cre-loxP recombination system of bacteriophage P1 to generate a mouse strain in which the JH segments and the intron enhancer in the IgH locus are deleted. By analysis of immunoglobulin isotype switch recombination in heterozygous mutant B cells activated by lipopolysaccharide plus interleukin-4, they showed that, on the mutant chromosome, switch recombination at the mu gene switch region is strongly suppressed, whereas the switch region of the gamma 1 gene is efficiently rearranged (563).

 

Leu-Fen H. Lin (US), Daniel H. Doherty (US), Jack D. Lile (US), Susan Bektesh (US), and Frank Collins (US) were the first to isolate glial cell line-derived neurotrophic factor (GDNF). It functions as a survival and differentiation factor for midbrain dopaminergic neurons (877).

 

Mary Sym (US), JoAnne Engebrecht (US), and G. Shirleen Roeder (US) proposed that ZIP1 is a novel meiosis-specific gene, which acts as a molecular zipper to bring homologous chromosomes in close apposition in Saccharomyces cerevisiae (1428).

 

Michel Rohmer (FR), M’hamed Knani (FR), Pascale Simonin (FR), Bertrand Sutter (FR), and Hermann Sahm (FR) described the glyceraldehyde-3-phosphate (GAP)-pyruvate pathway to the production of isopentyl diphosphate (IPP). The IPP is synthesized by the condensation of pyruvate and glyceraldehyde-3-phosphate, via 1-deoxyxylulose-5-phosphate (DXP) as the first intermediate (1250). The isoprenoids are composed of repeating five-carbon, isopentenyl diphosphate (IPP) subunits. Eubacterial hopanoids and plastid-associated isoprenoids of algae and higher plants are produced via this pathway.

 

Sydney Brenner (GB), Greg Elgar (GB), Richard Sandford (GB), Alexander D. Macrae (GB), Byrappa Venkatesh (SG), and Samuel Aparicio (GB) characterized the small genome (400 Mb) of the tetraodontoid fish, Fugu rubripes. A random sequencing approach supported by gene probing shows that the haploid genome contains 400 Mb of DNA, of which more that 90% is unique. This genome is 7.5 times smaller than the human genome and because it has a similar gene repertoire it is the best model genome for the discovery of human genes(160).

 

Kazimierz Tye Tycowski (US), Mei-Di Shu (US), and Joan Elaine Argetsinger Steitz (US) discovered that introns, which were thought to be inert, code for snRNAs that target the modification of other cellular RNAs during their maturation (1490-1492).

Shobha Vasudevan (US), YingchunTong (US), and Joan Elaine Argetsinger Steitz (US) proposed that translation regulation by microRNPs oscillates between repression and activation during the cell cycle (1505).

 

Craig M. Thompson (US), Anthony J. Koleske (US), David M. Chao (US), and Richard A. Young (US) defined the Saccharomyces cerevisiae Mediator complex in detail and provided evidence for its role in the regulation of transcription (1452). Note: The Mediator complex appears in all eukaryotes. It is a protein complex physically associated with RNA polymerase II during transcription.

 

Edward M. Brown (US), Gerardo Gamba (MX), Daniela Riccardi (US), Michael Lombardi (US), Robert Butters (US), Olga Kifor (US), Adam Sun (US), Matthias A. Hediger (US), Jonathan Lytton (US), and Steven C. Hebert (US) reported the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor (168).

 

Kazutoshi Mori (JP-US), Peter Walter (US), Wenzhen Ma (JP-US), Mary-Jane Gething (US), Joseph F. Sambrook (US), Tetsushi Kawahara (JP), Hiderou Yoshida (JP), Hideki Yanagi (JP), Takashi Yura (JP), Kyosuke Haze (JP), Toshie Matsui (JP), Akira Yamamoto (JP), Tetsuya Okada (JP), Yoshimi Sato (JP), Satomi Nadanaka (JP), Tetsuya Okada (JP), and Katsuya Okawa (JP) Jeffery S. Cox (US), Caroline E. Shamu (US), Carmela Sidrauski (US), Tania N. Gonzalez (US), Silke Dörfler (US), Alexei V. Korennykh (US), Pascal F. Egea (US), Andrei A. Korostelev (US), Janet Finer-Moore (US), Chao Zhang (US), Kevan M. Shokat (US), Robert M. Stroud (US), Brooke M. Gardner (US), David Pincus (US), Katja Gotthardt (US), and Ciara M. Gallagher (US) discovered the unfolded protein response, an intracellular quality-control system that detects harmful misfolded proteins in the endoplasmic reticulum and signals the nucleus to carry out corrective measures (289; 290; 465; 510; 609; 743; 797; 1018; 1019; 1281; 1338; 1612).

 

Carol Beadling (US), Kirk W. Johnson (US), and Kendall A. Smith (US) isolated interleukin 2-induced immediate-early genes (104).

 

Frauke Melchior (US), Bryce M. Paschal (US), Janice Evans (US), and Larry Gerace (US) found in HeLa cells that a GTPase named Ran, promotes nuclear uptake of proteins sporting a nuclear localization sequence (NLS) (984).

Mary Shannon Moore (US) and Günter Klaus-Joachim Blobel (DE-US) made a similar finding in Xenopus oocytes (1013).

Stephen A. Adam (US), Larry Gerace (US), Ermoné J.H. Adam (US), Dirk Görlich (DE), Siegfried Prehn (DE), Ronald A. Laskey (GB), Enno Hartmann (DE), Aurelian Radu (US), Günter Klaus-Joachim Blobel (DE-US), and Mary Shannon Moore (US) revealed the importin proteins responsible for transporting molecules into the nucleus (13; 14; 516; 1197).

 

Ramsay Fuleihan (US), Narayanaswamy Ramesh (US), Richard Loh (US), Haifa Jabara (US), Fred S. Rosen (US), Talal Chatila (US), Shu Man Fu (US), Ivan Stamenkovic (US), and Raif S. Geha (US) obtained results suggesting that defective expression of the CD40 ligand underlies the failure of isotype switching in X chromosome-linked immunoglobulin deficiency disease (448).

 

Paritosh Ghosh (US), Tse-Hua Tan (US), Nancy R. Rice (US), Antonio Sica (US), and Howard A. Young (US) found that the interleukin 2 CD28-responsive complex contains at least three members of the NF-kB family: c-Rel, p50, and p65 (487).

 

Steven E. Macatonia (US), Chyi-Song Hsieh (US), Kenneth M. Murphy (US), and Anna O'Garra (US) discovered that dendritic cells and macrophages are required for T-helper 1(Th1) development of CD4+ T cells. They also determined that interleukin 12 (IL-12) substitution for macrophages to stimulate IFN-gamma production is IFN-gamma-dependent (920).

 

Dale I. Godfrey (US), Jacqueline Kennedy (US), Takashi Suda (US), and Albert Zlotnik (US) subdivided mouse CD4-CD8-CD3- triple-negative (TN) thymocytes into four subsets based upon expression of CD44 and CD25, including CD44+CD25-, CD44+CD25+, CD44-CD25+ and CD44-CD25-. The repopulation potential of these subsets in 2-deoxyguanosine-treated fetal thymic lobes supports the following maturation sequence: CD44+CD25- -->CD44+CD25+ -->CD44-CD25+ -->CD44-CD25- (504).

 

Yoichi Shinkai (US), Shigeo Koyasu (US), Kei-ichi Nakayama (US), Kenneth M. Murphy (US), Dennis Y. Loh (US), Ellis L. Reinherz (US), and Frederick W. Alt (US) found that introduction of TCR alpha transgene, TCR beta transgene, or both into RAG-2-/-mice differentially rescues T cell development (1335).

 

Satoshi Tsukada (US), Douglas C. Saffran (US), David J. Rawlings (US), Ornella Parolini (US), R.Cutler Allen (US), Ivana Klisak (US), Robert S. Sparkes (US), Hiromi Kubagawa (US), Thuluvancheri Mohandas (US), Shirley Quan (US), John W. Belmont (US), Max D. Cooper (US), Mary Ellen Conley (US), and Owen N. Witte (US) described a novel cytoplasmic tyrosine kinase, termed BPK (B cell progenitor kinase), which is expressed in all stages of the B lineage and in myeloid cells. BPK was evaluated as a candidate for human X-linked agammaglobulinemia (XLA), an inherited immunodeficiency characterized by a severe deficit of B and plasma cells and profound hypogammaglobulinemia (1477).

David Vetrie (GB), Igor Vorechovsky (SE), Paschalis Sideras (SE), Jill Holland (GB), Angela Davies (GB), Frances Flinter (GB), Lennart Hammarstrom (SE), Christine Kinnon (GB), Roland Levinsky (GB), Martin Bobrow (GB), C. I. Edvard Smith (SE), and David R. Bentley (GB) isolated a novel gene which maps to the XLA locus, is expressed in B cells, and shows mutations in families with the disorder. The gene is a member of the src family of proto-oncogenes which encode protein-tyrosine kinases. This was among the first evidence that mutations in a src-related gene are involved in human genetic disease (1514).

 

James L. Ferrara (US), Sunil Abdhyankar (US), and Dwight Gary Gilliland (US) were the first to use the phrase “cytokine storm,” which appeared in their article on graft-versus-host disease (405). Note: The use of this phrase in infectious disease research began in early 2000 in reports on cytomegalovirus (88), Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (678), group A streptococcus (128), influenza virus (1611), variola virus (703), and severe acute respiratory syndrome coronavirus (SARS-CoV) (661). The phrase appears to have first been applied in the context of avian H5N1 influenza virus infection in 2005 (1618).

 

Shixin Qin (GB), Stephen P. Cobbold (GB), Heather Pope (GB), James Elliott (GB), Dimitris Kioussis (GB), Joanna Davies (GB), and Hermann Waldmann (GB) were the first to show that CD4+ T cells from transplantation tolerant mice disabled naïve lymphocytes so that they too could not reject the graft. The naïve lymphocytes that had been so disabled also became tolerant and, in turn, developed the capacity to specifically disable other naïve lymphocytes. This process of "infectious" tolerance explains why no further immunosuppression is needed to maintain long-term transplantation tolerance (1194).

Shimon Sakaguchi (JP), Noriko Sakaguchi (JP), Masanao Asano (JP), Misako Itoh (JP), and Masaaki Toda (JP) presented results indicating that CD4+CD25+ T cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ T cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases (56; 1271).

Joanna D. Davies (GB), Louise Y.W. Leong (GB), Andrew L. Mellor (GB), Stephen P. Cobbold (GB), and Hermann Waldmann (GB) were the first to demonstrate that dominant tolerance maintained by Treg cells to one set of antigens in a tissue could spread to prevent immune attack directed to other antigens in the same tissue (319).

Fabienne Van de Keere (US), Susumu Tonegawa (US), Danyvid Olivares-Villagomez (US) Yijie Wang (US), and Juan J. Lafaille (US) showed that CD4+ T cell populations contain a regulatory subset that can prevent the development of experimental autoimmune encephalomyelitis in a transgenic mouse model (1105; 1498).

Benedict Seddon (GB) and Don Mason (GB) were the first to provide evidence that target organ specificity of Treg cells provides protection against organ-specific autoimmunity (1314).

Luis Graca (GB), Stephen P. Cobbold (GB), and Hermann Waldmann (GB) were the first to provide a clear demonstration that Treg cells can be found in the tolerant tissues, opening testable hypotheses on acquired immunological privilege (526).

Chun-Yen Lin (), Luis Graca (GB), Stephen P. Cobbold (GB), and Hermann Waldmann (GB) provided data linking tolerance to chronic viruses with transplantation tolerance and possibly tumor tolerance. This finding indicated that Tregcell-mediated suppression at the level of effector function rather than proliferation seems to be the same thing that happens in the induction of virus tolerance (875).

 

Viktor Steimle (CH), Luc A. Otten (CH), Madeleine Zufferey (CH), and Bernard Mach (CH) identified a splicing mutation that results in a 24 amino acid deletion in CIITA, resulting in loss of function of the transactivator. Hence, the CIITA gene is essential for MHC class II gene expression and has been shown to be responsible for hereditary MHC class II deficiency (1395). Note: Hereditary major histocompatibility complex (MHC) class II deficiency (or Bare Lymphocyte Syndrome) is a form of severe primary immunodeficiency with a total lack of MHC class II expression.

 

Denise Gay (US), Thomas Saunders (US), Sally Camper (US), and Martin Weigert (US) generated data suggesting that autoreactive transgenic B cells can rearrange endogenous L chain genes to alter surface receptors. Those L chains that compete successfully with the L tg for H chain binding, and that create a nonautoreactive receptor, allow the B cell to escape deletion. They suggested that this receptor editing is a mechanism used by immature autoreactive B cells to escape tolerance (477).

 

Susan L. Tiegs (US), David M. Russell (US), and David Nemazee (US) showed that transgenic bone marrow B cells encountering membrane-bound Kb or Kk proteins modify their receptors by expressing the V(D)J recombinase activator genes and assembling endogenously encoded immunoglobulin light chain variable genes. This (auto)antigen-directed change in the specificity of newly generated lymphocytes is termed receptor editing (1457).

 

Demetrius Moskophidis (CH), Franziska Lechner (CH), Hanspeter Pircher (CH), and Rolf Martin Zinkernagel (CH) found that some strains of non-cytopathic lymphocytic choriomeningitis virus (LCMV) persist after acute infection because they induce most of the specific antiviral CD8+ cytotoxic T cells so completely that they all disappear within a few days and therefore neither eliminate the virus nor cause lethal immunopathology (1026).

 

Masayuki Noguchi (US), Huafang Yi (US), Howard M. Rosenblatt (US), Alexandra H. Filipovich (US), Stephen Adelstein (US), William S. Modi (US), O. Wesley McBride (US), and Warren J. Leonard (US) localized the IL-2R gamma gene to human chromosome Xql3. Genetic linkage analysis indicates that the IL-2R gamma gene and the locus for X-linked severe combined immunodeficiency (XSCID) appear to be at the same position. These data establish that XSCID is associated with mutations of the IL-2R gamma gene product (1084). Note: The interleukin-2 (IL-2) receptor gamma chain (IL-2R gamma) is a component of high and intermediate affinity IL-2 receptors that is required to achieve full ligand binding affinity and internalization.

 

Julia M. Turner (GB) found that IL-2-dependent induction of G1 cyclins in primary T cells is not blocked by rapamycin or cyclosporin A. These observations suggest that cyclins D2 and D3 may monitor the interleukin 2-receptor (IL-2R) signal but that their induction does not guarantee entry into S phase (1487).

 

Chyi-Song Hsieh (US), Steven E. Macatonia (US), Catherine S. Tripp (US), Stanley F. Wolf (US), Anne O'Garra (US), and Kenneth M. Murphy (US) showed the development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages (658). Note: this regulatory pathway may have evolved to enable innate immune cells, through interactions with microbial pathogens, to direct development of specific immunity toward the appropriate TH phenotype.

 

Warren J. Strittmatter (US), Ann M. Saunders (US), Donald Schmechel (US), Margaret Pericak-Vance (US), Jan Enghild (US), Guy S. Salvesen (US), and Allen D. Roses (US) found that apolipoprotein E (a serum transporter of cholesterol) is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease (1409).

 

William R. Jacobs, Jr. (US), Raúl G. Barletta (US), Rupa A. Udani (US), John Chan (US), Gary Kalkut (US), Gabriel Sosne (US), Tobias Kieser (GB), Gary J. Sarkis (US), Graham F. Hatfull (GB-US), and Barry R. Bloom (US) developed luciferase reporter phages with which they could assess drug susceptibility based on the efficient production of photons by viable mycobacteria infected with specific reporter phages expressing the firefly luciferase gene. Cells killed by a drug would not emit light (700).

 

Galina A. Dubinina (RU), Natalia V. Leshcheva (RU), and Margarita Yu Grabovich (RU) reported that the colorless sulfur bacterium Thiodendron is actually a symbiotic association of spirochetes and sulfidogens (353; 354).

 

Friedrich Widdel (DE), Sylvia Schnell (DE), Silke Heising (DE), Armin Ehrenreich (DE), Bernhard Assmus (DE), and Bernhard Schink (DE) discovered that ferrous ions can serve as the electron donors for certain purple nonsulfur phototrophs (1573). Note: This provides an explanation for the banded iron oxide geological formations, which were deposited when the earth's atmosphere was anoxic: anoxic phototrophs very likely did it.

 

Guofeng You (US), Craig P. Smith (US), Yoshikatsu Kana (US), Wen-Sen Lee (US), Matthias Stelzner (US), and Matthias A. Hediger (US) successfully promoted the expression of a clone of the first urea transporter, now named UT-A2 (1615).

 

Vincent Brichard (BE), Aline van Pel (BE), Thomas Wölfel (DE), Catherine Wölfel (DE), Etienne De Plaen (BE), Bernard Lethé (BE), Pierre G. Coulie (BE), and Thierry Boon (BE) identified a tyrosine kinase gene coding for a melanoma antigen which offers a potential target for T-cell mediated immunotherapy (161).

 

Marc Stadler (DE), Timm Anke (DE), Johannes Dasenbrock (DE), and Wolfgang A. Steglich (DE) described a new hirsutane derivative, phellodonic acid (1); isolated from fermentations of Phellodon melaleucus strain 87113. Its structure was elucidated by spectroscopic methods. The compound exhibits antibiotic activities towards bacteria and fungi. It is the first bioactive metabolite from cultures of a species belonging to the family Thelephoraceae (1389).

 

Esther R. Angert (US), Kendall D. Clements (NZ), and Norman Richard Pace, Jr. (US) isolated the largest (600 microns by 80 microns) bacterium to be described so far. It is the morphologically peculiar microorganism Epulopiscium fishelsoni that inhabits the intestinal tract of Acanthurus nigrofuscus, a brown surgeonfish (family Acanthuridae), from the Red Sea. Similar microorganisms have been found in surgeonfish species from the Great Barrier Reef. They are considered to be specific symbionts of surgeonfish, although the nature of the symbiosis is unclear (42).

Esther R. Angert, (US), Austin E. Brooks (US), and Norman Richard Pace, Jr. (US) presented ribosomal RNA (rRNA) phylogenetic evidence placing this organism nearest the cellulolytic Clostridia (41).

 

Vincent Falanga (US) and Robert S. Kirsner (US) were the first to obtain vigorous growth and multiplication of isolated single euploid animal cells. They did this by reducing the oxygen tension from the usual 20% down to 2% (389).

 

René H. Medema (NL) and Johannes L. Bos (NL) found that Ras proteins are present in structurally altered forms that enable them to release a flux of mitogenic signals into cells, without ongoing stimulation by their normal upstream regulators (979).

Douglas Hanahan (US) and Robert Allan Weinberg (US) suspect that growth-signaling pathways suffer deregulation in all human tumors (592).

 

Thomas Söllner, Sidney W. Whiteheart (US), Michael Brunner (US), Hediye Erdjument-Bromage (US), Scott Geromanos (US), Paul Tempst (US), and James Edward Rothman (US) reported that the existence of numerous SNARE-related proteins, each apparently specific for a single kind of vesicle or target membrane, indicates that NSF and SNAPs may be universal components of a vesicle fusion apparatus common to both constitutive and regulated fusion (including neurotransmitter release), in which the SNAREs may help to ensure vesicle-to-target specificity. Note: N-ethylmaleimide-sensitive fusion protein = NSF; soluble NSF attachment proteins = SNAPs; SNAP receptors = SNAREs (1376).

 

Lee W. Janson (US) and D. Lansing Taylor (US) proposed that amoeboid motion could be explained by contraction of the cortical gel in mid-regions and near the rear of an advancing amoeba (704).

 

Julie R. Pear (US), Rick A. Sanders (US), Kristin R. Summerfelt (US), Belinda Martineau (US), and William Hiatt (US) produced the first genetically engineered vegetables to reach the market. They were tomatoes in which the action of polygalacturonase (PG), a pectinase contributing to normal ripening, was blocked by the insertion of an antisense gene (1139).

 

Kenichi Higo (JP), Yusuke Saito (JP), and Hiromi Higo (JP) created transgenic tobacco plants capable of producing epidermal growth factor; a mitogen (630).

 

Cynthia J. Kenyon (US), Jean Chang (US), Erin Gensch (US), Adam Rudner (US), Ramon Tabtiang (US), Kui Lin (CN), Jennie B. Dorman (US), and Aylin Rodan (US) found mutants of the hermaphroditic nematode Caenorhabditis elegans with reduced activity of the gene daf-2, a homolog of the insulin and insulin-like growth factor receptors, which live more than twice as long as wild-type. These mutants are active and fully fertile and have normal metabolic rates. The life-span extension caused by daf-2 mutations requires the activity of the gene daf-16. daf-16 appears to play a unique role in life-span regulation and encodes a member of the hepatocyte nuclear factor 3(HNF-3)/forkhead family of transcriptional regulators (751; 876).

Honor Hsin (US) and Cynthia J. Kenyon (US) demonstrated that signals from the reproductive system influence the lifespan of the nematode Caenorhabditis elegans. This study demonstrates an inherent relationship between the reproductive state of this animal and its lifespan, and may have implications for the co-evolution of reproductive capability and longevity (659).

 

Rosalind C. Lee (US), Rhonda L. Feinbaum (US), and Victor R. Ambros (US) made a comparison of the lin-4 genomic sequence from four species and site-directed mutagenesis of potential open reading frames. They found that lin-4 does not encode a protein. Two small lin-4 transcripts of approximately 22 and 61 nt were identified in Caenorhabditis elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin-4 regulates lin-14 translation via an antisense RNA-RNA interaction (844; 845). Note: lin-4 is essential for the normal temporal control of diverse postembryonic developmental events in C. elegans.

Amy E. Pasquinelli (US), Brenda J. Reinhart (US), Frank J. Slack (US), Betsy Maller (US), Mitzi I. Kurodo (US), Mark Q. Martindale (US), Ashok Srinivasan (US), Mark Fishman (US), David C. Hayward (US), Eldon E. Ball (US), Bernard Degnan (US), Peter Müller (US), John Finnerty (US), Michael Levine (US), Patrick Leahy (US), Eric Davidson (US), and Gary B. Ruvkun (US), discovered a second tiny regulatory RNA in worms of exactly the same size as the lin-4 RNA and in the same genetic pathway. Similar to the lin-4 RNA, this let-7 RNA dampens activity of its target gene through its 3' UTR. Furthermore, its sequence too resides within a larger molecule that folds up on itself to form a double-stranded hairpin structure (1133).

Brenda J. Reinhart (US), Frank J. Slack (US), Michael Basson (US), Amy E. Pasquinelli (US), Jill C. Bettinger (US), Ann E. Rougvie (US), H. Robert Horvitz (US), and Gary B. Ruvkun (US) found that many other creatures including humans, fruit flies, chickens, frogs, zebrafish, mollusks, and sea urchins, carry their own versions of let-7, which could also fold into hairpins. The apparent binding site for let-7 RNA in its target was conserved in some of these organisms as well. Moreover, let-7 RNA appeared and disappeared at similar points during development in many of the animals (1224).

Phillip D. Zamore (US), Thomas Tuschl (US), Phillip A. Sharp (US), and David P. Bartel (US) examined the molecular mechanism underlying RNAi. We find that RNAi is ATP dependent yet uncoupled from mRNA translation. During the RNAi reaction, both strands of the dsRNA are processed to RNA segments 21-23 nucleotides in length. Processing of the dsRNA to the small RNA fragments does not require the targeted mRNA. The mRNA is cleaved only within the region of identity with the dsRNA. Cleavage occurs at sites 21-23 nucleotides apart, the same interval observed for the dsRNA itself, suggesting that the 21-23 nucleotide fragments from the dsRNA are guiding mRNA cleavage (1622).

Note: Double-stranded RNA (dsRNA) directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi).

Note: In 2001, Victor R. Ambros's group (US), as well as those of David Bartel (US) and Thomas Tuschl (DE) discovered almost 100 of these small regulatory RNAs in flies, humans, and worms.

In 2001, the Mello, Ruvkun, and Fire groups collaborated to show that efficient liberation of the lin-4 and let-7 RNAs from the hairpin molecules relies on the C. elegans version of Dicer, an enzyme that Gregory Hannon (US) discovered and named for its ability to chop dsRNA into uniformly sized, small RNAs that direct mRNA destruction during RNAi. These results and others, including similar ones generated by Philip Zamore (US), cemented the connection between miRNAs and RNAi, thus providing one biological 'reason' for the RNAi machinery.

The human genome contains more than 500 and perhaps as many as 1000 miRNAs that could collectively control a third of all of our protein-producing genes. These regulatory molecules have been implicated in a wide range of normal and pathological activities. They play roles not only in embryonic development, but in blood-cell specialization, cancer, muscle function, heart disease, viral infections, and possibly neurological signaling and stem-cell behavior. Researchers are exploring the possibility of using miRNAs 'signatures' for diagnosis and prognosis and are considering manipulating their quantities for therapeutic purposes.

Frank Ratcliff (GB), Bryan D. Harrison (GB), David C. Baulcombe (GB), Andrew J. Hamilton (GB), Tamas Dalmay (GB), Stephen Rudd (GB), Susan Angell (GB), Olivier Voinnet (GB), and Louise Chappell (GB) established that small RNAs silence genes in plants as well, thus catalyzing discoveries of many such RNAs in a wide range of living things. Their findings led to the identification of the biochemical machinery that unifies numerous processes by which small RNAs govern gene activity (312; 585; 586; 1212). See, Fire 1991 and 1998

 

Claude Lévi (FR) introduced the use of reproductive characters for the higher classification of Demosponges (854; 855). He is commemorated by Acarnus claudei Van Soest et al., 1991; Acarnus levii Vacelet, 1960; Diacarnus levii Kelly-Borges & Vacelet, 1995; Levinella Borojevic & Boury-Esnault, 1986; Levinellidae Borojevic & Boury-Esnault, 1986; Microciona levii Sarà & Siribelli, 1960; Paresperella levii Uriz, 1989; Tethya levii Sarà, 1988; Lekanesphaera levii Argano & Ponticelli, 1981; and Seguenzia levii B.A. Marshall, 1991.

 

James C. Smith (GB) discovered mesoderm-inducing factors in Xenopus embryos (1364).

 

John A. Eisman (AU), Paul J. Kelly (AU), Nigel A. Morrison (AU), Nicholas A. Pocock (AU), Rosanna Yeoman (AU), Joan Birmingham (AU), and Philip N. Sambrook (AU) found that the vitamin D receptor is associated with variability in susceptibility to osteoporosis (370).

 

Peter Agre (US), Gregory M. Preston (US), Barbara L. Smith (US), Jin Sup Jung (US), Surabhi Raina (US), Chulso Moon (US), William B. Guggino (US), and Søren Nielsen (DK) discovered the aquaporin membrane water channels thus answering a long-standing biophysical question of how water specifically crosses biologic membranes, and provided insight, at the molecular level, into the fundamental physiology of water balance and the pathophysiology of water balance disorders (20).

 

The landmark national collaborative study called the DCCT (Diabetes Control and Complications Trial) was published. The DCCT conclusively demonstrated the value of tight glucose control in type 1 diabetes. The study clearly revealed that better control leads to better outcomes (252).

 

David M. Danks (AU) located the gene for Huntington’s disease on the short arm of chromosome number 4 (313).

 

Harry T. Orr (US), Ming-yi Chung (US), Sandro Banfi (US), Thomas J. Kwiatkowski Jr. (US), Antonio Servadio (US), Arthur L. Beaudet (US), Alanna E. McCall (US), Lisa A. Duvick (US), Laura P. W. Ranum (US), and Huda Y. Zoghbi (US) determined that spinocerebellar ataxia type 1 was caused by an expansion of the glutamine-coding CAG trinucleotide repeat in this gene (1111).

Sandro Banfi (US), Antonio Servadio (US), Ming-yi Chung (US), Thomas J. Kwiatkowski Jr. (US), Alanna E. McCall (US), Lisa A. Duvick (US), Ying Shen (US), Elizabeth J. Roth (US), Harry T. Orr (US), and Huda Y. Zoghbi (US) identified ATXN1 as the gene responsible for spinocerebellar ataxia type 1 (SCA1) (80).

Christopher J. Cummings (US), Michael A. Mancini (US), Barbara Antalffy (US), Donald B. DeFranco (US), Harry T. Orr (US), and Huda Y. Zoghbi (US) demonstrated that the misfolding, aggregation, and degradation of the protein product of this gene, ataxin-1, plays a role in the disorder, a finding relevant to other, more common neurodegenerative diseases such as Alzheimer's (300).

 

Huntington's Disease Collaborative Research Group (US), Huntington G. Willard (US), Russell G. Snell (GB), John C. MacMillan (GB), Jeremy P. Cheadle (GB), Iain Fenton (GB), Lazarus P. Lazarou (GB), Peter Davies (GB), Marcy E. MacDonald (US), James F. Gusella (US), Peter S. Harper (GB), Duncan J. Shaw (GB), Anne Norremolle (DK), Olaf Riess (DK), Jörg T. Epplen (DK), Kristen Fenger (DK), Liz Hasholt (DK), and Sven A. Sorensen (DK) found that near the middle of the gene associated with Huntington’s disease the trinucleotide CAG is repeated 9-34 times in the normal allele and 30-70 times in the disease allele (549; 1088; 1368; 1574). The Danish group determined that the normal allele produces a protein called Huntingtin.

 

Akitada Ichinose (JP) and Earl Warren Davie (US) reported the complete amino acid sequences of all the known blood coagulation factors and the DNA sequences coding for the genes for all the clotting factors (675).

 

Elaine Tuomanen (US) found that the agent of whooping cough, Bordetella pertussis, fools the body’s defense mechanisms by producing a chemical signal which interferes with the ability of patrolling white blood cells to recognize the address at their destination (1482). See, Tuomanen, 1988. Note: This chemical might be useful as a highly selective anti-inflammatory agent to treat inflammation in the brain, joints, eyes and other sites where the surrounding tissues must be protected from the immune system as well as from invaders.

 

Alan T. Hudson (GB) reported that atovaquone, a member of the hydroxynaphthoquinone family, is an outstanding antimalarial drug (664).

 

Yael Katz-Levy (IL), Susan L. Kirshner (IL), Michael Sela (IL), and Edna Mozes (IL) synthesized two immunodominant myasthenogenic T cell epitopes (p195–212 and p259–271) derived from an alpha-subunit of the nicotinic acetylcholine receptor (AchR) (741).

Miri Paas-Rozner (IL), Molly Dayan (IL), Yoav Paas (FR), Jean-Pierre Changeux (FR), Itzhak Wirguin (IL), Michael Sela (IL), and Edna Mozes (IL) found that when administered orally, the dual analog (p195–212 and p259–271) could treat experimental allergic myasthenia gravis (EAMG) induced in mice by immunization with the multideterminant native Torpedo AChR (TACHR) (1115). Note: Torpedo is a genus of electric ray fishes.

 

Maria Victoria Valero (CO), Luis Roberto Amador (CO), Claudia Galindo (CO), Jorge Figueroa (CO), Mary Stella Bello (CO), Luis Angel Murillo (CO), Ana Lucia Mora (CO), Gloria Patarroyo (CO), Claudia Lucia Rocha (CO), Mauricio Rojas (CO), John Jairo Aponte (CO), Luis Eduardo Sarmlento (CO), Diana M. Lozada (CO), Carlos Gustavo Coronell (CO), Norella M. Ortega (CO), Jaiver E. Rosas (CO), Manuel Elkin Patarroyo (CO), and Pedro Luis Alonso (ES) reported on the first successful large scale malaria vaccine trial in South America (1497).

 

Richard J. Cristiano (US), Louis C. Smith (US), Mark A. Kay (US), William R. Brinkley (US), Savio L.C. Woo (US), Steven Rothenberg (US), Charles N. Landen (US), Dwight A. Bellinger (US), Francis Leland (US), Carol Toman (US), Milton Finegold (US), Arthur R. Thompson (US), Marjorie S. Read (US), and Kenneth M. Brinkhous (US) announced that gene therapy in dogs with hemophilia B has provided short-term relief from bleeding, an important first step toward a permanent cure (296; 297; 746).

 

Jeffrey B. Ulmer (US), John J. Donnelly (US), Suezanne E. Parker (US), Gary H. Rhodes (US), Philip L. Felgner (US), Varavani J. Dwarki (US), Stanisiaw H. Gromkowski (US), R. Randall Deck (US), Corrille M. DeWitt (US), Arthur Friedman (US), Linda A. Hawe (US), Karen R. Leander (US), Douglas Martinez (US), Helen C. Perry (US), John W. Shiver (US), Donna L. Montgomery (US), and Margaret A. Liu (US) were among the first to successfully vaccinate animals with plasmid DNA encoding a specific gene, in their case influenza A nucleoprotein. They generated nucleoprotein-specific cytotoxic T lymphocytes and protection from a subsequent challenge with a heterologous strain of influenza A virus (1495). Note: This technology is now being used to generate immunity to a host of antigens, from malaria to cancer.

 

Seamas C. Donnelly (GB), Robert M. Strieter (GB), Steven L. Kunkel (GB), Alfred Walz (GB), Colin R. Robertson (GB), David C. Carter (GB), Ian S. Grant (GB), Antony J. Pollok (GB), and Christopher Haslett (GB) provided evidence of a relation between the presence of interleukin-8 in early bronchioalveolar lavage (BAL) samples and the development of acute respiratory distress syndrome (ARDS). The early appearance of interleukin-8 in BAL of patients at risk of ARDS may be an important prognostic indicator for the development of the disorder and reinforces the likely importance of neutrophils and the effects of their accumulation and activation in the pathogenesis of many cases of ARDS (344).

Rolf Rossaint (DE), Konrad J. Falke (DE), Frank Lopez (DE), Klaus Slama (DE), Ulrich Pison (DE), and Warren N. Zapol (DE) found that inhalation of nitric oxide by patients with severe adult respiratory distress syndrome (ARDS) reduces the pulmonary-artery pressure and increases arterial oxygenation by improving the matching of ventilation with perfusion, without producing systemic vasodilation (1256).

Gordon R. Bernard (US), Antonio Artigas (ES), Kenneth L. Brigham (US), Jean Carlet (FR), Konrad J. Falke (DE), Leonard Hudson (US), Maurice Lamy (FR), Jean Roger LeGall (FR), Alan Morris (US), Roger Spragg (US), and The Consensus Committee clarified and sharpened definitions, mechanisms, and relevant outcomes as they pertained to adult acute respiratory distress syndrome (ARDS). They also set up a mechanism for clinical trial coordination (119).

Alan H. Morris (US), C. Jane Wallace (US), Ronald L. Menlove (US), Terry P. Clemmer (US), James F. Orme, Jr. (US), Lindell K. Weaver (US), Nathan C. Dean (US), Frank Thomas (US), Thomas D. East (US), Nathan L. Pace (US), Mary R. Suchyta (US), Eduardo Beck (ES), Michela Bombino (ES), Dean F. Sittig (US), Stephen Böhm (US), Barbara Hoffmann (US), Hayo Becks (US), Samuel Butler (US), James E. Pearl (US), and Brad Rasmusson (US) performed controlled trials comparing extracorporal gas exchange (and thereby resting the injured lung) with mechanical ventilatory support (which may increase lung inflammation). They showed that survival was not significantly different in 19 patients subjected to mechanical ventilation and 21 patients undergoing extracorporal support for severe ARDS (1023).

G. Umberto Meduri (US), A. Stacey Headley (US), Emmel Golden (US), Stephanie J. Carson (US), Reba A. Umberger (US), Tiffany Kelso (US), and Elizabeth A. Tolley (US) determined that prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and multiple organ dysfunction syndrome (MODS) scores and reduced mortality (981).

 

Sheena Kinmond (GB), Thomas C. Aitchison (GB), Barbara M. Holland (GB), John G. Jones (GB), Tiffany L. Turner (GB), and Charles A.J. Wardrop (GB) found that among preterm infants randomized to delayed cord clamping for 30 seconds after birth required less cardiorespiratory intervention, less supplemental oxygen and fewer blood transfusions compared to controls (763).

 

Robert S. Kirsner (US), Vincent Falanga (US), and William H. Eaglstein (US) described the ability of skin allografts to release growth factors as well as to act as pharmacologic agents (770).

Alberto Bolgiani (AR) and Fortunato Benaim (AR) reported that skin allografts provided by tissue banks were routinely used in burn centers as a temporary cover for serious burn wounds (147; 155).

 

Georg Gosztonyi (DE) Bernhard Dietzschold (US), Moujahed Kao (DE), Charles E. Rupprecht (US), and Hilary Koprowski (US) determined that during rabies viral antigens are almost exclusively found on neurons (517).

 

The IFNB Multiple Sclerosis Study Group reported that interferon beta-1b (IFNB) is the only treatment that has substantially altered the natural history of multiple sclerosis (MS) in a properly controlled clinical trial (553).

 

Joan Goverman (US), Andrea Woods (US), Lisa Larson (US), Leslie P. Weiner (US), Leroy Hood (US), and Dennis M. Zaller (US) constructed a transgenic mouse model that mimics the human autoimmune disease multiple sclerosis in its spontaneous induction and pathology. This model system affords a unique opportunity to dissect the genetic and environmental variables that may contribute to the development of spontaneous autoimmune disease (522).

Juan J. Lafaille (US), Kumiko Nagashima (US), Motoya Katsuki (JP), and Susumu Tonegawa (US) produced data indicating that experimental autoimmune encephalomyelitis (EAE) can be mediated by CD4+ anti-myelin basic protein T cells in the absence of any other lymphocytes and that nontransgenic lymphocytes that are present in transgenic T/R+ but absent in T/R- mice have a protective effect. The data also suggested that spontaneous EAE may be triggered by an in situ activation of CD4+ anti-MBP cells in the nervous system (817).

 

Richard H.T. Edwards (GB), Henry Gibson (GB), John E. Clague (GB), and Timothy Helliwell (GB) reported that the symptoms of chronic fatigue syndrome or myalgic encephalitis (ME) were shown to be due to general fatigue rather than a myalgic disorder (368).

 

Thandavarayan Ramamurthy (IN), Surabhi Garg (IN), Rakhi Sharma (IN), Sujit K. Bhattacharya (IN), Gopinath Balakrish Nair (IN), Toshio Shimada (JP), Tae Takeda (JP), Tadahiro Karasawa (JP), Hisao Kurazano (JP), Amit Pal (PK), and Yoshifumi Takeda (JP) reported emergence of a novel strain of Vibrio cholerae with epidemic potential in southern and eastern India (250; 1205).

 

David R. Goudie (GB), Martin A.R. Yuille (GB), Margaret A. Leversha (GB), Robert A. Furlong (GB), Nigel P. Carter (GB), Michael J. Lush (GB), Nabeel A. Affara (GB), and Malcolm Andrew Ferguson-Smith (GB) reported that a gene (ESS 1) predisposing to the development of multiple invasive but self–healing skin tumours (squamous cell epitheliomata) is tightly linked to the polymorphic DNA marker D9S53 (9q31). Comparison of markers associated with ESS1 in independently ascertained families suggests a common origin of the disease and defines the location of ESS1. Haplotype studies indicate that the disease locus is most likely to lie between D9S29(9q31) and D9S1 (9q22.1–q22.2) (519).

 

Jack S. Mandel (US), John H. Bond (US), Timothy R. Church (US), Dale C. Snover (US), G. Mary Bradley (US), Leonard M. Schuman (US), Fred Ederer (US), et al. presented results from an National Cancer Institute-supported clinical trial which show that annual screening with guaiac fecal occult blood testing (FOBT) can reduce colorectal cancer mortality by about 33% (934).

 

Jeffrey Travis (US), Digamber S. Borgaonkar (IN-US), L.C. Schmidt (US), S. Eric Martin (US), Michael D. Kanzer (US), Lanny Edelsohn (US), John H. Growden (US), and Lindsay A. Farrer (US) found a linkage of late-onset Alzheimer's disease with apolipoprotein E type 4 on chromosome 19 (153; 1472).

 

Harris Philip Zeigler (US), and Hans-Joachim Bischof (US) wrote, Vision, Brain, and Behavior in Birds (1626).

 

Wolfgang Wiltschko (DE), Ursula Munro (GB), Hugh Ford (GB), Roswitha Wiltschko (DE), Manuela Zapka (DE), Dominik Heyers (DE), Christine M. Hein (DE), Svenja Engels (DE), Nils-Lasse Schneider (DE), Jörg Hans (DE), Simon Weiler (DE), David Dreyer (DE), Dmitry Kishkinev (DE), J. Martin Wild (NZ), and Henrik Mouritsen (DE) found that birds flying alone and often over great distances, use various directional cues including, crucially, a light-dependent magnetic compass (1579; 1623).

Peter J. Hore (GB), Henrik Mouritsen (DE), Thorsten Ritz (US), Salih Adem (US), Klaus Schulten (US), Peter Thalau (DE), John B. Phillips (US), Roswitha Wiltschko (DE), Wolfgang Wiltschko (DE), Svenja Engels (DE), Nils-Lasse Schneider (DE), Nele Lefeldt (DE), Christine Maira Hein (DE), Manuela Zapka (DE), Andreas Michalik (DE), Dana Elbers (DE), and Achim Kittel (DE) reported the mechanism of this compass has been suggested to rely on the quantum spin dynamics of photoinduced radical pairs in cryptochrome flavoproteins located in the retinas of the birds (376; 650; 1241; 1242).

Henrik Mouritsen (DE) notes that night-migratory songbirds are remarkably proficient navigators (1028).

Jingjing Xu (DE), Lauren E. Jarocha (GB), Tilo Zollitsch (GB), Marcin Konowalczyk (GB), Kevin B. Henbest (GB), Sabine Richert (DE), Matthew J. Golesworthy (GB), Jessica Schmidt (DE), Victoire Déjean (GB), Daniel J. C. Sowood (GB), Marco Bassetto (DE), Jiate Luo (GB), Jessica R. Walton (GB), Jessica Fleming (GB), Yujing Wei (GB), Tommy L. Pitcher (GB), Gabriel Moise (GB), Maike Herrmann (DE), Hang Yin (US), Haijia Wu (DE), Rabea Bartölke (DE), Stefanie J. Käsehagen (DE), Simon Horst (DE), Glen Dautaj (DE), Patrick D. F. Murton (GB), Angela S. Gehrckens (GB), Yogarany Chelliah (US), Joseph S. Takahashi (US), Karl-Wilhelm Koch (DE), Stefan Weber (DE), Ilia A. Solov’yov (DE), Can Xie (CN), Stuart R. Mackenzie (GB), Christiane R. Timmel (GB), Henrik Mouritsen (DE), and P. J. Hore (GB) showed that the photochemistry of cryptochrome 4 (CRY4) from the night-migratory European robin (Erithacus rubecula) is magnetically sensitive in vitro, and more so than CRY4 from two non-migratory bird species, chicken (Gallus gallus) and pigeon (Columba livia). Site-specific mutations of ErCRY4 reveal the roles of four successive flavin-tryptophan radical pairs in generating magnetic field effects and in stabilizing potential signalling states in a way that could enable sensing and signalling functions to be independently optimized in night-migratory birds (1603).

 

Michael F. Rotondo (US), C. William Schwab (US), Michael D. McGonigal (US), Gordon R. Phillips, 3rd (US), Todd M. Fruchterman (US), Donald R. Kauder (US), Barbara A. Latenser (US), and Peter B. Angood (US) in a study designed to compare the newly described three-phase approach of damage control surgery to definitive laparotomy concluded that damage control laparotomy may offer a survival benefit over conventional surgery in the exsanguinating patient with multiple penetrating abdominal vascular and visceral injuries (1258).

 

Antonio Torroni (IT), Rem I. Sukernik (RU), Yelena B. Starikovskaya (RU), Margaret F. Cabell (US), Michael H. Crawford (US), Anthony G. Comuzzie (US), James van Gundia Neel (US), Ramiro Barrantes (CR), Theodore G. Schurr (US) and Douglas C. Wallace (US) compared several DNA markers found in modern Native Americans and modern Siberians and estimated that if the Amerindians entered the New World as a single group, that entry would have occurred approximately 20,000-27,000 BCE (1468; 1469).

Johanna Nichols (US) suggests that the diversity of languages among Native Americans could have arisen only after humans had been in the New World for at least 20,000-30,000 years (1069).

 

1994

Alfred Goodman Gilman (US) and Martin Rodbell (US) were awarded the Nobel Prize in Physiology or Medicine for their discovery of G-proteins and the role of these proteins in signal transduction in cells.

 

Kenneth M. Towe (US) made a compelling case for Earth’s early atmosphere to have contained significant quantities of oxygen (1470).

 

Kyriacos Costa Nicolaou (CY-US), Zhen Yang (US), Jin-Jun Liu (US), Hiroski Ueno (US), Philippe G. Nantermet (US), Rodney Kiplin Guy (US), Christopher F. Claiborne (US), Johanne Renaud (GR), Elias A. Couladouros (GR), Kumarapandian Paulvannan (US), and Erik J. Sorensen (US) carried out the total synthesis of taxol, an anticancer agent (1071; 1076).

 

Leonard M. Adleman (US) noted that a small instance of the 'Hamiltonian path problem' is encoded in molecules of DNA and can be solved in a test tube using the tools of molecular biology. This is apparently the first example of computation carried out at the molecular level and suggests the possibility of fundamental connections between biology and computer science (19).

 

The Environmental Protection Agency (EPA) of The United States government compiled a Public Review Draft of its Dioxin Reassessment. It covers dioxin, dioxin-like PCBs and furans. The report concludes that these chemicals cause harm at levels similar to those seen in the general public. In addition to cancer, potential damage is seen to the immune, nervous and reproductive systems. This report was not released due to pressure from the chemical industry (364).

 

Daniel Picot (FR), Patrick J. Loll (US), and R. Michael Garavito (US) presented the x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1 (1161).

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and indomethacin work by inhibiting prostaglandin H2 synthase that produces prostaglandins—hormone-like messenger molecules that trigger many processes in the body, including inflammation.

Patrick J. Loll (US), Daniel Picot (FR), R. Michael Garavito (US) reported that aspirin splits into two parts and affixes one part to prostaglandin H2 synthase-1, permanently altering its chemical structure and blocking the reaction that produces prostaglandins (895). Note: Aspirin is the only NSAID known to work in this manner.

 

Bruno Canard (FR) and Simon Sarfati (FR) invented the "Illumina" dye sequencing technique used to determine the series of base pairs in DNA, also known as DNA sequencing. It is a reversible terminated chemistry concept (198; 199). Note: It can also be used for whole-genome and region sequencing, transcriptome analysis, metagenomics, small RNA discovery, methylation profiling, and genome-wide protein-nucleic acid interaction analysis.

"Ion semiconductor sequencing" is a method of DNA sequencing based on the detection of hydrogen ions that are released during the polymerization of DNA. This is a method of "sequencing by synthesis", during which a complementary strand is built based on the sequence of a template strand. The principle is straightforward: DNA to be sequenced is captured in a microwell, and unmodified nucleotides are floated across the wells, one at a time. The polymerase incorporates the appropriate oligonucleotide into the growing strand, and the hydrogen ion that is released changes the pH in the solution, which is detected by an ion sensor. This allows sequencing in real time (1263). Note: More than 100 different single cell omics methods have been published.

 

Antonio Lazcano (MX) theorizes that DNA evolved to replace RNA as the repository of hereditary information because, 1) DNA is much more resistant to harsh environmental conditions, 2) DNA is less prone to mutations which cannot be repaired, 3) cytosines in DNA are not as prone to spontaneously deaminate to uracil as they are in RNA, and 4) the duplex nature of DNA offered redundancy, which when coupled with repair mechanisms had a distinct advantage over simplex RNA without a repair mechanism (834).

 

Christine Guthrie (US) presented circumstantial evidence that the splicesome is, at least in part, a ribozyme (568).

 

Kevin J. Hacker (US) and Bruce Michael Alberts (US) proposed that, in both prokaryotes and eukaryotes, the DNA polymerase holoenzyme could sense a difference between being stopped by omission of a nucleotide and being stopped by the end of an Okazaki fragment. From their results, they concluded that ATP hydrolysis by the holoenzyme’s 44/62 proteins serves to load the ring-like 45 protein onto the DNA. Once loaded, the 45 protein, possibly along with the 44/62 complex, acts as a sliding clamp that tethers the DNA polymerase to the template (571).

Kevin J. Hacker (US) and Bruce Michael Alberts (US) noted that the DNA replicating mechanism allows a DNA polymerase holoenzyme to remain on the DNA template for many minutes when synthesizing DNA (or when stopped by nucleotide omission), while permitting rapid dissociation at the end of each Okazaki fragment. They concluded that, upon completing each Okazaki fragment, the holoenzyme senses an encounter with duplex DNA and then switches to a state that rapidly dissociates (28; 572).

 

Saulius Klimasauskas (LT), Sanjay Kumar (US), Richard J. Roberts (US), and Xiaodong Cheng (US) found that HhaI methyltransferase flips its target base out of the DNA helix thus exposing it for methylation (779).

 

Sean B. Carroll (US), Julie Gates (US), Dave N. Keys (US), Stephen W. Paddock (US), Grace E. Panganiban (US), Jayne E. Selegue (US), and Jim A. Williams cloned and analyzed expression patterns of several butterfly cognates of Drosophila appendage patterning genes to identify the molecular processes underlying the generation of wing patterns in butterflies. Butterfly wing patterns are organized by two spatial coordinate systems. One system specifies positional information with respect to the entire wing field and is conserved between fruit flies and butterflies. A second system, superimposed on the general system and involving several of the same genes, operates within each wing subdivision to elaborate discrete pattern elements. Eyespots, which form from discrete developmental organizers, are marked by Distal-less gene expression. These circular pattern elements appear to be generated by a process similar to, and perhaps evolved from, proximodistal pattern formation in insect appendages (205).

 

Kevin A. Pyke (GB) and Rachel M. Leech (GB) offered insight into the composition and function of the chloroplast division machinery in plants (1191).

 

Polly Matzinger (US) theorizes, “For many years immunologists have been well served by the viewpoint that the immune system's primary goal is to discriminate between self and non-self. I believe that it is time to change viewpoints and, in this essay, I discuss the possibility that the immune system does not care about self and non-self, that its primary driving force is the need to detect and protect against danger, and that it does not do the job alone, but receives positive and negative communications from an extended network of other bodily tissues” (960).

 

Charles D. Surh (US) and Jonathan Sprent (US) presented direct evidence for apoptosis in the normal thymus. Apoptosis in the thymic cortex is not reduced in MHC-deficient mice, which suggests that T-cell death is primarily a reflection of lack of positive selection rather than negative selection. Direct evidence for apoptosis due to negative selection was obtained (1422).

 

Glenn Dranoff (US), Alexander D. Crawford (US), Michael Sadelain (US), Beverly Ream (US), Asif Rashid (US), Roderick T. Bronson (US), G. Richard Dickersin (US), Cindy J. Bachurski (US), Eugene L. Mark (US), Jeffrey A. Whitsett (US), and Richard C. Mulligan (US) found that the microenvironment within the lungs is rich in granulocyte-macrophage colony-stimulating factor (GM-CSF) (346).

Catherine Fitting (FR), Suman Dhawan (FR), and Jean-Mart Cavaillion (FR) discoveredsthe microenvironment within the lungs, rich in GM‐CSF, is responsible for the inability of alveolar macrophages to develop endotoxin tolerance in contrast to any other mononuclear phagocytes (420).

 

Kristin A. Hogquist (US), Stephen C. Jameson (US), William R. Heath (AU), Jane L. Howard (AU), Michael John Bevan (GB-US), and Francis R. Carbone (AU) used organ culture of fetal thymic lobes from T cell receptor (TCR) transgenic β2M(−/−) mice to study the role of peptides in positive selection. The TCR used was from a CD8+ T cell specific for ovalbumin 257–264 in the context of Kb. Several peptides with the ability to induce positive selection were identified. These peptide-selected thymocytes have the same phenotype as mature CD8+ T cells and can respond to antigen. Those peptides with the ability to induce positive selection were all variants of the antigenic peptide and were identified as TCR antagonist peptides for this receptor (642).

 

R. Pat Bucy (US), Angela Panoskaltsis-Mortari (US), Guo-qiang Huang (US), Jimin Li (US), Laurel Karr (US), Martha Ross (US), John H. Russell (US), Kenneth M. Murphy (US), and Casey T. Weaver (US) discovered heterogeneity of single cell cytokine gene expression in clonal T cell populations (180).

 

Claude Saint-Ruf (FR), Katharina Ungewiss (CH), Marcus Groettrup (CH), Ludovica Bruno (CH), Hans Joerg Fehling (CH), and Harald von Boehmer (CH) described a developmentally controlled gene that encodes the pre-TCR alpha (pT alpha) chain, which covalently associates with T cell antigen rceptor (TCR) beta and with the CD3 proteins forms a pre-TCR complex that transduces signals in immature thymocytes (1269).

 

Pietro De Togni (US), Joseph Goellner (US), Nancy H. Ruddle (US), Philip R. Streeter (US), Fick Andrea (US), Sanjeev Mariathasan (US), Stacy C. Smith (US), Rebecca Carlson (US), Laurie P. Shornick (US), Jena Strauss-Schoenberger (US), John H. Russell (US), Robert Karr (US), and David D. Chaplin (US) reported that mice rendered deficient in lymphotoxin (LT) by gene targeting in embryonic stem cells have no morphologically detectable lymph nodes or Peyer's patches, although development of the thymus appears normal. Within the white pulp of the spleen, there is failure of normal segregation of B and T cells. Spleen and peripheral blood contain CD4+CD8- and CD4-CD8+ T cells in a normal ratio, and both T cells subsets have an apparently normal lytic function. Lymphocytes positive for immunoglobulin M are present in increased numbers in both the spleen and peripheral blood. These data suggest an essential role for LT in the normal development of peripheral lymphoid organs (1462).

 

Paul D. Crowe (US), Todd L. VanArsdale (US), Barbara N. Walter (US), Carl F. Ware (US), Catherine Hession (US), Barbara Ehrenfels (US), Jeffrey L. Browning (US), Wenie S. Din (US), Raymond G. Goodwin (US), and Craig A. Smith (US) identified a receptor specific for human LT-beta, which suggests that cell surface LT may have functions that are distinct from those of secreted LT-alpha (298). Note: Tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha) are members of a family of secreted and cell surface cytokines that participate in the regulation of immune and inflammatory responses.

 

Jack D. Burton (US), Richard N. Bamford (US), Christian Peters (US), Angus J. Grant (US), Gloria Kurys (US), Carolyn K. Goldman (US), Jennifer Brennan (US), Erich Roessler (US), and Thomas A. Waldmann (US) discovered a lymphokine, provisionally designated interleukin T (IL-T), which stimulates T cell proliferation and the induction of lymphokine-activated killer cells (187).

 

Youhai Chen (CN-US), Vijay K. Kuchroo (IN-US), Jun-ichi Inobe (US), David A. Hafler (US), Howard L. Weiner (US), Herve Groux (US), Anne O'Garra (US), Mike Bigler (US), Matthieu Rouleau (US), Svetlana Antonenko (US), Jan E. de Vries (AT-IT), and Maria-Grazia Roncarolo (AT-IT) showed that cytokine-dependent Treg cells can be produced from naive T cells and can be used therapeutically (237; 560).

 

Michael J. Elliott (GB), Ravinder Nath Maini (GB), Marc Feldmann (GB), Alice Long-Fox (GB), Peter Charles (GB), Hanny Bijl (GB), and James N. Woody (GB) reported that a chimeric monoclonal antibody to tumor necrosis factor alpha (cA2) may be useful therapy in the control of acute disease flares in rheumatoid arthritis and treatment programs including cA2 may be effective in the long term treatment of this disease (373).

 

Paul A. Garrity (US), Dan Chen (US), Ellen V. Rothenberg (US), and Barbara J. Wold (US) found that interleukin-2 transcription is regulated in vivo at the level of coordinated binding of both constitutive and regulated factors (471).

 

Kenneth H. Grabstein (US), June Eisenman (US), Kurt Shanebeck (US), Charles Rauch (US), Subhashini Srinivasan (US), Victor Fung (US), Courtney Beers (US), Jane Richardson (US), Michael A. Schoenborn (US), Minoo Ahdieh (US), Lisabeth Johnson (US), Mark R. Alderson (US), James Dewey Watson (US), Dirk M. Anderson (US), and Judith G. Giri (US) cloned a T cell growth factor (IL-15) that interacts with the beta chain of the interleukin-2 receptor (525).

 

Elizabeth R. Kearney (US), Kathryn A. Pape (US), Dennis Y. Loh (US), and Marc K. Jenkins (US) produced results which provided a physical basis for the classical finding that antigen-specific memory and tolerance can be influenced by the form of antigen administration, e.g. subcutaneous, intravenous, with or without adjuvant (748).

 

C. Alexander Turner, Jr. (US), David H. Mack (US), and Mark M. Davis (US) described a novel gene, Blimp-1 (for B lymphocyte-induced maturation protein), transcripts of which are rapidly induced during the differentiation of B lymphocytes into immunoglobulin secretory cells and whose expression is characteristic of late B and plasma cell lines. Blimp-1 protein appears to be a pleiotropic regulatory factor capable of at least partially driving the terminal differentiation of B cells (1486).

 

Larry L. Green (US), Margaret C. Hardy (US), Catherine E. Maynard-Currie (US), Hirohisa Tsuda (US), Donna M. Louie (US), Michael J. Mendez (US), Hadi Abderrahim (US), Masato Noguchi (US), Douglas H. Smith (US), Yongjun Zeng (US), Nathaniel E. David (US), Hitoshi Sasai (US), Dan Garza (US), Daniel G. Brenner (US), Joanna F. Hales (US), Ryan P. McGuinness (US), Daniel J. Capon (US), Sue Klapholz (US), and Aya Jakobovits (US) engineered antigen-specific human monoclonal antibodies from mice using human Ig heavy and light chain yeast artificial chromosomes (YACS) (535).

 

James A. Johnston (US), Masaru Kawamura (US), Robert A. Kirken (US), Yi-Qing Chen (US), Trevor B. Blake (US), Kyoichi Shibuya (US), John R. Ortaldo (US), Daniel W. McVicar (US), and John J. O'Shea (US) reported that a new member of the Janus family of kinases (JAK-3) is coupled to the interleukin 2 receptor (IL-2R) in human peripheral blood T cells and natural killer cells. Interaction with interleukin 2 (IL-2) leads to the phosphorylation and activation of JAK-3 (713).

 

Jamison Nourse (US), Eduardo Firpo (US), W. Michael Flanagan (US), Steve Coats (US), Kornella Polyak (US), Mong-Hong Lee (US), Josan Massague (US), Gerald R. Crabtree (US), and James M. Roberts (US) reported that interleukin 2 (IL-2) allows cyclin-dependent kinase (Cdk) activation by causing the elimination of the Cdk inhibitor protein p27klp1 and that this is prevented by rapamycin (1092).

 

Federica Sallusto (IT-CH) and Antonio Lanzavecchis (CH) found that efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and down regulated by tumor necrosis factor alpha (1274).

 

Makio Iwashima (US), Bryan A. Irving (US), Nicolai S. C. van Oers (US), Andrew C. Chan (US), and Arthur Weiss (US) explained that the T cell antigen receptor (TCR) initiates signals by interacting with cytoplasmic protein tyrosine kinases (PTKs) through a 17-residue sequence motif [called the antigen recognition activation motif (ARAM)] that is contained in the TCR zeta and CD3 chains. TCR stimulation induces the tyrosine phosphorylation of several cellular substrates, including the ARAMs. Lck kinase activity is required for phosphorylation of two conserved tyrosine residues in an ARAM. This phosphorylation leads to the recruitment of a second cytoplasmic PTK, ZAP-70, through both of the ZAP-70 Src homology 2 domains and its phosphorylation. Thus, TCR signal transduction is initiated by the sequential interaction of two PTKs with TCR ARAMs (692).

 

Diana L. Sylvestre (US), and Jeffrey V. Ravetch (US) found a murine strain deficient in Fc receptor expression could respond normally to other stimuli yet their inflammatory response to immune complexes was markedly attenuated. These results suggest that immune complex-triggered inflammation is initiated by cell bound Fc receptors and is then amplified by cellular mediators and activated complement (1426).

 

Lisa. L. Lau (US), Beth D. Jamieson (US), T. Somasundaram (US), and Rafi Ahmed (US) provide evidence that antigen is not essential for the maintenance of CD8+ T-cell memory. They show that memory CD8+ cytotoxic T lymphocytes persist indefinitely in the absence of priming antigen, retain the memory phenotype (CD44hi), and provide protection against virus challenge (830).

 

Jonathan M. J. Derry (US), Hans D. Ochs (US), and Uta Francke (US) isolated a novel gene mutated in Wiskott-Aldrich Syndrome (WAS), which is expressed in lymphocytes, spleen, and thymus. WASP encodes a 501 amino acid proline-rich protein that is likely to be a key regulator of lymphocyte and platelet function (333). Note: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, and recurrent infections. Linkage studies have placed the gene at Xp11.22-p11.23.

 

Jonas Bergquist (SE), Andrej Tarkowski (SE), Rolf Ekman (SE), Andrew Ewing (SE), Luitpold E. Miller (DE), Hans-peter Jüsten (DE), Jürgen Schcölmerich (DE), Rainer H. Straub (DE), Midge Ritchie (US), Satbir Rai (CA), András Szeitz (CA), Brent W. Roberts (CA), Quill Christie (CA), Wesley Didier (CA), Junho Eom (CA), Sang-Seon Yun (CA), David A. Close (CA), Kengo Funakoshi (JP), Masato Nakano (JP), Katherine L. Connor (US), Keri L. Colabroy (US), Barbara Gerratana (US), Robert Dantzer (US), Jason C. O'Connor (US), Gregory G. Freund (US), Rodney W. Johnson (US), Keith W. Kelley (US), Matthew E. Carter (US), Marta E. Soden (US), Larry S. Zweifel (US), Richard D. Palmiter (US), Erik Höglund (DK), Christina Sørensen (DK), Marit Jørgensen Bakke (DK), Göran E. Nilsson (DK), Oyvind Overli (DK), Tracy L. Clippinger (US), R. Avery Bennett (US), Calvin M. Johnson (US), Kent A. Vliet (US), Sharon L. Deem (US), Jorge Orós (ES), Elliott R. Jacobson (US), Isabella M. Schumacher (US), Daniel R. Brown (US), and Mary B. Brown (US) offered evidence that the immune, endocrine, and nervous systems have evolved over hundreds of millions of years, and to understand diseases in humans, including chronic inflammatory diseases (CIDs), the long evolutionary history of supersystems such as the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system must be taken into account (116; 207; 262; 272; 314; 449; 641; 916; 999; 1199; 1240). Note: When we observe crosstalk between the supersystems, many similar pathways are used in humans and other vertebrates to maintain homeostasis. If homeostasis is disturbed by stressful events such as infection (leading to inflammation), the different supersystems need to cooperate in order to overcome the threat.

 

Karl O. Stetter (DE) concluded that the origin of life probably took place under conditions of high temperature because the hyperthermophiles are grouped around and occupy all of the deepest branches of the three kingdom phylogenetic scheme. He also concluded that an anaerobic hyperthermophilic autotroph was very likely the original cell type (1401).

 

Mitchell Lloyd Sogin (US) declared that some microbial lineages seem never to have had mitochondria and chloroplasts, so may have diverged from the eukaryotic (Eucarya) line of descent prior to the incorporation of these organelles (1373).

 

Robert J. Isfort (US), Zheng Qian (US), Dan Jones (US), Robert F. Silva (US), Richard Witter (US), and Hsing-Jien Kung (US) discovered that a sequence of avian reticuloendotheliosis virus (REV) is contained within the genome of the avian alpha-herpesvirus, Marek's disease virus and the related turkey virus (685).

Mariano Barbacid (US), Eric Hunter (US), and Stuart A. Aaronson (US) found the avian reticuloendotheliosis virus (REV) genome within the genome of fowlpox virus (82).

 

Matthias J. Schnell (DE), Teshome Mebatsion (DE), and Karl-Klaus Conzelmann (DE) described generating infectious rabies virus (RV), a non‐segmented negative‐stranded RNA virus of the Rhabdoviridae family, entirely from cloned cDNA. Simultaneous intracellular expression of genetically marked full‐length RV antigenome‐like T7 RNA polymerase transcripts and RV N, P and L proteins from transfected plasmids resulted in formation of transcriptionally active nucleocapsids and subsequent assembly and budding of infectious rabies virions (1297).

 

Abigail M. Shefer (US), Jordan W. Tappero (US), Joseph S. Bresee (US), Clarence J. Peters (US), Michael S. Ascher (US), Sherif R. Zaki (US), Richard J. Jackson (US), S. Benson Werner (US), Pierre E. Rollin (US), Thomas G. Ksiazek (US), Stuart T. Nichol (US), Jack Bertman (US), Steven Parker (US), and Robert M. Failing (US) discovered Sin Nombre virus and its asssociation with hantavirus pulmonary syndrome (1330).

 

Yuan Chang (US), Ethel Cesarman (US), Melissa S. Pessin (US), Frank Lee (US), Janice Culpepper (US), Daniel M. Knowles (US), and Patrick S. Moore (US) isolated unique DNA sequences present in more than 90 percent of Kaposi's sarcoma (KS) tissues obtained from patients with acquired immunodeficiency syndrome (AIDS). These KS-associated herpesvirus-like (KSHV) sequences appear to define a new human herpesvirus (227). Note: This virus was later named herpesvirus 8.

 

Howard Ochman (US) and Eduardo A. Groisman (US) used multilocus electrophoresis and nucleotide sequence analysis to reevaluate the phylogenetic relationships within the genus Salmonella concluding that two species, Salmonella bongeri and Salmonella enterica emerged (1098; 1099). S. enterica has been further divided into subspecies designated by Roman numerals. S. enterica I is isolated almost exclusively from warm-blooded animals and is by far the most common clinical isolate. Among the S. enterica I, certain subtypes, like Typhi and Pullorum, show a remarkable host species preference (for humans and fowl, respectively). The other S. enterica subspecies and S. bongeri are isolated mainly from cold-blooded animals.

 

Bradley D. Jones (US), Nafisa Ghori (US), and Stanley Falkow (US) determined that Salmonella typhimurium initiates murine infection by penetrating and destroying the specialized epithelial M cells of the Peyer's patches (714).

 

An outbreak of cholera occurred within Rwandan refugee camps in the Democratic Republic of the Congo killing tens of thousands. ref

 

Stephen A. Wharton (GB), Robert B. Belshe (US), John J. Skehel (GB), and Alan J. Hay (GB) discovered the first virus ion channel (1565). The M2 protein enables hydrogen ions to enter the viral particle lowering the pH inside of the virus, thus causing dissociation of the viral matrix protein M1 from the ribonucleoprotein RNP. This is a necessary step in uncoating of the virus and exposing its content to the cytoplasm of the host cell.

 

Ken R. Schneider (US), Rebecca L. Smith (US), and Erin K. O'Shea (US) identified Pho81 as a cyclin kinase inhibitor (CKI) in Saccharomyces cerevisiae (1296). CKIs modulate cyclin-dependent kinases (CDKs), which regulate two important cell cycle transitions, from G1 to S phase and G2 to M phase.

Akio Toh-e (JP), Yoshinami Ueda (JP), Sei-Ichiro Kakimoto (JP), and Yasuji Oshima (JP) had earlier identified Pho81 as a genetic entity involved in the regulation of phosphate, however, they did not recognize it as a CKI (1463).

 

Werner Kühlbrandt (DE), Da Neng Wang (DE), and Yoshinori Fujiyoshi (JP) determined the atomic level structure of the largest antenna of photosystem 2, the light-harvesting complex II b (809).

Geery McDermott (GB), Steve M. Prince (GB), Andy A. Freer (GB), Anna M. Hawthornthwaite-Lawless (GB), Miroslav Z. Papiz (GB), Robert J. Cogdell (GB), Neil W. Isaacs (GB), Thomas Walz (CH), and Robin Ghosh (CH) have provided the atomic level structures of two light-harvesting antenna complexes of anoxygenic photosynthetic bacteria (970; 1532).

Eckhard Hofmann (DE), Pamela M. Wrench (AU), Frank P. Sharples (AU), Roger G. Hiller (AU), Wolfram Welte (DE), and Kay Dietrichs (DE) have provided the atomic level structure of the peridinin-chlorophyll protein complex of the dinoflagellate Amphidinium carterae (640).

 

Ralf Kölling (DE) and Cornelis P. Hollenberg (DE) found in yeast cells that membrane protein Ste6 is mainly associated with internal membranes and not with the cell surface. Ste6 is localized in the Golgi. The Ste6 protein is in contact with the cell surface, as demonstrated by the finding that Ste6 accumulates in the plasma membrane in endocytosis mutants. The Ste6 protein that accumulates in the plasma membrane in endocytosis mutants is ubiquitinated (792). The Ste6 protein is a member of the ABC-transporter family and is required for the secretion of the yeast mating pheromone a-factor.

Etienne Schwob (AT), Thomas Böhm (AT), Michael D. Mendenhall (US), and Kim Nasmyth (GB-AT-GB) found that in Saccharomyces cerevisiae DNA replication requires activation of Cdc28 protein kinase by B-type (Clb) cyclins. A sextuple clb1-6 mutant arrests as multibudded G1 cells that resemble cells lacking the Cdc34 ubiquitin-conjugating enzyme. Cdc34 mutants cannot enter S phase because they fail to destroy p40SIC1, which is a potent inhibitor of Clb but not Cln forms of the Cdc28 kinase. In wild-type cells, p40SIC1 protein appears at the end of mitosis and disappears shortly before S phase. Proteolysis of a cyclin-specific inhibitor of Cdc28 is therefore an essential aspect of the G1 to S phase transition (1308).

 

Peng Tian (US), Yanfang Hu (US), William P. Schilling (US), David A. Lindsay (US), Joseph Eiden (US), Mary Kolb Estes (US) reported that rotavirus infection of monkey kidney cells resulted in a significant increase in the concentration of intracellular calcium. This increase in intracellular calcium was associated with viral protein synthesis and cytopathic effects in infected cells. They presented results suggesting that the viral nonstructural glycoprotein NSP4 is responsible for the increase in cytosolic calcium (1456). Note: This was the first known example of a viral enterotoxin. NSP4 is one of the genes that plays a crucial role in the pathogenesis of diarrhea in the gnotobiotic piglet model. They hypothesize that the cytotoxicity of NSP4 is related to the increased intracellular calcium levels and the increased intracellular calcium levels are responsible for cell lysis and the release of mature virus particles during the late stage of the virus replication cycle.

 

Zhen Zhu (CN), Karen W. Hughes (US), Leaf Huang (CN-US), Baolin Sun (CN), Chunming Lui (CN), Yuing Li (CN), Yunde Hou (CN) and Xianghui Li (CN) produced transgenic rice plants capable of manufacturing alpha-interferon, which has potential use for viral protection and as an anti-cancer agent (1636).

 

Dirk Bosch (BE), Jean Smal (BE), and Enno Krebber (BE) created transgenic tobacco plants which could produce trout growth factor; a mitogen (154).

 

Jerry C.P. Yin (US), Jonathan S. Wallach (US), Maria Del Vecchio (US), Elizabeth L. Wilder (US), Hong Zhou (US), William G. Quinn (US), and Tim Tully (US) obtained results suggesting that long-term memory formation in Drosophila requires de novo gene expression; probably mediated by CREB family genes (1609; 1610). CREB (cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes.

 

Pascal Bailly (FR), Patricia Hermand (FR), Isabelle Callebaut (FR), Hans H. Sonneborn (FR), Samir Khamlichi (FR), Jean-Paul Mornon (FR), and Jean-Pierre Cartron (FR) cloned the human LW (Landsteiner-Wiener) blood group genes and found their glycoprotein products to be homologous to intercellular adhesion molecules (74).

 

Barbara L. Smith (US), Gregory M. Preston (US), Frances A. Spring (US), David J. Anstee (US), and Peter Agre (US) found that the Colton blood group antigens are located on the water channel protein, Aquaporin (1358).

Note: Peter Agre (US) would be awarded the 2003 Nobel Prize in Chemistry for his discovery of water channels.

 

Michael Nehls (DE), Dietmar Pfeifer (DE), Michael Schorpp (DE), Hans Hedrich (DE), and Thomas Boehm (DE) showed that one of the genes from this critical region (the mouse nude locus has been localized on chromosome 11), designated WHN, encodes a new member of the winged-helix domain family of transcription factors, and that it is disrupted on mouse nu and rat rnuN alleles. Mutant transcripts do not encode the characteristic DNA-binding domain, strongly suggesting that the WHN gene is the nude gene (1056).

 

Dominic A. Fantozzi (US), Alec T. Harootunian (US), Wei Wen (US), Susan S. Taylor (US), James R. Feramisco (US), Roger Y. Tsien (US), and Judy L. Meinkoth (US) demonstrated that a very small sequence of amino acids embedded in protein kinase inhibitor (PKI) constitutes a signal that instructs the catalytic (C) subunit to leave the cell nucleus and move out into the cytoplasm, where it becomes available for binding to a regulatory (R) subunit (391). This nuclear export signal (NES) is the first such signal identified.

 

Peter J. Svensson (SE) and Björn Dahlbäck (SE) discovered an autosomal dominant hereditary condition in which venous thrombosis results because of resistance to anticoagulant activated protein C (APC). The condition is due to a deficiency in a previously unrecognized anticoagulant factor that functions as a cofactor to activated protein C (1424).

 

Paolo Verdecchia (IT), Carlo Porcellati (IT), Giuseppe Schillaci (IT), Claudia Borgioni (IT), Antonella Ciucci (IT), Massimo Battistelli (IT), Massimo Guerrieri (IT), Camillo Gatteschi (IT), Ivano Zampi (IT), Antonella Santucci (IT), Carla Santucci (IT), and Gianpaolo Reboldi (IT) found that ambulatory blood pressure stratifies cardiovascular risk in essential hypertension independent of clinic blood pressure and other traditional risk markers including echocar- diographic left ventricular hypertrophy. Cardiovascular morbidity is low in white coat hypertension and exceedingly high in women with ambulatory hypertension and absent or blunted blood pressure reduction from day to night (1510).

 

Richard Wooster (GB), Susan L. Neuhausen (US), Jonathan Mangion (GB), Yvette Quirk (GB), Deborah Ford (GB), Nadine Collins (GB), Kim Nguyen (US), Sheila Seal (GB), Thao Tran (US), and David B. Averill (US) localized a second breast cancer susceptibility locus, BRCA2, to chromosome 13q12-13. Preliminary evidence suggests that BRCA2 confers a high risk of breast cancer but, unlike BRCA1, does not confer a substantially elevated risk of ovarian cancer (1592).

 

Rita Shiang (US), Leslie M. Thompson (US), Ya-Zhen Zhu (US), Deanna M. Church (US), Thomas J. Fielder (US), Maureen Bocian (US), Sara T. Winokur (US), and John J. Wasmuth (US) found that achondroplasia (ACH), the most common genetic form of dwarfism, is caused by alteration of the normal gene localized to 4p16.3. The ACH candidate region includes the gene encoding fibroblast growth factor receptor 3 (FGFR3) (1334).

 

Mitsuharu Hattori (JP), Hideki Adachi (JP), Masafumi Tsujimoto (JP), Hiroyuki Arai (JP), and Keizo Inoue (JP) found that the gene for Miller-Dieker lissencephaly encodes a subunit of the heteromeric platelet-activating factor, paf (607). Note: Paf affects neuronal growth cone morphology.

 

Alexander Sasha Kamb (US) pointed out the role of a cell cycle regulator (CDKN2A ) in hereditary and sporadic cancer (731).

 

Lyamine Azzi (FR), Laurent Meijer (FR), Anne-Carine Ostvold (NO), John Lew (CA), Jerry H. Wang (TW-CA), Qi-Quan Huang (CA), Zhong Qi (CA), Robert J. Winkfein (CA), Ruedi Aebersold (CA), and Tim Hunt (GB), discovered the active complex of cyclin-dependent kinase 5 (Cdk5) and identified two of its activators, opening new research fields in neuroscience (69; 862).

 

Conly L. Rieder (US), Adriene Schultz (US), Richard Cole (US), and Greenfield Sluder (US) determined that a single unattached kinetochore is enough to delay anaphase. But once the last kinetochore attaches to the spindle, anaphase will always proceed. The unattached kinetochore is doing something that shuts down the whole spindle system (1237).

 

S. Blair Hedges (US) analyzed DNA sequences from four slow-evolving genes (mitochondrial 12S and 16S rRNA, tRNAVal, and nuclear alpha-enolase) and found strong statistical support for a bird-crocodilian evolutionary relationship (613).

 

Henry A. Feldman (US), Irwin Goldstein (US), Dimitrios G. Hatzichristou (US), Robert J. Krane (US), and John B. McKinlay (US) provided normative data on the prevalence of impotence, and its physiological and psychosocial correlates in a general population; using results from the Massachusetts Male Aging Study. Trained interviewers in the subject’s home collected blood samples, physiological measures, socio-demographic variables, psychological indexes, and information on health status, medications, smoking and lifestyle. A self-administered sexual activity questionnaire was used to characterize erectile potency. The combined prevalence of minimal, moderate and complete impotence was 52%. The prevalence of complete impotence tripled from 5 to 15% between subject ages 40 and 70 years. Subject age was the variable most strongly associated with impotence. After adjustment for age, a higher probability of impotence was directly correlated with heart disease, hypertension, diabetes, associated medications, and indexes of anger and depression, and inversely correlated with serum dehydroepiandrosterone, high-density lipoprotein cholesterol and an index of dominant personality. Cigarette smoking was associated with a greater probability of complete impotence in men with heart disease and hypertension. They concluded that impotence is a major health concern in light of the high prevalence, is strongly associated with age, has multiple determinants, including some risk factors for vascular disease, and may be due partly to modifiable para-aging phenomena (396).

 

Edward M. Connor (US), Rhoda S. Sperling (US), Richard Gelber (US), Pavel Kiselev (US), Gwendolyn Scott (US), Mary Jo O'Sullivan (US), Russell VanDyke (US), Mohammed Bey (US), William Shearer (US), Ronert L. Jacobson (US), Eleanor Jimenez (US), Edward O'Neill (US), Brigette Bazin (US), Jean-Francois Delfraissy (US), Mary Culnane (US), Robert Coombs (US), Mary Elkins (US), Jack Moye (US), Pamela Stratton (US), and James Balsley (US) found that among pregnant women with human immunodeficiency virus (HIV) infection, antepartum, intrapartum and neonatal zidovudine therapy reduced maternal-fetal transmission of HIV by two-thirds (271).

Myron S. Cohen (US), Ying Q. Chen (US), Marybeth McCauley (US), Theresa Gamble (US), Mina C. Hosseinipour (MW), Nagalingeswaran Kumarasamy (IN), James G. Hakim (ZW), Johnstone Kumwenda (MW), Beatriz Grinsztejn (BR), Jose H.S. Pilotto (BR), Sheela V. Godbole (IN), Sanjay Mehendale (IN), Suwat Chariyalertsak (TH), Breno R. Santos (BR), Kenneth H. Mayer (US), Irving F. Hoffman (US), Susan H. Eshleman (US), Estelle Piwowar-Manning (US), Lei Wang (US), Joseph Makhema (BW), Lisa A. Mills (KE), Guy de Bruyn (ZA), Ian Sanne (ZA), Joseph Eron (US), Joel Gallant (US), Diane Havlir (US), Susan Swindells (US), Heather Ribaudo (US), Vanessa Elharrar (US), David Burns (US), Taha E. Taha (US), Karin Nielsen-Saines (US), David Celentano (US), Max Essex (US), Thomas R. Fleming (US), Leslie Cottle (US), Xinyi C. Zhang (US), Ravindre Panchia (ZA), Sharlaa Faesen (ZA), Sarah E. Hudelson (US), Andrew D. Redd (US), and HTPTN 052 Study Team reported that the early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, producing a sustained decrease in genetically linked HIV-1 infections in sexual partners indicating both personal and public health benefits from such therapy (265; 266).

 

Alfonse T. Masi (US) reported that it is widely accepted that the incidence rate of rheumatoid arthritis in women largely increases after menopause (949).

 

Robert E. Scully (US) chaired the committee on classification and nomenclature of the International Society of Gynecological Pathologists responsible for the World Health Organization classification of female genital tract tumors (1311).

 

Laurence Morel (US), Ulrich H. Rudofsky (US), Jeffrey A. Longmate (US), Joel Schiffenbauer (US), and Edward K. Wakeland (US) analyzed susceptibility to glomerulonephritis (GN) and anti-dsDNA autoantibody production in crosses using a newly developed systemic lupus erythematosus-susceptible inbred strain (NZM/Aeg2410) of mice. Three chromosomal intervals containing strong recessive GN susceptibility alleles were identified on chromosomes 1, 4, and 7. Logistic regression analysis indicated that each of these susceptibility alleles independently accounted for a component of GN susceptibility, and that susceptibility was inherited as a threshold genetic liability in this model system (1016).

 

Saulo Klahr (US), Andrew S. Levey (US), Gerald J. Beck (US), Arlene W. Caggiula (US), Lawrence Hunsicker (US), John W. Kusek (US), and Gary Striker (US) found that among patients with moderate renal insufficiency, the slower decline in renal function that started four months after the introduction of a low-protein diet suggests a small benefit of this dietary intervention. Among patients with more severe renal insufficiency, a very-low-protein diet, as compared with a low-protein diet, did not significantly slow the progression of renal disease (774).

 

Armando E. Giuliano (US), Daniel M. Kirgan (US), Joseph M. Guenther (US), Donald L. Morton (US), John J. Albertini (US), Gary H. Lyman (US), Charles Cox (US), Tim Yeatman (US), Ludovico Balducci (US), NiNi Ku (US), Steve Shivers (US), Claudia Berman (US), Karen Wells (US), David Rapaport (US), Alan Shons (US), John Horton (US), Harvey Greenberg (US), Santo Nicosia (US), Robert Clark (US), Alan Cantor (US), and Douglas S. Reintgen (US) showed that sentinel node biopsy is technically feasible in breast cancer patients and is an accurate way of detecting node-positive patients. The combination of blue-dye and radioisotope is the best method to use (27; 503).

Armando E. Giuliano (US), Kelly K. Hunt (US), Karla V. Ballman (US), Peter D. Beitsch (US), Pat W. Whitworth (US), Peter W. Blumencranz (US), A. Marilyn Leitch (US), Sukamal Saha (US), Linda M. McCall (US), and Monica Morrow (US) from their prospective multi-center randomized controlled trial showed that an axillary clearance is not necessary for patients with early /(T1/T2) cancer who have only one or two positive sentinel nodes (502).

 

Alex R. Attard (GB), Michael J. Corlett (GB), Nigel J. Kidner (GB), Apsara P. Leslie (GB), Ian A. Fraser (GB), Stephen H. Thomas (US), William Silen (US), Farah Cheema (US), Andrew Reisner (US), Sohail Aman (US), Joshua N. Goldstein (US), Alan M.Kumar (US), and Thomas O. Stair (US), showed that early administration of opiate analgesia to patients with acute abdominal pain can greatly reduce their pain . This does not interfere with diagnosis, which may even be facilitated despite a reduction in the severity of physical signs (61).

 

Stewart Sell (US) and G.Barry Pierce (US) analyzed the cellular origin of carcinomas of different organs. They found that there was in each instance, a determined stem cell required for tissue renewal that is the cell of origin for carcinomas (1317).

Dominique Bonnet (CA) and John E. Dick (CA) discovered cancer stem cells, several years before they were found in solid tumors (151).

 

William H. Bickell (US), Matthew J. Wall, Jr. (US), Paul E. Pepe (US), R. Russell Martin (US), Victoria F. Ginger (US), Mary K. Allen (US), and Kenneth L. Mattox (US) in a prospective single-center randomized trial determined that delayed intravenous intervention improves outcomes, including mortality, for hypotensive patients with penetrating torso injuries (126).

 

Tim D. White (US), Gen Suwa (Ethiopian), and Berhane Asfaw (Ethiopian) discovered hominid fossil remains of Ardipithecus ramidus at Aramis in Ethiopia dated at 4.4 million years. Most remains are skull fragments. Indirect evidence suggests that it was possibly bipedal, and that some individuals were about 122 cm (4'0") tall (1567; 1568).

Yohannes Haile-Selassie (US) reported new hominid specimens from the Middle Awash area of Ethiopia that date to 5.2-5.8 Myr and are associated with a wooded palaeoenvironment. These Late Miocene fossils are assigned to the hominid genus Ardipithecus and represent the earliest definitive evidence of the hominid clade (576).

 

Hagen Hass (DE), Thomas N. Taylor (US), Winfried Remy (PL-DE), and Hans Kerp (DE) found fossil hyphae in association with wood decay and fossil chytrids and Glomales-Endogenales representatives associated with plants of the Rhynie Chert from the Devonian Period (408-360 Ma) (606; 1226; 1227; 1442; 1443). Note: These findings strongly suggest that the ability to form an arbuscular-mycorrhizal symbiosis occurred early in the evolution of vascular plants.

 

1995

“Our bodies were designed over the course of millions of years for lives spent in small groups hunting and gathering on the plains of Africa. Natural selection has not had time to revise our bodies for coping with fatty diets, automobiles, drugs, artificial lights, and central heating. From this mismatch between our design and our environment arises much, perhaps most, preventable modern disease. The current epidemics of heart disease and breast cancer are tragic examples.” Randolph M. Neese (1063).

 

“What a marvelous cooperative arrangement—plants and animals each inhaling the other’s exhalations, a kind of planet-wide mutual mouth-to-stoma resuscitation, the entire elegant cycle powered by a star 150 million kilometers away.” Carl Sagan (US) (1268)

 

Edward B. Lewis (US), Christiane Jani Nüsslein-Volhard (DE) and Eric F. Wieschaus (US) shared the Nobel Prize in Physiology or Medicine for their discoveries concerning the genetic control of early embryonic development.

 

Rosamund M. J. Cleal (GB), Karen E. Walker (GB), and Richard Montague (GB) radiocarbon dated the first phase of Stonehenge, the outer ditch, which lies far outside the iconic stone structure. The ditch forms a nearly complete circle with an earthen bank on the inner side. (Now the bank is almost level with the ground due to age.) Radiocarbon dating of material found in the ditch in 1993-94 suggests it was built more than five thousand years ago, somewhat before 3000 BCE (261).

 

Kyriacos Costa Nicolaou (CY-US), Emmanuel A. Theodorakis (Greek-US), Floris P.J.T. Rutjes (NL), Jorg Tiebes (DE), Mitsunobu Sato (JP), Edouard Untersteller (FR), X.-Y. Xiao (US) carried out the total synthesis of brevitoxin B, the potent lipid-soluble neurotoxin produced by dinoflagellates such as Ptycodiscus brevis Davis (Gymnodynium breve Davis) and associated with red tide (1073; 1074).

 

Subhash C. Sinha (IL) and Ehud Keinan (IL) achieved the first total synthesis of a natural product via antibody catalysis (1346).

 

So Iwata (GB), Christian Ostermeier (DE), Bernd Ludwig (DE), and Hartmut Michel (DE) determined the structure of cytochrome c oxidase (a membrane embedded protein) from Paracoccus denitrificans at 2.8 A resolution (694).

 

David Mu (US), Chi-Hyun Park (US), Tsukasa Matsunaga (JP), David S. Hsu (US), Joyce T. Reardon (US), and Aziz Sancar (TR-US) purified the components known to be required for the incision reaction in Xeroderma pigmentosum and reconstituted the excision nuclease activity with these proteins. Using this system, they determined that the excised fragment remains associated with the post-incision DNA-protein complex, suggesting that accessory proteins are needed to release the excised oligomer (1030). Note: Xeroderma pigmentosum, a hereditary disease, is caused by a defect in nucleotide excision repair as a result of mutations in one of several genes: XPA through XPG.

 

Eva Nogales (US), Sharon Grayer Wolf (US), Israr A. Khan (US), Richard F. Luduena (US), and Kenneth H. Downing (US) presented a three-dimensional reconstruction of tubulin to a 6.5-angstrom resolution with a location of the taxol-binding site. It was obtained by electron crystallography of zinc-induced two-dimensional crystals of the protein (1083).

 

Norman Richard Pace, Jr. (US) indicated that the Archaea and Bacteria diverged from one another near the time that life arose on Earth. This changed the notion of evolutionary unity among prokaryotes. The phylogenetic data support the very early appearance of the eukaryotic nuclear line of descent. The Eucarya is as old as the prokaryotic lines Archaea and Bacteria. The idea that eukaryotes resulted from the fusion of two prokaryotes and are late arrivals on the evolutionary stage (1-1.5 billion years ago) is incorrect (1116).

 

Claire M. Fraser (US), Jeannine D. Gocayne (US), Owen White (US), Mark D. Adams (US), Rebecca A. Clayton (US), Robert D. Fleischmann (US), Carol J. Bult (US), Anthony R. Kerlavage (US), Granger G. Sutton (US), Jenny M. Kelley (US) Janice L. Fritchman (US), Janice F. Weidman (US), Keith V. Small (US), Mina Sandusky (US), Joyce Fuhrmann (US), David Nguyen (US), Teresa R. Utterback (US), Deborah M. Saudek (US), Cheryl A. Phillips (US), Joseph M. Merrick (US), Jean-Francois Tomb (US), Brian A. Dougherty (US), Kenneth F. Bott (US), Ping-Chuan Hu (US), and Thomas S. Lucier (US) determined the minimal gene complement of Mycoplasma genitalium (436).

Valerie C. Wasinger (AU), Stuart J. Cordwell (AU), Anne Cerpa-Poljak (AU), Jun X. Yan (AU), Andrew A. Gooley (AU), Marc R. Wilkins (AU), Mark W. Duncan (AU), Ray Harris (AU), Keith L. Williams (AU) and Ian Humphrey-Smith (AU), during their study of Mycoplasma genitalium, coined the term proteome to mean that portion of the genomic library that creates proteins (1542).

 

Andreas Hecht (US), Thierry Laroche (CH), Sabine Strahl-Bolsinger (US), Susan M. Gasser (CH), and Michael Grunstein (US), provided the first clue that gene-regulatory proteins directly interact with chromatin. In Saccharomyces cerevisiae, histones are packaged into regions of transcriptionally silent, inaccessible heterochromatin by repressor proteins, such as the silent information regulators SIR3 and SIR4. The N termini of histones H3 and H4 are bound by the SIRs, showing for the first time that histones interact with gene-regulatory proteins. Importantly, further analysis revealed that acetylation of the N terminus of H4 prevented its interaction with SIR3 (612). The amino (N)-terminal tails of histones are subject to a range of covalent modifications, which provide binding sites for regulatory proteins that drive specific patterns of gene expression.

 

Stefan Irniger (AT), Simonetta Platti (AT), Christine Michaelis (AT), and Kim Nasmyth (AT) found that 13-type cyclin destruction is necessary for exit from mitosis and the initiation of a new cell cycle in Saccharomyces cerevisiae. Through the isolation of mutants, they identified three essential yeast genes, CDC16, CDC23, and CSE1, which are required for proteolysis of the B-type cyclin CLB2 but not of other unstable proteins. Cdc23-1 mutants are defective in both entering and exiting anaphase. Their failure to exit anaphase can be explained by defective cyclin proteolysis. CDC23 is required at the metaphase/anaphase transition to separate sister chromatids. They speculated that CDC23 might promote proteolysis of proteins that hold sister chromatids together. Proteolysis of CLB2 is initiated in early anaphase, but a fraction of CLB2 remains stable until anaphase is complete (683).

 

Maria Costa (FR) and Francois Michel (FR) concluded that interaction of [CCUAAG...UAUGG] with GAAA loops is one of the most common solutions used by nature to solve the problem of compacting and bringing together RNA structural domains (286).

 

Feizhou Liu (US), Jack D. Thatcher (US), José Moreno (US), and Henry F. Epstein (US) discovered the glycolate cycle in the nematode Caenorhabditis elegans (885).

 

Kimberley A. Gavin (US), Masumi Hidaka (US), and Bruce Stillman (US) suggested that origin recognition complex (ORC) subunits are conserved and that the role of ORC is a general feature of eukaryotic DNA replication (476).

 

Steven J.M. Jones (GB) reported that protein-coding genes make up at most 5 percent of the human genome, and probably comprise only 1-2 percent (715).

 

Mark Schena (US), Dari Shalon (US), Ronald W. Davis (US) and Patrick O. Brown (US) invented a high-capacity system that allowed them to monitor the expression of 45 Arabidopsis genes in parallel. Microarrays prepared by high-speed robotic printing of complementary DNAs on glass were used for quantitative expression measurements of the corresponding genes. This 'array' was probed with a mixture of fluorescently labeled cDNAs that were derived from the reverse transcription of mRNAs extracted from a tissue sample (1289). Note: This became known as a DNA microarray.

Paul T. Spellman (US), Gavin Sherlock (US), Michael Q. Zhang (US), Vishwanath R. Iyer (US), Kirk Anders (US), Michael B. Eisen (US), Patrick O. Brown (US), David Botstein (US), and Bruce Futcher (US) used microarrays to monitor the expression of 800 genes throughout the yeast cell cycle. Subtle changes in overall gene-expression patterns over time were revealed. These could not have been detected by other methods (1382).

Charles M. Perou (US), Therese Serlie (US), Michael B. Eisen (US), Matt Van De Rijn (US), Stefanie S. Jeffrey (US), Christian A. Rees (US), Jonathan R. Pollack (US), Douglas T. Rossi (US), Hilde Johnsen (US), Lars A. Akslen (US), Oystein Fluge (US), Alexander Pergamenschikov (US), Cheryl Williams (US), Shirley X. Zhu (US), Per E. Lenning (US), Anne-Use Berresen-Dale (US), Patrick O. Brown (US), and David Botstein (US) used microarrays to study the expression of more than 8,000 genes in 65 human breast tumors. They generated 'molecular portraits' of gene expression that allowed them to distinguish between different classes of breast tumor and to identify two new categories that had been overlooked by traditional classification tools. They were also able to identify expression patterns that predicted the response to chemotherapy (1149).

 

Detlef Weigel (DE), Ove Nilsson (SE), Frederick D. Hempel (US), M. Alejandra Mandel (AR), Gary Ditta (US), Patricia C. Zambryski (US), Lewis J. Feldman (US), Martin F. Yanofsky (US), Miguel A. Blázquez (ES), Lara N. Soowal (US), Ilha Lee (Korean), Roland Green (US), Michael R. Sussman (US), Francois Parcy (FR), and Maximilian A. Busch (DE) identified a gene (LEAFY) that appears to be a key regulator in flowering; with the hormone gibberellin controlling its expression. They demonstrated that over expression of LFY protein causes early flowering. LFY also induces some of the homeotic genes that specify floral organ identity. LFY protein is transported between meristem cells and exhibits activity in the cells to which it has moved (137; 138; 623; 1124; 1558).

 

Dana L. Parmenter (CA), Joseph G. Boothe (CA), Gijs J.H. van Rooijen (NL-CA), Edward C. Yeung (CA), and Maurice M. Moloney (GB-CA) created transgenic canola plants capable of producing hirudin, a useful animal anticoagulant (1129).

 

Venkatesan Sundaresan (US), Patricia Springer (US), Thomas Volpe (US), Samuel Haward (GB), Jonathan D.G. Jones (GB), Caroline Dean (GB), Hong Ma (US), and Robert Martienssen (US) demonstrated that "enhancer trap" and "gene trap" transposable elements could be realized on a genome-wide scale in Arabidopsis to detect and clone genes in any plant process (1420).

 

Acaimo Gonzalez-Reyes (GB), Heather Elliott (GB), and Daniel St. Johnston (GB) found that in Drosophila the gurken gene (grk) produces a protein that sets up the anterior-posterior (AP) polarization of the microtubule cytoskeleton that directs the correct transport of bicoid and oskar mRNAs to opposite ends of the oocyte. As well as being crucial for setting up the anterior-posterior (AP) body axis, microtubule polarization is also essential for the dorso-ventral (DV) body axis polarity. The localized secretion of gurken that initiates dorsal follicle-cell fate depends on the movement of the oocyte nucleus along microtubules to the anterior–dorsal corner of the oocyte, leading to the accumulation of gurken mRNA close to the dorsal surface. The fact that this occurs after the posterior follicle cells have been specified indicates that the gurken-dependent microtubule polarization that initiates AP polarity might also be responsible for determining the position of the DV axis. This was confirmed when it was shown that the oocyte nucleus does not migrate to its correct position in gurken mutants. In addition, gurken mRNA fails to localize to the correct position at the anterior–dorsal corner of the oocyte when the gurken receptor in the follicle cells is absent (511).

 

Nathalie Auphan (FR), Joseph A. DiDonato (US), Caridad Rosette (US), Arno Helmberg (AT), and Michael Karin (US) show that glucocorticoids are potent inhibitors of nuclear factor kappa B (NF-kB) activation in mice and cultured cells. This inhibition is mediated by induction of the IkB alpha inhibitory protein, which traps activated NF-kB in inactive cytoplasmic complexes. Because NF-kB activates many immunoregulatoy genes in response to pro-inflammatory stimuli, the inhibition of its activity can be a major component of the anti-inflammatory activity of glucocorticoids (67).

 

Lynne Elizabeth Maquat (US), Guillaume Serin (FR), and Maximilian Wei Lin Popp (US) discovered nonsense-mediated mRNA decay (NMD) in human cells. NMD is a quality control mechanism that removes flawed messenger RNA molecules that, if left intact, would lead to the production of abnormal proteins that could be toxic to cells and initiate disease. Cells also use this pathway to better respond to changing environmental conditions. For example, breast cancer cells inhibit this pathway to augment their response to chemotherapy and hasten cell death (936-939; 1175).

 

Tetsuya Nosaka (US), Jan M. van Deursen (US), Ralph A. Tripp (US), William E. Thierfelder (US), Bruce A. Witthuhn (US), Anthony P. McMickle (US), Peter Charles Doherty (US), Gerard C. Grosveld (US), and James N. Ihle (US) found that the Janus tyrosine kinase Jak 3 plays a critical role in gamma signaling and lymphoid development (1091).

 

Jean-François Brunet (FR), François Denizot (FR), Marie-Françoise Luciani (FR), Magali Roux-Dosseto (FR), Marie Suzan (FR), Marie-Geneviève Mattei (FR), and Pierre Golstein (FR) identified cytotoxic T-lymphocyte antigen 4, or CTLA-4. CTLA-4 is mainly expressed in activated lymphocytes and is coinduced with T-cell-mediated cytotoxicity in inducible models of this process (174). Note: Functioning as an immune checkpoint, it downregulates immune responses.

Paul Waterhouse (CA), Josef M. Penninger (CA), Emma Timms (CA), Andrew Wakeham (CA), Arda Shahinian (CA), Kelvin P. Lee (US), Craig B. Thompson (US), Henrik Griesser, and Tak Wah Mak (CA) Elizabeth A. Tivol (US), Frank Borriello (US), A. Nicola Schweitzer (US), William P. Lynch (US), Jeffrey A. Bluestone (US), and Arlene H. Sharpe (US) demonstrated that CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis (1461; 1546).

 

Calman Prussin (US) and Dean D. Metcalfe (US) detected intracytoplasmic cytokine using flow cytometry and directly conjugated anti-cytokine antibodies (1190).

 

Peter Openshaw (GB), Erin E. Murphy (US), Nancy A. Hosken (US), Vernon Maino (US), Kenneth Davis (US), Kenneth Murphy (US), and Anne O'Garra (US) determined that 4 + T helper (Th) cells can be classified into different types based on their cytokine profile. Cells with these polarized patterns of cytokine production have been termed Thl and Th2, and can be distinguished functionally by the production of lFN-gamma and IL-4, respectively. Using immunofluorescent detection of intracellular IFN-gamma/and IL-4, they studied the emergence of Thl and Th2 cells in response to antigen exposure and the patterns of cytokine synthesis in established T cell clones. IFN-gamma production by Thl clones was detectable in almost all cells by 4 h, and it continued in most cells for >24 h. IL-4 production in Th2 cells peaked at 4 h, then declined rapidly. In Th0 cells containing both cytokines, fewer cells produced IFN-gamma, which did not appear until IL-4 synthesis declined (1110).

 

Lawrence H. Boise (US), Andy J. Minn (US), Patricia J. Noel (US), Carl H. June (US), Mary Ann Accavitti (US), Tullia Lindsten (US), and Craig B. Thompson (US) presented data demonstrating that CD28 costimulation enhances the in vitro survival of activated T cells. One mechanism for this enhancement is the ability of CD28 costimulation to augment the production of IL-2, which acts as an extrinsic survival factor for T cells. In addition, CD28 costimulation augments the intrinsic ability of T cells to resist apoptosis. Although CD28 signal transduction had no effect on Bcl-2 expression, CD28 costimulation was found to augment the expression of Bcl-XL substantially. Transfection experiments demonstrated that this level of Bcl-XL could prevent T cell death in response to TCR cross-linking, Fas cross-linking, or IL-2 withdrawal. These data suggest that an important role of CD28 costimulation is to augment T cell survival during antigen activation (146).

 

Zhengbin Yao (US), William C. Fanslow (US), Michael F. Seldin (US), Anne-Marie Rousseau (US), Sally L. Painter (US), Michael R. Comeau (US), Jeffrey I. Cohen (US), and Melanie K. Spriggs (US) produced experimental results that allowed them to define CTLA8 and HVS13 as novel cytokines that bind to a novel cytokine receptor. They proposed to call these molecules IL-17, vIL-17, and IL-17R, respectively (1608).

 

Matthew F. Krummel (US) and James P. Allison (US) reported data strongly suggesting that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTLA-4 (807).

Theresa L. Walunas (US), Deborah J. Lenschow (US), Christina Y. Bakker (US), Peter S. Linsley (US), Gordon J. Freeman (US), Jonathan M. Green (US), Craig B. Thompson (US), and Jeffrey A. Bluestone (US) had suggested that the monoclonal antibody may obstruct the interaction of CTLA-4 with its natural ligand and block a negative signal, or directly signal T cells to down-regulate immune function (1531).

 

Louis J. Picker (US), Manoj K. Singh (US), Zoran Zdraveski (US), John R. Treer (US), Sharr L. Waldrop (US), Paul R. Bergstresser (US), and Vernon C. Maino (US) report their findings using a multiparameter flow cytometric assay that allows simultaneous determination of an individual T cell's ability to produce multiple cytokines and its phenotype after only short (4 to 8 hours) in vitro incubation with an activating stimulus and the secretion inhibitor Brefeldin A. These data strongly support the in vivo existence of human memory/effector T cell subsets with "preprogrammed" cytokine synthesis potential, although they suggest that these subsets may be more complex than originally proposed in the THI/TH2 hypothesis (1159).

 

Robert I. Scheinman (US), Patricia C. Cogswell (US), Alan K. Lofquist (US), and Albert S. Baldwin, Jr. (US) helped explain the role of transcriptional activation of IkBa in mediation of immunosuppression by glucocorticoids (1286).

 

Joan Clària (US), Charles N. Serhan (US), Philip Needleman (US), Peter C. Isakson (US), Nan Chiang (US), Tomoko Takano (US), Clary B. Clish (US), Nicos A. Petasis (US), Hsin-Hsiung Tai (US), Edmund A. Bermudez (US), Paul M. Ridker (US), Shelley Hurwitz (US), Stefano Fiorucci (IT), Eleonora Distrutti (IT), Octavio Menezes de Lima (IT), Mario Romano (IT), Andrea Mencarelli (IT), Miriam barbanti (IT), Ernesto Palazzini (IT), Antonio Morelli (IT), John L. Wallace (IT), Aaron J. Marcus (US), M. Johan Broekman (IT), and Davis J. Pinsky (IT) explained that aspirin irreversibly inhibits cyclooxygenase (COX) by acetylation of an amino acid serine residue, and thus blocks the subsequent biosynthesis of prostaglandins and thromboxane. COX has at least two forms, COX-1 and COX-2. COX-1 is the main form present in mature platelets in the blood, where it transforms arachidonic acid to the intermediates PG-G/H, which are subsequently converted to thromboxane A2.

Aspirin acetylates (adds an acetyl group to ) COX-2 and re-directs COX-2’s catalytic activity away from generating intermediates of prostaglandins and thromboxanes and towards producing another compound (15R-HETE). This latter compound is converted to a different compound (15-epi-Lipoxin A4) by 5-lipoxygenase in activated neutrophils and then rapidly released. The new compound is termed aspirin-triggered 15-epi-lipoxin A4 (ATL). It is noteworthy that the ability to initiate ATL formation is unique to aspirin, as other widely used non-steroidal anti-inflammatory drugs (NSAIDs) of general COX inhibitors are unable to generate ATL. Along these lines, recent findings demonstrated that, in addition to arachidonic acid, the omega-3 poly-unsaturated fatty acids (found in fish oil), namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can also interact with aspirin-acetylated COX-2 to generate bioactive compounds, namely resolvins. Therefore, aspirin converts COX-2 into a “protective mediator-generating system” that produces arrays of novel mediators with anti-inflammatory and pro-resolving properties. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 (ATL) represent the first class of lipid mediators that evoke protective actions in a range of physiological and pathophysiological processes. Aspirin at clinically relevant doses increases anti-inflammatory ATL levels in healthy subjects. Thus, ATL formation may provide a novel mechanism underlying aspirin’s clinical benefits and could also be a sensitive new means to directly assess an individual’s anti-inflammatory response with low-dose aspirin therapy. In addition, the protective actions of these aspirin-triggered novel mediators (i.e., ATL and omega-3 fatty acid-derived resolvins) can promote the body’s natural “off switch” to stop inflammation rather than blocking the process from the outset (238-240; 258; 417; 940; 1055; 1322; 1323).

 

Dominique Campion (FR), Cozette Martin (FR), Roland Heilig (FR), Francoise Charbonnier (FR), Viviane Moreau (FR), Jean Michel Flaman (FR), Jean Louis Petit (FR), Didier Hannequin (FR), Alexis Brice (FR), and Thierry Frebourg (FR) mapped the NACP/synuclein gene to chromosome 4 and cloned three alternatively spliced transcripts in lymphocytes derived from a normal subject. The major component of the vascular and plaque amyloid deposits in Alzheimer disease is the amyloid beta peptide (A beta). A second intrinsic component of amyloid is the NAC (non-A beta component of amyloid) peptide (196).

 

Philip J. Heise (US), Linda R. Maxson (US), Herndon G. Dowling (US), and S. Blair Hedges (US) sequenced portions of two mitochondrial genes (12s and 16s ribosomal RNA) to determine the phylogenetic relationships among the major clades of snakes. Snakes were found to constitute a monophyletic group (confidence probability [CP] = 96%) with the scolecophidians (blind snakes) as the most basal lineages (CP = 99%). This finding supports the hypothesis that snakes underwent a subterranean period early in their evolution (617).

 

Michele Barry (US), Mark Russi (US), Lori Armstrong (US), David Geller (US), Robert Tesh (US), Louise Dembry (US), Jean Paul Gonzalez (US), Ali S. Khan (US), Clarence J. Peters (US), Frederick A. Murphy (US) and Karl M. Johnson (US) reported on Brazilian hemorrhagic fever acquired in the laboratory (87; 1039). Note: Brazilian hemorrhagic fever (BzHF) is an infectious disease caused by the Sabiá virus, an Arenavirus. The Sabiá virus is an enveloped RNA virus and is highly infectious and lethal. The only known case of naturally contracted Sabiá virus occurred in 1990 in a woman staying in the neighborhood of Jardim Sabiá, in Cotia, a city near Sao Paulo.

 

Keith Murray (AU), Russell Rogers (AU), Linda Selvey (AU), Paul Selleck (AU), Alex Hyatt (AU), Allan Gould (AU), Laurie Gleeson (AU), Peter Hooper (AU), and Harvey Westbury (AU) described a newly recorded disease of horses with an obvious zoonotic potential; moreover, the causative agent was previously unrecorded and is significantly different from other members of its genus, Morbillivirus (1040). Note: Genetic analyses show this virus, now called Hendra virus, to be only distantly related to the classic morbilliviruses rinderpest, measles, and canine distemper. Australia’s “Flying fox” bats (genus Pteropus) are the natural reservoir of Hendra virus.

 

Hiroyuki Suzuki (US), Xiaoling Zhou (US), Jing Yin (US), Jungi Lei (US), Hal Yan Jiang (US), Yukiko Suzuki (US), Tim Chan (US), Gregory J. Hannon (US), Wolfgang J. Mergner (US), John M. Abraham (US), and Stephen J. Melzer (US) found that the CDKN2A and CDKN2B genes, encoding p16 and p15 respectively, are located on chromosome 9p21, a locus at which frequent homozygous and heterozygous deletions occur in many primary human tumors, including esophageal carcinoma. CDKN2A and CDKN2B inhibit cyclin dependent kinase 4 (CDK4) and CDK6 and control cellular proliferation by preventing entry into the S phase of the cell cycle. Their inactivation may contribute to uncontrolled growth in human cancer (1423).

 

Jean Morissette (CA), Gilles Côté (CA), Jean-Louis Anctil (CA), Micheline Plante (CA), Marcel Amyot (CA), Élise Héon (CA), Graham Eric Trope (CA), Jean Weissenbach (CA), and Vincent Raymond (CA) demonstrated that the human GLC1A gene on chromosome 1 is responsible for both adult-onset (COAG) and juvenile glaucomas (JOAG) (1022).

 

Jose M. Fernandez-Canon (ES), Miguel A. Penalva (ES), Begona Granadino (ES), Daniel Beltran-Valero De Bernabe (ES), Mónica Renedo (ES), Elena Fernandez-Ruiz (ES), Miguel A. Penalva (ES), and Santiago Rodriguez de Cordoba (ES) created a mutant of the fungus Aspergillus which accumulated a purple pigment in the presence of phenylalanine: homogentisate. This mutation results in a defective gene for homogentisate dioxygenase, which in humans leads to the disease alkaptonuria. They located the defective gene within the fungal genome, made copies, and then used them to probe human DNA. The gene for homogentisate dioxygenase in humans was thus located on the long arm of chromosome number three (402-404; 1284).

 

Feng Chen (US) and Curtis A. Suttle (US) demonstrated that viral pathogens infect a variety of important marine primary producers, including diatoms, cryptophytes, prasinophytes, and chroococcoid cyanobacteria (231).

 

Sandra J. Holmes (US), Susan Reef (US), Stephen C. Hadler (US) Walter W. Williams (US), and Melinda Wharton (US) reported on the first vaccine—licensed in1995 in the US— effective in preventing any member of the herpesviridae family. This vaccine, known by the brand name Varivax, is a live varicella vaccine developed by Merck to prevent chickenpox (646).

Michael N. Oxman (US), Myron J. Levin (US), Gary Russell Johnson (US), Kenneth E. Schmader (US), Stephen E. Straus (US), Larry D. Gelb (US), Robert David Arbeit (US), Michael S. Simberkoff (US), Alperovich Gershon (US), Lisa E. Davis (US), Adriana Weinberg (US), Kathy D. Boardman (US), Heather MacLeod Williams (US), Jane Hongyuan Zhang (US), Peter N. Peduzzi (US), Christopher E. Beisel (US), Vicki A. Morrison (US), John Guatelli (US), Penelope A. Brooks (US), Carol A. Kauffman (US), Constance T. Pachucki (US), Kathleen M. Neuzil (US), Robert Betts (US), Peter Farnum Wright (US), Marie R. Griffin (US), Philip Alfred Brunell (US), Norberto E. Soto (US), Ana Raquel Figueiredo Marques (US), Susan K. Keay (US), Richard P. Goodman (US), Deborah Jean Cotton (US), John W. Gnann, Jr. (US), J. F. ed. Loutit (US), Mark Holodniy (US), Wendy A. Keitel (US), George E. Crawford (US), Shingshing S. Yeh (US), Zita Lobo (US), John F. Toney (US), Richard Neil Greenberg (US), Peter M. Keller (US), Rith Harbecke (US), Anthony R. Hayward (US), Michael R. Irwin (US), Tassos C. Kyriakides (US), Christina Y. Chan (US), Ivan Siu Fung Chan (US), Weixun Wang (US), Paula W. Annunziato (US), Jeffrey L. Silber (US), and the Shingles Prevention Study Group reported on a second vaccine against Varicella-Zoster Virus (VZV), this one for the prevention of herpes zoster (or shingles), was licensed to Merck in 2006. It is recommended for use in individuals older than 60 years old (1113).

 

Luigi Luca Cavalli-Sforza (IT) and Francesco Cavalli-Sforza (IT) reported that people with type O blood seem to be less susceptible to syphilis than those of other blood types. Type O blood was common among North American Indians. Syphilis appears to have been indigenous to North America prior to 1492. This idea has now been found suspect (218).

 

Michael F. Hammer (US) reported that the male-specific portion of the Y chromosome is especially useful for studies of human origins. Using such analysis he estimated the time back to a common ancestral human Y chromosome to be 188,000 years (588).

 

Keith Murray (AU), Paul Selleck (AU), Peter Hooper (AU), Alex Hyatt (AU), Allan Gould (AU), Laurie Gleeson (AU), Harvey Westbury (AU), Lester Hiley (AU), Linda Selvey (AU), Barry J. Rodwell (AU), and Peter J. Ketterer (AU) discovered the zoonotic Hendra virus (morbillivirus) as the cause of an explosive outbreak of zoonotic respiratory disease in a horse stable in Hendra, a suburb of Brisbane (1041).

 

Jacques Gilloteaux (US), James M. Jamison (US), Meenakshi Venugopal (US), David Giammar (US), and Jack L. Summers (US) rediscovered 30 year old previously ignored research by a Belgian scientist indicating that when vitamin C and vitamin K3 are combined with radiation or chemotherapy the combination is especially potent against cancer cells (499). In 1998, Gilloteaux and his colleagues coined the term autoschizis to describe this process. Henryk S. Taper of the Catholic University of Louvain in Belgium pioneered the vitamin therapy nearly 40 years ago. He also noted in Belgian-language publications that the vitamins prompted cancer cells to make enzymes that chop up their DNA and RNA.

 

Jacqueline A. Banks (GB), Nicola Hemming (GB), and Joyce Poole (GB) presented evidence that the Gya, Hy and Joa antigens belong to the Dombrock blood group system (81).

 

Sadahiko Iwamoto (JP), Toshinori Omi (JP), Eiji Kajii (JP), and Sigenori Ikemoto (JP) helped elucidate the molecular basis of Fya/Fyb blood antigens (691).

 

Stephen Frederick Parsons (GB), Gary Mallinson (GB), Christopher H. Holmes (GB), James M. Houlihan (GB), Kerryn L. Simpson (GB), William J. Mawby (GB), Nigel K. Spurr (GB), David S. Warne (GB), Alexander N. Barclay (GB), and David J. Anstee (GB) isolated glycoproteins expressed as Lutheran blood group antigens from human erythrocyte membranes and from human fetal liver. Using the amino acid sequence analyses they designed redundant oligonucleotides with which they generated a 459-bp, sequence-specific probe by PCR. A cDNA clone was isolated and sequenced, and the deduced amino acid sequence was studied. The predicted mature protein is a type 1 membrane protein of 597 amino acids (1130).

 

Ortrud K. Steinlein (DE), John C. Mulley (AU), Peter Propping (DE), Robyn H. Wallace (AU), Hilary A. Phillips (AU), Grant R. Sutherland (AU), Ingrid E. Scheffer (AU), and Samuel F. Berkovic (AU) determined that autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) involves a point mutation in the pore region of the alpha 4 nicotinic acetylcholinergic receptor subunit gene (1397).

 

Michael Levin (US), Randy L. Johnson (US), Claudio D. Stern (US), Michael Kuehn (US), and Clifford J. Tabin (US) discovered a cascade of genes regulating L/R organ asymmetry in the chick. The starting point for this work was the discovery of a transient asymmetry in Shh expression on the left side of Hensen's node — a midline structure that serves as a key source of patterning signals in the early embryo. Subsequently, Levin et al. stumbled on a second gene, Nodal, that was expressed immediately adjacent to Shh in a domain extending throughout the embryo's left side. Importantly, when they misexpressed Shh on the right side of the embryo, Nodal was induced ectopically and the normal rightward bending of the heart tube became randomized (856). Note: This study revealed, for the first time, the existence of genes with L/R asymmetric expression patterns that could influence the direction of subsequent L/R morphogenetic events.

Jérôme Collignon (FR), Isabella Varlet (US), Elizabeth J. Robertson (US), Linda A. Lowe (US), Dorothy M. Supp (US), Karuna Sampath (US), Takahiko Yokoyama (JP), Christopher V. Wright (US), S. Steven Potter (US), Paul Overbeek (US), and Michael R. Kuehn (US) showed that this asymmetry in Nodal expression is also present in mouse and Xenopus, identifying Nodal as a central player in a conserved vertebrate L/R pathway (270; 904).

Chikara Meno (JP), Akihiko Shimono (JP), Yukio Saijoh (JP), Kenta Yashiro (JP), Kyoko Mochida (JP), Sachiko Ohishi (JP), Sumihare Noji (JP), Hisato Kondoh (JP), and Hiroshi Hamada (JP) discovered another gene, which they called Lefty because of its striking expression in the left lateral plate mesoderm and in the left half of the prospective floor plate. The Lefty locus was subsequently found to contain two closely linked and highly related genes, Lefty-1 and Lefty-2.

The overlapping expression of Nodal and Lefty-2 in the left lateral plate mesoderm indicated that these genes might act together to impart left-sided identity to developing organs. However, an unexpected role for Lefty genes subsequently emerged from the analysis of Lefty-1 knockout mice: Lefty-1, rather than specifying 'leftness', is actually required for maintaining right-sided identity. As the primary site of Lefty-1 expression is in the left half of the prospective floor plate. It was proposed that Lefty-1 acts as a midline barrier, preventing left-sided signals, such as Nodal, from crossing the midline and conferring left identity to cells on the right (991).

Malcolm Logan (GB), Sylvia M. Pagan-Westphal (US), Devyn M. Smith (US), Laura Paganessi (US), and Clifford J. Tabin (US) found that the transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals (894).

M. Elisa Piedra (ES), Jose M. Icardo (ES), Marta Albajar (ES), Jose C. Rodriguez-Rey (ES), Marian A. Ros (ES), Aimee K. Ryan (US), Bruce Blumberg (US), Concepción Rodriguez-Esteban (US), Sayuri Yonei-Tamura (US), Koji Tamura (US), Tohru Tsukui (US), Jennifer de la Pena (US), Walid Sabbagh (US), Jason Greenwald (US), Senyon Choe (US), Dominic P. Norris (US), Elizabeth J. Robertson (US), Ronald M. Evans (US), Michael G. Rosenfeld (US), Juan Carlos Izpisúa Belmonte (US), Hidefumi Yoshioka (JP), Chikara Meno (JP), Kazuko Koshiba (JP), Minoru Sugihara (JP), Hiroyuki Itoh (JP), Yoshiyasu Ishimaru (JP), Takashi Inoue (JP), Hideyo Ohuchi (JP), Elena V. Semina (US), Jeffrey C. Murray (US), Hiroshi Hamada (JP), and Sumihare Noji (JP) reported that Pitx2, a bicoid-type homeobox gene expressed asymmetrically in the left lateral plate mesoderm, may be involved in determination of L-R asymmetry in both mouse and chick. Since Pitx2 appears to be downstream of Lefty-1 in the mouse pathway, they examined whether mouse Lefty proteins could affect the expression of Pitx2 in the chick. Their results indicate that a common pathway from Lefty-1 to Pitx2 likely exists for determination of L-R asymmetry in vertebrates (1162; 1264; 1614).

Shigenori Nonaka (JP), Yosuke Tanaka (JP), Yasushi Okada (JP), Sen Takeda (JP), Akihiro Harada (JP), Yoshimitsu Kanai (JP), Mizuho Kido (JP), and Nobutaka Hirokawa (JP) made the remarkable discovery that the mouse node contains a cluster of motile cilia which generate a leftward flow across the node's ventral surface. As the node is where the earliest L/R asymmetric expression patterns are seen, and directional flow could, in principle, arise from the inherent chirality of the ciliary apparatus without prior input of L/R information, these results indicated that ciliary motion might initiate L/R axis specification (1086).

 

Patrick Hwu (US), James C. Yang (US), Robert Cowherd (US), Jonathan Treisman (US), Gwen E. Shafer (US), Zelig Eshhar (IE), and Steven A. Rosenberg (US) performed studies indicating that T cells could be gene modified to react in vivo against tumor antigens, defined by monoclonal antibodies. This approach is potentially applicable to a number of neoplastic and infectious diseases and may allow adoptive immunotherapy against types of cancer not previously amenable to cellular immunotherapy (671). Note: This technique is frequently referred to as chimeric antigen receptor T-cell (CAR-T) therapy. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies.

 

J. Thomas Cox (US), Attila T. Lörincz (IE-US), Mark H. Schiffman (US), Mark E. Sherman (US), Allison Cullen (US), Robert J. Kurman (US), Scott Hall (US), Farida Shah (US), Fouad Abbas (US), Gerson Paull (US), and Keerti V. Shah (US) invented and disseminated the Hybrid Capture (HC) series of human papillomavirus tests. These nucleic acid amplification tests are generally recognized as the gold standard in routine human papillomavirus screening worldwide, with more that 10 million tests conducted annually (291; 581).

 

Sergio Oehninger (US), Lucinda L. Veeck (US), Susan Lanzendorf (US), Mary Maloney (US), James Toner (US), and Suheil Jamil Muasher (US) noted that among infertile couples with poor prognosis and/or severe male factor infertility, intracytoplasmic sperm injection (ICSI) was associated with higher fertilization, implantation, and pregnancy rates (1100).

 

Sharon L. Hillier (US), Robert P. Nugent (US), David A. Eschenbach (US), Marijane A. Krohn (US), Ronald S. Gibbs (US), David H. Martin (US), Mary Frances Cotch (US), Robert Edelman (US), Joseph G. Pastorek (US), A. Vijaya Rao (US), Donald McNellis (US), Joan A. Regan (US), J. Christopher Carey (US), and Mark A. Klebanoff (US) reported that bacterial vaginosis (BV) is associated with 40% increased odds of preterm delivery of a low birth weight (LBW) infant (631).

 

Ruth Arnon (IR) and Michael Sela (IR) developed a new drug application for the treatment of multiple sclerosis called Copolymer 1. Its chemical name is glatiramer acetate. It was submitted by the TEVA Pharmaceutical Company to the FDA for approval, under the name of Copaxone, on June 14, 1995 (50).

 

Klaus E. Matzel (DE), Uwe Stadelmaier (DE), Markus Hohenfellner (DE), Frans Paul Gall (DE), Michael A. Kamm (DE), Michael Stösser (DE), Cor G.M.I. Baeten (DE), John Christiansen (DE), Robert Madoff (DE), Anders Mellgren (DE), R. John Nicholls (DE), Josep Rius (DE), and Harald Rosen (DE) introduced, then refined, the concept of sacral nerve stimulation (SNS) to treat fecal incontinence. They reported that a multicenter prospective trial confirmed that sacral neuromodulation results in immediate and sustained improvements in fecal incontinence with associated improvement in quality of life (958; 959).

 

Lloyd E. Ratner (US), Lars J. Ciseck (US), Robert G. Moore (US), Francisco G. Cigarroa (US), Howard S. Kaufman (US), and Louis R. Kavoussi (US) performed the first laparoscopic live-donor kidney transplant. Using sharp-edged hollow cylinders, the team removed a kidney through an incision a few inches wide. They then used conventional surgical procedure to transplant the kidney into the recipient (1214). Laparoscopy reduces hospital and recuperation time.

 

Steven M. Strasberg (US), Martin Hertl (US), and Nathaniel J. Soper (US) concluded that biliary injury is the most significant problem in laproscopic cholecystectomy. The key is prevention, where meticulous dissection allows only structures that have been unequivocally and conclusively identified to be divided (1406).

 

The Scotia Study Group reported that resection following intra-operative irrigation is preferred treatment for left-sided malignant large bowel obstruction because it has a better functional outcome. The safety of a single-stage approach, with anastomotic leak <5% and mortality of around 10%, was also confirmed. Subtotal colectomy is recommended for perforation of the caecum or in the presence of synchronous tumors (555).

 

Allen S. Lichter (US) and Randall K. Ten Haken (US) advanced computerized systems that improve the accuracy of radiation therapy with better focusing on the tumor, reducing damage to surrounding healthy tissue (871).

 

Charles G. Moertel (US), Thomas R. Fleming (US), John S. Macdonald (US), Daniel G. Haller (US), John A. Laurie (US), Catherine M. Tangen (US), James S. Ungerleider (US), William A. Emerson (US), Douglass C. Tormey (US), John H. Glick (US), Michael H. Veeder (US), and James A. Mailliard (US) showed that fluorouracil plus levamisole is tolerable adjuvant therapy to surgery for colon cancer; it has been confirmed to substantially increase cure rates for patients with high-risk (stage III) colon cancer. It should be considered standard treatment for all such patients not entered into clinical trials (1007).

 

The Executive Committee for the Asymptomatic Carotid Atherosclerosis Study, Alison Halliday (GB), Averil O. Mansfield (GB), Joanna Marro (GB), C. Peto (GB), Richard Peto (GB), John Potter (GB), Dafydd Thomas (GB), and the M. R. C. Asymptomatic Carotid Surgery Trial Collaborative Group performed multi-center randomized studies of carotid endarterectomy surgery versus no surgery and immediate versus delayed surgery for asymptomatic patients with at least 60% stenosis of an internal carotid artery. In both scenarios, it was determined that surgery is effective in reducing the incidence of stroke in patients with asymptomatic severe carotid stenosis. The stroke rate at 5 years is approximately halved (583; 1410). Note: Richard Peto (GB) was made a Fellow of the Royal Society of London in 1989 for introducing meta-analyses of randomised trials.

 

Klas Malmberg (SE), Lars Rydén (SE), Suad Efendic (SE), Johan Herlitz (SE), Peter Nicol (SE), Anders Waldenstrom (SE), Hans Wedel (SE), Lennart Welin (SE) reported that insulin-glucose infusion followed by a multidose insulin regimen improved long-term prognosis in diabetic patients with acute myocardial infarction (933).

 

Masashi Nibuya (US), Shigeru Morinobu (US), and Ronald Stanton Duman (US) discovered that antidepressants increase the gene expression of Brain-Derived Neurotrophic Factor, or (BDNF) in the hippocampus (1068).

Ronald Stanton Duman (US), George R. Heninger (US), and Eric J. Nestler (US) formulated the hypothesis that depression is caused by a decrease in hippocampal neurogenesis caused by elevated cortisol levels. They posited that stress induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents (356).

Jessica E. Malberg (US), Amelia J. Eisch (US), Eric J. Nestler (US), and Ronald Stanton Duman (US) discovered that the downstream effect of BDNF is to increase neurogenesis or the formation of new neurons in the dentate gyrus of the hippocampus (932).

 

G. Brian Golding (CA) and Rodhey S. Gupta (CA) stated that protein-based phylogenies support a chimeric origin for the eukaryotic genome (506).

 

Wyn G. Jones (AU), Kenneth D. Hill (AU), and Jan M. Allen (AU) reported the 1994 discovery by David Noble (AU) in the Wollemi National Park in Australia of Wollemia nobilis, a new living genus and species in the Araucariaceae (the monkey-puzzle tree family). This type of pine may be 150 million years old (716).

 

Peter Funch (DK) and Reinhardt Møbjerg Kristensen (DK) described Cycliophora, a new meiofaunal phylum with affinities to Entoprocta and Ectoprocta (450).

Birgitta M.H. Winnepenninckx (DK), and Thierry Backeljau (DK) and Reinhardt Møbjerg Kristensen (DK) published the description and the molecular data (18S rRNA) of the new phylum Cycliophora (1581).

 

Lian-hai Hou (CN), Zhonghe Zhou (CN), Larry D. Martin (US), and Alan Feduccia (US) discovered avian remains close to the age (Jurrasic) of Archaeopteryx in the Liaoning Province of northeastern China provides the earliest evidence for a beaked, edentulous bird. The associated wing skeleton retains the primitive pattern found in Archaeopteryx, including a manus with unfused carpal elements and long digits. They named it Confuciusornis (654).

 

Michel Brunet (FR), Alain Beauvilain (FR), Yves Coppens (FR), Emile Heintz (FR), Aladji H. Moutaye (FR), and David Roger Pilbeam (US) discovered part of a fossilized jaw at Koro Toro, Chad (2,400 km west of the Eastern Rift Valley) which closely resembles that of Australopithecus afarensis. They named it Australopithecus bahrelghazali and dated it to between 3.3 and 3 Ma (175; 176).

 

Meave G. Leakey (GB-KE), Craig S. Feibel (US), Ian McDougall (AU), Carol Ward (US) and Alan Cyril Walker (GB-US) discovered Australopithecus anamensis at Kanapoi on the shore of Lake Turkana, Northern Kenya. The material consists of nine hominid dental, cranial and postcranial specimens from Kanapoi, Kenya, and 12 specimens from Allia Bay, Kenya. Anamensis existed between 4.2 and 3.9 million years ago, and has a mixture of primitive features in the skull, and advanced features in the body (837; 838).

Bryan Patterson (US) and William W. Howells (US), in 1965, discovered but did not identify Australopithecus anamensis from a site on the west side of Lake Turkana in Kenya (1136). Note: Some anthropologists regard this skeleton as exhibiting the earliest ‘clear evidence’ for bipedalism.

 

Tomothy Fridtjof Flannery (AU), John A. Long (AU), and Michael Archer (AU) published The Mammals Of New Guinea (Cornell Press) and Prehistoric Mammals Of Australia and New Guinea (Johns Hopkins Press), the most comprehensive reference works on the subjects (423; 896).

 

1996

“But every human life is a mystery and best weighed by its influence on others. Efraim Racker showed me that scientific exploration and art are but two manifestations of the same powerful spirit that makes us human, brings us joy, and gives us wings.” Gottfried Schatz (1285).

 

"The greatest adventure is what lies ahead.

Today and tomorrow are yet to be said.

The chances, the changes are all yours to make.

The mold of your life is in your hands to break." J.R.R. Tolkien (1464).

 

“The demonstration that a population of small lymphocytes can carry the property of immunological tolerance is strong evidence that they are involved in the inductive phase of antibody formation. The simplest view would be that small lymphocytes interact with antigen (or with antigen which has been ′processed′ by reticulo-endothelial phagocytes), become fixed in lymphoid tissue and give rise to a dividing cell line of the kind identified by Nossal and Mäkela [i.e., a plasma cell]. The cell line generates the cells, which eventually synthesize antibody. Although there is strong morphological evidence that small lymphocytes are the ultimate precursors of antibody forming cells, it must be emphasized that it has not yet been unequivocally demonstrated.” James Learmonth Gowans (523).

 

"...biogeography does more than ask Which species? and Where. It also asks Why? and, what is sometimes more crucial, Why not?." David Quammen (1195).

 

 In his acceptance of the Embryo Transfer Pioneer Award of the European Embryo Transfer Association, Steen Malte Willadsen (DK-GB-CA-US) explained that one thing he had always dreaded was "the shot pheasant syndrome," which, he said, "is the most common postdoctoral ailment of career scientists." He explained: "though still airborne with wings flapping, the bird is already dead." His aim, he said, was "not just to become a scientist, but to engage in great, absorbing endeavors while maintaining a high degree of freedom, and avoiding tedium and coercion." (790)

 

Peter Charles Doherty (AU-US) and Rolf Martin Zinkernagel (CH-US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning the specificity of the cell mediated immune defense.

 

Jeffrey E. Ingeman (US), Michael C. Plewa (US), Robert E. Okasinski (US), Randall W. King (US), and F. Barry Knotts US) concluded that emergency physicians with minimal training can use abdominal diagnostic ultrasonography (DUS) with fair sensitivity and good specificity and accuracy to rapidly detect free intraperitoneal fluid in both pediatric and adult blunt abdominal trauma (BAT) victims (679). Note: In 3-dimensional (3D) ultrasound imaging, the sound waves are reflected back at several different angles, creating a 3D image. With 4-dimensional (4D) ultrasound imaging, the user can visualize movement of 3D structures in real time. Ultrasound imaging is used in a wide variety of diagnostic settings with precise and safe results (109; 400).

 

Luda Diatchenko (US), Yun-fai Chris Lau (US), Aaron P. Campbell (US), Alex Chenchik (US), Fauzia Moqadam (US), Betty Huang (US), Sergey Lukyanov (RU), Konstantin Lukyanov (RU), Nadya Gurskaya (RU), Eugene D. Sverdlov (RU), and Paul D. Siebert (US) devised "suppression subtractive hybridization", a method for generating differentially regulated or tissue-specific cDNA probes and libraries. It is a versatile method for identifying differentially expressed genes (336).

 

Michael R. Emmert-Buck (US), Robert F. Bonner (US), Paul D. Smith (US), Rodrigo F. Chuaqui (US), Zhengping Zhuang (US), Seth R. Goldstein (US), Rhonda A. Weiss (US), and Lance A. Liotta (US) developed the laser capture microdissection (LCM) technique, which allows scientists for the first time to pinpoint and remove targets as small as one cell from a sample without damaging either the target or the surrounding tissue (374).

 

Jason D. Morrow (US), Joseph A. Awad (US), Aiping Wu (US), William E. Zackert (US), Vincent C. Daniel (US), and L. Jackson Roberts, II (US) discovered isothromboxanes, which are produced by nonenzymatic free radical-catalyzed peroxidation of arachidonoyl lipids (1024).

 

Don Grierson (GB) introduced gene-silencing manipulations. A gene is down regulated or suppressed using antisense or sense gene constructs to block protein synthesis (539). This technique was first used commercially to create tomatoes with a high solid content and a longer shelf life.

 

Norbert Krauss (DE), Wolf-Dieter Schubert (DE), Olaf Klukas (DE), Petra Fromme (DE), Horst Tobias Witt (DE), and Wolfgang Saenger (DE) described photosystem 1 at 4-angstrom resolution. This represents the first structural model of a joint photosynthetic reaction center and core antenna system (804).

 

Ravi G. Kurumbail (US), Anna M. Stevens (US), James K. Gierse (US), Joseph J. McDonald (US), Roderick A. Stegeman (US), Jina Y. Pak (US), Daniel Gildehaus (US), Julie M. Iyashiro (US), Thomas D. Penning (US), Karen Seibert (US), Peter C. Isakson (US), and William C. Stallings (US) reported the structure of prostaglandin synthase-II, a membrane embedded protein (814).

 

Juro Sakai (US), Elizabeth A. Duncan (US), Robert B. Rawson (US), Xianxin Hua (US), Michael S. Brown (US), and Joseph L. Goldstein (US) showed that the NH2-segment of sterol regulatory element binding proteins is released from membranes by two sequential cleavages. The first, regulated by sterols, occurs in the lumenal loop. The second, not regulated by sterols, occurs within the first transmembrane domain. The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake (1272). Note: Sterol regulatory element binding proteins (SREBPs) are transcription factors attached to the endoplasmic reticulum. The NH2-segment, which activates transcription, is connected to membranes by a hairpin anchor formed by two transmembrane sequences and a short lumenal loop.

 

John D. Altman (US), Paul A.H. Moss (GB), Philip J.R. Goulder (GB), Dan H. Barouch (GB), Michael G. McHeyzer-Williams (US), John I. Bell (GB), Andrew J. McMichael (GB), and Mark M. Davis (US) developed a methodology they call "tetramer binding" to identify those T cells which bind a specific infectious agent, tumor, or autoantigen (35).

 

George Grigoriadis (AU), Yifan Zhan (AU), Raelene J. Grumont (AU), Donald Metcalf (AU), Emanuella Handman (AU), Christina Cheers (AU), and Steve Gerondakis (AU) established that Rel (from the c-rel gene) in mice is a positive or negative regulator of transcription in macrophages and that Rel has distinct roles in different macrophage populations (540).

 

Joseph D. Fondell (US), Hui Ge (US), and Robert Gayle Roeder (US) discovered the major conduit for communication between gene-specific activators and the general transcription machinery in animal cells: a giant coactivator (TRAP/SMCC) that consists of about 25 different protein chains and is referred to as the human mediator after its counterpart in yeast (427).

 

Daniel S. Lyons (US), Stephanie A. Lieberman (US), Johannes Hampl (US), J. Jay Boniface (US), Yueh-hsiu Chien (US), Leslie J. Berg (US), and Mark M. Davis (US) found that a T cell receptor (TCR) binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists (915).

 

Ellen V. Rothenberg (US) and Susan B. Ward (US) reported that the interleukin-2 (IL-2) transcriptional apparatus integrates multiple types of biochemical information in determining whether or not the gene will be expressed, using multiple diverse transcription factors that are each optimally activated or inhibited by different signaling pathways (1257).

 

Diana L. Sylvestre (US) and Jeffrey V. Ravetch (US) demonstrated that experimental immune-complex–mediated injury in mice, as modeled by the cutaneous Arthus reaction, requires receptors for the Fc portion of the antibody, is unaffected by deficiencies in complement components. However, the responsible cell type(s) and Fc receptor(s) were not known. They now demonstrate by differential reconstitution in vivo that FcgRIII on mast cells is necessary for this inflammatory response. We propose a general model of antibody-mediated diseases as an immunopathologic spectrum whose specific manifestations are determined by the Fc receptor and cell type engaged (1427).

 

David N. Garboczi (US), Partho Ghosh (US), Ursula Utz (CA), Qing R. Fan (US), William E. Biddison (US), and Don C. Wiley (US) reported that recognition by a T-cell antigen receptor (TCR) of peptide complexed with a major histocompatibility complex (MHC) molecule occurs through variable loops in the TCR structure which bury almost all the available peptide and a much larger area of the MHC molecule. The TCR fits diagonally across the MHC peptide-binding site in a surface feature common to all class I and class II MHC molecules, providing evidence that the nature of binding is general. A broadly applicable binding mode has implications for the mechanism of repertoire selection and the magnitude of alloreactions (462).

 

K. Christopher Garcia (US), Massimo Degano (US), Robyn L. Stanfield (US), Anders Brunmark (US), Michael R. Jackson (US), Per A. Peterson (US), Luc Teyton (US), and Ian A. Wilson (US) reported the x-ray structure of the complete extracellular fragment of a glycosylated alphabeta TCR determined at 2.5 angstroms, and its orientation bound to a class I MHC-peptide (pMHC) complex was elucidated from crystals of the TCR-pMHC complex. The TCR resembles an antibody in the variable Valpha and Vbeta domains but deviates in the constant Calpha domain and in the interdomain pairing of Calpha with Cbeta. Four of seven possible asparagine-linked glycosylation sites have ordered carbohydrate moieties, one of which lies in the Calpha-Cbeta interface. The TCR combining site is relatively flat except for a deep hydrophobic cavity between the hypervariable CDR3s (complementarity-determining regions) of the alpha and beta chains. The 2C TCR covers the class I MHC H-2Kb binding groove so that the Valpha CDRs 1 and 2 are positioned over the amino-terminal region of the bound dEV8 peptide, the Vbeta chain CDRs 1 and 2 are over the carboxyl-terminal region of the peptide, and the Valpha and Vbeta CDR3s straddle the peptide between the helices around the central position of the peptide (463).

 

Steven Xanthoudakis (US), Joao P.B. Viola (US), Karen T.Y. Shaw (US), Chun Luo (US), James D. Wallace (US), Patricia T. Bozza (US), Tom Curran (US), and Anjano Rao (US) found evidence in mice that transcription factor NFAT1 exerts a negative regulatory influence on the immune response (1596).

 

Patricia Stanhope-Baker (US), Karen M. Hudson (US), Arthur L. Shaffer (US), Andrei Constantinescu (US), and Mark S. Schlissel (US), using an in vitro system, analyzed recombinase cleavage of recombination signal sequences (RSSs) flanking Ig and T cell receptor (TCR) gene segments in nuclei. They found that both the lineage-specificity and temporal ordering of gene rearrangement is reflected in the accessibility of RSSs within chromatin to in vitro cleavage (1393).

 

Michael Hahne (CH), Donata Rimoldi (CH), Michael Schröter (CH), Pedro Romero (CH), M.H. Schreier (CH), Lars French (CH), Pascal Schneider (CH), Thierry Bornand (CH), Adriano Fontana (CH), Danielle Lienard (CH), Jean-Charles Cerottini (CH), and Jürg Tschopp (CH) found that FasL might contribute to the immune privilege of tumors. Melanoma cells were found to express Fas (also called Apo-1 or CD95) ligand (FasL) (575).

 

Carole L. Cramer (US), Deborah L. Weissenborn (US), Karen K. Oishi (US), Elizabeth A. Grabau (US), Selester Bennett (US), Elvira Ponce (US), Gregory A. Grabowski (US) and David N. Radin (US) produced transgenic tobacco plants which could manufacture protein C; a useful anticoagulant (293).

Carole L. Cramer (US), Deborah L. Weissenborn (US), Karen K. Oishi (US), and David N. Radin (US) reported the creation of a transgenic tobacco plant capable of producing glucocerebrosidase, a lysosomal enzyme useful in the treatment of Gaucher’s disease (294). Note: The U.S. Patent and Trademark Office issued patent 5,929,304 to them on July 27, 1999.

 

Peter R. Ganz (CA), Anil Dudani (CA), Eileen S. Tackaberry (CA), Ravinder K. Sardana (CA), Connie Sauder (CA), Xiongying Cheng (CA) and Illimar Altosaar (CA) reported the creation of transgenic tobacco plants capable of producing the cytokine GM-CSF. This factor can stimulate leukopoiesis in bone marrow transplants (460).

 

Pascale Cossart (FR), Patrice Boquet SE), Staffan Normark (SE), and Rino Rappuoli (IT) offered the concept that microbes are better studied in the context of the cells they interact with (cellular microbiology) (285).

 

William D. Rawlinson (AU), Helen E. Farrell (AU), and Barclay George Barrell (GB) determined and analyzed the complete DNA sequence of murine cytomegalovirus (1215).

 

André Goffeau (BE), Barclay G. Barrell (GB), Howard Bussey (CA), Ronald W. Davis (US), Bernard Dujon (FR), Horst Feldmann (DE), Francis Galibert (FR), Jörg D. Hoheisel (DE), Claude Jacq (FR), Mark Johnston (US), Edward J. Louis (GB), H. Werner Mewes (DE), Yasafumi Murakami (JP), Peter Philippsen (CH), and Hervé Tettelin (BE-US) reported the completion of the Saccharomyces cerevisiae genome-sequencing project. This was the first eukaryote to be fully sequenced (505).

 

Susan M. Barns (US), Charles F. Delwiche (US), Jeffrey D. Palmer (US), and Norman Richard Pace, Jr. (US) discovered a member of the kingdom Archaea that may be the most primitive life form extant. They named it Korarchaeota (Gr. koros, young man or kore young woman, archaios ancient or primitive) (85).

 

Takakazu Kaneko (JP), Shusei Sato (JP), Hirokazu Kotani (JP), Ayumi Tanaka (JP), Erika Asamizu (JP), Yasukazu Nakamura (JP), Nobuyuki Miyajima (JP), Makoto Hirosawa (JP), Minoru Sugiura (JP), Shigemi Sasamoto (JP), Takaharu Kimura (JP), Tsutomo Hosouchi (JP), Ai Matsuno (JP), Akiko Muraki (JP), Naomi Nakazaki (JP), Kaoru Naruo (JP), Satomi Okumura (JP), Sayaka Shimpo (JP), Chie Takeuchi (JP), Tsuyuko Wada (JP), Akiko Watanabe (JP), Manabu Yamada (JP), Miho Yasuda (JP), and Satoshi Tabata (JP) determined the DNA base sequence of the unicellular cyanobacterium Synechocystis sp. strain PCC 6803 (734).

 

Derek W. Hood (GB), Mary E. Deadman (GB), Tina Allen (GB), Hussein Masoud (GB), Adèle Martin (GB), Jean-Robert Brisson (GB), Robert D. Fleischmann (US), John Craig Venter (US), James C. Richards (CA), and E. Richard Moxon (GB) investigated the biology of Haemophilus influenzae lipopolysaccharide (LPS)—a major virulence determinant of this human pathogen—by searching the H. influenzae genomic database, with sequences of known LPS biosynthetic genes from other organisms. This study is one of the first to demonstrate the rapidity, economy, and completeness with which novel biological information can be accessed once the complete genome sequence of an organism is available (648).

 

Elizabeth Bergogne-Bérézin, (FR) and Kevin J. Towner (GB) reported that Acinetobacter spp. are ubiquitous, nonfermentative, gram-negative bacilli which play a significant role in the colonization and infection of patients in intensive care units. Acinetobacter baumannii is the predominant species associated with outbreaks of nosocomial infections (114).

Louis B. Rice (US) reports that A. baumannii has also been identified as an ESKAPE pathogen (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa and Enterobacter species); a group of pathogens with a high rate of antibiotic resistance that are responsible for the majority of nosocomial infections (1231).

 

Kári Stefánsson (IS) and Jeffrey Gulcher (IS) created a computerized national genealogy database that linked all living Icelanders and included the majority of people who have ever lived in Iceland over the past eleven hundred years. This database, named deCODE, is overwhelmingly complete going back to the Icelandic census of 1703, the world's first complete national census and now part of UNESCO's registered world heritage, and extending back to before the arrival of the first inhabitants in the 9th century. As constructed, this database makes it possible to create pedigrees connecting the genetic and phenotypic data of any group of people in an anonymized manner.

 

Evelin Schröck (DE), Stanislas du Manoir (FR), Tim Veldman (US), Brigitte Schoell (DE), Johannes Wienberg (DE), Malcolm Andrew Ferguson-Smith (GB), Yi Ning (US), David H. Ledbetter (US), Irit Bar-Am (IL), and Dirk Soenksen (US) developed fluorescent in situ hybridization with DNA probes. This permitted whole-genome scanning by spectral karyotyping, thus allowing instantaneous visualization of defined emission spectra for each human chromosome. All human chromosomes from a cell could thus be identified simultaneously (1302). Note: This technique is called "multicolor spectral karyotyping" or "painting".

Malcolm Andrew Ferguson-Smith (GB) and Vladimir A. Trifonov (RU) used "multicolor spectral karyotyping" to study mammalian karyotype evolution. The chromosome complements (karyotypes) of animals display a great diversity in number and morphology. Against this background, the genomes of all species are remarkably conserved, not only in transcribed sequences, but also in some chromosome-specific non-coding sequences and in gene order. A close examination with chromosome painting shows that this conservation can be resolved into small numbers of large chromosomal segments. Rearrangement of these segments into different combinations explains much of the observed diversity in species karyotypes (401).

 

Juha Kere (FI), Anand K. Srivastava (IN-US), Outi Montonen (FI), Jonathan Zonana (US), Nick Thomas (US), Betsy Ferguson (US), Felix Munoz (US), Delyth Morgan (US), Angus Clarke (GB), Primo Baybayan (US), Ellson Y. Chen (US), Sini Ezer (FI), Ulpu Saarialho-Kere (FI), Albert de la Chapelle (FI), and David Schlessinger (US) described the X-linked anhidrotic ectodermal dysplasia (EDA) gene expressed in keratinocytes, hair follicles, and sweat glands, and in other adult and fetal tissues. They predicted the EDA protein may belong to a novel class with a role in epithelial-mesenchymal signaling (752).

 

Michael P. Yaffe (US), Dai Harata (GB), Fulvia Verde (GB), Mark Eddison (GB), Takashi Toda (GB), and Paul Maxime Nurse (GB) found that microtubules mediate mitochondrial distribution in fission yeast and thus provided the first genetic evidence for the role of microtubules in mitochondrial movement (1605).

 

Shaw-Jye Wu (TW), Lei Ding (CN-US), Jian-Kang Zhu (US), Manabu Ishitani (CO), Liming Xiong (CN-US), Hojoung Lee (KR), Becky Stevenson (US), Jiping Liu (US), Ursula Halfter (US), Cheol-Soo Kim (KR-US), Weiming Shi (US), and Huazhong Shi (CN-US), identified the SOS1, SOS2, SOS3, HOS1, and HOS5 genes whose expression contributes to environmental stress management by Arabidopsis thaliana (579; 687; 688; 886; 1332; 1595; 1599).

 

Da Luo (CN), Rosemary Carpenter (GB), Coral Vincent (DE), Lucy Copsey (GB), and Enrico Coen (GB) isolated a pair of genes, cycloidea (cyc) and dichotoma (dich) that play a key role in establishing dorsoventral asymmetry in Antirrhinum (snapdragon) flowers (911).

 

Li Jia (US), Celia Bonaventura (US), Joseph Bonaventura (US), Jonathan S. Stamler (US), Jerry P. Eu (US), Timothy J. McMahon (US), Ivan T. Demchenko (US), Kim Gernert (US), and Claude A. Piantadosi (US) showed that hemoglobin acts in the nitric acid cycle that aids in oxygen delivery to the tissues. A dynamic cycle exists in which hemoglobin is S-nitrosylated in the lung when erythrocytes are oxygenated, and the NO group is released during arterial–venous transit (707; 1390).

 

Richard Festenstein (GB), Mauro Tolaini (GB), Paola Corbella (GB), Clio Mamalaki (GB), Jenny Parrington (GB), Margaret Fox (GB), Antigoni Miliou (GR), Margaret Jones (GB), and Dimitris Kioussis (GB) discovered that a Locus Control Region is capable of preventing position effect variegation in T cell development (410).

 

Michael S. O'Reilly (US), Lars Holmgren (US), Catherine Chen (US), and Moses Judah Folkman (US) isolated and purified murine angiostatin, which inhibits angiogenesis and primary tumors (1096).

Michael S. O'Reilly (US), Thomas Boehm (US), Yuen Shing (US), Naomi Fukai (US), George Vasios (US), William S. Lane (US), Evelyn Flynn (US), James R. Birkhead (US), Bjorn R. Olsen (US), and Moses Judah Folkman (US) isolated and purified another angiogenesis inhibitor from a murine hemangioendothelioma. This inhibitor they named endostatin (1095).

 

Marc Tessier-Lavigne (US) and Corey Scott Goodman (US) reported that early in development, the framework of brain circuitry—the major neural pathways— is laid down according to strict genetically specified molecular rules (1447).

 

Lawrence C. Katz (US) and Carla Jo Shatz (US) reported that adult neural brain circuitry is superimposed on the juvenile circuitry and emerges through a process of synaptic remodeling. This process requires the functioning of the nervous system—action potentials and synaptic transmission. It is during this period that sensory experience can have a profound effect on brain wiring (740).

 

John N. Feder (US), Andreas Gnirke (US), Winston Thomas (US), Zenta Tsuchihashi (US), David A. Ruddy (US), Alivelu Basava (US), Farid Dormishian (US), Rodolfo Domingo, Jr. (US), Michael C. Ellis (US), Amy Fullan (US), Linda M. Hinton (US), N.L. Jones (US), Bruce E. Kimmel (US), Gregory S. Kronmal (US), Peter Lauer (US), Vincent K. Lee (US), Deborah B. Loeb (US), Felipa A. Mapa (US), Erin E. McClelland (US), Nicole C. Meyer (US), Gabriel A. Mintier (US), N. Moeller (US), Theodore Moore (US), Ebenezer Morikang (US), and Roger K. Wolff (US) discovered a mutation in a gene, now called HFE, which leads to uncontrolled absorption of iron and deposition of this potentially toxic heavy metal in different organs. The result is a disease state called hemochromatosis (394).

 

Richard P. Ebstein (IL), Olga Novick (IL), Roberto Umansky (IL), Beatrice Priel (IL), Yamima Osher (IL), Darren Blaine (IL), Estelle R. Bennett (IL), Lubov Nemanov (IL), Miri Katz (IL), and Robert H. Belmaker (IL) discovered a dopamine D4 receptor (D4DR) exon III polymorphism that is associated with the human personality trait of Novelty Seeking (367).

 

Amanda B. Spurdle (ZA-AU) and Trefor Jenkins (ZA) tested the oral tradition of the black Jews of the South African Lemba tribe that their priests are descendants of Aaron the brother of the biblical Moses. Allele frequencies at four different Y-specific polymorphic loci were analyzed, as well as extended-haplotype frequencies that included data from several loci. Their Y-specific genetic findings are consistent with Lemba oral tradition, and analysis of the history of Jewish people and their association with Africa indicates that the historical facts are not incompatible with theories concerning the origin of the Lemba (1388).

 

Amar J.S. Klar (US) proposed a model for a single gene (RGHT=Right- and r=random-handedness) controlling human hand preference (775).

 

Qing Liu (CN-US) and Gideon Dreyfuss (US) described a novel nuclear structure containing the survival of motor neurons (SMN) protein. They named these structures gems (889).

 

Shingo Murakami (JP), Mutsuhiko Mizobuchi (JP), Yuki Nakashiro (JP), Takashi Doi (JP), Naohito Hato (JP), and Naoaki Yanagihara (JP) detected herpes simplex virus type 1 genomes in 11 of 14 patients (79%) with Bell palsy but not in patients with the Ramsay-Hunt syndrome or in other controls. The nucleotide sequences of the PCR fragments were identical to those of the HSV-1 genome. They concluded that herpes simplex virus type 1 is the major etiologic agent in Bell palsy (1036).

 

David N. Fredericks (US) and David A. Relman (US) proposed a set of molecular guidelines using sequence-based technology for associating microbial pathogens with a disease. The importance of the scientific concordance of evidence in supporting causal associations is emphasized. The Henle-Koch postulates are revisited (439).

 

Scott M. Hammer (US), David A. Katzenstein (US), Michael D. Hughes (US), Holly Gundacker (US), Robert T. Schooley (US), Richard H. Haubrich (US), W. Keith Henry (US), Michael M. Lederman (US), John P. Phair (US), Manette Niu (US), Martin S. Hirsch (US), Thomas C. Merigan (US), J. Brooks Jackson (US), Susan Fiscus (US), Suraiya Rasheed (US), Tarek Elbeik (US), Richard Reichman (US), and Anthony Japour (US) developed the Highly Active Antiretroviral Therapy (HAART) treatment for acquired immunodeficiency syndrome (AIDS) (589; 742). Note: Highly Active Antiretroviral Therapy (HAART) are medications used to treat human immunodeficiency virus (HIV). These medications may also be called antiretroviral drugs (ART), antiretrovirals (ARVs), or anti-HIV drugs.

 

Yu Feng (US), Christopher C. Brode (US), Paul E. Kennedy (US), and Edward A. Berger (US), with the use of a novel functional complementary DNA (cDNA) cloning strategy, identified a cofactor for HIV-1 (human immunodeficiency virus-type 1) fusion and entry (399).

 

Christian P. Larsen (US), Eric T. Elwood (US), Diane Z. Alexander (US), Shannon C. Ritchie (US), Rose Hendrix (US), Carol Tucker-Burden (US), Hong Rae Cho (US), Alejandro Aruffo (US), Diane Hollenbaugh (US), Peter S. Linsley (US), Kevin J. Winn (US), and Thomas C. Pearson (US) reported that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses (828).

 

Len A. Pennacchio (US), Anna-Elina Lehesjoki (FI), Nancy E. Stone (US), Virginia L. Willour (US), Kimmo Virtaneva (FI), Jinmin Miao (FI), Elena d'Amato (FI), Lucia Ramirez (US), Malek Faham (US), Marjaleena Koskiniemi (FI), Janet A. Warrington (US), Reijo Norio (FI), Albert de la Chapelle (FI), David R. Cox (US), and Richard M. Myers (US) found that individuals exhibiting progressive myoclonic epilepsy (EPMI) with mental deterioration contain splice-site and stop-codon mutations for the CYSTATIN B gene (1146). Note: CYSTATIN B is one of a family of cysteine protease inhibitors expressed ubiquitously in the brain.

 

D. Bruce Gleb (US), Guo-Ping Shi (US), Harold A. Chapman (US), and Robert J. Desnick (US) characterized pycnodysostosis as an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature that maps to chromosome 1q21. CATHEPSIN K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the pycnodysostosis region (481). Note: The disease has been named Toulouse-Lautrec syndrome, after the French artist Henri de Toulouse-Lautrec, who may have had the disease.

 

Jay D. Iams (US), Robert L. Goldenberg (US), Paul J. Meis (US), Brian M. Mercer (US), Atef Moawad (US), Anita Das (US), Elizabeth Thom (US), Donald McNellis (US), Rachel L. Copper (US), Francee Johnson (US), and James M. Roberts (US) reported that the risk of spontaneous preterm delivery is increased in women who are found to have a short cervix by vaginal ultrasonography during pregnancy (674).

 

Timothy A. Rockall (GB), Robert F.A. Logan (GB), H. Brendan Devlin (GB), and Timothy C. Northfield (GB) reported that age, shock, comorbidity, diagnosis, major stigmata of recent hemorrhage, and rebleeding were found to be independent predictors of mortality following acute upper gastrointestinal hemorrhage (1245).

 

Andrea Kurz (US), Daniel I. Sessler (US), and Rainer Lenhardt (US) showed that hypothermia itself may delay healing and predispose patients to wound infections. Maintaining normothermia intraoperatively is likely to decrease the incidence of infectious complications in patients undergoing colorectal resection and to shorten their hospitalizations (815).

 

Randas J. Batista (BR), Jose L.V. Santos (BR), Noriaki Takeshita (BR), Lise Bocchino (BR), Paulo N. Lima (BR), and Marco A. Cunha (BR) reported a radical new surgical technique (partial left ventriculectomy) to treat a common form of heart failure in people with enlarged hearts. When the heart becomes diseased, it sometimes dilates or swells. The contractions become sluggish and the left ventricle is unable to squeeze out enough blood. Blood backs up in the heart and the lungs, resulting in congestive heart failure. Batista's idea was to cut a swath out of the left ventricle and sew the chamber back together, thereby reducing its size and increasing its efficiency (100).

 

Michael B. Sporn (US) reported that distant settlements of tumor cells—metastases—are the cause of 90% of human cancer deaths (1386).

 

James Patrick Allison (US), Dana R. Leach (US), Matthew F. Krummel (US), Andrea Van Elsas (NL), Arthur A. Hurwitz (US), Sergio A. Quezada (US), Karl S. Peggs (US), Michael A. Curran (US), Welby Montalvo (US), Hideo Yagita (US), Jedd D. Wolchok (US), F. Stephen Hodi (US), Jeffrey S. Weber (US), Walter J. Urba (US), Caroline Robert (FR), Steven J. O'Day (US), Axel Hoos (US), Rachel Humphrey (CA), David M. Berman (US), Nils Lonberg (US), Alan J. Korman (US), and Padmanee Sharma (US) discovered and developed a monoclonal antibody therapy that prompts the immune system to combat cancer. By blocking a protein that normally restrains the body’s natural ability to attack tumor cells, they devised a fundamentally new strategy for treating malignancies. Because this approach targets immune cells rather than specific tumors, it holds great promise to thwart diverse cancers (304; 836; 1196; 1327; 1328; 1502; 1584).

Hua Han (JP), Takashi Nomura (JP), Tasuku Honjo (JP), and Takeshi Tsubata (JP) found that p27Kip1 is likely to be a crucial target molecule of the negative signaling via sIg and the positive signaling via CD40 essential for T cell‐dependent immune responses (590). Note: The p27/kip1 (p27) tumor suppressor inhibits cyclin/cyclin-dependent kinase ( CDK) complexes and halts cell cycle progression.

Gordon J. Freeman (US), Andrew J. Long (US), Yoshiko Iwai (JP), Karen Bourque (US), Tatyana Chernova (US), Hiroyuki Nishimura (JP), Lori J. Fitz (US), Nelly Malenkovich (US), Taku Okazaki (JP), Michael C. Byrne (US), Heidi F. Horton (US), Lynette Fouser (US), Laura Carter (US), Vincent Ling (US), Michael R. Bowman (US), Beatriz M. Carreno (US), Mary Collins (US), Clive R. Wood (US), and Tasuku Honjo (JP) discovered that PD-L1 (the ligand of PD-1) expression on nonlymphoid tissues and its potential interaction with PD-1 (a type I transmembrane protein) may subsequently determine the extent of immune responses at sites of inflammation (441). Note: Today this concept is often referred to as immune checkpoint inhibition.

Ziming Du (US), Malak Abedalthagafi (US), Ayal A. Aizer (US), Allison R. McHenry (US), Heather H. Sun (US), Mark-Anthony Bray (US), Omar Viramontes (US), Revaz Machaidze (US), Priscilla K. Brastianos (US), David A. Reardon (US), Ian F. Dunn (US), Gordon J. Freeman (US), Keith L. Ligon (US), Anne E. Carpenter (US), Brian M. Alexander (US), Nathalie Y. Agar (US), Scott J. Rodig (US), Elizabeth M. Bradshaw (US), and Sandro Santagata (US) showed that cancer cells hijack the programmed death-1 (PD-1) pathway, turning off the immune system. These findings will hopefully translate into new treatments that free the immune system to fight tumors (349).

David A. Reardon (US), Prafulla C. Gokhale (US), Sarah R. Klein (US), Keith L. Ligon (US), Scott J. Rodig (US), Shakti H. Ramkissoon (US), Kristen L. Jones (US), Amy Saur Conway (US), Xiaoyun Liao (US), Jun Zhou (US), Patrick Y. Wen (US), Annick D. Van Den Abbeele (US), F. Stephen Hodi (US), Lei Qin (US), Nancy E. Kohl (US), Arlene Helen Sharpe (US), Glenn Dranoff (US), and Gordon J. Freeman (US) demonstrated that systemic administration of CTLA-4, PD-L1, and PD-1 inhibitors can improve survival for intracranial glioblastoma tumors (1218). Note: CTLA4 or CTLA-4, also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses, PD-L1 is programmed death-ligand 1, and PD-1 is programmed death 1.

Todd A. Triplett (US), Kendra C. Garrison (US), Nicholas Marshall (US), Moses Donkor (US), John Blazeck (US), Candice Lamb (US), Ahlam Qerqez (US), Joseph D. Dekker, Yuri Tanno (US), Wei-Cheng Lu (US), Christos S. Karamitros (US), Kyle Ford(US), Bing Tan (US), Xiaoyan M. Zhang (US), Karen McGovern (US), Silvia Coma (US), Yoichi Kumada (US), Mena S. Yamany (US), Enrique Sentandreu, George Fromm (US), Stefano Tiziani (US), Taylor H. Schreiber (US), Mark Manfredi (US), Lauren I.R. Ehrlich (US), Everett Stone (US), and George Georgiou (US) developed an enzyme therapy that stimulates a human immune system abnormally suppressed by cancer cells, unleashing the body's power to fight back against the disease.

Cancer manipulates the immune system to support tumor growth by sending signals to the immune cells to turn off. These researcher's treatment degrades that signal and allows the immune system to fight the cancer. The enzyme, PEG-KYNase, does not directly kill cancer cells but instead empowers the immune system to eradicate unwanted cells on its own. PEG-KYNase is designed to degrade kynurenine, a metabolite produced by numerous tumors that suppresses the immune system. Kynurenine acts as a roadblock to immune cells thereby impeding normal surveillance; PEG-KYNase removes this obstacle (1474).

 

Maybeth Howard (US), Raymond A. Frizzell (US), and David M. Bedwell (US) reported that 5% of the cases of severe cystic fibosis contain a premature stop mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Two common, disease−associated (cystic fibrosis) stop mutations can be suppressed by treating cells with low doses of the aminoglycoside antibiotic G−418. Another aminoglycoside, gentamicin, also promoted the expression of full−length cystic fibrosis transmembrane conductance regulator. These results suggest that treatment with aminoglycosides may provide a means of restoring cystic fibrosis transmembrane conductance regulator function in cystic fibosis patients with this class of mutation (656). Note: Codon skipping using antibiotics is now a mainstream idea that was first shown in this study.

 

Johann Cunningham (CA), Walley J. Temple (CA), Philip Mitchell (CA), James A. Nixon (CA), Roy M. Preshaw (CA), and Neil A. Hagen (CA) noted that standard open hernia repair was associated with long-term pain and numbness in more than 10% of patients. They also concluded that the most common type of pain following hernia surgery is somatic pain, which can be reproduced on pressure (302).

Torben Callesen (DK), Karsten Bech (DK), and Henrik Kehlet (DK) concluded that chronic pain was a significant problem after open groin hernia surgery and may be predicted by the severity of early post-operative pain (195).

 

Alfred Cuschieri (GB), Peter M. Fayers (GB), John W.L. Fielding (GB), John Craven (JM), John Bancewicz (GB), Vickram Joypaul (GB), Paula Cook (GB), Simon Weeden (GB), and Matthew R. Sydes (GB) showed that D2 gastric resections are associated with higher morbidity and mortality than D1 resections and with similar 5-year survival. The higher morbidity and mortality is mainly related to performing a pancreato-splenectomy (305; 306). Note: D1 and D2 refer to lymph nodes N1 and N2.

Muhammed Ashraf Memon (AU),Manjunath S. Subramanya (AU),Shahjahan Khan (AU),Md Belal Hossain (AU),Emma Osland (AU),and Breda Memon (AU) performed a meta-analysis of D1 and D2 removals associated with gastric resection to determine efficacy. They found that D2 gastrectomy was associated with an increased complication rate and no improvement in 5-year survival compared with D1 gastrectomy (989).

 

Jeremy M.T. Perkins (GB), Jack Collin (GB), Terence S. Creasy (GB), E. W.L. Fletcher (GB), and Peter J. Morris (GB), in randomized trials, showed that exercise training confers a greater improvement in claudication and maximum walking distance than percutaneous transluminal angioplasty (PTA), especially in patients with disease confined to the superficial femoral artery (1148).

Mark R. Whyman (GB), F. Gerald R. Fowkes (GB), E. M.G. Kerracher (GB), Ian N. Gillespie (GB), Amanda J. Lee (GB), Edward Housley (GB), and C. Vaughan Ruckley (GB) found that after two years of percutaneous transluminal angioplasty, patients had less extensive disease than medically treated patients, but this did not translate into a significant advantage in terms of improved walking or quality of life. There are important implications for patient management and future clinical research (1572).

Roger M. Greenhalgh (GB), Jill J.F. Belch (GB), Louise C. Brown (GB), Peter A. Gaines (GB), L. Gao (GB), J.A. Reise (GB), Simon G.Thompson (GB), and Mimic Trial Participants determined that percutaneous transluminal angioplasty confers adjuvant benefit over supervised exercise and best medical therapy in terms of walking distances and ankle brachial pressure index 24 months after percutaneous transluminal angioplasty in patients with stable mild to moderate intermittent claudication (537).

Fayyaz Ali Khan Mazari (GB), Junaid A. Khan (GB), Daniel Carradice (GB), Nehemiah Samuel (GB), Mohd Norhisham A. Abdul Rahman (GB), Sumit Gulati (GB), Hai Liang Darren Lee (GB), Tapan A. Mehta (GB), Peter T. Collum (GB), and Ian C. Chetter (GB) determined that for patients with intermittent claudication due to femoropopliteal disease, percutaneous transluminal angioplasty, supervised exercise program, and percutaneous transluminal angioplasty plus supervised exercise program were all equally effective in improving walking distance and quality of life after 12 months (964)

 

The Centers for Disease Control (CDC) reported morbidity data for the weeks ending June 8, 1946, and June 22, 1996, and described changes since 1946 both in the procedures for conducting surveillance and in the incidence of selected diseases (3).

The Council of State and Territorial Epidemiologists (CSTE) added prevalence of cigarette smoking to the list of conditions designated as reportable by states to CDC (2).

 

Ronald Lanner (US) reported how species participate in a pine–corvid mutualism. Lanner focused particularly upon the white-bark pine–Clark’s Nutcracker relationship. Clark’s Nutcracker Nucifraga columbiana has a beak large enough to open white-bark pinecones, which it stores underground in caches for later use. A single nutcracker has been known to harvest 129,000 seeds in one year, of which 76% were stored in caches. Where western pines are growing in an isolated clump, they indicate a cache, which a corvid never recovered (826). Note: Corvidae is a cosmopolitan family of oscine passerine birds that contains the crows, ravens, rooks, jackdaws, jays, magpies, treepies, choughs, and nutcrackers

 

S. Blair Hedges (US), Patrick H. Parker (US), Charles G. Sibley (US), and Sudhir Kumar (US) used a comprehensive set of genes that exhibit a constant rate of substitution to estimate the time at which avian and mammalian orders diverged. Their estimates of divergence times averaged about 50-90% earlier than those predicted by the classical methods, and show that the timing of these divergences coincides with the Mesozoic fragmentation of emergent land areas. This suggests that continental breakup may have been an important mechanism in the ordinal diversification of birds and mammals some 100 million years ago (614).

 

Patrick E. McGovern (US), Donald L. Glusker (US), Lawrence J. Exner (US), and Mary M. Voigt (US) found wine jars at Hajji Firuz Tepe in the Northern Zagros Mountains of Iran. The material was dated to c. 5400-5000 B.C.E. (972).

 

Descriptions of Old World cutaneous leishmaniasis, known as oriental sore, are found on tablets in the library of King Ashurbanipal from the 7th century BCE Some of these descriptions are most likely derived from earlier texts of 1500 to 2500 B.C.E. (935).

 

John Gatesy (US), Cheryl Hayashi (US), Mathew A. Cronin (US), and Peter Arctander (DK) provided molecular evidence that cetaceans are close relatives of hippopotamid artiodactyls (473). This is the origin of evidence for the so-called Whippo hypothesis (whale/hippopotamus).

 

Jean-Marie Chauvet (FR), Éliette Brunel-Deschamps (FR), and Christian Hillaire (FR) discovered the Chauvet-Pont-D’Arc cave near Ardéche in Southeast France. This area had been occupied by Paleolithic man of the Aurignacian culture—the first modern humans in Europe. The cave contains magnificent drawings of mammoths, rhinoceroses, lions, and cave bears dated to between 28,340 and 30,410 B.C.E. These drawings are of unsurpassed sophistication (173).

 

1997

“Time is passing very fast; remembering may help against the uneasiness thereby evoked, remembering with gratitude.” Erwin Schindler (1290).

 

"The role of experimental science is to break the so-called laws of nature." Steen Malte Willadsen (DK-GB-CA-US) (790)

 

Paul Delos Boyer (US) and John E. Walker (GB) for their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP) and Jens Christian Skou (DK) for the first discovery of an ion-transporting enzyme, Na+, K+-ATPase shared the Nobel Prize in Chemistry.

 

Stanley Benjamin Prusiner (US) was awarded the Nobel Prize in Physiology or Medicine for his discovery of prions—a new biological principle of infection.

 

Christopher P. McKay (US) reported that one meteorite from Mars contains evidence of a primitive Martian environment containing water and possibly life (975).

 

C. Page Chamberlain (US), Joel D.Blum (US), Richard T. Holmes (US), Xiahong Feng (US), Thomas W. Sherry (US), and Gary R. Graves (US) found that isotopes of hydrogen, carbon, and strontium could be used as markers with the potential for locating the breeding origins of migratory bird species on their winter areas, and for quantifying the degree of mixing of breeding populations on migratory and wintering sites (225).

 

Darryl E. Granger (US), James W. Kirchner (US), and Robert C. Finkel (US) developed the method whereby concentrations of the cosmogenic radionuclides 26Al and 10Be in white quartz can be used to date sediment burial (529). Note: This method is helping to more accurately date paleontological sites.

 

K. Ulrich Wendt (DE), Karl Poralla (DE), and Georg E. Schulz (DE) reported the structure and function of squalene-hopene cyclase, a membrane embedded protein (1562).

 

David P. King (US), Yaliang Zhao (US), Ashvin M. Sangoram (US), Lisa D. Wilsbacher (US), Minoru Tanaka (JP), Marina P. Antoch (US), Thomas D. L. Steeves (US), Martha Hotz Vitaterna (US), Jon M. Kornhauser (US), Phillip L. Lowrey (US), Fred W. Turek (US), and Joseph S. Takahashi (US) used positional cloning to identify the circadian Clock gene in mice. Clock is a large transcription unit with 24 exons spanning approximately 100,000 bp of DNA from which transcript classes of 7.5 and approximately 10 kb arise. CLOCK represents the second example of a PAS domain-containing clock protein (besides Drosophila PERIOD), which suggests that this motif may define an evolutionarily conserved feature of the circadian clock mechanism (761) .

 

Kai Simons (DE) and Elina Ikonen (FI) suggested that cell membranes contain rafts, relatively small structures (~ 50 nm) enriched in cholesterol and sphingolipids within which associated proteins are likely to be concentrated (1344).

 

Di Xia (US), Chang-An Yu (US), Hoeon Kim (US), Jia-Zhi Xia (US), Anatoly M. Kachurin (US), Li Zhang (US), Linda Yu (US), and Johann Deisenhofer (US) reported the crystal structure of the cytochrome bcl complex (a membrane embedded protein) from bovine heart mitochondria (1597).

 

Samuel E.Butcher (US), Thorsten Dieckmann (US), and Juli Feigon (US) used nuclear magnetic resonance (NMR) imagery to investigate and supplement crystal structures of an isolated tetraloop-receptor motif in RNA (188).

 

David A. Sinclair (US) and Leonard Guarente (US) showed that nucleolar changes are likely due to the accumulation of extrachromosomal rDNA circles (ERCs) in old cells and that, in fact, ERCs cause aging in yeast cells (1345).

Matt Kaeberlein (US), Mitch McVey (US), and Leonard Guarente (US) showed that SIR-2 regulates yeast aging (727). Note: The sirtuins are highly conserved enzyme homologues of the yeast SIR-2, with activities of NAD+ dependent deacetylase and/or mono ADP ribosyltransferase. A long line of evidence has implicated sirtuins in regulating the aging process of yeast, worms, flies, and rodents.

Heidi A. Tissenbaum (US) and Leonard Guarente (US) showed that in Caenorhabditis elegans SIR-2 overexpression extends lifespan (1460).

Shin-ichiro Imai (US), Christopher M. Armstrong (US), Matt Kaeberlein (US), and Leonard Guarente (US) proved that SIR2 is an NAD+ dependent deacetylase (677).

Haim Y. Cohen (US), Christine Miller (US), Kevin J. Bitterman (US), Nathan R. Wall (US), Brian Hekking (US), Benedikt Kessler (US), Konrad T. Howitz (US), Myriam Gorospe (US), Rafael de Cabo (US), David A. Sinclair (US) showed that SIR-1 is involved in the calorie restriction response which promotes mammalian cell survival (264). Note: Caloric restriction delays yeast chronological aging by remodeling carbohydrate and lipid metabolism, altering peroxisomal and mitochondrial functionalities, and postponing the onsets of apoptotic and liponecrotic modes of regulated cell death.

Blanka Rogina (US) and Stephen L. Helfand (US) showed that SIR-2 overexpression extends the lifespan of Drosophila melanogaster (1247).

Matt Kaeberlein (US) and Brian K. Kennedy (US) challenged the role of yeast sirtuins in regulating the effect of calorie restriction on yeast lifespan (726).

Camilla Burnett (GB), Sara Valentini (GB), Filipe Cabreiro (GB), Martin Goss (GB), Milán Somogyvári (HU), Matthew D. Piper (GB), Matthew Hoddinott (GB), George L. Sutphin (US), Vid Leko (US), Joshua J. McElwee (GB), Rafael P. Vazquez-Manrique (FR), Anne-Marie Orfila (FR), Daniel Ackerman (GB), Catherine Au (GB), Giovanna Vinti (GB), Michèle Riesen (GB), Ken Howard (GB), Christian Neri (FR), Antonio Bedalov (US), Matt Kaeberlein (US), Csaba Sőti (HU), Linda Partridge (GB), and David Gems (GB) challenged the role of worm and fly sirtuins in regulating lifespan (186).

Yariv Kanfi (IL), Shoshana Naiman (IL), Gail Amir (IL), Victoria Peshti (IL), Guy Zinman (US), Liat Nahum (IL), Ziv Bar-Joseph (US), and Haim Y. Cohen (IL) provided the first proof for a mammalian sirtuin (SIRT-6) in regulating lifespan (735).

 

Makoto Kuro-o (JP), Yutaka Matsumura (JP), Toshihiro Utsugi (JP), Yoshio Ohyama (JP), Masahiko Kurabayashi (JP), Tadashi Kaname (JP), Eisuke Kume (JP), Hitoshi Iwasaki (JP), Akihiro Iida (JP), Takako Shiraki-Iida (JP), Satoshi Nishikawa (JP), Ryozo Nagai (JP), and Yo-ichi Nabeshima (JP) identified and characterized the klotho gene as coding for klotho, a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in aging (813).

Claudio Franceschi (IT), Paolo Garagnani (IT), Giovanni Vitale (IT), Miriam Capri (IT), and Stefano Salvioli (IT) found that aging is associated with a progressive increase in inflammatory alterations in the brain and other organs, a process that has been dubbed "inflammaging." Biomarkers of inflammation are robust predictors of morbidity and mortality in older humans (434).

 Lei Zhu (US), Liana R. Stein (US), Daniel Kim (US), Kaitlyn Ho (US), Gui-Qiu Yu (US), Lihong Zhan (US), Tobias E. Larsson (SE), and Lennart Mucke (US) demonstrated that reducing klotho levels selectively in the choroid plexus disrupts the barrier between the immune system and the brain and promotes neuroinflammation (1634). Note: Global depletion of klotho accelerates aging, whereas klotho overexpression counteracts aging-related impairments.

Correne A. DeCarlo (CA), Holly A. Tuokko (CA), Dorothy Williams (CA), Roger A. Dixon (CA), and Stuart W. S. MacDonald (CA) favor a multivariate and mechanistic "BioAge" approach saying that it will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline (325).

 

Didier Casane (FR), Stephanie Boissinot (US), Benny H.J. Chang (US), Lawrence C. Shimmin (US), and Wen-Hsiung Li (CN-US) sequenced three argininosuccinate-synthetase-processed pseudogenes (PsiAS-A1, PsiAS-A3, PsiAS-3) and their noncoding flanking sequences in human, orangutan, baboon, and colobus. Their data showed that these pseudogenes were incorporated into the genome of the Old World monkeys after the divergence of the Old World and New World monkey lineages. The pseudogene flanking regions are long-standing unconstrained DNA sequences, whereas the pseudogenes were relieved of selection on their coding functions only around 30-40 million years ago (211). Note: Matthew White Ridley (GB) describes these pseudogenes as, “They now lie on the bottom of a genomic ocean, gradually growing rustier (that is accumulating more mutations) until they no longer even resemble the gene they once were” (1236).

 

Mitsuru Akita (JP), Erik Nielsen (US), and Kenneth Keegstra (US) noted that transport of cytoplasmically synthesized proteins into chloroplasts uses import machinery present in the envelope membranes. They proposed that each envelope membrane contains distinct translocation complexes and that a portion of these interact to form contact sites even in the absence of precursor proteins (24).

Erik Nielsen (US), Mitsuru Akita (JP), Jennifer Davila-Aponte (US), and Kenneth Keegstra (US) found that cytoplasmically synthesized precursors interact with translocation components in both the outer and inner envelope membranes during transport into chloroplasts (1078).

Diane T. Jackson (US), John E. Froehlich (US), and Kenneth Keegstra (US) proposed that the stromal protein Tic 110 might be involved in the recruitment of stromal factors, possibly molecular chaperones, to the translocation apparatus during protein import (697).

 

Bao Cai Tan (US), Steven H. Schwartz (US), Jan A.D. Zeevaart (NL-US), Donald R. McCarty (US), Maarten Koornneef (NL), and Karen M. Léon-Kloosterziel (NL) discovered that there is one universal pathway of abscisic acid biosynthesis (796; 1436; 1625).

 

Felipe Guhl (CO), Carlos Jaramillo (CO), Roxana Yockteng (CO), Gutavo A. Vallejo (US), and Felipe Cardenas-Arroyo (CO) detected Trypanosoma cruzi DNA in the heart and esophagus of mummified bodies from Peru and Northern Chile. These mummies were dated at 2000 B.C.E. to A.D. 1400 (565).

 

Tina Martino (CA), Feige Kaplan (CA), Stanley M. Diamond (CA), Ariell Oppenheim (IL), and Charles Robert Scriver (CA) discovered a newly identified mutation of thalassemia (948).

 

Michael A. Klein (CH), Rico Frigg (CH), Eckhard Flechsig (CH), Alex J. Raeber (CH), Ulrich Kalinke (CH), Horst Bluethmann (CH), Frank Bootz (CH), Marc Suter (CH), Rolf Martin Zinkernagel (CH-US), and Adriano Aguzzi (CH) concluded that differentiated B cells of the lymphoreticular system are crucial for neuroinvasion by scrapie, regardless of the specificity of their receptors (777).

 

Lita M. Proctor (US), and Jed A. Fuhrman (US) have shown that virus infection could be a significant mechanism of mortality in marine prokaryotes (444; 1186).

 

Jan C. de Jong (NL), Eric C.J. Claas (NL), Albert D.M.E.Osterhaus (NL), Robert G. Webster (US), and Wilina L. Lim (CN) identified an influenza A virus of the H5N in a human patient, raising discussions about its potential to spark a new human influenza pandemic (323). Note: Viruses carrying the H1N1, H2N2 and H3N2 combinations were responsible for the Spanish flu of 1918, the Asian flu in 1957 and Hong Kong flu in 1968, respectively (1553).

 

John W. Mellors (US), Alvaro Munoz (US), Janis V. Giorgi (US), Joseph B. Margolick (US), Charles J. Tassoni (US), Phalguni Gupta (US), Lawrence A. Kingsley (US), John A. Todd (US), Alfred J. Saah (US), Roger Detels (US), John P. Phair (US), and Charles R. Rinaldo, Jr. (US) determined that plasma viral load strongly predicts the rate of decrease in CD4+ lymphocyte count and progression to AIDS and death, but the prognosis of HIV-infected persons is more accurately defined by combined measurement of plasma HIV-1 RNA and CD4+ lymphocytes (985).

 

Frederick R. Blattner (US), Guy Plunkett, III (US), Craig A. Bloch (US), Nicole T. Perna (US), Valerie Burland (US), Monica Riley (US), Julio Collado-Vides (US), Jeremy D. Glasner (US), Christopher K. Rode (US), George F. Mayhew (US), Jason Gregor (US), Nelson Wayne Davis (US), Heather A. Kirkpatrick (US), Michael A. Goeden (US), Deb J. Rose (US), Robert Mau (US), and Ying Shao (US) determined the 4,639,221-base pair sequence of Escherichia coli K-12. Of its 4,288 protein-coding genes annotated, 38 percent have no attributed function. The genome contains insertion sequence (IS) elements, phage remnants, and many other patches of unusual composition indicating genome plasticity through horizontal transfer (134).

 

Jean-Francois Tomb (US), Owen White (US), Anthony R. Kerlavage (US), Rebecca A. Clayton (US), Granger G. Sutton (US), Robert D. Fleischmann (US), Karen A. Ketchum (US), Hans-Peter Klenk (US), Steven Gill (US), Brian A. Dougherty (US), Karen E. Nelson (US), John Quackenbush (US), Lixin Zhou (US), Ewen F. Kirkness (US), Scott Peterson (US), Brendan Loftus (US), Delwood L. Richardson (US), Robert J. Dodson (US), Hanif G. Khalak (US), Anna Glodek (US), Keith McKenney (US), Lisa M. Fitzegerald (US), Norman Lee (US), Mark D. Adams (US), Erin K. Hickey (US), Douglas E. Berg (US), Jeanine D. Gocayne (US), Teresa R. Utterback (US), Jeremy D. Peterson (US), Jenny M. Kelley (US), Matthew D. Cotton (US), Janice M. Weidman (US), Claire Fujii (US), Cheryl Bowman (US), Larry Wathey (US), Erik Wallin (US), William S. Hayes (US), Mark Borodovsky (RU-US), Peter D. Karp (US), Hamilton Othanel (US), Claire M. Fraser (US), and John Craig Venter (US) determined the complete genome sequence of the bacterium Helicobacter pylori (strain 26695) (1466).

 

Douglas R. Smith (US), Lynn A. Doucette-Stamm (US), Craig Deloughery (US), Hongmei Lee (US), JoAnn Dubois (US), Tyler Aldredge (US), Romina Bashirzadeh (US), Derron Blakely (US), Robin Cook (US), Katie Gilbert (US), Dawn Harrison (US), Lieu Hoang (US), Pamela Keagle (US), Wendy Lumm (US), Bryan Pothier (US), Dayong Qiu (US), Rob Spadafora (US), Rita Vicaire (US), Ying Wang (US), Jamey Wierzbowski (US), Rene Gibson (US), Nilofer Jiwani (US), Anthony Caruso (US), David Bush (US), Hershel Safer (US), Donivan Patwell (US), Shashi Prabhaker (US), Steve McDougall (US), George Shimer (US), Anil Goyal (US), Shmuel Pietrokowski (US), George Church (US), Charles J. Daniels (US), Jen-i Mao (US), Phil Rice (US), Joek Nolling (US), and John N. Reeve (US) determined the complete genome sequence of Methanobacterium thermoautotrophicum delta H: functional analysis and comparative genomics (1361). Note: This was the first Archaea to have its genome completely sequenced

 

Claire M. Fraser (US), Sherwood Casjens (US), Wai Mun Huang (US), Granger G. Sutton (US), Rebecca A. Clayton (US), Raju Lathigra (US), Owen White (US), Karen A. Ketchum (US), Robert J. Dodson (US), Erin K. Hickey (US), Michelle Gwinn (US), Brian A. Dougherty (US), Jean-Francois Tomb (US), Robert D. Fleischmann (US), Delwood L. Richardson (US), Jeremy D. Peterson (US), Anthony R. Kerlavage (US), John Quackenbush (US), Steven Salzberg (US), Mark Hanson (US), Rene van Vugt (US), Nanette Palmer (US), Mark D. Adams (US), Jeannine D. Gocayne (US), Janice F. Weidman (US), Teresa R. Utterback (US), Larry Watthey (US), Lisa A. McDonald (US), Patricia Artiach (US), Cheryl L. Bowman (US), Stacey Garland (US), Claire Y. Fujii (US), Matthew D. Cotton (US), Kurt Horst (US), Kevin Roberts (US), Bonnie Hatch (US), Hamilton Othanel (US), and John Craig Venter (US) determined the genomic sequence of the Lyme disease spirochete, Borrelia burgdorferi (435).

 

Hans-Peter Klenk (US), Rebecca A. Clayton (US), Jean-Francois Tomb (US), Owen White (US), Karen E. Nelson (US), Karen A. Ketchum (US), Robert J. Dodson (US), Michelle Gwinn (US), Erin K. Hickey (US), Jeremy D. Peterson (US), Delwood L. Richardson (US), Anthony R. Kerlavage (US), David E. Graham (US), Nikos C. Kyrpides (US), Robert D. Fleischmann (US), John Quackenbush (US), Norman H. Lee (US), Granger G. Sutton (US), Steven Gill (US), Ewen F. Kirkness (US), Brian A. Dougherty (US), Keith McKenney (US), Mark D. Adams (US), Brendan Loftus (US), Scott Peterson (US), Claudia I. Reich (US), Leslie K. McNeil (US), Jonathan H. Badger (US), Anna Glodek (US), Lixin Zhou (US), Ross Overbeek (US), Jeannine D. Gocayne (US), Janice F. Weidman (US), Lisa McDonald (US), Teresa Utterback (US), Matthew D. Cotton (US), Tracy Spriggs (US), Patricia Artiach (US), Brian P. Kaine (US), Sean M. Sykes (US), Paul W. Sadow (US), Kurt P. D’Andrea (US), Cheryl Bowman (US), Claire Fujii (US), Stacey A. Garland (US), Tanya M. Mason (US), Gary J. Olsen (US), Claire M. Fraser (US), Hamilton Othanel (US), Carl R. Woese (US), and John Craig Venter (US) determined the complete genome sequence of the hyperthermophilic, sulphate-reducing archaeon Archaeoglobus fulgidus (778).

 

Frank Kunst (FR), Naotake Ogasawara (JP), Ivan Moszer (FR), Alessandra M. Albertini (IT), G. Alloni (), Vasco Azevedo (BR), Michela G. Bertero (IT), Philippe Bessières (FR), Alexander Bolotin (FR), Stefan Borchert (DE), Rainer Borriss (DE), Laurent Boursier (FR), Alain Brans (BE), M. Richard Braun (), S. C. Brignell (), Sierd Bron (NL), Sophie Brouillet (FR), Carlo V. Bruschi (IT), Robert Caldwell (), Veronique Capuano (FR), Noel M. Carter (GB), Soo-Keun Choi (JP), Jean-Jacques Codani (FR), Ian F. Connerton (GB), Nicola J. Cummings (GB), Richard A. Daniel (GB), Francois Denizot (FR), Kevin M. Devine (GB), Andreas Düsterhöft (DE), S. Dusko Ehrlich (HR-FR), Peter T. Emmerson (GB), Karl Dieter Entian (DE), Jeffery Errington (GB), Céline Fabret (FR), Eugenio Ferrari (US), David Foulger (GB), Christian C. Fritz (GB), Masaya Fujita (JP-US), Yasutaro Fujita (JP), Shoichi Fuma (JP), Alessandro Galizzi (IT), Nathalie Galleron (FR), Sa-Youl Ghim (JP), Philippi Glaser (FR), André Goffeau (FR), Eric J. Golightly (US), Guido Grandi (IT), G. Guiseppi (), B. J. Guy (), Keiko Haga (JP), Jacques Haiech (FR), Colin R. Harwood (GB), Alain Hénaut (FR), Helmut Hilbert (DE), Siger Holsappel (NL), Seiyu Hosono (JP), Marie-Francoise Hullo (FR), Mitsuhiro Itaya (JP), Louis Jones (FR), Bernard Joris (FR), Dimitri Karamata (CH), Yasuhiro Kasahara (JP), Maude Klaerr-Blanchard (FR), C. Klein (), Yasuo Kobayashi (JP), P. Koetter (), Gregory Koningstein (NL), Susanne Krogh (DK), Miyuki Kumano (JP), Kei Kurita (JP), Alla Lapidus (US), S. Lardinois (), J. Lauber (), Vladimir Lazarevic (CH), S.-M. Lee (JP), Alain Levine (FR), Hsi Liu (JP), S. Masuda (), Catherine Mauël (CH), Claudine Médigue (FR), N. Medina (), Rafael P. Mellado (ES), M. Mizuno (), D. Moestl (), S. Nakai (), Michiel A. Noback (NL), David Noone (US), M. O'Reilly (), K. Ogawa (JP), Atushi Ogiwara (JP), Bauke Oudega (JP), Seung-Hwan Park (JP), Victor Parro (ES), Thomas M. Pohl (DE), Daniel Portetelle (BE), Steffen Porwollik (US), A. M. Prescott (), Elena Presecan (RO), Petar Pujic (HR), B. Purnelle (), Georges Rapoport (FR), M. Rey (), S. Reynolds (), Michael Rieger (DE), Carlo Rivolta (CH), Eduardo Rocha (PT-FR), B. Roche (), M. Rose (), Yoshito Sadaie (JP), Tsutomu Sato (JP), Elizabeth Scanlan (IE), S. Schleich (), R. Schroeter (), F. Scoffone (), Junichi Sekiguchi (JP), Agnieszka Sekowska (PL-FR), Simone J. Séror (FR), P. Serror (), Byung-Sik Shin (US), Blazenka Soldo (CH), Alexei Sorokin (FR), E. Tacconi (), Tatsuya Takagi (JP), Hideo Takahashi (JP), K. Takemaru (JP), Masayuki Takeuchi (JP), Atsuo Tamakoshi (JP), Toshihiro Tanaka (JP), Peter Terpstra (NL), Angelo Tognoni (CH), Shigeki Uchiyama (JP), Horoshi Yoshikawa (JP), and Antoine Danchin (FR) characterized and analyzed the genome of the bacterium Bacillus subtilis strain 168. Its genome of 4,214,810 base pairs comprises 4,100 protein-coding genes. The genome contains at least ten prophages or remnants of prophages, indicating that bacteriophage infection has played an important evolutionary role in horizontal gene transfer (811).

 

Kenneth H. Wolfe (IE) and Denis C. Shields (IE) suggested that the modern Saccharomyces cerevisiae genome originated from a whole-genome duplication (1586).

 

Xin-zhuan Su (US), Laura A. Kirkman (US), Hisashi Fujioka (JP-US), and Thomas E. Wellems (US) identified a gene, cg2, which makes Plasmodium falciparum resistant to chloroquine, the former mainstay, low-cost anti-malarial drug (1413).

 

Bonnie L. Bassler (US), Miriam Wright (US), Richard E. Showalter (US), Michael R. Silverman (US), E. Peter Greenberg (US), Ann M. Stevens (US), W. Clairborne Fuqua (US), and Stephen C. Winans (US) made key insights into the mechanism of 'quorum sensing', a process whereby bacteria communicate with each other and which offers innovative ways to interfere with bacterial pathogens or to modulate the microbiome for health applications (96-99; 451).

 

Wilfrid Dieryck (FR), Josée Pagnier (FR), Claude Poyart (FR), Michael C. Marden (FR), Véronique Gruber (FR), Philippe Bournat (FR), Sylvie Baudino (FR), and Bertrand Mérot (FR) reported the production of human hemoglobin, useful as a blood substitute, by transgenic tobacco plants (337).

 

Daniel K.X. Chong (US), W.K. Roberts (US), Takeshi Arakawa (US), Katalin Illes (US), Georgy Bagi (US), Charles W. Slattery (US), and William H.R. Langridge (US) reported the production of human b-casein by transgenic potato plants (251).

 

Laurence K. Grill (US) reported the production of gamma-interferon by transgenic tobacco plants. Gamma-interferon is potentially useful as a phagocyte activator (541).

 

Laurence K. Grill (US) reported the production of alpha-galactosidase by transgenic tobacco plants. This lysosomal enzyme has potential as a treatment for Fabry disease (541).

 

Laurence K. Grill (US) reported the production of NP1 defensin by transgenic tobacco plants (541). Note: NP1 is an antibiotic.

 

Bob B. Buchanan (US), Catherine Adamidi (US), Rosa M. Lozano (ES), Boihon C. Yee (US), Mitsuru Momma (JP), Karoly Kobrehel (FR), Richard W. Ermel (US), and Oscar L. Frick (US) found that thioredoxin, a ubiquitous 12-kD regulatory disulfide protein, will reduce disulfide bonds of allergens (convert SS to 2 SH) and thereby mitigate the allergenicity of commercial wheat preparations in the dog (179).

 

Shengwu Ma (CA), Dongling Zhao (CN), A. Yin (), R. Mukherjee (), Rohin Singh (), H. Qin (), Calvin R. Stiller (CA), and Anthony M. Jevnikar (CA) reported the production of glutamate decarboxylase by transgenic tobacco plants (918). Note: This enzyme is useful in the treatment of some cases of diabetes.

 

Susan C. Nagel (US), Fred S. vom Saal (US), Kristin A. Thayer (US), Minati G. Dhar (US), Mike Boechler (US), and Wade V. Welshons (US) showed that bisphenol-A, a component of polycarbonate plastic, can alter the reproductive development of lab mice at extremely low doses. Bisphenol-A mimics the natural sex hormone estrogen. Male mice exposed to this plastic during fetal development have permanently enlarged prostates and lower sperm counts (1049).

 

Toshiyuki Saito (JP), Yoichi Matsuda (JP), Takahiro Suzuki (JP), Akira Hayashi (JP), Xunmei Yuan (JP), Motoki Saito (JP), Jun-ichi Nakayama (JP), Tamaki Hori (JP), and Fuyuki Ishikawa (JP) determined the chromosomal locations of the human TEP1 (telomerase protein component 1) and mouse Tep1 genes, which were originally named TLP1 (telomerase protein 1) or TP1 (telomerase-associated protein 1). The human TEP1 and mouse Tep1 genes were mapped to human chromosome 14q11.2 and to the C2D1 band of mouse chromosome 14, respectively (1270). Note: This gene codes one protein component of telomerase.

 

A. Kay Steve (US) identified the clock gene, which controls circadian rhythm in mammals (1402).

 

Isabel Palmeirim (FR), Domingos Henrique (GB), David Ish-Horowicz (FR), and Olivier Pourquié (FR) showed that mRNA from the Hairy 1 gene appears as a wave that starts at the posterior end of the chick pre-somitic mesoderm (PSM) and moves towards the anterior, and that this wave of expression accompanies formation of each somite. Each cell in the PSM goes through a constant number of Hairy1 oscillations from the time it emerges from the primitive streak to the time when it is incorporated into a somite. This observation provided the first molecular evidence for the existence of a previously postulated molecular clock, or oscillator, that sets the periodicity with which the somite boundaries are laid during vertebrate somitogenesis (1121). Note: Subsequently, it was shown that expression of several Notch pathway components also cause oscillations in the PSM, establishing a link between Notch signaling and the segmentation clock. More recently, Wnt signaling has also been implicated in the segmentation clock mechanism.

 

Aman U. Buzdar (US), Walter Jonat (US), Anthony Howell (US), and Paul V. Plourde (US) reported that the Food and Drug Administration (FDA) approved anastrozole for the treatment of estrogen receptor-positive advanced breast cancer in postmenopausal women. Anastrozole is the first aromatase inhibitor (a drug that blocks the production of estrogen in the body) to be approved for cancer therapy (190).

 

Kathleen A. Cooney (US), Jenifer D. McCarthy (US), Ethan Lange (US), Li Huang (US), Susan Miesfeldt (US), James E. Montie (US), Joseph E. Oesterling (US), Howard M. Sandler (US), and Kenneth Lange (US) presented data confirming that human chromosome 1q24-25 is likely to contain a prostate cancer susceptibility gene (HPC1). When mutated this gene predisposes men to prostate cancer (280).

 

Frank Sicheri (US), Ismail Moarefi (US), John Kuriyan (US), Michelle LaFevre-Bernt (US), Morgan Huse (US), Chi-Hon Lee (US), and W. Todd Miller (US) discovered how changes in protein structure affect the regulation of Src kinases, a family of proteins important in several cancers. The protein Hck is a member of the Src family of non-receptor tyrosine kinases, which is preferentially expressed in hematopoietic cells of the myeloid and B-lymphoid lineages. Src kinases are inhibited by tyrosine-phosphorylation at a carboxy-terminal site. The SH2 domains of these enzymes play an essential role in this regulation by binding to the tyrosine-phosphorylated tail (1005; 1337).

Uwe Vinkemeier (US), Ismail Moarefi (US), James Edwin Darnell, Jr. (US), and John Kuriyan (US) determined the three dimensional structure one Src kinase and showed how its regulatory domains are important in "turning on" the kinase to send messages and then turn it off (1519).

 

Hua Zou (US), William J. Henzel (US), Xuesong Liu (US), Alexis Lutschg (US), and Xiaodong Wang (CN-US) developed an in vitro assay for the activation of the apoptosis related proteinase Caspase-3. This allowed the biochemical purification of a complex of Cytochrome c, Caspase-9 and the Apoptotic Protease Activating factor-1 (APAF1). These components are essential for forming a ternary complex called the apoptosome that activates Caspase-3 downstream of the intracellular or mitochondrial pathway of apoptosis (1642).

 

Liangbiao Chen (US) Arthur L. DeVries (US), and Chi-Hing Christina Cheng (US) found that the antifreeze glycoproteins (AFGPs) of the predominant Antarctic fish taxon, the notothenioids, evolved from a pancreatic trypsinogen. Transformation of the proteinase gene into the novel ice-binding protein gene occurred quite recently, about 5-14 million years ago (Mya), which is highly consistent with the estimated times of the freezing of the Antarctic Ocean at 10-14 Mya (233; 234).

 

David Lee Larom (US), Michael Garstang (US), Katharine B. Payne (US), Richard Raspet (US), and Malan Lindeque (NA) used computer modeling of low-frequency sound propagation in measured atmospheric conditions to predict that the calls of the savanna elephant at these frequencies can have ranges exceeding 10 km and that the calls will be highly directional in the presence of wind shear (827).

 

Stromectol (ivermectin) was approved by the Food and Drug Administration for treatment of onchocerciasis (intestinal threadworm), May 1997.

 

Claus Wedekind (CH), and Sandra Furi (CH) asked 121 men and women to score the odors of six T-shirts, worn by two women and four men. Their scorings of pleasantness correlated negatively with the degree of major histocompatibility complex (MHC) similarity between smeller and T-shirt-wearer in men and women who were not using the contraceptive pill (but not in Pill-users). This suggested that in human populations the MHC influences body odor preferences mainly, if not exclusively, by the degree of similarity or dissimilarity. The observed preferences would increase heterozygosity in the progeny.

They stated that several hypotheses suggest that certain MHC-allele combinations (usually heterozygous ones) are superior under selective pressure by pathogens. This could influence mate choice in a way that preferences function to create MHC-heterozygous offspring, or that they function to create specific allele combinations that are beneficial under the current environmental conditions through their complementary or epistatic effects (1555).

 

Yuk-Ming Dennis Lo (CN), Noemi Corbetta (IT), Paul F. Chamberlain (GB), Vik Rai (GB), Ian L. Sargent (GB), Christopher W.G. Redman (GB), and James S. Wainscoat (GB) found that they could use DNA and RNA in maternal plasma derived cells shed from the placenta to successfully determine fetal sex in the first trimester and to diagnose dominant disorders inherited from the father (891).

Yuk-Ming Dennis Lo (CN), Nancy Bo Yin Tsui (CN), Rossa Wai Kwun Chiu (CN), Tze K. Lau (CN), Tak N. Leung (CN), Macy M.S. Heung (CN), Ageliki Gerovassili (GB), Yoyo Y. Jin (CN), Kypros H. Nicolaides (GB), Charles R. Cantor (US), and Chunming Ding (CN) found that maternal plasma levels of placental mRNA are influenced by the dosage of alleles present in the fetus. Fetal trisomy 21 was detected noninvasively in 90% of cases and excluded in 96.5% of controls (890).

 

Yasushi Itoh (US) and Ronald N. Germain (US) recognized that T cell receptor recognition of peptide–major histocompatibility complex antigens could elicit a diverse array of effector activities. They simultaneously analyzed T cell receptor engagement and the production of multiple cytokines by individual cells in a clonal Th1 CD4+ cell population. Low concentrations of T cell receptor-ligand elicit only interferon gamma (IFNgamma) production. Increasing ligand recruits more cells into the IFNgamma pool, increases IFNgamma produced per cell, and also elicits IL-2, but only from cells already making IFNgamma. Most cells producing only IFNgamma show less T cell receptor down modulation than cells producing both cytokines, consistent with a requirement for more T cell receptor signaling to elicit IL-2 than to evoke IFNgamma synthesis. Their studies emphasize the hierarchical organization of T cell receptor signaling thresholds for induction of distinct cytokine responses, and demonstrate that this threshold phenomenon applies to individual cells. The existence of such thresholds suggests that antigen dose may dictate not only the extent, but also the quality of an immune response, by altering the ratios of the cytokines produced by activated T cells (689).

 

Wei-ping Zheng (US) and Richard A. Flavell (US) found that the transcription factor GATA-3 is necessary and sufficient for T helper 2 (Th2) cytokine gene expression in CD4 T cells (1632).

 

Holger Wesche (US), William J. Henzel (US), Wendy Shillinglaw (US), Shyun Li (US), and Zhaodan Cao (US) showed that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. MyD88 plays the same role in IL-1 signaling as TRADD and Tube do in tumor necrosis factor and Toll pathways In Toll it is required for the establishment of the dorsal-ventral axis in Drosophila embryos, and plays an important role in the response of larval and adult Drosophila to microbial infections. MyD88 couples a serine/threonine protein kinase to the receptor complex (1563).

Marta Muzio (US), Jian Ni (US), Ping Feng (US), and Vishva M. Dixit (US) identified two additional proximal mediators that are required for IL-1R-induced NF-kappaB activation: IRAK-2, a Pelle family member, and MyD88, a death domain-containing adapter molecule. Both associate with the IL-1R signaling complex (1044).

 

Hans-Willi Mittrücker (CA), Toshifumi Matsuyama (JP), Alex Grossman (CA), Thomas M. Kündig (CA), Julia Potter (CA), Arda Shahinian (CA), Andrew Wakeham (CA), Bruce Patterson (CA), Pamela S. Ohashi (CA), and Tak W. Mak (CA) reported that IRF4-deficient mice exhibited a profound reduction in serum immunoglobulin concentrations and did not mount detectable antibody responses. T lymphocyte function was also impaired in vivo; these mice could not generate cytotoxic or antitumor responses. Thus, IRF4 is essential for the function and homeostasis of both mature B and mature T lymphocytes (1004). Note: interferon regulatory factor (LSIRF) (now called IRF4) is a transcription factor expressed only in lymphocytes.

 

Tsutomu Nishizawa (JP), Hiroaki Okamoto (JP), Keiko Konishi (JP), Hiroshi Yoshizawa (JP), Yuzo Miyakawa (JP) and Makoto Mayumia (JP) were the first to detect the torque teno virus (TTV). It was found in the serum of a patient with post-transfusion hepatitis of unknown origin (non-A-non-G type) (1080).

 

Salvador Z. Tarun, Jr. (US), Sandra E. Wells (US), Julie A. Deardorff (US), and Alan B. Sachs (US) found that in Saccharomyces cerevisiae the translation initiation factor eIF4G mediates in vitro poly(A) tail-dependent translation (1441).

 

Michael J. Caterina (US), Mark A. Schumacher (US), Makoto Tominaga (JP), Tobias A. Rosen (US), Jon D. Levine (US), and David Julius (US) used expression cloning to identify transient receptor potential cation channel, subfamily V, member 1 (TRPV1), a capsaicin- and heat-activated ion channel (217).

Michael J. Caterina (US), Andreas Leffler (DE), Annika B. Malmberg (DE), William J. Martin (US), Jodie A. Trafton (US), Karla R. Petersen-Zeitz (US), Martin Koltzenburg (GB), Allan Irwin Basbaum (US), and David Julius (US) found that this non-selective channel was activated by heat with a threshold of 43°C, similar to the threshold for action potential firing in sensory neurons and for noxious heat sensations in psychophysical experiments (216). Analyses of TRPV1-deficient animals have revealed a key role for TRPV1 in both acute heat detection and thermal hypersensitivity. Thus, TRPV1 became of great interest as a drug target for treating pain and inflammation.

Diana M. Bautista (US), Jan Siemens (US), Joshua M. Glazer (US), Pamela R. Tsuruda (US), Allan I. Basbaum (US), Cheryl L. Stucky (US), Sven-Eric Jordt (US), David Julius (US) identified the cold- and menthol-activated ion channel, transient receptor potential cation channel, subfamily M, member 8 (TRPM8) (102).

Sven-Eric Jordt (US), Diana M. Bautista (US), Huai-hu Chuang (US), David D. McKemy (US), Peter M. Zygmunt (SE), Edward D. Högestätt (SE), Ian D. Meng (US), and David Julius (US) identified the wasabi receptor, transient receptor potential cation channel, subfamily A, member 1 (TRPA1) (721). both of which play key roles in acute and inflammatory pain. Note: changes in environmental temperature in mammals are detected by primary afferent somatosensory neurons. These neurons have cell bodies in the dorsal root ganglia (DRG) for the body and the trigeminal ganglia for the face/head, and have a pseudo-unipolar axon that innervates peripheral target organs (e.g., skin) and the dorsal spinal cord. Nociceptors are a specialized subset of primary afferent neurons that mediate responses to noxious thermal, mechanical and/or chemical stimuli. Nociceptors are activated when temperatures reach levels that are capable of causing tissue damage; heat-sensitive nociceptors are activated by temperatures that exceed 43°C, while cold-sensitive nociceptors are activated by temperatures that fall below 15°C. Such neurons display little activity at normal body temperature but display robust action potential firing in response to noxious thermal stimuli that in turn activates central neurons to trigger protective reflexes and irritating or painful sensations.

 

Clare Holden (GB) and Ruth Mace (GB) concluded from their analyses that high adult lactose digestion capacity is an adaptation to dairying but not an adaptation to high latitudes or highly arid environments (644).

 

Walburga Dieterich (DE), Tobias Ehnis (DE), Michael Bauer (DE), Peter Donner (DE), Umberto Volta (DE), Ernst Otto Riecken (DE), and Detlef Schuppan (DE) identified the pathogenic antigen in celiac disease (338).

 

The Digitalis Investigation Group (US) reported that digoxin significantly reduced hospitalizations but had no significant effect on mortality when used to treat patients with systolic heart failure. Digoxin was most beneficial in patients with low ejection fractions (<0.25) and poor functional status (NYHA III-IV) (552).

 

Lawrence J. Appel (US), Thomas J. Moore (US), Eva Obarzanek (US), William M. Vollmer (US), Laura P. Svetkey (US), Frank M. Sacks (US), George A. Bray (US), Thomas M. Vogt (US), Jeffrey A. Cutler (US), Marlene M. Windhauser (US), Pao-Hwa Lin (US), Njeri Karanja (US), Denise Simons-Morton (US), Marjorie McCullough (US), Janis Swain (US), Priscilla Steele (US), Marguerite A. Evans (US), Edgar R. Miller (US), and David W. Harsha (US) found that a “combination” diet rich in fruits and vegetables and low in saturated and total fat reduces blood pressure in comparison to the typical American diet.

Blood-pressure reductions were observed in the setting of stable weight, unchanged sodium intake, and consumption of no more than two alcoholic drinks per day (45).

 

Yves Mouton (FR), Serge Alfandari (FR), Michel Valette (FR), François Cartier (FR), Pierre Dellamonica (FR), Guy Humbert (FR), Jean Marie Lang (FR), Patrice Massip (FR), Denis Mechali (FR), Pascale Leclercq (FR), Jacques Modai (FR), Henri Portier, and Fédération Nationale des Centres de Lutte contre le SIDA performed a study that supports the extensive use of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infected patients (1029). Note: This "cocktail" approach to treatment where drugs are combined in different ways or different sequences has become a model for treating other diseases ranging from lung cancer to heart disease.

 

Maurizio Alimandi (US), Ling-Mei Wang (US), Donald Bottaro (US), Chong-Chou Lee (US), Angera Kuo (US), Mark Frankel (US), Paolo Fedi (US), Careen Tang (US), Marc Lippman (US), and Jacalyn H. Pierce (US) found cancer cells which had acquired the ability to synthesize growth factors to which they are responsive, creating a positive feedback signaling loop often termed autocrine stimulation (30).

 

Thomas D. Penning (US), John J. Talley (US), Stephen R. Bertenshaw (US), Jeffrey S. Carter (US), Paul W. Collins (US), Stephen Docter (US), Matthew J. Graneto (US), Len F. Lee (US), James W. Malecha (US), Julie M. Miyashiro (US), Roland S. Rogers (US), Donald J. Rogier (US), Stella S. Yu (US), Gary D. Anderson (US), Earl G. Burton (US), J. Nita Cogburn (US), Susan A. Gregory (US), Carol M. Koboldt (US), William E. Perkins (US), Karen Seibert (US), Amy W. Veenhuizen (US), Yan Y. Zhang (US), and Peter C. Isakson (US) identified 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), an inhibitor of cyclooxygenase-2 (COX-2), for the treatment of rheumatoid arthritis and osteoarthritis (1147). The trade name is Celebrex.

Christopher J. Smith (US), Yan Y. Zhang (US), Carol M. Koboldt (US), Jerry Muhammad (US), Ben S. Zweifel (US), Alex Shaffer (US), John J. Talley (US), Jamie L. Masferrer (US), Karen Seibert (US), and Peter C. Isakson (US) presented results suggesting that, in addition to the role of peripherally produced prostaglandins, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by cyclooxygenase-2 (COX-2) (1359). Note: The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions.

 

Russ A. Poldrack (US) and John D. Gabrieli (US) reported that long-term memory relies upon the cerebral cortex, basal ganglia, and cerebellum (1173).

 

Markus Jueptner (DE), Sean E. Ottinger (DE), Stuart J. Fellows (DE), J. Adamschewski (DE), Lars Flerich (DE), Stefan P. Muller (DE), Hans Christoph Diener (DE), Alfred F. Thilmann (DE), and Cornelius Weiller (DE) discovered that the cerebellum is involved in perceiving sensory input, challenging the prevailing view that it serves only in controlling muscles (725).

 

Juan Mier (MX), Enrique Luque-de Leon (MX), Armando Castillo (MX), Felipe Robledo (MX), and Roberto Blanco (MX) reported that a prospective, randomized study from a single institution clearly demonstrated that early intensive conservative treatment with late necrosectomy for selected cases is the current rational approach for severe necrotizing pancreatitis (994).

Marc G.H. Besselink (NL), Hjalmar C. van Santvoort (NL), Vincent B. Nieuwenhuijs (NL), Marja A. Boermeester (NL), Thomas L. Bollen (NL), Erik Buskens (NL), Cornelis H.C. Dejong (NL), Casper H.J. van Eijck (NL), Harry van Goor (NL), Sijbrand S. Hofker, (NL), Johan S. Lameris (NL), Maarten S. van Leeuwen (NL), Rutger J. Ploeg (NL), Bert van Ramshorst (NL), Alexander F.M. Schaapherder (NL), Miguel A. Cuesta (NL), Esther C.J. Consten (NL), Dirk J. Gouma (NL), Erwin van der Harst (NL), Eric J. Hesselink (NL), Lex P.J. Houdijk (NL), Tom M. Karsten (NL), Cees J.H.M. van Laarhoven (NL), Jean-Pierre E.N. Pierie (NL), Camiel Rosman (NL), Ernst Jan Spillenaar Bilgen (NL), Robin Timmer (NL), Ingeborg van der Tweel (NL), Ralph J. de Wit (NL), Ben J.M. Witteman (NL), Hein G. Gooszen (NL), Olaf J. Bakker (NL), H. Sijbrand Hofker (NL), Philip M. Kruyt (NL), Eric R. Manusama (NL), George P. van der Schelling (NL), Cornelis J. van Laarhoven (NL), Koop Bosscha (NL), Alexander P. Houdijk (NL), and The Dutch Acute Pancreatitis Study Group (NL) determined that the prefered treatment strategy for patients with necrotizing pancreatitis and secondary infection, from both a clinical and an economic point of view, is a minimally invasive step-up approach consisting of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy (121; 1279).

Yu Bai (CN), Jun Gao (CN), Duo-Wu Zou (CN), and Zhao-Shen Li (CN) showed that prophylactic antibiotics do not reduce infected pancreatic necrosis and mortality in patients with acute necrotizing pancreatitis. The mortality rate was reduced only in low-quality settings (single-center and single-blinded), and the significance was marginal (p = 0.04) (73).

 

Maria Grazia Spillantini (GB), Michael Goedert (GB), R. Anthony Crowther (GB), Jill R. Murrell (US), Martin R. Farlow (US), and Bernardino Ghetti (US) described and named the newly identified brain disorder familial multiple system tauopathy with presenile dementia. The name reflects the characteristics of the disease. It has an early onset, is inherited, and involves both the cortical and subcortical systems of the brain. In addition, tau, a microtubule associated protein found in the brain, is abnormal in these patients (1385).

 

Fotis Kalfarentzos (GR), Ioannis Kehagias (GR), Nancy Mead (GR), K. Kokkinis (GR), and Charalambos A. Gogos (GR) demonstrated that not only is enteral nutrition by the nasojejunal route tolerated in acute pancreatitis patients, but also it is safer and less costly. However, there are several criticisms. Firstly this trial, and those that followed, are in relatively small patient groups (n=38). Secondly, prophylactic antibiotics were used until the restoration of a normal C-reactive protein. Thirdly, one of the indications for surgical intervention was multi-organ failure after 5 days of intensive care. There are some cases where circumstances indicate parenteral nutrition (729).

 

John Buglass (GB) led the excavation of a large urban monastic site in the middle of Hull, England. Charlotte Roberts (GB), the team’s paleopathologist, found four cases of unmistakable pre-Columbian venereal syphilis in the remains of Europeans interred at this Augustinian Friary destroyed in 1539. The human remains were dated using dendrochronology of their caskets and radiocarbon dating of their bones. This evidence contradicts the long held belief that syphilis was brought to Europe from the New World by men who sailed with Christopher Columbus (383; 384).

 

Luca Gianaroli (IT), M. Cristina Magli (IT), Santiago Munne (IT), Agnese Fiorentino (IT), Nadia Montanaro (IT), and Anna P. Ferraretti (IT) found a way to screen out aneuploid embryos using a technique called fluorescence in situ hybridization (FISH). This enables an analysis of specific genetic information to be made from a single cell, abstracted from an embryo (489). Note: As women enter their 40s, there is an increased risk of the embryo containing the wrong number of chromosomes in the cells, increasing the chance of miscarriage or severe malformation of the fetus. The condition, aneuploidy, is one of the reasons for a lower success rate for in vitro fertilization (IVF) in woman over 38.

 

Marcia E. Herman-Giddens (US), Eric J. Slora (US), Richard C. Wasserman (US), Carlos J. Bourdony (US), Manju V. Bhapkar (US), Gary G. Koch (US), and Cynthia M. Hasemeier (US) found in a study population of girls 3-12 years of age, that African-American females developed secondary sexual characteristics at a significantly earlier age than white girls. African-American females had earlier menarche (the first occurrence of menstruation) at 12.16 years of age, compared to 12.88 years of age among white females (628).

 

Steven Pinker (CA-US) attempts to explain some of the human mind's poorly understood functions and quirks in evolutionary terms. A synthesis of many of the ideas of evolutionary psychology, a field which posits that we can gain insights into the way that the mind works if we view our cognitive capabilities as the adaptive result of evolution (1169).

 

Simon Easteal (AU) and Genevieve Herbert (AU) presented molecular evidence that humans and chimpanzees diverged 4.0-3.6 million years ago. This postdates the occurrence of Ardipithecus ramidus and the earliest occurrence of Australopithecus afarensis, suggesting that the common ancestor of humans and chimpanzees was bipedal and that the trait has been lost in chimpanzees rather than gained in humans (365).

 

Berhane Asfaw (ET), Tim D. White (US), C. Owen Lovejoy (US), Bruce Latimer (US), Scott Simpson (US), and Gen Suwa (ET), in 1997, discovered the hominid Australopithecus garhi near the village of Bouri, in the Afar region of Ethiopia. This 2.5 M species is known from a partial skull. The skull differs from previous australopithecine species in the combination of its features, notably the extremely large size of its teeth, especially the rear ones, and primitive skull morphology. Some nearby skeletal remains may belong to the same species. They show a human-like ratio of the humerus and femur, but an ape-like ratio of the lower and upper arm. This small-brained, large-toothed hominid was found near antelope bones, which had been butchered by stone tools (57). Note: Elizabeth Culotta (US) named this hominid (299).

 

Michael R. Waters (US), Steve L. Forman (US), and James M. Pierson (US) found Lower Paleolithic human artifacts at Diring Yuriakh, an archaeological site in Central Siberia. Thermoluminescence age-estimates from eolian sediments indicate that the cultural horizon is greater than 260,000 years old. Diring Yuriakh is an order of magnitude older than documented Paleolithic sites in Siberia and is important for understanding the timing of human expansion into the far north, early adaptations to cold climates, and the peopling of the Americas (1548).

 

José María Bermudez de Castro (ES), Juan Luis Arsuaga (ES), Eudaid Carbonell (ES), Antonio Rosas (ES), Ignacio Martinez (ES), and Marina Mosquera (ES) reported Homo fossils from Spain dated at over 780,000 years. These are the oldest confirmed European hominids. It is not yet clear what species they belong to, although the discoverers have named them Homo antecessor (117).

 

Matthias Krings (DE), Anne Stone (US), Ralf W. Schmitz (DE), Heike Krainitzki (DE), Mark Stoneking (US), and Svante Pääbo (DE) reported the first ever sequencing of Neanderthal DNA, a breakthrough in the study of modern human evolution. The DNA was extracted for the type specimen and the mitochondrial DNA sequence was determined. This sequence was compared to living human mtDNA sequences and found to be outside the range of variation in modern humans (806).

 

Sileshi Semaw (ET), Paul R. Renne (US), John W.K. Harris (US), Craig S. Feibel (US), Ray L. Bernor (US), Nardos Fesseka (ET), and Kenneth Mowbray (US) found 2.5 - 2.6 million-year-old stone tools at Gona, Ethiopia (1318).

 

Joseph M. McAvoy (US) and Lynn D. McAvoy (US) noted that the location, dating and technology represented by the Cactus Hill, Meadowcroft and Page-Ladson sites in the Eastern United States provide the ‘missing’ chronological and technological links between Solutrean and Clovis cultures (965). Cactus Hill was occupied 14,000 to 18,000 BP

Bruce A. Bradley (GB) and Dennis J. Stanford (US) placed the technological antecedents of North America's Clovis culture in Europe and posit that the first Americans crossed the Atlantic by boat and arrived earlier than previously thought. Presenting archaeological and oceanographic evidence to support this assertion, they dismantle the old paradigm while persuasively linking Clovis technology with the culture of Solutrean people who occupied France and Spain more than 20,000 years ago. "Solutrean" is named after the type-site of Crot du Charnier at Solutré in the Macon district, Saone-et-Loire, eastern France, and appeared around 21,000 BP (157; 1391).

Nelson J.R. Fagundes (BR), Ricardo Kanitz (BR), Roberta Eckert (BR), Ana C.S. Valls (BR), Mauricio R. Bogo (BR), Francisco M. Salzano (BR), David Glenn Smith (US), Wilson A. Silva, Jr. (BR), Marco A. Zago (BR), Andrea K. Ribeiro-dos-Santos (BR), Sidney E.B. Santos (BR), Maria Luiza Petzl-Erler (BR) and Sandro L. Bonatto (BR) found that mitochondrial population genomics supports a single pre-Clovis origin with a coastal route for the peopling of the Americas (388).

 

1998

“The cost of scientific advance is the humbling recognition that reality was not constructed to be easily grasped by the human mind. This is the cardinal tenet of scientific understanding: Our species and its way of thinking are a product of evolution, not the purpose of evolution.” Edward Osborne Wilson (1578).

 

“The universality of the deep chemistry of living things is indeed a fantastic and beautiful thing.” Richard Phillips Feynman (412).

 

"To me it's a question of being able to look backward and give the present a root... To give meaning to where we are today, we need to look at where we've come from." Richard Leakey (1513)

 

“…it finally dawned on me: biology is a doer’s field; you have got to run centrifuges and gels and not waste your time in deep thoughts.” George Feher (395).

 

“That is the principle of science. If there is an exception to any rule, and if it can be proved by observation, that rule is wrong.” Richard Phillips Feynman (412).

 

Robert F. Furchgott (US), Louis Joseph Ignarro (US), and Ferid Murad (US) shared the Nobel Prize in Physiology or Medicine for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system.

 

Lewis E. Kay (CA) led a group including: D. Ranjith Muhandiram (CA), Gert Wolf (CA), Steven E. Shoelson (CA), Julie D. Forman-Kay (CA), Pascale Legault (CA), Joyce Li (CA), Jeremy Mogridge (CA), Jack Greenblatt (CA), Kevin H. Gardner (CA), Nikolai R. Skrynnikov (CA), Natalie K. Goto (CA), Daiwen Yang (CA), Wing-Yiu Choy (CA), Joel R. Tolman (CA), Geoffrey A. Mueller (CA), and Anthony Mittermaier (CA) in the development of modern NMR spectroscopy for studies of biomolecular structure dynamics and function, including applications to molecular machines and rare protein conformations (466; 744; 745; 847; 1003; 1352).

 

Kyriacos Costa Nicolaou (CY-US), Zhen Yang (US), Guo-qiang Shi (US), Janet L. Gunzner (US), Konstantinos A. Agrios (US), and Peter Gartner (US) carried out the total synthesis of brevetoxin A, the most potent neurotoxin secreted by Gymnodinium breve Davis, a marine organism often associated with harmful algal blooms known as red tides (1077).

 

Mostafa Ronaghi (SE), Mathias Uhlén (SE), and Pal Nyrén (SE) presented pyrosequencing, a nucleotide sequencing technique that can be carried out on a solid support. In pyrosequencing, pyrophosphate — released upon nucleotide addition by DNA polymerase — is converted to ATP. This triggers a luciferase enzyme to produce light, which is used to detect an incorporation event, so that a sequence read can be built up over successive rounds using different deoxynucleotides. Importantly, because nucleotide addition is detected by the emission of photons, this method is well suited to detection using simple optics and automated data collection (1251).

 

Brent Ewing (US), Phil Green (US), LaDeana Hillier (US), Michael Wendl (US), David Gordon (US), and Chris Abajian (US) developed 'Phred' and 'Consed' to assemble short stretches of DNA sequences into a larger whole. Initially 'Phrap' assembles lists of bases from multiple reads (from short segments of DNA) into the most likely single path through all of the sequences. Users then view and edit the output with Consed, to generate higher-quality sequences as required. These programs were developed for, and used on, the public Human Genome Project (385; 386; 515).

Eugene W. Myers (US), Granger G. Sutton (US), Art L. Delcher (US), Ian M. Dew (US), Dan P. Fasulo (US), Michael J. Flanigan (US), Saul A. Kravitz (US), Clark M. Mobarry (US), Knut H. J. Reinert (US), Karin A. Remington (US), Eric L. Anson (US), Randall A. Bolanos (US), Hui-Hsien Chou (US), Catherine M. Jordan (US), Aaron L. Halpern (US), Stefano Lonardi (US), Ellen M. Beasley (US), Rhonda C. Brandon (US), Lin Chen (US), Patrick J. Dunn (US), Zhongwu Lai (US), Yong Liang (US), Deborah R. Nusskern (US), Ming Zhan (US), Qing Zhang (US), Xiangqun Zheng (US), Gerald M. Rubin (US), Mark D. Adams (US), and John Craig Venter (US) developed an algorithm that uses the end-pair information from sequencing subclones and can assemble larger sequences. They postulated that the whole genome could be cut into pieces, sequenced randomly and reconstructed given sufficient computational power. They demonstrated this approach on the genome of Drosophila melanogaster and famously went on to 'race' the publicly funded Human Genome Project using, in the end, a combination of their whole-genome assembly methods and data from the public project (1046).

 

Marjo Kestilä (FI), Ulla Lenkkeri (FI), Minna Männikkö (FI), Jane Lamerdin (FI), Paula McCready (FI), Heli Putaala (FI), Vesa Ruotsalainen (FI), Takako Morita (FI), Marja Nissinen (FI), Riitta Herva (FI), Clifford E Kashtan (FI), Leena Peltonen (FI), Christer Holmberg (FI), Anne Olsen (FI), and Karl Tryggvason (FI) presented evidence which demonstrated a crucial role for the protein nephrin in the development or function of the kidney filtration barrier (755). Note: Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal-recessive disorder, characterized by massive proteinuria in utero and nephrosis at birth. The NPHS1 gene product is termed nephrin.

 

Barbara S. Smith (US), Bostjan Kobe (US), Ravi G. Kurumbail (US), Susan K. Buchanan (GB), Lalitha Venkatramani (US), Dick van der Helm (US), and Johann Deisenhofer (US) crystallized and performed a preliminary x-ray analysis of ferric enterobactin receptor FepA, an integral membrane protein from Eschericia coli (1357).

 

So Iwata (GB), Joong W. Lee (US), Kengo Okada (JP), John Kyongwon Lee (US), Momi Iwata (SE), Bjarne Rasmussen (FR), Thomas A. Link (DE), Subramanian Ramaswamy (US), and Bing K. Jap (US) determined the complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex (693).

 

Geoffrey Chang (US), Robert H. Spencer (US), Allen T. Lee (US), Margaret T. Barclay (US), and Douglas C. Rees (US) reported the structure of the MSCL homologue from Mycobacterium tuberculosis: a gated mechanosensitive channel. This channel is created by membrane embedded protein (226).

 

The U.S. Food and Drug Administration approved the use of sildenafil citrate (Viagra), as a drug to correct erectile dysfunction. Viagra works on an enzyme in the corpus cavernosum (a spongy tissue at the base of the penis/clitoris) that acts as a gateway for blood to the penis/clitoris. It was first synthesized in 1989 in Sandwich, England, as compound UK-92,480. The team of Nick Terrett (GB), Andy Bell (GB), David Brown (GB) and Frank Burslem (GB) did this early work. They were looking for a drug to reduce hypertension.

 

Nenad Ban (HR-US-CH), Betty Freeborn (US), Poul Nissen (DK), Pawel Penczek (PL-US), Robert A. Grassucci (US), Robert M. Sweet (US), Joachim Frank (US), Peter B. Moore (US), Thomas A. Steitz (US), and Jeffrey L. Hansen (US) determined the complete atomic structure of the large ribosomal subunit from Haloarcula marismortui— a halophilic red archaeon—first at 9-angstroms then at 2.4-angstroms (78; 79).

 

Carol A. Gross (US), Cathy Chan (US), Alicia Dombroski (US), Tanja Gruber (US), Meghan Sharp (US), Jon Tupy (US), and Brian Young (US) revealed how the sigma factor from E. coli initiates transcription. They found that sigma is subject to auto-inhibition such that free sigma (i.e., free of core RNA polymerase) adopts a conformation in which its DNA-binding surfaces are masked. These surfaces are exposed and the enzyme activated when it binds to core RNA polymerase (543).

 

Elizabeth A. Winzeler (US), Dan R. Richards (US), Andrew R. Conway (US), Alan L. Goldstein (US), Sue Kalman (US), Michael J. McCullough (US), John H. McCusker (US), David A. Stevens (US), Lisa Wodicka (US), David J. Lockhart (US), and Ronald W. Davis (US) demonstrated that allelic variation in any two isolates of a species can be scanned, mapped, and scored directly and efficiently without allelic-specific polymerase chain reaction, without creating new strains or constructs, and without knowing the specific nature of the variation. Analyzing the patterns obtained when total genomic DNA from two different strains of yeast was hybridized to high-density oligonucleotide arrays identified a total of 3714 biallelic markers, spaced about every 3.5 kilobases. The markers were then used to simultaneously map a multidrug-resistant locus and four other loci with high resolution (11 to 64 kilobases) (1582).

Guri Giaever (US), Angela M. Chu (US), Li Ni (US), Carla Connelly (US), Linda Riles (US), Steeve Véronneau (US), Sally Dow (CA), Ankuta Lucau-Danila (US), Keith Anderson (US), Bruno André (BE), Adam P. Arkin (BE), Anna Astromoff (US), Mohamed El Bakkoury (US), Rhonda Bangham (US), Rocio Benito (BE), Sophie Brachat (US), Stefano Campanaro (CH), Matt Curtiss (US), Karen Davis (US), Adam Deutschbauer (US), Karl-Dieter Entian (IT), Patrick Flaherty (BE-DE), Francoise Foury (US), David J. Garfinkel (US), Mark Gerstein (US), Deanna Gotte (US), Ulrich Güldener (DE), Johannes H. Hegemann (DE), Svenja Hempel (IT), Zelek Herman (US), Daniel F. Jaramillo (US), Diane E. Kelly (GB), Steven L. Kelly (GB), Peter Kötter (IT), Darlene LaBonte (US), David C. Lamb (GB), Ning Lan (US), Hong Liang (US), Hong Liao (US), Lucy Liu (US), Chuanyun Luo (US), Marc Lussier (US), Rong Mao (US), Patrice Menard (US), Siew Loon Ooi (US), Jose L. Revuelta (BE), Christopher J. Roberts (CA), Matthias Rose (IT), Petra Ross-Macdonald (US), Bart Scherens (US), Greg Schimmack (CA), Brenda Shafer (US), Daniel D. Shoemaker (US), Sharon Sookhai-Mahadeo (US), Reginald K. Storms (CA), Jeffrey N. Strathern (US), Giorgio Valle (CH), Marleen Voet (BE), Guido Volckaert (BE), Ching-yun Wang (US), Teresa R. Ward (CA), Julie Wilhelmy (US), Elizabeth A. Winzeler (US), Yonghong Yang (US), Grace Yen (US), Elaine Youngman (US), Kexin Yu (US), Howard Bussey (US), Jef D. Boeke (US), Michael Snyde (US), Peter Philippsen (US), Ronald W. Davis (US), and Mark Johnston (US) systematically constructed a nearly complete collection of gene-deletion mutants (96% of annotated open reading frames, or ORFs) of the yeast Saccharomyces cerevisiae. DNA sequences dubbed 'molecular bar codes' uniquely identify each strain, enabling their growth to be analyzed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays. They found that previously known and new genes are necessary for optimal growth under six well-studied conditions: high salt, sorbitol, galactose, pH 8, minimal medium and nystatin treatment. Less than 7% of genes that exhibit a significant increase in messenger RNA expression are also required for optimal growth in four of the tested conditions. Their results validate the yeast gene-deletion collection as a valuable resource for functional genomics (488).

 

Shelley R. Hepworth (CA), Helena Friesen (CA), and Jacqueline Segall (CA) found that in Saccharomyces cerevisiae the middle-sporulation specific genes are expressed only on completion of meiotic recombination and subsequent generation of an active form of the protein Ndt80p (627). Note: Transition from expression of early meiotic genes to expression of middle sporulation-specific genes occurs at about the time that Saccharomyces cerevisiae cells exit from pachytene and form the meiosis I spindle.

 

René Strepp, Sirkka Scholz, Sven Kruse, Volker Speth, and Ralf Reski (DE) generated a knockout moss (Physcomitrella) by deleting an ftsZ gene and thus identified the first gene essential in the division of an organelle in any eukaryote (1408).

Justine Kiessling (DE), Sven Kruse (DE), Stefan A. Rensing (DE), Klaus Harter (DE), Eva L. Decker (DE), and Ralf Reski (DE) presented a new concept in cell biology of how chloroplasts, the green cell organelles of plants, change shape and divide (759; 1228).

 

Ge Sun (CN), David L. Dilcher (US), Shaoling Zheng (CN), and Zhe-Kun Zhou (CN) described the latest, best, and most unambiguous contender for the title of first true flower (angiosperm), Archaefructus sinensis. It was found in deposits from the Upper Jurassic (meaning Late Jurassic) of China (1418). Note: Angiosperms are defined as possessing carpels enclosing ovules.

 

Gwendalyn J. Randolph (US), Sylvie Beaulieu (US), Serge Lebecque (FR), Ralph M. Steinman (US), and William A. Muller (US) found that monocytes cultured with endothelium differentiated into dendritic cells within 2 days, particularly after phagocytosing particles in subendothelial collagen. These nascent dendritic cells migrated across the endothelium in the ablumenal-to-lumenal direction, as would occur during entry into lymphatics. Monocytes that remained in the subendothelial matrix became macrophages. Therefore, monocytes have two potential fates associated with distinct patterns of migration (1207).

 

Eric Z. Butz (US) and Michael John Bevan (GB-US) noted a massive expansion of antigen-specific CD8+ T cells during an acute virus infection (lymphocytic choriomeningitis virus) (189).

 

Andrea Cerutti (US), Hong Zan (US), Andras Schaffer (US), Leif Bergsagel (US), Nagaradona Harindranath (US), Edward E. Max (US), and Paolo Casali (US), in a human monoclonal B cell line (CL-01), induced coordinated Ig class switching, progression through germinal center phenotypic stages, and differentiation to memory B cells and plasma cells at the level of a single B clonotype. Their data suggested that these processes are likely regulated by a common maturation program, the activation of which may require CD40 ligand, IL-4, IL-10, and IL-6 only (222).

 

Kirsten J. Flynn (US), Gabrielle T. Belz (US), John D. Altman (US), Rali Ahmed (US), David L. Woodland (US), and Peter Charles Doherty (US) described the dual application of the tetramer-staining and peptide stimulation approaches to quantitate the primary and secondary CD8+ CTL response in mice with influenza pneumonia, being a description of the events occurring in a nonlymphoid site of virus-induced pathology. The results establish the influenza-specific CD8+ eCTL numbers are much greater than previously suspected and illustrate very clearly the durability, benefits, and limitations of virus-specific CD8+ T cell memory (426).

 

Awen Gallimore (CH), Ann Glithero (CH), Andrew Godkin (CH), Alain C. Tissot (CH), Andreas Pluckthun (CH), Tim Elliott (GB), Hans Hengartner (CH), and Rolf Martin Zinkernagel (CH) used soluble tetrameric major histocompatibility complex class I-peptide complexes to visualize induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes (458).

 

Colin R.F. Monks (US), Benjamin A. Freiberg (US), Hannah Kupfer (US), Noah Sciaky (US), and Abraham Kupfer (US) studied the responses of T cells to native ligands at the level of the single cell. They used a digital imaging system and analyzed the three-dimensional distribution of receptors and intracellular proteins that cluster at the contacts between T cells and antigen presenting cells (APCs) during antigen-specific interactions. Surprisingly, instead of showing uniform oligomerization, these proteins clustered into segregated three-dimensional domains within the cell contacts. The antigen-specific formation of these new spatially segregated supramolecular activation clusters may generate appropriate physiological responses and may explain the high sensitivity of the T cells to antigen (1009).

Arash Grakoui (US), Shannon K. Bromley (US), Cenk Sumen (US), Mark M. Davis (US), Andrey S. Shaw (US), Paul M. Allen (US), and Michael L. Dustin (US) visualized what they referred to as the "immunological synapse." They saw this structure as controlling T cell activation through a structure-function dynamic. A central cluster of T cell receptors is seen as surrounded by a ring of adhesion molecules. The synapse allows T cells to distinguish potential antigenic ligands. Initially, T cell receptor ligands were engaged in an outermost ring of the nascent synapse. Transport of these complexes into a central cluster is seen as dependent on T cell receptor-ligand interaction kinetics. Finally, formation of a stable central cluster at the heart of the synapse is a determinative event for T cell proliferation (527).

 

Kaja Murali-Krishna (US), John D. Altman (US), M. Suresh (US), David J.D. Sourdive (US), Allan J. Zajac (US), Joseph D. Miller (US), Jill Slansky (US), and Rafi Ahmed (US) used tetramers of MHC class I molecules containing viral peptides to directly visualize antigen-specific CD8 T cells during acute lymphocytic choriomeningitis virus infection of mice. Based on tetramer binding and two sensitive assays measuring interferon-gamma production at the single-cell level, they found that 50%–70% of the activated T cells were lymphocytic choriomeningitis virus (LCMV) specific (2X107 virus-specific cells/spleen). Following viral clearance, antigen-specific CD8 T cell numbers dropped to 106 per spleen and were maintained at this level for the life of the mouse (1038).

 

Arpita Maiti (CA), Guitta Maki (CA), and Pauline Johnson (GB-CA) defined the mechanisms regulating the interactions of the cell adhesion molecule CD44 with the matrix component, hyaluronan (930). Note: Regulation of cell adhesion is important for immune system function. CD44 is a tightly regulated cell adhesion molecule present on leukocytes and implicated in their attachment to endothelium during an inflammatory immune response.

 

Angela M. Thornton (US) and Ethan M. Shevach (US) presented data to support the concept that the CD4+CD25+ T cells in normal mice may represent a distinct lineage of “professional” suppressor cells (1455).

 

Gerard A. Schellekens (NL), Ben A. W. de Jong (NL), Frank H. J. van den Hoogen (NL), Leo B. A. van de Putte (NL), and Walther J. van Venrooij (NL) discovered that citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis–specific autoantibodies (1288).

 

Joseph R. Tumang (US), Alexander Owyang (US), Sofija Andjelic (US), Zhuang Jin (US), Richard R. Hardy (US), Mei-Ling Liou (US), and Hsiou-Chi Liou (US) found that c-Rel, a lymphoid-specific member of the NF-kappaB/Rel family of transcriptional factors, is essential for B lymphocyte survival and cell cycle progression (1479).

Hsiou-Chi Liou (US), Zhuang Jin (US), Joseph R. Tumang (US), Sofija Andjelic (US), Kendall A. Smith (US), and Mei-Ling Liou (US) provided data suggesting that c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells (883).

 

Flavio Vincenti (US), Robert Kirkman (US), Susan Light (US), Ginny Bumgardner (US), Mark Pescovitz (US), Philip Halloran (CA), John Neylan (US), Alan Wilkinson (US), Henrik Ekberg (SE), Robert Gaston (US), Lars Backman (SE), and James Burdick (US) found that Daclizumab reduces the frequency of acute rejection in kidney-transplant recipients (1518). Note: Monoclonal antibodies that block the high-affinity interleukin-2 receptor expressed on alloantigen- reactive T lymphocytes may cause selective immunosuppression. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the a chain of the interleukin-2 receptor and may thus reduce the risk of rejection after renal transplantation.

Ainat Beniaminovitz (US), Silviu Itescu (US), Katherine Lietz (US), Mary Donovan (US), Elizabeth Burke (US), Barbara D. Groff (US), Niloo Edwards (US), and Donna M. Mancini (US) found that induction therapy with daclizumab safely reduces the frequency and severity of cardiac allograft rejection during the induction period.

This prevention of rejection in cardiac transplantation is accomplished by blockade of the interleukin-2 receptor with a monoclonal antibody (110).

Henrik Ekberg (SE), Helio Tedesco-Silva (BR), Alper Demirbas (TR), Štefan Vítko (CZ), Björn Nashan (DE), Alp Gürkan (TR), Raimund Margreiter (AT), Christian Hugo (DE), Josep M. Grinyó (ES), Ulrich Frei (DE), Yves Vanrenterghem (BE), Pierre Daloze (CA), Philip F. Halloran (CA), and The ELITE–Symphony Study, from their randomized controlled trial, concluded that a regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction (371).

 

Erwin G. Zoetendal (NL), Antoon D. Akkermans (NL), Willem M. De Vos (NL), Peter J. Turnbaugh (US), Ruth E. Ley (US), Micah Hamady (US), Claire M. Fraser-Liggett (US), Rob Knight (US), Jeffrey I. Gordon (US), Hermie J. M. Harmsen (NL), Gerwin C. Raangs (NL), Tao He (NL), John E. Degener (NL), Gjalt W. Welling (NL), Francesca Turroni (IE), Angela Ribbera (IT), Elena Foroni (IT), Douwe van Sinderen (IE), and Marco Ventura (IT) reported that each healthy adult's gut appears to have a unique and relatively stable microbiota, which is a reflection of the numerous different phylogenetic clusters among the Firmicutes, Clostridium clusters IV, IX and XIVa, including the predominant genera Clostridium, Eubacterium, Roseburia and Ruminococcus. Furthermore, the Actinobacteria that encompass mainly the genera Bifidobacterium and Atopobium, also represent important members of the gut microbial community (598; 1484; 1489; 1638).

Fredrik Bäckhed (US), Ruth E. Ley (US), Justin L. Sonnenburg (US), Daniel A. Peterson (US), Jeffrey I.Gordon (US), Michael Blaut (DE), Thomas Clavel (DE), Mirjana Rajilic-Stojanovic (NL), Hauke Smidt (NL), and Willem M. de Vos (NL) estimated that the diversity of the human gut microbial ecosystem may encompass more than 1000 species and a multitude of strains (71; 135; 1201).

Erwin G. Zoetendal (NL), Elaine E. Vaughan (NL), and Willem M. de Vos (NL) showed that more than 90% of the bacterial phylotypes present in the intestinal microbiota in healthy humans are members of only three bacterial divisions: the Bacteroidetes, the Firmicutes and the Actinobacteria (1640).

Ruth E. Ley (US), Peter J. Turnbaugh (US), Samuel Klein (US), Jeffrey I. Gordon (US), Micah Hamady (US), Tanya Yatsunenko (US), Brandi L. Cantarel (US), Alexis Duncan (US), Mitchell L. Sogin (US), William J. Jones (US), Bruce A. Roe (US), Jason P. Affourtit (US), Michael Egholm (US), Bernard Henrissat (US), Andrew C. Heath (US), Rob Knight (US), Vanessa K. Ridaura (US), Jeremiah J. Faith (US), Federico E. Rey (US), Rob Knight (US), Erwin G. Zoetendal (NL), Mirjana Rajilic-Stojanovic (NL), and Willem M. de Vos (NL) reported that gut microbiota composition studies in humans discovered that aberrations in the microbiome composition are present in obese individuals; as well as in individuals with a variety of other diseases (864; 1483; 1639).

Manimozhiyan Arumugam (DE), Jeroen Raes (BE), Eric Pelletier (FR), Denis Le Paslier (FR), Takuji Yamada (DE), Daniel R. Mende (DE), Gabriel R. Fernandes (BR), Julien Tap (FR), Thomas Bruls (FR), Jean-Michel Batto (FR), Marcelo Bertalan (DK), Natalia Borruel (ES), Francesc Casellas (ES), Leyden Fernandez (ES), Laurent Gautier (DK), Torben Hansen (DK), Masahira Hattori (JP), Tetsuya Hayashi (JP), Michiel Kleerebezem (NL), Ken Kurokawa (JP), Marion Leclerc (FR), Florence Levenez (FR), Chaysavanh Manichanh (ES), H. Bjørn Nielsen (DK), Trine Nielsen (DK), Nicolas Pons (FR), Julie Poulain (FR), Junjie Qin (CN), Thomas Sicheritz-Ponten (DK), Sebastian Tims (NL), David Torrents (ES), Edgardo Ugarte (FR), Erwin G. Zoetendal (NL), Jun Wang (CN), Francisco Guarner (ES), Oluf Pedersen (DK), Willem M. de Vos (FI), Søren Brunak (DK), Joel Doré (FR), Meta HIT Consortium (additional members), Jean Weissenbach (FR), S. Dusko Ehrlich (FR), and Peer Bork (DE) combined 22 newly sequenced fecal metagenomes of individuals from four countries with previously published data sets. Here they identify three robust clusters (referred to as enterotypes) that are not nation or continent specific. They also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host–microbial symbiotic states that might respond differently to diet and drug intake (54).

 

Richard S. Stephens (US), Sue Kalman (US), Claudia Lammel (US), Jun Fan (US), Rekha Marathe (US), L. Iyer Aravind (US), Wayne Mitchell (US), Lynn Olinger (US), Roman L. Tatusov (US), Qixun Zhao (US), Eugene V. Koonin (RU-US), and Ronald W. Davis (US) determined the genome sequence of Chlamydia trachomatis, an obligate intracellular pathogen of humans (1398).

 

Gerard Deckert (US), Patrick V. Warren (US), Terry Gaasterland (US), William G. Young (US), Anna L. Lenox (US), David E. Graham (US), Ross Overbeek (US), Marjory A. Snead (US), Martin Keller (US), Monette Aujay (US), Robert Huber (DE), Robert A. Feldman (US), Jay M. Short (US), Gary J. Olsen (US), and Ronald V. Swanson (US) determined the complete genome sequence of the hyperthermophilic bacterium Aquifex aeolicus (326).

 

Claire M. Fraser (US), Steven J. Norris (US), George M. Weinstock (US), Owen White (US), Granger G. Sutton (US), Robert J. Dodson (US), Michelle Gwinn (US), Erin K. Hickey (US), Rebecca A. Clayton (US), Karen A. Ketchum (US), Erica Sodergren (US), John M. Hardham (US), Michael P. McLeod (US), Steven Salzberg (US), Jeremy D. Peterson (US), Hanif Khalak (US), Delwood L. Richardson (US), Jerrilyn K. Howell (US), Monjula Chidambaram (US), Teresa R. Utterback (US), Lisa A. McDonald (US), Patricia Artiach (US), Cheryl Bowman (US), Matthew D. Cotton (US), and John Craig Venter (US) determined the complete genome sequence of Treponema pallidum, the spirochete of syphilis. A comparison of the T. pallidum genome sequence with that of another pathogenic spirochete, Borrelia burgdorferi, the agent of Lyme disease, identified unique and common genes and substantiates the considerable diversity observed among pathogenic spirochetes (437).

 

Gerald B. Pier (US), Martha Grout (US), Tanweer S. Zaidi (US), Gloria J. Meluleni (US), Simone S. Mueschenborn (US), George Banting (US), Rosemary Ratcliff (US), Martin John Evans (US), William H. Colledge (US), and Deborah Josefson (US) found that Salmonella typhi, but not the related murine pathogen Salmonella typhimurium, uses cystic fibrosis transmembrane conductance regulator (CFTR) for entry into epithelial cells. To be susceptible to S. typhi the host must be homozygous for the CFTR allele. Heterozygotes (carriers) are resistant to entry by S. typhi. Increased resistance to infectious diseases may help maintain mutant CFTR alleles at high levels in selected populations (722; 1163).

 

Stewart T. Cole (FR), Roland Brosch (FR), Julian Parkhill (GB), Thierry Garnier (FR), Carol M. Churcher (GB), David Harris (GB), Stephen V. Gordon (FR), Karin Eiglmeier (FR), Shahinaz Gas (FR), Clifton E. Barry, 3rd (US), Fredj Tekaia (FR), Karen L. Badcock (GB), David Basham (GB), David Brown (GB), Tracey Chillingworth (GB), Ruth Connor (GB), Rob Davies (GB), Karen Devlin (GB), Theresa Feltwell (GB), S. Gentles (GB), Nancy Hamlin (GB), Simon Holroyd (GB), T. Hornsby (GB), Kay Jagels (GB), Anders Krogh (DK), J. McLean (GB), Sharon Moule (GB), Lee Murphy (GB), Karen Oliver (GB), John Osborne (GB), Michael A. Quail (GB), Maire-AdeÁle Rajandream (GB), Jane Rogers (GB), Simon Rutter (GB), Kathy Seeger (GB), Jason Skelton (GB), Robert Squares (GB), Steven Squares (GB), John Edward Sulston (GB), K. Taylor (GB), Sally Whitehead (GB) and Barclay George Barrell (GB) determined and analyzed the complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv. The genome comprises 4,411,529 base pairs, contains around 4,000 genes, and has a very high guanine + cytosine content that is reflected in the biased amino acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the production of enzymes involved in lipogenesis and lipolysis, and to two new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation (267).

 

An informal group of researchers from major institutions worldwide came together under the title of the 'Angiosperm Phylogeny Group' or APG. Their intention was to provide a widely accepted and more stable point of reference for angiosperm classification. Their initial 1998 paper made angiosperms the first large group of organisms to be systematically re-classified primarily on the basis of genetic characteristics (44).

 

Kent D. Chapman (US), Swati Tripathy (US), Barney J. Venables (US), and Arland D. Desouza (US) presented evidence that N-acetylethanolamine may participate in the early signal transduction events leading defense responses in plants (228).

 

John Edward Sulston (GB), Robert Waterston (US), Rachael Ainscough (GB), Simon Bardill (GB), Karen Barlow (GB), Victoria Basham (GB), Caroline Baynes (GB), Lisa Beard (GB), Alastair Beasley (GB), Mary Berks (GB), James Bonfield (GB), Jacqueline Brown (GB), Christine Burrows (GB), John Burton (GB), Connie Chui (GB), Emma Clark (GB), Louise Clark (GB), Gerard Colville (GB), Theresa Copsey (GB), Amanda Cottage (GB), Alan R. Coulson (GB), Molly Craxton (GB), Auli Cummings (GB), Paul Cummings (GB), Simon Dear (GB), Thomas Dibling (GB), Richard Dobson (GB), Jonathan Doggett (GB), Richard Durbin (GB), Jullian Durham (GB), Andrew Ellington (GB), David Evans (GB), Kerry Fleming (GB), John Fowler (GB), Debbie Frame (GB), Audrey Fraser (GB), Alison Gardner (GB), Jane Garnett (GB), Iain Gray (GB), Jane Gregory (GB), Mark Griffiths (GB), Sarah Hall (GB), Barbara Harris (GB), Trevor Hawkins (GB), Cathy Hembry (GB), Sarah Holmes (GB), Bijay Jassal (GB), Matt Jones (GB), Steve Jones (GB), Ann Joy (GB), Paul Kelly (GB), Joanna Kershaw (GB), Andrew Kimberley (GB), Yuji Kohara (GB), Neil Laister (GB), Dan Lawson (GB), Nicola Lennard (GB), Julia Lightning (GB), Simon Limbrey (GB), Sarah Lindsay (GB), Christine Lloyd (GB), Simon Margerison (GB), Anna Marrone (GB), Lucy Matthews (GB), Paul Matthews (GB), Rebecca Mayes (GB), Kirstin McLay (GB), Amanda McMurray (GB), Mark Metzstein (GB), Simon Miles (GB), Nicholas Mills (GB), Maryam Mohammadi (GB), Beverley Mortimore (GB), Mary O’Callaghan (GB), Anthony Osborn (GB), Sophie Palmer (GB), Chantal Percy (GB), Adelaide Pettett (GB), Emma Playford (GB), Michelle Pound (GB), Rebecca Rocheford (GB), Jane Rogers (GB), David Saunders (GB), Maggie Searle (GB), Katherine Seeger (GB), Ratna Shownkeen (GB), Matthew Sims (GB), Nicola Smaldon (GB), Andrew Smith (GB), Michelle Smith (GB), Mike Smith (GB), Rebekah Smye (GB), Erik Sonnhammer (GB), Rodger Staden (GB), Charles Steward (GB), June Swinburne (GB), Ruth Taylor (GB), Louise Tee (GB), Jean Thierry-Mieg (GB), Karen Thomas (GB), Jeanette Usher (GB), Mellanie Wall (GB), Justine Wallis (GB), Andy Watson (GB), Sarah White (GB), Anna Wild (GB), Jane Wilkinson (GB), Leanne Williams (GB), Jenny Winster (GB), Isabel Wragg (GB), Amanda Abbott (US), Jane Abu-Threideh (US), Craig Ahrens (US), Ella Alexander (US), Johar Ali (US), Mark Ames (US), Kirsten Anderson (US), Stephanie Andrews (US), Susanna Angell (US), Paul Antonacci (US), Lucinda Antonacci-Fulton (US), Bessie Antoniou (US), Damon Baisden (US), Lilla Bartko (US), Shiv Basu (US), Chris Bauer (US), Cathy Beck (US), Michael Becker (US), Louis Begnel (US), Kirk Behymer (US), Gary Bemis (US), Dan Bentley (US), Zachary Bevins (US), Thomas Biewald (US), Linda Blackwood (US), Donald Blair (US), Mary Blanchard (US), Mary Blandford (US), Elizabeth Boatright (US), Sherell Bourne (US), Kyle Bova (US), Holland Bradshaw (US), Ryan Brinkman(US), Rose Brockhouse(US), Michelle Broy (US), Christina Budnicki (US), Jennifer Burkhart (US), Tracy Caffrey (US), Kelly Carpenter (US), Tim Carter (US), Brandi Chiapelli (US), Asif Chinwalla (US), Stephanie Chissoe (US), Kathleen Clarke (US), Sandy Clifton, Jim Cloud, Molly Cofman, Megan Connell (US), Mark Cook (US), Judy Cooper (US), Matt Cooper (US), Matthew Cordes (US), Marc Cotton (US), Jennifer Couch (US), Laura Courtney (US), Krista Creason (US), Robin Crocker (US), Jye’Mon Crockett (US), Taquilla Crum (US), Michael Dante (US), Betty Darron (US), Ruth Davenport (US), Michelle David (US), Sharon Davidson (US), Teresa Davidson (US), Shanoa Davis (US), Andy Delehaunty (US), Sandy Dempsey (US), Jasna Despot (US), Hong Ding (US), Maggie Dotson (US), Kristy Drone (US), Hui Du (US), Zijin Du (US), Chad Dubbelde (US), Treasa DuBuque (US), Grant Duckels (US), Sean Eddy (US), Jennifer Edwards (US), Glendoria Elliott (US), Efrem Exum (US), Anthony Favello (US), Ginger Fewell (US), Tanya Fiedler (US), Lisa Flagg (US), William Fronick (US), Bob Fulton (US), Tony Gaige (US), Stacie Gattung (US), Cynthia Geisel (US), Steve Geisel (US), Alicia Gibson (US), Candi Giddings (US), Barbara Gillam (US), Warren Gish (US), Danielle Glossip (US), Jennifer Godfrey (US), Deepa Goela (US), Norma Goins (US), Tina Graves (US), Tracie Greco (US), Phil Green (US), Serena Gregory (US), William Haakenson (US), Priscilla Hale (US), Charles Harkins (US), Gwen Harmon (US), Mark Harper (US), Anthony Harris (US), Michelle Harrison (US), James Hawkins (US), Maria Hawkins (US), Clay Hawryszko (US), Chuck Heidbrink (US), John Henkhaus (US), LaDeana Hillier (US), Kurt Hinds (US), Michael Holman (US), Andrea Holmes (US), Donna Hopson (US), Melissa Hotic (US), Monica Hultman (US), Ann Jacobs (US), Craig Jenkins (US), Mohamed Jier (US), Doug Johnson (US), Mark Johnston (US), Brenda Jones (US), Kimberly Jones (US), Paula Kassos (US), Kimberly Keen (US), Jennifer Kellen (US), Kimberly Kemp (US), Deana Keppler (US), Amy Kerstetter (US), Melissa Ketterman (US), Kyung Kim (US), Mark King (US), Jennifer Kirsten (US), Bill Klinke (US), Jeremy Kock (US), Sara Kohlberg (US), Ian Korf (US), Amy Kozlowicz (US), Jason Kramer (US), Rebecca Krauss (US), Tamara Kucaba (US), Michelle Lacy (US), Thomas Lakanen (US), Betty Lamar (US), Yvonne Langston (US), Yvonne LaPlant (US), John Latreille (US), Daniel Layman (US), Thomas Le (US), Thuy-Tien Le (US), Tri-Tin Le (US), John Ledwith (US), Lynn Lehnert (US), Darcy Leimbach (US), Sarah Lennox (US), Shawn Leonard (US), Lili Li (US), Paul Lowery (US), Terrie Lynch (US), Chris Macri (US), Len Maggi (US), Maggi Maher (US), Elaine Mardis (US), Marco Marra (US), Gabor Marth (US), John Martin (US), Rachel Maupin (US), Ken McDonald (US), Ramonna McDonald (US), Rebecca McGrane (US), Kelly Mead (US), Becky Meininger (US), Sandra Menezes (US), Brian Merry (US), Rebecca Miko (US), Kevin Miller (US), Nancy Miller (US), Walt Miller (US), Brian Minges (US), Patrick Minx (US), Tonya Modde (US), Bradley Moore (US), Matthew Morris (US), Garrett Mullen (US), Molly Mullen (US), Jennifer Murray (US), Diane Nelson (US), Joanne Nelson (US), Amy Nguyen (US), Christine Nguyen (US), Nham Nhan (US), Susan Nichols (US), Laura Niemann (US), David O’Brien (US), Darla O’Neal (US), Ben Oberkfell (US), Amy Ozanich (US), Philip Ozersky (US), Dimitrios Panussis (US), Kimberly Pape (US), Jeremy Parsons (US), Adele Pauley (US), Charlene Pearman (US), Dale Paluso (US), Kymberlie Pepin (US), Denise Peterson (US), Amy Phillips (US), Craig Pohl (US), Faye Prevedell (US), Tim Raichle (US), Jennifer Randall (US), Mary Reynolds (US), Carrie Rhine (US), Lorrie Rice (US), Joanne Rieff (US), Lisa Rifkin (US), Linda Riles (US), Judy Robertson (US), Kerry Robinson (US), David Rohleder (US), Tracy Rohlfing (US), Chris Rose (US), Ellen Ryan (US), Laura Sammons (US), Brent Sandberg (US), Jill Sansone (US), Lisa Sapetti (US), Mark Schaller (US), Carrie Schaus (US), Paul Scheet (US), Emilie Scherger (US), Ann Schrader (US), Brian Schultz (US), Doug Scronce (US), Shawn Shafer (US), Kimberly Shih (US), Arthur Simonyan (US), Joanne Small (US), Aimee Smith (US), Reene Smith (US), Jackie Snider (US), Lisa Spalding (US), John Spieth (US), Peter St. Zachary (US), David States (US), Shayla Stein (US), Laurita Stellyes (US), Nathan Stitziel (US), Tamberlyn Stoneking (US), Cindy Strong (US), Joe Strong (US), Catrina Stowmatt (US), Eric Stuebe (US), Jessica Stunpf (US), Veronika Sudnekevich (US), Carrie Sutterer (US), Alison Taich (US), Sameer Talcherkar (US), Aye Tin-Wollam (US), Evanne Trevaskis (US), Susan Tucci (US), Bradley Twyman (US), Karen Underwood (US), Phillip Valencia (US), Scott Valentine (US), Mark Vaudin (US), Kevin Vaughan (US), Joelle Veizer (US), Dana Vignati (US), Caryn Wagner-McPherson (US), Christopher Walker (US), Pamela Wamsley (US), Lori Weinstock (US), Michael Wendl (US), Rod White (US), Lori Wilcox (US), Alma Willis (US), Curtis Wilson (US), Richard Wilson (US), Mark Winkelmann (US), Jeffrey Woessner (US), Patricia Wohldmann (US), Cliff Wollam (US), Kimberly Woods (US), Xiaoyun Wu (US), Shiaw-Pyng Yang (US), Martin Yoakum (US), Xiao Zheng (US), Hui Zhu (US), and Michael Zidanic (US) were the first to determine the complete DNA sequence of an animal genome. The animal was a small invertebrate, the nematode (or roundworm) Caenorhabditis elegans, and the sequence consists of about 97 million base pairs of DNA, approximately one-thirtieth the number in the human genome. This is eight times the size of Saccharomyces cerevisiae, the only other eukaryote (Eucarya) sequenced to this date (11 December) (1416).

 

Anna C. Sharman (DE) and Michael Brand (DE) knocked out the Otx and Emx genes in Drosophila by deliberately mutating them then rescuing them by inserting human Hox genes. Thus they demonstrated in a very dramatic way the equivalency of fly and human genes (1329).

 

Jay C. Dunlap (US) proposed a model to explain the molecular biology of circadian rhythms. It proposes that proteins with PAS domains form heterodimers that bind DNA at specific sites, called E-boxes. E boxes are located in the promoter region of oscillator genes such as Drosphila per and tim. Binding of the heterodimer to the E box leads to the transcription of the oscillator genes. The proteins produced then feedback to ultimately inhibit their own production (361). Note: PAS domains are involved in many signaling proteins where they are used as a signal sensor domain. The PAS domain was named after three proteins in which it occurs: Per- period circadian protein, Arnt- Ah receptor nuclear translocator protein, and Sim- single-minded protein.

 

Sarah C. Gilbert (GB), Magdalena Plebanski (GB), Sunetra Gupta (GB), Joanna Morris, Martin Cox (GB), Michael Aidoo (GB), Dominic Kwiatkowski (GB), Brian M. Greenwood (GB), Hilton C. Whittle (GB), and Adrian V.S. Hill (GB) discovered that in African children infected with the malarial parasite Plasmodium falciparum, the parasitic variants present are influenced by the presence of a human leukocyte antigen (HLA) type that restricts the immune response to this epitope (496).

 

David Garrick (AU), Steven Fiering (AU), David I.K. Martin (AU), and Emma Whitelaw (AU) established that the presence of multiple homologous copies of a transgene within a concatameric array could have a repressive effect upon gene expression in mammalian systems (470).

 

Marsha Willis-Karp (US), Jackie Luyimbazi (US), Xueying Xu (US), Brian Schofield (US), Tamlyn Y. Neben (US), Christopher L. Karp (US), and Debra D. Donaldson (US) discovered that the type 2 cytokine IL-13 (interleukin-13), which shares a receptor component and signaling pathway with IL-4, is necessary and sufficient for expression of allergic asthma (1577).

 

Joan Sayos (IL), Caroline Wu (CA), Massimo Morra (US), Ninghai Wang (US), Xingmin Aaron Zhang (US), Deborah Allen (US), Sandrijn van Schaik (US), Luigi Daniele Notarangelo (US), Raif Geha (US), Maria G. Roncarolo (IT), Hans C. Oettgen (US), Jan E. De Vries (NL), Gregorio Aversa (US), and Cox Terhorst (US) found that the gene encoding SLAM-associated protein (SAP) maps to the same area of the X chromosome as the locus for X-linked lymphoproliferative disease (XLP) and they found mutations in the (SAP) gene in three XLP patients. Absence of the inhibitor SAP in XLP patients affects T/B-cell interactions induced by SLAM, leading to an inability to control B-cell proliferation caused by Epstein-Barr virus infections (1283). Note: The protein SLAM (also known as CDw150), is present on the surface of B and T cells.

 

Haig H. Kazazian, Jr. (US), and John V. Moran (US) reported that the Alu retrotransposon (180-280 bp) might be repeated a million times in the human genome (747).

 

Tohru Kitada (JP), Shuichi Asakawa (JP), Nobutaka Hattori (JP), Hiroto Matsumine (JP), Yasuhiro Yamamura (JP), Shinsei Minoshima (JP), Masayuki Yokochi (JP), Yoshikuni Mizuno (JP), and Nobuyoshi Shimizu (JP) discovered that mutations in the PARKIN gene cause autosomal recessive juvenile parkinsonism (771).

 

Amanda Swain (GB), Veronica Narvaez (MX), Paul S. Burgoyne (GB), Giovanna Camerino (IT), and Robin H. Lovell-Badge (GB) reported that the Dax gene on the X chromosome and Sry, the male determining gene on the Y chromosome, are antagonistic to each other. One Sry defeats one Dax, but two copies of Dax defeat one Sry (1425). Note: Sry begins the cascade of events that leads to the masculinization of the embryo.

 

Adrian W. Philbey (AU), Peter D. Kirkland (AU), Anthony D. Ross (AU), Rodney J. Davis (AU), Anne B. Gleeson (AU), Robert J. Love (AU), Peter W. Daniels (AU), Allan R. Gould (AU), and Alex D. Hyatt (AU) isolated a previously unknown virus, Menangle virus (Men V). It came from deformed stillborn piglets collected at a large commercial piggery in New South Wales, Australia. Affected stillborn piglets frequently had severe degeneration of the brain and spinal cord, arthrogryposis, brachygnatha, and occasionally fibrinous body cavity effusions and pulmonary hypoplasis (1157).

 

Julio I. Maiztegui (AR), Kelly T. McKee, Jr. (US), Julio G. Barrera Oro (AR-US), Lee H. Harrison (US), Paul H. Gibbs (US), Maria R. Feuillade (AR), Delia A. Enria (AR), Ana M. Briggiler (AR), Silvana C. Levis (AR), Ana M. Ambrosio (AR), Neal A. Halsey (US), and Clarence J. Peters (US) reported the efficacy of a live attenuated virus vaccine for treating Argentine hemorrhagic fever (AHF). This is an acute disease caused by Junin virus (JUNV, Arenaviridae), which has been an important issue to public health in Argentina since the early 1950s. The field rodent Calomys musculinus is the natural reservoir of JUNV and human disease is a consequence of contact with infected rodents (931). Note: The vaccine was developed in 1985.

 

The United Kingdom Prospective Diabetes Study (UKPDS), a compilation over 20 years, confirmed the value of tight glucose control in type 2 diabetes (1488).

 

Peter S. Eriksson (SE), Ekaterina Perfilieva (SE), Thomas Bjorj-Eriksson (SE), Ann-Marie Alborn (SE), Claes Nordborg (SE), Daniel A. Peterson (US), and Fred H. Gage (US) observed that neurons do grow and divide in the hippocampus region of the adult human brain (381). Note: This was the first evidence of the genesis of new neurons in the human brain.

 

Akira Kakizuka (JP) noted that many human diseases are caused by expanded three-letter word repeats (e.g. CAG repeated within an allele many times more than is normal)—the so called polyglutamic diseases. The resulting elongated proteins tend to accumulate in indigestible lumps within the cells causing severe cellular malfunction (728).

 

Stefan W. Henning (GB), Doreen Ann Cantrell (GB), Leslie V. Parise (US), Jung Weon Lee (US), Rudoph L. Juliano (US), Claus Liebmann (DE), Yiwen Li (US), Marco I. Gonzalez (US), Judy L. Meinkoth (US), Jeffrey Field (US), Marcelo G. Kazanietz (US), Gihan I. Tennekoon (US), Kayoko Kinbara (US), Lawrence E. Goldfinger (US), Malene F. Hansen (US), Fan-Li Chou (US), Mark H. Ginsberg (US), Bret B. Friday (US), and Alex A. Adjei (US) reported that the mitogen-activated protein kinase (MAPK) cascade is a key intracellular signaling pathway that regulates diverse cellular functions including cell proliferation, cell cycle regulation, cell survival, angiogenesis, and cell migration (Fig. 1). The cascade includes a diverse group of members, but is generally described as a linear signaling pathway initiated by receptor tyrosine kinases at the cell surface and culminates in the regulation of gene transcription in the nucleus directed by the extracellular signal–regulated kinase (Erk). Although conceptually linear, considerable cross talk occurs between the Ras/Raf/MAPK/Erk kinase (MEK)/Erk MAPK pathway and other MAPK pathways, as well as, many other signaling cascades. The pivotal role of the Ras/Raf/MEK/Erk MAPK pathway in multiple cellular functions underlies the importance of the cascade in oncogenesis and growth of transformed cells. As such, the MAPK pathway has been a focus of intense investigation for therapeutic targeting.

Classic activation of the MAPK cascade occurs following ligand binding to a receptor tyrosine kinase at the cell surface, but a vast array of other receptors have the ability to activate the cascade as well, such as integrins, serpentine receptors, hetero- trimeric G-proteins, and cytokine receptors (201; 442; 626; 760; 870; 873; 1126).

 

Aihui Wang (US), Yong Liang (US), Robert A. Fridell (US), Frank J. Probst (US), Edward R. Wilcox (US), Jeffrey W. Touchman (US), Cynthia C. Morton (US), Robert J. Morell (US), Konrad Noben-Trauth (US), Sally A. Camper (US), and Thomas B. Friedman (US) identified mutations in a newly discovered gene, MYO15, that can cause one of the most common forms of inherited deafness, nonsyndromic recessive deafness (1534). Note: Research on a similar protein in mice led scientists to speculate that MYO15 plays an important role in the functioning of the inner ear hair cells.

 

Mihaela Skobe (US) and Norbert E. Fusenig (DE) demonstrated that an activated stromal environment could promote tumorigenic conversion of nontumorigenic keratinocytes by inducing sustained epithelial hyperproliferation. This effect is apparently caused by a dual action of platelet-derived growth factor (PDGF-BB): (i) PDGF-BB can promote tumor growth by inducing angiogenesis and stromal formation, and (ii) PDGF-activated stromal cells maintain elevated keratinocyte proliferation via a paracrine mechanism. Thus, PDGF, a major factor activated in wound healing, may play an important role as an endogenous promoter in epithelial tumor formation (1351).

 

Kenneth W. Kinzler (US), Bert Vogelstein (US), Aria F. Olumi (US), Gary D. Grossfeld (US), Simon W. Hayward (US), Peter R. Carroll (US), Thea D. Tisty (US), and Gerald R. Cunha (US) discovered that in some tumors, cooperating cells (non-cancerous cells secreting growth factors) can eventually depart from normalcy, coevolving with their malignant neighbors in order to sustain the growth of the latter (764; 1107).

 

Gail A. Leget (US) and Myron S. Czuczman (US) reported that rituximab is the first monoclonal antibody approved by the US Food and DrugAdministration for the treatment of cancer. Rituximab, is a monoclonal antibody, for use in patients with treatment-resistant, low-grade or follicular B-cell non-Hodgkin lymphoma (NHL). Rituximab was later approved as an initial treatment for these types of NHL, for another type of NHL called diffuse large B-cell lymphoma, and for chronic lymphocytic leukemia (849).

 

He-Ping Yan (US), Clint E. Carter (US), En-ze Wang (US), David L. Page (US), Kay Washington (US), Barbara D. Wamil (US), F. Michael Yakes (US), Gary B. Thurman (US), and Carl Gustaf Hellerqvist (US) reported that Group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress produces a polysaccharide exotoxin (CM101) which has been previously described as GBS toxin. CM101 infused i.v. into tumor-bearing mice causes rapid tumor neovascularitis, infiltration of inflammatory cells, inhibition of tumor growth and tumor apoptosis. CM101 has successfully completed phase I studies in refractory cancer patients with very encouraging results. They have now demonstrated a mechanism of action for CM101. Using a normal mouse tumor model, they examined tumor and normal tissues, which were harvested at 0, 5, 15, 30 and 60 min post-infusion of either CM101 or dextran. They presented evidence that CM101 is rapidly (within the first 5min) bound to the tumor neovasculature. Complement is activated by the alternative pathway (C3) and leukocytes start to infiltrate the tumor within the first 5min. Through RT-PCR and immunohistochemical techniques, they demonstrate that proinflammatory cytokines, interleukin-6 and tumor necrosis factor (TNF)-alpha, are up-regulated in infiltrating leukocytes and TNF receptor 2 is up- regulated in the targeted tumor neovasculature. Combined, these events constitute possible explanations for the observed pathophysiology of tumor ablation (1607).

 

Artur W. Wamil (US), Barbara D. Wamil (US), and Carl Gustaf Hellerqvist (US) administered CM101, an antiangiogenic polysaccharide derived from group B Streptococcus, by intravenous injection 1 hr. post-spinal-cord crush injury in an effort to prevent inflammatory angiogenesis and gliosis (scarring) in a mouse model. Electrophysiologic measurements on isolated central nervous system and neurons in culture showed that CM101 protected axons from Wallerian degeneration; reversed gamma-aminobutyrate-mediated depolarization occurring in traumatized neurons; and improved recovery of neuronal conductivity of isolated central nervous system in culture (1533).

 

David Gozal (US) found that sleep-associated gas exchange abnormalities were highly prevalent among a first-grade study cohort with poor academic performance. About 18% of participants had oxygenation abnormalities assessed during overnight observation. School performance, as gauged by grades, improved significantly among children who received surgical intervention for abnormal breathing patterns during sleep. Symptoms of disordered sleep, as assessed by follow-up questionnaire, were significantly worse among children who did not undergo surgical tonsillectomy and adenoidectomy (524).

 

Mark D. Pegram (US), Allen Lipton (US), Daniel F. Hayes (US), Barbara L. Weber (US), Jose M. Baselga (US), Debu Tripathy (US), Debbie Baly (US), Sharon A. Baughman (US), Tom Twaddel (US), John A. Glaspy (US), Dennis J. Slamon (US), Brian Leyland-Jones (US), Steven Shak (US), Hank Fuchs (US), Virginia Paton (US), Alex Bajamonde (US), Thomas Fleming (US), Wolfgang Eiermann (DE), Janet Wolter (US), and Larry Norton (US) report that patients with HER-2/neu-positive metastatic breast cancer who were treated with chemotherapy plus trastuzumab (Herceptin) lived longer and their tumors showed a greater decrease in size compared with those in patients who received chemotherapy alone (1142; 1353).

 

Mark N. Levine (CA), Vivien H. Bramwell (CA), Kathleen I. Pritchard (CA), Brian D. Norris (CA), Lois E. Shepherd (CA), Hakam Abu-Zahra (CA), Brian Findlay (CA), David Warr (CA), David M. Bowman (CA), James Myles (CA), Andrew Arnold (CA), Ted Vandenberg (CA), Robert MacKenzie (CA), Nicholas J. Robert (US), Jon Ottaway (CA), Margot Burnell (CA), Charlotte K. Williams (CA), and Dongsheng Tu (CA) showed the superiority of a regimen of cyclophosphamide, epirubicin, and fluorouracil over cyclophosphamide, methotrexate, and fluorouracil in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer (857). Note: These drugs are anthracyclines.

Miguel Martin (ES), Tadeusz Pienkowski (ES), John Mackey (ES), Marek Pawlicki (ES), Jean-Paul Guastalla (ES), Charles Weaver (ES), Eva Tomiak (ES), Taher Al-Tweigeri (ES), Linnea Chap (ES), Eva Juhos (ES), Raymond Guevin, Anthony Howell (ES), Tommy Fornander (ES), John Hainsworth (ES), Robert Coleman (ES), Jeferson Vinholes (ES), Manuel Modiano (ES), Tamas Pinter (ES), Shou C Tang (ES), Bruce Colwell (ES), Catherine Prady (ES), Louise Provencher (ES), David Walde (ES), Alvaro Rodriguez-Lescure (ES), Judith Hugh (ES), Camille Loret (ES), Matthieu Rupin (ES), Sandra Blitz (ES), Philip Jacobs (ES), Michael Murawsky (ES), Alessandro Riva (ES), Charles Vogel (ES), and The Breast Cancer International Research Group 001 Investigators used a prospective multi-center randomized controlled trial to show that the addition of a taxane to anthracycline-based chemotherapy can significantly improve disease-free and overall survival (947).

 

Tomohiko Maehama (JP) and Jack E. Dixon (US) identified the substrate of the tumor suppressor, phosphatase and tensin homolog (PTEN). It is a phospholipid, phosphatidylinositol 3,4,5-trisphosphate. Phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) is a key molecule involved in cell growth signaling. This was the first reported example of a protein-tyrosine phosphatase (PTPase) that functioned to dephosphorylate a lipid second messenger, and it also established the biological function of PTEN. The discovery explained why and how PTEN functioned as a tumor suppressor gene, and this in turn suggested which signaling pathway could be targeted in treating cancers where there was a loss of this gene (926).

Michael P. Myers (US), Ian Pass (GB), Ian H. Batty (GB), Jeroen Van der Kaay (GB), Javor P. Stolarov (US), Brian A. Hemmings (CH), Michael H. Wigler (US), C. Peter Downes (GB), and Nicholas K. Tonks (US) showed that the lipid phosphatase activity of PTEN is critical for its tumor suppressor function (1047). Note: This observation focused attention on the PI3K pathway in cancer development, which became an important area of drug development.

 

Kathryn L. Burgio (US), Julie L. Locher (US), Patricia S. Goode (US), J. Michael Hardin (US), B. Joan McDowell (US), Marianne Dombrowski (US), and Dorothy Candib (US) found that for treatment of urgency incontinence, behavioral intervention was associated with the greatest reduction in incontinence episodes and the highest patient satisfaction rates compared to standard drug treatment with oxybutynin or placebo (184).

 

The Collaborative Normal-Tension Glaucoma Study Group (US) reported that reduction of intra-ocular pressure (IOP) with topical medications in normal-tension glaucoma significantly reduced risk of progression to visual field impairment and/or optic disc damage (546; 547).

 

Gary P. Jacobson (US) and Craig W. Newman (US) developed the 25-item Dizziness Handicap Inventory (DHI) to evaluate the self-perceived handicapping effects imposed by vestibular system disease. The development of the preliminary (37 items) and final versions (25 items) of the DHI are described (701).

 

Paul A. Luce (US) and David B. Pisoni (US) demonstrated that the number and nature of words in a similarity neighborhood affect the speed and accuracy of word recognition. The results of these experiments have important implications for current conceptions of auditory word recognition in normal and hearing impaired populations of children and adults (908).

 

Lennart Hansson (NL), Alberto Zanchetti (IT), S. George Carruthers (CA), Björn Dahlöf (SE), Dag Elmfeldt (NL), Stevo Julius (US),Joel Ménard (FR), Karl Heinz Rahn (DE), Hans Wedel (SE), and Sten Westerling(SE) reported the principal results of the Hypertension Optimal Treatment (HOT) randomised trial as: 1) intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events, 2) the HOT Study shows the benefits of lowering the diastolic blood pressure down to 82·6 mm Hg, 3) acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction, 4) there was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common (594).

 

The United Kingdom Prospective Diabetes Study (UKPDS) Group found that the use of pharmacologic agents (i.e., sulfonylureas, insulin, and metformin) in patients with type 2 diabetes mellitus (T2DM) significantly reduces their risk for developing microvascular complications. Because metformin is linked with reduced diabetes-related mortality, all-cause mortality, and lower risk of hypoglycemia, it is often considered the first-line pharmacotherapy in managing T2DM. Moreover, tight blood pressure control has been shown to significantly reduce the incidence of microvascular and macrovascular complications, as well as diabetes-related mortality. The long duration, effective randomization, and large study population of the UKPDS are factors that have made its findings highly influential (557-559).

The Diabetes Prevention Program Research Group (US) concluded that lifestyle changes and treatment with Metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than Metformin (781).

 

Colin B. Begg (US), Laura D. Cramer (US), William J. Hoskins (US), Murray F. Brennan (US), Emily V. Finlayson (US), Philip P. Goodney (US), John D. Birkmeyer (US), Sheraz R. Markar (US), Alan Karthikesalingam (GB), Sri Thrumurthy GB, and Donald E. Low (US) showed that mortality post-esophagectomy is inversely proportinal to hospital volume, although many other factors such as case-mix may be just as relevant. They noted that many low volume units have demonstrated excellent results (105; 416; 944).

 

Increasingly, the amphibian chytrid fungus (Batrachochytrium dendrobatidis) has been implicated as a major contributor to global catastrophic declines in frog populations.

Lee Berger (AU), Rick Speare (AU), Peter Daszak (AU), D. Earl Green (AU), Andrew A. Cunningham (AU), C. Louise Goggin (AU), Ron Slocombe (AU), Mark A. Ragan (AU), Alex D. Hyatt (AU), Keith R. McDonald (AU), Harry B. Hines (AU), Karen R. Lips (AU), Gerry Marantelli (AU), and Helen Parkes (AU) concluded that cutaneous chytridiomycosis is a fatal disease of anurans, and they hypothesized that it is the proximate cause of recent amphibian declines (112).

Ché Weldon (ZA), Louis H. du Preez (ZA), Alex D. Hyatt (AU), Reinhold Muller (AU), and Rick Speare (AU) proposed that Africa is the origin of the amphibian chytrid Batrachochytrium dendrobatidis and that the international trade in Xenopus laevis that began in the mid-1930s was the means of dissemination (1561).

 

Maciej Henneberg (AU) and Renato J. Henneberg (AU) found dental evidence in the Greek colony of Metaponto, in Southern Italy, that syphilis existed in Mediterranean populations as early as 600 BCE (625).

 

Arthur L. Burnett (US), Devin G. Johns (US), Lance J. Kriegsfeld (US), Sabra L. Klein (US), David C. Calvin (US), Gregory E. Demas (US), Lawrence P. Schramm (US), Susumu Tonegawa (US), Randy J. Nelson (US), Solomon Halbert Snyder (US), and Kenneth D. Poss (US) implicated carbon monoxide (CO) in neurotransmission associated with male copulatory activity in mice (185).

 

Irwin Goldstein (US), Tom F. Lue (US), Harin Padma-Nathan (US), Raymond C. Rosen (US), William D. Steers (US), and Pierre A. Wicker (US) evaluated the efficacy and safety of sildenafil (Revatio; Viagra), administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic, psychogenic, and mixed causes. They found that oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction (507).

 

The UK Perspective Diabetes Study Group found that tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity (556).

 

Hervé Decousus (FR), Alain Leizorovicz (FR), Florence Parent (FR), Yves Page (FR), Bernard Tardy (FR), Philippe Girard (FR), Silvy Laporte (FR), René Faivre (FR), Bernard Charbonnier (FR), Fabrice-Guy Barral (FR), Yann Huet (FR), and Gérald Simonneau (FR) showed in high-risk patients with proximal deep-vein thrombosis, the initial beneficial effect of vena caval filters for the prevention of pulmonary embolism was counterbalanced by an excess of recurrent deep-vein thrombosis, without any difference in mortality. Our data also confirmed that low-molecular-weight heparin was as effective and safe as unfractionated heparin for the prevention of pulmonary embolism (327).

 

The UK Small Aneurysm Trial Participants conducted a multi-center randomised controlled trial to determine whether early prophylactic open surgery is the best management for smaller abdominal aortic aneurysms of 4.0-5.5 cm in diameter. They concluded that no long-term survival advantage is attendant to early open surgery (1131).

 

William C. Nichols (IL), Uri Seligsohn (IL), Ariella Zivelin (IL), Valeri H. Terry (US), Colette E. Hertel (US), Matthew A. Wheatley (US), Micheline J. Moussalli (US), Hans-Peter Hauri (CH), Nicola Ciavarella (IT), Randal J. Kaufman (US), and David Ginsburg (US) studied the pathogenesis of the combined factor V and VIII deficiency, a very rare hereditary bleeding disorder. The genetic locus of this disorder was mapped to chromosome 18q, and LMAN1 (ERGIC‐53) was unexpectedly identified as the gene responsible for the disorder with mutations of this gene found in patients (1070).

 

Lloyd B. Minor (US), David Solomon (US), James S. Zihreich (US), David S. Zee (US), Wade W. Chien (US), and John P. Carey (US) found that sound and/or pressure-induced vertigo can be due to bone dehiscence of the superior semicircular canal. They proposed surgical plugging of the superior semicircular canal dehiscence via a middle caranial fossa craniotomy as a therapeutic intervention (241; 1001; 1002).

 

Bernard Fisher (US), James Dignam (US), Norman Wolmark (US), Eleftherios P. Mamounas (US), Joseph Costantino (US), William Poller (US), Edwin R. Fisher (US), D. Lawrence Wickerham (US), Melvin Deutsch (US), Richard G. Margolese (CA), Nikolay V. Dimitrov (US), Maureen T. Kavanah (US) Roy Smith (US), Mirsada Begovic (US), Carl G. Kardinal (US), Louis Fehrenbacher (US), and Robert H. Oshi (US), from prospective randomized controlled trials, concluded that radiotherapy halves the risk of developing recurrent ductal carcinoma in situ and also reduces the risk of developing invasive cancer of the breast following local surgery. Tamoxifen also has a beneficial effect in this setting by reducing the risk of breast cancer, primarily in the contralateral breast (418; 419).

 

Eric Steven Lander (US) and Joseph J. Ellis (US) presented evidence from DNA analysis that the third U.S. President, Thomas Jefferson, fathered at least one child by his slave, Sally Hemings (822).

 

Rodhey S. Gupta (CA) concluded “ all eukaryotic cells, including amitochondriate and aplastidic cells received major genetic contributions to the nuclear genome from both an archaebacterium (very probably of the eocyte, i.e., thermoacidophil group and a gram-negative bacterium…[t]he ancestral eukaryotic cell never directly descended from archaebacteria but instead was a chimera formed by fusion and integration of the genomes of an archaebacterium and a gram-negative bacterium” (567).

 

Ji Qiang (CN), Philip J. Currie (CA), Mark A. Norell (US), and Ji Shu-an (CN) found two species of dinosaur in Northeast China, which possess feathers. Protoarchaeopteryx robusta and Caudipteryx zoui show regiges, rectrices and plumulaceous feather impressions. Further, they are not birds, lacking a reverted (backwards facing) big toe and a quadratojugal squamosal contact, having a quadratojugal joined to the quatrate by a ligament and a reduced or absent process of the ischium. These and other characters group Protoarchaeopteryx and Caudipteryx with maniraptoran coelurosaurs rather than birds (1193).

 

Paul F. Hoffman (US), Alan J. Kaufman (US), Galen P. Halverson (US), and Daniel P. Schrag (US) theorized that the explosion of life forms in the Cambrian resulted following extended glaciation during which the entire Earth was covered thus killing most life forms. Volcanic eruptions then released enough carbon dioxide to warm the Earth creating vast shallow seas in which rapid evolution occurred. They called it neoproterozoic snowball Earth (638; 639).

 

Sudhir Kumar (US) and S. Blair Hedges (US) presented evidence that at least five lineages of placental mammals arose more than 100 million years ago, and that most of the modern orders of animals seem to have diversified before the Cretaceous/Tertiary extinction of the dinosaurs (810).

 

Michael J. Stanhope (GB), Victor G. Waddell (GB), Ole Madsen (NL), Wilfried de Jong (NL), S. Blair Hedges (US), Gregory C. Cleven (US), Diana Kao (US), and Mark S. Springer (US) presented molecular evidence for multiple origins of the Insectivora and for a new order of endemic African insectivore mammals (1392).

 

Theunis Piersma (NL) and Robert E. Gill, Jr. (NL) found that Bar-tailed Godwits (Limosa lapponica baueri) from Alaska have relative fat loads that are among the highest ever recorded in birds (ca. 55% of fresh body mass). Compared with northbound godwits from New Zealand, the Alaskan birds have very small gizzards, livers, kidneys, and guts. This suggests that upon departure, long-distance migrants dispense with parts of their "metabolic machinery" that are not directly necessary during flight, and rebuild these organs upon arrival at the migratory destination (1164). See, Rowan, 1925. Note: A juvenile bar-tailed-godwit– known only by its satellite tag number 234684 – flew 13,560 kilometres from Alaska to the Australian state of Tasmania without stopping, appearing to set a new world record for marathon bird flights.

The five-month-old bird set off from Alaska on 13 October and satellite data appeared to show it did not stop during its marathon flight which took 11 days and one hour.

Tagged in Alaska, the bar-tailed godwit, Limosa lapponica, flew at least 13,560km (8,435 miles) before touching down at Ansons Bay in north-east Tasmania (1217).

 

Paul C. Sereno (US), Allison L. Beck (US), Didier B. Dutheil (FR), Boubacar Gado (Nigerian), Hans C. E. Larsson (CA), Gabrielle H. Lyon (US), Jonathan D. Marcot (US), Oliver W. M. Rauhut (DE), Rudyard W. Sadlier (US), Christian A. Sidor (US), David J. Varricchio (US), Gregory P. Wilson (US), and Jeffrey A. Wilson (US) made one of the most important dinosaur finds of the 20th century in Niger, Africa. Later named Suchomimus tenerensis, this dinosaur was a massive, sailed back, fish eater, which lived 100 million years ago (1321).

 

Jean Le Loeuff (FR) and Eric Buffetaut (FR) reported and named Variraptor mechinorum. This dinosaur was unearthed in France and is amazingly similar to the famous raptors of Jurassic Park lore. It lived during the late Cretaceous period, about 70 million years ago, toward the end of the Mesozoic Era (835).

 

Christiano Dal Sasso (IT) and Marco Signore (IT) reported from near Naples, Italy a very small theropod dinosaur from the Early Cretaceous discovered by Giovanni Todesco. They named it Scipionyx samniticus. This dinosaur fossil, Italy’s first, contained organ imprints—the first ever seen in dinosaurs (310).

 

Kenneth A. Farley (US), Alessandro Montanari (IT), Eugene M. Shoemaker (US), and Carolyn Shoemaker (US) presented geochemical evidence from a rock quarry in Northern Italy that a shower of comets hit Earth about 36 million years ago.

The findings not only account for the huge craters at Popagai in Siberia and at Chesapeake Bay in Maryland, but posit that they were but a tiny fraction of the comets active during a period of two or three million years in the late Eocene period (392).

 

1999

“The reason for this textual confusion is that the genome is a book that wrote itself, continually adding, deleting and amending over four billion years. Documents that write themselves have unusual properties. In particular, they are prone to parasitism.” Matt Ridley (1236).

 

Günter Klaus-Joachim Blobel (DE-US) was awarded the Nobel Prize in Physiology or Medicine for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell.

 

Kyriacos Costa Nicolaou (CY-US), Fiona Murphy (CH), Sofia Barluenga (US), Takashi Ohshima (US), Heng-xu Wei (US), Jinyou Xu (US), David L. Gray (US), and Olivier Baudoin (FR) performed the total synthesis of the immunosuppressive agent sanglifehrin A (1072; 1075).

 

Gongyi Zhang (US), Elizabeth A. Campbell (US), Leonid Minakhin (US), Catherine Richter (US), Konstantin Severinov (US), and Seth A. Darst (US) solved the structure of the RNA polymerase (RNAP) core of the bacterial thermophile Thermus aquaticus to 3.3-angstrom resolution (1629).

Patrick Cramer (US), David A. Bushnell (US), Jianhua Fu (US), Averell L. Gnatt (US), Barbara Maier-Davis (US), Nancy E. Thompson (US), Richard R. Burgess (US), Aled M. Edwards (CA), Peter R. David (US), and Roger David Kornberg (US) determined the structure of yeast RNA polymerase II (RNAP II) to 3.5-angstroms (295). Note: Both of these enzyme structures revealed a crab-claw-shaped molecule with two pincers and a central cleft. The active center was located on the floor of the cleft, where three absolutely conserved aspartic-acid residues chelated one Mg2+ ion.

 

L. Iyer Aravind (US), D. Roland Walker (US), and Eugene V. Koonin (RU-US) discovered conserved domains in DNA repair proteins and evolution of repair systems (46).

 

Judith E. Sleeman (GB) and Angus Lamond (GB) showed that small nuclear ribonuclear proteins (snRNPs) that have just entered the nucleus gather in the Cajal bodies (1354). See, Santiago Ramón y Cajal, 1903

Beáta E. Jády (FR), Xavier Darzacq (FR), Karen E. Tucker (US), A. Gregory Matera (US), Edouard Bertrand (FR), and Tamás Kiss (FR) discovered that snRNPs then travel to the interchromatin granules and acquire their finishing touches, maturing into functional particles (702).

 

Carla M. Koehler (CH), Sabeeha Merchant (US), Gottfried Schatz (CH), Danielle Leuenberger (CH), Anja Renold (CH), and Tina Junne (CH) reported that a newly discovered family of small proteins in the yeast mitochondrial intermembrane space mediates import of hydrophobic proteins from the cytoplasm into the inner membrane. Loss of one of these chaperone-like proteins from human mitochondria results in a disease that causes deafness, muscle weakness and blindness (784; 785).

 

Adam C. Bell (US), Adam G. West (US), and Gary Felsenfeld (US) identified a 42 bp fragment of the chicken beta-globin insulator that is both necessary and sufficient for enhancer blocking activity in human cells. We show that this sequence is the binding site for CTCF, a previously identified eleven-zinc finger DNA-binding protein that is highly conserved in vertebrates. CTCF sites are present in all of the vertebrate enhancer-blocking elements we have examined. We suggest that directional enhancer blocking by CTCF is a conserved component of gene regulation in vertebrates (107). Note: An insulator is a DNA sequence that can act as a barrier to the influences of neighboring cis-acting elements, preventing gene activation, for example, when located between an enhancer and a promoter.

 

Filippo G. Giancotti (US) and Erkki Ruoslahti (US) reported that many integrin signals converge on cell cycle regulation, directing cells to live or die, to proliferate, or to exit the cell cycle and differentiate (490). Note: Integrins are glycoprotein cell surface molecules, which receive signals from the extracellular matrix.

 

Andrew S. Levy (US), Juan P. Bosch (US), Julia Breyer Lewis (US), Tom Greene (US), Nancy Rogers (US), David Roth (US) developed an equation to predict glomerular filtration rate (GFR) from serum creatinine concentration and other factors (858).

 

James L. van Etten (US) and Russel H. Meints (US) described Paramecium bursaria chlorella virus (PBCV-1) as the prototype of a family of large, icosahedral, plaque-forming, double-stranded-DNA-containing viruses that replicate in certain unicellular, eukaryotic chlorella-like green algae (1503).

 

Andreas Nebenführ (US), Larry A. Gallagher (US), Terri G. Dunahay (US), Jennifer A. Frohlick (US), Anna M. Mazurkiewicz (US), Janet B. Meehl (US), and L. Andrew Staehelin (US) demonstrated that movement of plant Golgi bodies occurs along actin filaments and that transport takes place in a “stop-and-go” manner. This means that Golgi bodies can move along actin filaments, but they can also temporarily stop at precise locations in the plant cell. Constant transport guarantees that Golgi bodies are uniformly distributed in the cell, while the stop phase is required for production of vesicles at specific sites, ultimately optimizing trafficking between endoplasmic reticulum (ER) to Golgi and Golgi to cell wall (1054).

 

Norbert Weidner (US), Armin Blesch (US), Ray J. Grill (US), and Mark H. Tuszynski (US) found that signals expressed on Schwann cells that modulate peripheral axonal regeneration and myelination are also recognized in the CNS and that the modification of Schwann cells to over express growth factors significantly augments their capacity to support extensive axonal growth in models of CNS injury (1557).

 

Matt Kaeberlein (US), Mitch McVey (US), and Leonard Guarente (US) showed that life span regulation by the Sir proteins is independent of their role in nonhomologous end joining. The short life span of a sir3 or sir4 mutant is due to the simultaneous expression of a and α mating-type information, which indirectly causes an increase in rDNA recombination and likely increases the production of extrachromosomal rDNA circles. The short life span of a sir2 mutant also reveals a direct failure to repress recombination generated by the Fob1p-mediated replication block in the rDNA. Sir2p is a limiting component in promoting yeast longevity, and increasing the gene dosage extends the life span in wild-type cells. A possible role of the conserved SIR2 in mammalian aging is discussed(727). Note: The SIR genes are determinants of life span in yeast mother cells. The consequences of this early postnatal programming are thought to persist throughout life and to impact significantly on whole body health.

Yoshinori Umesaki (JP), Hiromi Setoyama (JP), Satoshi Matsumoto (JP), Akemi Imaoka (JP), and Kikuji Itoh (JP) noted that an important concept is that commensal bacteria differ in their ability both to promote development of the gut-associated lymphoid tissues and to maintain their function (1496).

Andrew S. Neish (US), Andrew T. Gewirtz (US), Hui Zeng (US), Andrew N. Young (US), Michael E. Hobert (US), Vinit Karmali (US), Anjali S. Rao (US), James L. Madara (US), Dominique Granato (CH), Gabriela E. Bergonzelli (CH), Raymond David Pridmore (CH), Laure Marvin (CH), Martine Rouvet (CH), and Irène E. Corthésy-Theulaz (CH) observed similarly, the expression of specific surface structures, such as elongation factor Tu in Lactobacillus johnsonii and flagellin in commensal Salmonella, could be important for intimate contact with the host, facilitating other effector processes involved in immune modulation (528; 1058).

Jian Xu (US), Magnus K. Bjursell (US), Jason Himrod (US), Su Deng (US), Lynn K. Carmichael (US), Herbert C. Chiang (US), Lora V. Hooper (US), and Jeffrey I. Gordon (US), R. David Pridmore (CH), Bernard Berger (CH), Frank Desiere (CH), David Vilanova (CH), Caroline Barretto (CH), Anne-Cecile Pittet (CH), Marie-Camille Zwahlen (CH), Martine Rouvet (CH), Eric Altermann (CH), Rodolphe Barrangou (CH), Beat Mollet (CH), Annick Mercenier (CH), Todd Klaenhammer (CH), Fabrizio Arigoni (CH), Mark A. Schell (CH), Lora V.Hooper (US), Melissa H. Wong (US), Anders Thelin (US), Lennart Hansson (US), Per G. Falk (US), and Jeffrey I. Gordon (US) found that the genome sequences of several commensal bacterial species provide insights into how bacteria have evolved to perform their various metabolic functions within the host gut (649; 1184; 1602).

Lora V.Hooper (US), Melissa H. Wong (US), Anders Thelin (US), Lennart Hansson (US), Per G. Falk (US), Jeffrey I. Gordon (US), Takeshi Yamanaka (NO), Lars Helgeland (NO), Inger Nina Farstad (NO), Hisanori Fukushima (NO), Tore Midtvedt (NO), and Per Brandtzaeg (NO) showed that with the initiation of bacterial colonization, gross changes in immune architecture occur with the expansion and phenotypic differentiation of specific cell lineages of the mucosal immune system (649; 1606).

Mark A. Schell (CH), Maria Karmirantzou (CH), Berend Snel (CH), David Vilanova (CH), Bernard Berger (CH), Gabriella Pessi (CH), Marie-Camille Zwahlen (CH), Frank Desiere (CH), Peer Bork (CH), Michelle Delley (CH), R. David Pridmore (CH), and Fabrizio Arigon (CH) suggest that although the detection and assignment of a functional role for bacterial genes involved in metabolism has been relatively straightforward, the identification of genes in commensal bacteria involved in host immune modulation provides more of a challenge. Hypothetically, for example, the immunomodulatory effect of B. longum might involve a eukaryotic-type serine protease inhibitor (serpin) found in its genome sequence (1287).

Vanessa Sperandio (US), Alfredo G. Torres (US), James B. Kaper (US), Justin Merritt (US), Fengxia Qi (US), Steven D. Goodman (US), Maxwell H. Anderson (US), and Wenyuan Shi (US) found that quorum-sensing autoinducers (AIs), which are communication molecules released by bacteria at high densities, might also modulate host responses through regulation of commensal genes involved in gut colonization and host signalling (992; 1384).

Jian Xu (US), Magnus K. Bjursell (US), Jason Himrod (US), Su Deng (US), Lynn K. Carmichael (US), Herbert C. Chiang (US), Lora V. Hooper (US), Jeffrey I. Gordon (US), Mark A. Schell (CH), Maria Karmirantzou (CH), Berend Snel (CH), David Vilanova (CH), Bernard Berger (CH), Gabriella Pessi (CH), Marie-Camille Zwahlen (CH), Frank Desiere (CH), Peer Bork (CH), Michelle Delley (CH), R. David Pridmore (CH), and Fabrizio Arigoni (CH) found that large numbers of genes involved in dietary polysaccharide metabolism are encoded within the genomic sequences of two gut commensals, Bacteroides thetaiotaomicron and Bifidobacterium longum [Xu, 2003 #27457;Schell, 2002 #27462}.

Jian Xu (US), Magnus K. Bjursell (US), Jason Himrod (US), Su Deng (US), Lynn K. Carmichael (US), Herbert C. Chiang (US), Lora V. Hooper (US), and Jeffrey I. Gordon (US) reported that the human colonic microbiota comprises >500 distinct bacterial species and has an important role in human nutrition and health, by promoting nutrient supply, preventing pathogen colonization and shaping and maintaining normal mucosal immunity (1602).

Vanessa Sperandio (US), Alfredo G. Torres (US), Bruce Jarvis (US), James P. Nataro (US), and James B. Kaper (US) discovered mammalian gut hormones that mimic autoinducer (AI) signalling molecules thus further highlighting the complexity of this crosstalk (1383).

Fredrik Bäckhed (US), Hao Ding (US), Ting Wang (US), Lora V. Hooper (US), Gou Young Koh (US), Andras Nagy (US), Clay F. Semenkovich (US), and Jeffrey I. Gordon (US), Daniel A. Peterson (US), Justin L. Sonnenburg (US), and Ruth E. Ley (US), from studies on mono-associated and conventionalized mice, provided evidence that host nutrition is supplemented by the metabolic capabilities of the resident gut microflora, which, unlike germ-free animals, are able to capture and store as energy, by-products released by bacterial degradation of undigested dietary substrates (70; 71).

Denise Kelly (GB), Jamie I. Campbell (GB), Timothy P. King (GB), George Grant (GB), Emmelie A. Jansson (GB), Alistair G. P. Coutts (GB), Sven Pettersson (GB), Shaun Conway (GB), Michael J. Coyne (US), Barbara Reinap (US), Martin M. Lee (US), and Laurie E. Comstock (US) noted that alternatively, both the mucinase activity and the L-fucose-rich polysaccharides and glycoproteins of B. thetaiotaomicron might permit close contact between viable bacteria and host epithelial cells and could be important for the immunosuppressive effects of this bacterium (292; 749).

Justin L. Sonnenburg (US), Jian Xu (US), Douglas D. Leip (US), Chien-Huan Chen (US), Benjamin P. Westover (US), Jeremy Weatherford (US), Jeremy D. Buhler (US), and Jeffrey I. Gordon (US), found that other metabolic genes enable these bacteria to target host glycoconjugates as alternative energy sources, in situations of limited lumenal nutrient availability, further illustrating the fine-tuning of this evolutionary adaptation (1377).

Graham A. W. Rook (GB) and Laura Rosa Brunet (GB) remind us that although the molecular basis for this functional distinction is currently unknown, the ‘hygiene hypothesis’, which links reduced exposure to important gut bacteria with the rising incidence of human allergies and autoimmune diseases, embraces this view-point (1252). Note: It can thus be postulated that functionally significant bacteria of the normal commensal microflora, are required to maintain immune homeostasis in both the developing and adult gut. It might be possible that the mutualism that exists between these bacteria and the healthy host gut can be exploited for treatments of diseases, such as inflammatory bowel disease (IBD), in which inappropriate immune responses to components of the normal microflora exist.

R. Randal Bollinger (US), Andrew S. Barbas (US), Errol L. Bush (US), Shu S. Lin (US), and William Parker (US) proposed that the human appendix is well suited as a "safe house" for commensal bacteria, providing support for bacterial growth and potentially facilitating re-inoculation of the colon in the event that the contents of the intestinal tract are purged following exposure to a pathogen. This is based (a) on a recently acquired understanding of immune-mediated biofilm formation by commensal bacteria in the mammalian gut, (b) on biofilm distribution in the large bowel, (c) the association of lymphoid tissue with the appendix, (d) the potential for biofilms to protect and support colonization by commensal bacteria, and (e) on the architecture of the human bowel (148).

 

Scientists of the Genome Consortium determined the complete sequence and gene map of a human major histocompatibility complex (278).

 

Arash Grakoui (US), Shannon K. Bromley (US), Cenk Sumen (US), Mark M. Davis (US), Andrey S. Shaw (US), Paul M. Allen (US), and Michael L. Dustin (US) visualized what they referred to as the "immunological synapse." They saw this structure as controlling T cell activation through a structure-function dynamic. A central cluster of T cell receptors is seen as surrounded by a ring of adhesion molecules. The synapse allows T cells to distinguish potential antigenic ligands. Initially, T cell receptor ligands were engaged in an outermost ring of the nascent synapse. Transport of these complexes into a central cluster is seen as dependent on T cell receptor-ligand interaction kinetics. Finally, formation of a stable central cluster at the heart of the synapse is a determinative event for T cell proliferation (527).

 

Stephen L. Nutt (AT), Barry Heavey (AT), Antonius G. Rolink (CH), and Meinrad Busslinger (AT) found that the PAX5 gene plays an essential role in B-lineage commitment by suppressing alternative lineage choices (1093). Note: The PAX5 gene encoding the B-cell-specific activator protein (BSAP) is expressed within the haematopoietic system exclusively in the B-lymphoid lineage, where it is required in vivo for progression beyond the pro-B-cell stage.

 

Richard Moriggl (US), David J. Topham (US), Stephan Teglund (US), Veronika Sexl (US), Catriona McKay (US), Demin Wang (US), Angelika Hoffmeyer (US), Jan van Deursen (US), Mark Y. Sangster (US), Kevin D. Bunting (US), Gerard C. Grosveld (US), and James N. Ihle (US) demonstrated that, while lymphoid development is normal, peripheral T cells of Stat5a/b mutants are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression. In addition, these mice lack natural killer (NK) cells, develop splenomegaly, and have T cells with an activated phenotype, phenotypes seen in IL-2 receptor beta chain-deficient mice. These phenotypes are not seen in mice lacking Stat5a or Stat5b alone. The results demonstrate that the Stat5 proteins, redundantly, are essential mediators of IL-2 signaling in T cells (1020). Note: STATs are signal transducers and activators of transcription.

 

Federica Sallusto (CH), Danielle Lenig (CH), Reinhold Forster (CH), Martin Lipp (CH), and Antonio Lanzavecchia (CH) showed that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response (1275).

David Masopust (US), Vaiva Vezys (US), Amanda L. Marzo (US), and Leo Lefrancois (US) showed that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection (952).

 

Daniel H. Present (US), Paul Rutgeerts (BE), Stephan Targan (US), Stephen B. Hanauer (US), Lloyd Mayer (US), R.A. van Hogezand (NL), Daniel K. Podolsky (US), Bruce E. Sands (US), Tanja Braakman (US), Kimberly L. DeWoody (US), Thomas F. Schaible (US), and Sander J.H. van Deventer (NL) conducted a randomized, multicenter, double-blind, placebo-controlled trial of Infliximab for the treatment of fistulas in patients with Crohn’s disease. Infliximab is a chimeric monoclonal antibody to tumor necrosis factor a. They concluded that Infliximab is an efficacious treatment for fistulas in patients with Crohn’s disease (1181).

 

Ellis L. Reinherz (US), Kemin Tan (US), Lei Tang (US), Petra Kern (BE), Jin-huan Liu (US), Yi Xiong (US), Rebecca E. Hussey (US), Alex Smolyar (US), Brian Hare (US), Rongguang Zhang (US), Andrzej Joachimiak (US), Hsiu-Ching Chang (US), Gerhard Wagner (US), and Jia-huai Wang (US) determined the crystal structure of a T cell receptor in complex with peptide and MHC class II (1225).

 

Frederick P. Siegal (US), Norimitsu Kadowaki (US), Michael Shodell (US), Patricia A. Fitzgerald-Bocarsly (US), Kokila Shah (US), Stephen Ho (US), Svetlana Antonenko (US), and Yong-Jun Liu (US) showed that natural interferon type 1 producing cells of peripheral blood are the CD4(+)CD11c- type 2 dendritic cell precursors (pDC2s) (1339).

 

Xiaoying Lin (US), Samir Kaul (US), Steve Rounsley (US), Terrance P. Shea (US), Maria-Ines Benito (US), Christopher D. Town (US), Claire Y. Fujii (US), Tanya Mason (US), Cheryl L. Bowman (US), Mary Barnstead (US), Tamara V. Feldblyum (US), C. Robin Buell (US), Karen A. Ketchum (US), John Lee (US), Catherine M. Ronning (US), Hean L. Koo (US), Kelly S. Moffat (US), Lisa A. Cronin (US), Mian Shen (US), Grace Pai (US), Susan Van Aken (US), Lowell Umayam (US), Luke J. Tallon (US), John E. Gill (US), Mark D. Adams (US), Ana J. Carrera (US), Todd H. Creasy (US), Howard Michael Goodman (US), Christopher R. Somerville (US), Greg P. Copenhaver (US), Daphne Preuss (US), William C. Nierman (US), Owen White (US), Jonathan A. Eisen (US), Steven L. Salzberg (US), Claire M. Fraser (US), and John Craig Venter (US) determined the sequence and analysis of chromosome 2 of the plant Arabidopsis thaliana (a member of the mustard family commonly called Thale cress). Arabidopsis thaliana is unique among plant model organisms in having a small genome (130-140 Mb), excellent physical and genetic maps, and little repetitive DNA (878).

 

Klaus Mayer (DE), Christine Schuller (DE), Rolf Wambutt (DE), George Murphy (GB), Guido Volckaert (BE), Thomas Pohl (DE), Andreas Dusterhoft (DE), Willem J. Stiekema (NL), Karl-Dieter Entian (DE), Nancy Terryn (BE), Bruce A. Harris (GB), Wilhelm Ansorge (CZ-DE), Petra Brandt (DE), Les A. Grivell (NL), Michael Rieger (DE), Michael Weichselgartner (DE), Vincenzo de Simone (IT), Brigitte Obermaier (DE), Regis Mache (FR), Margarete Muller (AT), Martin Kreis (FR), Michael Delseny (FR), Pere Puigdomenech (ES), Marc B. Watson (GB), T. Schmidtheini (CH), B. Reichert (NL), D. Portatelle (BE), Manuel Perez-Alonso (ES), Marc Boutry (BE), Ian Bancroft (GB), Pieter Vos (NL), Joerg Hoheisel (DE), Wolfgang Zimmermann (DE), Holger Wedler (DE), P. Ridley (GB), S.A. Langham (GB), Beth McCullagh (GB), Loralei J. Bilham (GB), Johan Robben (BE), Jan Van der Schueren (BE), Barbara Grymonprez (BE), Yi-jen Chuang (BE), Filip Vandenbussche (BE), M. Braeken (BE), I. Weltjens (BE), Marleen Voet (BE), Israel Philippe Bastiaens (BE), Rita Aert (BE), Els Defoor (BE), Thomas Weitzenegger (DE), Gordana Bothe (DE), Uwe Ramsperger (DE), Helmut Hilbert (DE), M. Braun (DE), E. Holzer (DE), A. Brandt (DE), Sander Peters (NL), Marjo van Staveren (NL), W. Dirske (NL), Paul Mooijman (NL), Rene Klein Lankhorst (NL), Matthias Rose (DE), Jörg Hauf (DE), Peter Kotter (DE), Simone Berneiser (DE), Svenja Hempel (DE), Mareika Feldpausch (DE), Stefanie Lamberth (DE), Hilde Van den Daele (BE), Annick De Keyser (BE), C. Buysshaert (BE), Jan Gielen (BE), Richard Villarroel (BE), Rebecca De Clercq (BE), Marc Van Montagu (BE), Jane Rogers (GB), Ann Cronin (GB), Michael A. Quail (GB), Sarah Bray-Allen (GB), Lynn Clark (GB), Jonathon Doggett (GB), S. Hall (GB), Michael Kay (GB), Nicola Lennard (GB), Kirsten McLay (GB), Rick Mayes (GB), Adelaide Pettett (GB), Marie-Adéle Rajandream (GB), Mike Lyne (GB), Vladamir Benes (DE), S. Rechmann (DE), Dana Borkova (DE), Helmut Blöcker (DE), Maren Scharfe (DE), M. Grimm (DE), Tschong-Hun Löhnert (DE), S. Dose (DE), M. de Haan (NL), Ammy C. Maarse (NL), M. Schafer (DE), S. Muller-Auer (DE), Christopher Gabel (DE), Martin Fuchs (DE), Berthold Fartmann (DE), K. Granderath (DE), D. Dauner (DE), A. Herzl (DE), S. Neumann (DE), Anagnostis Argiriou (IT), D. Vitale (IT), Rosario Liguori (IT), E. Piravandi (DE), O. Massenet (FR), Francoise Quigley (FR), G. Clabauld (FR), Axel Mundlein (AT), R. Felber (AT), S. Schnabl (AT), R. Hiller (AT), W. Schmidt (AT), Alain Lecharny (FR), Sébastien Aubourg (FR), Francoise Chefdor (FR), Richard Cooke (FR), C. Berger (FR), A. Montfort (FR), Elena Casacuberta (FR), T. Gibbons (GB), N. Weber (CH), Micheline Vandenbol (BE), Mónica Bargues (ES), Javier Terol (ES), Arielle Torres (ES), A. Perez-Perez (ES), Bénédicte Purnelle (BE), Elizabeth Bent (GB), Sam Johnson (GB), Daryl Tacon (GB), T. Jesse (NL), Leo Heijnen (NL), S. Schwarz (DE), Patrik Scholler (DE), Steffan Heber (DE), P. Francs (DE), Cord Bielke (DE), Dmitrij Frishman (DE), Dirk Haase (DE), Kai Lemcke (DE), Hans Werner Mewes (DE), S. Stocker (DE), P. Zaccaria (DE), M. Bevan (GB), Richard K. Wilson (US), Melissa de la Bastide (US), Kristina Habermann (US), Laurence Parnell (US), Neilay Dedhia (US), Lidia Gnoj (US), Kristin Schutz (US), Emily Huang (US), Lori Spiegel (US), Mundeep Sehkon (US), Jennifer Murray (US), Paul Sheet (US), Matt Cordes (US), Jane Kemp Abu-Threideh (US), Tamberlyn Stoneking (US), Joelle Kalicki (US), Tina Graves (US), Gwen Harmon (US), Jennifer Edwards (US), Phil Latreille (US), Laura Courtney (US), Jim Cloud (US), Amanda Abbott (US), K. Scott (US), Dabney Johnson (US), Patrick Minx (US), Dan Bentley (US), Bob Fulton (US), Nancy Miller (US), Tracie Greco (US), Kimberly Kemp (US), Jason B. Kramer (US), Lucinda Fulton (US), Elaine R. Mardis (US), Michael Dante (US), Kymberlie H. Pepin (US), LaDeana W. Hillier (US), Joanne Nelson (US), John Spieth (US), Ellen Ryan (US), Stephanie Andrews (US), Cynthia Geisel (US), Don Layman (US), Hui Du (US), Johar Ali (US), Amy Berghoff (US), K. Jones (US), Kristy Drone (US), Marc Cotton (US), Corrie Joshu (US), B. Antonoiu (US), Michael Zidanic (US), C. Strong (US), H. Sun (US), B. Lamar (US), Cristina Yordan (US), P. Ma (US), Jinhui Zhong (US), Roanne Preston (US), Danielle Vil (US), Monica Shekher (US), Anthony Matero (US), Ravi Shah (US), I’Kori Swaby (US), Andrew L. O'Shaughnessy (US), Milkia Rodriguez (US), Jane Hoffmann (US), Sally Till (US), Susan Granat (US), Nadim Shohdy (US), Amy Hasegawa (US), Aliyah Hameed (US), Mauhammad Lodhi (US), A. Johnson (US), Ellson Chen (US), Marco Marra (US), Robert A. Martienssen (US), and W. Richard McCombie (US) determined the sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana (mustard family). Arabidopsis thaliana is unique among plant model organisms in having a small genome (130-140 Mb), excellent physical and genetic maps, and little repetitive DNA (962).

 

Catherine Sanchez (FR), Corinne Lachaize (FR), Florence Janody (FR), Bernard Bellon (FR), Laurence Röder (FR), Jérôme Euzenat (FR), François Rechenmann (FR), and Bernard Jacq (FR) coined the word interactome when they stated, "It will also be essential in the future to consider interactions and regulatory networks at the level of a complete genome. One possible new way to look at genomes is to consider that a crucial aspect of their function is to code for products which are programmed to establish specific interactions. According to this view, the total number of genes of an organism is less important than the complete repertoire of interactions potentially encoded by its genome (the interactome)" (1277). Note: It was later determined that most interactome networks refer to protein–protein interaction (PPI) network (PIN) or subsets thereof. Another extensively studied type of interactome is the protein–DNA interactome, also called a gene-regulatory network, a network formed by transcription factors, chromatin regulatory proteins, and their target genes.

Denis Dupuy (US), Nicolas Bertin (US), César A. Hidalgo (US), Kavitha Venkatesan (US), Domena Tu (US), David Lee (US), Jennifer Rosenberg (US), Nenad Svrzikapa (US), Aurélie Blanc (US), Alain Carnec (US), Anne-Ruxandra Carvunis (US), Rock Pulak (US), Jane Shingles (US), John Reece-Hoyes (US), Rebecca Hunt-Newbury (US), Ryan Viveiros (US), William A. Mohler (US), Murat Tasan (US, Frederick P. Roth (US), Christian Le Peuch (US), Ian A. Hope (US), Robert Johnsen (US), Donald G. Moerman (US), Albert-László Barabási (US), David Baillie (US), and Marc Vidal (US) presented an in vivo spatiotemporal analysis for approximately 900 predicted Caenorhabditis elegans promoters (approximately 5% of the predicted protein-coding genes), each driving the expression of green fluorescent protein (GFP). They found that automated comparison and clustering of the in vivo expression patterns show that genes coexpressed in space and time tend to belong to common functional categories. Moreover, integration of this data set with C. elegans protein-protein interactome data sets enables prediction of anatomical and temporal interaction territories between protein partners (362).

Michael P. H. Stumpf (UK), Thomas Thorne (UK), Eric de Silva (UK), Ronald Stewart (UK), Hyeong Jun An (DK), Michael Lappe (DK), and Carsten Wiuf (DE) discovered that the number of genes in organisms as diverse as fruit flies, nematodes, and humans does not reflect our perception of their relative complexity. They provided reliable evidence that the size of protein interaction networks in different organisms appears to correlate much better with their apparent biological complexity (1411).

Michael Costanzo (CA), Anastasia Baryshinikova (CA), Jeremy Bellay (US), Yungil Kim (US), Eric D. Spear (CA), Carolyn S. Sevier (US), Huiming Ding (CA), Judice L.Y. Koh (CA), Kiana Toufighi (CA), Sara Mostafavi (CA), Jeany Pinz (CA), Robert P. St. Onge (US), Benjamin Vandersluis (US), Taras Makhnevych (CA), Franco J. Vizeacoumar (CA), Solmaz Alizadeh (CA), Sondra Bahr (CA), Renee L. Brost (CA), Yiqun Chen (CA), Murat Cokol (US), Raamesh Deshpande (US), Zhijian Li (CA), Zhen-Yuan Lin (CA), Wendy Liang (CA), Michaela Marback (CA), Jadine Paw (CA), Bryan-Joseph San Luis (CA), Ermira Shuteriqi (CA), Amy Hin Yan Tong (CA), Nydia Van Dyk (CA), Iain M. Wallace (CA), Joseph A. Whitney (CA), Matthew T. Weirauch (US), Guoqing Zhong (CA), Hongwei Zhu (CA), Walid A. Houry (CA), Michael Brudno (CA), Sasan Ragibizadeh (CA), Balázs Rapp (HU), Csaba Pál (HU), Frederick P. Roth (US), Guri Giaever (HU), Corey Nislow (CA), Olga G. Troyanskaya (US), Howard Bussey (CA), Gary D. Bader (CA), Anne-Claude Gingras (CA), Quaid D. Morris (CA), Philip M. Kim (CA), Chris A. Kaiser (US), Chad L. Myers (US), Brenda J. Andrews (CA), and Charles Boone (CA) presented the most "complete" gene interactome produced to date. It was compiled from about 5.4 million two-gene comparisons to describe "the interaction profiles for ~75% of all genes in the budding yeast"(Saccharomyces cerevisiae), with ~170,000 gene interactions. The genes were grouped based on similar function so as to build a functional map of the cell's processes. Using this method the study was able to predict known gene functions better than any other genome-scale data set as well as adding functional information for genes that hadn't been previously described. From this model genetic interactions can be observed at multiple scales which will assist in the study of concepts such as gene conservation. Some of the observations made from this study are that there were twice as many negative as positive interactions, negative interactions were more informative than positive interactions, and genes with more connections were more likely to result in lethality when disrupted (287).

 

Alessandro Vitale (IT), Natasha V. Raikhel (RU-US), Haiyan Zheng (CN), Gabriele Fischer von Mollard (DE), Valentina Kovaleva (US), Tom H. Stevens (US), Sharif U. Ahmed (JP), Enrique Rojo (ES), Sridhar Venkataraman (IN), James E. Dombrowski (US), Ken Matsuoka (JP), Daine C. Bassham (US), and Anton A. Sanderfoot (US) found that secretory proteins are sorted to plant cell vacuoles or are retained within the secretory pathway by mechanisms that require specific targeting information contained within the structure of the protein. They demonstrated that secretory proteins lacking such information follow a default pathway and are secreted. Most soluble proteins are transported through the secretory system via a series of transport vesicles that bud from one compartment and fuse specifically with the next. Two of these sorting signals, an N-terminal propeptide (NTPP) and a C-terminal propeptide (CTPP) are directed to the vacuole by distinct pathways. They have characterized several components of the machinery involved in the sorting of NTPP-type cargo, including a trans-Golgi network (TGN)-localized cargo receptor and many SNARE components involved in vesicular traffic between the TGN and the prevacuolar compartment of the model plant Arabidopsis (21; 93-95; 1521; 1631).

 

Yoshinori Watanabe (JP) and Paul Maxime Nurse (GB) proposed that the persistence of Rec8 protein at centromeres during meiosis I maintains sister-chromatid cohesion, and that its presence in the centromere-adjacent regions orients the kinetochores so that sister chromatids move to the same pole. This results in the reductional pattern of chromosome segregation necessary to reduce a diploid zygote to haploid gametes (1543).

 

Ya-Ping Tang (US), Eiji Shimizu (US), Gilles R. Dube (US), Claire Rampon (US), Geoffrey A. Kerchner (US), Min Zhuo (US), Guosong Liu (US), and Joe Z. Tsien (US) boosted the intelligence of mice by adding a gene during the zygote stage of development. The inserted gene created more of a protein subunit called NR2B. This subunit is part of a complex of proteins that form the NMDA receptor, a channel that sits on the surface of brain neurons. Their results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible (1439).

 

The blood manufacturing community began implementation of nucleic acid amplification testing (NAT) under the FDA’s Investigational New Drug (IND) application process. NAT employs a testing technology that directly detects the genetic materials of viruses like HCV and HIV.

 

Xin-zhuan Su (US), Michael T. Ferdig (US), Yaming Huang (CH), Chuong Q. Huynh (US), Anna Liu (US), Jingtao You (US), John C. Wootton (US), Thomas E. Wellems (US), Zhongwu Lai (US), Junping Jing (US), Christopher Aston (US), Virginia Clarke (US), Jennifer Apodaca (US), Eileen T. Dimalanta (US), Daniel J. Carucci (US), Malcolm J. Gardner (US), Bud Mishra (US), Thomas S. Anantharaman (US), Salvatore Paxia (US), Stephen L. Hoffman (US), John Craig Venter (US), Edward J. Huff (US), and David C. Schwartz (US) completed a high-resolution genetic map of Plasmodium falciparum, the deadliest of the malarial parasites. This accomplishment will help scientists find new targets for improved diagnostic tools, therapies, and vaccines. Each year P. falciparum malaria affects up to 500 million people worldwide and kills more than 2 million, primarily young children in sub-Saharan Africa (821; 1412).

 

Suchismita Roy (GB), Angela J. Frodsham (GB), Bibhuti Saha (GB), Sunil K. Hazra (GB), C.G. Nicholas Mascie-Taylor (GB), and Adrian V.S. Hill (GB) found in a study of Bengali leprosy patients from Calcutta that variation in the vitamin D receptor (VDR) gene is associated with susceptibility to leprosy. In this population, homozygotes for the alternate alleles of the VDR polymorphism are associated, respectively, with lepromatous and tuberculoid leprosy (1261).

 

Christoph Sachse (DE), Jürgen Brockmöller (DE), Steffen Bauer (DE), and Ivar Roots (DE) determined that an A to C substitution at position 734 (CYP1A2*1F) in the CYP1A2 gene decreases enzyme inducibility as measured by plasma or urinary [caffeine]/[caffeine metabolite] ratio after a dose of caffeine, resulting in impaired caffeine metabolism (1266).

Ahmed El-Sohemy (CA), Marilyn C. Cornelis (CA), Edmond K. Kabagambe (US), and Hannia Campo (CR) found that intake of coffee was associated with an increased risk of myocardial infarction only among those with impaired caffeine metabolism, suggesting that caffeine plays a major role in this association (372).

 

Ian Dunham (GB), Adrienne R. Hunt (GB), John E. Collins (GB), Richard Bruskiewich (GB), David M. Beare (GB), Michele Clamp (GB), Luc J. Smink (GB), Rachael Ainscough (GB), Jeff P. Almeida (GB), Anne Babbage (GB), Claire Bagguley (GB), Jonathan Bailey (GB), Karen Barlow (GB), Karen N. Bates (GB), Oliver Beasley (GB), Christine P. Bird (GB), Sarah Blakey (GB), Anne M. Bridgeman (SE), David Buck (SE), Joanne Burgess (SE), Wayne D. Burrill (GB), John Burton (GB), Carol Carder (GB), Nigel P. Carter (GB), Yuan Chen (GB), Graham Clark(GB), Sheila M. Clegg (GB), Victoria Cobley (GB), Charlotte G. Cole (GB), Rachael E. Collier (GB), Richard E. Connor (SE), Donald Conroy (SE), Nicole Corby (GB), Gez J. Coville (GB), Anthony V. Cox (GB), John Davis (SE), Elisabeth Dawson (GB), Pawandeep D. Dhami (GB), Catherine Dockree (GB), Steve J. Dodsworth (SE), Richard M. Durbin (GB), Andrew Ellington (GB), Kathryn L. Evans (GB), James M. Fey (GB), Kerry Fleming (GB), Lisa French (GB), Andrea A. Garner (GB), James G. R. Gilbert (GB), Melanie Elizabeth Anne Goward (GB), Darren Grafham (GB), Mark N. Griffiths (GB), C. Hall (SE), Rebekah Hall (GB), Greta Hall-Tamlyn (GB), Rosemary W. Heathcott (SE), Sara-Jane Ho (SE), Sarah J. Holmes (GB), Sarah E. Hunt (GB), Matthew C. Jones (GB), Joanne K. Kershaw (GB), Andrew Kimberley (GB), Andrew King (GB), Gavin K. Laird (GB), Cordelia F. Langford (GB), Margaret A. Leversha (GB), Christine Lloyd (GB), David M. Lloyd (GB), I. D. Martyn (GB), Maryam Mashreghi-Mohammadi (GB), Lucy H. Matthews (GB), Owen T. McCann (GB), Joseph McClay (GB), Stuart J. McLaren (GB), Amanda A. McMurray (GB), Sarah A. Milne (GB), Beverley J. Mortimore (GB), Christopher N. Odell (GB), Rebecca R Pavitt (GB), Alex V. Pearce (GB), Danita M. Pearson (GB), Ben J. Phillimore (GB), Samantha H. Phillips (GB), Robert W. Plumb (GB), Helen Ramsay (GB), Yvonne Ramsey (GB), Lisa Rogers (GB), Mark T. Ross (GB), Carol E. Scott (GB), Harminder K. Sehra (GB), Carl D. Skuce (GB), Susan L. Smalley (GB), Michelle L. Smith (GB), Carol A. Soderlund (GB), Lee Spraggon (GB), Charles A. Steward (GB), John Edward Sulston (GB), R. Mark Swann (GB), Mark Vaudin (SE), Melanie Wall (GB), Justine M. Wallis (GB), Mathew N. Whiteley (SE), David L. Willey (GB), Leanne Williams (GB), Sophie Williams (GB), Helen Williamson (SE), Tamsin E. Wilmer (GB), Laurens Wilming (GB), Charmain L. Wright (GB), Tim J. P. Hubbard (GB), David R. Bentley (GB), Stephan Beck (GB), Jane Rogers (GB), Nobuyoshi Shimizu (JP), Shinsei Minoshima (JP), Katsumi Kawasaki (JP), Takashi Sasaki (JP), Shuichi Asakawa (JP), Jun Kudoh (JP), Ai Shintani (JP), Kazunori Shibuya (JP), Yuko Yoshizaki (JP), Norie Aoki (JP), Susumu Mitsuyama (JP), Bruce A. Roe (US), Fang Chen (US), L. Chu (US), Judy S. Crabtree (US), Stéphane Deschamps (US), Ahn Do (US), Trang Do (US), Angela Dorman (US), Fang Fang (US), Ying Fu (GB), Ping Hu (US), Axin Hua (US), Steve Kenton (US), Hongshing Lai (US), Hio Leong Lao (US), Jennifer Lewis (US), Suzanna E. Lewis (US), Shaoping Lin (US), Phoebe Loh (US), Eda Malaj (US), Thu Nguyen (US), HuaQuin Pan (US), Stacey Phan (US), Sulan Qi (US), Y. Qian (US), Linda Ray (US), Qun Ren (US), Steve Shaull (US), Danica Sloan (US), Lin Song (US), Qiaoyan Wang (US), Yimin Wang (US), Zhili Wang (US), Jennifer White (US), Diana Willingham (US), Honglong Wu (US), Zhijian Yao (US), Ming Zhan (US), Guangyu Zhang (US), Stephanie L. Chissoe (US), Jennifer Murray (US), Nancy Miller (US), Patrick J. Minx (US), Robert S. Fulton (US), David Johnson (US), Gary Bemis (US), David Bentley (US), Holly Bradshaw (US), S. Bourne (US), Matt Cordes (US), Z. Du (US), Lucinda A. Fulton (US), Deepa Goela (US), Tina Graves (US), Jim Hawkins (US), Kurt Hinds (US), Kimberley Kemp (US), Phil Latreille (US), Dan Layman (US), Philip Ozersky (US), Theresa Rohlfing (US), Paul Scheet (US), Christopher Walker (US), A. Wamsley (US), Patty Wohldmann (US), Kymberlie H. Pepin (US), Joanne O. Nelson (US), Ian Korf (US), Joseph A. Bedell (US), Ladeana W. Hillier (US), Elaine R. Mardis (US), Robert H. Waterston (US), Richard K. Wilson (US), Beverly S. Emanuel (US), Tamim H. Shaikh (US), Hiroki Kurahashi (JP), Sulagna C. Saitta (US), Marcia L. Budarf (CA), Heather E. McDermid (CA), A. Johnson (CA), Andrew C. C. Wong (CA), Bernice E. Morrow (US), Lisa Edelmann (US), Ung-Jin Kim (US), Hiroaki Shizuya (US), Melvin I. Simon (US), Jan P. Dumanski (SE), Myriam Peyrard (SE), Darek Kedra (SE), Eyal Seroussi (SE), Ingegerd Fransson (SE), Isabel Tapia (SE), Carl E. G. Bruder (SE), and Kevin P. O'Brien (SE) reported the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes. It provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome (360).

 

Francisco García-Del Portillo (ES), M. Graciela Pucciarelli (ES), Josep Casadesus (ES), Douglas M. Heithoff (US), Robert L. Sinsheimer (US), David A. Low (US), Elena Y. Enioutina (US), Raymond A. Daynes (US), Nathan J. Weyand (US), and Michael J. Mahan (US) found that mutants of Salmonella typhimurium lacking the DNA adenine methylase (Dam) gene were fully proficient in colonization of mucosal sites but showed severe defects in colonization of deeper tissue sites. These Dam- mutants were totally avirulent and were effective as live vaccines against murine typhoid fever. Dam regulated the expression of at least 20 genes known to be induced during infection; a subset of these genes is among those activated by the PhoP global virulence regulator. PhoP, in turn, affected Dam methylation at specific genomic sites, as evidenced by alterations in DNA methylation patterns. Dam inhibitors are likely to have broad antimicrobial action, and Dam- derivatives of these pathogens may serve as live attenuated vaccines (464; 618-620; 902).

 

Martin Joel Do (GB), Joel M. Harp (GB), Kimberly C. Norris (GB), Kavin J. Gaston (GB), Ian D. Gauld (GB), M. Pajak (GB), Anna T. Watson (GB), Mark A. O'Neill (GB), and Ian J. Kitching (GB) played important rolls in the development of the digital automated identification system (DAISY). This video automated species identification system was optimised for the rapid screening of invertebrates (e.g. insects) by non-experts (e.g. parataxonomists) (343; 475; 1097; 1120; 1549).

 

David E. Smith (US), Jeffrey Warren Roberts (US), Fred H. Gage (US), and Mark H. Tuszynski (US) used rhesus monkeys (Macacus rhesus), the best animal model of human aging, in which they described, for the first time, the reversal of the loss of neurons in subcortical cholinergic basal forebrain regions by human nerve growth factor gene delivery. These findings (i) identify reversible cellular atrophy as a potential mechanism contributing to age-related cognitive decline in primates, (ii) suggest, when considered with other studies, that subcortical brain regions exhibit greater vulnerability to the effects of aging than cortical regions, and (iii) indicate that neurotrophin gene transfer may be an effective means of preventing neuronal atrophy or degeneration in age-related neurodegenerative disorders (1360).

Neil Q. McDonald (GB), Risto Lapatto (GB), Judith Murray-Rust (GB), Jennifer Gunning (GB), Alexander Wlodawer (US), and Tom L. Blundell (GB) solved the structure of nerve growth factor (NGF) by x-ray crystallography (971).

 

James E. Haddow (US), Glenn E. Palomaki (US), Walter C. Allan (US), Josephine R. Williams (US), George J. Knight (US), June Gagnon (US), Cheryl E. O'Heir (US), Marvin L. Mitchell (US), Rosalie J. Hermos (US), Susan E. Waisbren (US), James D. Faix (US), and Robert Z. Klein (US) reported that children born to mothers with untreated hypothyroidism during pregnancy were found to score lower on IQ tests than children of healthy mothers, suggesting that early detection and treatment of hypothyroidism in pregnant women may be a critical part of prenatal care (574).

 

Larry G. Young (US), Roger Nilsen (US), Katrina G. Waymire (US), Grant R. MacGregor (US), and Thomas R. Insel (US) found that a single gene could make laboratory mice more friendly and affectionate toward their cage mates. Receptors for the hormone vasopressin were taken from the sociable prairie vole and put into laboratory mice. When vasopressin was injected into mice, they became more affectionate (1616). Note: This study is the first to show that a single gene can radically affect complex social behavior.

 

Deborah S. Asnis (US), Rick Conetta (US), Alex A. Teixeira (US), Glenn Waldman (US), and Barbara A. Sampson (US) reported that during the month of August 1999, a cluster of 5 patients with fever, confusion, and weakness were admitted to the intensive care unit of the same hospital in New York City. Ultimately 4 of the 5 developed flaccid paralysis and required ventilatory support. Three patients with less-severe cases presented shortly thereafter. With the assistance of the New York City and New York State health departments and the Centers for Disease Control and Prevention, these were documented as the first cases of West Nile Virus infection in North America (58).

 

Pau Sort (ES), Miquel Navasa (ES), Vicente Arroyo (ES), Xavier Aldeguer (ES), Ramon Planas (ES), Luis Ruiz-del-Arbol (ES), Lluis Castells (ES), Victor Vargas (ES), Germán Soriano (ES), Mónica Guevara (ES), Pere Ginès (ES) and Joan Rodés (ES) reported that in cirrhotic patients with spontaneous bacterial peritonitis, albumin infusion on days 1 and 3 of treatment in addition to antibiotics significantly reduces the risk of developing renal impairment and mortality when compared with antibiotics alone (1379).

 

Susan E. Stepp (US), Remi Dufourcq-Lagelouse (FR), Francoise Le Deist (FR), Sadhna Bhawan (US), Stephanie Certain (FR), Porunelloor A. Mathew (US), Jan-Inge Henter (SE), Michael Bennett (US), Alain Fischer (FR), Genevieve de Saint Basile (FR), and Vinay Kumar (US) determined that defects in the perforin gene are responsible for 10q21-22-linked familial hemophagocytic lymphohistiocytosis (FHL). Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation (1399). Note: Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK cells).

 

Derek J. Parks (US), Steven G. Blanchard (US), Randy K. Bledsoe (US), Gyan Chandra (US), Thomas G. Consler (US), Steven A. Kliewer (US), Julie B. Stimmel (US), Timothy M. Willson (US), Ann Marie Zavacki (US), David D. Moore (US), Jürgen M. Lehmann (US), Haibo Wang (US), Jasmine Chen (US), Kevin Hollister (US), Lawrence C. Sowers (US), and Barry M. Forman (US) established that bile acids could function as signaling molecules when they discovered that bile acids are natural ligands of the nuclear receptor, farnesoid × receptor (FXR) (1128; 1536).

 

Bertram Pitt (CH-US), Faiez Zannad (TN-FR), Willem J. Remme (NL), Robert J. Cody (US), Alain Castaigne (FR), Alfonso T. Perez (US), Jolie Palensky (US), and Janet Wittes (US) found that adding 25 mg of spironolactone to standard therapy reduces all-cause mortality in heart failure patients with an ejection fraction <35% (1170).

 

Karin Nelson (US) and Judith Grether (US) showed that current evidence suggests in utero infection may predispose very preterm and more mature infants to cerebral palsy and that antenatal exposure to steroids may be somewhat protective (1059).

 

Michael J. Kupferminc (IL), Amiram Eldor (IL), Nitzan Steinman (IL), Ariel Many (IL), Amiram (IL), Ariel Jaffa (IL), Gideon Fait (IL), and Joseph B. Lessing (IL) found that the incidence of genetic thrombophilias was higher in women with adverse pregnancy outcomes (812).

 

The postmenopausal CR/XL Randomised Intervention Trial in Congestive Heart Failure Group (MERIT-HF) (GB) found in patients with symptomatic heart failure and reduced ejection fraction, the addition of metoprolol to standard therapy reduced all-cause mortality by 34% compared to placebo. Similar findings were reported by the CIBIS-II trial (550).

 

David S. Freedman (US), William H. Dietz (US), Sathanur R. Srinivasan (US), and Gerald S. Berenson (US) reported that children recruited for weight and cardiovascular risk assessment were found to have higher frequencies of cardiac risks factors as their body mass indices increased. Among the cardiovascular risk factors assessed, overweight youth had the highest odds of having elevated insulin levels (440).

 

Todd R. Golub (US), Donna K. Slonim (US), Pablo Tamayo (US), Christine Huard (US), Michelle Gaasenbeek (US), Jill P. Mesirov (US), Hilary Coller (US), Mignon L. Loh (US), James R. Downing (US), Mark A. Caligiuri (US), Clara D. Bloomfield (US), and Eric Steven Lander (US) provided the first evidence that gene-expression profiling can distinguish between cancer types. In addition to distinguishing between two types of leukemia on the basis of expression-profile differences the method could also predict their responsiveness to chemotherapy (509).

 

Stefan Bauer (US), Veronika Groh (US), Jun Wu (US), Alexander Steinle (US), Joseph H. Phillips (US), Lewis L. Lanier (US), and Thomas Spies (US) detected a receptor for major-histocompatibility-complex class I-related chain A antigens (MICA) on most gamma delta T cells, CD8+ alpha beta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gamma delta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA (101). Note: Major-histocompatibility-complex class I polypeptide–related sequence A (MICA) is a highly polymorphic cell surface glycoprotein encoded by the MICA gene located within major-histocompatibility-complex locus. Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gamma delta T cells and is frequently expressed in epithelial tumors.

 

Reinhold Forster (DE), Andreas Schubel (DE), Dagmar Breitfeld (DE), Elisabeth Kremmer (DE), Ingrid Renner-Muller (DE), Eckhard Wolf (DE), and Martin Lipp (DE) identified the chemokine receptor CCR7 as an important organizer of the primary immune response (432).

 

Katsuaki Hoshino (JP), Osamu Takeuchi (JP), Taro Kawai (JP), Hideki Sanjo (JP), Tomohiko Ogawa (JP), Yoshifumi Takeda (JP), Kiyoshi Takeda (JP), and Shizuo Akira (JP) demonstrated that Toll-like receptor (TLR4) is the gene product that regulates endotoxin unresponsive gene locus (LPS) response in mice (653).

 

Ruthie E. Amir (US), Ignatia B. Van den Veyver (US), Mimi Wan (US), Charles Q. Tran (US), Uta Francke (US), and Huda Y. Zoghbi (US) found that Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 (37). Xinsheng Nan (GB) and Adrian P. Bird (GB) reached similar conclusions (1052).

 

Thomas H. Lee (US), Edward Ralph Marcantonio (US), Carol M. Mangione (US), Eric J. Thomas (US), Carisi Anne Polanczyk (BR), E. Francis Cook (US), David John Sugarbaker (US), Magruder C. Donaldson (US), Robert Poss (US), Kalon K. L. Ho (US), Lynn E. Ludwig (US), Alex Pedan (US) and Lee Goldman (US) developed the “Lee Index”, a prospectively validated model that predicts the risk of a cardiac event in patients undergoing noncardiac surgery. The six independent predictors are as follows: 1) high-risk surgery, 2) history of ischemic heart disease, 3) history of congestive heart failure, 4) history of cerebrovascular disease, 5) preoperative treatment with insulin, 6) preoperative serum creatinine >2.0 mg/dL (>177 µmol/L) (846).

 

Milton Packer (US), Philip A. Poole-Wilson (US), Paul W. Armstrong (US), John G. F. Cleland (US), John D. Horowitz (US), Barry M. Massie (US), Lars Rydén (US), Kristian Thygesen (US) and Barry F. Uretsky (US) revealed that compared to a lower dose, high-dose angiotensin-converting-enzyme inhibitor significantly reduced the risk of hospitalization or death in patients with chronic heart failure (1117).

 

The MRC Laparoscopic Groin Hernia Trial Group (GB-IE), Leigh Neumayer (US), Anita Giobbie-Hurder (US), Olga Jonasson (US), Robert Fitzgibbons, Jr. (US), Dorothy Dunlop (US), James Gibbs (US), Domenic Reda (US), William Henderson (US), Veterans Affairs Cooperative Studies Program 456 Investigators (US), Dag Arvidsson (SE), Fritz H. Bernden (SE), Lars-Göran Larsson (SE), Carl-Eric Leijonmarck (SE), Gunnar Rimbeck (SE), Claes Rudberg (SE), Sam Smedberg (SE), Leif Spangen (SE), and Agneta Montgomery (SE) confirmed that laproscopic repair of inguinal hernia was associated with a shorter length of hospital stay and quicker return to normal activities. Some studies also reported less chronic pain with the laproscopic procedure. However, there are serious risks associated with the laproscopic approach which do not occur during open surgery. The cost of laproscopic surgery has been shown to be significantly greater than that of open surgery, even without the use of disposable instruments (55; 554; 1065).

 

Richard W. Childs (US), Emmanuel Clave (US), John Tisdale (US), Michelle Plante (US), Nancy Hensel (US), A. John Barrett (US), Allen Chernoff (US), Natalie Contentin (US), Erkut Bahceci (US), David Schrump (US), Susan Leitman (US), Elizabeth J. Read (US), Cynthia Dunbar (US), W. Marston Linehan (US), and Neal S. Young (US) reported successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: evidence for a graft-versus-tumor effect (242-244).

 

Paul C. Hébert (CA), George Wells (CA), Morris A. Blajchman (CA), John Marshall (CA), Claudio Martin (CA), Giuseppe Pagliarello (CA), Martin Tweeddale (CA), Irwin Schweitzer (CA), and Elizabeth Yetisir (CA), using a restrictive transfusion strategy in critically ill patients did not significantly increase 30-day mortality when compared with a liberal transfusion strategy. Subgroup analyses demonstrated that a restrictive transfusion strategy was associated with significantly lower mortality in patients with APACHE II score ≤20 and age <55 years (611). Note: The Acute Physiologic Assessment and Chronic Health Evaluation (Apache) II Score estimates ICU mortality based on a number of laboratory values and patient signs taking both acute and chronic disease into account.

 

Jean-Michel Dubernard (FR), Earl Owen (FR), Nicole Lefrancois (FR), Palmina Petruzzo (FR), Xavier Martin (FR), Marwan Dawahra (FR), Denis Jullien (FR), Jean Kanitakis (FR), Camille Frances (FR), Xavier Preville (FR), Lucette Gebuhrer (FR), Nadey S. Hakim (FR), Marco Lanzettà (FR), Hari Kapila (FR), Guillaume Herzberg (FR), and Jean-Pierre Revillard (FR) successfully transplanted the right distal forearm and hand of a brain-dead man aged 41 years on to a man aged 48 years who had had traumatic amputation of the distal third of his right forearm (350; 351). Note: This was the first hand transplantation.

Jean-Michel Dubernard (FR), Palmina Petruzzo (FR), Marco Lanzetta (FR), Helen Parmentier (FR), Xavier Martin (FR), Marwan Dawahra (FR), Nadey S. Hakim (FR), and Earl Owen (FR) performed the first human double-hand transplantation (352).

 

Anders Hellberg (SE), Claes Rudberg (SE), Erik Kullman (SE), Lars Enochsson (SE), György Fenyo (SE), Hans Graffner (SE), Bengt Hallerbäck (SE), Bo Johansson (SE), Bengt Anderberg (SE), Jögen Wenner (SE), Ivar Ringqvist (SE), Stefan Sorensen (SE), Anders Gorm Pedersen (DK), Olav B. Petersen (DK), Paul Wara (DK), Hanne Rønning (DK), Niels Qvist (DK), and Søren Laurberg (DK) showed that laproscopy is as safe as open appendectomy and has the advantage of allowing a quicker recovery, fewer wound infections, faster overall recovery, earlier return to work, and improved cosmesis (621; 1140).

 

Yuman Fong (US), Joseph Fortner (US), Ruth L. Sun (US), Murray F. Brennan (US), and Leslie H. Blumgart (US) found that resection of hepatic colorectal metastases may produce long-term survival and cure. Long-term outcome can be predicted from five criteria that are readily available for all patients considered for resection. Patients with up to two criteria can have a favorable outcome (428).

 

Daniel H. Present (US), Paul Rutgeerts (BE), Stephan Targan (US), Stephen B. Hanauer (US), Lloyd Mayer (US), Ruud A. van Hogezand (NL), Daniel K. Podolsky (US), Bruce E. Sands (US), Tanja Braakman (US), Kimberly L. DeWoody (US), Thomas F. Schaible (US), and Sander J.H. van Deventer (NL) found that Infliximab (immunosuppressive drug) is an efficacious treatment for fistulas in patients with Crohn's disease (1180).

 

Giuseppe Brisinda (IT), Giorgio Maria (IT), Anna Rita Bentivoglio (IT), Emanuele Cassetta (IT), Daniele Gui (IT), and Alberto Albanese (IT) found that Botox (botulinum toxin) and GTN (glyceryl trinitrate) are effective treatments for chronic anal fissure, although better results were seen with Botox .(163)

 

Salim Ali (IN) and Sidney Dillon Ripley II (US) produced, Handbook of the Birds of India and Pakistan: Together with Those of Bangladesh, Nepal, Sikkim, Bhutan, and Sri Lanka.The contents of this ten volume magnum opus were collected from 1964 through 1974 (29).

 

 Alan Thorne (AU), Rainer Grun (AU), Graham Mortimer (AU), Nigel A. Spooner (AU), John J. Simpson (AU), Malcolm McCulloch (AU), Lois Taylor (AU), and Darren Curnoe (AU) presented evidence that people who were skeletally within the range of the present Australian indigenous population colonized the continent during or before 57,000-71,000 years ago (1454).

 

S. Blair Hedges (US) and Laura L. Polong (US), Ying Cao (JP), Michael D. Sorenson (US), Yoshinori Kumazawa (JP), David P. Mindell (US), and Masami Hasegawa (JP) reported in a study of both nuclear DNA and mitochondrial DNA that the turtle is anapsid and the crocodile's closest living relative. The results apparently establish a phylogenetic joining of crocodilians with turtles and place squamates at the base of the tree. This work presents molecular time estimates to support a Triassic origin for the major groups of living reptiles and supports the previous findings of James E. Platz (US), J. Michael Colon (US), John W.A. Kirsch (US), Gregory Christian Mayer (US), Rafael Zardoya (ES), and Axel Meyer (DE) (203; 615; 769; 1171; 1624).

 

Patrick E. McGovern (US), Donald L. Glusker (US), Robert A. Moreau (US), Alberto Nuñez (US), Curt W. Beck (US), Elizabeth Simpson (US), Eric D. Butrym (US), Lawrence J. Exner (US), and Edith C. Stout (US) found the oldest evidence for the existence of wine. It comes from Neolithic villagers in the Zagros Mountains, in what is now Northwestern Iran. Evidence of wine has been found in jars that were once placed along the kitchen walls of a mud-brick structure. The wine may have resembled Greek retsina. Recent chemical and related tests of a yellowish residue found in the jars point to wine. First, salts of tartaric acid, found naturally in large amounts only in grapes, were identified. Secondly, resin from the terebinth tree, used in antiquity to preserve wine, was also discovered. Additionally, the jars had narrow necks and stoppers were found nearby (973). Note: Pistacia terebinthus, a native plant of Iran and the Western Mediterranean countries, is tapped for turpentine, P. palaestina, a similar species, is common in the eastern Mediterranean countries. These trees are both known as terebinth. Because it has the ability to kill certain bacteria, terebinth resin was widely used as a preservative in ancient wine.

 

Francoise Jouy-Avantin (FR), Claude Combes (FR), Henry de Lumley (FR), Jean-Claude Miskovsky (FR), and Helene Mone (FR) discovered dicrocoelid (liver fluke) eggs in animal coprolites collected in an archeological layer dated earlier than 550,000 B.C.E. from the Caune de l'Arago cave (Tautavel, Pyrenees-Orientales, France). It is the first trematode egg finding in an isolated coprolite from the Middle Pleistocene (723).

 

Roger E. Summons (AU), Linda L. Jahnke (AU), Janet M. Hope (AU), Graham A. Logan (AU), Jochen J. Brocks (AU), and Roger Buick (AU) found molecular fossils of biological lipids preserved in 2.7-billion-year-old shales from the Pilbara Craton, Australia. This makes these the oldest known biomolecules. The presence of abundant 2 alpha-methylhopanes, which are characteristic of cyanobacteria, indicates that oxygenic photosynthesis evolved well before the atmosphere became oxidizing. The presence of steranes, particularly cholestane and its 28- to 30-carbon analogs, provides persuasive evidence for the existence of eukaryotes 500 million to 1 billion years before the extant fossil record indicates that the lineage arose (165; 1417).

 

Samuel A. Bowring (US) and Ian S. Williams (US) identified the oldest rocks found on Earth as granite-like rocks called gneiss from the Acasta Gneiss Complex near Great Slave Lake, Northwest Territory, Canada—4.03 Ga—and the Isua Supracrustal rocks in West Greenland—3.7 to 3.8 Ga. They were dated using the uranium 235 to lead 207 method (156).

 

2000

Arvid Carlsson (SE), Paul Greengard (US) and Eric Richard Kandel (US) were jointly awarded the Nobel Prize in physiology and medicine for their discoveries concerning signal transduction in the nervous system.

 

Alessandro Morbidelli (IT), John Chambers (US), Jonathan I. Lunine (US), Jean-Marc Petit (IT), Francois Robert (FR), Giovanni B. Valsecchi (IT), and Kim E. Cyr (US) proposed that as the solar system formed, Jupiter's powerful gravity perturbed asteroids to accrete into larger and larger objects — terrestrial "embryos" as big as Mars or bigger — then tossed them into very unstable elliptical orbits. Those that hit Earth when flung toward the inner solar system delivered the water that now fills Earth's oceans. That happened when Earth was about half its present size (1015).

 

Karin M. Höld (US), Nilantha S. Sirisoma (US), Tomoko Ikeda (US), Toshio Narahashi (US), and John Edward Casida (US) discovered that alpha-thujone is the active component of absinthe, exhibiting neurotoxicity by gamma-aminobutyric acid type A receptor modulation and metabolic detoxification (643).

 

Frank Schluenzen (DE), Ante Tocilj (DE), Raz Zarivach (IL), Jörg Harms (DE), Marco Gluehmann (DE), Daniela Janell (DE), Anat Bashan (DE), Heike Bartels (DE), Ilana Agmon (DE), Francois Franceschi (DE), Ada E. Yonath (IL), Brian T. Wimberly (US), Ditlev E. Brodersen (GB), William M. Clemons, Jr. (GB), Robert J. Morgan-Warren (GB), Andrew P. Carter (GB), Clemens Vonrhein (GB), Thomas Hartsch (DE), and Venkatraman Ramakrishnan (IN-US-GB) determined the structure of the 30S ribosomal subunit (206; 1292; 1580).

 

Jeff Abramson (SE), Sirpa Riistama (FI), Gisela Larsson (SE), Audrius Jasaitis (FI), Margareta Svensson-Ek (SE), Liisa Laakkonen (FI), Anne Puustinen (FI), So Iwata (GB), and Marten Wikstrom (FI) determined the structure of the ubiquinol oxidase from Escherichia coli and its ubiquinone-binding site (11).

 

Russell H. Vreeland (US), William D. Rosenzweig (US), and Dennis W. Powers (US) reported the isolation and growth of a previously unrecognized spore-forming bacterium (Bacillus species, designated 2-9-3) from a brine inclusion within a 250 million-year-old salt crystal from the Permian Salado Formation. Complete gene sequences of the 16S ribosomal DNA show that the organism is part of the lineage of Bacillus marismortui and Virgibacillus pantothenticus (1525).

 

Xiao-Ping Li (US), Olle Björkman (US), Connie Shih (US), Arthur R. Grossman (US), Magnus Rosenquist (SE), Stefan Jansson (SE), and Krishna K. Niyogi (US) found that the gene encoding PsbS, an intrinsic chlorophyll-binding protein of photosystem 2, is necessary for nonphotochemical quenching but not for efficient light harvesting and photosynthesis in Arabidopsis thaliana (869). Note: Absorption of light that exceeds a plant's capacity for fixation of CO2 results in thermal dissipation of excitation energy in the pigment antenna of photosystem 2 by a poorly understood mechanism. This regulatory process, termed nonphotochemical quenching, maintains the balance between dissipation and utilization of light energy to minimize generation of oxidizing molecules, thereby protecting the plant against photo-oxidative damage.

 

Cecilia S. Lai (GB), Simon E. Fisher (GB), Jane A. Hurst (GB), Elaine R. Levy (GB), Shirley Hodgson (GB), Margaret Fox (GB), Stephen Jeremiah (GB), Susan Povey (GB), D. Curtis Jamison (US), Eric D. Green (US), Faraneh Vargha-Khadem (GB), and Anthony P. Monaco (GB) reported the discovery of the FOXP2 ("forkhead box P2") gene. It produces a member of the large FOX family of transcription factors. Information from known human mutations and mouse studies suggest that FOXP2 regulates genes involved in the development of tissues such as brain, lung, and gut (819). Note: Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene.

 

John F. Heidelberg (US), Jonathan A. Eisen (US), William C. Nelson (US), Rebecca A. Clayton (US), Michelle L. Gwinn (US), Robert J. Dodson (US), Daniel H. Haft (US), Erin K. Hickey (US), Jeremy D. Peterson (US), Lowell Umayam (US), Steven R. Gill (US), Karen E. Nelson (US), Timothy D. Read (US), Herv Tettelin (US), Delwood Richardson (US), Maria D. Ermolaeva (US), Jessica Vamathevan (US), Steven Bass (US), Haiying Qin (US), Ioana Dragoi (US), Patrick Sellers (US), Lisa McDonald (US), Teresa Utterback (US), Robert D. Fleishmann (US), William C. Nierman (US), Owen White (US), Steven L. Salzberg (US), Hamilton Othanel (US), Rita R. Colwell (US), John J. Mekalanos (US), John Craig Venter (US), and Claire M. Fraser (US) determined the complete genomic sequence of the gram negative, Proteobacterium Vibrio cholerae El Tor N16961 to be 4,033,460 base pairs (bp). The genome consists of two circular chromosomes of 2,961,146 bp and 1,072,314 bp that together encode 3,885 open reading frames (616).

 

Athanasios Theologis (US), Joseph R. Ecker (US), Curtis J. Palm (US), Nancy A. Federspiel (US), Samir Kaul (US), Owen White (US), Jose Alonso (US), Hootan Altafi (US), Rina Araujo (US), Cheryl L. Bowman (US), Shelise Y. Brooks (US), Eugen Buehler (US), April Chan (US), Qimin Chao (US), Huaming Chen (US), Rosa F. Cheuk (US), Christina W. Chin (US), Mike K. Chung (US), Lane Conn (US), Aaron B. Conway (US), Andrew R. Conway (US), Todd H. Creasy (US), Ken Dewar (US), Patrick Dunn (US), Pelin Etgu (US), Tamara V. Feldblyum (US), Jidong Feng (US), Betty Fong (US), Claire Y. Fujii (US), John E. Gill (US), Andrew D. Goldsmith (US), Brian Haas (US), Nancy F. Hansen (US), Beth Hughes (US), Lucas Huizar (US), Jonathan L. Hunter (US), Jennifer Jenkins (US), Chanda Johnson-Hopson (US), Shehnaz Khan (US), Elizabeth Khaykin (US), Christopher J. Kim (US), Hean L. Koo (US), Irina Kremenetskaia (US), David B. Kurtz (US), Andrea Kwan (US), Bao Lam (US), Stephanie Langin-Hooper (US), Andrew Lee (US), Jeong Mi Lee (US), Catherine A. Lenz (US), Joyce H. Li (US), Yaping Li (US), Xiaoying Lin (US), Shirley X. Liu (US), Zhaoying A. Liu (US), Jason S. Luros (US), Rama Maiti (US), Andre Marziali (US), Jennifer Militscher (US), Molly Miranda (US), Michelle Nguyen (US), William C. Nierman (US), Brian I. Osborne (US), Grace Pai (US), Jeremy D. Peterson (US), Paul K. Pham (US), Michael Rizzo (US), Timothy Rooney (US), Don Rowley (US), Hitomi Sakano (US), Steven Salzberg (US), Jody R. Schwartz (US), Paul Shinn (US), Audrey M. Southwick (US), Hui Sun (US), Luke J. Tallon (US), Gabriel Tambunga (US), Mitsue J. Toriumi (US), Christopher D. Town (US), Teresa R. Utterback (US), Sarah Van Aken (US), Maria Vaysberg (US), Valentina S. Vysotskaia (US), Michelle Walker (US), Dongying Wu (US), Guixia Yu (US), Claire M. Fraser (US), John Craig Venter (US), and Ronald W. Davis (US) determined the sequence and analysis of chromosome 1 of the plant Arabidopsis thaliana (a member of the mustard family commonly called Thale cress). Arabidopsis thaliana is unique among plant model organisms in having a small genome (130-140 Mb), excellent physical and genetic maps, and little repetitive DNA (1449).

 

Clarence A. Ryan (US) discovered systemin, an 18-amino-acid polypeptide released from wound sites on tomato leaves caused by insects or other mechanical damage. Systemin regulates the activation of over 20 defensive genes in tomato plants (1265).

 

Marcel Salanoubat (FR), Kai Lemcke (DE), Michael Rieger (DE), Wilhelm Ansorge (CZ-DE), Michael Unseld (DE), Berthold Fartmann (DE), Giorgio Valle (IT), Helmut Blocker (DE), Manuel Perez-Alonso (ES), Brigitte Obermaier (DE), Michael Delseny (FR), Marc Boutry (BE), Les A. Grivell (NL), Regis Mache (FR), Pere Puigdomenech (ES), Vincenzo de Simone (IT), Nathalie Choisne (FR), Francois Artiguenave (FR), Catherine Robert (FR), Phillipe Brottier (FR), Patrick Wincker (DE), Laurence Cattolico (FR), Jean Weissenbach (FR), William Saurin (FR), Francis Quétier (FR), Melanie Schäfer (DE), Silke Muller-Auer (DE), Christopher Gabel (DE), Martin Fuchs (DE), Vladimir Benes (DE), Elisa Wurmbach (US), Heiko Drzonek (DE), Holger Erfle (DE), Nicolette Jordan (), Stephanie Rogers Bangert (US), R. Wiedelmann (), Harald D. Kranz (DE), Hartmut Voss (DE), Rudi Holland (DE), Petra Brandt (DE), Gerald J. Nyakatura (), Alessandro Vezzi (IT), Michela D'Angelo (IT), Alberto Pallavicini (IT), Stefano Toppo (IT), Barbara Simionati (IT), Ansgar Conrad (DE-US), Klaus Hornischer (DE), Gerhard Kauer (DE), Tschong-Hun Löhnert (DE), Gabriele Nordsiek (DE), Joachim Reichelt (DE), Maren Scharfe (DE), Oliver Schön (DE), Monica Bargues (ES), Javier Terol (ES), Joan Climent (ES), Pilar Navarro (ES), Carmen Collado (ES), Angela Pérez-Pérez (ES), Birgit Ottenwälder (AT), David Duchemin (US), Richard Cooke (FR), Michèle Laudié (FR), Christel Llauro-Berger (FR), Bénédicte Purnelle (BE), David Masuy (BE), Muus de Haan (NL), Ammy C. Maarse (NL), Jean-Pierre Alcaraz (DE), Annick Cottet (FR), Elena Casacuberta (ES), Amparo Monfort (ES), Anagnostis Argiriou (GR), Margarita Flores (MX), Rocco Liguori (IT), Domenico Vitale (IT), Gertrud Mannhaupt (DE), Dirk Haase (DE), Heiko Schoof (DE), Stephen Rudd (DE), Paolo Zaccaria (DE), Hans-Werner Mewes (DE), Klaus Mayer (DE), Samir Kaul (US), Christopher D. Town (US), Hean L. Koo (US), Luke J. Tallon (US), Jennifer Jenkins (US), Timothy Rooney (US), Michael Rizzo (US), Avram Walts (US), Teresa R. Utterback (US), Claire Y. Fujii (US), Terrence P. Shea (US), Todd H. Creasy (US), Brian Haas (US), Rama Maiti (US), Dongying Wu (US), Jeremy D. Peterson (US), Susan Van Aken (US), Grace Pai (US), Jennifer Militscher (US), Patrick Sellers (US), John E. Gill (US), Tamara V. Feldblyum (US), Daphne Preuss (US), Xiaoying Lin (US), William C. Nierman (US), Steven L. Salzberg (US), Owen White (US), John Craig Venter (US), Claire M. Fraser (US), Takakazu Kaneko (JP), Yasukazu Nakamura (JP), Shusei Sato (JP), Tomohiko Kato (JP), Erika Asamizu (JP), Shigemi Sasamoto (JP), Takaharu Kimura (JP), Kumi Idesawa (JP), Kumiko Kawashima (JP), Yoshie Kishida (JP), Chiaki Kiyokawa (JP), Mitsuyo Kohara (JP), Midori Matsumoto (JP), Ai Matsuno (JP), Akiko Muraki (JP), Shinobu Nakayama (JP), Naomi Nakazaki (JP), Sayaka Shinpo (JP), Chie Takeuchi (JP), Tsuyuko Wada (JP), Akiko Watanabe (JP), Manabu Yamada (JP), Miho Yasuda (JP) and Satoshi Tabata (JP) determined the sequence and analysis of chromosome 3 of the plant Arabidopsis thaliana (a member of the mustard family commonly called Thale cress). Arabidopsis thaliana is unique among plant model organisms in having a small genome (130-140 Mb), excellent physical and genetic maps, and little repetitive DNA (1273).

 

Satoshi Tabata (JP), Takakazu Kaneko (JP), Yasukazu Nakamura (JP), Hirokazu Kotani (JP), Tomohiko Kato (JP), Erika Asamizu (JP), Nobuyuki Miyajima (JP), Shigemi Sasamoto (JP), Takaharu Kimura (JP), Tsutomo Hosouchi (JP), Kumiko Kawashima (JP), Mitsuyo Kohara (JP), Midori Matsumoto (JP), Ai Matsuno (JP), Akiko Muraki (JP), Shinobu Nakayama (JP), Naomi Nakazaki (JP), Kaoru Naruo (JP), Satomi Okumura (JP), Sayaka Shinpo (JP), Chie Takeuchi (JP), Tsuyuko Wada (JP), Akiko Watanabe (JP), Manabu Yamada (JP), Miho Yasuda (JP), Shusei Sato (JP), Melissa de la Bastide (US), Emily Huang (US), Lori Spiegel (US), Lidia Gnoj (US), Andrew O'Shaughnessy (US), Ray Preston (US), Kristina Habermann (US), Jennifer Murray (US), David Johnson (US), Tracy Rohlfing (US), Joanne Nelson (US), Tamberlyn Stoneking (US), Kymberlie H. Pepin (US), John Spieth (US), Mandeep Sekhon (US), Jon Armstrong (US), Michael C. Becker (US), Edward Belter (US), Holland Cordum (US), Matthew Cordes (US), Laura Courtney (US), William Courtney (US), Michael Dante (US), Hui Du (US), Jennifer Edwards (US), Johanna Fryman (US), William Haakensen (US), Elizabeth Lamar (US), John P. Latreille (US), Leonard (US), Sharon Rick Meyer (US), Elizabeth Mulvaney (US), Philip Ozersky (US), Julie Riley (US), Catrina Strowmatt (US), Caryn Wagner-McPherson (US), Aye Tin-Wollam (US), Martin Yoakum (US), Maureen Bell (US), Neilay Dedhia (US), Laurence Parnell (US), Ravi Shah (US), Mika Rodriguez (US), L. Hoon See (US), Danielle Vil (US), Joshua Baker (US), Kristin Kirchoff (US), Krisztina Toth (US), Lisa King (US), Ariana Bahret (US), Beth F. Miller (US), Marco A. Marra (US), Rob Martienssen (US), W. Richard McCombie (US), Richard K. Wilson (US), George Murphy (GB), Ian Bancroft (GB), Guido Volckaert (BE), Rolf Wambutt (DE), Andreas Dusterhoft (DE), Willem J. Stiekema (NL), Thomas Pohl (DE). Karl-Dieter Entian (DE), Nancy Terryn (BE), Nigel Hartley (GB), E. Bent (GB), Samantha Johnson (GB), Sally A. Langham (GB), Bethany McCullagh (GB), Johan Robben (BE), Barbara Grymonprez (BE), Wolfgang Zimmermann (DE), Uwe Ramsperger (DE), Holgar Wedler (DE), Kathleen Balke (DE), Erika Wedler (DE), Sander Peters (NL), Marjo van Staveren (NL), Wim Dirkse (NL), Paul Mooijman (NL), Rene Klein-Lankhorst (NL), Thomas Weitzenegger (DE), Gordana Bothe (DE), M. Rose (DE), J. Hauf (DE), S. Berneiser (DE), S. Hempel (DE), M. Feldpausch (DE), S. Lamberth (DE), Raimundo Villarroel (BE), Jan Gielen (BE), Wilson Ardiles (BE), Ole Bents (DE), Kai Lemcke (DE), Grigorij Kolesov (DE), Klaus Mayer (DE), Stephen Rudd (DE), Heiko Schoof (DE), Christine Schueller (DE), Paolo Zaccaria (DE), Hans-Werner Mewes (DE), Michael John Bevan (GB-US), and Paul Fransz (NL) determined the sequence and analysis of chromosome 5 of the plant Arabidopsis thaliana (a member of the mustard family commonly called Thale cress). Arabidopsis thaliana is unique among plant model organisms in having a small genome (130-140 Mb), excellent physical and genetic maps, and little repetitive DNA (1430).

 

Mark D. Adams (US), Susan E. Celniker (US), Robert A. Holt (US), Cheryl A. Evans (US), Jeannine D. Gocayne (US), Peter G. Amanatides (US), Steven E. Scherer (US), Peter W. Li (US), Roger A. Hoskins (US), Richard F. Galle (US), Reed A. George (US), Suzanna E. Lewis (US), Stephen Richards (US), Michael Ashburner (US), Scott N. Henderson (US), Granger G. Sutton (US), Jennifer R. Wortman (US), Mark D. Yandell (US), Qing Zhang (US), Lin X. Chen (US), Rhonda C. Brandon (US), Yu-Hui C. Rogers (US), Robert G. Blazej (US), Mark Champe (US), Barret D. Pfeiffer (US), Kenneth H. Wan (US), Clare Doyle (US), Evan G. Baxter (US), Gregg Helt (US), Catherine R. Nelson (US), George L. Gabor Miklos (US), Josep F. Abril (US), Anna Agbayani (US), Hui-Jin An (US), Cynthia Andrews-Pfannkoch (US), Danita Baldwin (US), Richard M. Ballew (US), Anand Basu (US), James Baxendale (US), Leyla Bayraktaroglu (US), Ellen M. Beasley (US), Karen Y. Beeson (US), Panayiotis V. Benos (US), Benjamin P. Berman (US), Deepali Bhandari (US), Slava Bolshakov (US), Dana Borkova (US), Michael R. Botchan (US), John Bouck (US), Peter Brokstein (US), Phillipe Brottier (US), Kenneth C. Burtis (US), Dana A. Busam (US), Heather Butler (US), Edouard Cadieu (US), Angela Center (US), Ishwar Chandra (US), J. Michael Cherry (US), Simon Cawley (US), Carl Dahlke (US), Lionel B. Davenport (US), Peter Davies (US), Beatriz de Pablos (US), Arthur Delcher (US), Zuoming Deng (US), Anne Deslattes Mays (US), Ian Dew (US), Suzanne M. Dietz (US), Kristina Dodson (US), Lisa E. Doup (US), Michael Downes (US), Shannon Dugan-Rocha (US), Boris C. Dunkov (US), Patrick Dunn (US), Kenneth J. Durbin (US), Carlos C. Evangelista (US), Concepcion Ferraz (US), Steven Ferriera (US), Wolfgang Fleischmann (US), Carl Fosler (US), Andrei E. Gabrielian (US), Neha S. Garg (US), William M. Gelbart (US), Ken Glasser (US), Anna Glodek (US), Fangcheng Gong (US), J. Harley Gorrell (US), Zhiping Gu (US), Ping Guan (US), Michael Harris (US), Nomi L. Harris (US), Damon Harvey (US), Thomas J. Heiman (US), Judith R. Hernandez (US), Jarrett Houck (US), Damon Hostin (US), Kathryn A. Houston (US), Timothy J. Howland (US), Ming-Hui Wei (US), Chinyere Ibegwam (US), Mena Jalali (US), Francis Kalush (US), Gary H. Karpen (US), Zhaoxi Ke (US), James A. Kennison (US), Karen A. Ketchum (US), Bruce E. Kimmel (US), Chinnappa D. Kodira (US), Cheryl Kraft (US), Saul Kravitz (US), David Kulp (US), Zhongwu Lai (US), Paul Lasko (US), Yiding Lei (US), Alexander A. Levitsky (US), Jiayin Li (US), Zhenya Li (US), Yong Liang (US), Xiaoying Lin (US), Xiangjun Liu (US), Bettina Mattei (US), Tina C. McIntosh (US), Michael P. McLeod (US), Duncan McPherson (US), Gennady Merkulov (US), Natalia V. Milshina (US), Clark Mobarry (US), Joe Morris (US), Ali Moshrefi (US), Stephen M. Mount (US), Mee Moy (US), Brian Murphy (US), Lee Murphy (US), Donna M. Muzny (US), David L. Nelson (US), David R. Nelson (US), Keith A. Nelson (US), Katherine Nixon (US), Deborah R. Nusskern (US), Joanne M. Pacleb (US), Michael Palazzolo (US), Gjange S. Pittman (US), Sue Pan (US), John Pollard (US), Vinita Puri (US), Martin G. Reese (US), Knut Reinert (US), Karin Remington (US), Robert D. C. Saunders (US), Frederick Scheeler (US), Hua Shen (US), Bixiang Christopher Shue (US), Inga Sidén-Kiamos (US), Michael Simpson (US), Marian P. Skupski (US), Tom Smith (US), Eugene Spier (US), Allan Charles Spradling (US), Mark Stapleton (US), Renee Strong (US), Eric Sun (US), Robert Svirskas (US), Cyndee Tector (US), Russell Turner (US), Eli Venter (US), Aihui H. Wang (US), Xin Wang (US), Zhen-Yuan Wang (US), David A. Wassarman (US), George M. Weinstock (US), Jean Weissenbach (US), Sherita M. Williams (US), Trevor Woodage (US), Kim C. Worley (US), David Wu (US), Song Yang (US), Q. Alison Yao (US), Jane Ye (US), Ru-Fang Yeh (US), Jayshree S. Zaveri (US), Ming Zhan (US), Guangren Zhang (US), Qi Zhao (US), Liansheng Zheng (US), Xiangqun H. Zheng (US), Fei N. Zhong (US), Wenyan Zhong (US), Xiaojun Zhou (US), Shiaoping Zhu (US), Xiaohong Zhu (US), Hamilton Othanel (US), Richard A. Gibbs (US), Eugene W. Myers (US), Gerald M. Rubin (US), and John Craig Venter (US) determined the genomic sequence of Drosophila melanogaster (15).

 

Simon Melov (US), Joanne Ravenscroft (GB), Sarwatt Malik (GB), Matt S. Gill (GB), David W. Walker (GB), Peter E. Clayton (GB), Douglas C. Wallace (US), Bernard Malfroy (US), Susan R. Doctrow (US), and Gordon J. Lithgow (GB) tested the theory that reactive oxygen species cause aging. They augmented the natural antioxidant systems of the nematode Caenorhabditis elegans with small synthetic superoxide dismutase/catalase mimetics. Treatment of wild-type worms increased their mean lifespan by a mean of 44 percent, and treatment of prematurely aging worms resulted in normalization of their lifespan (a 67 percent increase). It appears that oxidative stress is a major determinant of lifespan and that it can be counteracted by pharmacological intervention (986).

 

Anthony V. Furano (US) reported that mammalian LINE-1 (L1) elements belong to the superfamily of autonomously replicating retrotransposable elements that lack the long terminal repeated (LTR) sequences typical of retroviruses and retroviral-like retrotransposons. The non-LTR superfamily is very ancient and L1-like elements are ubiquitous in nature, having been found in plants, fungi, invertebrates, and various vertebrate classes from fish to mammals. L1 elements have been replicating and evolving in mammals for at least the past 100 million years and now constitute 20% or more of some mammalian genomes. Therefore, L1 elements presumably have had a profound, perhaps defining, effect on the evolution, structure, and function of mammalian genomes. L1 elements contain regulatory signals and encode two proteins: one is an RNA-binding protein and the second one presumably functions as an integrase-replicase, because it has both endonuclease and reverse transcriptase activities. This work reviews the structure and biological properties of L1 elements, including their regulation, replication, evolution, and interaction with their mammalian hosts. Although each of these processes is incompletely understood, what is known indicates that they represent challenging and fascinating biological phenomena, the resolution of which will be essential for fully understanding the biology of mammals (452). Note: These retrotransposons might represent the smallest of parasites yet discovered or is it the Alus (Alu sing.), which have dropped the reverse transcriptase sequence in lieu of endogenous reverse transcriptase.

 

Timothy S. Gardner (US), Charles R. Cantor (US), and James J. Collins (US) constructed a genetic toggle switch—a synthetic, bistable gene-regulatory network—in Escherichia coli and provided a simple theory that predicts the conditions necessary for bistability. The toggle is constructed from any two repressible promoters arranged in a mutually inhibitory network. It is flipped between stable states using transient chemical or thermal induction and exhibits a nearly ideal switching threshold (469).

 

Lynda Chiodetti (US), Daniel L. Barber (US), and Ronald H. Schwartz (US) argue that the IL-2 locus can be expressed biallelically under optimum stimulation conditions (245).

 

Michelle Taylor McMurry (US) and Michael S. Krangel (US) proposed histone H3 hyperacetylation as a molecular mechanism coupling enhancer activity to accessibility for VDJ recombination (977).

 

Charles D. Mills (US), Kristi Kincaid (US), Jennifer M. Alt (US), Michelle J. Heilman (US), and Annette M. Hill (US) produced results indicating that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur (1000).

 

Hiroaki Hemmi (JP), Osamu Takeuchi (JP), Tare Kawai (JP), Tsuneyasu Kaisho (JP), Shintaro Sato (JP), Hideki Sanjo (JP), Makoto Matsumoto (JP), Katsuald Hoshino (JP), Hermann Wagner (DE), Kiyoshi Takeda (JP), and Shizuo Akira (JP) found that a mammalian cellular response to bacterial CpG DNA is mediated by a Toll-like receptor, TLR9 (622).

 

Richard J. Gibbons (GB) and Douglas Higgs (GB) demonstrated an X-linked helicase deficiency in some male human patients and subtelomeric deletions on chromosome 16 in others that were shown to be responsible for reduced alpha globin gene expression and were presumably responsible for the mental retardation in X-linked α thalassemia/mental retardation (ATR-X) syndrome, Carpenter syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, and X-linked mental retardation with spastic paraplegia (491).

 

Thomas Schindler (US), William Bormmann (US), Patricia Pellicena (US), W. Todd Miller (US), Bayard Clarkson (US), and John Kuriyan (US) discovered that the anticancer drug Gleevec (STI-571) works by recognizing the unique "switched-off" form of BCR-Abi. BCR-Abi kinase is an abnormal protein that causes most cases of chronic myelogenous leukemia. When Gleevec binds to that kinase, it stops it from triggering the growth of leukemia cells. Gleevec binds to only two or three of the 500 human protein kinases making it a powerful drug (with few side effects) against chronic myelogenous leukemia, but not against similar cancers (1291).

 

A.M. James Shapiro (CA), Jonathan R.T. Lakey (CA), Edmond A. Ryan (CA), Gregory S. Korbutt (CA), Ellen Toth (CA), Garth L. Warnock (CA), Norman M. Kneteman (CA), and Ray V. Rajotte (CA) performed islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen (1326).

 

Oliver Smithies (US), Hyung-Suk Kim (US), Nobuyuki Takahashi (US), and Marshall H. Edgall (US) proposed that, “it is very likely that essential hypertension is a quantitative genetic trait that can arise from different combinations of genetic variants, many of which individually have only a modest effect on blood pressure.” (1367)

 

Susanne Szabo (US), Sean T. Kim (US), Gina L. Costa (US), Xiankui Zhang (US), C. Garrison Fathman (US), and Laurie H. Glimcher (US) reported the isolation of T-bet, a Th1- specific T box transcription factor that controls the expression of the hallmark Th1 cytokine, IFNgamma. T-bet initiates Th1 lineage development from naive Thp cells both by activating Th1 genetic programs and by repressing the opposing Th2 programs (1429).

 

Teruhiko Wakayama (US), Yoichi Shinkai (JP), Kellie L. K. Tamashiro (US), Hiroyuki Niida (US), D. Caroline Blanchard (US), Robert J. Blanchard (US), Atsuo Ogura (JP), Kentaro Tanemura (JP), Makoto Tachibana (JP), Anthony C. F. Perry (US), Diana F. Colgan (US), Peter Mombaerts (US), and Ryuzo Yanagimachi (US) cloned mice through six generations and found that they showed no signs of premature aging. This study contradicts a 1999 study in cloned sheep, which showed the protective tips of sheep chromosomes, known as telomeres, were showing signs of early wear and tear (1527).

 

Derk C. Bergquist (US), Frederick M. Williams (US), Charles R. Fisher (US) discovered 200 year old tube worms living at a cold methane seep ecosystem in the Gulf of Mexico. This makes them the oldest known invertebrates. These and other members of this ecosystem depend on methane oxidizing microorganisms as primary producers (115).

 

Andrew Whiten (GB), Christophe Boesch (DE), Valerie Jane van Lawick-Goodall (GB), William C. McGrew (US), Toshisada Nishida (JP), Vernon Reynolds (GB), Yukimaru Sugiyama (JP), Caroline E.G. Tutin (GB), Richard W. Wrangham (US), Daniel John Povinelli (US), and Theodore J. Povinelli (US) found that chimpanzees (Pan troglodytes) display remarkable behaviors that can only be described as social customs passed on from generation to generation. This is the culmination of many field studies begun in the 1960s by Goodall and Nishida at two different field stations in Tanzania and all told represents more than 150 years of observing chimpanzees (145; 974; 1569-1571). Note: As early as 1973, Goodall recorded 13 forms of the use of tools, as well as, eight social activities among chimpanzees. She stated that some variations in chimp populations have a cultural origin.

 

Thomas C. Thannickal (US), Robert Y. Moore (US), Robert Nienhuis (US), Lalini Ramanathan (US), Seeme Gulyani (US), Michael Aldrich (US), Marsha Cornford (US), Jerome M. Siegel (US) Christelle Peyron (US), Juliette Faraco (US), William Rogers (US), Beth Ripley (US), Sebastiaan Overeem (NL), Yves Charnay (US), Sona Nevsimalova (US), David V. Reynolds (US), Roger Albin (US), Robin Li (US), (US), Marcel Hungs (US), Mario Pedrazzoli (US), Muralidhara Padigaru (US), Melanie Kucherlapati (US), Jun Fan (US), Richard Maki (US), Gert Jan Lammers (US), Constantin Bouras (US), Raju Kucherlapati (US), Seljl Nishino (US), and Emmanuel Mignot (US) found that most cases of human narcolepsy are associated with a deficient hypocretin (orexin) system. Hypocretin (orexin) is a neurotransmitter (1153; 1448).

 

Enders Kwok Wai Ng (CN), Yuk-hoi Lam (CN), Joseph Jao-yiu Sung (CN), Man Yee Yung (CN), Ka Fai To (CN), Angus Chi-Wai Chan Chan (CN), Danny Wai-Hung Lee (CN), Bonita K.B. Law (CN), James Yun Wong Lau (CN), Thomas K.W. Ling (CN), Wan-Yee Lau (CN), and Sydney Sheung-Chee Chung (CN) reported that duodenal ulcer recurrence rates are low after simple suture repair of the perforation followed by eradiation therapy. Acid-reducing surgery is not required as part of the emergency procedure (1067).

James Yun Wong Lau (CN), Joseph Jao-yiu Sung (CN), Kang Kyu Lee (CN), Man Yee Yung (CN), Simon Kin-hung Wong (CN), Justin Che Yuen Wu (CN), Francis Ka-leung Chan (CN), Enders Kwok Wai Ng (CN), Jung Hyun You (CN), Cheol Whan Lee (CN), Angus Chi-Wai Chan (CN), Sydney Sheung-Chee Chung (CN), Alan Barkun (CA), Ernst J. Kuipers (NL), Joachim Mossner (DE), Dennis M. Jensen (US), Robert Stuart (GB), Henrik Ahlbom (SE), Jan Kilhamn (SE), Tore Lind (SE), and The Peptic Ulcer Bleed Study Group showed that after endoscopic treatment, intravenous omeprazole significantly reduces the risk of re-bleeding in patients with peptic ulcers at 3, 7, and 30 days (829; 1421).

 

Jeffrey S. Hyams (US), James Marowitz (US), and Robert Wyllie (US) found that severity of Crohn’s disease as assessed by the Pediatric Crohn’s Disease Activity Index in patients recruited from 3 pediatric specialty centers decreased significantly over the course of a 12-week treatment regimen with infliximab (a novel chimeric antibody to tumor necrosis factor-α). All patients were on corticosteroids at the start of the study; however, steroid administration decreased significantly over the course of the investigation (672).

 

Stephanie J. Schrag (US), Sara Zywicki (US), Monica M. Farley (US), Arthur L. Reingold (US), Lee H. Harrison (US), Lewis B. Lefkowitz (US), James L. Hadler (US), Richard Danila (US), Paul R. Cieslak (US), and Anne Schuchat (US) found that during the 1990-1998 study period, which included the 1996 initiation of national Group B Streptococcus guidelines, a significant, 65% decrease in early-onset neonatal disease was observed. During the study’s final year, an estimated 3900 early-onset neonatal Group B Streptococcus cases along with 200 early- and late-onset neonatal deaths were believed to have been prevented through the use of recommended antibiotic prophylaxis (1300).

 

Oded Langer (US), Deborah L. Conway (US), Michael D. Berkus (US), Elly M.-J. Xenakis (US), and Olga Gonzales (US) reported that among women with gestational diabetes requiring treatment, those randomized to glyburide achieved similar glycemic control to women in the insulin control group (825). Note: Alan Peaceman, MD said, “This landmark trial was the first to demonstrate that glyburide is an effective alternative to insulin for treatment of gestational diabetes. Findings suggest that this oral agent is an efficacious treatment, though multicenter investigation with longer-term follow-up data is merited.”

 

Giancarlo Mari (US), Russell L. Deter (US), Robert L. Carpenter (US), Feryal Rahman (SA), Roland Zimmerman (CH), Kenneth J. Moise, Jr. (US), Karen F. Dorman (US), Avi Ludomirsky (US), Rogelio Gonzalez (CL), Ricardo Gomez (CL), Utku Oz (US), Laura Detti (US), Joshua A. Copel (US), Ray Bahado-Singh (US), Stanley Berry (US), Juan Martinez-Poyer (US) and Sean C. Blackwell (US) reported that among fetuses at risk for maternal red cell alloimmunization, peak systolic velocity in the middle cerebral artery is a sensitive predictor of moderate or severe fetal anemia (942).

 

Enrico Brugnera (US), Avinash Bhandoola (US), Ricardo Cibotti (US), Qing Yu (US), Terry I. Guinter (US), Yoshio Yamashita (US), Susan O. Sharrow (US), and Alfred Singer (US) demonstrated that signaled CD4+8+ (DP) thymocytes initially terminate CD8 transcription even when differentiating into CD8+ T cells. Remarkably, thymocytes that have selectively terminated CD8 transcription can be signaled by IL-7 to differentiate into CD8+ T cells by silencing CD4 transcription and reinitiating CD8 transcription, events referred to as "coreceptor reversal." (172)

 

Dale Woodbury (US), Emily J. Schwarz (US), Darwin J. Prockop (US), and Ira B. Black (US) cultured stem cells out of marrow from rats and adult humans. They found that with the appropriate culture medium they could force up to 80% of the cells to send out neuron-like arms and to express some of the proteins common to neurons (1591).

 

Kyrill Reznikov (SE), Larissa Kolesnikova (SE), Aladdin Pramanik (SE), Koichin Tan-No (SE), Irina Gileva (SE), Tatjina Yakovleva (SE), Rudolf Rigler (SE), Lars Terenius (SE), and Georgy Bakalkin (SE) discovered the important role of hydrogen peroxide for bystander killing (1229). Apoptotic cells may kill surrounding cells, a process called bystander killing. Bystander killing appears to be a basis, for example, of the propagation of brain injury in cerebral ischemia. It may also contribute to the propagation of tissue injury in chronic diseases and after low levels of ionizing irradiation. In cancer therapy, a pharmaceutical agent designed to promote bystander killing could increase treatment efficacy.

 

Xiao-Ching Li (US), Erich D. Jarvis (US), Benjamin Alvarez-Borda (US), Daniel A. Lim (US), and Fernando Nottebohm (US) reported that the high vocal center (HVC) controls song production in songbirds and sends a projection to the robust nucleus of the archistriatum (RA) of the descending vocal pathway. HVC receives new neurons in adulthood. Most of the new neurons project to RA and replace other neurons of the same kind. It is show here that singing enhances mRNA and protein expression of brain-derived neurotrophic factor (BDNF) in the HVC of adult male canaries, Serinus canaria. The increased BDNF expression is proportional to the number of songs produced per unit time. Singing-induced BDNF expression in HVC occurs mainly in the RA-projecting neurons. Neuronal survival was compared among birds that did or did not sing during days 31-38 after BrdUrd injection. Survival of new HVC neurons is greater in the singing birds than in the nonsinging birds. A positive causal link between pathway use, neurotrophin expression, and new neuron survival may be common among systems that recruit new neurons in adulthood (868).

 

Anne M. Moon (US) and Mario Renato Capecchi (IT-US) found that in mice the Fgf8 gene is required for outgrowth and patterning of the limbs. This gene controls the production of fibroblast growth factor-8 (FGF8) (1010).

 

Lalita Ramakrishnan (US), Nancy A. Federspiel (US), and Stanley Falkow (US) identified several genes preferentially expressed when Mycobacterium marinum, the cause of fish and amphibian tuberculosis, resides in host granulomas and/or macrophages. Two were homologs of M. tuberculosis PE-PE/PGRS genes, a family encoding numerous repetitive glycine-rich proteins of unknown function (1204).

 

Paul Kaw Bing Chua (Malaysian), William J. Bellini (US), Paul A. Rota (US), Brian H. Harcourt (US), Azaibi Tamin (US), Sai Kit Lam (Malaysian), Thomas G. Ksiazek (US), Pierre E. Rollin (US), Sherif R. Zaki (US), Wun-Ju Shieh (US), Cynthia S. Goldsmith (US), Duane J. Gubler (US), John T. Roehrig (US), Bryan T. Eaton (AU), Allan R. Gould (AU), James G. Olson (US), Hugh J. Field (AU), Peter W. Daniels (AU), Ai E. Ling (CN), Clarence J. Peters (US), Larry J. Anderson (US), and Brian W.J. Mahy (US) identified Nipah virus (NiV) as the causative agent of an extensive outbreak of disease in pigs and humans in Peninsular Malaysia (253).

 

Edwin A. Clark (US), Todd R. Golub (US), Eric Steven Lander (US), and Richard O. Hynes (US) identified a protein called RhoC that can cause metastasis in melanoma cells (259).

 

Ash A. Alizadeh (US), Michael B. Eisen (US), R. Eric Davis (US), Chi Ma (US), Izidore S. Lossos (US), Andreas Rosenwald (US), Jennifer C. Boldrick (US), Hajeer Sabet (US), Truc Tran (US), Xin Yu (US), John I. Powell (US), Liming Yang (US), Gerald E. Marti (US), Troy Moore (US), James Hudson, Jr. (US), Lisheng Lu (US), David B. Lewis (US), Robert Tibshirani (US), Gavin Sherlock (US), Wing C. Chan (US), Timothy C. Greiner (US), Dennis D. Weisenburger (US), James O. Armitage (US), Roger Warnke (US), Ronald Levy (US), Wyndham Wilson (US), Michael R. Grever (US), John C. Byrd (US), David Botstein (US), Patrick O. Brown (US) and Louis M. Staudt (US) used DNA microarrays to conduct a systematic characterization of gene expression in diffuse large B cell lymphomas (DLBCL). They found diversity in gene expression among the tumors of DLBCL patients; apparently reflecting the variation in tumor proliferation rate, host response, and differentiation state of the tumor. They identified two molecularly distinct forms of DLBCL, which had gene expression patterns indicative of different stages of B cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival rate than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer (31).

 

Ruth SoRelle (US) identified the gene for bone morphogenetic protein receptor, type 2 (serine/threonine kinase) (BMPR2), a familial primary pulmonary hypertension in humans (1378).

 

Toshihiro Yoshimura (JP), Michihiro Yoshimura (JP), Ai Tabata (JP), Yukio Shimasaki (JP), Masafumi Nakayama (JP), Yoshihiro Miyamoto (JP), Yoshihiko Saito (JP), Kazuma Nakao (JP), Hirofumi Yasue (JP), and Hitoshi Okamura (JP) recently identified a variant within exon 7 of the endothelial NO synthase (eNOS) gene and noted that the frequency of the variant (Glu298Asp) was significantly higher in the severe preeclampsia group (28.8%). They concluded that the presence of the Glu298Asp eNOS gene could be a marker of increased risk of developing severe preeclampsia (1613).

 

Marina Cavazzana-Calvo (FR), Salima Hacein-Bey (FR), Geneviève de Saint Basile (FR), Fabian Gross (FR), Eric Yvon (FR), Patrick Nusbaum (FR), Françoise Selz (FR), Christophe Hue (FR), Stéphanie Certain (FR), Jean-Laurent Casanova (FR), Philippe Bousso (FR), Françoise Le Deist (FR), and Alain Fischer (FR) reported two patients with X-linked severe combined immunodeficiency were treated with a retroviral-vector containing γc receptor for IL-2 with full clinical reversal after ten months. No side effects were reported during the study period (219).

 

Faith T. Fitzgerald (US) deduced that Wolfgang Amadeus Mozart most likely died of rheumatic fever. Late in 1791, during a fever epidemic, Mozart suddenly developed a high fever, headache, sweats, and severe swelling and pain in his hands and feet (421).

 

The Heart Outcomes Prevention Evaluation Study Investigators (US) found that ramipril significantly reduces cardiovascular events including myocardial infarction (MI), stroke and death in high risk-patients in the absence of left ventricular dysfunction (681).

 

Judith M. Mathias (US) reported that a simple and inexpensive change in basic surgical procedures–giving patients more oxygen during and immediately after surgery–can cut the rate of wound infections in half, thus saving millions of dollars in hospital costs by helping to prevent post-surgical wound infection, nausea and vomiting (953).

 

Linda Basse (DK), Dorthe Hjort Jakobsen (DK), Per Billesbolle (DK), Mads Werner (DK), and Henrik Kehlet (DK) showed that a multimodal rehabilitation program may significantly reduce the postoperative hospital stay in high-risk patients undergoing colonic resection. Such a program may also reduce postoperative ileus and cardiopulmonary complications. These results may have important implications for the care of patients after colonic surgery and in the future assessment of open versus laparoscopic colonic resection (92).

 

Oliver Blatchford (GB), William R. Murray (GB), and Mary Blatchford (GB) developed the Glasgow-Blatchford score which is a sensitive tool for predicting need for intervention in upper gastrointestinal bleeding (133).

 

Douglas Hanahan (US) and Robert Allan Weinberg (US) suggested that the vast catalog of cancer cell genotypes is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth: self-sufficiency in growth signals, insensitivity to growth-inhibitory (antigrowth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis (592).

 

Joanne Wolfe (US), Holcombe E. Grier (US), Neil Klar (US), Sarah B. Levin (US), Jeffrey M. Ellenbogen (US), Susanne Salem-Schatz (US), Ezekiel J. Emanuel (US), and Jane C. Weeks (US) noted that when interviews with parents who lost children to cancer were compared to patient hospital records, researchers found that many children experienced substantial suffering toward the end of life with poorly managed symptoms. There was significant discordance between parent and physician reports of patient discomfort, with parents being significantly more likely to report patient symptoms than physicians (1585).

 

Mary E. Hannah (CA), Walter J. Hannah (CA), Sheila A. Hewson (CA), Ellen D. Hodnett (CA), Saroj Saigal (IN-CA), and Andrew R. Willan (CA) found that among women with term fetuses in breech malpresentation, cesarean delivery was associated with reduction in perinatal and neonatal mortality and morbidity (593).

 

Ivan A. Casas (US) and Walter J. Dobrogosz (US) validated the probiotic concept by showing that dietary Lactobacillus reuteri confers broad-spectrum protection against disease in humans and animals (212).

 

The Acute Respiratory Distress Syndrome Network (US) found that in patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use (1064).

 

Jean Régis (FR), Fabrice Bartolomei (FR), Bertrand de Toffol (FR), Pierre Genton (FR), Tatsuya Kobayashi (US), Yoshimasa Mori (JP), Kintomo Takakura (JP), Tomokatsu Hori (JP), Hiroshi K. Inoue (JP), Oskar Schröttner (AT), Gerhard Pendl (AT), Aizik Wolf (US), Kazunori Arita (JP), and Patrick Chauvel (FR) report work demonstrating that gamma knife surgery can be a safe and effective treatment for epilepsy related to hypothalamic hamartomas. They advocate marginal doses greater than or equal to 17 Gy and partial dose-planning when necessary, for avoidance of critical surrounding structures (1219). Note: radiation dose is usually measured in grays, where one gray (Gy) is the absorption of one joule per kilogram of mass.

 

Hans-Peter Hartung (AT) and Bernd C. Kieseler (AT) highlighted in vitro as well as in vivo findings, which support the importance of matrix metalloproteinases in the pathogenesis of inflammatory demyelinating disorders of the central and peripheral nervous system (602).

 

Jean-Marc Nabholtz (US), Aman U. Buzdar (US), Michael N. Pollak (CA), William N. Harwin (US), Gary von Burton (US), Aroop Mangalik (US), Mark Steinberg (US), Alan Webster (GB), Mikael von Euler (SE), Jacques M. Bonneterre (FR), Beat Thürlimann (CH), John F. R. Robertson (GB), Maciej Krzakowski (PO), Louis Mauriac (FR), Piotr Koralewski (PO), and Ignace Vergote (BE) found that postmenopausal women with advanced breast cancer randomized to anastrazole as first-line therapy experienced an increase in time to progression and a more favorable side effect profile compared to women randomized to tamoxifen treatment (152; 1048).

 

Douglas Hanahan (US-CH) and Robert A. Weinberg (US) presented the six biological capabilities that they see as hallmarks of cancer acquired during the multistep development of human tumors. They include: 1) sustaining proliferative signaling, 2) evading growth suppressors, 3) resisting cell death, 4) enabling replicative immortality, 5) inducing angiogenesis, and 6) activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list: 1) reprogramming of energy metabolism and 2) evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." (592)

 

Martin H. Teicher (US) and Jacqueline A. Samson (US) identified four types of brain abnormalities associated with abuse and neglect experienced in childhood (1444; 1445).

 

Harold Lisle Gibbs (CA), Michael D. Sorenson (CA), Karen Marchetti (CA), Nick Davies (CA), M. de L. Brooke (CA) and Hiroshi Nakamura (CA) note that the common cuckoo Cuculus canorus is divided into host-specific races (gentes). Females of each race lay a distinctive egg type that tends to match the host's eggs. The authors show that there is differentiation between gentes in maternally inherited mitochondrial DNA, but not in microsatellite loci of nuclear DNA. This supports recent behavioural evidence that female, but not male, common cuckoos specialize on a particular host, and is consistent with the possibility that genes affecting cuckoo egg type are located on the female-specific W sex chromosome (492).

 

Birger Rasmussen (AU) discovered pyritic filaments, the probable fossil remains of thread-like microorganisms, in a massive 3,235-million-year-old deep-sea sulphide deposit laid down in the Pilbara Craton of Australia by volcanic activity (1210). Note: From their mode of occurrence, the microorganisms were probably thermophilic chemotropic prokaryotes, which inhabited sub-sea-floor hydrothermal environments. They represent the oldest fossil evidence for microbial life in a Precambrian submarine thermal spring system, and extend the known range of submarine hydrothermal biota by more than 2,700 million years. Such environments may have hosted the first living systems on Earth, consistent with proposals for a thermophilic origin of life. See Corliss, 1981.

 

Leo Gabunia (GE), Abesalom Vekua (GE), David Lordkipanidze (GE), Carl C. Swisher, III (US), Reid Ferring (US), Antje Justus (DE), Medea Nioradze (GE), Merab Tvalchrelidze (GE), Susan C. Antón (US), Gerhard Bosinski (DE), Olaf Jöris (DE), Marie-Antonette de Lumley (FR), Givi Majsuradze (GE), and Aleksander Mouskhelishvili (GE) at the site of Dmanisi in the Republic of Georgia uncovered two partial early Pleistocene hominid crania. Data from Dmanisi all indicate an earliest Pleistocene age of about 1.7 million years. In contrast with Pleistocene hominids (Homo erectus) from Western Europe and Eastern Asia, they show clear African affinity and may represent the species that first migrated out of Africa (456).

 

Max Ingman (SE), Henrick Kaessmann (CH), Svante Pääbo (DE), and Ulf Gyllensten (SE) suggested that all modern humans emerged from Africa within the past 100,000 years and came from a breeding stock of no more than 10,000 individuals. Their suggestion was based on analysis of mitochondrial DNA of fifty-three people (680).

 

2001

As Katherine Knight (US) so eloquently eulogized Alfred Nisonoff (US) at the Keystone meeting on B cells in April 2001: "His goal was only to learn the truth. That he did it with collegiality and humor is why his influence is still felt so profoundly today." (1396)

 

Leland Harrison Hartwell (US), Tim Hunt; Richard Timothy Hunt (GB), and Paul Maxime Nurse (GB) were awarded the Nobel Prize in Physiology or Medicine for their discovery of key regulators of the cell cycle.

 

Gilbert Stork (US), Deqiang Niu (US), Roger Aki Fujimoto (US), Emil R. Koft (US), James Michael Balkovec (US), James R. Tata (GB), and Gregory R. Dake (US) reported the first entirely stereoselective total synthesis of (-)-quinine (1405).

 

Marat M. Yusupov (FR), Gulnara Z. Yusupova (FR), Albion Baucom (US), Kate Lieberman (US), Thomas N. Earnest (US), Jamie H.D. Cate (US), and Harry F. Noller, Jr. (US) presented an atomic model for the 70S ribosome from Thermus thermophilus that is based on a 5.5-angstrom electron density map interpreted using the high-resolution structures of the two subunits (1620).

 

Trey Ideker (US), Vesteinn Thorsson (US), Jeffrey A. Ranish (US), Rowan Christmas (US), Jeremy Buhler (US), Jimmy K. Eng (US), Roger Bumgarner (US), David R. Goodlett (US), Ruedi Aebersold (US), and Leroy Hood (US) identified 997 messenger RNAs responding to 20 systematic perturbations of the yeast galactose-utilization pathway, providing evidence that approximately 15 of 289 detected proteins are regulated posttranscriptionally, and identify explicit physical interactions governing the cellular response to each perturbation. They refined the model through further iterations of perturbation and global measurements, suggesting hypotheses about the regulation of galactose utilization and physical interactions between this and a variety of other metabolic pathways (676).

 

Elena V. Voznesenskaya (RU), Vincent R. Franceschi (US), Olavi Kiirats (US), Elena G. Artyusheva (RU), Helmut Freitag (DE), and Gerald E. Edwards (US) provided proof of C4 photosynthesis without Kranz anatomy—the arrangement of palisade mesophyll cells in a circle around the vascular bundle of C4 plants—in Bienertia cycloptera (Chenopodiaceae) (1523; 1524).

 

Andrew Grupe (US), Soren Germer (US), Jonathan Usuka (US), Dee Aud (US), John K. Belknap (US), Robert F. Klein (US), Mandeep K. Ahluwalia (US), Russell Higuchi (US), and Gary Peltz (US) developed a computational method for predicting chromosomal regions regulating phenotypic traits and a murine database of single nucleotide polymorphisms (561).

 

Joseph J. Ferretti (US), William M. McShan (US), Dragana Ajdic (US), Dragutin J. Savic (US), Gorana Savic (US), Kevin Lyon (US), Charles Primeaux (US), Steven Sezate (US), Alexander N. Suvorov (RU), Steve Kenton (US), Hong Shing Lai (US), Shao Ping Lin (US), Yudong Qian (US), Hong Gui Jia (US), Fares Z. Najar (US), Qun Ren (US), Hua Zhu (US), Lin Song (US), Jim White (US), Xiling Yuan (US), Sandra W. Clifton (US), Bruce A. Roe (US), and Robert McLaughlin (US) determined the complete genome sequence of an M1 strain of Streptococcus pyogenes (407).

 

John Craig Venter (US), Mark D. Adams (US), Eugene W. Myers (US), Peter W. Li (US), Richard J. Mural (US), Granger G. Sutton (US), Hamilton Othanel (US), Mark Yandell (US), Cheryl A. Evans (US), Robert A. Holt (US), Jeannine D. Gocayne (US), Peter Amanatides (US), Richard M. Ballew (US), Daniel H. Huson (US), Jennifer Russo Wortman (US), Qing Zhang (US), Chinnappa D. Kodira (US), Xiangqun H. Zheng (US), Lin Chen (US), Marian Skupski (US), Gangadharan Subramanian (US), Paul D. Thomas (US), Jinghui Zhang (US), George L. Gabor Miklos (US), Catherine Nelson (US), Samuel Broder (US), Andrew G. Clark (US), Joe Nadeau (US), Victor A. McKusick (US), Norton David Zinder (US), Arnold J. Levine (US), Richard John Roberts (US), Mel Simon (US), Carolyn Slayman (US), Michael W. Hunkapiller (US), Randall Bolanos (US), Arthur Delcher (US), Ian Dew (US), Daniel Fasulo (US), Michael Flanigan (US), Liliana Florea (US), Aaron Halpern (US), Sridhar Hannenhalli (US), Saul Kravitz (US), Samuel Levy (US), Clark Mobarry (US), Knut Reinert (US), Karin Remington (US), Jane Abu-Threideh (US), Ellen Beasley (US), Kendra Biddick (US), Vivien Bonazzi (US), Rhonda C. Brandon (US), Michele Cargill (US), Ishwar Chandramouliswaran (US), Rosane Charlab (US), Kabir Chaturvedi (US), Zuoming Deng (US), Valentina Di Francesco (US), Patrick Dunn (US), Karen Eilbeck (US), Carlos Evangelista (US), Andrei E. Gabrielian (US), Weiniu Gan (US), Wangmao Ge (US), Fangcheng Gong (US), Zhiping Gu (US), Ping Guan (US), Thomas J. Heiman (US), Maureen E. Higgins (US), Rui-Ru Ji (US), Zhaoxi Ke (US), Karen A. Ketchum (US), Zhongwu Lai (US), Yiding Lei (US), Zhenya Li (US), Jiayin Li (US), Yong Liang (US), Xiaoying Lin (US), Fu Lu (US), Gennady V. Merkulov (US), Natalia Milshina (US), Helen M. Moore (US), Ashwinikumar K Naik (US), Vaibhav A. Narayan (US), Beena Neelam (US), Deborah Nusskern (US), Douglas B. Rusch (US), Steven Salzberg (US), Wei Shao (US), Bixiong Shue (US), Jingtao Sun (US), Zhen Yuan Wang (US), Aihui Wang (US), Xin Wang (US), Jian Wang (US), Ming-Hui Wei (US), Ron Wides (US), Chunlin Xiao (US), Chunhua Yan (US), Alison Yao (US), Jane Ye (US), Ming Zhan (US), Weiqing Zhang (US), Hongyu Zhang (US), Qi Zhao (US), Liansheng Zheng (US), Fei Zhong (US), Wenyan Zhong (US), Shiaoping C. Zhu (US), Shaying Zhao (US), Dennis Gilbert (US), Suzanna Baumhueter (US), Gene Spier (US), Christine Carter (US), Anibal Cravchik (US), Trevor Woodage (US), Feroze Ali (US), Huijin An (US), Aderonke Awe (US), Danita Baldwin (US), Holly Baden (US), Mary Barnstead (US), Ian Barrow (US), Karen Y. Beeson (US), Dana Busam (US), Amy Carver (US), Angela Center (US), Ming Lai Cheng (US), Liz Curry (US), Steve Danaher (US), Lionel Davenport (US), Raymond Desilets (US), Susanne Dietz (US), Kristina Dodson (US), Lisa Doup (US), Steven Ferriera (US), Neha Garg (US), Andres Gluecksmann (US), Brit Hart (US), Jason Haynes (US), Charles Haynes (US), Cheryl Heiner (US), Suzanne Hladun (US), Damon Hostin (US), Jarrett Houck (US), Timothy Howland (US), Chinyere Ibegwam (US), Jeffery Johnson (US), Francis Kalush (US), Lesley Kline (US), Shashi Koduru (US), Amy Love (US), Felecia Mann (US), David May (US), Steven McCawley (US), Tina McIntosh (US), Ivy McMullen (US), Mee Moy (US), Linda Moy (US), Brian Murphy (US), Keith A. Nelson (US), Cynthia Pfannkoch (US), Eric Pratts (US), Vinita Puri (US), Hina Qureshi (US), Matthew Reardon (US), Robert Rodriguez (US), Yu-Hui Rogers (US), Deanna Romblad (US), Bob Ruhfel (US), Richard Scott (US), Cynthia Sitter (US), Michelle Smallwood (US), Erin Stewart (US), Renee Strong (US), Ellen Suh (US), Reginald Thomas (US), Ni Ni Tint (US), Sukyee Tse (US), Claire Vech (US), Gary Wang (US), Jeremy Wetter (US), Sherita Williams (US), Monica Williams (US), Sandra Windsor (US), Emily Winn-Deen (US), Keriellen Wolfe (US), Jayshree Zaveri (US), Karena Zaveri (US), Josep F. Abril (US), Roderic Guigó (US), Michael J. Campbell (US), Kimmen V. Sjolander (US), Brian Karlak (US), Anish Kejariwal (US), Huaiyu Mi (US), Betty Lazareva (US), Thomas Hatton (US), Apurva Narechania (US), Karen Diemer (US), Anushya Muruganujan (US), Nan Guo (US), Shinji Sato (US), Vineet Bafna (US), Sorin Istrail (US), Ross Lippert (US), Russell Schwartz (US), Brian Walenz (US), Shibu Yooseph (US), David Allen (US), Anand Basu (US), James Baxendale (US), Louis Blick (US), Marcelo Caminha (US), John Carnes-Stine (US), Parris Caulk (US), Yen-Hui Chiang (US), My Coyne (US), Carl Dahlke (US), Anne Deslattes Mays (US), Maria Dombroski (US), Michael Donnelly (US), Dale Ely (US), Shiva Esparham (US), Carl Fosler (US), Harold Gire (US), Stephen Glanowski (US), Kenneth Glasser (US), Anna Glodek (US), Mark Gorokhov (US), Ken Graham (US), Barry Gropman (US), Michael Harris (US), Jeremy Heil (US), Scott N. Henderson (US), Jeffrey Hoover (US), Donald Jennings (US), Catherine Jordan (US), James Jordan (US), John Kasha (US), Leonid Kagan (US), Cheryl Kraft (US), Alexander Levitsky (US), Mark Lewis (US), Xiangjun Liu (US), John Lopez (US), Daniel Ma (US), William Majoros (US), Joe McDaniel (US), Sean Murphy (US), Matthew Newman (US), Trung Nguyen (US), Ngoc Nguyen (US), Marc Nodell (US), Sue Pan (US), Jim Peck (US), Marshall Peterson (US), William Rowe (US), Robert Sanders (US), John Scott (US), Michael Simpson (US), Thomas Smith (US), Arlan Sprague (US), Timothy Stockwell (US), Russell Turner (US), Eli Venter (US), Mei Wang (US), Meiyuan Wen (US), David Wu (US), Mitchell Wu (US), Ashley Xia (US), Ali Zandieh (US), and Xiaohong Zhu (US) determined the DNA base sequence of the human genome (1509).

 

Eric Steven Lander (US), Lauren M. Linton (GB), Bruce Birren (GB), Chad Nusbaum (GB), Michael C. Zody (GB), Jennifer Baldwin (GB), Keri Devon (GB), Ken Dewar (GB), Michael Doyle (GB), William Fitzhugh (GB), Roel Funke (GB), Diane Gage (GB), Katrina Harris (GB), Andrew Heaford (GB), John Howland (GB), Lisa Kann (GB), Jessica Lehoczky (GB), Rosie Levine (GB), Paul McEwan (GB), Kevin McKernan (GB), James Meldrim (GB), Jill P. Mesirov (GB), Cher Miranda (GB), William Morris (GB), Jerome Naylor (GB), Christina Raymond (GB), Mark Rosetti (GB), Ralph Santos (GB), Andrew Sheridan (GB), Carrie Sougnez (GB), Nicole Stange-Thomann (GB), Nikola Stojanovic (GB), Aravind Subramanian (GB), Dudley Wyman (GB), Jane Rogers (GB), John Edward Sulston (GB), Rachel Ainscough (GB), Stephan Beck (GB), David Bentley (GB), John Burton (GB), Christopher Clee (GB), Nigel P. Carter (GB), Alan R. Coulson (GB), Rebecca Deadman (GB), Panagiotis Deloukas (GB), Andrew Dunham (GB), Ian Dunham (GB), Richard Durbin(GB), Lisa French (GB), Darren Grafham (GB), Simon Gregory (GB), Tim J.P. Hubbard (GB), Sean Humphray (GB), Adrienne Hunt (GB), Matthew Jones (GB), Christine Lloyd (GB), Amanda McMurray (GB), Lucy Matthews (GB), Simon Mercer (GB), Sarah Milne (GB), James C. Mullikin (GB), Andrew Mungall (GB), Robert W. Plumb (GB), Mark Ross (GB), Ratna Shownkeen (GB), Sarah Sims (GB), Robert H. Waterston (US), Richard K. Wilson (US), Ladeana W. Hillier (US), John D. McPherson (US), Marco A. Marra (US), Elaine R. Mardis (US), Lucinda A. Fulton (US), Asif T. Chinwalla (US), Kymberlie H. Pepin (US), Warren R. Gish (US), Stephanie L. Chissoe (US), Michael C. Wendl (US), Kim D. Delehaunty (US), Tracie L. Miner (US), Andrew Delehaunty (US), Jason B. Kramer (US), Lisa L. Cook (US), Robert S. Fulton (US), Douglas L. Johnson (US), Patrick J. Minx (US), Sandra W. Clifton (US), Trevor Hawkins (US), Elbert Branscomb (US), Paul Predki (US), Paul Richardson (US), Sarah Wenning (US), Tom Slezak (US), Norman Doggett (US), Jan-Fang Cheng (US), Anne Olsen (US), Susan Lucas (US), Christopher Elkin (US), Edward Uberbacher (US), Marvin Frazier (US), Richard A. Gibbs (US), Donna M. Muzny (US), Steven E. Scherer (US), John B. Bouck (US), Erica J. Sodergren (US), Kim C. Worley (US), Catherine M. Rives (US), James H. Gorrell (US), Michael L. Metzker (US), Susan L. Naylor (US), Raju S. Kucherlapati (US), David L. Nelson (US), George M. Weinstock (US), Yoshiyuki Sakaki (JP), Asao Fujiyama (JP), Masahira Hattori (JP), Tetsushi Yada (JP), Atsushi Toyoda (JP), Takehiko Itoh (JP), Chiharu Kawagoe (JP), Hidemi Watanabe (JP), Yasushi Totoki (JP), Todd Taylor (JP), Jean Weissenbach (FR), Roland Heilig (FR), William Saurin (FR), Francois Artiguenave (FR), Philippe Brottier (FR), Thomas Bruls (FR), Eric Pelletier (FR), Catherine Robert (FR), Patrick Wincker (FR), Douglas R. Smith (US), Lynn A. Doucette-Stamm (US), Marc Rubenfield (US), Keith Weinstock (US), Hong Mei Lee (US), Joann Dubois (US), André Rosenthal (DE), Matthias Platzer (DE), Gerald Nyakatura (DE), Stefan Taudien (DE), Andreas Rump (DE), Huanming Yang (CN), Jun Yu (CN), Jian Wang (CN), Guyang Huang (CN), Jun Gu (CN), Leroy Edward Hood (US), Lee Rowen (US), Anup Madan (US), Shizen Qin (US), Ronald W. Davis (US), Nancy A. Federspiel (US), A. Pia Abola (US), Michael J. Proctor (US), Richard M. Myers (US), Jeremy Schmutz (US), Mark Dickson (US), Jane Grimwood (US), David R. Cox (US), Maynard V. Olson (US), Rajinder Kaul (US), Christopher Raymond (US), Nobuyoshi Shimizu (JP), Kazuhiko Kawasaki (JP), Shinsei Minoshima (JP), Glen A. Evans (US), Maria Athanasiou (US), Roger Schultz (US), Bruce A. Roe (US), Feng Chen (US), Huaqin Pan (US), Juliane Ramser (DE), Hans Lehrach (DE), Richard Reinhardt (DE), W. Richard McCombie (US), Melissa De La Bastide (US), Neilay Dedhia (US), Helmut Blöcker (DE), Klaus Hornischer (DE), Gabriele Nordsiek (DE), Richa Agarwala (US), L. Iyer Aravind (US), Jeffrey A. Bailey (US), Alex Bateman (GB), Serafim Batzoglou (US), Ewan Birney (GB), Peer Bork (DE), Daniel G. Brown (US), Christopher B. Burge (US), Lorenzo Cerutti (GB), Hsiu-Chuan Chen (US), Deanna Church (US), Michele Clamp (GB), Richard R. Copley (DE), Tobias S. Doerks (DE), Sean R. Eddy (US), Evan E. Eichler (US), Terrence S. Furey (US), James Galagan (US), James G. R. Gilbert (GB), Cyrus Harmon (US), Yoshihide Hayashizaki (JP), David Haussler (US), Henning Hermjakob (GB), Karsten Hokamp (GB), Wonhee Jang (US), L. Steven Johnson (US), Thomas A. Jones (US), Simon Kasif (US), Arek Kaspryzk (GB), Scot Kennedy (US), W. James Kent (US), Paul Kitts (US), Eugene V. Koonin (RU-US), Ian Korf (US), David Kulp (US), Doron Lancet (IL), Todd M. Lowe (US), Aoife McLysaght (GB), Tarjei Mikkelsen (US), John V. Moran (US), Nicola Mulder (GB), Victor J. Pollara (US), Chris P. Ponting (GB), Greg Schuler (US), Jörg Schultz (DE), Guy Slater (GB), Arian F. A. Smit (US), Elia Stupka (GB), Joseph Szustakowki (US), Danielle Thierry-Mieg (US), Jean Thierry-Mieg (US), Lukas Wagner (US), John Wallis (US), Raymond Wheeler (US), Alan Williams (US), Yuri I. Wolf (US), Kenneth H. Wolfe (GB), Shiaw-Pyng Yang (US), Ru-Fang Yeh (US), Francis Collins (US), Mark S. Guyer (US), Jane Peterson (US), Adam Felsenfeld (US), Kris A. Wetterstrand (US), Aristides Patrinos (US), and Michael J. Morgan (GB) determined the DNA base sequence of the euchromatic portion of the human genome and found that it contains less than 25,000 genes instead of the 80,000 that had been initially predicted (823).

On April 14, 2003 the National Human Genome Research Institute (NHGRI), the Department of Energy (DOE) and their partners in the International Human Genome Sequencing Consortium announced the successful completion of the Human Genome Project. Only euchromatic portions were sequenced.

The Human Genome Sequencing Consortium provided an update on the human genome sequence (euchromatic regions and not heterochromatic) (275).

Simon G. Gregory (US-GB), Karen F. Barlow (GB), Kirsten E. McLay (GB), Rajinder Kaul (US), David Swarbreck (GB), Andrew Dunham (GB), Carol E. Scott (GB), Kevin L. Howe (GB), Kathryn Woodfine (GB), Chris C. Spencer (GB), Matthew C. Jones (GB), Christopher J. Gillson (GB), Stephen M.J. Searle (GB), Yang Zhou (US), Felix Kokocinski (GB), Louise McDonald (GB), Richard S. Evans (GB), Kimbly J. Phillips (GB), Andrea Atkinson (GB), Rachel Cooper (GB), Claire Jones (GB), Rebekah E. Hall (GB), T. Daniel Andrews (GB), Christine Lloyd (GB), Rachael Ainscough (GB), Jeff P. Almeida (GB), Kerrie D. Ambrose (GB), Robert W. Andrew (GB), Robert I.S. Ashwell (GB), Keith Aubin (GB), Anne K. Babbage (GB), Claire L. Bagguley (GB), Jonathan Bailey (GB), Helen Beasley (GB), Graeme Bethel (GB), Christine P. Bird (GB), Sarah Bray-Allen (GB), Jacqui Y. Brown (GB), Andrew J. Brown (GB), D. Buckley (US), John Burton (GB), Jackie M. Bye (GB), Carol Carder (GB), Joanne C. Chapman (GB), Sue Y. Clark (GB), Graham Clarke (GB), Chris M. Clee (GB), Vickie Cobley (GB), Rachael E. Collier (GB), Nicole Corby (GB), Gez J. Coville (GB), Joy Davies (GB), Rebecca Deadman (GB), Matthew Dunn (GB), Mark Earthrowl (GB), Andrew G. Ellington (GB), Helen Errington (GB), Adam Frankish (GB), John Frankland (GB), Lisa French (GB), Patrick Garner (GB), Jane Garnett (GB), Laura Gay (GB), Mohammed J.R. Ghori (GB), Jason R. Gibson (US), Lisa M. Gilby (GB), Will Gillett (US), Rebecca J. Glithero (GB), French Anderson (US), Darren V. Grafham (GB), Coline Griffiths (GB), Sam Griffiths-Jones (GB), Russell Grocock (GB), Sian Hammond (GB), Elliott S. Harrison (GB), Elizabeth A. Hart (GB), Eric Haugen (GB), Paul D. Heath (GB), Sarah Holmes (GB), Karen Holt (GB), Phillip J. Howden (GB), Adrienne R. Hunt (GB), Sarah E. Hunt (GB), Giselle Hunter (GB), Judith Isherwood (GB), R. James (GB), Cheryl Johnson (GB), David Johnson (GB), Ann Joy (GB), Michael Kay (GB), Joanne K. Kershaw (GB), Miho Kibukawa (GB), Andrew M. Kimberley (GB), Andrew King (GB), Andrew J. Knights (GB), Heena Lad (GB), Gavin K. Laird (GB), Stephanie Lawlor (GB), Daniel A. Leongamornlert (GB), David M. Lloyd (GB), Jane E. Loveland (GB), Jamieson D. Lovell (GB), Michael J. Lush (GB), Rachael Lyne (GB), Sancha Martin (GB), Lucy H. Matthews (GB), Nick S. Matthews (GB), Stuart McLaren (GB), Sarah Milne (GB), Miho Kibukawa (US), Shailesh L. Mistry (GB), Madeline J. Moore (GB), Tim Nickerson (GB), Christopher N. O'Dell (GB), Karen Oliver (GB), Anthony Palmeiri (US), Sophie A. Palmer (GB), Adrian Parker (GB), Dina Patel (GB), Alex V. Pearce (GB), Anna I. Peck (GB), Sarah Pelan (GB), Karen Phelps (US), Benjamin J. Phillimore (GB), Robert Plumb (GB), Jeena Rajan (GB), Chris Raymond (US), Gregory Rouse (US), Channakhone Saenphimmachak (US), Harminder K. Sehra (GB), Elizabeth M. Sheridan (GB), Ratna Shownkeen (GB), Sarah Sims (GB), Carl D.Skuce (GB), Michelle L. Smith (GB), Charles A. Steward (GB), Sandhya Subramanian (US), Neil Sycamore (GB), Alan Tracey (GB), Anthony Tromans (GB), Zoe Van Helmond (GB), Melanie Wall (GB), Justine M. Wallis (GB), Simon White (GB), Siobhan L. Whitehead (GB), Jane E. Wilkinson (GB), David L. Willey (GB), H. Williams (GB), Laurens G. Wilming (GB), Paul W. Wray (GB), Zaining Wu (US), Alan Coulson (GB), Mark Vaudin (GB), John E. Sulston (GB), Richard Durbin (GB), Tim J. Hubbard (GB), Richard Wooster (GB), Ian Dunham (GB), Nigel P. Carter (GB), Gil McVean (GB), Mark T. Ross (GB), Jennifer Harrow (GB), Maynard V. Olson (US), Stephan Beck (GB), Jane Rogers (GB), David R. Bentley (GB), Ruby Banerjee (GB), Nathaniel P. Bryant (GB), Deborah C. Burford (GB), Wayne D. Burrill (GB), Sheila M. Clegg (GB), Pawandeep Dhami (GB), Oliver M. Dovey (GB), Louisa M. Faulkner (GB), Susan M. Gribble (GB), Cordelia F. Langford (GB), Richard D. Pandian (GB), Keith M. Porter (GB), and Elena Prigmore (GB) reported the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes, 991 pseudogenes, and many coding sequences that overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and other diseases (538). Note: this completed the sequencing of the euchromatic portion of the human genome (538).

 

The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, molecularly characterized over 20,000 primary cancers and matched normal samples spanning 33 cancer types. The TCGA program has generated, analyzed, and made available genomic sequence, expression, methylation, and copy number variation data on over 11,000 individuals who represent over 30 different types of cancer. This joint effort between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) began in 2006. A number of marker papers were issued and a practical guide to The Cancer Genome Atlas offered in 2016 (1540).

 

Cecilia S. L. Lai (GB), Simon E. Fisher (GB), Jane A. Hurst (GB), Faraneh Vargha-Khadem (GB), Anthony P. Monaco (GB), Kay D. MacDermot (GB), Elena Bonora (IT), Nuala Sykes(GB), Anne-Marie Coupe (GB), Cecilia S.L. Lai (GB), Sonja C. Vernes (GB), Faraneh Vargha-Khadem (GB), Fiona McKenzie (AU), Robert L. Smith (AU), Anthony P. Monaco (GB), Simon E. Fisher (GB), Lars Feuk (US), Aino Kalervo (FI), Marita Lipsanen-Nyman (FI), Jennifer Skaug (US), Kazuhiko Nakabayashi (JP), Brenda Finucane (US), Danielle Hartung (US), Micheil Innes (CA), Batsheva Kerem (IL), Małgorzata J. Nowaczyk (CA), Joseph Rivlin (CN), Wendy Roberts (US), Lili Senman (US), Anne Summers (US), Peter Szatmari (CA), Virginia Wong (CN), John B. Vincent (CA), Susan Zeesman (CA), Lucy R. Osborne (CA), Janis Oram Cardy (CA), Juha Kere (SE), Stephen W. Scherer (CA), and Katariina Hannula-Jouppi (FI) reported that currently the transcription factor FOXP2 (forkhead box P2) is the only gene implicated in Mendelian forms of human speech and language dysfunction (411; 820; 921).

Wolfgang Enard (DE), Molly Przeworski (DE), Simon E. Fisher (GB), Cecilia S.L. Lai (GB), Victor Wiebe (DE), Takashi Kitano (DE), Anthony P. Monaco (GB), Svante Pääbo (DE), Jianzhi Zhang (US), David M. Webb (US), and Ondrej Podlaha (US) proposed that the amino acid composition in the human variant of FOXP2 has undergone accelerated evolution with this two-amino-acid change having occurred around the time of language emergence in humans (375; 1630).

Johannes Krause (DE), Carles Lalueza-Fox (ES), Ludovic Orlando (FR), Wolfgang Enard (DE), Richard E. Green (DE), Hernán A. Burbano (DE), Jean-Jacques Hublin (DE), Catherine Hänni (FR), Javier Fortea (ES), Marcode la Rasilla (ES), Jaume Bertranpetit (ES), Antonio Rosas (ES), and Svante Pääbo (DE) found that our closest extinct relatives, the Neandertals, share with modern humans two evolutionary changes in FOXP2, a gene that has been implicated in the development of speech and language. They found that in Neandertals, these changes lie on the common modern human haplotype, which previously was shown to have been subject to a selective sweep. These results suggest that these genetic changes and the selective sweep predate the common ancestor (which existed about 300,000–400,000 years ago) of modern human and Neandertal populations (803).

Eriko Fujita (JP), Yuko Tanabe (JP), Akira Shiota (JP), Masatsugu Ueda (JP), Kiyotaka Suwa (JP), Mariko Y. Momoi (JP), and Takashi Momoi (JP) showed evidence for a common molecular mechanism shared between human speech and mouse ultrasonic vocalizations (USVs) and discussed the defect of this molecular mechanism and immature development of cerebellum in the FOXP2 (R552H)-KI mice (447).

Tomislav Maricic (DE), Viola Günther (CH), Oleg Georgiev (CH), Sabine Gehre (DE), Marija Ćurlin (HR), Christiane Schreiweis (DE), Ronald Naumann (DE), Hernán A. Burbano (DE), Matthias Meyer (DE), Carles Lalueza-Fox (ES), Marco de la Rasilla (ES), Antonio Rosas (ES), Srećko Gajović (HR), Janet Kelso (DE), Wolfgang Enard (DE), Walter Schaffner (CH), and Svante Pääbo (DE) identified substitutions in the FOXP2 gene shared by nearly all present-day humans but absent or polymorphic in Neandertals. One such substitution is localized in intron 8 and affects a binding site for the transcription factor POU3F2, which is highly conserved among vertebrates. We find that the derived allele of this site is less efficient than the ancestral allele in activating transcription from a reporter construct. The derived allele also binds less POU3F2 dimers than POU3F2 monomers compared with the ancestral allele. Because the substitution in the POU3F2 binding site is likely to alter the regulation of FOXP2 expression, and because it is localized in a region of the gene associated with a previously described signal of positive selection, it is a plausible candidate for having caused a recent selective sweep in the FOXP2 gene (943).

Christiane Schreiweis (DE), Ulrich Bornschein (DE), Eric Burguière (FR), Cemil Kerimoglu (DE), Sven Schreiter (DE), Michael Dannemann (DE), Shubhi Goyal (US), Ellis Rea(DE), Catherine A. French (GB), Rathi Puliyadi (FR), Matthias Groszer (FR), Simon E. Fisher (NL), Roger Mundry (DE), Christine Winter (DE), Wulf Hevers (DE), Svante Pääbo (DE), Wolfgang Enard (DE), and Ann M. Graybiel (US) produced findings raising the possibility that the humanized FOXP2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition (1301).

Haruka Ebisu (JP), Lena Iwai-Takekoshi (JP), Eriko Fujita-Jimbo (JP), Takashi Momoi (JP), and Hiroshi Kawasaki (JP) uncovered important roles of FOXP2 in thalamic patterning and thalamocortical projections during development (366).

 

Vijay Shankaran (US), Hiroaki Ikeda (US), Allen T. Bruce (US), J. Michael White (US), Paul E. Swanson (US), Lloyd J. Old (US), and Robert D. Schreiber (US) showed that lymphocytes and interferon gamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity. The immune response thus functions as an effective extrinsic tumour-suppressor system. However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals (1325).

 

Jens Derbinski (DE), Antje Schulte (DE), Bruno Kyewski (DE), and Ludger Klein (DE) identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. They found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. The array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens (332).

 

Hal M. Hoffman (US), James L. Mueller (US), David H. Broide (US), Alan A. Wanderer (US), and Richard D. Kolodner (US) discovered that mutations in the gene NALP3 are associated with auto-inflammatory diseases such as familial cold autoinflammatory syndrome (FCAS), commonly known as familial cold urticaria (FCU), and Muckle-Wells syndrome (MWS) (637).

Ying Jin (US), Christina M. Mailloux (US), Katherine Gowan (US), Sheri L. Riccardi (US), Greggory LaBerge (US), Dorothy C. Bennett (US), Pamela R. Fain (US), and Richard A. Spritz (US) found that DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders (709). Note: NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NLRP proteins are part of the innate immunity and detect conserved pathogen characteristics such as peptidoglycan.

 

Gallia G. Levy (US), William C. Nichols (US), Eric C. Lian (US), Tatiana Foroud (US), Jeanette N. McClintick (US), Beth M. McGee (US), Angela Y. Yang (US), David R. Siemieniak (US), Kenneth R. Stark (US), Ralph Gruppo (US), Ravindra Sarode (US), Susan B. Shurin (US), Visalam Chandrasekaran (US), Sally P. Stabler (US), Hernan Sabio (US), Eric E. Bouhassira (US), Jefferson D. Upshaw Jr. (US), David Ginsburg (US), and Han-Mou Tsai (US) discovered the pathogenesis of familial thrombotic thrombocytopenic purpura (TTP) when the disease locus was mapped to chromosome 9q34 by a linkage analysis of families with TTP. The responsible gene was identified as ADAMTS13, which encodes a novel metalloprotease, ADAMTS13 (860).

Helena E. Gerritsen (CH), Rodolfo Robles (CH), Bernhard Lämmle (CH), Miha Furlan (CH), Kazuo Fujikawa (US), Hiroshi Suzuki (US), Brad McMullen (US), and Dominic Chung (US), had previously identified ADAMTS13 as the von Willebrand factor-cleaving protease (VWF‐cleaving protease) (446; 484).

 

Salim Al-Babili (SA), Xudong Ye (US), Paola Lucca (IT), Ingo Potrykus (DE-CH), Peter Beyer (DE), Patrick Schaub (DE), and Ralf Welsch (DE) developed Golden rice, a new variety of rice providing vitamin A (25; 124).

 

Adrian L.R. Thomas (GB) and Graham K. Taylor (GB) wrote the first paper to lay out a theoretical groundwork for how birds and other flying animals achieve stability, the trait that keeps them from being pushed in the wrong direction (1450).

Christina Harvey (US), Vikram B.Baliga (CA), Jasmin C. M.Wong (CA), Douglas L. Altshuler (CA), and Daniel J. Inman (US) presented their comprehensive analysis of avian inertial characteristics thus providing the key features required to establish a theoretical model of avian manoeuvrability (604).

 

Paul Kaw Bing Chua (MY), Lin-Fa Wang (AU), Sai Kit Lam (MY), Gary Crameri (AU), Meng Yu (AU), Terry G. Wise (MY), David B. Boyle (AU), Alex D. Hyatt (Au), and Bryan T. Eaton (AU) isolated Tioman virus (TiV) from the urine of flying foxes (P. hypomelanus) found on Tioman island off the eastern coast of peninsular Malaysia (254).

 

Sarah A. Tishkoff (US), Andrew J. Pakstis (US), Mark Stoneking (DE), Judith R. Kidd (US), Giovanni Destro-Bisol (IT), Antti Sanjantila (FI), Ru Band Lu (TW), Amos S. Deinard (US), Giorgio Sirugo (GM), Trefor Jenkins (ZA), Kenneth K. Kidd (US), and Andrew G. Clark (US) presented human genomic evidence suggesting that about 150,000 years ago Homo sapiens emerged in Eastern Africa (1459).

 

Ole Madsen (NL), Mark Scally (US-GB), Christophe J. Douady (IE-US), Diana J. Kao (IE-US), Ronald W. DeBry (US), Ronald Adkins (US), Heather M. Amrine (IE-US), Michael J. Stanhope (US), Wilfried W. deJong (NL), and Mark S. Springer (US) performed analysis of DNA sequences which provided strong support for the grouping Afrotheria. This group includes a variety of placental mammals from elephants to elephant shrews including aardvarks, manatees, and hyraxes (924).

 

During 2001, the United Kingdom experienced an outbreak of foot-and-mouth disease that originated in hogs which had eaten infected meat scraps from a tourist steamship that had stocked meat in Argentina. Over 6 million cows and sheep were killed in the successful attempt to halt the disease (780).

 

Bernadette G. van den Hoogen (NL), Jan C. de Jong (NL), Jan Groen (NL), Thijs Kulken (NL), Ronald de Groot (NL), Ron A.M. Fouchier (NL), and Albert D.M.E. Osterhaus (NL) discovered metapneumovirus (hMPV) during epidemiologic studies of children with conditions ranging from upper respiratory tract disease to severe bronchiolitis and pneumonia. Serological studies showed that by the age of five years, virtually all children in the Netherlands have been exposed to human metapneumovirus and that the virus has been circulating in humans for at least 50 years (1500). Note: This virus appears to be a major cause of acute respiratory tract disease in normal infants and children worldwide.

 

Achim Kramer (US), Fu-Chia Yang (US), Pamela Snodgrass (US), Xiaodong Li (US), Thomas E. Scammell (US), Fred C. Davis (US), and Charles J. Weitz (US) studying a tiny cluster of nerve cells behind the eye discovered a pathway involved in how the brain’s circadian clock sends signals that control the body’s daily rhythms (801).

 

Carole Sophie Isabelle Peyssonnaux (FR) and Alain Eychéne (FR) noted the emergence of new concepts in the activation and regulation of the Raf/MEK/ERK module. In particular, the preponderant role of B-Raf is underlined. It is probably one of the best known signal transduction pathways among biologists because of its implication in a wide variety of cellular functions as diverse -and occasionally contradictory- as cell proliferation, cell-cycle arrest, terminal differentiation and apoptosis. They report that BRAF somatic missense mutations occur in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma. (1154).

Walter Kolch (GB), Carole Sophie Isabelle Peyssonnaux (FR) Alain Eychéne (FR), Joseph A. Avruch (US), Andrei Khokhlatchev (US), John M. Kyriakis (US), Zhijun Luo (US), Guri Tzzivion (US), Demetrios Vavvas (US), and Xian-Feng Zhang (US) report that RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS (68; 791; 1154).

 

Michael Girardi (GB), David E. Oppenheim (GB), Carrie R. Steele (GB), Julia M. Lewis (GB), Earl Glusac (GB), Renata Filler (GB), Paul Hobby (GB), Brian Sutton (GB), Robert E. Tigelaar (GB), and Adrian C. Hayday (GB) showed that, in vitro, skin-associated NKG2d+ gamma delta cells killed skin carcinoma cells by a mechanism that was sensitive to blocking NKG2d engagement. Thus, local T cells may use evolutionarily conserved proteins to negatively regulate malignancy (501).

 

Brian J. Druker (US), Charles L. Sawyers (US), Hagop Kantarjian (US), Debra J. Resta (US), Sofia Fernandes Reese (US), John M. Ford (US), Renaud Capdeville (US), and Moshe Talpaz (US) found that the blast crisis acute leukemia tyrosine kinase inhibitor STI571 is well tolerated and has substantial activity in the blast crises of chronic myeloid leukemia and in Philadelphia-chromosome–positive acute lymphoblastic leukemia (348).

Note: Novartis announced that the United States Food and Drug Administration (FDA) approved its signal transduction inhibitor Gleevec (imatinib mesylate) as an oral therapy for the treatment of patients with chronic myeloid leukemia (CML) in the blast crisis, accelerated phase or in chronic phase after failure of interferon-alpha therapy. This drug targets a unique protein produced by the Philadelphia chromosome.The effectiveness of Gleevec, also known as STI 571, is based on overall hematologic and cytogenetic response rates (4). Note: Gleevec was subsequently shown to be effective in the treatment of gastrointestinal stromal tumors (GIST).

 

Marcus E. Raichle (US), Ann Mary MacLeod (US), Abraham Z. Snyder (US), William J. Powers (US), Debra A. Gusnard (US), and Gordon L. Shulman (US) identified a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed) (1200).

 

Robert M. May (AU), Sunetra Gupta (AU), and Angela R. McLean (AU) showed that for a pathogen to cross a species barrier is one thing, but for it to successfully maintain itself in the new population it must have a 'basic reproductive number', R0, which satisfies R0 > 1. Behavioural factors interweave with the basic biology of the production of transmission stages by the pathogen, all subject to possible secular changes, to determine the magnatude of R0 (961).

 

John S. Macdonald (US), Stephen R. Smalley (US), Jacqueline Benedetti (US), Scott A. Hundahl (US), Norman C. Estes (US), Grant N. Stemmermann (US), Daniel G. Haller (US), Jaffer A. Ajani (US), Leonard L. Gunderson (US), J. Milburn Jessup (US), and James A. Martenson (US) concluded that postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection (922).

The Medical Research Council Oesophageal Cancer Working, Group (GB) found that two cycles of preoperative cisplatin and fluorouracil improve survival without additional serious adverse events in the treatment of patients with resectable esophageal cancer (980).

David Cunningham (GB), William H. Allum (GB), Sally P. Stenning (GB), Jeremy N. Thompson (GB), Cornelis J.H. Van de Velde (NL), Marianne Nicolson (GB), J. Howard Scarffe (GB), Fiona J. Lofts (GB), Stephen J. Falk (GB), Timothy J. Iveson (GB), David B. Smith (GB), Ruth E. Langley (GB), et al., and MAGIC Trial Participants concluded that in patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of epirubicin, cisplatin and 5-fluorouracil decreased tumor size and stage and significantly improved progression-free and overall survival (301).

Katrin M. Sjoquist (AU), Bryan H. Burmeister (AU), B. Mark Smithers (AU), John R. Zalcberg (AU), R. John Simes (AU), Andrew Barbour (AU), Val Gebski (AU), and the Australasian Gastro-Intestinal Trials Group (AU) in their meta-analysis, provided strong evidence for survival benefit of neoadjuvant chemoradiotherapy or chemotherapy over surgery alonein patients with esophageal carcinoma . A clear advantage of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy could not be established (1348).

 

Emanuel Rivers (US), Bryant Nguyen (US), Suzanne Havstad (US), Julie Ressler (US), Alexandria Muzzin (US), Bernhard Knoblich (US), Edward Peterson (US), Michael Tomlanovich (US), and the Early Goal-Directed Therapy Collaborative Group (US) evaluated the effects of early goal-directed therapy to balance tissue oxygen demand and oxygen delivery in sepsis prior to admission to intensive care. This methodology provided them with an early identification of patients at high risk for cardiovascular collapse and early therapeutic intervention to restore the balance between oxygen delivery and oxygen demand (1243). Note: Sepsis and related syndromes are the principal cause of multi-organ failure and death in critically ill patients. Infection provokes an inflammatory cascade which can result in vasodilatation, hypotension, and tissue hypoxia.

 

John P. Neoptolemos (GB), Deborah D. Stocken (GB), Helmut Friess (GB), Claudio Bassi (GB), Janet A. Dunn (GB), Helen Hickey (GB), Hans Beger (GB), Laureano Fernandez-Cruz (GB), Christos Dervenis (GB), François Lacaine (GB), Massimo Falconi (GB), Paolo Pederzoli (GB), Akos Pap (GB), David Spooner (GB), David J. Kerr (GB), Markus W. Büchler (GB), and The European Study Group for Pancreatic Cancer reported that adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival (1060; 1061).

 

Helen J. Dallal (GB), Graeme D. Smith (GB), Douglas C. Grieve (GB), Subrata Ghosh (GB), Ian D. Penman (GB), and Kelvin R. Palmer (GB) reported that when treating dysphagia in advanced esophageal cancer laser therapy provides a more satisfactory swallow and better quality of life than self-expanding metal stents, but at increased cost and patient stay (311).

Joep F.W.M. Bartelsman (NL), Jan J. Bvan Lanschot (NL), Harm K. Wijrdeman (NL), Chris J.J. Mulder (NL), Janny G. Reinders (NL),Henk Boot (NL), Berthe M.P. Aleman (NL), Ernst J. Kuipers (NL), Peter D. Siersema (NL), and The Dutch SIREC Study Group (NL) reported that brachytherapy should be used as a first-line palliation in patients with esophageal cancer (647).

 

Zhe-Xi Luo (US), Alfred W. Crompton (US), and Ai-Lin Sun (CN) discovered an extinct mammaliaform that lived during the Sinemurian stage of the Early Jurassic, approximately 195 million years ago, in the Lufeng basin in what is now the Yunnan province in Southwestern China. It is the earliest known example of several features possessed only by mammals, including the middle-ear structure characteristic of modern mammals and a relatively large brain cavity (913).

 

Meave G. Leakey (GB-KE), Fred Spoor (GB), Frank H. Brown (US), Patrick N. Gathogo (US), Christopher Kiarie (KE), Louise N. Leakey (KE), and Ian McDougall (AU) announced the discovery of the hominid, Kenyanthropus platyops, identified from a partial skull found on the western shore of Lake Turkana in Northern Kenya. It is dated at 3.5 million years old. The size of the skull is similar to Australopithecus afarensis and Australopithecus africanus, and has a large, flat face and small teeth (839).

 

Brigitte Senut (FR), Martin Pickford (FR), Dominique Gommery (FR), Pierre Mein (FR), Kiptalam Cheboi (KE), and Yves Coppens (FR) of The Kenya Palaeontology Expedition (KPE), reported in December 2000, the discovery at Kapsomin in Kenya's Baringo district of what is almost certainly a new species of hominid. It was named Orrorin tugenensis. The remains, found in six-million-year-old rocks, included a left femur, pieces of jaw with teeth, isolated upper and lower teeth, arm bones, and a finger bone. Preliminary analyses suggested the hominid, the size of a chimpanzee, was an agile climber and that it walked on two legs when on the ground. The tentative date of six million years indicate a date very close to the common ancestor of humans and chimpanzees, although this date may now need to be pushed back (1160; 1319; 1320).

 

2002

"I regard it as ethically unacceptable and impractical to censor any aspect of trying to understand the nature of our world." Lewis Wolpert (1587).

 

Sydney Brenner (GB), Howard Robert Horvitz (US), and John Edward Sulston (GB) were awarded the Nobel Prize in Physiology or Medicine for discoveries concerning genetic regulation of organ development and programmed cell death (apoptosis).

 

John B. Fenn (US) and Koichi Tanaka (JP), and Kurt Wüthrich (CH) were awarded the 2002 Nobel Prize in Chemistry. Fenn and Tanaka for their development of soft desorption ionization methods for mass spectrometric analyses of biological macromolecules. Working independently, they improved a technique known as mass spectrometry to identify proteins by how quickly they are accelerated in an electric field. Now, biologists can determine the proteins in a sample in seconds rather than weeks. Wüthrich for development of techniques to identify and analyze proteins and other large molecules.

 

The Mouse Genome Sequencing Consortium reported the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. They also presented an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences (276).

 

Augustine Kong (IS), Daniel F. Gudbjartsson (IS), Jesus Sainz (IS), Gudrun M. Jonsdottir (IS), Sigurjon A. Gudjonsson (IS), Bjorgvin Richardsson (IS), Sigrun Sigurdardottir (IS), John Barnard (IS), Bjorn Hallbeck (IS), Gisli Masson (IS), Adam Shlien (IS), Stefan T. Palsson (IS), Michael L. Frigge (IS), Thorgeir E. Thorgeirsson (IS), Jeffrey R. Gulcher (IS) and Kári Stefánsson (IS) detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates, i.e. quantifying the reshuffling of the genome that goes into the making of eggs and sperm revealed that women recombine 1.6 times more than men (795).

Augustine Kong (IS), John Barnard (IS), Daniel F. Gudbjartsson (IS), Gudmar Thorleifsson (IS), Gudrun Jonsdottir (IS), Sigrun Sigurdardottir (IS), Bjorgvin Richardsson (IS), Jonina Jonsdottir (IS), Thorgeir Thorgeirsson (IS), Michael L. Frigge (IS), Neil E. Lamb (IS), Stephanie Sherman (IS), Jeffrey R. Gulcher (IS) and Kári Stefánsson (IS) showed that older women recombine more than younger women; that higher recombination correlates with higher fertility (793).

 

Svend K. Petersen-Mahrt (GB), Reuben S. Harris (GB), and Michael S. Neuberger (GB) proposed that diversification of functional immunoglobulin genes is triggered by activation-induced cytidine deaminase-mediated deamination of dC residues in the immunoglobulin locus with the outcome--that is, hypermutation phases 1 and 2, gene conversion or switch recombination-dependent on the way in which the initiating dU/dG lesion is resolved (1150).

 

Kai Ge (US), Mohamed Guermah (US),Chao-Xing Yuan (US), Mitsuhiro Ito (US), Annika E. Wallberg (US), Bruce M. Spiegelman (US), and Robert Gayle Roeder (US) showed that only a single component (TRAP220) of the mediator is essential for the formation of fat cells — a finding that may one day contribute to new treatments for diabetes, heart disease, cancer and other conditions in which the fat-making process breaks down (479).

 

David Wang (US), Laurent Coscoy (US), Maxine Zylberberg (US), Pedro C. Avila (US), Homer A. Boushey (US), Don Ganem (US), and Joseph L. DeRisi (US) developed a genomic strategy for highly parallel viral screening. The cornerstone of this approach is a long oligonucleotide (70-mer) DNA microarray capable of simultaneously detecting hundreds of viruses. Using virally infected cell cultures, they were able to efficiently detect and identify many diverse viruses. Related viral serotypes could be distinguished by the unique pattern of hybridization generated by each virus. Furthermore, by selecting microarray elements derived from highly conserved regions within viral families, individual viruses that were not explicitly represented on the microarray were still detected, raising the possibility that this approach could be used for virus discovery. Finally, by using a random PCR amplification strategy in conjunction with the microarray, they were able to detect multiple viruses in human respiratory specimens without the use of sequence-specific or degenerate primers (1535).

Philippa J.M. Jack (AU), Rachel N. Amos-Ritchie (AU), Antonio Reverter (AU), Gustavo Palacios (US), Phuong-Lan Quan (US), Omar Jabado (US), Thomas Briese (US), W. Ian Lipkin (US), and David B. Boyle (AU) described the application of a long oligonucleotide microarray assay to the identification of viruses known to cause vesicular or vesicular-like lesions in livestock animals. Eighteen virus isolates from cell culture were successfully identified to genus level (696).

 

Jeronimo Cello (US), Aniko V. Paul (US), and Eckard Wimmer (US) synthesized full-length poliovirus complementary DNA (cDNA) by assembling oligonucleotides of plus and minus strand polarity. The synthetic poliovirus cDNA was transcribed by RNA polymerase into viral RNA, which translated and replicated in a cell-free extract, resulting in the de novo synthesis of infectious poliovirus (220).

 

 R. Douglas Fields (US) and Beth Stevens-Graham (US) determined that two-way communication between neurons and glial cells is actually essential for axonal conduction, synaptic transmission, and information processing (413).

 

Kouichi Ozaki (JP), Yozo Ohnishi (JP), Aritoshi Lida (JP), Akihiko Sekine (JP), Ryo Yamada (JP), Tatsuhiko Tsunoda (JP), Hiroshi Sato (JP), Masatsugu Hori (JP), Yusuke Nakamura (JP), and Toshihiro Tanaka (JP) by means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, identified a candidate locus on chromosome 6p21 associated with susceptibility to myocardial infarction. These results indicate that variants in the LTA (encoding lymphotoxin-alpha) are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder (1114).

 

Thierry Poynard (FR), John McHutchison (US), Michael Manns (DE), Christian Trepo (FR), Karen Lindsay (US), Zachary Goodman (US), Mei–Hsiu Ling (US), and Janice Albrecht (US) found that pegylated interferon (polyethylene glycol interferon) and ribavirin (antiviral drug) combination significantly reduced the rate of fibrosis progression in patients with hepatitis C (1177).

 

Attila T. Lörincz (IE-US), Philip E. Castle (US), Mark E. Sherman (US), David R. Scott (US), Andrew G. Glass (US), Sholom Wacholder (US), Brenda B. Rush (US), Patti E. Gravitt (US), John E. Schussler (US), and Mark Schiffman (US) were the first to show key differences in the relative risks of human papillomavirus types and led to the low, medium and high risk classification system of human papillomavirus cancer risk (898).

 

Céline Brochier (FR) and Hervé Philippe (FR) performed a phylogenetic analysis of phyla of bacteria via the slow-fast method showing that if only slowly evolving nucleotide sites of 16S rRNA aligned sequences are chosen for phylogenetic analysis, planctomycetes rather than phyla of hyperthermophiles are the deepest branching phylum of the bacteria (164).

 

Bernd Mueller-Roeber (DE) and Christophe Pical (DE) performed a diligent and careful survey of the Arabidopsis genome for sequences related to lipid signaling. This was the first comprehensive compilation of the major families of enzymes involved in inositol phospholipid metabolism in plants. In addition to providing an overview of the relevant plant gene families and establishing a uniform nomenclature they discussed the differences in plant and animal phosphoinositide metabolism and clarified discrepancies/controversies arising from the comparison of different biological systems (1031).

 

Joshua H. Wong (US), Yong-Bum Kim (US), Pei-Hsien Ren (US), Nick Cai (US), Myeong-Je Cho (US), Peter Hedden (GB), Peggy G. Lemaux (US), and Bob B. Buchanan (US) implicated thioredoxin h in the reserve breakdown that sustains early seedling growth of germinating cereal seeds (1590).

 

Klaus Klass (DK), Oliver Zompro (DE), Niels Kristensen (DK), and Joachim Ulrich Adis (DE) described a new order of insects, Mantophasmatodea. This boosts the total number of insect orders (e.g. the beetles, flies, fleas, etc.) to 30. The description was based, on just two museum specimens from Tanzania and Namibia (776).

 

Maria L. Tomaro (AR) and Alcira M.C. Batlle (AR) presented evidence that bilirubin, formerly dismissed as a waste product might play a role in protecting cells from injury (1465).

 

Philippe Gabant (BE), Lesley Forrester (BE), Jennifer Nichols (BE), Thierry Van Reeth (BE), Christelle De Mees (BE), Bernard Pajack (BE), Alistair Watt (BE), Johan Smitz (BE), Henri Alexandre (BE), Claude Szpirer (BE), Josiane Szpirer (BE), Jean-François Laes (BE), Julie Bakker (BE), Benoît Hennuy (BE), Pascale Van Vooren (BE), Quentin Douhard (BE), and Jacques Balthazart (BE) concluded that alpha-fetoprotein (AFP) serves to sequester estrogen during development of the mouse brain, thus protecting the developing female mice from defeminization (75; 455; 982).

 

Helen Davies (GB), Graham R. Bignell (GB), Charles Cox (GB), Philip Stephens (GB), Sarah Edkins (GB), Sheila Clegg (GB), Jon Teague (GB), Hayley Woffendin (GB), Mathew J. Garnett (GB), William Bottomley (GB), Neil Davis (GB), Ed Dicks (GB), Rebecca Ewing (GB), Yvonne Floyd (GB), Kristian Gray (GB), Sarah Hall (GB), Rachel Hawes (GB), Jaime Hughes (GB), Vivian Kosmidou (GB), Andrew Menzies (GB), Catherine Mould (GB), Adrian Parker (GB), Claire Stevens (GB), Stephen Watt (GB), Steven Hooper (GB), Rebecca Wilson (GB), Hiran Jayatilake (GB), Barry A. Gusterson (GB), Colin Cooper (GB), Janet Shipley (GB), Darren Hargrave (GB), Katherine Pritchard-Jones (GB), Norman Maitland (GB), Georgia Chenevix-Trench (AU), Gregory J. Riggins (US), Darell D. Bigner (US), Giuseppe Palmieri (IT), Antonio Cossu (IT), Adrienne Flanagan (GB), Andrew Nicholson (GB), Judy W. C. Ho (CN), Suet Y. Leung (CN), Siu T. Yuen (CN), Barbara L. Weber (US), Hilliard F. Seigler (US), Timothy L. Darrow (US), Hugh Paterson (GB), Richard Marais (GB), Christopher J. Marshall (GB), Richard Wooster (GB), Michael R. Stratton (GB), and P. Andrew Futreal (GB) report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer (318). Note: This offered renewed hope in the battle against metastatic and recurring melanomas; it provided an opportunity for tumor genotypes to be translated into clinically effective targeted therapies.

Venessa Gray-Schopfer (GB), Claudia Wellbrock (GB), and Richard Marais (GB) found that aberrant components of the mitogen-activated protein kinase (MAPK) pathway, in which BRAF is a key constituent, are responsible for unrestrained cellular proliferation in more than 90% of melanomas (534).

 

Kathrin Maedler (CH), Pavel Sergeev (CH), Frédéric Ris (CH), José Oberholzer (CH), Helen I. Joller-Jemelka (CH), Giatgen A. Spinas (CH), Nurit Kaiser (IL), Philippe A. Halban (CH), Marc Y. Donath (CH), Antonio Abbate (US), Fadi N. Salloum (US), Elena Vecile (US), Anindita Das (US), Nicholas N. Hoke (US), Stefania Straino (US), Giuseppe G.L. Biondi-Zoccai (US), Jon-Erik Houser (US), Ian Z. Qureshi (US), Evan D. Ownby (US), Edoardo Gustini (US), Luigi M. Biasucci (US), Anna Severino (US), Maurizio C. Capogrossi (US), George W. Vetrovec (US), Filippo Crea (US), Alfonso Baldi (US), Rakesh C. Kukreja (US), Aldo Dobrina (US), Marianne Böni-Schnetzler (CH), Jeffrey Thorne (CH), Géraldine Parnaud (CH), Lorella Marselli (CH), Jan A. Ehses (CH), Julie Kerr-Conte (CH), Francois Pattou (CH), and Gordon C. Weir (CH), from animal studies and clinical research, gave considerable support to the concept that chronic heart failure and type 2 diabetes are driven by the auto‐inflammatory circuit of interleukin‐1‐induced interleukin‐1 (7; 150; 925).

 

John R.A. Rigg (AU), Konrad Jamrozik (AU), Paul S. Myles (AU), Brendan S. Silbert (AU), Phillip J. Peyton (AU), Richard W. Parsons (AU), and Karen S. Collins (AU) found that perioperative epidural analgesia in high-risk patients undergoing major abdominal surgery improves analgesia but does not have other morbidity or mortality benefits (1238).

 

Michael Pignone (US), Melissa Rich (US), Steven M. Teutsch (US), Alfred O. Berg (US), and Kathleen N. Lohr (US) concluded that colorectal cancer screening reduces death from colorectal cancer and can decrease the incidence of disease through removal of adenomatous polyps. Several available screening options seem to be effective, but the single best screening approach cannot be determined because data are insufficient (1167).

 

Arthur J. Moss (US), Wojciech Zareba (US), W. Jackson Hall (US), Helmut Klein (US), David J. Wilber (US), David S. Cannom (US), James P. Daubert (US), Steven L. Higgins (US), Mary W. Brown (US), and Mark L. Andrews, for the Multicenter Automatic Defibrillator Implantation Trial II Investigators released their study showing that in patients with a prior myocardial infarction and advanced left ventricular dysfunction, prophylactic implantation of a defibrillator improves survival and should be considered as a recommended therapy (1027). Note: Applying the recommendation threatens to bankrupt the entire health care industry of the United States with its cost burden on the government (a one-time cost of > $250 billion, with yearly expenditures of about 10% of that).

 

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) concluded that thiazide-type diuretics are superior in preventing 1 or more major forms of cardiovascular disease (CVD) and are less expensive. They should be preferred for first-step antihypertensive therapy (544).

 

Edmund A. Bermudez (US) and Paul M. Ridker (US) found that C-reactive protein predicts the chances of developing heart disease, leading to new guidelines for predicting cardiovascular disease (118). Note: Whether measurement of high sensitivity C-reactive protein (hsCRP) levels provides consistent, clinically meaningful incremental predictive value in risk prediction and reclassification beyond conventional factors remains debated.

 

Ching‐Hsuan Tung (US), Yuhui Lin (US), Woo Kyung Moon (US), and Ralph Weissleder (US) developed an optical probe designed for in vivo tumor detection. It consists of near‐infrared fluorochrome and folic acid that binds strongly to tumor‐associated folate receptors both in vitro and in vivo. After intravenous injection of the probe, an intense fluorescence signal was observed in a mouse ovarian tumor model. Modification of fluorochromes with small molecules may thus be used in many biological and medicinal applications (1481).

 

Laura A. Koutsky (US), Kevin A. Ault (US), Cosette M. Wheeler (US), Darron R. Brown (US), Eliav Barr (US), Frances B. Alvarez (US), Lisa M. Chiacchierini (US), Kathrin U. Jansen (US), Diane M. Harper (US), Eduardo L. Franco (US), Cosette Wheeler (US), Daron G. Ferris (US), David Jenkins (US), Anne Schuind (US), Toufik Zahaf (US), Bruce Innis (US), Paulo Naud (US), Newton S. De Carvalho (US), Cecilia M. Roteli-Martins (US), Julio Teixeira (US), Mark M. Blatter (US), Abner P. Korn (US), Wim Quint (US), Gary Dubin (US), and GlaxoSmithKline HPV Vaccine Study Group developed vaccines against cancer causing human papilloma viruses (600; 799).

 

Lisa M. Coussens (US) and Zina Werb (US) reported that the closest relationship between chronic inflammation and cancer can be observed in chronic ulcerating colitis and Crohn’s disease, which increase the risk of colorectal cancer tenfold (288).

 

Dileep N. Lobo (GB), Kate A. Bostock (GB), Keith R. Neal (GB), Alan C. Perkins (GB), Brian J. Rowlands (GB), and Simon P. Allison (GB) found that positive salt and water balance sufficient to cause a 3 kg weight gain after surgery delays return of gastrointestinal function and prolongs hospital stay in patients undergoing elective colonic resection (892).

 

John D. Birkmeyer (US), Andrea E. Siewers (US), Emily V. Finlayson (US), Theresa A.Stukel (US), F. Lee Lucas (US), Ida Batista (US), H. Gilbert Welch (US), and David E. Wennberg (US) concluded from their research data that high-volume hospitals had lower observed and operative mortality rates for a wide range of operative procedures. The greatest difference in mortality between hospitals with very low and very high volumes was seen in complex surgeries including pancreatic resection and oesophagectomy (127).

 

Chaan S. Ng (GB), Christopher J. Watson (GB), Christopher R. Palmer (GB), Teik Choon See (GB), Nigel A. Beharry (GB), Barbara A. Housden (GB), J. Andrew Bradley (GB), and Adrian K. Dixon (GB) showed that early abdominopelvic computerized tomography for acute abdominal pain improves the accuracy of diagnosis and may reduce length of hospital stay and mortality (1066).

 

Jan B.F. Hulscher (NL), Johanna W. van Sandick (NL), Angela G.E.M. de Boer (NL), Bas P.L. Wijnhoven (NL), Jan G.P. Tijssen (NL), Paul Fockens (NL), Peep F.M. Stalmeier (NL), Fiebo J.W. ten Kate (NL), Herman van Dekken (NL), Huug Obertop (NL), Hugo W. Tilanus (NL), and J. Jan B. van Lanschot (NL) found the outcome to be no different whether an esophagectomy was performed trans thoracic or trans-hiatal (665).

 

Antonio M. Lacy (ES), Juan C. García-Valdecasas (ES), Salvadora Delgado (ES), Antoni Castells (ES), Pilar Taurá (ES), Josep M. Piqué (ES), Josep Visa (ES), Ruben Veldkamp (NL), Esther Kuhry (NL), Wim C.J. Hop (NL), Johannes Jeekel (NL), Geert Kazemier (NL), H. Jaap Bonjer (NL), Eva Haglind (NL), Lars Påhlman (NL), Miguel A. Cuesta (NL), Simon Msika (NL), Mario Morino (NL), Antonio M. Lacy(NL), COlon cancer Laparoscopic or Open Resection Study Group (COLOR) (NL), Pierre J. Guillou (GB), Philip Quirke (GB), Helen Thorpe (GB), Joanne Walker (GB), David G. Jayne (GB), Adrian M.H. Smith (GB), Richard M. Heath (GB), Julia M. Brown (GB), and MRC CLASICC trial group (GB) concluded that laproscopic colon and rectal surgery was safe and provided effective oncological surgery (6; 566; 816; 1508).

 

Peter R. Grant (US) and B. Rosemary Grant (US) found from their 30-year study of Darwin's Finches that evolution can be predicted in the short term from knowledge of selection and inheritance. However, in the long term evolution is unpredictable because environments, which determine the directions and magnitudes of selection coefficients, fluctuate unpredictably (530-532).

 

Qiang Ji (CN), Zhe-Xi Luo (US), Chong-Xi Yuan (CN), John R. Wible (US), Jian-Ping Zhang (CN), and Justin A. Georgi (US) described Juramaia sinensis, a small shrew-like mammal that lived in China 160 million years ago during the Jurassic. Juramaia is the earliest known fossil of eutherians–the group that evolved to include all placental mammals, which provide nourishment to unborn young via a placenta (706).

Shundong Bi (CN), Xiaoting Zheng (CN), Xiaoli Wang (CN), Natalie E. Cignetti (US), Shiling Yang (CN), and John R. Wible (US) report a new Jehol eutherian, Ambolestes zhoui, with a nearly complete skeleton that preserves anatomical details that are unknown from contemporaneous mammals, including the ectotympanic and hyoid apparatus. This new fossil demonstrates that Sinodelphys is a eutherian, and that postcranial differences between Sinodelphys and the Jehol eutherian Eomaia—previously thought to indicate separate invasions of a scansorial niche by eutherians and metatherians—are instead variations among the early members of the placental lineage (125).

 

Michel Brunet (FR), Franck Guy (FR), David Pilbeam (FR), Hassane Taisso Mackaye (TD), Andossa Likius (FR), Djimdoumalbaye Ahounta (TD), Alain Beauvilain (FR), Cécile Blondel (FR), Hervé Bocherens (FR), Jean-Renaud Boisserie (FR), Louis De Bonis (FR), Yves Coppens (FR), Jean Dejax (FR), Christiane Denys (FR), Philippe Duringer (FR), Véra Eisenmann (FR), Gongdibé Fanone (TD), Pierre Fronty (FR), Denis Geraads (FR), Thomas Lehmann (FR), Fabrice Lihoreau (FR), Antoine Louchart (FR), Adoum Mahamat (TD), Gildas Merceron (FR), Guy Mouchelin (FR), Olga Otero (FR), Pablo Pelaez Campomanes (ES), Marcia Ponce De Leon (CH), Jean-Claude Rage (FR), Michel Sapanet (FR), Mathieu Schuster (FR), Jean Sudre (FR), Pascal Tassy (FR), Xavier Valentin (FR), Patrick Vignaud (FR), Laurent Viriot (FR), Antoine Zazzo (FR) and Christoph Zollikofer (CH) discovered the skull of Sahelanthropus tchadensis in the Sahel region of Chad. The skull possesses both human and ape-like characteristics, with a chimpanzee-sized braincase, teeth that are human-like, and a foramen magnum placed further back than in a chimpanzee or gorilla. Based on the location of the foramen magnum, the French team suggested that this creature was bipedal (177).

 

2003

“Every living thing is an elaboration on a single original plan. As humans we are mere increments—each of us a musty archive of adjustments, adaptations, modifications, and providential tinkering stretching back 3.8 billion years. Remarkably, we are even quite closely related to fruit and vegetables. About half the chemical functions that take place in a banana are fundamentally the same as the chemical functions that take place in you.

It cannot be said too often: all life is one. That is, and I suspect will forever prove to be, the most profound true statement there is.” Bill Bryson (178).

 

Paul Christian Lauterbur (US) and Peter Mansfield (GB) were awarded the Nobel Prize in Physiology or Medicine for their development of magnetic resonance imaging (MRI).

 

Peter Agre (US) was awarded the Nobel Prize in Chemistry for his discoveries regarding water channels and ion channels in cells.

 

Arthur J. Kornberg (US) gave us the Ten Commandments of Enzymology: “Thou shalt… (1) Rely on enzymology to resolve and reconstitute biologic events, (2) Trust the universality of biochemistry and the power of microbiology, (3) Not believe something just because you can explain it, (4) Not waste clean thinking on dirty enzymes (the late Efraim Racker enunciated this commandment), (5) Not waste clean enzymes on dirty substrates, (6) Use genetics and genomics, (7) Be aware that cells are molecularly crowded, (8) Depend on viruses to open windows, (9) Remain mindful of the power of radioactive tracers, and (10) Employ enzymes as unique reagents” (798).

 

Hamilton O. Smith (US), Clyde A. Hutchison, 3rd (US), Cynthia Pfannkoch (US), and J. Craig Venter (US) accomplished the first synthesis of an entire viral genome, phiX174 (1363). Note: The phi X 174 (or ΦX174) bacteriophage is a single-stranded DNA (ssDNA) virus that infects Escherichia coli, and the first DNA-based genome to be sequenced.

 

Bernard La Scola (FR), Stéphane Audic (FR), Catherine Robert (FR), Liang Jungang (FR), Xavier de Lamballerie (FR), Michel Drancourt (FR), Richard Birtles (FR), Jean-Michel Claverie (FR), and Didier Raoult (FR) identified the very large Acanthamoeba polyphaga mimivirus. It was given the name "mimivirus" (for "mimicking microbe") as it resembles a bacterium on Gram staining (1309).

Bernard La Scola (FR), Christelle Desnues (FR), Isabelle Pagnier (FR), Catherine Robert (FR), Lina Barrassi (FR), Ghislain Fournous (FR), Michèle Merchat (FR), Marie Suzan-Monti (FR), Patrick Forterre (FR), Eugene Koonin (FR), and Didier Raoult (FR) described an icosahedral small virus, "Sputnik", 50 nm in size, found associated with a new strain of Acanthamoeba polyphaga mimivirus (APMV), with a 400 nm icosahedral capsid, the 4th largest known virus. "Sputnik" cannot multiply in Acanthamoeba castellanii but grows rapidly, after an eclipse phase, in the giant virus factory found in amoebae co-infected with APMV4. "Sputnik" growth is deleterious to APMV and results in the production of abortive forms and abnormal capsid assembly of the host virus. "Sputnik" represents a currently unknown family of viruses. Considering its functional analogy with bacteriophages, we classify this virus as a virophage (1310).

Eric Ghigo (FR), Jürgen Kartenbeck (CH), Pham Lien (FR), Lucas Pelkmans (CH), Christian Capo (FR), Jean-Louis Mege (FR), and Didier Raoult (FR) presented evidence that mimivirus can infect macrophages (486).

Defne Arslan (FR), Matthieu Legendre (FR), Virginie Seltzer (FR), Chantal Abergel (FR), and Jean-Michel Claverie (FR) isolated Megavirus chilensis, a giant virus isolated off the coast of Chile, but capable of replicating in fresh water acanthamoeba. Its 1,259,197-bp genome is the largest viral genome fully sequenced so far. It encodes 1,120 putative proteins (53).

Nadège Philippe (FR), Matthieu Legendre (FR), Gabriel Doutre (FR), Yohann Couté (FR), Olivier Poirot (FR), Magali Lescot (FR), Defne Arslan (FR), Virginie Seltzer (FR), Lionel Bertaux (FR), Christophe Bruley (FR), Jérome Garin (FR), Jean-Michel Claverie (FR), and Chantal Abergal (FR) reported the isolation of two giant viruses, one off the coast of central Chile, the other from a freshwater pond near Melbourne (Australia), without morphological or genomic resemblance to any previously defined virus families. Their micrometer-sized ovoid particles contain DNA genomes of at least 2.5 and 1.9 megabases, respectively. These viruses are the first members of the proposed Pandoravirus genus (1158).

Matthieu Legendre (FR), Julia Bartoli (FR), Lyubov Shmakova (RU), Sandra Jeudy (FR), Karine Labadie (FR), Annie Adrait (FR), Magali Lescot (FR), Olivier Poirot (FR), Lionel Bertaux (FR), Christophe Bruley (FR), Yohann Couté (FR), Elizaveta Rivkina (RU), Chantal Abergel (FR), and Jean-Michel Claverie (FR) isolated a new virus called Pithovirus sibericum from 30,000 year old Siberian permafrost. It is the oldest DNA virus of eukaryotes ever isolated, showing that viruses can retain infectivity in nature for very long periods of time. Although the Pithovirus particle is larger than Pandoravirus, the viral genome – which is a double-stranded molecule of DNA – is smaller, at 610,033 base pairs.

Pithovirus was isolated by inoculating cultures of the amoeba Acanthamoeba castellani with samples taken in the year 2000 from 30 meters below the surface of a late Pleistocene sediment in the Kolyma lowland region (848).

 

Wout Boerjan (BE), John Ralph (BE), Marie Baucher (BE) presented a current picture of monolignol biosynthesis, polymerization, and lignin structure. They noted that it was not until the rise of tracheophytes, which had developed the ability to deposit the phenylpropanoid polymer lignin in their cell wall, that land plants truly flourished and began their dominance of the terrestrial ecosystem. Lignin bestowed the early tracheophytes with the physical rigidity to stand upright, strengthened the water-conducting cells for long-distance water transport, and allowed plants to expand significantly in body size compared with their sister group, the bryophytes. The nature and randomness of the linkages in lignin also made lignin one of the hardest biopolymers to degrade, an ideal characteristic for a defensive barrier against the pathogens and herbivores that would soon co-evolve with vascular plants (144).

Dimitrios Floudas (US), Manfred Binder (US), Robert Riley (US), Kerrie Barry (US), Robert A. Blanchette (US), Bernard Henrissat (FR), Angel T. Martínez (ES), Robert Otillar (US), Joseph W. Spatafora (US), Jagjit S. Yadav (US), Andrea Aerts (US), Isabelle Benoit (NL), Alex Boyd (US), Alexis Carlson (US), Alex Copeland (US), Pedro M. Coutinho (FR), Ronald P. de Vries (NL), Patricia Ferreira (ES), Keisha Findley (US), Brian Foster (US), Jill Gaskell (US), Dylan Glotzer (US), Paweł Górecki (PL), Joseph Heitman (US), Cedar Hesse (US), Chiaki Hori (JP), Kiyohiko Igarashi (JP), Joel A. Jurgens (US), Nathan Kallen (US), Phil Kersten (US), Annegret Kohler (FR), Ursula Kües (DE), T. K. Arun Kumar (US), Alan Kuo (US), Kurt LaButti (US), Luis F. Larrondo (CL), Erika Lindquist (US), Albee Ling (US), Vincent Lombard (FR), Susan Lucas (US), Taina Lundell (FI), Rachael Martin (US), David J. McLaughlin (US), Ingo Morgenstern (CA), Emanuelle Morin (FR), Claude Murat (FR), Laszlo G. Nagy (US), Matt Nolan (US), Robin A. Ohm (US), Aleksandrina Patyshakuliyeva (NL), Antonis Rokas (US), Francisco J. Ruiz-Dueñas (ES), Grzegorz Sabat (US), Asaf Salamov (US), Masahiro Samejima (JP), Jeremy Schmutz (US), Jason C. Slot (US), Franz St. John (US), Jan Stenlid (SE), Hui Sun (US), Sheng Sun (US), Khajamohiddin Syed (US), Adrian Tsang (CA), Ad Wiebenga (NL), Darcy Young (US), Antonio Pisabarro (ES), Daniel C. Eastwood (GB) Francis Martin (FR), Dan Cullen (US), Igor V. Grigoriev (US), and David S. Hibbett (US) tell us that the only organisms capable of substantial lignin decay are white rot fungi in the Agaricomycetes, which also contains non–lignin-degrading brown rot and ectomycorrhizal species. These fungi first appeared in the Paleozoic (425). Note: Organic carbon accumulated at an exceptionally high rate during the Carboniferous and Permian, resulting in the formation of vast coal deposits derived primarily from lignin not yet exposed to white rot.

 

Sandra Blaise (FR), Nathalie de Parseval (FR), Laurence Bénit (FR), and Thierry Heidmann (FR) showed that syncytin-2, also known as endogenous retrovirus group FRD member 1, is a protein that in humans is encoded by the ERVFRD-1 gene (132).

Amandine Vargas (CA), Julie Moreau (CA), Sébastien Landry (CA), Frédérique LeBellego (CA), Chirine Toufaily (CA), Éric Rassart (CA), Julie Lafond (CA), and Benoit Barbeau (CA) discovered that this protein (syncytin-2) plays a key role in the implantation of human embryos in the womb (1504).

Christian Lavialle (FR), Guillaume Cornelis (FR), Anne Dupressoir (FR), Cécile Esnault (FR), Odile Heidmann (FR), Cécile Vernochet (FR), and Thierry Heidmann (FR) found that this gene (syncytin-2) is conserved among all primates, with an estimated age of 45 million years. The receptor for this fusogenic env protein is MFSD2. The mouse syncytins are not true orthologues (833).

 

Mark W. Westneat (US), Oliver Betz (DE), Richard W. Blob (US), Kamel Fezzaa (US), W. James Cooper (US), and Wah-Keat Lee (US) watched the tracheae deflate and inflate inside the head and thorax of ground beetles (Platynus decentis), carpenter ants (Camponotus pennsylvanicus) and house crickets (Acheta domesticus) at rest. These parts of the insect are covered in a hard outer shell and cannot pump air in by external movement. Their conclusion was that these tracheal systems expanded and contracted thus pumping oxygen to surrounding tissues. Prior to this discovery insect tracheal tubes were thought to be fairly rigid and passive (1564).

 

Catherine Rougeot (FR), Michaël Messaoudi (FR), Véronique Hermitte (FR), Anne Gaëlle Rigault (FR), Thierry Blisnick (FR), Christophe Dugave (FR), Didier Desor (FR), and François Rougeon (FR) reported salivary gland Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity (1259).

Anne Wisner (FR), Evelyne Dufour (FR), Michaël Messaoudi (FR), Amine Nejdi (FR), Audrey Marcel (FR), Marie-Noelle Ungeheuer (FR), and Catherine Rougeot (FR) discovered the human equivalent of Sialorphin, which they named Opiorphin. They demonstrated the functional specificity in vivo of human Opiorphin. The pain-suppressive potency of Opiorphin is as effective as morphine in the behavioral rat model of acute mechanical pain, the pin-pain test (1583).

Philippe Sitbon (FR), Alain Van Elstraete (FR), Leila Hamdi (FR), Victor Juarez-Perez (FR), Jean-Xavier Mazoit (FR), Dan Benhamou (FR), and Catherine Rougeot (FR) reported that intravenous infusion of opiorphin and STR-324 (a chemically stable form of opiorphin) produced significant antinociceptive effect in a post-operative pain model. This study demonstrates that STR-324 is effective in post-operative pain management due to its strong antihyperalgesic effects mediated via opioid-dependent antinociceptive pathways. Opiorphin analog should represent a new class of potent and safe analgesics (1347).

 

Xolair (omalizumab) was FDA-approved in 2003 as the first biologic medication specifically created to treat moderate-to-severe persistent allergic asthma. It was also approved for use in treating chronic urticaria (hives) (5). Note: Asthma caused by allergies results from the immune system's over-reaction to inhaled allergens such as dust mites or animal dander. The body forms antibodies in response to the allergen, and this immune system reaction prompts inflammation that causes airway narrowing and other symptoms. Xolair (omalizumab) is a genetically engineered protein that blocks this immune response. The treatment is given as an injection under the skin.

 

Kenyatta Cosby (US), Kristine S. Partovi (US), Jack H. Crawford (US), Rakesh P. Patel (US), Christopher D. Reiter (US), Sabrina Martyr (US), Benjamin K. Yang (US), Myron A. Waclawiw (US), Gloria Zalos (US), Xiuli Xu (US), Kris T Huang (US), Howard Shields (US), Daniel B Kim-Shapiro (US), Alan N Schechter (US), Richard O Cannon III (US), and Mark T Gladwin (US) changed our views about nitric oxide function by experimental results suggesting that nitrite represents a major bioavailable pool of NO. They described a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation (283).

 

Sally E. Smith (AU), F. Andrew Smith (AU), and Iver Jakobsen (AU) determined that plants receive all of their phosphorus via their fungal symbiont (1365).

 

Bin Zhang (US), Michael A. Cunningham (US), William C. Nichols (US), John A. Bernat (US), Uri Seligsohn (US), Steven W. Pipe (US), John H. McVey (US), Ursula Schulte-Overberg (US), Norma B. de Bosch (US), Arlette Ruiz-Saez (US), Gilbert C. White (US), E. G. D. Tuddenham (US), Randal J. Kaufman (US), and David Ginsburg (US) showed that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1. MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1. These findings suggest that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins (1628).

 

Shohei Hori (JP),Takashi Nomura (JP), and Shimon Sakaguchi (JP) showed that forkhead transcription gene FOXP3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells. Furthermore, retroviral gene transfer of FOXP3 converts naïve T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+ regulatory T cells. Thus, FOXP3 is a key regulatory gene for the development of regulatory T cells (651).

Jason D. Fontenot (US), Marc A. Gavin (US), and Alexander Y. Rudensky (US) note that CD4+CD25+ regulatory T cells are essential for the active suppression of autoimmunity. Here they report that the forkhead transcription factor FOXP3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development. The lethal autoimmune syndrome observed in FOXP3-mutant scurfy mice and FOXP3-null mice results from a CD4+CD25+ regulatory T cell deficiency and not from a cell-intrinsic defect of CD4+CD25- T cells. CD4+CD25+ regulatory T cells rescue disease development and preferentially expand when transferred into neonatal FOXP3-deficient mice. Furthermore, ectopic expression of FOXP3 confers suppressor function on peripheral CD4+CD25- T cells. Thus, FOXP3 is a critical regulator of CD4+CD25+ regulatory T cell development and function (430).

Roli Khattri (US), Tom Cox (US), Sue-Ann Yasayko (US), and Fred Ramsdell (US) provided evidence that Scurfin and CTLA-4 pathways may intersect, providing further insight into the CD4+CD25+ regulatory T cells (TR) cell lineage (756). Note: Scurfin is a transcription factor also known as forkhead box P3 and encoded by FOXP3.

 

WanJun Chen (US), Wenwen Jin (US), Neil Hardegen (US), Ke-jian Lei (US), Li Li (US), Nancy Marinos (US), George McGrady (US), and Sharon M. Wahl (US) presented evidence that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor β (TGF-β). They showed in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-β–converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-β–induced suppressor T cells prevented house dust mite–induced allergic pathogenesis in lungs (236).

 

Takuya Matsuo (JP), Shun Yamaguchi (JP), Shigeru Mitsui (JP), Aki Emi (JP), Fukuko Shimoda (JP), and Hitoshi Okamura (JP) showed that in the regenerating liver (of mice) that the circadian clock controls the expression of cell cycle–related genes that in turn modulate the expression of active cyclin B1-Cdc2 kinase, a key regulator of mitosis. Among these genes, expression of wee1 was directly regulated by the molecular components of the circadian clockwork. In contrast, the circadian clockwork oscillated independently of the cell cycle in single cells. Thus, the intracellular circadian clockwork can control the cell-division cycle directly and unidirectionally in proliferating cells (955).

 

Michael S. Benninger (US), Berrylin J. Ferguson (US), James A. Hadley (US), Daniel L. Hamilos (US), Michael Jacobs (US), David W. Kennedy (US), Donald C. Lanza (US), Bradley F. Marple (US), J. David Osguthorpe (US), James A. Stankiewicz (US), Jack Anon (US), James Denneny (US), Ivor Emanuel (US), and Howard Levine (US) defined chronic rhinosinusitis as, “Chronic rhinosinusitis is a group of disorders characterized by inflammation of the mucosa of the nose and paranasal sinuses of at least 12 weeks duration” (111).

 

Nir Barzilai (US), Gil Atzmon (US), Clyde Schechter (US), Ernst J. Schaefer (US), Adrienne L. Cupples (US), Richard Bruce Lipton (US), Suzanne Cheng (US), and Alan R. Shuldiner (US) found that individuals with exceptional longevity and their offspring have significantly larger HDL and LDL particle sizes. This phenotype is associated with a lower prevalence of hypertension, cardiovascular disease, the metabolic syndrome, and increased homozygosity for the I405V variant in human cholesteryl ester transfer protein(CETP). These findings suggest that lipoprotein particle sizes are heritable and promote a healthy aging phenotype (90).

Gil Atzmon (US), Marielisa Rincon (US), Clyde B. Schechter (US), Alan R. Shuldiner (US), Richard Bruce Lipton (US), Aviv Bergman (US), and Nir Barzilai (US) showed that homozygosity of the apolipoprotein C3 gene (APOC3−641C) allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity in humans. This "longevity gene" controls serum levels of apolipoprotein C3 (APOC3) (64).

Gil Atzmon (US), Toni I. Pollin (US), Jill Crandall (US), Keith Tanner (US), Clyde B. Schechter (US), Philipp E. Scherer (US), Marielisa Rincon (US), Glenn Siegel (US), Micol Katz (US), Richard Bruce Lipton (US), Alan R. Shuldiner (US), and Nir Barzilai (US) discovered that serum levels of adiponectin and genotype ADIPOQ is a strong candidate for a regulator, "longevity gene," of life span in humans (63).

Yousin Suh (US), Gil Atzmon (US), Mi-Ook Cho (US), David Hwang (US), Bingrong Liu (US), Daniel J. Leahy (US), Nir Barzilai (US), and Pinchas Cohen (US) discovered the human "longevity gene" named insulin-like growth factor 1 (IGF1R) (1415).

Gil Atzmon (US), Nir Barzilai (US), Martin I. Surks (US), and Ilan Gabriely (US) observed that genetic predisposition to elevated serum thyrotropin (TSH) is associated with exceptional longevity. The TSHR gene can be considered a "longevity gene" (62).

 

Sharon E. Maynard (US), Jiang-Yong Min (US), Jaime Merchan (US), Kee-Hak Lim (US), Jianyi Li (US), Susanta Mondal (US), Towia A. Libermann (US), James P. Morgan (US),Frank W. Sellke (US), Isaac E. Stillman (US), Franklin H. Epstein (US), Vikas P. Sukhatme (US), and S. Ananth Karumanchi (US) pinpoint the source of preeclampsia, a life-threatening complication of pregnancy and one of the leading causes of maternal and infant mortality worldwide. They confirmed that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. Their observations suggest that excess circulating sFlt1 contributes to endothelial dysfunction, hypertension, and proteinuria in preeclampsia (963).

 

The Million Women Study Collaborators (GB) concluded that current use of hormone replacement therapy (HRT) is associated with an increased risk of incident and fatal breast cancer; the effect is substantially greater for estrogen-progestagen combinations than for other types of HRT (269).

 

Paul G. Richardson (US), Bart Barlogie (US), James Berenson (US), Seema Singhal (US), Sundar Jagannath (US), David Irwin (US), S. Vincent Rajkumar (US), Gordan Srkalovic (US), Melissa Alsina (US), Raymond Alexanian (US), David Siegel (US), Robert Z. Orlowski (US), David Kuter (US), Steven A. Limentani (US), Stephanie Lee (US), Teru Hideshima (US), Dixie-Lee Esseltine (US), Michael Kauffman (US), Julian Adams (US), David P. Schenkein (US), and Kenneth C. Anderson (US) showed that Bortezomib (Velcade), a member of a new class of anticancer drugs that target the ubiquitin protein degradation system, was active in patients with relapsed multiple myeloma that was refractory to conventional chemotherapy (1232).

 

Ian M. Thompson (US), Phyllis J. Goodman (US), Catherine M. Tangen (US), M. Scott Lucia (US), Gary J. Miller (US), Leslie G. Ford (US), Michael M. Lieber (US), R. Duane Cespedes (US), James N. Atkins (US), Scott M. Lippman (US), Susie M. Carlin (US), Anne Ryan (US), et al. presented results of the National Cancer Institute's-sponsored Prostate Cancer Prevention Trial (PCPT) showing that the drug finasteride, which reduces the production of male hormones in the body, lowers a man's risk of prostate cancer by about 25%. Finasteride prevents or delays the appearance of prostate cancer, but this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer (1453).

 

Joseph Sriyal Malik Peiris (LK-CN), S.T. Lai (CN), Leo Lit Man Poon (CN), Yi Guan (CN), Loretta Y.C. Yam (CN), Wilina W.L. Lim (CN), John Malcolm Nicholls (CN), W.K.S. Yee (CN), Wing Wa Yan (CN), M.T. Cheung (CN), Vincent C.C. Cheng (CN), Kwok Hung Chan (CN), D.N.C. Tsang (CN), R.W.H. Yung (CN), T.K. Ng (CN), and Kwok Yung Yuen (CN) confirmed that a novel β coronavirus, serere acute respiratory syndrome coronavirus (SARS-CoV) of lineage B was the cause of the atypical pneumonia cases on March 22, 2003 in Hong Kong, China (1143). Note: Severe acute respiratory syndrome coronavirus (SARS-CoV), emerged from China and rapidly spread worldwide. Over 8098 people fell ill and 774 died before the epidemic ended in July 2003. Chinese horseshoe bats were found to carry SARS-like CoVs in 2005.

 

Attila A. Priplata (US), James B. Niemi (US), Jason D. Harry (US), Lewis A. Lipsitz (US), and James J. Collins (US) realizing that somatosensory function declines with age, and such changes have been associated with diminished motor performance tested noise-based devices, such as randomly vibrating insoles. These insoles were found to ameliorate age-related impairments in balance control (1185).

 

Timothy S. Gardner (US), Diego di Bernard (US), David Lorenz (US), and James J. Collins (US) used systematic transcriptional perturbations to construct a first-order model of regulatory interactions in a nine-gene subnetwork of the SOS pathway in Escherichia coli. The model correctly identified the major regulatory genes and the transcriptional targets of mitomycin C activity in the subnetwork. This approach, which is experimentally and computationally scalable, provides a framework for elucidating the functional properties of genetic networks and identifying molecular targets of pharmacological compounds (468).

Diego di Bernardo (IT-US), Michael J. Thompson (IT-US), Timothy S. Gardner (IT-US), Sarah E. Chobot (US), Erin L. Eastwood (US), Andrew P. Wojtovich (US), Sean J. Elliott (US), Scott E. Schaus (US), and James J. Collins (US) observed that a major challenge in drug discovery is to distinguish the molecular targets of a bioactive compound from the hundreds to thousands of additional gene products that respond indirectly to changes in the activity of the targets. Here, they presented an integrated computational-experimental approach for computing the likelihood that gene products and associated pathways are targets of a compound. This is achieved by filtering the mRNA expression profile of compound-exposed cells using a reverse-engineered model of the cell's gene regulatory network. They applied the method to a set of 515 whole-genome yeast expression profiles resulting from a variety of treatments (compounds, knockouts and induced expression), and correctly enrich for the known targets and associated pathways in the majority of compounds examined. They demonstrated their approach with PTSB, a growth inhibitory compound with a previously unknown mode of action, by predicting and validating thioredoxin and thioredoxin reductase as its target (120).

 

Jose M. Carmena (US), Mikhail A. Lebedev (US), Roy E. Crist (US), Joseph E. O'Doherty (US), David M. Santucci (US), Dragan F. Dimitrov (US), Parag G. Patil (US), Craig S. Henriquez (US), and Miguel A. L. Nicolelis (US) implanted electrodes in monkeys’ brains to control a robotic arm and pick up food. Monkeys succeeded in producing robot reach-and-grasp movements even when their arms did not move. Learning to operate the brain–machine interface was paralleled by functional reorganization in multiple cortical areas, suggesting that the dynamic properties of the brain–machine interface were incorporated into motor and sensory cortical representations (204). Note: In 2009, amputee Pierpaolo Petruzziello became the first person to make complex movements with a robotic limb, including wiggling a finger, grabbing objects, and making a fist, using just his thoughts through a biomechanical hand connected to his arm nerves with electrodes. This technology has progressed and become more widely used by amputees.

 

David Mahon (GB), Michael J.C. Rhodes (GB), Bart Decadt (GB), Andrew Hindmarsh (GB), Richard Lowndes (GB), Ian J. Beckingham (GB), Bonguk Koo (GB), and Robert G. Newcombe (GB) showed that laparoscopic Nissen fundoplication leads to significantly less acid exposure of the lower esophagus at 3 months and significantly greater improvements in both gastrointestinal and general well-being after 12 months compared with proton-pump inhibitor treatment (929).

Paulina Salminen (FI), Saija Hurme (FI), and Jari Ovaska (FI) confirmed in a fifteen-year study, greater patient satisfaction, fewer disrupted wraps, and fewer incisional hernias within the laproscopic group anti-reflux surgery (1276).

Joris A. Broeders (GB), David J. Roks (NL), Usama Ahmed Ali (NL), Werner A. Draaisma (NL), André J.P.M. Smout (NL), and Eric J. Hazebroek (NL) in their meta analyses found that esophageal acid exposure time and the prevalence of heartburn are higher after laproscopic anterior fundoplication than after laproscopic posterior fundoplication(166).

 

Patrick J. O'Dwyer (GB), Michael G. Serpell (GB), Keith Millar (GB), Caron Paterson Alan(GB), David L. Young (GB), Alan Hair (GB), Carol-Ann Courtney, (GB), Paul Horgan (GB), Sudhir Kumar (GB), Andrew Walker (GB), Ian Ford (GB), concluded that there are no differences in patient recovery after local anaesthesia or general anaesthesia hernia surgery (1094).

Pär Nordin (SE), Henrik Zetterström (SE), Ulf Gunnarsson (SE), and Erik Nilsson (SE) concluded that local anaesthesia had substantial advantages over general anaesthesia/regional anaesthesia (1087).

 

James D. Luketich (US), Miguel Alvelo-Rivera (US), Percival O. Buenaventura (US), Neil A. Christie (US), James S. McCaughan (US), Virginia R. Litle (US), Philip R. Schauer (US), John M. Close (US), Hiran C. Fernando (US), Cristiano G. S. Huscher (IT), Andrea Mingoli (IT), Giovanna Sgarzini (IT), Andrea Sansonetti (IT), Massimiliano Di Paola (IT), Achille Recher (IT), and Cecilia Ponzano (IT) suggested then confirmed that minimally invasive esophagectomy (laproscopic) could be safely performed (668; 910). Note: By 2009, 30% of all esophagectomies and 13% of all gastrectomies in the United Kingdom were performed by minimally invasive surgery (National Oesophago-Gastric Cancer Audit).

 

Petr Dite (CZ), Milos Ruzicka (CZ), Vladimir Zboril (CZ), Ivo Novotny (CZ), Djuna L. Cahen (NL), Dirk J. Gouma (NL), Yung Nio (NL), Erik A. J. Rauws (NL), Marja A. Boermeester (NL), Olivier R. Busch (NL), Jaap Stoker (NL),Johan S. Laméris (NL), Marcel G.W. Dijkgraaf (NL), Kees Huibregtse (NL),and Marco J. Bruno (NL) found that open surgery is superior to endoscopic intervention for long-term pain control in patients with painful obstructive chronic pancreatitis. Better selection of patients for endoscopy might maximize results, and because of its low degree of invasiveness it could be offered as a first-line treatment, reserving open surgery for failure or recurrence of symptoms (192; 341).

 

Stanisa Raspopovic (IT), Marco Capogrosso (IT), Francesco Maria Petrini (IT), Marco Bonizzato (CH), Jacopo Rigosa (IT), Giovanni Di Pino (IT), Jacopo Carpaneto (IT), Marco Controzzi (IT), Tim Boretius (DE), Eduardo Fernandez (IT), Giuseppe Granata (IT), Calogero Maria Oddo (IT), Luca Citi (GB), Anna Lisa Ciancio (IT), Christian Cipriani (IT), Maria Chiara Carrozza (IT), Winnie Jensen (DK), Eugenio Guglielmelli (IT), Thomas Stieglitz (DE),Paolo Maria Rossini (IT), and Silvestro Micera (IT) showed that by stimulating the median and ulnar nerve fascicles using transversal multichannel intrafascicular electrodes, according to the information provided by the artificial sensors from a hand prosthesis, physiologically appropriate (near-natural) sensory information can be provided to an amputee during the real-time decoding of different grasping tasks to control a dexterous hand prosthesis. This feedback enabled the participant to effectively modulate the grasping force of the prosthesis with no visual or auditory feedback. Three different force levels were distinguished and consistently used by the subject. The results also demonstrate that a high complexity of perception can be obtained, allowing the subject to identify the stiffness and shape of three different objects by exploiting different characteristics of the elicited sensations. This approach could improve the efficacy and “life-like” quality of hand prostheses, resulting in a keystone strategy for the near-natural replacement of missing hands (1211). Note: In 2014, the U.S. Food and Drug Administration approved the first prosthesis controlled by neural signals from the wearer’s brain for use by the general public. This is the culmination of almost two decades of biomedical research.

 

Richard O. Prum (US) supported Charles William Beebe's Tetrapteryx hypothesis by the discovery of Microraptor gui, a small feathered dinosaur which possessed asymmetrical flight feathers on both its front and hind limbs (1189).

 

Malcolm Lillie (UK), Michael P. Richards (UK), and Kenneth Jacobs (CA) analysed bone collagen extracted from 21 humans from the Epipalaeolithic cemetery of Vasilyevka III. This particular cemetery is one of the three early sites from the Dnieper Rapids region, Ukraine, with Vasilyevka III being dated to the period 10,400–9200 c. BCE on the basis of three radiocarbon determinations. Analyses provided insights into the nature of the diet of these populations during a stage of major restructuring of the landscapes in the European mainland (874).

 

Now, cancer genome sequencing is integrated into medical care facilities. It characterizes and identifies DNA or RNA sequences of cancer cells.

 

2004

"Choose your mentors well. The art of scientific research is not learned in books. It is, like the crafts in the Middle Ages, learned at the bench under the direction of a master. It has been my good fortune to work under and with a number of such masters, each of whom has taught the importance of technical excellence, rigorous reasoning, and intellectual honesty. …This self-evident yet rarely recognized truth that science, at least its spearhead called basic research, explores the unknown and is therefore unable, by definition, to predict how useful or profitable its discoveries will be. " Christian Rene de Duve (322).

 

Richard Axel (US) and Linda B. Buck (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries of odorant receptors and the organization of the olfactory system. They discovered there are hundreds of genes in our DNA code for the odorant sensors located in the olfactory sensory neurons in our noses. Each receptor is a protein that changes when an odorant attaches itself to the receptor. This causes an electric signal to be sent to the brain. Small differences between different odorant sensors mean that certain odorants cause a signal to be released from a certain receptor. Smells are composed of a large number of different substances and we interpret the varying signals from our receptors as specific scents.

 

Aaron Ciechanover (IL), Avram Hershko (IL), and Irwin Rose (US) were awarded the Nobel Prize in Chemistry for their discovery of ubiquitin-mediated protein degradation.

 

Philip Zimmermann (CH), Matthias Hirsch-Hoffmann (CH), Lars Henning (CH), and Wilhelm Gruissem (CH), developed Genevestigator, a suite of Web-based analysis tools that allow researchers to “rapidly find out in which tissues, at which stages of development, and to what stimuli, drug treatments, diseases, or genetic modifications genes of given organisms are activated” (1637).

Although initially centered on Arabidopsis, Genevestigator has been rereleased and now provides gene expression metaprofiles for not only plants (Arabidopsis, soybean, rice, barley) but also animals (mice, rats, humans) and microorganisms (yeast and Escherichia coli (657).

 

Initiation of The ENCyclopedia Of DNA Elements (ENCODE) Project which aims to identify all functional elements in the human genome sequence (274).

 

Yujiang Shi (US), Fei Lan (US), Caitlin Matson (US), Peter Mulligan (US), Johnathan R. Whetstine (US), Philip A. Cole (US), Robert A. Casero (US), and Yang Shi (US) provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. Lysine demethylation occurs via an oxidation reaction that generates formaldehyde. Importantly, RNAi inhibition of LSD1 causes an increase in H3 lysine 4 methylation and concomitant derepression of target genes, suggesting that LSD1 represses transcription via histone demethylation. The results thus identify a histone demethylase conserved from S. pombe to human and reveal dynamic regulation of histone methylation by both histone methylases and demethylases (1333).

 

Farren J. Isaacs (US), Daniel J. Dwyer (US), Chunming Ding (US), Dmitri D. Pervouchine (US), Charles R. Cantor (US), and James J. Collins (US) presented a post-transcriptional regulation system in Escherichia coli that uses RNA to both silence and activate gene expression. They inserted a complementary cis sequence directly upstream of the ribosome binding site in a target gene. Upon transcription, this cis-repressive sequence causes a stem-loop structure to form at the 5'-untranslated region of the mRNA. The stem-loop structure interferes with ribosome binding, silencing gene expression. A small noncoding RNA that is expressed in trans targets the cis-repressed RNA with high specificity, causing an alteration in the stem-loop structure that activates expression (684).

 

Hanno Hock (US), Melanie J. Hamblen (US), Heather M. Rooke (US), Jeffrey W. Schindler (US), Shireen Saleque (US), Yuko Fujiwara (US), and Stuart H. Orkin (US) identified the first regulatory molecule (Gfi-1) that puts the brakes on the proliferation of blood stem cells and also preserves the integrity of those stem cells, enabling them to produce functional blood cells over a long period of time (633).

 

Bert van den Berg (US), William M. Clemons Jr. (US), Ian Collinson (US), Yorgo Modis (US), Enno Hartmann (US), Stephen C. Harrison (US) and Tom A. Rapoport (US) discovered the architecture of the first transmembrane protein-conducting channel, paving the way for an understanding of how proteins are transferred. The crystal structure of the complex was from Methanococcus jannaschii at a resolution of 3.2 Å.(1499).

 

Darryl R. Overby (US), Francis J. Alenghat (US), Martín Montoya-Zavala (US), HuCheng Bei (US), Philmo Oh (US), John Karavitis (US), and Donald E. Ingber (US) developed magnetic cellular switches to enable magnetic control of intracellular functions in living mammalian cells, including receptor signal transduction and gene transcription. Their approach took advantage of the mechanosensitivity of adenosine 3',5'-monophosphate (cAMP) induction and downstream transcription controlled by the cAMP regulatory element (CRE) to engineer gene constructs that optically report gene expression in living cells (1112).

 

Zeev Pancer (US), Chris T. Amemiya (US), Götz R. A. Ehrhardt (US), Jill Ceitlin (US), G. Larry Gartland (US), and Max D. Cooper (US) discovered that different evolutionary strategies were used to generate highly diverse lymphocyte receptors through rearrangement of leucine-rich repeat (LRR) modules in agnathans (jawless fish) and of immunoglobulin gene segments in gnathostomes (jawed vertebrates) (1123).

 

Seth Rakoff-Nahoum (US), Justin Paglino (US), Fatima Eslami-Varzaneh (US), Stephen Edberg (US), and Ruslan Medzhitov (US) showed that commensal bacteria are recognized by toll-like receptors (TLRs) under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, they found that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions (1202).

 

Ali Canbay (US), Scott L. Friedman (US), and Gregory J. Gores (US) reported that apoptosis of damaged hepatocytes stimulates the fibrogenic actions of liver myofibroblasts (200).

Alessandro Casini (IT), Elisabetta Ceni (IT), Renata Salzano (IT), Paola Biondi (IT) (IT), Maurizio Parola (IT), Andrea Galli (IT), Marco Foschi (IT), Alessandra Caligiuri (IT), Massimo Pinzani (IT), and Calogero Surrenti (IT) showed that inflammatory cells, either lymphocytes or polymorphonuclear cells, activate hepatic stellate cells to secrete collagen (213).

Odette Viñas (ES), Ramón Bataller (ES), Pau Sancho‐Bru (ES), Pere Ginès (ES), Cristina Berenguer (ES), Carlos Enrich (ES), Josep M. Nicolás (ES), Guadalupe Ercilla (ES), Teresa Gallart (ES), Jordi Vives (ES), Vicente Arroyo (ES), and Juan Rodés (ES) found that activated hepatic stellate cells secrete inflammatory chemokines, express cell adhesion molecules, and modulate the activation of lymphocytes (1517).

Jacquelyn J. Maher (US) suggested a vicious circle in which inflammatory and fibrogenic cells stimulate each other is likely to occur (927).

 

Montserrat Arrasate (ES), Siddhartha Mitra (US), Erik S. Schweitzer (US), Mark R. Segal (US), and Steven Finkbeiner (US) showed, by survival analysis, that neurons in Huntington’s disease die in a time-independent fashion but one that is dependent on mutant huntingtin dose and polyglutamine expansion; many neurons die without forming an inclusion body. Rather, the amount of diffuse intracellular huntingtin predicts whether and when inclusion body formation or death will occur. Surprisingly, inclusion body formation predicts improved survival and leads to decreased levels of mutant huntingtin elsewhere in a neuron. Thus, inclusion body formation can function as a coping response to toxic mutant huntingtin (52).

 

Herbert Ira Hurwitz (US), Louis Fehrenbacher (US), William Novotny (US), Thomas Cartwright (US), John Hainsworth (US), William Heim (US), Jordan Berlin (US), Ari Baron (US), Susan Griffing (US), Eric Holmgren (US), Napoleone Ferrara (IT-US), Gwen Fyfe (US), Beth Rogers (US), Robert Ross (US), and Fairooz Kabbinavar (US) showed that the addition of bevacizumab (Avastin) to conventional fluorouracil-based combination chemotherapy resulted in improved survival in patients with metastatic colorectal cancer (667).

 

Peter S. Sebel (US), T. Andrew Bowdle (US), Mohamed M. Ghoneim (US), Ira J. Rampil (US), Roger E. Padilla (US), Tong Joo Gan (US), and Karen B. Domino (US) reported that the incidence of awareness-with-recall under general anesthesia in the United States is 1-2 cases per 1,000 patients (1313).

 

Harald Furnes (NO), Neil R. Banerjee (CA), Karlis Muehlenbachs (CA), Hubert Staudigel (US), and Maarten De Wit (NL) found tiny holes in volcanic glass. They suggested that microorganisms etched these tiny holes, c. 3.5 Ga (453).

 

Dina M. Fonseca (US), Nusha Keyghobadi (US), Colin A. Malcolm (US), Ceylan Mehmet (US), Francis Schaffner (US), Motoyoshi Mogi (US), Robert C. Fleischer (US), and Richard C. Wilkerson (US) reported that in the Old World, some mosquitoes in the Culex pipiens complex are excellent enzootic vectors of West Nile virus, circulating the virus among birds, whereas others bite mainly humans and other mammals. Here they show that, in northern Europe, such forms differing in behavior and physiology have unique microsatellite fingerprints with no evidence of gene flow between them, as would be expected from distinct species. In the United States, however, hybrids between these forms are ubiquitous. Such hybrids between human-biters and bird-biters may be the bridge vectors contributing to the unprecedented severity and range of the West Nile virus epidemic in North America (429).

 

Lars Sjöström (SE), Kristina Narbro (SE), C. David Sjöström (SE), Kristjan Karason (SE), Bo Larsson (SE), Hans Wedel (SE), Ted Lystig (SE), Marianne Sullivan (SE), Claude Bouchard (US), Björn Carlsson (SE), Calle Bengtsson (SE), Sven Dahlgren (SE), Anders Gummesson (SE), Peter Jacobson (SE), Jan Karlsson (SE), Anna-Karin Lindroos (GB), Hans Lönroth (SE), Ingmar Näslund (SE), Torsten Olbers (SE), Kaj Stenlöf (SE), Jarl Torgerson (SE), Göran Ågren (SE), Lena M.S. Carlsson (SE), and The Swedish Obese Subjects Study provided good evidence that bariatric surgery has a beneficial effect on diabetes, sleep apnea, joint pain and mobility, health-related quality of life, and survival(1349; 1350). Note: Bariatric refers to the branch of medicine that deals with the study and treatment of obesity.

 

James Hemphill Brown (US), James F. Gillooly (US), Andrew P. Allen (US), Van M. Savage (US), and Geoffrey B. West (US) developed a quantitative theory for how metabolic rate varies with body size and temperature. Metabolic theory predicts how metabolic rate, by setting the rates of resource uptake from the environment and resource allocation to survival, growth, and reproduction, controls ecological processes at all levels of organization from individuals to the biosphere(169) .

 

Rolf Sauer (DE), Heinz Becker (DE), Werner Hohenberger (DE), Claus Rödel (DE), Christian Wittekind (DE), Rainer Fietkau (DE), Peter Martus (DE), Jörg Tschmelitsch (DE), Eva Hager (DE), Clemens F. Hess (DE), Johann-H. Karstens (DE), Torsten Liersch (DE), Heinz Schmidberger (DE), Rudolf Raab (DE), and The German Rectal Cancer Study Group*, in their randomized controlled trial, found that pre-operative chemoradiotherapy results in improved local control in patients with T3/T4 rectal cancer compared with post-operative chemoradiotherapy (1282).

Mark S. Roh (US), Linda H. Colangelo (US), Michael J. O'Connell (US), Greg Yothers (US), Melvin Deutsch (US), Carmen J. Allegra (US), Morton S. Kahlenberg (US), Luis Baez-Diaz (US), Carol S. Ursiny (US), Nicholas J. Petrelli (US), and Norman Wolmark (US) , in their randomized controlled trial, found that administration of neoadjuvant radiotherapy and chemotherapy in patients with T3/T4 rectal cancer significantly reduces local recurrence, but does not significantly affect overall survival (1249).

 

Jamie R. Barwell (GB), Colin E. Davies (GB), Jane Deacona (GB), Kate Harvey (GB), Julia Minora (GB), Antonio Sassano (GB), Maxine Taylor (GB), Jenny Usher (GB), Clare Wakely (GB), Jonathan J. Earnshaw (GB), Brian P. Heather (GB), David C. Mitchell (GB), Mark R. Whyman (GB), and Keith R. Poskitt (GB) learned from a randomized controlled trial that surgical correction of superficial venous reflux reduces 12-month ulcer recurrence. Most patients with chronic venous ulceration will benefit from the addition of simple venous surgery (89).

 

Gabriella Pellegriti (IT), Claudia Scollo (IT), Gabriella Lumera (IT), Concetto Regalbuto (IT), Riccardo Vigneri (IT), Antonino Belfiore (IT), Jong-Lyel Roh (KR), Jin-Man Kim (KR), and Chan Il Park (KR) from single-institution retrospective cohart studies concluded that papillary thyroid microcarcinoma is associated with a high rate of central lymph node metastasis to ipsilateral and pre-tracheal nodes. The presence of lymph node metastases and bilateral disease are the strongest predictors for recurrent or persisting disease (1144; 1248).

 

Peter Brown (AU), Thomas Sutikna (AU), Mike J. Morwood (AU), Raden Pandji Soejono (ID), Jatmiko (?), E.Wahyu Saptomo (AU), and Rokus Awe Due (AU) discovered at Liang Bua on the island of Flores in Indonesia, the remains of an individual that would have stood about 3.5 feet (1.1 m) in height. Homo floresiensis ("Flores Man"; nicknamed "hobbit") is an extinct species in the genus Homo. Extensive stratigraphic and chronological work has pushed the dating of the most recent evidence of their existence back to 50 K B.C.E. (170).

 

2005

“By any objective measure, a gathering of Maurice Hilleman’s scientific peers would not fill a telephone booth.” Alan Dove (345).

 

"Experimentation is all-important here as an independent, rational (and therefore democratic) form of authority. And it is this, the authority of the experiment, the authority of the scientific method, independent of the status of the individual scientist, his proximity to God or to his king, and as revealed and reinforced via myriad technologies, which we can all share that underlies the modern world. The cumulative nature of science also makes it a far less fragile form of knowledge. This is what makes the experiment such an important idea. The scientific method, apart from its other attractions, is probably the purest form of democracy there is." Peter Watson (GB) (1552).

 

Barry James Marshall (AU) and John Robin Warren (AU) were awarded the Nobel Prize in Physiology or Medicine for their discovery of bacteria's role in peptic ulcer disease.

 

Elio A. Abbondanzieri (US), William J. Greenleaf (US), Joshua W. Shaevitz (US), Robert Landick (US), and Steven Michael Block (US) noted that during transcription, RNA polymerase (RNAP) moves processively along a DNA template, creating a complementary RNA. Here they present the development of an ultra-stable optical trapping system with ångström-level resolution, which was used to monitor transcriptional elongation by single molecules of Escherichia coli RNAP. By combining their results with quantitative gel analysis, they concluded that RNAP advances along DNA by a single base pair per nucleotide addition to the nascent RNA (8).

 

Thomas B.L. Kirkwood (GB) reveals that most biogerontologists would now agree that aging starts with molecular damage, leading to cell, tissue and ultimately organ dysfunction (765; 766).

Brendan A.I. Payne (GB), Patrick F. Chinnery (GB), Rebecca K. Lane (GB), Tyler Hilsabeck (GB), and Shane L. Rea (GB) report that heteroplasmy for deleterious mitochondrial DNA (mtDNA) can also arise in somatic tissues during development and in adulthood. It accumulates throughout life, and is thought to contribute to diseases of aging that include neurodegeneration, metabolic disorders, cancer, heart disease and sarcopenia (824; 1138). Note: cells carrying mtDNA of different genotypes is a condition known as heteroplasmy.

Nikolay P. Kandul (US), Ting Zhang (US), Bruce A. Hay (US), and Ming Guo (US) showed that an adult post-mitotic tissue can be cleansed of a deleterious genome, suggesting that therapeutic removal of mutant mtDNA can be achieved (733).

 

Kerstin Lindblad-Toh (SE-US), Claire M. Wade (US), Tarjei S. Mikkelsen (US), Elinor K. Karlsson (US), David B. Jaffe (US), Michael Kamal (US), Michele Clamp (US), Jean L. Chang (US), Edward J. Kulbokas, III (US), Michael C. Zody (US), Evan Mauceli (US), Xiaohui Xie (US), Matthew Breen (US), Robert K. Wayne (US), Elaine A. Ostrander (US), Chris P. Ponting (GB), Francis Galibert (FR), Douglas R. Smith (US), Pieter J. deJong (US), Ewen Kirkness (US), Pablo Alvarez (US), Tara Biagi (US), William Brockman (US), Jonathan Butler (US), Chee-Wye Chin (US), April Cook (US), James Cuff (US), Mark J. Daly (US), David DeCapri (US), Sante Gnerre (US), Manfred Grabherr (US), Manolis Kellis (US), Michael Kleber (US), Carolyne Bardeleben (US), Leo Goodstadt (GB), Andreas Heger (GB), Christophe Hitte (FR), Lisa Kim (US), Klaus-Peter Koepfli (US), Heidi G. Parker (US), John P. Pollinger (US), Stephen M. J. Searle (GB), Nathan B. Sutter (US), Rachael Thomas (US), Caleb Webber (GB), Jennifer Baldwin (US), Adal Abebe (US), Amr Abouelleil (US), Lynne Aftuck (US), Mostafa Ait-zahra (US), Tyler Aldredge (US), Nicole Allen (US), Peter An (US), Scott Anderson (US), Claudel Antoine (US), Harindra Arachchi (US), Ali Aslam (US), Laura Ayotte (US), Pasang Bachantsang (US), Andrew Barry (US), Tashi Bayul (US), Mostafa Benamara (US), Aaron Berlin (US), Daniel Bessette (US), Berta Blitshteyn (US), Toby Bloom (US), Jason Blye (US), Leonid Boguslavskiy (US), Claude Bonnet (US), Boris Boukhgalter (US), Adam Brown (US), Patrick Cahill (US), Nadia Calixte (US), Jody Camarata (US), Yama Cheshatsang (US), Jeffrey Chu (US), Mieke Citroen (US), Alville Collymore (US), Patrick Cooke (US), Tenzin Dawoe (US), Riza Daza (US), Karin Decktor (US), Stuart DeGray (US), Norbu Dhargay (US), Kimberly Dooley (US), Kathleen Dooley (US), Passang Dorje (US), Kunsang Dorjee (US), Lester Dorris (US), Noah Duffey (US), Alan Dupes (US), Osebhajajeme Egbiremolen (US), Richard Elong (US), Jill Falk (US), Abderrahim Farina (US), Susan Faro (US), Diallo Ferguson (US), Patricia Ferreira (US), Sheila Fisher (US), Mike FitzGerald (US), Karen Foley (US), Chelsea Foley (US), Alicia Franke (US), Dennis Friedrich (US), Diane Gage (US), Manuel Garber (US), Gary Gearin (US), Georgia Giannoukos (US), Tina Goode (US), Audra Goyette (US), Joseph Graham (US), Edward Grandbois (US), Kunsang Gyaltsen (US), Nabil Hafez (US), Daniel Hagopian (US), Birhane Hagos (US), Jennifer Hall (US), Claire Healy (US), Ryan Hegarty (US), Tracey Honan (US), Andrea Horn (US), Nathan Houde ( US), Leanne Hughes (US), Leigh Hunnicutt (US), M. Husby (US), Benjamin Jester (US), Charlien Jones (US), Asha Kamat (US), Ben Kanga (US), Cristyn Kells (US), Dmitry Khazanovich (US), Alix Chinh Kieu (US), Peter Kisner (US), Mayank Kumar (US), Krista Lance (US), Thomas Landers (US), Marcia Lara (US), William Lee (US), Jean-Pierre Leger (US), Niall Lennon (US), Lisa Leuper (US), Sarah LeVine (US), Jinlei Liu (US), Xiaohong Liu (US), Yeshi Lokyitsang (US), Tashi Lokyitsang (US), Annie Lui (US), Jan Macdonald (US), John Major (US), Richard Marabella (US), Kebede Maru (US), Charles Matthews (US), Susan McDonough (US), Teena Mehta( US), James Meldrim (US), Alexandre Melnikov (US), Louis Meneus (US), Atanas Mihalev (US), Tanya Mihova (US), Karen Miller (US), Rachel Mittelman (US), Valentine Mlenga (US), Leonidas Mulrain (US), Glen Munson (US), Adam Navidi (US), Jerome Naylor (US), Tuyen Nguyen (US), Nga Nguyen (US), Cindy Nguyen (US), Thu Nguyen (US), Robert Nicol (US), Nyima Norbu (US), Choe Norbu (US), Nathaniel Novod (US), Tenchoe Nyima (US), Peter Olandt (US), Barry O'Neill (US), Keith O'Neill (US), Sahal Osman (US), Lucien Oyono (US), Christopher Patti (US), Danielle Perrin (US), Pema Phunkhang (US), Fritz Pierre (US), Margaret Priest (US), Anthony Rachupka (US), Sujaa Raghuraman (US), Rayale Rameau (US), Verneda Ray (US), Christina Raymond (US), Filip Rege (US), Cecil Rise (US), Julie Rogers (US), Peter Rogov (US), Julie Sahalie (US), Sampath Settipalli (US), Theodore Sharpe (US), Terrance Shea (US), Mechele Sheehan (US), Ngawang Sherpa (US), Jianying Shi (US), Diana Shih (US), Jessie Sloan (US), Cherylyn Smith (US), Todd Sparrow (US), John Stalker (US), Nicole Stange-Thomann (US), Sharon Stavropoulos (US), Catherine Stone (US), Sabrina Stone (US), Sean Sykes (US), Pierre Tchuinga (US), Pema Tenzing (US), Senait Tesfaye (US), Dawa Thoulutsang (US), Yama Thoulutsang (US), Kerri Topham (US), Ira Topping (US), Tsamla Tsamla (US), Helen Vassiliev (US), Vijay Venkataraman (US), Andy Vo (US), Tsering Wangchuk (US), Tsering Wangdi (US), Michael Weiand (US), Jane Wilkinson (US), Adam Wilson (US), Shailendra Yadav (US), Shuli Yang (US), Xiaoping Yang (US), Geneva Young (US), Qing Yu (US), Joanne Zainoun (US), Lisa Zembek (US), Andrew Zimmer (US), and Eric Steven Lander (US), using the shotgun sequencing technique, determined the first complete DNA sequence of the dog genome (a female boxer). Domestic dogs vary wildly in appearance, yet their genomes are 99.85% similar. Much of the non-coding DNA in dogs is the same as that in humans, indicating that it is under strong natural selection (881).

 

Mark T. Ross (GB), Darren V. Grafham (GB), Alison J. Coffey (GB), Steven Scherer (US), Kirsten McLay (GB), Donna Muzny (US), Matthias Platzer (DE), Gareth R. Howell (GB), Christine Burrows (GB), Christine P. Bird (GB), Adam Frankish (GB), Frances L. Lovell (GB), Kevin L. Howe (GB), Jennifer L. Ashurst (GB), Robert S. Fulton (US), Ralf Sudbrak (DE), Gaiping Wen (DE), Matthew C. Jones (GB), Matthew E. Hurles (GB), T. Daniel Andrews (GB), Carol E. Scott (GB), Stephen Searle (GB), Juliane Ramser (DE), Adam Whittaker (GB), Rebecca Deadman (GB), Nigel P. Carter (GB), Sarah E. Hunt (GB), Rui Chen (US), Andrew Cree (US), Preethi Gunaratne (US), Paul Havlak (US), Anne Hodgson (US), Michael L. Metzker (US), Stephen Richards (US), Graham Scott (US), David Steffen (US), Erica Sodergren (US), David A. Wheeler (US), Kim C. Worley (US), Rachael Ainscough (GB), Kerrie D. Ambrose (GB), M. Ali Ansari-Lari (US), Swaroop Aradhya (US), Robert I. S. Ashwell (GB), Anne K. Babbage (GB), Claire L. Bagguley (GB), Andrea Ballabio (US), Ruby Banerjee (GB), Gary E. Barker (GB), Karen F. Barlow (GB), Ian P. Barrett (GB), Karen N. Bates (GB), David M. Beare (GB), Helen Beasley (GB), Oliver Beasley (GB), Alfred Beck (DE), Graeme Bethel (GB), Karin Blechschmidt (DE), Nicola Brady (GB), Sarah Bray-Allen (GB), Anne M. Bridgeman (GB), Andrew J. Brown (GB), Mary J. Brown (US), David Bonnin (US), Elspeth A. Bruford (GB), Christian Buhay (US), Paula Burch (US), Deborah Burford (GB), Joanne Burgess (GB), Wayne Burrill (GB), John Burton (GB), Jackie M. Bye (GB), Carol Carder (GB), Laura Carrel (US), Joseph Chako (US), Joanne C. Chapman (GB), Dean Chavez (US), Ellson Chen (US), Guan Chen (US), Yuan Chen (GB), Zhijian Chen (US), Craig Chinault (US), Alfredo Ciccodicola (IT), Sue Y. Clark (GB), Graham Clarke (GB), Chris M. Clee (GB), Sheila Clegg (GB), Kerstin Clerc-Blankenburg (US), Karen Clifford (GB), Vicky Cobley (GB), Charlotte G. Cole (GB), Jen S. Conquer (GB), Nicole Corby (GB), Richard E. Connor (GB), Robert David (US), Joy Davies (GB), Clay Davis (US), John Davis (GB), Oliver Delgado (US), Denise DeShazo (US), Pawandeep Dhami (GB), Yan Ding (US), Huyen Dinh (US), Steve Dodsworth (GB), Heather Draper (US), Shannon Dugan-Rocha (US), Andrew Dunham (GB), Matthew Dunn (GB), K. James Durbin (US), Ireena Dutta (GB), Tamsin Eades (GB), Matthew Ellwood (GB), Alexandra Emery-Cohen (US), Helen Errington (GB), Kathryn L. Evans (GB), Louisa Faulkner (GB), Fiona Francis (FR), John Frankland (GB), Audrey E. Fraser (GB), Petra Galgoczy (DE), James Gilbert (GB), Rachel Gill (US), Gernot Glöckner (DE), Simon G. Gregory (GB), Susan Gribble (GB), Coline Griffiths (GB), Russell Grocock (GB), Yanghong Gu (US), Rhian Gwilliam (GB), Cerissa Hamilton (US), Elizabeth A. Hart (GB), Alicia Hawes (US), Paul D. Heath (GB), Katja Heitmann (DE), Steffen Hennig (DE), Judith Hernandez (US), Bernd Hinzmann (DE), Sarah Ho (GB), Michael Hoffs (GB), Phillip J. Howden (GB), Elizabeth J. Huckle (GB), Jennifer Hume (US), Paul J. Hunt (GB), Adrienne R. Hunt (GB), Judith Isherwood (GB), Leni Jacob (US), David Johnson (GB), Sally Jones (US), Pieter J. de Jong (US), Shirin S. Joseph (GB), Stephen Keenan (GB), Susan Kelly (US), Joanne K. Kershaw (GB), Ziad Khan (US), Petra Kioschis (DE), Sven Klages (DE), Andrew J. Knights (GB), Anna Kosiura (DE), Christie Kovar-Smith (US), Gavin K. Laird (GB), Cordelia Langford (GB), Stephanie Lawlor (GB), Margaret Leversha (GB), Lora Lewis (US), Wen Liu (US), Christine Lloyd (GB), David M. Lloyd (GB), Hermela Loulseged (US), Jane E. Loveland (GB), Jamieson D. Lovell (GB), Ryan Lozado (US), Jing Lu (US), Rachael Lyne (GB), Jie Ma (US), Manjula Maheshwari (US), Lucy H. Matthews (GB), Jennifer McDowall (GB), Stuart McLaren (GB), Amanda McMurray (GB), Patrick Meidl (GB), Thomas Meitinger (DE), Sarah Milne (GB), George Miner (US), Shailesh L. Mistry (GB), Margaret Morgan (US), Sidney Morris (US), Ines Müller (DE), James C. Mullikin (US), Ngoc Nguyen (US), Gabriele Nordsiek (DE), Gerald Nyakatura (DE), Christopher N. O'Dell (GB), Geoffery Okwuonu (US), Sophie Palmer (GB), Richard Pandian (GB), David Parker (US), Julia Parrish (US), Shiran Pasternak (US), Dina Patel (GB), Alex V. Pearce (GB), Danita M. Pearson (GB), Sarah E. Pelan (GB), Lesette Perez (US), Keith M. Porter (GB), Yvonne Ramsey (GB), Kathrin Reichwald (DE), Susan Rhodes (GB), Kerry A. Ridler (GB), David Schlessinger (US), Mary G. Schueler (US), Harminder K. Sehra (GB), Charles Shaw-Smith (GB), Hua Shen (US), Elizabeth M. Sheridan (GB), Ratna Shownkeen (GB), Carl D. Skuce (GB), Michelle L. Smith (GB), Elizabeth C. Sotheran (GB), Helen E. Steingruber (GB), Charles A. Steward (GB), Roy Storey (GB), R. Mark Swann (GB), David Swarbreck (GB), Paul E. Tabor (US), Stefan Taudien (DE), Tineace Taylor (US), Brian Teague (US), Karen Thomas (GB), Andrea Thorpe (GB), Kirsten Timms (US), Alan Tracey (GB), Steve Trevanion (GB), Anthony C. Tromans (GB), Michele d'Urso (IT), Daniel Verduzco (US), Donna Villasana (US), Lenee Waldron (US), Melanie Wall (GB), Qiaoyan Wang (US), James Warren (US), Georgina L. Warry (GB), Xuehong Wei (US), Anthony West (GB), Siobhan L. Whitehead (GB), Mathew N. Whiteley (GB), Jane E. Wilkinson (GB), David L. Willey (GB), Gabrielle Williams (US), Leanne Williams (GB), Angela Williamson (US), Helen Williamson (GB), Laurens Wilming (GB), Rebecca L. Woodmansey (GB), Paul W. Wray (GB), Jennifer Yen (US), Jingkun Zhang (US), Jianling Zhou (US), Huda Y. Zoghbi (US), Sara Zorilla (US), David Buck (GB), Richard Reinhardt (DE), Annemarie Poustka (DE), André Rosenthal (DE), Hans Lehrach (DE), Alfons Meindl (DE), Patrick J. Minx (US), LaDeana W. Hillier (US), Huntington F. Willard (US), Richard K. Wilson (US), Robert H. Waterston (US), Catherine M. Rice (GB), Mark Vaudin (GB), Alan Coulson (GB), David L. Nelson (US), George Weinstock (US), John Edward Sulston (GB), Richard Durbin (GB), Tim Hubbard (GB), Richard A. Gibbs (US), Stephan Beck (GB), Jane Rogers (GB), and David R. Bentley (GB) determined the DNA base sequence of the human X chromosome (1255).

 

Stefan K. Hetz (DE) and Timothy J. Bradley (US) suggested that while oxygen is vital to an insect, too much can damage tissue. The opening and closing of spiracles is controlled in a way that exhales carbon dioxide as needed without inhaling too much oxygen (629).

 

Douglas R. Warrick (US), Bret W. Tobalske (US), and Donald R. Powers (US) published their research on the aerodynamics of the hovering hummingbird (1541).

 

Masayasu Kojima (JP), Hiroshi Hosoda (JP), Yukari Date (JP), Masamitsu Nakazato (JP), Hisayuki Matsuo (JP), and Kenji Kangawa (JP) discovered the endogenous ligand for growth-hormone secretagogue receptor (GHS-R). They purified it from the stomach and named it ghrelin, after the word root “ghre" in Proto-Indo-European languages meaning “grow", since ghrelin has potent growth hormone (GH) releasing activity. Ghrelin plays important roles for maintaining growth hormone release and energy homeostasis in vertebrates (788).

 

Allan Ming-Tak Wong (US) used the fruit fly, Drosophila melanogaster, as a model system to understand the principles of olfaction. He showed that the anatomical connectivity of the olfactory system is precise and allows for a spatial representation of odors in the antennal lobe and the protocerebrum (1589).

 

Eric Blackstone (US), Mike Morrison (US), and Mark B. Roth (US) reported that hydrogen sulfide can induce a suspended animation-like state in a nonhibernating species, the house mouse (Mus musculus). This state is readily reversible and does not appear to harm the animal. This suggests the possibility of inducing suspended animation-like states for medical applications. These states are all characterized by marked decreases in metabolic rate, followed by a loss of homeothermic control in which the animal's core body temperature approaches that of the environment (130).

 

Sara Calattini (FR), Sébastien Alain Chevalier (FR), Renan Duprez (FR), Sylviane Bassot (FR), Alain Froment (FR), Renaud Mahieux (FR), and Antoine Gessain (FR) discovered human lymphotropic viruses 3 and 4 (194; 928).

 

Eric M. Leroy (GA), Brice Kumulungui (GA), Xavier Pourrut (GA), Pierre Rouquet (GA), Alexandre Hassanin (GA), Philippe Yaba (GA), André Délicat (GA), Janusz T. Paweska (GA), Jean-Paul Gonzalez (GA), and Robert Swanepoel (ZA) found evidence of asymptomatic infection by Ebola virus in three species of fruit bat, indicating that these animals may be acting as a reservoir for this deadly virus (851). (GA)

Jonathan S. Towner (US), Xavier Pourrut (US), César G. Albariño (US), Chimène Nze Nkogue (US), Brian H. Bird (US), Gilda Grard (US), Thomas G. Ksiazek (US), Jean-Paul Gonzalez (GA-US), Stuart T. Nichol (US), and Eric M. Leroy (GA-US) reported the discovery of Marburg virus in a common species of fruit bat (Rousettus aegyptiacus) in Gabon as shown by finding virus-specific RNA and IgG antibody in individual bats. These Marburg virus positive bats represent the first naturally infected non-primate animals identified. Furthermore, this is the first report of Marburg virus being present in this area of Africa, thus extending the known range of the virus. These data imply that more areas are at risk for Marburg hemorrhagic fever outbreaks than previously realized (1471).

 

Terrence M. Tumpey (US), Christopher F. Basler (US), Patricia V. Aguilar (US), Hui Zeng (US), Alicia Solórzano (US), David E. Swayne (US), Nancy J. Cox (US), Jacqueline M. Katz (US), Jeffery K. Taubenberger (US), Peter Palese (US), and Adolfo García-Sastre (US) used reverse genetics to generate an influenza virus bearing all eight gene segments of the pandemic virus to study the properties associated with its extraordinary virulence. In stark contrast to contemporary human influenza H1N1 viruses, the 1918 pandemic virus had the ability to replicate in the absence of trypsin, caused death in mice and embryonated chicken eggs, and displayed a high-growth phenotype in human bronchial epithelial cells. Moreover, the coordinated expression of the 1918 virus genes most certainly confers the unique high-virulence phenotype observed with this pandemic virus (1480).

 

Takaji Wakita (JP), Thomas Pietschmann (JP), Takanobu Kato (JP), Tomoko Date (JP), Michiko Miyamoto (JP), Zijiang Zhao (JP), KrishnaMurthy (JP), Anja Habermann (JP), Hans-Georg Kräusslich (JP), Masashi Mizokami (JP), Ralf F.W.Bartenschlager (DE), and T. Jake Liang (JP) developed a hepatitis C virus infection system in culture cells using the JFH-1 strain. The full-length JFH-1 RNA was transfected into Huh7 cells. Subsequently, viral RNA efficiently replicated in transfected cells and viral particles were secreted. Furthermore, secreted virus displayed infectivity for naive Huh7 cells (739; 1528).

Brett D. Lindenbach (US), Matthew J. Evans (US), Andrew J. Syder (US), Benno Wölk (US), Timothy L. Tellinghuisen (US), Christopher C. Liu (US), Toshiaki Maruyama (US), Richard O. Hynes (US), Dennis R. Burton (US), Jane A. McKeating (US), and Charles M. Rice (US) obtained complete replication of hepatitis C virus in cell culture (882).

Michael J. Sofia (US), Donghui Bao (US), Wonsuk Chang (US), Jinfa Du (US), Dhanapalan Nagarathnam (US), Suguna Rachakonda (US), P. Ganapati Reddy (US), Bruce S. Ross (US), Peiyuan Wang (US), Hai-Ren Zhang (US), Shalini Bansal (US), Christine Espiritu (US), Megan Keilman (US), Angela M. Lam (US), Holly M. Micolochick Steuer (US), Congrong Niu (US), Michael J. Otto (US), and Phillip A. Furman (US) discovered β-ᴅ-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus (1370-1372).

 

Tobias Allander (SE), Martti Tammi (SE), Margareta Ericksson (CN), Annelie Bjerkner (SE), Annika Tiveijung-Lindell (SE), and Björn Andersson (SE) were the first to isolate the parvovirus, provisionally named human bocavirus (HBoV). It was detected in 17 patients who were part of a retrospective clinical study associated with infections of the lower respiratory tract in children (33).

 

Tsunemi Kubodera (JP) and Kyoichi Mori (JP) lowered a bait-laden video camera 900 metres under the sea and snapped around 50 images of the giant squid, Architeuthis in action. The footage showed the squid lunging, tentacles first, out of the gloom (808).

 

Bennet I. Omalu (NG-US), Steven T. DeKosky (US), Ryan L. Minster (US), M. Ilyas Kamboh (PK-US), Ronald L. Hamilton (US), and Cyril H. Wecht (US) reported on a patient who was a retired professional football player. He revealed neuropathological changes consistent with long-term repetitive concussive brain injury. The patient's premortem medical history included symptoms of cognitive impairment, a mood disorder, and parkinsonian symptoms.

Autopsy confirmed the presence of coronary atherosclerotic disease with dilated cardiomyopathy. The substantia nigra revealed mild pallor with mild dropout of pigmented neurons. There was mild neuronal dropout in the frontal, parietal, and temporal neocortex. Chronic traumatic encephalopathy was evident with many diffuse amyloid plaques as well as sparse neurofibrillary tangles and tau-positive neuritic threads in neocortical areas. The apolipoprotein E genotype was E3/E3. This case highlighted potential long-term neurodegenerative outcomes in retired professional National Football League players subjected to repeated mild traumatic brain injury (1108).

 

John W. Hamilton (GB) showed that ancillary use of the KTP (potassium titanyl phosphate) laser in cholesteatoma surgery is a treatment that significantly improves complete removal of disease (587).

Jameel Muzaffar (GB), Christopher Metcalfe (GB), Steve Colley (GB), and Chris Coulson (GB) reported that diffusion‐weighted MRI (magnetic resonance imaging) is both sensitive and specific for the detection of recurrent or residual cholesteatoma following ear surgery. Non‐EPI (non-echoplanar imaging) techniques are superior to EPI techniques (1043).

 

Lin He (US), J. Michael Thomson (US), Michael T. Hemann (US), Eva Hernando-Monge (US), David Mu (US), Summer Goodson (US), Scott Powers (US), Carlos Cordon-Cardo (US), Scott W. Lowe (US), Gregory J. Hannon (US), Scott M. Hammond (US), Jun Lu (US), Gad Getz (US), Eric A. Miska (US), Ezequiel Alvarez-Saavedra (US), Justin Lamb (US), David Peck (US), Alejandro Sweet-Cordero (US), Benjamin L. Ebert (US), Raymond H. Mak (US), Adolfo A. Ferrando (US), James R. Downing (US), Tyler Jacks (US), H. Robert Horvitz (US), Todd R. Golub (US), Marilena V. Iorio (US), Manuela Ferracin (US), Chang-Gong Liu (US), Angelo Veronese (US), Riccardo Spizzo (US), Silvia Sabbioni (US), Eros Magri (US), Massimo Pedriali (US), Muller Fabbri (US), Manuela Campiglio (US), Sylvie Menard (US), Juan P. Palazzo (US), Anne Rosenberg (US), Piero Musiani (US), Stefano Volinia (US), Italo Nenci (US), George A. Calin (US), Patrizia Querzoli (US), Massimo Negrini (US), Carlo M. Croce (US) presented work showing that small, non-coding RNAs may play a role in the development of cancer. This has challenged the long-standing belief that proteins were the principal functional products of the genome (610; 682; 905).

 

Hreinn Stefánsson (IS), Agnar Helgason (IS), Gudmar Thorleifsson (IS), Valgerdur Steinthorsdottir (IS), Gisli Masson (IS), John Barnard (IS), Adam Baker (IS), Aslaug Jonasdottir (IS), Andres Ingason (IS), Vala G. Gudnadottir (IS), Natasa Desnica (IS), Andrew Hicks (IS), Arnaldur Gylfason (IS), Daniel F. Gudbjartsson (IS), Gudrun M. Jonsdottir (IS), Jesus Sainz (IS), Kari Agnarsson (IS), Birgitta Birgisdottir (IS), Shyamali Ghosh (IS), Adalheidur Olafsdottir (IS), Jean-Baptiste Cazier (IS), Kristleifur Kristjansson (IS), Michael L. Frigge (IS), Thorgeir E Thorgeirsson (IS), Jeffrey R. Gulcher (IS), Augustine Kong (IS), and Kári Stefánsson (IS) showed that a large inversion on chromosome 17 is at present under positive evolutionary selection in European populations, with carriers having higher recombination and fertility rates than non-carriers (1394).

 

Josep C. Jimenez-Chillaron (US), Marcelino Hernandez-Valencia (US), Carolyn Reamer (US), Simon Fisher (US), Allison Joszi (US), Michael Hirshman (US), Aysin Oge (US), Shana Walrond (US), Roberta Przybyla (US), Carol Boozer (US), Laurie J. Goodyear (US), and Mary-Elizabeth Patti (US), using a murine model, showed that poor prenatal nutrition permanently damages the function of insulin-producing cells in the embryo’s pancreas, raising the risk that the offspring will later develop type 2 diabetes (708).

 

Piero Ruggenenti (IT), Annalisa Perna (IT), Giacomina Loriga (IT), Maria Ganeva (IT), Bogdan Ene-Iordache (IT), Marta Turturro (IT), Maria Lesti (IT), Elena Perticucci (IT), Ivan Nediyalkov Chakarski (IT), Daniela Leonardis (IT), Giovanni Garini (IT), Adalberto Sessa (IT), Carlo Basile (IT), Mirella Alpa (IT), Renzo Scanziani (IT), Gianbattista Sorba (IT), Carmine Zoccali (IT), Giuseppe Remuzzi (IT), and REIN-2 Study Group (IT) found that in patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown (1262).

 

John K. Ramage (GB), Albert H.G. Davies (GB), Joy E.S. Ardill (GB), Nigel Bax (GB), Martyn E. Caplin (GB), Ashley B. Grossman (GB), Robert E. Hawkins (GB), Anne Marie McNicol (GB), Nicholas Reed (GB), Robert Sutton (GB), Rajesh Thakker (GB), Simon J.B. Aylwin (GB), David J. Breen (GB), Keith E. Britton (GB), Keith D. Buchanan (GB), Pippa G. Corrie (GB), Alice Gillams (GB), Val Lewington (GB), David R. McCance (GB), Karim Meeran (GB), Anthony F. Watkinson (GB), and The UKNETwork for Neuroendocrine Tumours provided guidelines for the management of neuroendocrine tumors (1203).

 

Donald J. Adam (GB), Jonathan D. Beard (GB), Trevor Cleveland (GB), Jocelyn Bell (GB), Andrew W. Bradbury (GB), John F. Forbes (GB), F. Gerry Fowkes (GB), Ian Gillepsie (GB), Charles Vaughan Ruckley (GB), Gillian Raab (GB), Helen R. Storkey (GB), and The Basil Trial Participants found that in patients presenting with severe limb ischaemia due to infra-inguinal disease and who are suitable for surgery and angioplasty, a bypass-surgery-first and a balloon-angioplasty-first strategy are associated with broadly similar outcomes in terms of amputation-free survival, and in the short-term, surgery is more expensive than angioplasty (12).

 

2006

"For every breakthrough identified with an individual, there are her or his many colleagues, coworkers, staff and assistants— the person who developed the technological step that allowed the research to go forward, the statistician who showed that the work was relevant, the secretarial and administrative staff who kept the absent-minded professors free to pursue their scientific goals, and especially their colleagues, who provided a support system and added ideas and information that allowed them to go forward." T. Jock Murray (1042).

 

"The stirring or animating power of music entails emotional no less than motor arousal. We turn to music, we need it, because of its ability to move us, to induce feelings and moods, states of mind. Therapeutically, this power can be very striking in people with autism or frontal lobe syndromes, who may otherwise have little access to strong emotional states. And the evocative power of music can also be of immense value in people with Alzheimer's disease or other dementias, who may have become unable to understand or respond to language, but can still be profoundly moved—and often regain their cognitive focus, at least for a while—when exposed to music, especially familiar music that may evoke for them memories of earlier events, encounters or states of mind that cannot be called up in any other way. Music may bring them back briefly to a time when the world was much richer for them." Oliver W. Sacks (1267).

 

Andrew Zachary Fire (US) and Craig Cameron Mello (US) were awarded the Nobel Prize in Physiology or Medicine for their discovery of RNA interference—gene silencng by double-stranded RNA.

 

Roger D. Kornberg (US) was awarded the Nobel Prize in Chemistry for work on the molecular basis of eukaryotic transcription.

 

Gregory J. Porreca (US), Jay Shendure (US), and George M. Church (US) developed "polony DNA sequencing" that provides an inexpensive, accurate, high-throughput way to resequence genomes of interest by comparison to a reference genome. Mate-paired in vitro shotgun genomic libraries are produced and clonally amplified on microbeads by emulsion PCR. These serve as templates for sequencing by fluorescent nonamer ligation reactions on a microscope slide. Each sequencing run results in millions of 26-bp reads that can be aligned to the reference genome, allowing the identification of differences between sequences (1176).

 

Ivaylo I. Ivanov (US), Brent S. McKenzie (US), Liang Zhou (US), Carlos E. Tadokoro (US), Alice Lepelley (US), Juan J. Lafaille (US), Daniel J. Cua (US), and Dan R. Littman (US) show here that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage. RORgammat induces transcription of the genes encoding IL-17 and the related cytokine IL-17F in naïve CD4(+) T helper cells and is required for their expression in response to IL-6 and TGF-beta, the cytokines known to induce IL-17. Their studies suggest that RORgammat is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases (690). Note: IL-17-producing T lymphocytes have been recently shown to comprise a distinct lineage of proinflammatory T helper cells, termed Th17 cells, that are major contributors to autoimmune disease.

 

Richard A. Morgan (US), Mark E. Dudley (US), John R. Wunderlich (US), Marybeth S. Hughes (US), James C. Yang (US), Richard M. Sherry (US), Richard E. Royal (US), Suzanne L. Topalian (US), Udai S. Kammula (US), Nicholas P. Restifo (US), Zhili Zheng (US), Azam Nahvi (US), Christiaan R. de Vries (US), Linda J. Rogers-Freezer (US), Sharon A. Mavroukakis (US), Steven A. Rosenberg (US) reported the ability to specifically confer recognition of metastatic melanoma by autologous lymphocytes from peripheral blood by using a retrovirus to encode a T cell receptor. In the clinic they accomplished cancer regression in patients after transfer of genetically engineered lymphocytes (1017).

Els M. E. Verdegaal (NL), Noel F. C. C. de Miranda (NL), Marten Visser (NL), Tom Harryvan (NL), Marit M. van Buuren (NL), Rikke S. Andersen (DK), Sine R. Hadrup (DK), Caroline E. van der Minne (NL), Remko Schotte (NL), Hergen Spits (NL), John B. A. G. Haanen (NL), Ellen H. W. Kapiteijn (NL), Ton N. Schumacher (NL), and Sjoerd H. van der Burg (NL) demonstrated that tumor-infiltrating lymphocytes can target neoantigens in melanoma thus providing evidence for the rationale of using tumor-infiltrating lymphocyte therapy (1511).

 

Kazutoshi Takahashi (JP) and Shinya Yamanaka (JP) established for the first time murine embryonic stem (ES)-like cell lines from mouse embryonic fibroblasts (MEFs) and skin fibroblasts by simply expressing four transcription factor genes encoding Oct4, Sox2, Klf4, and c-Myc. They called these somatic cell-derived cell lines induced pluripotent stem (iPS) cells. These iPS cell lines exhibit similar morphology and growth properties as ES cells and express ES cell-specific genes. Transplantation of iPS cells into immunodeficient mice resulted in the formation of germ-cell-tumor (teratoma)-containing tissues from all three germ layers, confirming the pluripotent potential of iPS cells (1433).

Kazutoshi Takahashi (JP), Koji Tanabe (JP), Mari Ohnuki (JP), Megumi Narita (JP), Tomoko Ichisaka (JP), Kiichiro Tomoda (JP), and Shinya Yamanaka (JP) showed that their mouse technique works with human cells as well. They used a retrovirus to ferry into adult cells the same four genes they had previously used to reprogram mouse cells: OCT3/4, SOX2, KLF4, and c-MYC. They reprogrammed cells taken from the facial skin of a 36-year-old woman and from connective tissue from a 69-year-old man (1432).

Junying Yu (US), Maxim A. Vodyanik (US), Kim Smuga-Otto (US), Jessica Antosiewicz-Bourget (US), Jennifer L. Frane (US), Shulan Tian (US), Jeff Nie (US), Gudrun A. Jonsdottir (US), Victor Ruotti (US), Ron Stewart (US), Igor I. Slukvin (US), and James A. Thomson (US) started from scratch, identifying a list of 14 candidate reprogramming genes. Like Yamanaka's group, the team used a systematic process of elimination to identify four factors: OCT3 and SOX2, as Yamanaka used, and two different genes, NANOG and LIN28. They successfully reprogrammed human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem (ES) cells (1617).

 

Napoleone Ferrara (IT-US), Lisa Damico (US), Naveed Shams (US), Henry Lowman (US), and Robert Kim (US) showed that ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, is therapy for wet neovascular age-related macular degeneration. It improves sight in many patients after a year of monthly injections; its effects persisted through the second year of the study (406).

 

J. Scott Weese (CA), Hani L.N. Dick (CA), Barbara M. Willey (CA), Allison McGreer (CA), Barry N. Kreiswirth (US), B.L.Innis (US), and Donald E. Low (CA) demonstrated transmission of methicillin resistant Staphylococcus aureus (MRSA) between humans and animals, in both directions. MRSA appears to be an emerging veterinary and zoonotic pathogen (1556).

 

John S. Mattick (AU) and Igor V. Makunin (AU) explained that the term non-coding RNA (ncRNA) is commonly employed for RNA that does not encode a protein, but this does not mean that such RNAs do not contain information nor have function. Although it has been generally assumed that most genetic information is transacted by proteins, recent evidence suggests that the majority of the genomes of mammals and other complex organisms is in fact transcribed into ncRNAs, many of which are alternatively spliced and/or processed into smaller products. These ncRNAs include microRNAs and snoRNAs (many if not most of which remain to be identified), as well as likely other classes of yet-to-be-discovered small regulatory RNAs, and tens of thousands of longer transcripts (including complex patterns of interlacing and overlapping sense and antisense transcripts), most of whose functions are unknown. These RNAs (including those derived from introns) appear to comprise a hidden layer of internal signals that control various levels of gene expression in physiology and development, including chromatin architecture/epigenetic memory, transcription, RNA splicing, editing, translation and turnover. RNA regulatory networks may determine most of our complex characteristics, play a significant role in disease and constitute an unexplored world of genetic variation both within and between species (957).

Kerstin Lindblad-Toh (SE-US), Manuel Garber (US), Or Zuk (US), Michael F. Lin (US), Brian J. Parker (DK), Stefan Washietl (US), Pouya Kheradpour (US), Jason Ernst (US), Gregory Jordan (GB), Evan Mauceli (US), Lucas D. Ward (US), Craig B. Lowe (US), Alisha K. Holloway (US), Michele Clamp (US), Sante Gnerre (US), Jessica Alföldi (US), Kathryn Beal (GB), Jean Chang (US), Hiram Clawson (US), James Cuff (US), Federica Di Palma (US), Stephen Fitzgerald (GB), Paul Flicek (GB) (US), Mitchell Guttman (US), Melissa J. Hubisz (US), David B. Jaffe (US), Irwin Jungreis (US), W. James Kent (US), Dennis Kostka (US), Marcia Lara (US), Andre L. Martins (US), Tim Massingham (GB), Ida Moltke (DK), Brian J. Raney (US), Matthew D. Rasmussen (US), Jim Robinson (US), Alexander Stark (AT), Albert J. Vilella (GB), Jiayu Wen (GB), Xiaohui Xie (US), Michael C. Zody (US), Broad Institute Sequencing Platform and Whole Genome Assembly Team (US), Kim C. Worley (US), Christie L. Kovar (US), Donna M. Muzny (US), Richard A. Gibbs (US), Baylor College of Medicine Human Genome Sequencing Center Sequencing Team (US), Wesley C. Warren (US), Elaine R. Mardis (US), George M. Weinstock (US), Richard K. Wilson (US), Genome Institute at Washington University (US), Ewan Birney (GB), Elliott H. Margulies (US), Javier Herrero (GB), Eric D. Green (US), David Haussler (US), Adam Siepel (US), Nick Goldman (GB), Katherine S. Pollard (US), Jakob S. Pedersen (DK), Eric S. Lander (US), and Manolis Kellis (US) reported the sequencing and comparative analysis of 29 eutherian genomes. They confirmed that at least 5.5% of the human genome has undergone purifying selection, and located constrained elements covering ∼4.2% of the genome. They used evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. They found 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. They reported specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that their findings will be relevant for studies of human biology, health and disease (880).

The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled assigning biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provided new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research (277).

 

Lee Siggens (SE) and Karl Ekwall (SE) emphasized that the organization of the genome into functional units, such as enhancers and active or repressed promoters, was associated with distinct patterns of DNA and histone modifications. The Encyclopedia of DNA Elements (ENCODE) project advanced our understanding of the principles of genome, epigenome and chromatin organization, identifying hundreds of thousands of potential regulatory regions and transcription factor binding sites. Part of the ENCODE consortium, GENCODE, has annotated the human genome with novel transcripts including new noncoding RNAs and pseudogenes, highlighting transcriptional complexity. Many disease variants identified in genome-wide association studies are located within putative enhancer regions defined by the ENCODE project (1342).

 

Susan L. Fink (US) and Brad T. Cookson (US) demonstrated DNA cleavage during pyroptosis results from caspase-1-stimulated nuclease activity (415). Note: Salmonella enterica serovar Typhimurium invades host macrophages and induces a unique caspase-1-dependent pathway of cell death termed pyroptosis, which is activated during bacterial infection in vivo.

 

Colin N.A. Palmer (GB), Alan D. Irvine (GB), Ana Terron-Kwiatkowski (GB), Yiwei Zhao (GB), Haihui Liao (GB), Simon P. Lee (GB), David R. Goudie (GB), Aileen Sandilands (GB), Linda E. Campbell (GB), Frances J.D. Smith (GB), Gráinne M. O'Regan (GB), Rosemarie M. Watson (GB), Jo E. Cecil (GB), Sherri J. Bale (US), John G. Compton (US), John J. DiGiovanna (US), Philip Fleckman (US), Sue Lewis-Jones (GB), Gehan Arseculeratne (GB), Ann Sergeant (GB), Colin S. Munro (GB), Brahim El Houate (FR), Ken McElreavey (FR), Liselotte B. Halkjaer (DK), Hans Bisgaard (DK), Somnath Mukhopadhyay (GB), and W.H Irwin McLean (GB) unravelled the genetic component of atopic disease (atopic dermatitis, eczema, allergy, and asthma). The identification of 2 common polymorphisms associated with atopic disease signifies the single most significant breakthrough in understanding the genetic aspects involved in the complex etiology of this very common disease (1122).

Frances J.D. Smith (GB), Alan D. Irvine (GB), Ana Terron-Kwiatkowski (GB), Aileen Sandilands (GB), Linda E. Campbell (GB), Yiwei Zhao (GB), Haihui Liao (GB), Alan T. Evans (GB), David R. Goudie (GB), Sue Lewis-Jones (GB), Gehan Arseculeratne (GB), Colin S. Munro (GB), Ann Sergeant (US), Gráinne M. O'Regan (GB), Sherri J. Bale (US), John G. Compton (US), John J. DiGiovanna (US), Richard B. Presland (US), Philip Fleckman (US), and W.H. Irwin McLean (GB) found that the loss-of-function mutation in the filaggrin (filament-aggregating protein) gene is also central to the pathogenesis of ichthyosis vulgaris, the most commonly inherited disorder of keratinization, which is highly prevalent and typified by excessively dry skin and an associated fine white scale (1362).

Sara J. Brown (GB) and Alan D. Irvine (GB) found that the filaggrin protein plays a key role in maintaining the mechanical integrity of the skin, providing a permeability barrier to water and allergens, and imparting natural cutaneous hydration. Its deficiency, at least in part, helps to explain the dryness and inflammation characteristic of atopic disease (171).

Aileen Sandilands (GB), Calum Sutherland (GB), Alan D. Irvine (GB), and W.H. Irwin McLean (GB) reported that null mutations in the filaggrin (filament-aggregating protein) gene lead to epidermal barrier dysfunction. The filaggrin protein assists in the formation of a cornified cell envelope during terminal epidermal differentiation (1278).

David P. Kelsell (GB), Elizabeth E. Norgett (GB), Harriet Unsworth (GB), Muy-Teck The (GB), Thomas Cullup (GB), Charles A. Mein (GB), Patricia J. Dopping-Hepenstal (GB), Beverly A. Dale (US), Gianluca Tadini (IT), Philip Fleckman (US), Karen G. Stephens (US), Virginia P. Sybert (US), Susan B. Mallory (US), Bernard V. North (GB), David R. Witt (US), Eli Sprecher (IE), Aileen E. M. Taylor (GB), Andrew Ilchyshyn (GB), Cameron T. Kennedy (GB), Helen Goodyear (GB), Celia Moss (GB), David Paige (GB), John I. Harper (GB), Bryan D. Young (GB), Irene M. Leigh (GB), Robin A. J. Eady (GB), and Edel A. O’Toole (GB) found that mutations in the human ABCA12 gene underlies the severe congenital skin disease harlequin ichthyosis (750).

Diana C. Blaydon (GB), Daniela Nitoiu (GB), Katja-Martina Eckl (DE), Rita M. Cabral (GB), Philip Bland (GB), Ingrid Hausser (DE), David A. van Heel (GB), Shefali Rajpopat (GB), Judith Fischer (DE), Vinzenz Oji (DE), Alex Zvulunov (IE), Heiko Traupe (DE), Hans Christian Hennies (DE), and David P. Kelsell (GB) reported that mutations in the CSTA gene, encoding cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion (136).

Zhimiao Lin (CN), Quan Chen (CN), Mingyang Lee (CN), Xu Cao (CN), Jie Zhang (CN), Donglai Ma (CN), Long Chen (CN), Xiaoping Hu (CN), Huijun Wang (CN), Xiaowen Wang (CN), Peng Zhang (CN), Xuanzhu Liu (CN), Liping Guan (CN), Yiquan Tang (CN), Haizhen Yang (CN), Ping Tu (CN), Dingfang Bu (CN), Xuejun Zhu (CN), KeWei Wang (CN), Ruoyu Li (CN), and Yong Yang (CN) used exome sequencing to reveal mutations in the TRPV3 gene as a cause of Olmsted syndrome (879). Note: Olmsted syndrome is a keratoderma of the palms and soles, with flexion deformity of the digits, that begins in infancy.

 

Laura M. Speck (US) and Stephen K. Tyring (US) reported that the Food and Drug Administration (FDA) approved the human papilloma virus (HPV) vaccine Gardasil, which protects against infection by the two types of HPV that cause approximately 70% of all cases of cervical cancer. The National Cancer Institute scientists developed the underlying technology used to make Gardasil (1381).

The Centers for Disease Control and Prevention (CDC) reported that the Food and Drug Administration (FDA) approved Cervarix, a second vaccine that protects against infection by the two types of the human papilloma virus (HPV) that cause approximately 70% of all cases of cervical cancer worldwide. The National Cancer Institute scientists developed the underlying technology used to make Cervarix (1183).

 

Victor G.Vogel (US), Joseph P. Constantino (US), D. Lawrence Wickerham (US), Walter M. Cronin (US), Reena S. Cecchini (US), James N. Atkins (US), Therese B. Bevers (US), Louis Fehrenbacher (US), Eduardo R. Pajon, Jr. (US), James L. Wade, 3rd. (US), André Robidoux (CA), Richard G. Margolese (CA), Joan James (US), Scott M. Lippman (US), Carolyn D. Runowicz (US), Patricia A. Ganz (US), Steven E. Reis (US), Worta McCaskill-Stevens (US), Leslie G. Ford (US), V. Craig Jordan (US), and Norman Wolmark (US) presented results of the National Cancer Institute's Study of Tamoxifen and Raloxifene (STAR) showing that postmenopausal women at increased risk of breast cancer can reduce their risk of developing the disease if they take the antiestrogen drug raloxifene. The risk of serious side effects is lower with raloxifene than with tamoxifen (1522).

 

Gustavo Hadad (AR), Luis Bassagasteguy (AR), Ricardo L. Carrau (AR), Juan C. Mataza (AR), Amin Kassam (AR), Carl H. Snyderman (AR), and Arlan Mintz (AR) found that the Hadad-Bassagasteguy flap (HBF) is a versatile and reliable reconstructive technique for defects of the anterior, middle, clival, and parasellar skull base. Its use has resulted in a sharp decrease in the incidence of postoperative cerebrospinal fluid leaks after endonasal skull base surgery and is recommended for the reconstruction of large dural defects and when postoperative radiation therapy is anticipated (573).

 

Andrew S. Levey (US), Josef Coresh (US), Tom Greene (US), Lesley A. Stevens (US), Yaping Lucy Zhang (US), Stephen Hendriksen (US), John W. Kusek (US), and Frederick Van Lente (US) concluded that the 4-variable modification of diet in renal disease (MDRD) study equation provides reasonably accurate glomerular filtration rate (GFR) estimates in patients with chronic kidney disease and a measured GFR of less than 90 mL/min per 1.73 m2. By using the reexpressed MDRD Study equation with the standardized serum creatinine assay, clinical laboratories can report more accurate GFR estimates (853).

 

Risto Kerkelä (US), Luanda Grazette (US), Rinat Yacobi (US), Cezar Iliescu (US), Richard Patten (US), Cara Beahm (US), Brian Walters (US), Sergei Shevtsov (US), Stéphanie Pesant (US), Fred J. Clubb (US), Anthony Rosenzweig (US), Robert N. Salomon (US), Richard A. Van Etten (US), Joseph Alroy (US), Jean-Bernard Durand (US), and Thomas Force (US) provided the first study to raise the issue of the toxic effects of clinically relevant protein kinase inhibitors on the heart(753).

 

The United States Food and Drug Administration licensed a quadrivalent human papillomavirus (HPV) vaccine for use in 2006. The vaccine protects against the two most prevalent cancer-causing HPVs and two wart-causing strains. HPVs cause almost all cervical cancers, and they can also cause anal and head and neck cancers in males and females, vaginal cancers, and penile cancers. A nine-valent vaccine would be licensed in 2014 and recommended in 2015 (988).

 

Robert J. Fitzgibbons, Jr. (US), Anita Giobbie-Hurder (US), James O. Gibbs (US), Dorothy D. Dunlop (US), Domenic J. Reda (US), Martin McCarthy, Jr. (US), Leigh A. Neumayer (US), Jeffrey S. T. Barkun (US), James L. Hoehn (US), Joseph T. Murphy (US), George A. Sarosi Jr. (US), William C. Syme (US), Jon S. Thompson (US), Jia Wang (US), and Olga Jonasson (US) concluded that observation only is a reasonable option for men with an asymptomatic hernia because of the low risk of acute strangulation (422).

Lucia Chung (GB), John Norrie (GB), and Patrick J. O’Dwyer (GB) concluded from their study that the majority of asymptomatic hernias develop pain over time, and therefore surgical intervention is recommended (255).

 

Niels F. M. Kok (NL), May Y. Lind (NL), Birgitta M. E. Hansson (NL), Desiree Pilzecker (NL), Ingrid R. A. M. Mertens zur Borg (NL), Ben C. Knipscheer (NL), Eric J. Hazebroek (NL), Ine M. Dooper (NL), Willem Weimar (NL), Wim C. J. Hop (NL), Eddy M. M. Adang (NL), Gert Jan van der Wilt (NL), Hendrik J. Bonjer (NL), Jordanus A. van der Vliet (NL), and Jan N. M. IJzermans (NL), from their single-blind randomized controlled trial, determined that laparoscopic donor nephrectomy results in a better quality of life compared with mini incision open donor nephrectomy but equal safety and graft function (789).

 

André D'Hoore (BE) and Freddy Penninckx (BE) showed that laproscopic ventral mesh rectopexy is an acceptable approach to full-thickness rectal prolapse and may have fewer functional side effects than other techniques (308).

 

Suresh T. Chari (US), Thomas C. Smyrk (US), Michael J. Levy (US), Mark D. Topazian (US), Naoki Takahashi (US), Lizhi Zhang (US), Jonathan E. Clain (US), Randall K. Pearson (US), Bret T. Petersen (US), Santhi Swaroop Vege (US), and Michael B. Farnell (US) proposed criteria to reflect the current understanding of autoimmune pancreatitis as a systemic steroid-response disorder characterized by tissue infiltration with IgG4-positive cells. They identify a wider spectrum of manifestations than the Japanese criteria (229).

 

Masao Tanaka (JP), Suresh Chari (JP), Volkan Adsay (JP), Carlos Fernandez-del Castillo (JP), Massimo Falconi (JP), Michio Shimizu (JP), Koji Yamaguchi (JP), Kenji Yamao (JP), Seiki Matsuno (JP), and The International Association of Pancreatology recommended that all patients with main-duct intraductal papillary mucinous neoplasms within the pancreas should undergo resection (1437).

J. Ruben Rodriguez (US), Roberto Salvia (US), Stefano Crippa (US), Andrew L. Warshaw (US), Claudio Bassi (US), Massimo Falconi (US), Sarah P. Thayer (US), Gregory Y. Lauwers (US), Paola Capelli (US), Mari Mino-Kenudson (US), Oswaldo Razo (US), Deborah McGrath (US), Paolo Pederzoli (US), and Carlos Fernández-Del Castillo (US), from multicenter data, recommended resection of all main-duct and mixed-variant intraductal papillary mucinous neoplasms if the patient was a good surgical candidate with reasonable life expectancy (1246).

 

The U.S. Advisory Committee on Immunization Practices (ACIP) recommended routine hepatitis-A vaccination of all children older than age 1 in a two-dose schedule (988).

 

The U.S. Advisory Committee on Immunization Practices recommended routine infant immunization with three doses of the recently licensed Rotavirus Vaccine, Live, Oral, Pentavalent (tradename RotaTeq), developed by H. Fred Clark (US), Paul A. Offit (US), Stanley A. Plotkin (US), and Penny M. Heaton (US) (260; 988).

The Food and Drug Administration licensed another rotavirus vaccine, Rotarix, for use in the United States (673; 988). Note: Worldwide, rotavirus continues to take a toll. More than 500,000 children under age 5 die each year from rotavirus illness.

 

Edward B. Daeschler (US), Neil H. Shubin (US), and Farish A. Jenkins (US) unearthed a fossil they named "Tiktaalik" on Ellesmere Island in the Arctic region of Canada. It is a monospecific genus of extinct sarcopterygian (lobe-finned fish) from the Late Devonian Period, about 375 Ma (million years ago), having many features akin to those of tetrapods (four-legged animals). It is technically a fish, complete with scales and gills - but it has the flattened head of a crocodile and unusual fins. Its fins have thin ray bones for paddling like most fish, but they also have sturdy interior bones that would have allowed "Tiktaalik" to prop itself up in shallow water and use its limbs for support as most four-legged animals do. Those fins and a suite of other characteristics set "Tiktaalik" apart as something special; it has a combination of features that show the evolutionary transition between swimming fish and their descendants, the four-legged vertebrates - a clade which includes amphibians, reptiles, birds and mammals (309). Note: The name "Tiktaalik" is an Inuktitut word meaning "large freshwater fish."

 

Xing Xu (CN) suggested that recent discoveries of feathered dinosaurs from Early Cretaceous deposits in Liaoning, China, have not only lent strongest support for the dinosaurian hypothesis of bird origins, but have also provided much‐needed information about the origins of feathers and avian flight. Preliminary analysis of character evolution suggests that the major avian osteological characters were acquired during the early evolution of maniraptoran dinosaurs. The available evidence also suggests that the first feathers with a filamentous morphology probably evolved in basal coelurosaurs and pennaceous feathers (including those with aerodynamic features) were developed in non‐avian maniraptorans, indicating that feathers evolved before the origin of birds and their flight (1604).

 

2007

“The first great achievement of analytical organic chemistry in the nineteenth century was the isolation of active principles of plants, including morphine from opium and quinine from cinchona bark, and their characterization as members of a new chemical class, the alkaloids.” John E. Lesch (852).

 

Mario Renato Capecchi (IT-US), Martin John Evans (GB), and Oliver Smithies (US) were awarded the Nobel Prize in Physiology or Medicine for their discovery of principles for introducing specific gene modifications into mice using embryonic stem cells.

 

John L. Rinn (US), Michael Kertesz (US), Jordon K. Wang (US), Sharon L. Squazzo (US), Xiao Xu (US), Samantha A. Brugmann (US), L. Henry Goodnough (US), Jill A. Helms (US), Peggy J. Farnham (US), Eran Segal (US), and Howard Y. Chang (US) produced data suggesting that transcription of noncoding RNAs (ncRNA) may demarcate chromosomal domains of gene silencing at a distance; these results have broad implications for gene regulation in development and disease states (1239).

 

Patrick Seale (US), Shingo Kajimura (US), Wenli Yang (US), Sherry Chin (US), Lindsay M. Rohas (US), Marc Uldry (US), Geneviève Tavernier (US), Dominique Langin (US), and Bruce M. Spiegelman (US) identified a molecular switch in mice that turns on the development of beneficial brown-fat cells, which generate heat and counter obesity (1312).

 

Samuel Levy (US), Granger G. Sutton, 3rd (US), Pauline C. Ng (US), Lars Feuk (US), Aaron L. Halpern (US), Brian P. Walenz (US), Nelson Axelrod (US), Jiaqi Huang (US), Ewen F. Kirkness (US), Gennady Denisov (US), Yuan Lin (US), Jeffrey R. MacDonald (US), Andy Wing Chun Pang (US), Mary Shago (US), Timothy B. Stockwell (US), Alexia Tsiamouri (US), Vineet Bafna (US), Vikas Bansal (US), Saul A. Kravitz (US), Dana A. Busam (US), Karen Y. Beeson (US), Tina C. McIntosh (US), Karin A. Remington (US), Josep F. Abril (US), John Gill (US), Jon Borman (US), Yu-Hui Rogers (US), Marvin E. Frazier (US), Stephen W. Scherer (US), Robert L. Strausberg (US) and John Craig Venter (US) presented the first, genome sequence of an individual human. It was produced from approximately 32 million random DNA fragments, sequenced by Sanger dideoxy technology and assembled into 4,528 scaffolds, comprising 2,810 million bases (Mb) of contiguous sequence with approximately 7.5-fold coverage for any given region. They developed a modified version of the Celera assembler to facilitate the identification and comparison of alternate alleles within this individual diploid genome. Comparison of this genome and the National Center for Biotechnology Information human reference assembly revealed more than 4.1 million DNA variants, encompassing 12.3 Mb. These variants (of which 1,288,319 were novel) included 3,213,401 single nucleotide polymorphisms (SNPs), 53,823 block substitutions (2-206 bp), 292,102 heterozygous insertion/deletion events (indels)(1-571 bp), 559,473 homozygous indels (1-82,711 bp), 90 inversions, as well as numerous segmental duplications and copy number variation regions. Non-SNP DNA variation accounts for 22% of all events identified in the donor, however they involve 74% of all variant bases. This suggested an important role for non-SNP genetic alterations in defining the diploid genome structure. Moreover, 44% of genes were heterozygous for one or more variants. Using a novel haplotype assembly strategy, they were able to span 1.5 Gb of genome sequence in segments >200 kb, providing further precision to the diploid nature of the genome. These data depict a definitive molecular portrait of a diploid human genome that provides a starting point for future genome comparisons and enables an era of individualized genomic information (861).

 

David L Duffy (AU), Grant W.Montgomery (AU), Weizu Chen (AU), Zhen Zhen Zhao (AU), Lien Le (AU), Michael R. James (AU), Nicholas K. Hayward (AU), Nicholas G. Martin (AU), and Richard A. Sturm (AU) showed that a three-single-nucleotide polymorphism haplotype in intron 1 of the OCA2 gene on chromosome 15 explains most human eye-color variation (355).

 

Ayla Ergün (US), Carolyn A. Lawrence (US), Michael A. Kohanski (US), Timothy A. Brennan (US), and James J. Collins (US) showed that reverse-engineered gene networks can be combined with expression profiles to compute the likelihood that genes and associated pathways are mediators of a disease. They used this technique to identify the androgen receptor gene (AR) among the top genetic mediators and the AR pathway as a highly enriched pathway for metastatic prostate cancer (380).

 

Michael A. Kohanski (US), Daniel J. Dwyer (US), Boris Hayete (US), Carolyn A. Lawrence (US), and James J. Collins (US) discovered, using systems biology approaches, that all classes of bactericidal antibiotics induce a common oxidative damage cellular death pathway (787). Note: This finding indicates that targeting bacterials systems that remediate oxidative damage, including the SOS DNA damage response, is a viable means of enhancing the effectiveness of all major classes of antibiotics and limiting the emergence of antibiotic resistance.

 

Tobias Allander (SE), Kalle Andreasson (SE), Shawon Gupta (SE), Annelie Bjerkner (SE), Gordana Bogdanovic (SE), Mats A A Persson (SE), Tina Dalianis (SE), Torbjörn Ramqvist (SE), Björn Andersson (SE) reported the discovery of a new human polyomavirus, KI virus, in respiratory secretions from patients with acute respiratory tract infection (32).

Anne M. Gaynor (US), Michael D. Nissen (AU), David M. Whiley (AU), Ian M. Mackay (AU), Stephen B. Lambert (AU), Guang Wu (US), Daniel C. Brennan (US), Gregory A. Storch (US), Theo P. Sloots (AU), and David Wang (US) reported the identification of a novel polyomavirus, designated WU, present in respiratory secretions from human patients with symptoms of acute respiratory tract infection. The virus was initially detected in a nasopharyngeal aspirate from a 3-year-old child from Australia diagnosed with pneumonia (478).

Huichen Feng (US), Masahiro Shuda (US), Yuan Chang (US), and Patrick S. Moore (US) isolated a new polyomavirus that was associated with Merkel Cell Carcinoma, naming it MCV (398). See, both Gardner and Padgett, 1971

 

Farhan H. Zaidi (GB), Joseph T. Hull (GB), Stuart N. Peirson (GB), Katharina Wulff (GB), Daniel Aeschbach (GB), Joshua J. Gooley (GB), George C. Brainard (GB), Kevin Gregory-Evans (GB), Joseph F. Rizzo 3rd (GB), Charles A. Czeisler (GB), Russell G. Foster (GB), Merrick J. Moseley (GB), and Steven W. Lockley (GB) presented data showing that photosensitive retinal ganglion cells (pRGCs) contribute to both circadian physiology and rudimentary visual awareness in humans and challenge the assumption that rod- and cone-based photoreception mediate all "visual" responses to light (1621). Note: These photoreceptors have nothing to do with vision but exist simply to detect brightness—to know when it is daytime and when night. They pass this information on to two tiny bundles of neurons within the brain, roughly the size of a pinhead, embedded in the hypothalamus and known as suprachiasmatic nuclei. These two bundles (one in each hemisphere) control our circadian rhythms. This third type of receptor functions completely independent of sight.

Kathryn J. Reid (US), Anne-Marie Chang (US), and Phyllis C. Zee (US) showed that he suprachiasmatic nucleus (SCN) receives input from specialized photosensitive ganglion cells in the retina via the retinohypothalamic tract. Neurons in the ventrolateral SCN (vlSCN) have the ability for light-induced gene expression. Melanopsin-containing ganglion cells in the retina have a direct connection to the ventrolateral SCN via the retinohypothalamic tract. When the retina receives light, the vlSCN relays this information throughout the SCN allowing entrainment, synchronization, of the person's or animal's daily rhythms to the 24-hour cycle in nature. The importance of entraining organisms, including humans, to exogenous cues such as the light/dark cycle, is reflected by several circadian rhythm sleep disorders, where this process does not function normally (1222).

 

Pollyana Maria F. Soares (BR), Eduardo Ferreira Borba (BR), Eloisa Bonfá (BR), Jorge Hallak (BR), André Luiz Corrêa (BR), Clovis Artur Almeida Silva (BR), Ricardo Maisse Suehiro (BR), Thelma Suely Okay (BR), Marcello Cocuzza (BR), Maria E. J. Deen (BR), Marilia V. Febrônio (BR), Sheila K. Oliveira (BR), Maria T. Terreri (BR), Silvana B. Sacchetti (BR), Flavio R. Sztajnbok (BR), Roberto. Marini (BR), Maria V. Quintero (BR), Blanca E. Bica (BR), Rosa M. Pereira (BR), Virginia P. Ferriani (BR), Teresa C. Robazzi (BR), Claudia S. Magalhães (BR), Maria O. Hilário (BR), Peter M. Villiger (CH), Gion Caliezi (CH), Véronique Cottin (CH), Frauke Förger (CH), Alfred Senn (CH), Monika Østensen (CH), Jutta G. Richter (DE), Arnd Becker (DE), C. Specker (DE), Matthias Schneider (DE), Nadia Emi Aikawa (BR), Adriana Malufss Elias Sallum (BR), Marta Miranda Leal (BR), Eloisa Bonfá (BR), Rosa Maria R. Pereira (BR), Clovis Artur Almeida Silva (BR), Marianne Wallenius(NO), Johan F. Skomsvoll (NO), Lorentz M. Irgens (NO), Kjell Å Salvesen (NO), Bjorn-Yngvar Nordvåg (NO), Wenche Koldingsnes (NO), Knut Mikkelsen (NO), Cecilie Kaufmann (NO), and Tore K. Kvien (NO) provided evidence that chronic inflammatory diseases (CIDs) directly influence reproductive success by decreasing fecundity (23; 1234; 1343; 1369; 1414; 1516; 1529).

Mary E. Watson (US), Robert J. Newman (US), A. Matthew Payne (US), Maged Abdelrahim (US), Gary L. Francis (US), Andrew V. Turnbull (US), Catherine Rivier (US), Matthias S. Gruschwitz (DE), Ruth Brezinschek (DE), Hans-Peter Brezinschek (DE), Nadine Gérard (FR), Maud Caillaud (FR), Alain Martoriati (FR), Ghylène Goudet (FR), Anne-Chrisine Lalmanach (FR), Eli Y. Adashi (US), Carol E. Resnick (US), Carol S. Croft (US), Donna W. Payne (US), Martin D. Fray (GB), G. E. Mann (GB), E. C. L. Bleach (GB), P. G. Knight (GB), M. C. Clarke (GB), B. Charleston (GB), Ennian Xiao (US), and Michel Ferin (US) provided evidence that the reproductve system is switched-off in both sexes during inflammation (17; 438; 483; 562; 1485; 1551; 1598).

 

Adrian Peter Bird (GB), Jacky Guy (GB), Jian Gan (GB), Jim Selfridge (GB), and Stuart Cobb (GB) described a proof-of-principle that the murine equivalent of Rett syndrome could be successfully reversed in laboratory mice. This was accomplished by reintroducing a functional MeCP2 gene and proved successful even when the condition was at an advanced stage, hinting at the possibility of a gene therapy approach to curing the human disease in the future (569).

 

Mercedes Vergara (ES), Xavier Calvet (ES), and Javier P. Gisbert (ES), in the treatment for peptic ulcer bleeding, showed that endoscopic hemostasis using injection of adrenaline and a second therapeuric agent during the index endoscopy reduced the risk of re-bleeding and surgery compared with adrenaline alone (1512).

 

Torbjörn Holm (SE), A. Ljung (SE), Tom Häggmark (SE), Göran Jurell (SE), and Jesper Lagergren (SE) reported that the extended posterior perineal approach with gluteus maximus flap reconstruction in abdomino-perineal excision of the rectum has a low risk of bowel perforation, circumferential resection margin involvement and local perineal wound complications. The rate of local recurrence may be lower than with conventional abdomino-perineal excision of the rectum (645).

The UKCCCR Anal Cancer Trial Working Party (GB), John Northover (GB), Robert Glynne-Jones (GB), David Sebag-Montefiore (GB), Roger James (GB), Helen Meadows (GB), Susan Wan (GB), Mark Jitlal (GB), and Jonathan Andrew Ledermann (GB) showed in randomized trials that the addition of 5-fluorouracil and mitomycin chemotherapy to radiotherapy reduces the rate of local failure and requirement for radical anal cancer surgery . There is also an improvement in cancer-specific survival with combined modality therapy (1089; 1132).

 

Leslie Alexander Geddes (GB-CA-US), Ann E. Rundell (US), Aaron E. Lottes (US), Andre E. Kemeny (US), Michael P. Otlewski (US), and Michael Pargett (US) designed a simple tool for effective cardiopulmonary resuscitation that can easily provide 100 pounds of force without danger of cracking a rib or the sternum (480; 1125).

 

Yakov Krelin (IL), Elena Voronov (IL), Shahar Dotan (IL), Moshe Elkabets (IL), Eli Reich (IL), Mina Fogel (IL), Monika Huszar (IL), Yoichiro Iwakura (JP), Shraga Segal (IL), Charles A. Dinarello (US), and Ron N. Apte (IL) reported that in mice deficient in interleukin‐1β, chemical carcinogenesis was significantly reduced whereas in mice deficient in interleukin‐1Ra (antagonist of IL-1), cancer transformation is increased compared with the wild‐type mice (805). Note: Chronic inflammation contributes to carcinogenesis and interleukin‐1β may play a significant roll.

 

Mary Higby Schweitzer (US), Zhiyong Suo (US), John M. Asara (US), Mark A. Allen (US), Fernando Teran Arce (US), and John R. Horner (US) performed multiple analyses of Tyrannosaurus rex fibrous cortical and medullary tissues remaining after demineralization. The results indicate that collagen I, the main organic component of bone, has been preserved in low concentrations in these tissues. The findings were independently confirmed by mass spectrometry. They propose a possible chemical pathway that may contribute to this preservation. The presence of endogenous protein in dinosaur bone may validate hypotheses about evolutionary relationships, rates, and patterns of molecular change and degradation, as well as the chemical stability of molecules over time (1306).

Mary Higby Schweitzer (US), Jennifer L. Wittmeyer (US), and John R. Horner (US) found soft tissues and cell-like microstructures derived from skeletal elements of a well-preserved Tyrannosaurus rex (MOR 1125) were represented by four components in fragments of demineralized cortical and/or medullary bone: flexible and fibrous bone matrix; transparent, hollow and pliable blood vessels; intravascular material, including in some cases, structures morphologically reminiscent of vertebrate red blood cells; and osteocytes with intracellular contents and flexible filipodia. Their results suggest that present models of fossilization processes may be incomplete and that soft tissue elements may be more commonly preserved, even in older specimens, than previously thought. Additionally, in many cases, osteocytes with defined nuclei are preserved, and may represent an important source for informative molecular data (1307).

 

Tanya M. Smith (DE), Paul Tafforeau (FR), Donald J. Reid (GB),Rainer Grün (AU), Stephen Eggins (AU), Mohamed Boutakiout (MA), and Jean-Jacques Hublin (DE) provided evidence from Jebel Irhoud in Morocco for the earliest evidence of modern human life history in North African early Homo sapiens dated at 158K B.C.E.)(1366).

Daniel Richter (DE), Rainer Grün (AU), Renaud Joannes-Boyau (AU), Teresa E. Steele (DE), Fethi Amani (MA), Mathieu Rué (FR), Paul Fernandes (FR), Jean-Paul Raynal (DE), Denis Geraads (DE), Abdelouahed Ben-Ncer (MC), Jean-Jacques Hublin (DE), and Shannon P. McPherron (DE) reported "the ages, determined by thermoluminescence dating, of fire-heated flint artefacts obtained from new excavations at the Middle Stone Age site of Jebel Irhoud, Morocco, which are directly associated with newly discovered remains of H. sapiens. A weighted average age places these Middle Stone Age artefacts and fossils at 315 ± 34 thousand years ago. Support is obtained through the recalculated uranium series with electron spin resonance date of 286 ± 32 thousand years ago for a tooth from the Irhoud 3 hominin mandible. These ages are also consistent with the faunal and microfaunal assemblages and almost double the previous age estimates for the lower part of the deposits. The north African site of Jebel Irhoud contains one of the earliest directly dated Middle Stone Age assemblages, and its associated human remains are the oldest reported for H. sapiens. The emergence of our species and of the Middle Stone Age appear to be close in time, and these data suggest a larger scale, potentially pan-African, origin for both." (1233)

 

Massimo Pigliucci (US) and Gerd B. Müller (AT) reconceptualized the extended evolutionary synthesis (1033; 1165; 1166).

2008

"It is not birth, marriage, or death, but gastrulation which is truly the most important event in your life". Lewis Wolpert (1588).

 

Francoise Barré-Sinoussi (FR), Luc Montagnier (FR), and Harald zur Hausen (DE) were awarded the Nobel Prize in Physiology or Medicine. Barré-Sinoussi and Montagnier for their discovery of human immunodeficiency virus. Zur Hausen for his discovery of human papilloma viruses causing cervical cancer.

 

Martin Chalfie (US), Osamu Shimomura (US), and Roger Y. Tsien (US) were awarded the Nobel Prize in Chemistry for their discovery and development of the green fluorescent protein, GFP.

 

David A. Wheeler (US), Maithreyan Srinivasan (US), Michael Egholm (US), Yufeng Shen (US), Lei Chen (US), Amy McGuire (US), Wen He (US), Yi-Ju Chen (US), Vinod Makhijani (US), G. Thomas Roth (US), Xavier Gomes (US), Karrie Tartaro (US), Faheem Niazi (US), Cynthia L. Turcotte (US), Gerard P. Irzyk(US), James R. Lupski (US), Craig Chinault (US), Xing-zhi Song (US), Yue Liu (US), Ye Yuan (US), Lynne Nazareth (US), Xiang Qin (US), Donna M. Muzny (US), Marcel Margulies (US), George M. Weinstock (US), Richard A. Gibbs (US), and Jonathan M. Rothberg (US) reported the DNA sequence of a diploid genome of a single individual, James D. Watson, sequenced to 7.4-fold redundancy in two months using massively parallel sequencing in picolitre-size reaction vessels. This sequence was completed in two months at a cost of 1.5 million US; approximately one-hundredth of the cost of traditional capillary electrophoresis methods. (1526; 1566) Note: James Watson's is not the first full genome to be published; that distinction goes to genomics entrepreneur John Craig Venter (US), whose genome was sequenced using previous-generation machines at a cost of $100 million US.

 

Daniel G. Gibson (US), Gwynedd A. Benders (US), Cynthia Andrews-Pfannkoch (US), Evgeniya A. Denisova (US), Holly Baden-Tillson (US), Jayshree Zaveri (US), Timothy B. Stockwell (US), Anushka Brownley (US), David W. Thomas (US), Mikkel A. Algire (US), Chuck Merryman (US), Lei Young (US), Vladimir N. Noskov (US), John I. Glass (US), John Craig Venter (US), Clyde A. Hutchison, 3rd (US), and Hamilton O. Smith (US) were the first to synthesize the complete genome of a bacterium, Mycoplasma genitalium (493).

 

Cédric Feschotte (US) noted that transposable elements, have been a rich source of material for the assembly and tinkering of eukaryotic gene regulatory systems (409).

Julius Judd (US), Hayley Sanderson (US), and Cédric Feschotte (US) suggested that the birth of enhancers from transposons is predicated both by the sequence of the transposon and by the cis-regulatory landscape surrounding their genomic integration site (724).

Rachel L. Cosby (US), Julius Judd (US), Ruiling Zhang (US), Alan Zhong (US), Nathaniel Garry (US), Ellen J. Pritham (US), and Cédric Feschotte (US) suggested that genes with novel cellular functions may evolve through exon shuffling which can assemble unique protein architectures. They showed that DNA transposons provide a recurrent supply of materials to assemble protein-coding genes via exon-shuffling. They found that transposase domains have been captured, primarily via alternative splicing, to form fusion proteins at least 94 times independently over ~350 million years of tetrapod evolution (284).

 

Mihir M. Desai (US), Pradeep P. Rao (US), Monish Aron (US), Georges Pascal‐Haber (US), Mahesh R. Desai (US), Shashikant Mishra (US), Jihad H. Kaouk (US), and Inderbir S. Gill (US) reported the first clinical cases of scarless, single port, transumbilical nephrectomy and pyeloplasty (334).

 

Navtej Toor (US), Kevin S.Keating (US), Sean D. Taylor (US), and Anna Marie Pyle (US) reported the crystal structure of an intact, self-spliced group II intron from Oceanobacillus iheyensis at 3.1 Ångstrom resolution. An extensive network of tertiary interactions facilitates the ordered packing of intron subdomains around a ribozyme core that includes catalytic domain V. Structural and functional analogies support the hypothesis that group II introns and the spliceosome share a common ancestor (1467).

 

Hans Eiberg (DK), Jesper Troelsen (DK), Mette Nielsen (DK), Annemette Mikkelsen (DK), Jonas Mengel-From (DK), Klaus W. Kjaer (DK), and Lars Hansen (DK) provided data suggesting a common founder mutation in an OCA2 locus inhibiting regulatory element as the cause of blue eye color in humans. In addition, an LOD score of Z = 4.21 between hair color and D14S72 was obtained in the large family, indicating that RABGGTA is a candidate gene for hair color (369). Note: The human eye color is a quantitative trait displaying multifactorial inheritance. Several studies have shown that the OCA2 locus is the major contributor to the human eye color variation.

 

Shenghua Li (US), Paul Brazhnik (US), Bruno Sobral (US), and John J. Tyson (US) proposed a molecular mechanism for control of the cell division cycle in Caulobacter crescentus. The mechanism, which is based on the synthesis and degradation of three “master regulator” proteins (CtrA, GcrA, and DnaA), is converted into a quantitative model, in order to study the temporal dynamics of these and other cell cycle proteins. The model accounts for important details of the physiology, biochemistry, and genetics of cell cycle control in the stalked C. crescentus cell. It reproduces protein time courses in wild-type cells, mimics correctly the phenotypes of many mutant strains, and predicts the phenotypes of currently uncharacterized mutants (867).

 

Richard Robinson (CH), David Brawand (CH), Walter Wahli (CH), and Henrik Kaessmann (CH) showed that the three ancestral vitellogenin-encoding genes were progressively lost during mammalian evolution (until around 30–70 M years ago) in all but the egg-laying monotremes, which have retained a functional vitellogenin gene. Their analyses also provided evidence that the major milk resource genes, caseins, which have similar functional properties as vitellogenins, appeared in the common mammalian ancestor 200–310 M. Together, their data are compatible with the hypothesis that the emergence of lactation in the common mammalian ancestor and the development of placentation in eutherian and marsupial mammals allowed for the gradual loss of yolk-dependent nourishment during mammalian evolution (158; 1244).

 

Karen Bulloch (US), Melinda M. Miller (US), Judit Gal-Toth (US), Teresa A. Milner (US), Andres Gottfried-Blackmore (US), Elizabeth M. Waters (US), Ulrike W. Kaunzner (US), Kang Liu (US), Randall Lindquist (US), Michel C. Nussenzweig (US), Ralph M. Steinman (US), Bruce Sherman McEwen (US), Juliana Idoyaga (US), and Jennifer C. Felger (US) identified a population of dendritic cells, the sentinels of the immune system, that are native to the brain. They showed that these brain dendritic cells can muster the immune system’s soldier T cells when confronted by certain threats (182; 518).

Jennifer C. Felger (US), Takato Abe (US), Ulrike W. Kaunzner (US), Andres Gottfried-Blackmore (US), Judit Gal-Toth (US), Bruce Sherman McEwen (US), Costantino Iadecola (US), and Karen Bulloch (US) showed that, unlike dendritic cells from elsewhere in the body, brain dendritic cells line up along the periphery of stroke-damaged brain tissue, perhaps as a barricade protecting the healthy cells outside (397).

 

James Schummers (US), Hongbo Yu (US), and Mriganka Sur (US) discovered that astrocytes have remarkably specific functional properties and mediate blood flow to active brain regions. This work revealed the mechanism for noninvasive brain imaging methods such as functional magnetic resonance imaging (fMRI) (1304).

 

Lizzia Raffaghello (IT), Changhan W. Lee (US), Fernando M. Safdie (US), Min Wei (US), Federica Madia (IT), Giovanna Bianchi (IT), and Valter D. Longo (IT-US) performed studies that described a starvation-based differential stress resistance (DSR) strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells (1198).

Changhan W. Lee (US), Lizzia Raffaghello (IT), Sebastian Brandhorst (DE-US), Fernando M. Safdie (US), Giovanna Bianchi (IT), Alejandro Martin-Montalvo (US), Vito Pistoia (IT), Min Wei (US), Saewon Hwang (US), Annalisa Merlino (US), Laura Emionite (IT), Rafael de Cabo (US), Valter D. Longo (IT-US) and Mark P. Mattson (US) noted that fasting has been practiced for millennia, but, only recently, studies have shed light on its role in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism, and bolster cellular protection. In lower eukaryotes, chronic fasting extends longevity, in part, by reprogramming metabolic and stress resistance pathways. In rodents intermittent or periodic fasting protects against diabetes, cancers, heart disease, and neurodegeneration, while in humans it helps reduce obesity, hypertension, asthma, and rheumatoid arthritis. Thus, fasting has the potential to delay aging and help prevent and treat diseases while minimizing the side effects caused by chronic dietary interventions (842; 897).

 

Wei Meng (US), Bruce A. Ellsworth (US), Alexandra A. Nirsch (US), Peggy J. McCann (US), Manorama Patel (US), Ravindar N. Girotra (US), Gang Wu (US), Philip M. Sher (US), Eamonn P. Morrison (US), Scott A. Biller (US), Robert Zahler (US), Prashant P. Deshpande (US), Annie Pullockaran (US), Deborah L. Hagan (US), Nathan Morgan (US), Joseph R. Taylor (US), Mary T. Obermeier (US), William G. Humphreys (US), Ashish Khanna (US), Lorell Discenza (US), James G. Robertson (US), Aiying Wang (US), Songping Han (US), John R. Wetterau (US), Evan B. Janovitz (US), Oliver P. Flint (US), Jean M. Whale (US), and William N. Washburn (US) identified C-aryl glucoside 6 (dapagliflozin) as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable absorption, distribution, metabolism, and excretion (ADME) profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes (990).

 

Gala Trial Collaborative Group (GB), Stephanie C. Lewis (GB), Charles P. Warlow (GB), Andrew R. Bodenham (GB), Bridget Colam (GB), Peter M. Rothwell (GB), David Torgerson (GB), Demosthenes Dellagrammaticas (SE), Michael Horrocks (GB), Christos D. Liapis (GR), Adrian P. Banning (GB), Mike Gough (GB), and Michael J. Gough (US), in a prospective randomized study, found that the hypothesis that carotid surgery under local anaesthesia carried a lower risk of morbidity is incorrect (548).

 

Gail D. Lewis Phillips (US), Guangmin Li (US), Debra L. Dugger (US), Lisa M. Crocker (US), Kathryn L. Parsons (US), Elaine Mai (US), Walter A. Blättler (US), John M. Lambert (US), Ravi V.J. Chari (US), Robert J. Lutz (US), Wai Lee T. Wong (US), Frederic S. Jacobson (US), Hartmut Koeppen (US), Ralph H. Schwall (US), Sara R. Kenkare-Mitra (US), Susan D. Spencer (US), and Mark X. Sliwkowski (US) demonstrated that ado-trastuzumab emtansine (T-DM1) shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells (863). Note: T-DM1 is an immunotoxin (an antibody-drug conjugate) that is made by chemically linking the monoclonal antibody trastuzumab to the cytotoxic agent mertansine, which inhibits cell proliferation by blocking the formation of microtubules. Human epidermal growth factor receptor 2 (HER2), in excess amounts promotes the growth of cancer cells. In about 1 of every 5 breast cancers, the cancer cells have a gene mutation that makes an excess of the HER2 protein.

Kate Traynor (US) reported that FDA and Genentech announced the FDA approval of ado-trastuzumab emtansine, an antibody– drug conjugate, for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (1473).

 

Reinhard Dummer (CH), Axel Hauschild (CH), Juergen C. Becker (CH), Jean-Jacques Grob (CH), Dirk Schadendorf (CH), Veronica Tebbs (CH), Jeannine Skalsky (CH), Katharina C. Kaehler (CH), Stephanie Moosbauer (CH), Ruth Clark (CH), Tze-Chiang Meng (CH) and Mirjana Urosevic (CH) reported that intravenous 852A (a toll-like-receptor 7 agonist) was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy (357).

 

Stewart S. Sell (US) explained how study of the production of alpha-fetoprotein during chemical hepatocarcinogenesis led to reaffirmation of the stem cell theory of cancer (1316).

 

Stephen A. Harrison (US), Dana Oliver (US), Hays L. Arnold (US), Sudhanshu Gogia (US), and Brent A. Neuschwandet-Tetri (US) proposed the "BARD scoring system", which takes into account body-mass index (BMI), AST/ALT ratio (AAR), and presence of type 2 diabetes mellitus (DMt2). These three simple variables were combined in a weighted sum to form a score for predicting advanced fibrosis. A score of 2-4 was associated with an odds ratio for advanced fibrosis of 17 (95% CI: 9.2 to 31.9) and a negative predictive value of 96%. This score markedly reduced the need for liver biopsies in patients with non-alcoholic fatty liver disease (601).

 

Helena Genberg (SE), Gunilla Kumlien (SE), Lars Wennberg (SE), Ulla Berg (SE), Gunnar Tyden (SE) concluded from their comparative retrospective cross-sectional study that ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab is equivalent to ABO-compatible living donor kidney transplantation. ABO-incompatible transplantation after this protocol does not have a negative impact on long-term graft function (482).

 

Eddie Myers (IE), M. Hurley (IE), Gerald C. O'Sullivan (IE), Dara Oliver Kavanagh (IE), Ian Wilson (IE), and Des C. Winter (IE) showed that laproscopic washout is a reasonable alternative to the traditional open resection for Hinchey grades 2 and 3 perforated diverticulitis with generalized peritonitis. With a documented low mortality rate, this approach avoids formation of a colostomy (1045).

 

Inderbir S. Gill (US), David Canes (US), Monish Aron (US), Georges-Pascal Haber (US), David A. Goldfarb (US), Stuart Flechner (US), Mahesh R. Desai (US), Jihad H. Kaouk (US), and Mihir M. Desai (US) began removing healthy intact kidneys through a single incision in the patient's navel. With the new technique, donors averaged 25 days for a full recovery, took pain pills for only three days and returned to work four weeks earlier than those whose kidneys were removed through the abdomen (497).

Mihir M. Desai (US), Robert Stein (US), Prashanth Rao (US), David Canes (US), Monish Aron (US), Pradeep P. Rao (US), Georges-Pascal Haber (US), Amr Fergany (US), Jihad Kaouk (US), and Inderbir S. Gill (US) presented the initial experience with advanced laparoscopic reconstruction through a single intraumbilical port (335).

 

Mary L. Droser (US) and James G. Gehling (AU) believe they have found the earliest fossil evidence for sexual reproduction. It occurred in Funisia, an Ediacaran "animal" whose relationship to other animals is unknown (347).

 

M. Thomas P. Gilbert (DK), Dennis L. Jenkins (US), Anders Götherstrom (SE), Nuria Naveran (ES), Juan J. Sanchez (ES), Michael Hofreiter (DE), Philip Francis Thomsen (DK), Jonas Binladen (DK), Thomas F.G. Higham (GB), Robert M. Yohe, II (US), Robert Parr (US), Linda Scott Cummings (US), and Eske Willerslev (DK) established that humans were present at Paisley 5 Mile Point Caves, in south-central Oregon, by 10.3K B.C.E., through the recovery of human mitochondrial DNA (mtDNA) from coprolites, directly dated by accelerator mass spectrometry (495).

 

2009

Elizabeth H. Blackburn (US), Carol W. Creider (US), and Jack W. Szostak (US) were awarded the Nobel Prize in Physiology or Medicine for their discovery of how chromosomes are protected by telomeres and the enzyme telomerase.

 

Venkatraman Ramakrishnan (US), Thomas Steitz (US), and Ada Yonath (IL) were awarded the Nobel Prize in Chemistry for their studies of the structure and function of the ribosome.

 

Murim Choi (US), Ute I. Scholl (US), Weizhen Ji (US), Tiewen Liu (US), Irina R. Tikhonova (US), Paul Zumbo (US), Ahmet Nayir (US), Ayşin Bakkaloğlu (US), Seza Ozen (US), Sami Sanjad (US), Carol Nelson-Williams (US), Anita Farhi (US), Shrikant Mane (US), and Richard P. Lifton (US) reported the first diagnosis resolved by whole-exome-sequencing (WES) in a patient misdiagnosed with Bartter syndrome; WES revealed a novel homozygous mutation in SLC26A3 , a gene in which previous mutations were causal for congenital chloride-losing diarrhoea (CLD). Re-evaluation of the clinical phenotype confirmed the diagnosis of CLD (249).

Elizabeth A. Worthey (US), Alan N. Mayer (US), Grant D. Syverson (US), Daniel Helbling (US), Benedetta B. Bonacci (US), Brennan Decker (US), Jaime M. Serpe (US), Trivikram Dasu (US), Michael R. Tschannen (US), Regan L. Veith (US), Monica J. Basehore (US), Ulrich Broeckel (US), Aoy Tomita-Mitchell (US), Marjorie J. Arca (US), James T. Casper (US), David A. Margolis (US), David P. Bick (US), Martin J. Hessner (US), John M. Routes (US), James W. Verbsky (US), Howard J. Jacob (US), and David P. Dimmock (US) published the first clinical case using exome sequencing to diagnose and cure a rare form of inflammatory bowel disease (1594).

Alexandros Onoufriadis (GB), Amelia Shoemark (GB), Mustafa M. Munye (GB), Chela T. James (GB), Miriam Schmidts (GB), Mitali Patel (GB), Elisabeth M. Rosser (GB), Chiara Bacchelli (GB), Philip L. Beales (GB), Peter J. Scambler (GB), Stephen L. Hart (GB), Jeannette E. Danke-Roelse (GB), John J. Sloper (GB), Sarah Hull (GB), Claire Hogg (GB), Richard D. Emes (GB), Gerard Pals (GB), Anthony T. Moore (GB), Eddie M. K. Chung (GB), and Hannah M. Mitchison (GB) combined exome and whole-genome sequencing to identify mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm (1109).

 

Xavier Morin (FR), Yohannis Bellaïche (FR), Taryn E. Gillies (US), Clemens Cabernard (US), Michelle S. Lu (US), Christopher A. Johnston (US), Christopher Q. Doe (US), Scott E. Williams (US), Slobodan Beronja (US), H. Amalia Pasolli (US), and Elaine Fuchs (US) reported that for dividing animal cells to generate and maintain organized tissues, the mitotic spindle must be oriented relative to the position of surrounding cells (191; 498; 906; 1021; 1576).

Xavier Morin (FR), Yohannis Bellaïche (FR), Taryn E. Gillies (US), Clemens Cabernard (US), Yu-ichiro Nakajima (US), Emily J. Meyer (US), Amanda Kroesen (US), Sean A. McKinney (US), and Matthew C. Gibson (US) reported that cells that orient the spindle parallel to the epithelial plane, for example, expand the tissue; those that rotate it orthogonally to the plane escape the epithelium, as in epithelial-mesenchymal transitions during development (498; 1021; 1051).

Michelle S. Lu (US), Christopher A. Johnston (US), Keiko Hirono (US), Kenneth E. Prehoda (US), Christopher Q. Doe (US), and Sarah E. Siegrest (US) identified a protein complex that mediates robust positioning of the mitotic spindle by using a scaffolding protein to link the spindle’s astral microtubules to a molecular marker that is localized on the cell’s cortex by external signals (712; 906; 1340; 1341).

Michael J. Harms (US), Joseph W. Thornton (US), Geeta N. Eick (US), Devrishi Goswami (US), Jennifer K. Colucci (US), Patrick R. Griffin (US), and Eric A. Ortlund (US) found that the vertical evolutionary analysis of ancestral protein reconstruction – phylogenetic inference of ancestral sequences followed by gene synthesis, genetic manipulation, and experimental characterization – has proven to be an effective strategy for elucidating the molecular mechanisms by which the functions of these proteins evolved (596; 597).

Douglas P. Anderson (US), Dustin S. Whitney (US), Victor Hanson-Smith (US), Arielle Woznica (US), William Campodonico-Burnett (US), Brian F. Volkman (US), Nicole King (US), Joseph W. Thornton (US), and Kenneth E. Prehoda (US) applied ancestral protein reconstruction to investigate the historical trajectory, timing, and mechanisms of the evolution of a new protein function important to organized multicellularity in diverse animal phyla. They illuminated how a complex evolved and commandeered control of spindle orientation from a more ancient mechanism. This change revealed and repurposed an ancient molecular surface that previously had a radically different function. They showed how the physical simplicity of this binding interface enabled the evolution of a new protein function now essential to the biological complexity of many animals (39).

 

Patrick S. Schnable (US), Doreen Ware (US), Robert S. Fulton (US), Joshua C. Stein (US), Fusheng Wei (US), Shiran Pasternak (US), Chengzhi Liang (US), Jianwei Zhang (US), Lucinda Fulton (US), Tina A. Graves (US), Patrick Minx (US), Amy Denise Reily (US), Laura Courtney (US), Scott S. Kruchowski (US), Chad Tomlinson (US), Cindy Strong (US), Kim Delehaunty (US), Catrina Fronick (US), Bill Courtney (US), Susan M. Rock (US), Eddie Belter (US), Feiyu Du (US), Kyung Kim (US), Rachel M. Abbott (US), Marc Cotton (US), Andy Levy (US), Pamela Marchetto (US), Kerri Ochoa (US), Stephanie M. Jackson (US), Barbara Gillam (US), Weizu Chen (US), Le Yan (US), Jamey Higginbotham (US), Marco Cardenas (US), Jason Waligorski (US), Elizabeth Applebaum (US), Lindsey Phelps (US), Jason Falcone (US), Krishna Kanchi (US), Thynn Thane (US), Adam Scimone (US), Nay Thane (US), Jessica Henke (US), Tom Wang (US), Jessica Ruppert (US), Neha Shah (US), Kelsi Rotter (US), Jennifer Hodges (US), Elizabeth Ingenthron (US), Matt Cordes (US), Sara Kohlberg (US), Jennifer Sgro (US), Brandon Delgado (US), Kelly Mead (US), Asif Chinwalla (US), Shawn Leonard (US), Kevin Crouse (US), Kristi Collura (US), Dave Kudrna (US), Jennifer Currie (US), Ruifeng He (US), Angelina Angelova (US), Shanmugam Rajasekar (US), Teri Mueller (US), Rene Lomeli (US), Gabriel Scara (US), Ara Ko (US), Krista Delaney (US), Marina Wissotski (US), Georgina Lopez (US), David Campos (US), Michele Braidotti (US), Elizabeth Ashley (US), Wolfgang Golser (US),HyeRan Kim (US), Seunghee Lee (US), Jinke Lin (US), Zeljko Dujmic (US), Woojin Kim (US), Jayson Talag (US), Andrea Zuccolo (US), Chuanzhu Fan (US), Aswathy Sebastian (US), Melissa Kramer (US), Lori Spiegel (US), Lidia Nascimento (US), Theresa Zutavern (US), Beth Miller (US), Claude Ambroise (US), Stephanie Muller (US), Will Spooner (US), Apurva Narechania (US), Liya Ren (US), Sharon Wei (US), Sunita Kumari (US), Ben Faga (US), Michael J. Levy (US), Linda McMahan (US), Peter Van Buren (US), Matthew W. Vaughn (US), Kai Ying (US), Cheng-Ting Yeh (US), Scott J. Emrich (US), Yi Jia (US), Ananth Kalyanaraman (US), An-Ping Hsia (US), W. Brad Barbazuk (US), Regina S. Baucom (US), Thomas P. Brutnell (US), Nicholas C. Carpita (US), Cristian Chaparro (US), Jer-Ming Chia (US), Jean-Marc Deragon (US), James C. Estill (US), Yan Fu (US), Jeffrey A. Jeddeloh (US), Yujun Han (US), Hyeran Lee (US), Pinghua Li (US), Damon R. Lisch (US), Sanzhen Liu (US), Zhijie Liu (US), Dawn Holligan Nagel (US), Maureen C. McCann (US), Phillip SanMiguel (US), Alan M. Myers (US), Dan Nettleton (US), John Nguyen (US), Bryan W. Penning (US), Lalit Ponnala (US), Kevin L. Schneider (US), David C. Schwartz (US), Anupma Sharma (US), Carol Soderlund (US), Nathan M. Springer (US), Qi Sun (US), Hao Wang (US), Michael Waterman (US), Richard Westerman (US), Thomas K. Wolfgruber (US), Lixing Yang (US), Yeisoo Yu (US), Lifang Zhang (US), Shiguo Zhou (US), Qihui Zhu (US), Jeffrey L. Bennetzen (US), R. Kelly Dawe (US), Jiming Jian (US), Ning Jiang (US), Gernot G. Presting (US), Susan R. Wessler (US), Srinivas Aluru (US), Robert A. Martienssen (US), Sandra W. Clifton (US), W. Richard McCombie (US), Rod A. Wing (US), and Richard K. Wilson (US) reported an improved draft nucleotide sequence of the 2.3-gigabase genome of maize. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. They reported on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state (1295).

 

Eva Jablonka (IL) and Gal Raz (IL) gave evidence to support transgenerational epigenetic inheritance (695). Note: This is the ability of parents to pass their adaptations to their offspring. In other words, a specific genotype can express itself differently due to an ability to respond in different ways to variations in environmental factors.

 

Jonathan P. Fadok (US), Tavis M. K. Dickerson (US), Richard D. Palmiter (US), Akira Uematsu (JP), Bao Zhen Tan (JP), Edgar A. Ycu (JP), Jessica Sulkes Cuevas (JP), Jenny Koivumaa (JP), Felix Junyent (FR), Eric J. Kremer (FR), Ilana B. Witten (US), Karl Deisseroth (US), Joshua P. Johansen (JP), Wei Tang (CH), Olexiy Kochubey (CH), Michael Kintscher (CH), and Ralf Schneggenburger (CH) provided evidence that multiple neuromodulators acting in the amygdala regulates the formation of emotional memories (387; 1438; 1494).

 

Philip R. Johnson (US), Bruce C. Schnepp (US), Jianchao Zhang (US), Mary J. Connell (US), Sean M. Greene (US), Eloisa Yuste (US), Ronald C. Desrosiers (US), and K. Reed Clark (US) delivered to muscle of an adeno-associated virus gene transfer vector expressing antibodies or antibody-like immunoadhesins having predetermined Simian-Immunodeficiency Virus (SIV) specificity. With this approach, SIV-specific molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, they generated long-lasting neutralizing activity in serum and observed complete protection against intravenous challenge with virulent SIV (711).

 

Nathalie Cartier (FR), Salima Hacein-Bey-Abina (FR), Cynthia C. Bartholomae (DE), Gabor Veres (US), Manfred Schmidt (DE), Ina Kutschera (DE), Michel Vidaud (FR), Ulrich Abel (DE), Liliane Dal-Cortivo (FR), Laure Caccavelli (FR), Nizar Mahlaoui (FR), Véronique Kiermer (US), Denice Mittelstaedt (US), Céline Bellesme (FR), Najiba Lahlou (FR), François Lefrère (FR), Stéphane Blanche (FR), Muriel Audit (FR), Emmanuel Payen (FR), Philippe Leboulch (FR-US), Bruno l’Homme (FR), Pierre Bougnères (FR), Christof Von Kalle (DE), Alain Fischer (FR), Marina Cavazzana-Calvo (FR), and Patrick Aubourg (FR) used a modified acquired immune deficiency syndrome (AIDS) virus to halt a devastating brain disease in two young boys. The treatment, in which the virus delivered a therapeutic gene, marks the first time gene therapy has been successfully used against X-linked adrenoleukodystrophy (ALD)--a disorder that is always fatal if untreated (210).

 

Gero Hütter (DE), Daniel Nowak (DE), Maximilian Mossner (DE), Susanne Ganepola (DE), Arne Müßig (DE), Kristina Allers (DE), Thomas Schneider (DE), Jörg Hofmann (DE), Claudia Kücherer (DE), Olga Blau (DE), Igor W. Blau (DE), and Wolf K. Hofmann (DE) discovered that infection with the human immunodeficiency virus type 1 (HIV-1) requires the presence of a CD4 receptor and a chemokine receptor, principally chemokine receptor 5 (CCR5). Homozygosity for a 32-bp deletion in the CCR5 allele provides resistance against HIV-1 acquisition. They transplanted stem cells from a donor who was homozygous for CCR5 delta32 into a patient with acute myeloid leukemia and HIV-1 infection. The patient remained without viral rebound 20 months after transplantation and discontinuation of antiretroviral therapy. This outcome demonstrates the critical role CCR5 plays in maintaining HIV-1 infection (669).

 

Claudia Scholl (US), Stefan Fröhling (US), Ian F. Dunn (US), Anna C. Schinzel (US), David A. Barbie (US), So Young Kim (US), Serena J. Silver (US), Pablo Tamayo (US), Raymond C. Wadlow (US), Sridhar Ramaswamy (US), Konstanze Döhner (DE), Lars Bullinger (DE), Peter Sandy (US), Jesse S. Boehm (US), David E. Root (US), Tyler Jacks (US), William C. Hahn (US), and D. Gary Gilliland (US) used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with "undruggable" genetic alterations (1299). Note: KRAS ( K-ras or Ki-ras) is a gene that acts as an on/off switch in cell signalling. ... When it is mutated, negative signalling is disrupted. Thus, cells can continuously proliferate, and often develop into cancer.

 

Jihad H. Kaouk (US), Wesley M. Whiten (UF, Raj K. Goel (US), Stacy Brethauer (US), Sebastien Crouzet (US), Raymond R. Rackley (US), Courtenay Moore (US), Michael S. Ingber (US), and Georges-Pascal Haber (US) presented the operative outcomes of the first natural orifice translumenal endoscopic surgery (NOTES), a transvaginal nephrectomy (737).

 

Guilherme M. Campos (US), Eric Vittinghoff (US), Charlotte Rabl (US), Mark Takata (US), Michael Gadenstätter (US), Feng Lin (US), Ruxandra Ciovica (US), Lan Wang (CN), You-Ming Li (CN), and Lan Li (CN), in meta-analyses, concluded that laproscopic myotomy is the most effective and long-lasting treatment for achalasia (197; 1537). Note: Achalasia is a rare disorder of esophageal motility.

Guy E. Boeckxstaens (BE), Vito Annese (IT), Stanislas Bruley des Varannes (FR), Stanislas Chaussade (FR), Mario Costantini (IT), Antonello Cuttitta (IT), J. Ignasi Elizalde (ES), Uberto Fumagalli (IT), Marianne Gaudric (FR), Wout O. Rohof (NL), André J. Smout (NL), Jan Tack, M.D. (BE), Aeilko H. Zwinderman (NL), Giovanni Zaninotto (IT), Olivier R. Busch (NL), and The European Achalasia Trial Investigators, in a randomized trial, concluded that laproscopic myotomy and pneumatic dilation are both effective treatments for achalasia (143).

 

Cyril Moers (NL), Jacqueline M. Smits (NL), Mark-Hugo J. Maathuis (NL), Jürgen Treckmann (DE), Frank van Gelder (BE), Bogdan P. Napieralski (DE), Margitta van Kasterop-Kutz (NL), Jaap J. Homan van der Heide (NL), Jean-Paul Squifflet (BE), Ernest van Heurn (NL), Günter R. Kirste (DE), Axel Rahmel (NL), Henri G.D. Leuvenink (NL), Andreas Paul (DE), Jacques Pirenne (BE), and Rutger J. Ploeg (NL), in their European Multicenter Randomized Controlled Trial, compared delayed graft function between machine perfused and cold storage kidneys. They concluded that machine perfusion significantly reduces the risk of delayed graft function in deceased donor kidney transplantation and the duration of delayed graft function when it occurred (1006).

Christopher J.E. Watson (GB), Antonia C. Wells (GB), Rebecca J. Roberts (GB), Jacob A. Akoh (GB), Peter J. Friend (GB), Murat Akyol (GB), Francis R. Calder (GB), Joanne E. Allen (GB), Mark N. Jones (GB), Dave Collett (GB), and J. Andrew Bradley (GB) conducted the United Kingdom Multicenter Randomized Controlled Trial of cold machine perfusion versus static cold storage of kidneys donated after cardiac death. They concluded there is no significant difference (1550).

 

Marcin Barczynski (PL), Aleksander Konturek (PL), and Stanislaw Cichon (PL) used a prospective single-institution randomized controlled trial to show that during thyroid surgery nerve monitoring decreased the incidence of transient but not permanent recurrent laryngeal nerve paresis compared with visualization alone, particularly in high-risk patients (84).

 

 A list of terms relevant to the human embryo was needed for clarity. The Federative International Committee for Anatomical Terminology (FICAT), placed the official list on the Internet in 2009. A hard copy of the terms, including an index, was published in 2013 titled Terminologia Embryologica (TE). .Since there are no branchial or gill arches in the human, the arches are now more appropriately named “pharyngeal aches."

 

Nicholas J. Conrad (US-DE) discovered a female mammoth-ivory figurine in the basal Aurignacian deposit at Hohle Fels Cave in the Swabian Jura of southwestern Germany during excavations in 2008. This figurine was produced at least 35,000 calendar years ago, making it one of the oldest known examples of figurative art. This discovery predates the well-known Venuses from the Gravettian culture by at least 5,000 years and radically changes our views of the context and meaning of the earliest Palaeolithic art (273).

 

Klaus Schmidt (DE) and his team made a startling archaeological discovery between 1995 and 2007: massive carved stones about 11,000 years old, crafted and arranged by prehistoric people who had not yet developed metal tools or even pottery. The megaliths predate Stonehenge by some 6,000 years. The place is called Gobekli Tepe, near the Turkish/Syrian border. Schmidt is convinced it's the site of the world's oldest temple (1294).

 

2010

"The human body is a living, breathing example of the power of nanotechnology. Almost everything happens at the atomic level. Individual molecules are captured and sorted, and individual atoms in these molecules are shuffled from place to place, building entirely new molecules. …These tasks, however, are molecule-sized tasks and the molecular machines in cells have been perfected to operate at the level of atoms." David S. Goodsell (US) (514)

 

Robert Geoffrey Edwards (GB) was awarded the Nobel Prize in Physiology or Medicine for his development of in vitro fertilization. A woman's Fallopian tubes may be blocked or there can be too few eggs or sperm cells. Edwards saw a solution to this: removing an egg from the woman, allowing it to be fertilized in a test tube and then replacing it in the woman. He explained how eggs mature and how sperm is activated, and in cooperation with Patrick Steptoe, found a method for removing eggs from the ovaries. In 1978 the first child was born as a result of in vitro fertilization.

 

János Peti-Peterdi (US) and Arnold Sipos (US) discuss the application, advantages, and limitations of multiphoton excitation fluorescence microscopy for the study of the glomerular filtration barrier and the controversy it recently generated regarding the glomerular filtration of macromolecules. Time-lapse imaging provides new details and important in vivo confirmation of the dynamics of podocyte movement, shedding, replacement, and the role of the parietal epithelial cells and Bowman's capsule in the pathology of glomerulosclerosis (1151).

 

Daniel G. Gibson (US), John I. Glass (US), Carole Lartigue (US), Vladimir N. Noskov (US), Ray-Yuan Chuang (US), Mikkel A. Algire (US), Gwynedd A. Benders (US), Michael G. Montague (US), Li Ma (US), Monzia M. Moodie (US), Chuck Merryman (US), Sanjay Vashee (US), Radha Krishnakumar (US), Nacyra Assad-Garcia (US), Cynthia Andrews-Pfannkoch (US), Evgeniya A. Denisova (US), Lei Young (US), Zhi-Qing Qi (US), Thomas H. Segall-Shapiro (US), Christopher H. Calvey (US), Prashanth P. Parmar (US), Clyde A. Hutchison III (US), Hamilton Othanel (US), and John Craig Venter (US) report the design, synthesis, and assembly of the 1.08–mega–base pair Mycoplasma mycoides JCVI-syn1.0 genome starting from digitized genome sequence information and its transplantation into a M. capricolum recipient cell to create new M. mycoides cells that are controlled only by the synthetic chromosome. The only DNA in the cells is the designed synthetic DNA sequence, including “watermark” sequences and other designed gene deletions and polymorphisms, and mutations acquired during the building process. The new cells have expected phenotypic properties and are capable of continuous self-replication (494).

 

Basel Khraiwesh (DE), M. Asif Arif (DE), Gotelinde I. Seumel (DE), Stephan Ossowski (DE), Detlef Weigel (DE), Ralf Reski (DE), and Wolfgang Frank (DE) discovered a new mechanism of gene regulation; the epigenetic gene silencing by microRNAs. MicroRNAs (miRNAs) control gene expression in animals and plants. Like another class of small RNAs, siRNAs, they affect gene expression posttranscriptionally. While siRNAs in addition act in transcriptional gene silencing, a role of miRNAs in transcriptional regulation has been less clear (758).

 

Daniel R. Neill (GB), See Heng Wong (GB), Agustin Bellosi (GB), Robin J. Flynn (GB), Maria Daly (GB), Theresa K. A. Langford (GB), Christine Bucks (GB), Colleen M. Kane (GB), Padraic G. Fallon (GB), Richard Pannell (GB), Helen E. Jolin (GB), and Andrew N. J. McKenzie (GB) discovered a new innate effector leukocyte (nuocyte) that mediates type‐2 immunity (1057). Note: Type-2 immunity is responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13.

 

Thomas Vierbuchen (US), Austin Ostermeier (US), Zhiping P. Pang (US), Yuko Kokubu (US), Thomas Christian Südhof (US), and Marius Wernig (US) showed that it is possible to directly transform mouse fibroblasts, or skin cells, into neurons (1515).

Samuele Marro (US), Zhiping P. Pang (US), Nan Yang (US), Miao-Chih Tsai (US), Kun Qu (US), Howard Y. Chang (US), Thomas C. Südhof (US), and Marius Wernig (US) demonstrated that terminally differentiated hepatocytes can be directly converted into functional neuronal cells. Importantly, single-cell and genome-wide expression analyses showed that fibroblast- and hepatocyte-derived neuronal cells not only induced a neuronal transcriptional program, but also silenced their donor transcriptome (946).

 

Philip W. Kantoff (US), Celestia S. Higano (US), Neal D. Shore (US), E. Roy Berger (US), Eric Jay Small (US), David F. Penson (US), Charles H. Redfern (US), Anna C. Ferrari (US), Robert Dreicer (US), Robert B. Sims (US), Yi Xu (US), Mark W. Frohlich (US), Paul F. Schellhammer (US), et al. reported that the Food and Drug Administration (FDA) approved sipuleucel-T, a cancer treatment vaccine that is made using a patient's own immune system cells (dendritic cells), for the treatment of metastatic prostate cancer that no longer responds to hormonal therapy. It is the first (and so far only) human cancer treatment vaccine to be approved (736).

 

Michael A. Kohanski (US), Mark A. DePristo (US), and James J. Collins (US) discovered that sublethal levels of antibiotics activate mutagenesis by stimulating the production of reactive oxygen species, leading to multidrug resistance (786). Note: This discovery has important implications for the widespread use and misuse of antibiotics.

 

Henry H. Lee (US), Michael N. Molla (US), Charles R. Cantor (US), and James J. Collins (US) using their systems approaches, discovered a population-based resistance mechanism constituting a form of kin selection whereby a small number of resistant bacterial mutants, in the face of antibiotic stress, can, at some cost to themselves, provide protection to other more vulnerable, cells, enhancing the survival capacity of the overall population in stressful environments (843).

 

Pieter J. de Jonge (NL), Mark van Blankenstein (NL), Caspar W Looman (NL), Mariël K. Casparie (NL), Gerrit A. Meijer (NL), and Ernst J. Kuipers (NL) concluded that the risk of incident esophageal adenocarcinoma among patients with Barritt's esophagus is so minor that, in the absence of dysplasis, routine surveillance of such patients is of doubtful value (324).

Frederik Hvid-Jensen (DK),Lars Pedersen (DK),Asbjørn M. Drewes (DK), Henrik T. Sorensen (DK), and Peter Funch-Jensen (DK) confirmed the conclusion of the de Jonge group above (670).

 

Niels A. van der Gaag (NL), Erik A. J. Rauws (NL), Casper H. J. van Eijck (NL), Marco J. Bruno (NL), Erwin van der Harst (NL), Frank J. G.M. Kubben (NL), Josephus J. G. M. Gerritsen (NL), Jan Willem Greve (NL), Michael F. Gerhards (NL), Ignace H. J. T. de Hingh (NL), Jean H. Klinkenbijl (NL), Chung Y. Nio (NL), Steve M. M. de Castro (NL), Olivier R. C. Busch (NL), Thomas M. van Gulik (NL), Patrick M. M. Bossuyt (NL), and Dirk J. Gouma (NL) used a randomized controlled trial to explore the value of pre-operative biliary drainage for the head of pancreas cancer. They concluded that routine pre-operative biliary drainage in patients undergoing surgery for cancer of the pancreatic head increases the rate of complications (454).

 

Ahmed Al-Khamis (GB), Iain McCallum (GB), Peter M. King (GB), and Julie Bruce (GB) from their meta-analysis of seventeen studies of surgery for pilonidal sinus disease showed a clear benefit in favor of off-midline closure. Overall, open-wound healing results in a lower risk of recurrence than primary closure, but that must be balanced against a longer healing time (26).

 

Wendy S. Atkin (GB), Rob Edwards (GB), Ines Kralj-Hans (GB), Kate Wooldrage (GB), Andrew R. Hart (GB), John M.A. Northover (GB), D. Max Parkin (GB), Jane Wardle (GB), Stephen W. Duffy (GB), Jack Cuzick (GB), and The UK Flexible Sigmoidoscopy Trial Investigators used their multi-center randomized controlled trial to establish that flexible sigmoidoscopy is a safe and practical test which confers a substantial and long-lasting protection from colorectal cancer (59).

 

CRASH-2 Trial Collaborators used an international multi-center randomised placebo-controlled trial to assess the effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage. Tranexamic acid can reduce bleeding in patients undergoing elective surgery. They found that a short course of tranexamic acid given early after injury reduced the risk of death in bleeding trauma patients. There was no increase in vascular occlusive events associated with the use of tranexamic acid in their patient population (268).

 

Rabih O. Darouiche (US), Matthew J. Wall Jr. (US), Kamal M. F. Itani (US), Mary F. Otterson (US), Alexandra L. Webb (US), Matthew M. Carrick (US), Harold J. Miller (US), Samir S. Awad (US), Cynthia T. Crosby (US), Michael C. Mosier (US), Atef Alsharif (US), and David H. Berger (US) showed that pre-operative cleansing of the patient's skin with chlorhexidine-alcohol is superior to cleansing with povidone-iodine for preventing surgical-site infection after clean-contaminated surgery (315). Note: ClinicalTrials.gov number, NCT00290290.

 

Giovanni Battista Gasbarrini (IT), Luca Miele (IT), Gino R. Corazza (IT), and Antonio Gasbarrini (IT) reported the “case of Cosa”, which revealed a skeleton of a first century A.D. young woman at the archaeological site of Cosa, southwest of Tuscany, Italy. She was an 18-20 year-old woman, with signs of failure to thrive and malnutrition. The skeleton showed typical celiac disease damage and the presence of HLA-DQ2.5 (472).

 

Zahi Hawass (EG), Yehia Z. Gad (EG), Somaia Ismail (EG), Rabab Khairat (DE), Dina Fathalla (EG), Naglaa Hasan (EG), Amal Ahmed (EG), Hisham Elleithy (EG), Markus Ball (DE), Fawzi Gaballah (EG), Sally Wasef (EG), Mohamed Fateen (EG), Hany Amer (EG), Paul Gostner (IT), Ashraf Selim (EG), Albert Zink (DE), and Carsten M. Pusch (DE) used genetic fingerprinting to construct a 5-generation pedigree of Pharoah Tutankhamun's immediate lineage. The KV55 mummy and KV35YL were identified as the parents of Tutankhamun. No signs of gynecomastia and craniosynostoses (e.g., Antley-Bixler syndrome) or Marfan syndrome were found, but an accumulation of malformations in Tutankhamun's family was evident. Several pathologies including Köhler disease II were diagnosed in Tutankhamun; none alone would have caused death. Genetic testing for STEVOR, AMA1, or MSP1 genes specific for Plasmodium falciparum revealed indications of malaria tropica in 4 mummies, including Tutankhamun's. These results suggest avascular bone necrosis in conjunction with the malarial infection as the most likely cause of death in Tutankhamun. Walking impairment and malarial disease sustained by Tutankhamun is supported by the discovery of canes and an afterlife pharmacy in his tomb (608).

 

Johannes Krause (DE), Qiaomei Fu (DE), Jeffrey M.Good (US), Bence Viola (DE-AT), Michael V. Shunkov (RU), Anatoli P. Derevianko (RU), and Svante Pääbo (DE), in March 2010, announced the discovery of a finger bone fragment of a juvenile female who lived about 41,000 years ago, found in the remote Denisova Cave in the Altai Mountains in Siberia, a cave that has also been inhabited by Neanderthals and modern humans (802).

David Reich (US-DE), Richard E. Green (DE-US), Martin Kircher (DE), Johannes Krause (DE), Nick Patterson (US), Eric Y. Durand (US), Bence Viola (DE-DE), Adrian W. Briggs (US-DE), Udo Stenzel (DE), Philip L. F. Johnson (US), Tomislav Maricic (DE), Jeffrey M. Good (US), Tomas Marques-Bonet (US-ES), Can Alkan (US), Qiaomei Fu (DE-CN), Swapan Mallick (US), Heng Li (US), Matthias Meyer (DE), Evan E. Eichler (US), Mark Stoneking (DE), Michael Richards (DE-CA), Sahra Talamo (DE), Michael V. Shunkov (RU), Anatoli P. Derevianko (RU), Jean-Jacques Hublin (DE), Janet Kelso (DE), Montgomery Slatkin (US), and Svante Pääbo (DE) sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4-6% of its genetic material to the genomes of present-day Melanesians. They designated this hominin population 'Denisovans' and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans (1220).

Richard E. Green (US-DE), Johannes Krause (DE), Adrian W. Briggs (DE), Tomislav Maricic (DE), Udo Stenzel (DE), Martin Kircher (DE), Nick Patterson (US),Heng Li (US), WeiWei Zhai (CN), Hsi-Yang Fritz (GB), Nancy F.Hansen (US), Eric Y. Durand (US), Anna-Sapfo Malaspinas (US), Jeffrey D. Jensen (US), Tomas Marques-Bonet(US-ES), Can Alkan (US), Kay Prufer (DE), Matthias Meyer (DE), He Rnán A. Burbano (DE), Jeffrey M. Good (US), Rigo Schultz (DE), Ayinuer Aximu-Petri (DE), Anne Butthof (DE), Barbara Hober (DE), Barbara Hoffner (DE), Madlen Siegemund (DE), Antje Weihmann (DE), Chad Nusbaum (US), Eric S. Lander (US), Carsten Russ (US), Nathaniel Novod (US), Jason A. Affourtit (US), Michael Egholm (US), Christine Verna (DE), Pavao Rudan (HR), Dejana Brajkovic (HR), Zeljko Kucan (HR), Gusic Ivan (HR), Vladimir B. Doronichev (RU), Liubov V. Golovanova (RU), Carles Lalueza-Fox (ES), Marco de la Rasilla (ES), Javier Fortea (ES), Antonio Rosas (ES), Ralf W. Schmitz (DE), Philip L. F. Johnson (US), Evan E. Eichler (US), Daniel Falush (IE), Ewan Birney (GB), James C. Mullikin (US), Montgomery Slatkin (US), Rasmus Nielsen (US), Janet Kelso (DE), Michael Lachmann (DE), David Reich (US), and Svante Paabo (DE) provided a draft sequence of the Neanderthal genome (536).

 

Viviane Slon (DE), Fabrizio Mafessoni (DE), Benjamin Vernot (DE), Cesare de Filippo (DE), Steffi Grote (DE), Bence Viola (CA-RU), Mateja Hajdinjak (DE), Stéphane Peyrégne (DE), Sarah Nagel (DE), Samantha Brown (DE), Katerina Douka (DE-GB), Tom Higham (GB), Maxim B. Kozlikin (RU), Michael V. Shunkov (RU), Anatoly P. Derevianko (RU), Janet Kelso (DE), Matthias Meyer (DE), Kay Prüfer (DE), and Svante Pääbo (DE) presented the genome of 'Denisova 11', a bone fragment from Denisova Cave (Russia) and show that it comes from an individual who had a Neanderthal mother and a Denisovan father (1356). Note: The Denisovan or Denisova hominin is an extinct species or subspecies of human in the genus Homo. Pending its status as either species or subspecies it currently carries the temporary name Homo sp. Altai, and Homo sapiens ssp. Denisova.

 

2011

Bruce Alan Beutler (US), Jules Alphonse Hoffmann (LU-FR), and Ralph Marvin Steinman (CA) were awarded the Nobel Prize in Physiology or Medicine. Beutler and Hoffmann contributed to our understanding of how so-called receptors detect microorganisms and activate our innate immunity. In 1996, by studying fruit flies with mutations, Hoffmann showed that the so-called Toll-gene is active in the development of receptors which are crucial for the immune system of the fly, and Steinman for his discovery of the dendritic cell and its role in adaptive immunity.

 

Ravi Prakash (CA), Reginald Paul (CA), and Karan V.I.S. Kaler (CA) announced a microchip for blood tests. Dubbed a microemulsion, a droplet of blood captured inside a layer of another substance. It can control the exact size and spacing of the droplets. The new device could improve the efficiency, accuracy and speed of laboratory tests while also doing it cheaply. A finger prick can be dispensed and made into nano- or picolitre droplets (1178).

 

Ivan K. Dimov (IE-US-CL), Lourdes Basabe-Desmonts (IE), Jose L. Garcia-Cordero (IE), Benjamin M. Ross (US), Antonio J. Ricco (IE), and Luke P. Lee (IE) presented a self-powered integrated microfluidic blood analysis system (SIMBAS) that does not require any external connections, tethers, or tubing to deliver and analyze a raw whole-blood sample. SIMBAS only requires the user to place a 5 μL droplet of whole-blood at the inlet port of the device, whereupon the stand-alone SIMBAS performs on-chip removal of red and white cells, without external valving or pumping mechanisms, followed by analyte detection in platelet-containing plasma. Five complete biotin-streptavidin sample-to-answer assays are performed in 10 min; the limit of detection is 1.5 pM. Red and white blood cells are removed by trapping them in an integral trench structure. Simulations and experimental data show 99.9% to 100% blood cell retention in the passive structure. Powered by pre-evacuation of its PDMS substrate, SIMBAS' guiding design principle is the integration of the minimal number of components without sacrificing effectiveness in performing rapid complete bioassays, a critical step towards point-of-care molecular diagnostics (340).

 

Abdel Karim Khawaldeh (AU), Sandra Marrero Morales (AU), Belinda Dillon (AU), Zemphira Alavidze (US), Andrew N. Ginn (AU), L. Michael Thomas (AU), Scott J. Chapman (AU), Alain Dublanchet (FR), Anthony Smithyman (AU), and Jonathan R. Iredell (AU) describe the success of adjunctive bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection in the context of bilateral ureteric stents and bladder ulceration, after repeated failure of antibiotics alone. No bacteriophage-resistant bacteria arose, and the kinetics of bacteriophage and bacteria in urine suggest self-sustaining and self-limiting infection (757).

 

Judith E. Epstein (US), K. Tewari (US), Kirsten E. Lyke (US), Betty Kim Lee Sim (US), Peter F. Billingsley (US), Matthew B. Laurens (US), Anusha Gunasekera (US), Sumana Chakravarty (US), E. Robinson James (US), Martha Sedegah (US), Adam D. Richman (US), Soundarapaandian Velmurugan (US), Sharina Reyes (US), Minglin Li (US), Kathryn Tucker (US), Adriana Ahumada (US), Adam J. Ruben (US), Tao Li (US), Richard Stafford (US), Abraham G. Eappen (US), Cindy Tamminga (US), Jason W. Bennett (US), Christian F. Ockenhouse (US), Jittawadee R. Murphy (US), Jack L. Komisar (US), Niezold Thomas (US), Mark Loyevsky (US), Airket J. Birkett (US), Christopher V. Plowe (US), Christian Loucq (US), Robert R. Edelman (US), Thomas L. Richie (US), Robert A. Seder (US), and Stephen L. Hoffman (US), using animal studies, demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8(+), IFN-γ-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice). Their results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Plasmodium falciparum malaria (378).

Kirsten E. Lyke (US), Andrew S. Ishizuka (US), Andrea A. Berry (US), Sumana Chakravarty (US), Adam DeZure (US), Mary E. Enama (US), Eric R. James (US), Peter F. Billingsley (US), Anusha Gunasekera (US), Anita Manoj (US), Minglin Li (US), Adam J. Ruben (US), Tao Li (US), Abraham G. Eappen (US), Richard E. Stafford (US), Natasha KC (US), Tooba Murshedkar (US), Floreliz H. Mendoza (US), Ingelise J. Gordon (US), Kathryn L. Zephir (US), LaSonji A. Holman (US), Sarah H. Plummer (US), Cynthia S. Hendel (US), Laura Novik (US), Pamela J. M. Costner (US), Jamie G. Saunders (US), Nina M. Berkowitz (US), Barbara J. Flynn (US), Martha C. Nason (US), Lindsay S. Garver (US), Matthew B. Laurens (US), Christopher V. Plowe (US), Thomas L. Richie (US), Barney S. Graham (US), Mario Roederer (US), B. Kim Lee Sim (US), Julie E. Ledgerwood (US), Stephen L. Hoffman (US), and Robert A. Seder (US) found that a live-attenuated malaria vaccine—Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine)—confers sterile protection against controlled human malaria infection (CHMI) with Plasmodium falciparum (Pf) parasites homologous to the vaccine strain up to 14 months after final vaccination (914).

 

Adriano Boasso (IT-GB), Caroline M. Royle (GB), Spyridon Doumazos (GB), Veronica N. Aquino (US), Maria Biasin (IT), Luca Piacentini (IT), Barbara Tavano (IT), Dietmar Fuchs (AT), Fancesco Mazzott (IT), Sergio Lo Caputo (IT), Gene M. Shearer (US), Mario Clerici (IT), and David R. Graham (US) found that cholesterol is pivotal in maintaining human immunodeficiency virus (HIV) envelope integrity and allowing HIV-cell interaction. By depleting envelope-associated cholesterol to different degrees, they generated virions with reduced ability to activate plasmacytoid dendritic cells (pDC). They found that antigen presenting cell (APC) activation was dissociated from the induction of type I interferon (IFN-α/β) and indoleamine 2,3-dioxygenase-mediated immunosuppression in vitro. Extensive cholesterol withdrawal, resulting in partial protein and RNA loss from the virions, rendered HIV a more powerful recall immunogen for stimulating memory CD8 T cell responses in HIV-exposed uninfected individuals. These enhanced responses were dependent on the inability of cholesterol-depleted HIV to induce IFN-α/β (141).

 

George S. Stergiou (GR) and Ioannis A. Bliziotis (GR) reported there is conclusive evidence that home blood pressure monitoring is useful for the initial diagnosis and the long-term follow-up of treated hypertension. These data are useful for the optimal application of home blood pressure monitoring, which is widely used in clinical practice. More studies on the cost-effectiveness of home blood pressure monitoring are needed (1400).

 

Denise R. Aberle (US), Amanda M. Adams (US), Sarah DeMallo (US), Christine D. Berg (US), William C. Black (US), Jonathan D. Clapp (US), Brenda Brewer (US), Timothy R. Church (US), Kathy L. Clingan (US), Fenghai Duan (US), Richard M. Fagerstrom, Ilana F. Gareen (US), Constantine A. Gatsonis (US), David S. Giarada (US), Pamela M. Marcus (US), JoRean D. Sicks (US), et al., showed that initial results of the National Cancer Institute-sponsored National Lung Cancer Screening Trial (NLST) found that screening with low-dose helical computerized tomography (CT) reduced lung cancer deaths by about 20% in a large group of current and former heavy smokers (9; 10).

 

Marcus G. Pezzolesi (US), G. David Poznik (US), Jan Skupien (US), Adam M. Smiles (US), Josyf C. Mychaleckyj (US), Stephen S. Rich (US), James H. Warram (US), and Andrzej S. Krolewski (US) identified two novel markers that, when elevated in the bloodstream, accurately predict the risk of kidney failure in patients with type 1 and type 2 diabetes (1155).

 

Han-Xiang Deng (US), Wenjie Chen (US), Seong-Tshool Hong (US), Kym M. Boycott (US), George H. Gorrie (US), Nailah Siddique (US), Yi Yang (US), Faisal Fecto (US), Yong Shi (US), Hong Zhai (US), Hujun Jiang (US), Makito Hirano (US), Evadnie Rampersaud (US), Gerard H. Jansen (US), Sandra Donkervoort (US), Eileen H. Bigio (US), Benjamin R. Brooks (US), Kaouther Ajroud (US), Robert L. Sufit (US), Jonathan L. Haines (US), Enrico Mugnaini (US), Margaret A. Pericak-Vance (US), and Teepu Siddique (US) discovered that the basis of the disorder called amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease is a broken down protein recycling system in the neurons of the spinal cord and the brain. Optimal functioning of the neurons relies on efficient recycling of the protein building blocks in the cells. In ALS, that recycling system is broken. The cell can’t repair or maintain itself and becomes severely damaged.

Functional analysis showed that mutations in the UBQLN2 gene lead to an impairment of protein degradation. Therefore, their findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention (330).

 

ACCORD Study Group (US), Hertzel C. Gerstein (CA), Michael E. MillerSaul Genuth (US), Faramarz Ismail-Beigi (US), John B. Buse (US), David C. Goff, Jr. (US), Jeffrey L. Probstfield (US), William C. Cushman (US), Henry N. Ginsberg (US), J. Thomas Bigger (US), Richard H. Grimm, Jr. (US), Robert P. Byington (US), Yves D. Rosenberg (US), and William T. Friedewald (US) concluded that as compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; Clinical Trials. gov number, NCT00000620.) (545).

 

Heidi Ledford (GB) reported that the Food and Drug Administration (FDA) approved the use of ipilimumab, a monoclonal antibody, for the treatment of inoperable or metastatic melanoma. Ipilimumab stimulates the immune system to attack cancer cells by removing a "brake" that normally controls the intensity of immune responses (841).

Omid Hamid (US), Caroline Robert (US), Adil Daud (US), F. Stephen Hodi (US), Wen-Jen Hwu (US), Richard Kefford (US), Jedd D. Wolchok (US), Peter Hersey (US), Richard W. Joseph (US), Jeffrey S. Weber (US), Roxana Dronca (US), Tara C. Gangadhar (US), Amita Patnaik (US), Hassane Zarour (US), Anthony M. Joshua (US), Kevin Gergich (US), Jeroen Elassaiss-Schaap (US), Alain Algazi (US), Christine Mateus (US), Peter Boasberg (US), Paul C. Tumeh (US), Bartosz Chmielowski (US), Scot W. Ebbinghaus (US), Xiaoyun Nicole Li (US), S. Peter Kang (US), and Antoni Ribas (US) found that in patients with advanced I melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects (584). Note: The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. Lambrolizumab is an anti-PD-1 antibody.

 

Juan P. Barret (ES), Joan Gavaldà (ES), Javier Bueno (ES), Xavier Nuvials (ES), Teresa Pont (ES), Nuria Masnou (ES), Maria J. Colomina (ES), Jordi Serracanta (ES), Anna Arno (ES), Pere Huguet (ES), Jose M. Collado (ES), Pere Salamero (ES), Carlos Moreno (ES), Roser Deulofeu (ES), and Vicenç Martínez-Ibáñez (ES) reported a "full" face transplant including all intact aesthetic and functional units. In a 24-hour operation, a Spanish farmer who had accidentally shot himself had the remains of his face removed, leaving just his eyeballs and tongue. The rest was replaced by the entire face of a dead donor. The patient was discharged from the hospital at 4 months post-transplant with; near-total sensation and partial-motor recovery, no psychological complications and excellent acceptance of his new facial appearance (86).

 

Katia F. Güenaga (BR), Delcio Matos (BR), and Peer Wille‐Jørgensen (DK) concluded from their meta-analysis survey with a total of 5805 participants, there is no statistically significant evidence that patients benefit from mechanical bowel preparation, nor the use of rectal enemas. In colonic surgery the bowel cleansing can be safely omitted and induces no lower complication rate (564).

 

Craig Nesbitt (GB), Ron K.G. Eifell (GB), Peter Coyne (GB), Hassan Badri (GB), Vish Bhattacharya (GB), and Gerard Stansby (GB) reported that currently available clinical trial evidence suggests radiofrequency ablation and endovenous laser therapy are at least as effective as surgery in the treatment of great saphenous varicose veins. There were insufficient data to comment on ultrasound‐guided foam sclerotherapy (1062).

 

Alyssa Bell (US) and Mike Everhart (US) found a Late Cretaceous (~ 86 mya) fossil skeleton of Ichthyornis dispar in Russell County, north-central Kansas. This transitional bird fossil possessed anatomical features of both dinosaurs and birds (106).

 

Michael R. Waters (US), Steven L. Foreman (US), Thomas A. Jennings (US), Lee C. Nordt (US), Steven G. Driese (US), Joshua M. Feinberg (US), Joshua L. Keene (US), Jessi Halligan (US), James Pierson (US), Charles T. Hallmark (US), Michael B. Collins (US), and James E. Wiederhold (US) provided archaeological evidence of a human presence in the Americas that pre-dates the Clovis peoples, who until recently were thought to be the first humans to explore and settle North America. The site's pre-Clovis occupation is supported by numerous lines of evidence including optically stimulated luminescence(OSL) dates ranging from 13,200-15,500 before present, undisturbed stratigraphy, and an extensive stone tool assemblage (1547). Note: OSL is a technique that analyzes light energy trapped in sediment particles to identify the last time the soil was exposed to sunlight.

 

Tudor Rus (RU), Spedova Stei (RU), Mihai Besesek (RU), Valentin Alexandru Radu (RU), Roxana Laura Tociu (RU), Marius Kenesz (RU), Viorel Traian Lascu (RO), and Calin Ghemis (RO) discovered that Coliboaia Cave located in the Sighistel Valley, near the village of Campani, Bihor County, Romania, contained cave paintings from c. 29,000 BCE These painting correspond to the Aurignacian and Gravettian cultures of the Paleolithic period. A French team of archaeologists composed of Marcel Meyssonnier, Valerie Plichon, Michel Philippe, Francoise Prud'homme, Jean Clottes, and Bernard Gély attested to the authenticity of the paintings (77; 263; 1641).

 

2012

John Bertrand Gurdon (GB) and Shinya Yamanaka (JP) were awarded the Nobel Prize in Physiology or Medicine for discovery that mature cells can be reprogrammed to become pluripotent.

 

Brian K. Kobilka (US) was awarded the Nobel Prize in Chemistry for studies of G-protein-coupled receptors.

 

Amy K. Barczak (US), James E. Gomez (US), Benjamin B. Kaufmann (US), Ella R. Hinson (US), Lisa Cosimi (US), Mark L. Borowsky (US), Andrew B. Onderdonk (US), Sarah A. Stanley (US), Devinder Kaur (US), Kevin F. Bryant (US), David M. Knipe (US), Alexander Sloutsky (US), and Deborah T. Hung (US) showed that a detailed RNA signature of specific pathogens can identify a broad spectrum of infectious agents, forming the basis of a diagnostic platform to earlier determine the best treatment option for infectious diseases (83).

 

Jordan S. Miller (US), Kelly R. Stevens (US), Michael T. Yang (US), Brendon M. Baker (US), Duc-Huy T. Nguyen (US), Daniel M. Cohen (US), Esteban Toro (US), Alice A. Chen (US), Peter A. Galie (US), Xiang Yu (US), Ritika Chaturvedi (US), Sangeeta N. Bhatia (US), and Christopher S. Chen (US) developed a new technique for creating blood vessel networks using a 3D printer and some sugar. The two are used to build a template for the vessel network — first scientists design the network, before feeding the design into a RepRap 3D printer, which then builds it using sugar. Once the sugar gets suitably hard it's coated with a gel containing liver cells. Then, after the gel sets, the sugar is flushed out through the vessels, leaving behind a functional vascular network (998)

Lothar Koch (DE), Andrea Deiwick (DE), Sabrina Schlie (DE), Stefanie Michael (DE), Martin Gruene (DE), Vincent Coger (DE), Daniela Zychlinski (DE), Axel Schambach (DE), Kerstin Reimers (DE), Peter M. Vogt (DE), and Boris Chichkov (DE) demonstrated for the first time the 3D arrangement of vital cells by Laser-assisted BioPrinting (LaBP) as multicellular grafts analogous to native archetype and the formation of tissue by these cells. For this purpose, fibroblasts and keratinocytes embedded in collagen were printed in 3D as a simple example for skin tissue. To study cell functions and tissue formation process in 3D, different characteristics, such as cell localisation and proliferation were investigated. They further analysed the formation of adhering and gap junctions, which are fundamental for tissue morphogenesis and cohesion. In this study, it was demonstrated that LaBP is an outstanding tool for the generation of multicellular 3D constructs mimicking tissue functions (783).

Alyssa J. Reiffel (US), Concepcion Kafka (US), Karina A. Hernandez (US), Samantha Popa (US), Justin L. Perez (US), Sherry Zhou (US), Satadru Pramanik (US), Bryan N. Brown (US), Won Seuk Ryu (US), Lawrence J. Bonassar (US), and Jason A. Spector (US) used computerized scanning, 3D printers and cartilage from cows to create living prosthetic ears. Over a three-month period, these flexible ears grew cartilage to replace the collagen that was used to mold them (1223).

 

Richard Harris Epstein (CH), Antoinette Bolle (CH), and Charles M. Steinberg (US) isolated a large number of mutants of bacteriophage T4D that are unable to form plaques on strain B of Escherichia coli, but are able to grow (nearly) normally on some other strains of E. coli, in particular strain CR63. These mutants, designated amber (am), have been characterized by complementation tests, by genetic crosses, and by their response to chemical mutagens. It is concluded that a particular subclass of base substitution mutations may give rise to amber mutants and that such mutants occur in many genes, which are widely distributed over the T4 genome (379). Note: This work was done in 1962, however the results were not publisher until 50 years later. The amber-mutants of the T4 bacteriophage led to the recognition of stop codons.

 

Anthony L. Forget (US) and Stephen C. Kowalczykowski (US) proposed a model for the DNA homology search process termed ‘intersegmental contact sampling’, in which the intrinsic multivalent nature of the RecA nucleoprotein filament is used to search DNA sequence space within 3D domains of DNA, exploiting multiple weak contacts to rapidly search for homology. Our findings highlight the importance of the 3D conformational dynamics of DNA, reveal a previously unknown facet of the homology search, and provide insight into the mechanism of DNA target location by this member of a universal family of proteins (431). Note: DNA breaks can be repaired with high fidelity by homologous recombination. A ubiquitous protein that is essential for this DNA template-directed repair is RecA1. After resection of broken DNA to produce single-stranded DNA (ssDNA), RecA assembles on this ssDNA into a filament with the unique capacity to search and find DNA sequences in double-stranded DNA (dsDNA) that are homologous to the ssDNA. This homology search is vital to recombinational DNA repair, and results in homologous pairing and exchange of DNA strands. Homologous pairing involves DNA sequence-specific target location by the RecA–ssDNA complex. Despite decades of study, the mechanism of this enigmatic search process remains unknown.

 

William C. Ratcliff (US), R. Ford Denison (US), Mark Borrello (US), and Michael Travisano (US) showed that key steps in the transition from unicellular to multicellular life style could have occurred quickly. They subjected the unicellular yeast Saccharomyces cerevisiae to an environment in which they expected multicellularity to be adaptive. A rapid evolution of clustering genotypes that display a novel multicellular life history characterized by reproduction via multicellular propagules, a juvenile phase, and determinate growth was observed. The multicellular clusters are uniclonal, minimizing within-cluster geneticconflicts of interest. Simple among-cell division of labor rapidly evolved (1213).

 

Lavinia Paternoster (GB), Alexei I. Zhurov (GB), Arshed M. Toma (GB), John P. Kemp (GB), Beate St. Pourcain (GB), Nicholas J. Timpson (GB), George McMahon (GB), Wendy McArdle (GB), Susan M. Ring (GB), George Davey Smith (GB), Stephen Richmond (GB), and David M.Evans (GB), in a genome-wide association study of human facial morphology, identified an association between rs7559271 and nasion (nose) position in a population cohort of 15-year-olds. They noted that common variants within this gene also influence normal craniofacial development (1135).

Catia Attanasio (US), Alex S. Nord (US), Yiwen Zhu (US), Matthew J. Blow (US), Zirong Li (US), Denise K. Liberton (CA), Harris Morrison (GB), Ingrid Plajzer-Frick(US), Amy Holt (US), Roya Hosseini (US), Sengthavy Phouanenavong (US), Jennifer A. Akiyama (US), Malak Shoukry (US), Veena Afzal (US), Edward M. Rubin (US) David R. FitzPatrick (GB) Bing Ren (US), Benedikt Hallgrímsson (CA), Len A. Pennacchio (US), and Axel Visel (US) identified more than 4000 candidate enhancer sequences predicted to be active in the developing craniofacial complex (60).

Peter Claes (BE), Harold Hill (AU), and Mark D. Shriver (US) made the first effort at generating human facial composites from DNA information (256).

Jasmien Roosenboom (BE), Greet Hens (BE), Brooke C. Mattern (US), Mark D. Shriver (US), and Peter Clae (BE) focused on the various sources of knowledge regarding the genes that affect patterns of craniofacial development (1253).

John R. Shaffer (US), Ekaterina Orlova (US), Myoung Keun Lee (US), Elizabeth J. Leslie (US), Zachary D. Raffensperger (US),Carrie L. Heike (US),Michael L. Cunningham (US), Jacqueline T. Hecht (US), Chung How Kau (US), Nichole L. Nidey (US), Lina M. Moreno (US), George L. Wehby (US), Jeffrey C. Murray (US), Cecelia A. Laurie (US), Cathy C. Laurie (US), Joanne Cole (US), Tracey Ferrara (US), Stephanie Santorico (US), Ophir Klein (US), Washington Mio (US), Eleanor Feingold (US), Benedikt Hallgrimsson (CA), Richard A. Spritz (US), Mary L. Marazita (US), and Seth M. Weinberg (US) provided further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features (1324).

Peter Claes (BE), Jasmien Roosenboom (US), Julie D. White (US), Tomek Swigut (US), Dzemila Sero (BE), Jiarui Li (BE) (US), Myoung Keun Lee (US), Arslan Zaidi (US), Brooke C. Mattern (US), Corey Liebowitz (US), Laurel Pearson (US), Tomás González (US), Elizabeth J. Leslie (US), Jenna C. Carlson (US), Ekaterina Orlova (US), Paul Suetens (BE), Dirk Vandermeulen (BE), Eleanor Feingold (US), Mary L. Marazita (US), John R. Shaffer (US), Joanna Wysocka (US), Mark D. Shriver (US), and Seth M. Weinberg (US) reported a data-driven approach to phenotyping facial shape at multiple levels of organization, allowing for an open-ended description of facial variation while preserving statistical power (257).

 Ziyi Xiong (CN), Gabriela Dankova (NL), Laurence J. Howe (GB), Myoung Keun Lee (US), Pirro G. Hysi (GB), Markus A. de Jong (NL), Gu Zhu, Kaustubh Adhikari (GB), Dan Li (CN), Yi Li (CN), Bo Pan (CN), Eleanor Feingold (US), Mary L. Marazita (US), John R. Shaffer (US), Kerrie McAloney (AU), Shuhua Xu (CN), Li Jin (CN), Sijia Wang (CN), Femke M. de Vrij (NL), Bas Lendemeijer (NL), Stephen Richmond (GB), Alexei Zhurov (GB), Sarah Lewis GB), Gemma Sharp (GB), Lavinia Paternoster (GB), Holly Thompson (GB), Rolando Gonzalez-Jose (AR), Maria Catira Bortolini (BR), Samuel Canizales-Quinteros (MX), Carla Gallo (PE), Giovanni Poletti (PE), Gabriel Bedoya (CO), Francisco Rothhammer (CL), André G. Uitterlinden (NL), M. Arfan Ikram (NL), Eppo B. Wolvius (NL), Steven A. Kushner (NL), Tamar Nijsten (NL), Robert-Jan Palstra (NL), Stefan Boehringer (NL), Sarah E. Medland (AU), Kun Tang (CN), Andrés Ruiz-Linares (CN), Nicholas G. Martin (AU), Timothy D. Spector (GB), Evie Stergiakouli (GB), Seth M. Weinberg (US), Fan Liu (CN-NL), and Manfred Kayser (NL), on behalf of the International Visible Trait Genetics (VisiGen) Consortium advanced our understanding of the genetic basis underlying human facial variation and provided candidates for future in-vivo functional studies (1600).

 

Augustine Kong (IS), Michael L. Frigge (IS), Gisli Masson (IS), Soren Besenbacher (IS), Patrick Sulem (IS), Gisli Magnusson (IS), Sigurjon A. Gudjonsson (IS), Asgeir Sigurdsson (IS), Aslaug Jonasdottir (IS), Adalbjorg Jonasdottir (IS), Wendy S. W. Wong (GB), Gunnar Sigurdsson (IS), G. Bragi Walters (IS), Stacy Steinberg (IS), Hannes Helgason (IS), Gudmar Thorleifsson, Daniel F. Gudbjartsson (IS), Agnar Helgason (IS), Olafur Th. Magnusson (IS), Unnur Thorsteinsdottir (IS), and Kári Stefánsson (IS) demonstrated that the number of de novo mutations — variants that appear in the genomes of children but are not inherited from either parent — increases with paternal age and constitute a major source of rare diseases of childhood (794).

Hákon Jónsson (IS), Patrick Sulem (IS), Birte Kehr (IS), Snaedis Kristmundsdottir (IS), Florian Zink (IS), Eirikur Hjartarson (IS), Marteinn T. Hardarson (IS), Kristjan E. Hjorleifsson (IS), Hannes P. Eggertsson (IS), Sigurjon Axel Gudjonsson (IS), Lucas D. Ward (IS), Gudny A. Arnadottir (IS), Einar A. Helgason (IS), Hannes Helgason (IS), Arnaldur Gylfason (IS), Adalbjorg Jonasdottir (IS), Aslaug Jonasdottir (IS), Thorunn Rafnar (IS), Mike Frigge (IS), Simon N. Stacey (IS), Olafur Th. Magnusson, (IS) Unnur Thorsteinsdottir (IS), Gisli Masson (IS), Augustine Kong (IS), Bjarni V. Halldorsson (IS), Agnar Helgason (IS), Daniel F. Gudbjartsson (IS), and Kári Stefánsson (IS) performed a detailed analysis of the different types and distribution of maternal and paternal de novo mutations (718).

Hákon Jónsson (IS), Patrick Sulem (IS),Gudny A. Arnadottir (IS), Gunnar Pálsson (IS), Hannes P. Eggertsson (IS), Snaedis Kristmundsdottir (IS), Florian Zink (IS), Birte Kehr (IS), Kristjan E. Hjorleifsson (IS), Brynjar Ö. Jensson (IS), Ingileif Jonsdottir (IS), Sigurdur Einar Marelsson (IS), Sigurjon Axel Gudjonsson (IS), Arnaldur Gylfason (IS), Adalbjorg Jonasdottir (IS), Aslaug Jonasdottir (IS), Simon N. Stacey (IS), Olafur Th. Magnusson (IS), Unnur Thorsteinsdottir (IS), Gisli Masson (IS), Augustine Kong (IS), Bjarni V. Halldorsson (IS), Agnar Helgason (IS), Daniel F. Gudbjartsson (IS), and Kári Stefánsson (IS) demonstrated how de novo mutations in parents can be passed on to offspring (717).

 

Thorlakur Jonsson (IS), Jasvinder K. Atwal (US), Stacy Steinberg (IS), Jon Snaedal (IS), Palmi V. Jonsson (IS), Sigurbjorn Bjornsson (IS), Hreinn Stefánsson (IS), Patrick Sulem (IS), Daniel Gudbjartsson (IS), Janice Maloney (US), Kwame Hoyte (US), Amy Gustafson (US), Yichin Liu (US), Yanmei Lu (US), Tushar Bhangale (US), Robert R. Graham (US), Johanna Huttenlocher (IS), Gyda Bjornsdottir (IS), Ole A. Andreassen (NO), Erik G. Jönsson (SE), Aarno Palotie (FI), Timothy W. Behrens (US), Olafur T. Magnusson (IS), Augustine Kong (IS), Unnur Thorsteinsdottir (IS), Ryan J. Watts (US), and Kári Stefánsson (IS) discovered a variant in the Amyloid Beta Precursor Protein (APP) gene that protects carriers against Alzheimer's disease (AD) and protects the elderly from cognitive decline. It has been widely cited and used to inform the development of BACE1 inhibitors as potential treatments (719).

Thorlakur Jonsson (IS), Hreinn Stefánsson (IS), Stacy Steinberg (IS), Ingileif Jonsdottir (IS), Palmi V. Jonsson (IS), Jon Snaedal (IS), Sigurbjorn Bjornsson (IS), Johanna Huttenlocher (DE), Allan I. Levey (US), James J. Lah (US), Dan Rujescu (DE), Harald Hampel (DE), Ina Giegling (DE), Ole A. Andreassen (NO), Knut Engedal (NO), Ingun Ulstein (NO), Srdjan Djurovic (NO), Carla Ibrahim-Verbaas (NL), Albert Hofman (NL), M. Arfan Ikram (NL), Cornelia M. van Duijn (NL), Unnur Thorsteinsdottir (IS), Augustine Kong (IS), and Kári Stefánsson (IS) discovered variants in the Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and ATP-binding cassette A7 (ABCA7), genes that increase risk of Alzheimer's disease (AD) (720).

 

Jun Ma (US), Denise G. Grant-Lanza (US), Ian Guest (US), Chang Uk-Lim (US), Anna G. Glinskii (US), Gennadi Glinsky (US), and Stewart S. Sell (US) characterized breast cancer stem cells using a mouse model (533; 917).

 

Abbas Chabok (SE), Lars Pahlman (SE), Fredrik Hjern (SE), Staffan Haapaniemi (SE), Kenneth Smedh (SE), Pär Myrelid (SE), Tryggvi Stefánsson (IS), M. Sudén (?), Urban Ersson (SE), Helena Laurell (SE), Göran Liljegren (SE), A. Fara (?), and the Avod Study Group determined that the use of antibiotics for uncomplicated diverticulitis does not accelerate recovery, reduce complications, or prevent recurrence (223).

 

Robert E. Schoen (US), Paul F. Pinsky (US), Joel L. Weissfeld (US), Lance A. Yokochi (US), Timothy Church (US), Adeyinka O. Laiyemo (US), Robert Bresalier (US), Gerald L. Andriole (US), Saundra S. Buys (US), E. David Crawford (US), Mona N. Fouad (US), Claudine Isaacs (US), et al. reported results of the National Cancer Institute-sponsored Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which confirmed that screening people 55 years of age and older for colorectal cancer using flexible sigmoidoscopy reduces colorectal cancer incidence and mortality. In the PLCO, screened individuals had a 21% lower risk of developing colorectal cancer and a 26% lower risk of dying from the disease than the control subjects (1298).

 

David Emil Reich (US), Nick Patterson (US), Desmond Campbell (US), Arti Tandon (US), Stéphane Mazieres (US), Nicolas Ray (US), Maria V. Parra (US), Winston Rojas (US), Constanza Duque (US), Natalia Mesa (US), Luis F. García (US), Omar Triana (US), Silvia Blair (US), Amanda Maestre (US), Juan C. Dib (US), Claudio M. Bravi (US), Graciela Bailliet (US), Daniel Corach (US), Tábita Hünemeier (US), Maria Cátira Bortolini (US), Francisco M. Salzano (US), María Luiza Petzl-Erler (US), Victor Acuña-Alonzo (US), Carlos Aguilar-Salinas (US), Samuel Canizales-Quinteros (US), Teresa Tusié-Luna (US), Laura Riba (US), Maricela Rodríguez-Cruz (US), Mardia Lopez-Alarcón (US), Ramón Coral-Vazquez (US), Thelma Canto-Cetina (US), Irma Silva-Zolezzi (US), Juan Carlos Fernandez-Lopez (US), Alejandra V. Contreras (US), Gerardo Jimenez-Sanchez (US), Maria José Gómez-Vázquez (US), Julio Molina (US), Ángel Carracedo (US), Antonio Salas (US), Carla Gallo (US), Giovanni Poletti (US), David B. Witonsky (US), Gorka Alkorta-Aranburu (US), Rem I. Sukernik (US), Ludmila Osipova (US), Sardana A. Fedorova (US), René Vasquez (US), Mercedes Villena (US), Claudia Moreau (US), Ramiro Barrantes (US), David Pauls (US), Laurent Excoffier (US), Gabriel Bedoya (US), Francisco Rothhammer (US), Jean-Michel Dugoujon (US), Georges Larrouy (US), William Klitz (US), Damian Labuda (US-CA), Judith Kidd (US), Kenneth Kidd (US), Anna Di Rienzo (US), Nelson B. Freimer (US), Alkes L. Price (US), and Andrés Ruiz-Linares (US) analyzed more than 300,000 DNA sequence variations from Native American and Siberian human populations. They revealed that North and South America were populated in three ancient waves of migration (1221).

 

By circa 2012 digital databases were assembled that contain the restored morphology of the best specimens sectioned in the Carnegie Human Embryo Collection at each of the 23 stages (one stage came from the Boyd Collection in Cambridge, England). At least one database was assembled for each stage. As many as 40 structures are labeled in each section image at the lowest magnification (i.e., zoom level 1), using the official terminology from Terminologia Embryologica throughout. Overall, the project produced approximately 34 gigabytes of human embryonic imagery that is now housed in the Computer Imaging Lab in the LSUHSC Department of Cell Biology and Anatomy in New Orleans, Louisiana. All of the databases can be viewed on the Internet at: http://virtualhumaembryo.lsuhsc.edu.

 

 In 2012, a team of geneticists and historians announced they had excavated the remains of Richard III, former king of England. The skeleton showed signs of spinal curvature and DNA evidence from his descendants supported the find.

 

Darren Curnoe (AU), Ji Xueping (CN), Andy I. R. Herries (AU), Bai Kanning (CN), Paul S. C. Taçon (AU), Bao Zhende (CN), David Fink (AU), Zhu Yunsheng (CN), John Hellstrom (AU), Luo Yun (CN), Gerasimos Cassis (AU), Su Bing (CN), Stephen Wroe (AU), Hong Shi (CN), William C. H. Parr (AU), Huang Shengmin (CN), and Natalie Rogers (AU) reported that the Red Deer Cave People were the most recent known prehistoric archaic human population. Their fossils, dated to between 14,500 and 11,500 years old, were found in Red Deer Cave and Longlin Cave in China. Tentatively they are thought to be a separate species of humans that persisted until recent times and became extinct without contributing to the gene pool of modern humans (303).

 

Yadong Sun (CN), Michael M. Joachimski (DE), Paul B. Wignall (GB), Chunbo Yan (CN), Yanlong Chen (AT), Haishui Jiang (CN), Lina Wang (CN), and Xulong Lai (CN) suggested that the "Siberian Traps" are the primary cause of the Permian–Triassic extinction event, the most severe extinction event in the geologic record (1419). Note: The "Siberian Traps" is a large region of volcanic rock, known as a large igneous province, in Siberia, Russia. The massive eruptive event that formed the traps is one of the largest known volcanic events in the last 500 million years. The eruptions continued for roughly two million years and spanned the Permian–Triassic boundry, or P–T boundary, which occurred around 251.9 million years ago.

 

2013

James Edward Rothman (US), Randy Wayne Schekman (US), and Thomas Christian Südhof (DE-US) were awarded the Nobel Prize in Physiology or Medicine for discoveries of machinery regulating vesicle traffic, a major transport mechanism in cells.

 

Brenda L. Bloodgood (US), Nikhil Sharma (US), Heidi Adlman Browne (US), Alissa Z. Trepman (US), and Michael E. Greenberg (US) found that environmental stimuli activate certain sections of DNA, enhancing the process by which messenger RNAs are created, and that these “enhancer regions” play a role in driving gene expression, the first evidence of widespread enhancer transcription (139).

 

Sutada Lotinun (US), Riku Kiviranta (US), Takuma Matsubara (US), Jorge A. Alzate (US), Lynn Neff (US), Anja Lüth (US), Ilpo Koskivirta (US), Burkhard Kleuser (US), Jean Vacher (US), Eero Vuorio (US), William C. Horne (US), and Roland Baron (US) revealed pathways by which the gene cathepsin K promotes bone resorption and formation, pointing to potential new therapies for osteoporosis (899).

 

Erik L. Brincks (US), Alan D. Roberts (US), Tres Cookenham (US), Stewart S. Sell (US), Jacob E. Kohlmeier (US), Marcia A. Blackman (US), and David L. Woodland (US) demonstrated the existence of a previously undescribed population of Ag-specific memory regulatory CD4(+)Foxp3(+) T cells (Tregs) that shape the cellular immune response to secondary influenza virus challenges and offer an additional parameter to consider when determining the efficacy of vaccinations (162).

 

Jose Agustin Arguedas (CR), Viriam Leiva (CR), and James M. Wright (CR) found that at the present time, evidence from randomized trials does not support blood pressure targets lower than the standard targets in people with elevated blood pressure and diabetes. More randomized controlled trials are needed, with future trials reporting total mortality, total serious adverse events as well as cardiovascular and renal events (47).

 

The SPS3 Study Group investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. Although the reduction in stroke was not significant, their results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial (551).

 

George Bakris (US), Alexandros Briasoulis (US), Bjorn Dahlof (SE), Kenneth Jamerson (US), Michael A. Weber (US), Roxzana Y. Kelly (US), Allen Hester (US), Tsushung Hua (US), Dion Zappe (US), Bertram Pitt (US), and ACCOMPLISH Investigators (US) presented findings suggesting that the combination of benazepril plus amlodipine should be preferentially used for older patients with high-risk, stage 2 hypertension (76).

 

Rodrigo P. Pedrosa (BR), Luciano F. Drager (BR), Lílian K. G. de Paula (BR), Aline C. S. Amaro (BR), Luiz A. Bortolotto (BR), and Geraldo Lorenzi-Filho (BR) found that treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) significantly reduces daytime blood pressure in patients with resistant hypertension. Therefore, their study reinforces the importance of recognizing and treating obstructive sleep apnea in patients with resistant hypertensin. ClinicalTrials.gov; No.: NCT00812695 (1141).

 

Albert Tsao (NO), May-Britt Moser (NO), Edvard Ingjald Moser (NO), Jørgen Sugar (NO), Li Lu (US-NO), Cheng Wang (US), and James J. Knierim (US) reported that populations of lateral entorhinal cortex neurons represent time inherently through the encoding of experience. This representation of episodic time may be integrated with spatial inputs from the medial entorhinal cortex in the hippocampus, allowing the hippocampus to store a unified representation of what, where and when (1475; 1476).

 

Lawrence T. Goodnough (US), Jerrold H. Levy (US), Michael F. Murphy (US), and Donat R. Spahn (CH) reported that clinicians in the Stanford Hospital, California were encouraged to reduce orders for red blood cell transfusions except when absolutely required. In five years, transfusions at the hospital fell by twenty-five percent. The result was not only a $1.6 million savings in costs but fewer deaths, quicker average discharges, and a reduction in post-treatment complications (512; 513; 1380).

 

Tamas David-Barrett (GB) and Robert Ian MacDonald Dunbar (GB) formulated Dunbar's number, a measurement of the "cognitive limit to the number of individuals with whom any one person can maintain stable relationships" (358; 359).

 

2014

Edvard Ingjald Moser (NO), May-Britt Moser (NO), and John O´Keefe (US-GB) were awarded the Nobel Prize in Physiology or Medicine for discoveries of cells that constitute a positioning system in the brain.

 

Eric Betzig (US), Stefan W. Hell (DE), and William E. Moerner (US) were awarded the Nobel Prize in Chemistry for their development of super-resolved fluorescence microscopy.

 

Jonah Riddell (US), Roi Gazit (US), Brian S. Garrison (US), Guoji Guo (US), Assieh Saadatpour (US), Pankaj K. Mandal (US), Wataru Ebina (US), Guo-Cheng Yuan (US), Stuart H. Orkin (US), and Derrick J. Rossi (US) reprogrammed mature blood cells into blood-forming hematopoietic stem cells, thereby extending the possibility of transplantation to patients for whom a histocompatible donor cannot be identified (1235).

 

Felicia W. Pagliuca (US), Jeffrey R. Millman (US), Mads Gürtler (US), Michael Segel (US), Alana Van Dervort (US), Jennifer H. Ryu (US), Quinn P. Peterson (US), Dale Greiner (US), and Douglas A. Melton (US) successfully generated mature human insulin-producing pancreatic beta cells from stem cells in vitro, which, when transplanted into mice, secreted insulin appropriately in response to glucose level (1118).

 

Kyle W. McCracken (US), Emily M. Catá (US), Katie L. Sinagoga (US), Michael Schumacher (US), Briana E. Rockich (US), Yu-Hwai Tsai (US), Christopher N. Mayhew (US), Jason R. Spence (US), Yana Zavros (US), Eitaro Aihara (US), Baptiste Martin (US), Calyn M. Crawford (US), Taylor Broda (US), Julie Treguier (US), Xinghao Zhang (US), John M. Shannon (US), Marshall H. Montrose (US), and James M. Wells (US) differentiated human pluripotent stem cells (hPSCs) into gastric organoids containing fundic epithelium by first identifying and then recapitulating key events in embryonic fundus development (967; 968).

 

Atlántida M. Raya-Rivera (MX), Diego Esquiliano (MX), Reyna Fierro-Pastrana (MX), Esther López-Bayghen (MX), Pedro Valencia (MX), Ricardo Ordorica-Flores (MX), Shay Soker (US), James J. Yoo (US), and Anthony Atala (US) assessed the use of engineered vaginal organs in four patients with vaginal aplasia caused by Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) (1216).

 

Ebola virus disease (EVD) emerged at unprecedented epidemic levels in 2014. The center of the epidemic occurred in Sierra Leone, Guinea, and Liberia. Nigeria and Senegal saw small outbreaks related to importations from more heavily affected countries, but they were able to contain spread of the disease. In total, 15,261 confirmed, probable, and suspected deaths occurred, including two in the United States. More than 28,000 cases of EVD were reported (988).

 

Chetan Bettegowda (US), Mark Sausen (US), Rebecca J. Leary (US), Isaac Kinde (US), Yuxuan Wang (US), Nishant Agrawal (US), Bjarne R. Bartlett (US), Hao Wang (US), Brandon Luber (US), Rhoda M. Alani (US), Emmanuel S. Antonarakis (US), Nilofer S. Azad (US), Alberto Bardelli (IT), Henry Brem (US), John L. Cameron (US), Clarence C. Lee (US), Leslie A. Fecher (US), Gary L. Gallia (US), Peter Gibbs (AU), Dung Le (US), Robert L. Giuntoli (US), Michael Goggins (US), Michael D. Hogarty (US), Matthias Holdhoff (US), Seung-Mo Hong (KR-US, Yuchen Jiao (US), Hartmut H. Juhl (DE), Jenny J. Kim (US), Giulia Siravegna (IT), Daniel A. Laheru (US), Calogero Lauricella (IT), Michael Lim (US), Evan J. Lipson (US), Suely Kazue Nagahashi Marie (BR), George J. Netto (US), Kelly S. Oliner (US), Alessandro Olivi (US), Louise Olsson (SE), Gregory J. Riggins (US), Andrea Sartore-Bianchi (IT), Kerstin Schmidt (US), le-Ming Shih (US), Sueli Mieko Oba-Shinjo (BR), Salvatore Siena (IT), Dan Theodorescu (US), Jeanne Tie (AU), Timothy T. Harkins (US), Silvio Veronese (IT), Tian-Li Wang (US), Jon D. Weingart (US), Christopher L. Wolfgang (US), Laura D. Wood (US), Dongmei Xing (US), Ralph H. Hruban (US), Jian Wu (US), Peter J. Allen (US), C. Max Schmidt (US), Michael A. Choti (US), Kenneth W. Kinzler (US), Bert Vogelstein (US), Nickolas Papadopoulos (US), and Luis A. Diaz Jr. (US) used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. They found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively (122).

 

Yukinori Okada (US), Di Wu (US), Gosia Trynka (US), Towfique Raj (US), Chikashi Terao (JP), Katsunori Ikari (JP), Yuta Kochi (JP), Koichiro Ohmura (JP), Akari Suzuki (JP), Shinji Yoshida (JP), Robert R. Graham (US), Arun Manoharan (US), Ward Ortmann (US), Tushar Bhangale (US), Joshua C. Denny (US), Robert J. Carroll (US), Anne E. Eyler (US), Jeffrey D. Greenberg (US), Joel M. Kremer (US), Dimitrios A. Pappas (US), Lei Jiang (CN), Jian Yin (CN), Lingying Ye (CN), Ding-Feng Su (CN), Jian Yang (AU), Gang Xie (CA), Ed Keystone (CA), Harm-Jan Westra (NL), Tõnu Esko (US), Andres Metspalu (EE), Xuezhong Zho (CN), Namrata Gupta (US), Daniel Mirel (US), Eli A. Stahl (US), Dorothée Diogo (US), Jing Cui (US), Katherine Liao (US), Michael H. Guo (US), Keiko Myouzen (JP), Takahisa Kawaguchi (JP), Marieke J. H. Coenen (NL), Piet L. C. M. van Riel (NL), Mart A. F. J. van de Laar (NL), Henk-Jan Guchelaar (NL), Tom W. J. Huizinga (NL), Philippe Dieudé (FR), Xavier Mariette (FR), S. Louis Bridges, Jr. (US), Alexandra Zhernakova (NL), Rene E. M. Toes (NL), Paul P. Tak (NL), Corinne Miceli-Richard (FR), So-Young Bang (KR), Hye-Soon Lee (KR), Javier Martin (ES), Miguel A. Gonzalez-Gay (ES), Luis Rodriguez-Rodriguez (ES), Solbritt Rantapää-Dahlqvist (SE), Lisbeth Arlestig (SE), Hyon K. Choi (US), Yoichiro Kamatani (FR), Pilar Galan (FR), Mark Lathrop (CA), RACI consortium; GARNET consortium; Steve Eyre (GB), John Bowes (GB), Anne Barton (GB), Niek de Vries (NL), Larry W. Moreland (US), Lindsey A. Criswell (US), Elizabeth W. Karlson (US), Atsuo Taniguchi (JP), Ryo Yamada (JP), Michiaki Kubo (JP), Jun S. Liu (US), Sang-Cheol Bae (KR), Jane Worthington (GB), Leonid Padyukov (SE), Lars Klareskog (SE), Peter K. Gregersen (US), Soumya Raychaudhuri (US), Barbara E. Stranger (US), Philip L. De Jager (US), Lude Franke (NL), Peter M. Visscher (AU), Matthew A. Brown (AU), Hisashi Yamanaka (JP), Tsuneyo Mimori (JP), Atsushi Takahashi (JP), Huji Xu (CN), Timothy W. Behrens (US), Katherine A. Siminovitch (CA), Shigeki Momohara (JP), Fumihiko Matsuda (JP), Kazuhiko Yamamoto (JP), and Robert M. Plenge (US) performed a comprehensive genetic study that sheds light on fundamental genes, pathways, and cell types that contribute to rheumatoid arthritis pathogenesis, and provides empirical evidence that the genetics of rheumatoid arthritis can provide important information for drug discovery. They performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 rheumatoid arthritis cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. Ninety-eight biological candidate genes were identified at 101 risk loci (1103).

 

Christopher J. Cooper (US), Timothy P. Murphy (US), Donald E. Cutlip (US), Kenneth Jamerson (US), William Henrich (US), Diane M. Reid (US), David J. Cohen (US), Alan H. Matsumoto (US), Michael Steffes (US), Michael R. Jaff (US), Martin R. Prince (US), Eldrin F. Lewis (US), Katherine R. Tuttle (US), Joseph I. Shapiro (US), John H. Rundback (US), Joseph M Massaro (US), Ralph B. D'Agostino Sr. (US), Lance D. Dworkin (US), and CORAL Investigators (US) found that renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731.) (281).

 

Mary E. Tinetti (US), Ling Han (US), David S. H. Lee (US), Gail J. McAvay (US), Peter Peduzzi (US), Cary P. Gross (US), Bingqing Zhou (US), and Haiqun Lin (US) concluded that antihypertensive medications were associated with an increased risk of serious fall injuries, particularly among those with previous fall injuries. The potential harms vs benefits of antihypertensive medications should be weighed in deciding to continue treatment with antihypertensive medications in older adults with multiple chronic conditions (1458).

 

 Jason Flannick (US), Gudmar Thorleifsson, (IS) Nicola L. Beer (US-GB), Suzanne B. R. Jacobs (US), Niels Grarup (DK), Noël P Burtt (US), Anubha Mahajan (GB), Christian Fuchsberger (US), Gil Atzmon (US), Rafn Benediktsson (IS), John Blangero (US), Don W. Bowden (US), Ivan Brandslund (DK), Julia Brosnan (US), Frank Burslem (GB), John Chambers (GB), Yoon Shin Cho (KR), Cramer Christensen (DK), Desirée A. Douglas (SE), Ravindranath Duggirala (US), Zachary Dymek (US), Yossi Farjoun (US), Timothy Fennell (US), Pierre Fontanillas (US), Tom Forsén (FI), Stacey Gabriel (US), Benjamin Glaser (IL), Daniel F. Gudbjartsson (IS), Craig Hanis (US), Torben Hansen (DK), Astradur B. Hreidarsson (IS), Kristian Hveem (NO), Erik Ingelsson (GB-SE), Bo Isomaa (FI), Stefan Johansson (NO), Torben Jørgensen (DK), Marit Eika Jørgensen (DK), Sekar Kathiresan (US), Augustine Kong (IS), Jaspal Kooner (GB), Jasmina Kravic (SE), Markku Laakso (FI), Jong-Young Lee (KR), Lars Lind (SE), Cecilia M. Lindgren (US), Allan Linneberg (DK), Gisli Masson (IS), Thomas Meitinger (DE), Karen L. Mohlke (US), Anders Molven (NO), Andrew P. Morris (GB), Shobha Potluri (US), Rainer Rauramaa (FI), Rasmus Ribel-Madsen (DK), Ann-Marie Richard (US), Tim Rolph (US), Veikko Salomaa (FI), Ayellet V. Segrè (US), Hanna Skärstrand (SE), Valgerdur Steinthorsdottir (IS), Heather M. Stringham (US), Patrick Sulem (IS), E. Shyong Tai (SG), Yik Ying Teo (SG), Tanya Teslovich (US), Unnur Thorsteinsdottir (IS), Jeff K. Trimmer (US), Tiinamaija Tuomi (FI), Jaakko Tuomilehto (AT-FI), Fariba Vaziri-Sani (FI), Benjamin F. Voight (US), James G. Wilson (US), Michael Boehnke (US), Mark I. McCarthy (GB), Pål R. Njølstad (NO), Oluf Pedersen (DK), Go-T2D Consortium (SE-NO), T2D-GENES Consortium (SE-NO), Leif Groop (SE-FI), David R. Cox (US), Kári Stefánsson (IS), and David Altshuler (US) discovered that the gene SLC30A8, which encodes an islet zinc transporter (ZnT8), can exist as a loss-of-function mutation in humans. This loss-of-function mutation protects against type two diabetes (T2D) suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention (424).

 

In 2014, Drug Innovation Ventures at Emory (DRIVE) began a screening project funded by the Defense Threat Reduction Agency to find an antiviral drug targeting Venezuelan equine encephalitis virus (VEEV), which led to the discovery of EIDD-1931. When turned into the prodrug EIDD-2801 (molnupiravir), the compound also showed activity against other RNA viruses including influenza, Ebola, chikungunya, and various coronaviruses (578). Note: Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase (903).

 

As part of The Cancer Genome Atlas (TCGA) project, the genome and proteome of gastric cancer has been extensively characterized to uncover molecular subtypes and identify dysregulated pathways and potential therapeutic targets. Integrative analysis of multiple genomic and proteomic data from gastric cancer tissues revealed 4 molecular subtypes: (i) Epstein-Barr virus (EBV) subtype with extreme DNA hypermethylation, (ii) microsatellite instability (MSI) subtype with elevated mutation rates and hypermethylation, (iii) genomically stable (GS) subtype with less distinctive genomic alterations, and (iv) chromosomal instability (CIN) subtype with marked aneuploidy and frequent focal amplification of receptor tyrosine kinases (1187).

Bo Hwa Sohn (US), Jun-Eul Hwang (KR), Hee-Jin Jang (US), Hyun-Sung Lee (US), Sang Cheul Oh (KR), Jae-Jun Shim (KR), Keun-Wook Lee (KR), Eui Hyun Kim (US), Sun Young Yim (US), Sang Ho Lee (KR), Jae-Ho Cheong (KR), Woojin Jeong (KR), Jae Yong Cho (KR), Joohee Kim (US), Jungsoo Chae (KR), Jeeyun Lee (KR), Won Ki Kang (KR), Sung Kim (KR), Sung Hoon Noh (KR), Jaffer A. Ajani (US), and Ju-Seog Lee (US), based on the TCGA project (see above), investigated the relationship between subtypes and prognosis of patients with gastric cancer. They found that their model could successfully place stratified patients by survival and adjuvant chemotherapy outcomes (1374).

 

Turi E. King (GB), Gloria Gonzalez Fortes (GB-DE), Patricia Balaresque (FR), Mark G. Thomas (GB), David Balding (GB), Pierpaolo Maisano Delser (GB), Rita Neumann (GB), Walther Parson (AT-US), Michael Knapp (GB), Susan Walsh (US-NL), Laure Tonasso (FR), John Holt (GB), Manfred Kayser (NL), Jo Appleby (GB), Peter Forster (GB), David Ekserdjian (GB), Michael Hofreiter (GB-DE), and Kevin Schürer (GB), in 2012, excavated a skeleton at the presumed site of the Grey Friars friary in Leicester (UK) the last-known resting place of King Richard III. Archaeological, osteological and radiocarbon dating data were consistent with these being his remains. They reported DNA analyses of both the skeletal remains and living relatives of Richard III, finding a perfect mitochondrial DNA match between the sequence obtained from the remains and one living relative, and a single-base substitution when compared with a second relative. Y-chromosome haplotypes from male-line relatives and the remains do not match, which could be attributed to a false-paternity event occurring in any of the intervening generations. DNA-predicted hair and eye color are consistent with Richard's appearance in an early portrait. They calculated likelihood ratios for the non-genetic and genetic data separately, and combined, and concluded that the evidence for the remains being those of Richard III was overwhelming (762).

 

Kay Prüfer (DE), Fernando Racimo (US), Nick Patterson (US), Flora Jay (US), Sriram Sankararaman (US), Susanna Sawyer (DE), Anja Heinze (DE), Gabriel Renaud (DE), Peter H. Sudmant (US), Cesare de Filippo (DE), Heng Li (US), Swapan Mallick (US), Michael Dannemann (DE), Qiaomei Fu (CN), Martin Kircher (DE), Martin Kuhlwilm (DE), Michael Lachmann (DE), Matthias Meyer (DE), Matthias Ongyerth (DE), Michael Siebauer (DE), Christoph Theunert (DE), Arti Tandon (US), Priya Moorjani (US), Joseph Pickrell (US), James C. Mullikin (US), Samuel H. Vohr (US), Richard E. Green (US), Ines Hellmann (DE), Philip L. F. Johnson (US), Hélène Blanche (FR), Howard Cann (FR), Jacob O. Kitzman (US), Jay Shendure (US), Evan E. Eichler (US), Ed S. Lein (US), Trygve E. Bakken (US), Liubov V. Golovanova (RU), Vladimir B. Doronichev (RU), Michael V. Shunkov (RU), Anatoli P. Derevianko (RU), Bence Viola (DE), Montgomery Slatkin (US), David Emil Reich (US), Janet Kelso (DE), and Svante Pääbo (SE-DE) presented a high-quality genome sequence of a Neanderthal woman from Siberia. They showed that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. They also sequenced the genome of a Neanderthal from the Caucasus to low coverage. Their analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allowed them to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans (1188).

 

Maxime Aubert (AU), Adam Brumm (AU), Muhammad Ramli (ID), Thomas Sutikna (ID), E. Wahyu Saptomo (ID), Budianto Hakim (ID), Michael J. Morwood (AU), Gert D. van den Bergh (AU), Les Kinsley (AU), and Antonio Dosseto (AU) discovered prehistoric graffiti on Sulawesi Island in Indonesia that's at least 40,000 years old, potentially usurping Europe as the location of the world’s oldest cave art (66).

 

2015

William Cecil Campbell (IE-US), Satoshi Ömura (JP), and Tu Youyou (CN) were awarded the Nobel Prize in Physiology or Medicine. Campbell and Ömura for discoveries concerning a novel therapy against infections caused by roundworm parasites and Youyou for discoveries concerning a novel therapy against malaria.

 

Tomas Robert Lindahl (SE-GB), Paul L. Modrich (US), and Aziz Sancar (TR) were awarded the Nobel Prize in Chemistry for their mechanistic studies of DNA repair.

 

Peter T.S. van der Gulik (NL) and Dave Speijer (NL) argue for a “coevolutionary” theory in which amino acids and (very small) peptides as well as small RNAs existed together and where their separate abilities not only reinforced each other’s survival, but allowed life to more quickly climb the ladder of complexity (1501). Note: The “RNA world” hypothesis is seen as one of the main contenders for a viable theory on the origin of life.

 

Yin Lu (US), Byung-hoon Lee (US), Randall W. King (US), Daniel Finley (US), and Marc W. Kirschner (US) discovered the molecular processes involved in the disposal of malfunctioning or damaged proteins. These proteins are tagged with ubiquitin, which signals a cellular machine called the proteasome to pulverize the defective protein (907).

 

Michael A. Lodato (US), Mollie B. Woodworth (US), Semin Lee (US), Gilad D. Evrony (US), Bhaven K. Mehta (US), Amir Karger (US), Soohyun Lee (US), Thomas W. Chittenden (US), Alissa M. D’Gama (US), Xuyu Cai (US), Lovelace J. Luquette (US), Eunjung Lee (US), Peter J. Park (US), and Christopher A. Walsh (US) were the first to demonstrate that somatic mutations are common in brain cells among genes that neurons use most (893).

 

Zhen Ma (US), Jason Wang (US), Peter Loskill (US), Nathaniel Huebsch (US), Sangmo Koo (US), Felicia L. Svedlund (US), Natalie C. Marks (US), Ethan W. Hua (US), Costas P. Grigoropoulos (US), Bruce R. Conklin (US), and Kevin E. Healy (US) prompted stem cells to develop into heart muscle and connective tissue, and then organize into tiny chambers and "beat" (919).

 

Minoru Takasato (AU), Pei X. Er (AU), Han S. Chiu (AU), Barbara Maier (AU), Gregory J. Baillie (AU), Charles Ferguson (AU), Robert G. Parton (AU), Ernst J. Wolvetang (AU), Matthias S. Roost (NL), Susana M. Chuva de Sousa Lopes (NL), and Melissa H. Little (AU) perfected a method of growing mini-kidneys (organoids) from stem cells for use in drug screening, disease modelling and cell therapy. They succeeded in growing an organ that forms all the cell types normally present in the human kidney (1434).

 

Briana R. Dye (US), David R. Hill (US), Michael A. H. Ferguson (US), Yu-Hwai Tsai (US), Melinda S. Nagy (US), Rachel Dyal (US), James M. Wells (US), Christopher N. Mayhew (US), Roy Nattiv (US), Ophir D. Klein (US), Eric S. White (US), Gail H. Deutsch (US), and Jason R. Spence (US) report the step-wise differentiation of human pluripotent stem cells (hPSCs) (embryonic and induced) into lung organoids. By manipulating developmental signaling pathways hPSCs generate ventral-anterior foregut spheroids, which are then expanded into human lung organoids (HLOs) (363).

Alyssa J. Miller (US), Briana R. Dye (US), Daysha Ferrer-Torres (US), David R. Hill (US), Arend W. Overeem (NL), Lonnie D. Shea (US), and Jason R. Spence (US) generated lung organoids that exhibited endoderm induction, anterior-posterior and dorsal-ventral patterning, lung specification, lung budding, branching morphogenesis, and, finally, maturation (995).

 

Eric W F. W. Alton (GB), David K. Armstrong (GB), Deborah Ashby (GB), Katie J. Bayfield (GB), Diana Bilton (GB), Emily V. Bloomfield (GB), A. Christopher Boyd (GB), June Brand (GB), Ruaridh Buchan (GB), Roberto Calcedo (US), Paula Carvelli (GB), Mario Chan (GB), Seng H. Cheng (GB), D. David S. Collie (GB), Steve Cunningham (GB), Heather E. Davidson (GB), Gwyneth Davies (GB), Jane C. Davies (GB), Lee A. Davies (GB), Maria H. Dewar (GB), Ann Doherty (GB), Jackie Donovan (GB), Natalie S. Dwyer (GB), Hala I. Elgmati (GB), Rosanna F. Featherstone (GB), Jemyr Gavino (GB), Sabrina Gea-Sorli (GB), Duncan M. Geddes (GB), James S. R. Gibson (GB), Deborah R. Gill (GB), Andrew P. Greening (GB), Uta Griesenbach (GB), David M. Hansell (GB), Katharine Harman (GB), Tracy E. Higgins (GB), Samantha L. Hodges (GB), Stephen C. Hyde (GB), Laura Hyndman (GB), J. Alastair Innes (GB), Joseph Jacob (GB), Nancy Jones (GB), Brian F. Keogh (GB), Maria P. Limberis (US), Paul Lloyd-Evans (GB), Alan W. Maclean (GB), Michelle C. Manvell (GB), Dominique McCormick (GB), Michael McGovern (GB), Gerry McLachlan (GB), Cuixiang Meng (GB), M. Angeles Montero (GB), Hazel Milligan (GB), Laura J. Moyce (GB), Gordon D. Murray (GB), Andrew G. Nicholson (GB), Tina Osadolor (GB), Javier Parra-Leiton(GB), David J. Porteous (GB), Ian A. Pringle (GB), Emma K. Punch (GB), Kamila M. Pytel (GB), Alexandra L. Quittner (GB), Gina Rivellini (GB), Clare J. Saunders (GB), Ronald K. Scheule (GB), Sarah Sheard (GB), Nicholas J. Simmonds (GB), Keith Smith (GB), Stephen N. Smith (GB), Najwa Soussi (GB), Samia Soussi (GB), Emma J. Spearing (US), Barbara J. Stevenson (GB), Stephanie G. Sumner-Jones (GB), Minna Turkkila (GB), Rosa P. Ureta (GB), , Michael D. Waller (GB), Marguerite Y. Wasowicz (GB), James M. Wilson (US), and Paul Wolstenholme-Hogg (GB) reported that monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in forced expiratory volume in 1 s (FEV1) compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care (36).

 

Matthew R. Gardner (US), Lisa M. Kattenhorn (US), Hema R. Kondur (US), Markus von Schaewen (US), Tatyana Dorfman (US), Jessica J. Chiang (US), Kevin G. Haworth (US), Julie M. Decker (US), Michael D. Alpert (US), Charles C. Bailey (US), Ernest S. Neale Jr. (US), Christopher H. Fellinger (US), Vinita R. Joshi (US), Sebastian P. Fuchs (US), Jose M. Martinez-Navio (US), Brian D. Quinlan (US), Annie Y. Yao (US), Hugo Mouquet (FR), Jason Gorman (US), Baoshan Zhang (US), Pascal Poignard (US), Michel C. Nussenzweig (US), Denis R. Burton (US), Peter D. Kwong (US), Michael Piatak Jr. (US), Jeffrey D. Lifson (US), Guangong Gao (US), Ronald C. Desrosiers (US), David T. Evans (US), Beatrice H. Hahn (US), Alexander Ploss (US), Paula M. Cannon (US), Michael S. Seaman (US), and Michael Farzan (US) put a gene for eCD4-Ig into a harmless virus and infected four monkeys; the virus forces the monkey’s cells to mass produce the construct. When they “challenged” these monkeys and four controls with successively higher doses of an AIDS virus for up to 34 weeks, none of the animals that received eCD4-Ig became infected, whereas all of the untreated ones did (467).

 

Ana Maria Henao-Restrepo (CH), Ira M. Longini (US), Matthias Egger (CH), Natalie E. Dean (US), W. John Edmunds (GB), Anton Camacho (GB), Miles W. Carroll (GB), Moussa Doumbia (ML), Bertrand Draguez (BE), Sophie Duraffour (GB), Godwin Enwere (CH), Rebecca Grais (FR), Stephan Gunther (CH), Stefanie Hossmann (CH), Mandy Kader Kondé (GN), Souleymane Kone (CH), Eeva Kuisma (GB), Myron M. Levine (US), Sema Mandal (GB), Gunnstein Norheim (NO), Ximena Riveros (CH), Aboubacar Soumah (FR), Sven Trelle (CH), Andrea S. Vicari (CH), Conall H. Watson (GB), Sakoba Kéïta (GN), Marie Paule Kieny (CH), and John-Arne Røttingen (NO-US) showed that a recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. They reported the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa (624).

 

Mirjana Kessler (DE), Karen Hoffmann (DE), Volker Brinkmann (DE), Oliver Thieck (DE), Susan Jackisch (DE), Benjamin Toelle (DE), Hilmar Berger (DE), Hans-Joachim Mollenkopf (DE), Mandy Mangler (DE), Jalid Sehouli (DE), Christina Fotopoulou (DE), and Thomas F. Meyer (DE) devised a new method to grow the inner cellular layer in the lab. They removed epithelial cells with potential stem cell properties from fallopian tube samples provided by donors and then cultivated them under specific environmental conditions. The resulting organoids shared the features and shapes that are particular to full-size fallopian tubes (754; 993).

 

Gahl Levy (IL), David Bomze (IL), Stefan Heinz (DE), Sarada Devi Ramachandran (DE), Astrid Noerenberg (DE), Merav Cohen (IL), Oren Shibolet (IL), Ella Sklan (IL), Joris Braspenning (DE), and Yaakov Nahmias (IL), for the first time, successfully cultivated hepatocytes in the laboratory. Though not a full-fledged organ (or even an organoid), this development holds promising implications for clinical study (859).

 

René Anand (US) and Virginia Gewin (US) cultivated a lab-grown brain the size of a pencil eraser from skin cells. It was structurally and genetically similar to the brain of a 5-week-old human fetus. This organoid has functioning neurons with signal-carrying extensions like axons and dendrites. René Anand said, "this 'brain' models early-developmental tissue and is roughly 2–3 millimetres long. It expresses more than 98% of the genes present in a human brain at 5 weeks of development. We are not capable of addressing higher-order function, such as memory, learning or cognition. But we can see structures of the brain, and perhaps use the model to see how it responds to drugs. The organoid might be useful for high-throughput screening for therapeutic-drug discovery or toxicity testing" (38; 485).

 

 The Centers for Disease Control and Prevention in Atlanta, GA presented updated guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 2010;59 [No. RR-12]). These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment-related implications; 5) updated human papillomavirus (HPV) vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with human immunodeficiency virus (HIV) infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection. Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs (1593).

 

Sharon P.G. Fowler (US), Ken Williams (US), and Helen P. Hazuda (US) found a striking dose-response relationship, indicating that increasing diet soda intake was associated with escalating abdominal obesity, a potential pathway for heightened cardiometabolic risk in the aging bi-ethnic population represented in the bi-ethnic San Antonio Longitudinal Study of Aging (433).

 

Antoine Louveau (US), Igor Smirnov (US), Timothy J. Keyes (US), Jacob D. Eccles (US), Sherin J. Rouhani (US), J. David Peske (US), Noel C. Derecki (US), David Castle (US), James W. Mandell (US), Kevin S. Lee (US), Tajie H. Harris (US), and Jonathan Kipnis (US) found functional lymphatic vessels located in the meninges (in the dura mater), through which cerebrospinal fluid (CSF) drains into the deep cervical lymph nodes (dCLNs) (901).

Anthony J. Filiano (US), Sachin P. Gadani (US), and Jonathan Kipnis (US) found dural meninges to harbor a variety of immune cells (414).

Ji Hoon Ahn (KR), Hyunsoo Cho (KR), Jun-Hee Kim (KR), Shin Heun Kim (KR), Je-Seok Ham (KR), Intae Park (KR), Sang Heon Suh (KR), Seon Pyo Hong (KR), Joo-Hye Song (KR), Young-Kwon Hong (KR-US), Yong Jeong (KR), Sung-Hong Park (KR), and Gou Young Koh (KR) demonstrated that the basal part of the skull meningeal lymphatic vessels efficiently drain cerebrospinal fluid (CSF) (22).

Antoine Louveau (US), Jasmin Herz (US), Maria Nordheim Alme (US), Andrea Francesca Salvador (US), Michael Q. Dong (US), Kenneth E. Viar (US), S. Grace Herod (US), James Knopp (US), Joshua C. Setliff (US), Alexander L. Lupi (US), Sandro Da Mesquita (US), Elizabeth L. Frost (US), Alban Gaultier (US), Tajie H. Harris (US), Rui Cao (US), Song Hu (US), John R. Lukens (US), Igor Smirnov (US), Christopher C. Overall (US), Guillermo Oliver (US), and Jonathan Kipnis (US) showed that meningeal lymphatic vasculature drains immune cells and plays a key role in neuroinflammation (900).

Xueting Hu (CN), Qiuping Deng (CN), Lu Ma (CN), Qingqing Li (CN) , Yidong Chen (CN), Yuhan Liao (CN), Fan Zhou (CN), Chen Zhang (CN), Linlin Shao (CN), Jun Feng (CN), Tubao He (CN), Weihai Ning (CN), Yan Kong (CN), Yingqing Huo (CN), Aibin He (CN), Bing Liu (CN), Jingjing Zhang (CN), Ralf Adams (DE), Yulong He (CN), Fuchou Tan (CN), Xiuwu Bian (CN), and Jincai Luo (CN) demonstrated that the brain’s rejection of glioma can be facilitated by expansion of the meningeal lymphatic vessels (660).

 

Lara M. Cassidy (IE) and Daniel G. Bradley (IE) suggest that it is clear that migrations at or around the transitions leading to the adoption of farming and prior to the bronze Age have been major determinants of European genetic ancestry. The first four ancient Irish genomes sequenced have shown that two migration waves of profound effect—that of Anatolian farmers carrying the Neolithic (c. 7K B.C.E.) into the continent and that of third-millennium migrations from the steppe—washed all the way to Ireland (214).

 

Lee R. Berger (ZA), John Hawks (ZA-US), Darryl J. de Ruiter (ZA-US), Steven E. Churchill (ZA-US), Peter Schmid (ZA-CH), Lucas K. Delezene (ZA-US), Tracy L. Kivell (ZA-GB-DE), Heather M. Garvin (ZA-US), Scott A. Williams (ZA-US), Jeremy M. DeSilva (ZA-US), Matthew M. Skinner (ZA-GB-DE), Charles M. Musiba (ZA-US), Noel Cameron (ZA-GB), Trenton W. Holliday (ZA-US), William Harcourt-Smith (ZA-US), Rebecca R. Ackermann (ZA), Markus Bastir (ZA-ES), Barry Bogin (ZA-GB), Debra Bolter (ZA-US), Juliet Brophy (ZA-US), Zachary D. Cofran(ZA-KZ), Kimberly A. Congdon (ZA-US), Andrew S. Deane (ZA-US), Mana Dembo (ZA-CA), Michelle Drapeau (CA), Marina C. Elliott (ZA-CA), Elen M. Feuerriegel (ZA-AU), Daniel Garcia-Martinez (ZA-ES), David J. Green (ZA-US), Alia Gurtov (ZA-US), Joel D. Irish (ZA-GB), Ashley Kruger (ZA), Myra F. Laird (ZA-US), Damiano Marchi (ZA-IT), Marc R. Meyer (ZA-US), Shahed Nalla (ZA), Enquye W. Negash (ZA-US), Caley M. Orr (ZA-US), Davorka Radovcic (ZA-HR), Lauren Schroeder (ZA), Jill E. Scott (ZA-US), Zachary Throckmorton (ZA-US), Matthew W. Tocheri (US-CA), Caroline VanSickle (ZA-US), Christopher S. Walker (ZA-US), Pianpian Wei (ZA-CN), and Bernhard Zipfel (ZA) discovered Homo naledi, a previously-unknown species of extinct hominin within the Dinaledi Chamber of the Rising Star cave system, Cradle of Humankind, South Africa. This species is characterized by body mass and stature similar to small-bodied human populations but a small endocranial volume similar to australopiths (113).

 

2016

Yoshinori Ohsumi (JP) was awarded the Nobel Prize in Physiology or Medicine for discoveries of mechanisms for autophagy.

 

Christine E. Brown (US), Darya Alizadeh (US), Renate Starr (US), Lihong Weng (US), Jamie R. Wagner (US), Araceli Naranjo (US), Julie R. Ostberg (US), M. Suzette Blanchard (US), Julie Kilpatrick (US), Jennifer Simpson (US), Anita Kurien (US), Saul J. Priceman (US), Xiuli Wang (US), Todd L. Harshbarger (US), Massimo D’Apuzzo (US), Julie A. Ressler (US), Michael C. Jensen (US), Michael E. Barish (US), Mike Chen (US), Jana Portnow (US), Stephen J. Forman (US), and Behnam Badie (US) reported on a patient with recurrent multifocal glioblastoma who received chimeric antigen receptor (CAR)–engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes — infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy (167).

 

Nelly A. Horst (DE), Aviva Katz (DE), Idan Pereman (DE), Eva L. Decker (DE), Nir Ohad (DE), and Ralf Reski (DE) identified a homeobox gene as master regulator for embryonic development in the moss Physcomitrella patens (652).

 

Caspar C. Chater (MX), Robert S. Caine (GB), Marta Tomek (DE), Simon Wallace (GB), Yasuko Kamisugi (GB), Andrew C. Cuming (GB), Daniel Lang (DE), Cora A. MacAlister (US), Stuart Casson (GB), Dominique C. Bergmann (US), Eva L. Decker (DE), Wolfgang Frank (DE), Julie E. Gray (GB), Andrew Fleming (GB), Ralf Reski (DE), and David J. Beerling (GB) showed that genes encoding the two basic helix–loop–helix proteins PpSMF1 (SPEECH, MUTE and FAMA-like) and PpSCREAM1 (SCRM1) in the moss Physcomitrella patens are orthologous to transcriptional regulators of stomatal development in the flowering plant Arabidopsis thaliana and essential for stomata formation in moss (230).

 

Rainer H. Straub (DE) and Carsten Schradin (FR) proposed that the antagonistic pleiotropy theory applies to the situation occuring in chronic inflammatory diseases, with genes being adaptive at an early age, but maladaptive at older age (another somatic environment), leading to an overall increase in Darwinian fitness, even though causing disease and suffering at older age (1407). See, George C. Williams, 1957.

 

Kaustubh Adhikari (GB), Macarena Fuentes-Guajardo (GB), Mirsha Quinto-Sánchez (AR), Javier Mendoza-Revilla (GB), Juan Camilo Chacón-Duque (GB), Victor Acuña-Alonzo (GB), Claudia Jaramillo (CO), William Arias (CO), Rodrigo Barquera Lozano (MX), Gastón Macín Pérez (MX), Jorge Gómez-Valdés (MX), Hugo Villamil-Ramírez (MX), Tábita Hunemeier (BR), Virginia Ramallo (AR), Caio C. Silva de Cerqueira (AR), Malena Hurtado (PE), Valeria Villegas (PE), Vanessa Granja (PE), Carla Gallo (PE), Giovanni Poletti (PE), Lavinia Schuler-Faccini (BR), Francisco M. Salzano (BR), Maria-Cátira Bortolini (BR), Samuel Canizales-Quinteros (MX), Michael Cheeseman (GB), Javier Rosique (CO), Gabriel Bedoya (CO), Francisco Rothhammer (CL), Denis Headon (GB), Rolando González-José (AR), David Balding (GB), and Andrés Ruiz-Linares (GB) reported a genome-wide association scan for facial features in ∼6,000 Latin Americans. They evaluated 14 traits on an ordinal scale and found significant association (P values<5 × 10(-8)) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of ∼3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar funtion(18).

 

Jacques P. Guyette (US), Jonathan M. Charest (US), Robert W. Mills (US), Bernhard J. Jank (US), Philipp T. Moser (US), Sarah E. Gilpin (US), Joshua R. Gershlak (US), Tatsuya Okamoto (US), Gabriel Gonzalez (US), David J. Milan (US), Glenn R. Gaudette (US), and Harald C. Ott (US) have successfully grown functional human heart tissue from stem cells created from skin cells (570).

 

Cassidy Blundell (US), Emily R Tess (US), Ariana S. R. Schanzer (US), Christos Coutifaris (US), Emily J. Su (US), Samuel Parry (US), and Dongeun Huh (US) presented a microengineered device that provides a novel platform to mimic the structural and functional complexity of the placenta in vitro. They created a multilayered microfluidic system that enables co-culture of human trophoblast cells and human fetal endothelial cells in a physiologically relevant spatial arrangement to replicate the characteristic architecture of the human placental barrier. This "placenta-on-a-chip" platform represents an important advance in the development of new technologies to model and study the physiological complexity of the human placenta for a wide variety of applications (140).

 

Khalil Ettayebi (US), Sue E. Crawford (US), Kosuke Murakami (US), James R. Broughman (US), Umesh Karandikar (US), Victoria R. Tenge (US), Frederick H. Neill (US), Sarah E. Blutt (US), Xi-Lei Zeng (US), Lin Qu, Baijun Kou (US), Antone R. Opekun (US), Douglas Burrin (US), David Y. Graham (US), Sasirekha Ramani (US), Robert L. Atmar (US), and Mary Kolb Estes (US) were the first to succeed at growing noroviruses in human intestinal cell cultures (382).

 

The World Health Organization announced that the spread of Zika virus was a public health emergency of international concern. At the time, the WHO's Emergency Committee had sufficient information to announce that a strong association existed between Zika virus infection in pregnant women and microcephaly and other birth defects in their infants. Over the next months, this evidence, and evidence that Zika virus infection could lead to Guillain Barre Syndrome, would grow more convincing. Zika virus is transmitted mainly via the bite of infected mosquitoes, but it can also be spread sexually (988).

 

Jean-Christophe Lagier (FR), Serge Cammilleri (FR), and Didier Raoult (FR) discovered that Whipple's disease is a complex infectious disease caused by Tropheryma whipplei. Its classic form generally affects the gastrointestinal tract and joints, and causes diarrhoea, weight loss, and arthralgia. Endocarditis has been reported in classic Whipple's disease, but this symptom can also occur in isolation (818). Note: Tropheryma whippelii, the causative organism of Whipple's disease, is a small (1-2 µm long, 0.25 µm in diameter) organism in which the rods are typically found free within macrophages of the intestine. The bacilli have a thick (approximately 20 nm) outer cell wall with a trilaminar membrane. Bacteria replicate extracellularly but are typically ingested by macrophages and digested into intracellular myelin figures, in which case histiocytes are seen distended with lysosomes that are filled with serpiginous membranes.

 

Hayden R. Schmidt (US), Sanduo Zheng (US), Esin Gurpinar (US), Antonio Koehl (US), Aashish Manglik (US), and Andrew C. Kruse (US) were the first to reveal the molecular structure of the sigma-1 receptor, a cellular protein implicated in amyotrophic lateral sclerosis (ALS), a discovery that opens the door to potential therapeutic targets (1293).

 

Richard L. Mort (GB), Robert J. H. Ross (GB), Kirsten J. Hainey (GB), Olivia J. Harrison (GB), Margaret A. Keighren (GB), Gabriel Landini (GB), Ruth E. Baker (GB), Kevin J. Painter (GB), Ian J. Jackson (GB), and Christian A. Yates (GB) reported that "Piebaldism is actually a disease caused by a gene called KIT. It’s caused by cells in the early embryo failing to migrate correctly....failing to get to the right place. The cells which we’re interested in, that cause piebaldism, are called melanocytes and they’re responsible for pigmentation of hair and of the skin. These cells start at the back of the embryo and they try to migrate round through the skin and cover the whole of the (embryo’s) skin. When they fail to do that properly you tend to get regions of skin or hair which are lacking in pigment, often regions at the front of an animal. This is common in cats......tuxedo cats, and it’s also common in horses and pigs and even in humans.” (1025) Note: Although the effects of piebaldism are relatively mild, it is one of a range of more serious defects called neurocristopathies. These result from defects in the development of tissues and can manifest as heart problems, deafness, digestive problems and even cancer. The diseases are all linked by their reliance on a family of embryonic cells called neural crest cells.

 

Dupixent (dupilumab) was FDA-approved in 2017 to treat moderate-to-severe eczema that does not respond well to other prescription topical therapies. T helper 2 type responses have emerged as a unifying feature of various inflammatory and allergic diseases, such as eczema and asthma. As a result, type 2 cytokines — including interleukin 4 (IL-4) and IL-13 — have come under the spotlight as promising targets for selective treatment of these indications. Dupilumab is a first-in-class monoclonal antibody (mAb) that modulates both IL-4 and IL-13 signalling; the mAb binds to the IL-4 receptor subunit alpha (IL-4Rα), which can also dimerize with a subunit of the IL-13 receptor to control IL-13 signalling(459; 1032).

 

Yemen experienced an outbreak of cholera lasting into 2021.

 

Hiroshige Matsuoka (JP), Nao Kusuhashi (JP), and Ian J. Corfe (FI) uncovered dozens of fossilized teeth in Kuwajima, Japan, and identified this as a new species of tritylodontid, an animal family that links the evolution of mammals from reptiles. The finding suggests that tritylodontids co-existed with some of the earliest mammal species for millions of years, overturning beliefs that mammals wiped out mammal-like reptiles soon after they emerged (956).

 

Qiaomei Fu (CN-US-DE), Cosimo Posth (DE), Mateja Hajdinjak (DE), Martin Petr (DE), Swapan Mallick (US), Daniel Fernandes (IE-PT), Anja Furtwängler (DE), Wolfgang Haak (DE-AU), Matthias Meyer (DE), Alissa Mittnik (DE), Birgit Nickel (DE), Alexander Peltzer (DE), Nadin Rohland (US), Viviane Slon (DE), Sahra Talamo (DE), Iosif Lazaridis (US), Mark Lipson (US), Iain Mathieson (US), Stephan Schiffels (DE), Pontus Skoglund (US), Anatoly P. Derevianko (RU), Nikolai Drozdov (RU), Vyacheslav Slavinsky (RU), Alexander Tsybankov (RU), Renata Grifoni Cremonesi (IT), Francesco Mallegni (IT), Bernard Gély (FR), Eligio Vacca (IT), Manuel R. González Morales (ES), Lawrence G. Straus (US-ES), Christine Neugebauer-Maresch (AT), Maria Teschler-Nicola (AT), Silviu Constantin (RO), Oana Teodora Moldovan (RO), Stefano Benazzi (DE-IT), Marco Peresani (IT), Donato Coppola (IT), Martina Lari (IT), Stefano Ricci (IT), Annamaria Ronchitelli (IT), Frédérique Valentin (FR), Corinne Thevenet (FR), Kurt Wehrberger (DE), Dan Grigorescu (RO), Hélène Rougier (US), Isabelle Crevecoeur (FR), Damien Flas (FR), Patrick Semal (BE), Marcello A. Mannino (DE), Christophe Cupillard (FR), Hervé Bocherens (DE), Nicholas J. Conard (DE), Katerina Harvati (DE), Vyacheslav Moiseyev (RU), Dorothée G. Drucker (DE), Jiří Svoboda (CZ), Michael P. Richards (CA-DE), David Caramelli (IT), Ron Pinhasi (IE), Janet Kelso (DE), Nick Patterson (US), Johannes Krause (DE), Svante Pääbo (SE-DE), and David Emil Reich (US) analyzed genome-wide data from 51 Eurasians from ~45,000–7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3–6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory (443).

 

2017

Jeffrey Connor Hall (US), Michael Morris Rosbash (US), and Michael Warren Young (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries of molecular mechanisms controlling the circadian rhythm.

 

Jacques Dubochet (CH), Joachim Frank (DE-US), and Richard Henderson (GB) were awarded the Nobel Prize in Chemistry for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution.

 

Tom C. M. Seegar (US), Lauren B. Killingsworth (US), Nayanendu Saha (US), Peter A. Meyer (US), Dhabaleswar Patra (US), Brandon Zimmerman (US), Peter W. Janes (US), Eric Rubinstein (FR), Dimitar B. Nikolov (US), Georgios Skiniotis (US), Andrew C. Kruse (US), and Stephen C. Blacklow (US) present the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated (1315). Note: Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer's precursor protein (APP).

 

Benjamin J. Andreone (US), Brian Wai Chow (US), Aleksandra Tata (US), Baptiste Lacoste (CA), Ayal Ben-Zvi (IL), Kevin Bullock (US), Amy A. Deik (US), David D. Ginty (US), Clary B. Clish (US), and Chenghua Gu (US) provided the first molecular explanation for how the blood-brain barrier remains closed—by suppressing the process for transporting molecules across cells in vesicles, or small bubbles (40).

 

Shane A. Liddelow (AU), Kevin A. Guttenplan (US), Laura E. Clarke (US), Frederick C. Bennett (US), Christopher J. Bohlen (AU), Lucas Schirmer (US), Mariko L. Bennett (US), Alexandra E. Münch (US), Won-Suk Chung (US), Todd C. Peterson (US), Daniel K. Wilton(US), Arnaud Frouin (US), Brooke A. Napier (US), Nikhil Panicker (US), Manoj Kumar (US), Marion S. Buckwalter (US), David H. Rowitch (US), Valina L. Dawson (US), Ted M. Dawson (US), Beth Stevens (US), Ben A. Barres (US) noted that reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here they show that a subtype of reactive astrocytes, which they termed A1, is induced by classically activated neuroinflammatory microglia. They show that activated microglia induce A1 astrocytes by secreting Il-1alpha, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes (872). Note: Glial cells might contribute to the degeneration of brain tissue that is a hallmark of Alzheimer’s and Parkinson’s diseases, as well as multiple sclerosis, amyotrophic lateral sclerosis (Lou Gehrig’s disease), glaucoma and other conditions.

Seung Pil Yun (US), Tae-In Kam (US), Nikhil Panicker (US), SangMin Kim (US), Yumin Oh (US), Jong-Sung Park (US), Seung-Hwan Kwon (US), Yong Joo Park (US), Senthilkumar S. Karuppagounder (US), Hyejin Park (US), Sangjune Kim (US), Nayeon Oh (US), Nayoung Alice Ki (US), Saebom Lee (US), Saurav Brahmachari (US), Xiaobo Mao (US), Jun Hee Lee (US), Manoj Kumar (US), Daniel An (US), Sung-Ung Kang (US), Yunjong Lee (KR), Kang Choon Lee (US), Dong Hee Na (US), Donghoon Kim (US), Sang Hun Lee, Viktor V. Roschke (US), Shane A. Liddelow (US), Zoltan Mari (US), Ben A. Barres (US), Valina L. Dawson (US), Ted M. Dawson (US), and Han Seok Ko (US) found that NLY01(brain-penetrant long-acting GLP1R agonist) is a potent GLP1R (glucagon-like peptide-1 receptor) agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson's disease and related neurologic disorders characterized by microglial activation (1619).

 

Deepak A. Rao (US), Michael F. Gurish (US), Jennifer L. Marshall (GB), Kamil Slowikowski (US), Chamith Y. Fonseka (US), Yanyan Liu (US), Laura T. Donlin (US), Lauren A. Henderson (US), Kevin Wei (US), Fumitaka Mizoguchi (US), Nikola C. Teslovich (US), Michael E. Weinblatt (US), Elena M. Massarotti (US), Jonathan S. Coblyn (US), Simon M. Helfgott (US), Yvonne C. Lee (US), Derrick J. Todd (US), Vivian P. Bykerk (US), Susan M. Goodman (US), Alessandra B. Pernis (US), Lionel B. Ivashkiv (US), Elizabeth W. Karlson (US), Peter A. Nigrovic (US), Andrew Filer (GB), Christopher D. Buckley (GB), James A. Lederer (US), Soumya Raychaudhuri (US), and Michael B. Brenner (US), upon examining material from patients with rheumatoid arthritis, discovered a striking subset of T cells that drives B cells. This finding helps illuminate a path toward more precise treatments focused only on the most relevant immune cells (1209).

 

 Jean-Antoine Ribeil (FR), Salima Hacein-Bey-Abina (FR), Emmanuel Payen (FR), Alessandra Magnan (FR), Michaela Semeraro (FR), Elisa Magrin (FR), Laure Caccavelli (FR), Benedicte Neven (FR), Philippe Bourget (FR), Wassim El Nemer (FR), Pablo Bartolucci (FR), Leslie Weber (FR), Hervé Puy (FR), Jean-François Meritet (FR), David Grevent (FR), Yves Beuzard (FR), Stany Chrétien (FR), Thibaud Lefebvre (FR), Robert W. Ross (FR), Olivier Negre (FR), Gabor Veres (FR), Laura Sandler (FR), Sandeep Soni (FR), Mariane de Montalembert (FR), Stéphane Blanche (FR), Philippe Leboulch (FR), and Marina Cavazzana (FR) described the first patient treated with lentiviral vector-mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling β-globin remained high (approximately 50% of β-like-globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease (1230).

 

Michael E. Wechsler (US), Praveen Akuthota (US), David Jayne (US), Paneez Khoury (US), Amy Klion (US), Carol A. Langford (US), Peter A. Merkel (US), Frank Moosig (US), Ulrich Specks (US), Maria C. Cid (US), Raashid Luqmani (US), Judith Brown (US), Stephen Mallett (US), Richard Philipson (US), Steve W. Yancey (US), Jonathan Steinfeld (US), Peter F. Weller (US), Gerald J. Gleich (US), and the EGPA Mepolizumab Study Team reported that mepolizumab (Nucala), a monoclonal antibody targeting IL-5, an important cytokine in the differentiation and maturation of eosinophils, was authorized by the FDA for the treatment of Eosinophilic Granulomatosis with Polyangiitis (EGPA) (1554).

Fasenra (benralizumab) Severe eosinophilic asthma patients who have not seen improvement with other prescription medications may finally breathe easier thanks to Fasenra, a biologic approved by the FDA in 2017(945). Note: Eosinophils aid healthy immune systems in the fight against infections and parasites.

 

Waseem Qasim (GB) , Hong Zhan (GB) , Sujith Samarasinghe (GB), Stuart Adams (GB) , Persis Amrolia (GB) , Sian Stafford (GB), Katie Butler (GB) , Christine Rivat (GB) , Gary Wright (GB), Kathy Somana (GB) , Sara Ghorashian (GB) , Danielle Pinner (GB), Gul Ahsan (GB), Kimberly Gilmour (GB) , Giovanna Lucchini (GB), Sarah Inglott (GB), William Mifsud (GB), Robert Chiesa (GB) , Karl S. Peggs (GB) , Lucas Chan (GB) , Farzin Farzeneh (GB) , Adrian J. Thrasher (GB) , Ajay Vora (GB) , Martin Pule (GB) , and Paul Veys (GB) used autologous T cells that were engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) to achieve marked leukemic remissions in early-phase trials. Although difficult to manufacture, especially in infants or heavily treated patients they generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci (1192).

 

A cholera epidemic began in Yemen in April 2017, raging through a country whose water, sanitation, and health infrastructures had been damaged by conflict. As of mid-August, about 500,000 cholera cases leading to nearly 2,000 deaths had been identified (988).

 

2018

The 2018 Nobel Prize in Physiology or Medicine was jointly awarded to James Patrick Allison (US) and Tasuku Honjo (JP) for their discovery of cancer therapy by inhibition of negative immune regulation. The Royal Swedish Academy of Sciences said, "by stimulating the inherent ability of our immune system to attack tumor cells this year’s Nobel Laureates have established an entirely new principle for cancer therapy."

 

Frances Hamilton Arnold (US), George Pearson Smith (US), and Gregory Paul Winter (GB) were awarded the Nobel Prize in Chemistry. Arnold for the first directed evolution of enzymes. Smith for development of phage display, a method in which a bacteriophage can be used to evolve new proteins and Winter for work using the phage display method for the directed evolution of antibodies.

 

Ming Wang (DE), Martin Schäfer (DE), Dapeng Li (DE), Rayko Halitschke (DE), Chuanfu Dong (DE), Erica McGale (DE), Christian Paetz (DE), Yuanyuan Song (DE), Suhua Li (DE), Junfu Dong (DE), Sven Heiling (DE), Karin Groten (DE), Philipp Franken (DE), Michael Bitterlich (DE), Maria J Harrison (DE), Uta Paszkowski (DE), and Ian T. Baldwin (DE) found substances that accumulate in the leaves when arbuscular mycorrhizal fungi successfully colonize plant roots. It has been known for a while that these substances, so-called blumenol C derivates, are produced in the roots exclusively after colonization with the mutualistic fungi (1538).

 

Angela Pena-Gonzalez (US), Luis M. Rodriguez-R (US), Chung K. Marston (US), Jay E. Gee (US), Christopher A. Gulvik (US), Cari B. Kolton (US), Elke Saile, Michael Frace (US), Alex R. Hoffmaster (US), and Konstantinos T. Konstantinidis (US) found by analyzing genomic sequences from more than 400 strains of the bacterium that causes anthrax, they could provide the first evidence that the severity – technically known as virulence – of specific strains may be related to the number of copies of certain plasmids they carry. Plasmids are genetic structures of the cell that can reproduce independently, and are responsible for producing the anthrax toxin and other virulence factors (1145).

 

Chi-Min Ho (US), Josh R. Beck (US), Mason Lai (US), Yanxiang Cui (US), Daniel E. Goldberg (US), Pascal F. Egea (US), and Z. Hong Zhou (US) showed that the putative Plasmodium translocon of exported proteins (PTEX) is essential for transport of malarial effector proteins across a parasite-encasing vacuolar membrane into host erythrocytes, but the mechanism of this process remains unknown. Here they show that PTEX is a bona fide translocon by determining structures of the PTEX core complex at near-atomic resolution using cryo-electron microscopy. Their work reveals the mechanism of Plasmodium falciparum effector export, and will inform structure-based design of drugs targeting this unique translocon (632).

 

Junyue Cao (US), Darren A. Cusanovich (US), Vijay Ramani (US), Delasa Aghamirzaie (US), Hannah A. Pliner (US), Andrew J. Hill (US), Riza M. Daza (US), Jose L. McFaline-Figueroa (US), Jonathan S. Packer (US), Lena Christiansen (US), Frank J. Steemers (US), Andrew C. Adey (US), Cole Trapnell (US), and Jay Shendure (US) developed an assay that concurrently profiles both the epigenome and transcriptome of each of thousands of single cells. These assays, among their other features, incorporate unique barcodes for the nucleic acid contents of cells or of the cell nucleus, which contains the main control center for living cells. The scientists' method for labeling and sorting cells lets them link the messenger RNA and chromatin accessibility profiles of individual cells. This made possible joint profiling of chromatin accessibility and gene expression in thousands of single cells (202).

 

Matthew R. Ponte (CA), Alexander D. Hudson (CA), and Kalaichelvi Saravanamuttu (CA) noted that many of the extraordinary three-dimensional architectures that pattern our physical world emerge from complex nonlinear systems or dynamic populations whose individual constituents are only weakly correlated to each other. Shoals of fish, murmuration behaviors in birds, congestion patterns in traffic, and even networks of social conventions are examples of spontaneous pattern formation, which cannot be predicted from the properties of individual elements alone. They found that populations of randomly distributed, optochemical waves synergistically and collectively shift in space to form highly ordered lattices of specific symmetries (1174). See, Edward Sylvester Morse, 1916.

 

Jeffrey A. Farrell (US), Yiqun Wang (US), Samantha J. Riesenfeld (US), Karthik Shekhar (US), Aviv Regev (US), and Alexander F. Schier (US) traced the fates of individual cells over the first 24 hours of the life of an embryo, recapitulating decades of research on the decisions cells make in the earliest stages of life and generating a detailed roadmap of which genes are turned on or off, and when, as embryonic cells transition into new cell states and types (393).

 

Kenta Tsutsui (US), Oliver J. Monfredi (US-GB), Syevda G. Sirenko-Tagirova (US), Larissa A. Maltseva (US), Rostislav Bychkov (US), Mary S. Kim (US), Bruce D. Ziman (US), Kirill V. Tarasov (US), Yelena S. Tarasova (US), Jing Zhang (US), Mingyi Wang (US), Alexander V. Maltsev (US), Jaclyn A. Brennan (US), Igor R. Efimov (US), Michael D. Stern (US), Victor A. Maltsev (US), and Edward G. Lakatta (US) showed that a coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells. Spontaneous rhythmic local Ca2+releases generated by a Ca2+ clock were coupled to electrogenic surface membrane molecules (the M clock) to trigger rhythmic action potentials, and that Ca2+-cAMP-protein kinase A (PKA) signaling regulated clock coupling (1478).

 

Erika Harno (GB), Thanuja Gali Ramamoorthy (GB), Anthony P. Coll (GB), and Anne White (GB) determined that adrenocorticotropic hormone (ACTH) is synthesized from high molecular weight (266 amino acids) precursor protein, proopiomelanocortin (POMC), in the anterior pituitary (599).

 

Yanting Zeng (CN), Jianan Li (CN), Guanglei Li (CN),, Shisheng Huang (CN), Wenxia Yu (CN), Yu Zhang (CN), Dunjin Chen (CN), Jia Chen (CN), Jianqiao Liu (CN), and Xingxu Huang (CN) corrected a Marfan syndrome pathogenic mutation, FBN1T7498C. They first tested the feasibility in mutant cells, then successfully achieved genetic correction in heterozygous human embryos. The results showed that the BE3 mediated perfect correction at the efficiency of about 89%. Importantly, no off-target and indels were detected in any tested sites in samples by high-throughput deep sequencing combined with whole-genome sequencing analysis. Their study therefore suggests the efficiency and genetic safety of correcting a Marfan syndrome (MFS) pathogenic mutation in embryos by base editing. The authors noted that there are urgent demands for efficient treatment of heritable genetic diseases and that base editing technology has displayed its efficiency and precision in base substitution in human embryos, providing a potential early-stage treatment for genetic diseases (1627).

 

Carla Nasca (US), Benedetta Bigio (US), Francis S. Lee (US), Sarah P. Young (US), Marin M. Kautz (US), Ashly Albright (US), James Beasley (US), David S. Millington (US), Aleksander A. Mathé (SE), James H. Kocsis (US), James W. Murrough (US), Bruce Sherman McEwen (US), and Natalie Rasgon (US) found that acetyl-1-carnitine (LAC) levels, and not those of free carnitine, were decreased in patients with major depressive disorder (MDD). Exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD (1053). Note: LAC level may suggest individualized treatments in biologically based depression subtypes.

 

Donovan H. Parks (AU), Maria Chuvochina (AU), David W. Waite (AU), Christian Rinke (AU), Adam Skarshewski (AU), Pierre-Alain Chaumeil (AU), and Philip Hugenholtz (AU) used genomic blueprints to construct a giant evolutionary tree of bacteria based on 120 genes that are highly conserved across the bacterial domain. Bacterial classification was given a complete makeover (1127).

 

Ilya Bobrovskiy (AU), Janet M. Hope (AU), Andrey Ivantsov (RU), Benjamin J. Nettersheim (DE), Christian Hallmann (DE), Jochen J. Brooks (AU) used lipid biomarkers obtained from Dickinsonia fossils and found that the fossils contained almost exclusively cholesteroids, a marker found only in animals. Thus, Dickinsonia were basal animals. This supports the idea that the Ediacaran biota may have been a precursor to the explosion of animal forms later observed in the Cambrian, about 500 million years ago (142).

 

Li Liu (US), Jiajing Wang (US), Danny Rosenberg (IL), Hao Zhao (CN), György Lengyel (PL), and Dani Nadel (IL) reported the earliest archaeological evidence for cereal-based beer brewing by a semi-sedentary, foraging people. The current project incorporates experimental study, contextual examination, and use-wear and residue analyses of three stone mortars from a Natufian burial site at Raqefet Cave, Israel (13,700–11,700 c. BP). (887).

 

Iain Mathieson (US), Songül Alpaslan-Roodenberg (US), Cosimo Posth (DE), Anna Szécsényi-Nagy (HU), Nadin Rohland (US), Swapan Mallick (US), Iñigo Olalde (US), Nasreen Broomandkhoshbacht (US), Francesca Candilio (IE), Olivia Cheronet (IE), Daniel Fernandes (PT), Matthew Ferry (US), Beatriz Gamarra (IE), Gloria González Fortes (IT), Wolfgang Haak (DE-AU), Eadaoin Harney (US), Eppie Jones (IE-GB), Denise Keating (IE), Ben Krause-Kyora (DE), Isil Kucukkalipci (DE), Megan Michel (US), Alissa Mittnik (DE), Kathrin Nägele (DE), Mario Novak (IE-HR), Jonas Oppenheimer (US), Nick Patterson (US), Saskia Pfrengle (DE), Kendra Sirak (IE-US), Kristin Stewardson (US), Stefania Vai (IT), Stefan Alexandrov (BG), Kurt W. Alt (AT), Radian Andreescu (RO), Dragana Antonović (CS), Abigail Ash (IE), Nadezhda Atanassova (BU), Krum Bacvarov (BG), Mende Balázs Gusztáv (HU), Hervé Bocherens (DE), Michael Bolus (DE), Adina Boroneanţ (RO), Yavor Boyadzhiev (BG), Alicja Budnik (PL), Josip Burmaz (HR), Stefan Chohadzhiev (BG), Nicholas J. Conard (DE), Richard Cottiaux (FR), Maja Čuka (HR), Christophe Cupillard (FR), Dorothée G. Drucker (DE), Nedko Elenski (BG), Michael Francken (DE), Borislava Galabova (BG), Georgi Ganetsovski BG), Bernard Gély (FR), Tamás Hajdu (HU), Veneta Handzhyiska (BG), Katerina Harvati (DE), Thomas Higham (GB), Stanislav Iliev (BG), Ivor Janković (HR), Ivor Karavanić (BG), Douglas J. Kennett (US), Darko Komšo (HR), Alexandra Kozak (UA), Damian Labuda (CA), Martina Lari (IT), Catalin Lazar (RO), Maleen Leppek (DE), Krassimir Leshtakov (BG), Domenico Lo Vetro (IT), Dženi Los (HR), Ivaylo Lozanov (BG), Maria Malina (DE), Fabio Martini (IT), Kath McSweeney (GB), Harald Meller (DE), Marko Menđušić (HR), Pavel Mirea (RO), Vyacheslav Moiseyev (RU), Vanya Petrova (BG), T. Douglas Price (US), Angela Simalcsik (RO), Luca Sineo (IT), Mario Šlaus (HR), Vladimir Slavchev (BG), Petar Stanev (BG), Andrej Starović (CS), Tamás Szeniczey (HU), Sahra Talamo (DE), Maria Teschler-Nicola (AT), Corinne Thevenet FR), Ivan Valchev (BG), Frédérique Valentin (FR), Sergey Vasilyev (RU), Fanica Veljanovska (MK), Svetlana Venelinova (BG), Elizaveta Veselovskaya (RU), Bence Viola (CA-RU), Cristian Virag (RO), Joško Zaninović (BG), Steve Zäuner (DE), Philipp W. Stockhammer (DE), Giulio Catalano (IT), Raiko Krauß (DE), David Caramelli (IT), Gunita Zariņa (LV), Bisserka Gaydarska (GB), Malcolm Lillie (GB), Alexey G. Nikitin (US), Inna Potekhina (UA), Anastasia Papathanasiou (GR), Dušan Borić (US), Clive Bonsall (GB), Johannes Krause (DE), Ron Pinhasi (IE), and David Emil Reich (US) analysed genome-wide ancient DNA data from 225 individuals who lived in southeastern Europe and surrounding regions between 12K and 500K B.C.E. They documented a west–east cline of ancestry in indigenous hunter-gatherers and, in eastern Europe, the early stages in the formation of Bronze Age steppe ancestry. They show that the first farmers of northern and western Europe dispersed through southeastern Europe with limited hunter-gatherer admixture, but that some early groups in the southeast mixed extensively with hunter-gatherers without the sex-biased admixture that prevailed later in the north and west. They also show that southeastern Europe continued to be a nexus between east and west after the arrival of farmers, with intermittent genetic contact with steppe populations occurring up to 2,000 years earlier than the migrations from the steppe that ultimately replaced much of the population of northern Europe (954). Note: Farming was first introduced to Europe in the mid-seventh millennium B.C.E., and was associated with migrants from Anatolia who settled in the southeast before spreading throughout Europe.

 

Amaia Arranz-Otaegui (DK), Lara Gonzalez Carretero (GB), Monica N. Ramsey (GB), Dorian Q. Fuller (GB), and Tobias Richter (DK) analyzed a total of 24 charred food remains from Shubayqa 1, a Natufian hunter-gatherer site located in northeastern Jordan and dated to 12.6K-9.6K B.C.E. This provided empirical data to demonstrate that the preparation and consumption of bread-like products predated the emergence of agriculture by at least 4,000 years. The interdisciplinary analyses indicate the use of some of the "founder crops" of southwest Asian agriculture (e.g., Triticum boeoticum, wild einkorn) and root foods (e.g., Bolboschoenus glaucus, club-rush tubers) to produce flat bread-like products (51).

 

2019

The Nobel Prize in Physiology or Medicine was jointly awarded to William G. Kaelin, Jr. (US), Peter J. Ratcliffe (GB) and Gregg L. Semenza (US) for their discoveries of “how cells sense and adapt to oxygen availability.” They discovered the molecular mechanisms which enable cells to sense oxygen levels, a discovery which laid the groundwork for greater understanding of several biological processes and associated diseases.

 

Fu-Shuang Li (US), Pyae Phyo (US), Joseph Jacobowitz (US), Mei Hong (US), Jing-Ke Weng (US) published the first complete structure of sporopollenin, a ubiquitous and extremely chemically inert biopolymer that constitutes the outer wall of all land-plant spores and pollen grains. They showed that pine sporopollenin is primarily composed of aliphatic-polyketide-derived polyvinyl alcohol units and 7-O-p-coumaroylated C16 aliphatic units, crosslinked through a distinctive dioxane moiety featuring an acetal. Naringenin was also identified as a minor component of pine sporopollenin (865).

 

Pei-Shan Hou (JP), Goichi Miyoshi (JP), and Carina Hanashima (JP) identified the earliest molecular program that preselects projection neuron types in the sensory neocortex. Mechanistically, FOXG1 binds to an H3K4me1-enriched enhancer site to repress COUP-TFI, where ectopic acquisition of FOXG1 in layer 4 cells transforms local projection neurons to callosal projection neurons with pyramidal morphologies. Removal of FOXG1 in long-range projection neurons, in turn, derepresses COUP-TFI and activates a layer 4 neuron-specific program. The earliest segregation of projection subtypes is achieved through repression of FOXG1 in layer 4 precursors by early growth response genes, the major targets of the transforming growth factor-β signaling pathway. These findings describe the earliest cortex-intrinsic program that restricts neuronal connectivity in sensory circuits, a fundamental step towards the acquisition of mammalian perceptual behavior (655).

 

Bjarni V. Halldorsson (IS), Gunnar Palsson (IS), Olafur A. Stefánsson (IS), Hakon Jonsson (IS), Marteinn T. Hardarson (IS), Hannes P. Eggertsson (IS), Bjarni Gunnarsson (IS), Asmundur Oddsson (IS), Gisli H. Halldorsson (IS), Florian Zink (IS), Sigurjon A. Gudjonsson (IS), Michael L. Frigge (IS), Gudmar Thorleifsson (IS), Asgeir Sigurdsson (IS), Simon N. Stacey (IS), Patrick Sulem (IS), Gisli Masson (IS), Agnar Helgason (IS), Daniel F. Gudbjartsson (IS), Unnur Thorsteinsdottir (IS), and Kári Stefánsson (IS) at deCODE in Iceland, utilized the genealogies, the large number of whole genome sequences (WGS) that it had completed in the preceding years, and genoytping data on the majority of the population, to publish a third recombination map of the human genome (582).

Hyung Suk Oh (US), Werner M. Neuhausser (US), Pierce Eggan (US), Magdalena Angelova (US), Rory Kirchner (US), Kevin C. Eggan (US), and David M. Knipe (US) used CRISPR-Cas9 gene editing to disrupt both actively replicating and dormant pools of herpes simplex virus in human fibroblast cells, revealing a possible strategy for achieving permanent viral control (1102).

 

Prasanta K. Dash (US), Rafal Kaminski (US), Ramona Bella (US), Hang Su (US), Saumi Mathews (US), Taha M. Ahooyi (US),Chen Chen (US), Pietro Mancuso (US), Rahsan Sariyer (US), Pasquale Ferrante (US), Martina Donadoni (US), Jake A. Robinson (US), Brady Sillman (US), Zhiyi Lin (US), James R. Hilaire (US), Mary Banoub (US), Monalisha Elango (US), Nagsen Gautam (US), R. Lee Mosley (US), Larisa Y. Poluektova (US), JoEllyn McMillan (US), Aditya N. Bade (US), Santhi Gorantla (US), Ilker K. Sariyer (US), Tricia H. Burdo (US), Won-Bin Young (US), Shohreh Amini (US), Jennifer Gordon (US), Jeffrey M. Jacobson (US), Benson Edagwa (US), Kamel Khalili (US), and Howard E. Gendelman (US) used sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 to demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice (316).

 

Qiyun Zhu (US), Uyen Mai (US), Wayne Pfeiffer (US), Stefan Janssen (DE), Francesco Asnicar (IT), Jon G. Sanders (US), Pedro Belda-Ferre (US), Gabriel A. Al-Ghalith (US), Evguenia Kopylova (US), Daniel McDonald (US), Tomasz Kosciolek (PL), John B. Yin (US), Shi Huang (CN), Nimaichand Salam (CN), Jian-Yu Jiao (CN), Zijun Wu (US), Zhenjiang Z. Xu (US), Kalen Cantrell (US), Yimeng Yang (US), Erfan Sayyari (US), Maryam Rabiee (US), James T. Morton (US), Sheila Podell (US), Dan Knights (US), Wen-Jun Li (CN), Curtis Huttenhower (US), Nicola Segata (IT), Larry Smarr (US), Siavash Mirarab (PL), and Rob Knight (US) built a reference phylogeny of 10,575 evenly-sampled bacterial and archaeal genomes, based on a comprehensive set of 381 markers, using multiple strategies. Their trees indicate remarkably closer evolutionary proximity between Archaea and Bacteria than previous estimates that were limited to fewer “core” genes, such as the ribosomal proteins. Results provide an updated view of domain-level relationships (1635).

 

Takashi Shiratori (JP), Shigekatsu Suzuki (JP), Yukako Kakizawa (JP), and Ken-ichiro Ishida (JP) describe a planctomycete bacterium, ‘Candidatus Uab amorphum’, which is able to engulf other bacteria and small eukaryotic cells through a phagocytosis-like mechanism. Observations via light and electron microscopy suggest that this bacterium digests prey cells in specific compartments. With the possible exception of a gene encoding an actin-like protein, analysis of the ‘Ca. Uab amorphum’ genomic sequence does not reveal any genes homologous to eukaryotic phagocytosis genes, suggesting that cell engulfment in this microorganism is probably not homologous to eukaryotic phagocytosis (1336).

 

The Coronavirus disease (COVID-19) pandemic occurred. This highly infectious disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first identified in December 2019 in Wuhan, the capital of China's Hubei province, it then spread globally. Common symptoms included fever, cough, and shortness of breath. Other symptoms may include fatigue, muscle pain, diarrhea, sore throat, loss of smell, and abdominal pain. The time from exposure to onset of symptoms was typically around five days but ranged from two to fourteen days. While the majority of cases resulted in mild symptoms, some progressed to viral pneumonia and multi-organ failure. An immunological tragedy called a "cytokine storm" typically precipitated the most severe cases (279).

 

Koichiro Haruwaka (JP), Ako Ikegami (JP), Yoshihisa Tachibana (JP), Nobuhiko Ohno (JP), Hiroyuki Konishi (JP), Akari Hashimoto (JP), Mami Matsumoto (JP), Daisuke Kato (JP), Riho Ono (JP), Hiroshi Kiyama (JP), Andrew J. Moorhouse (AU), Junichi Nabekura (JP), and Hiroaki Wake (JP) demonstrated that microglia respond to inflammation by migrating towards and accumulating around cerebral vessels, where they initially maintain blood brain barrier (BBB) functional integrity via expression of the tight-junction protein Claudin-5 before switching, during sustained inflammation, to phagocytically remove astrocytic end-feet resulting in impaired BBB functional integrity (603).

 

Miguel A. Muñoz-Lorente (ES), Alba C. Cano-Martin (ES), and Maria A. Blasco (ES) using mice, demonstrated that telomeres longer than normal in a given species are not deleterious but instead, show beneficial effects (1035).

 

Shunsuke Hasegawa (JP), Hotaka Fukushima (JP), Hiroshi Hosoda (JP), Tatsurou Serita (JP), Rie Ishikawa (JP), Tomohiro Rokukawa (JP), Ryouka Kawahara-Miki (JP), Yue Zhang (JP), Miho Ohta (JP), Shintaro Okada (JP), Toshiyuki Tanimizu (JP), Sheena A. Josselyn (CA), Paul W. Frankland (CA), and Satoshi Kida (JP) showed that the hippocampal clock controlled by the circadian-dependent transcription factor BMAL1 regulates time-of-day retrieval profile. Their findings suggest mechanisms underlying regulation of retrieval by hippocampal clock through D1/5R-cAMP-PKA-mediated GluA1 phosphorylation (605). Note: Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening.

 

Masahiro Okamato (JP), Jason D. Gray (US), Chloe S. Larson (US), Syed Faraz Kazim (US), Hideaki Soya (US), Bruce Sherman McEwen (US), and Ana C. Pereira (US) found that Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer's disease (1104).

 

Joana I. Meier (GB-CH), Rike B. Stelkens (SE-CH), Domino A. Joyce (GB), Salome Mwaiko (CH), Numel Phiri (ZW), Ulrich K. Schliewen (DE), Oliver M. Selz (CH), Catherine E. Wagner (US-CH), Cyprian Katongo (ZW), and Ole Seehausen (CH) provided data suggesting that the presence of several related lineages does not necessarily prevent adaptive radiation, although it constrains the trajectories of morphological diversification. It might instead facilitate adaptive radiation when hybridization generates genetic variation, without which radiation may start much later, progress more slowly or never occur (983).

 

Taiping Gao (CN), Xiangchu Yin (CN), Chungkun Shih (CN), Alexandr P. Rasnitsyn (RU), Xing Xu (CN), Sha Chen (CN), Chen Wang (CN), and Dong Ren (CN) reported ten nymph specimens of a new lineage of insect, Mesophthirus engeli gen et. sp. nov. within Mesophthiridae fam. nov. from the mid-Cretaceous (ca. 100 Mya) Myanmar (Burmese) amber. This new insect clade shows a series of ectoparasitic morphological characters such as tiny wingless body, head with strong chewing mouthparts, robust and short antennae having long setae, legs with only one single tarsal claw associated with two additional long setae, etc. Most significantly, these insects are preserved with partially damaged dinosaur feathers, the damage of which was probably made by these insects’ integument-feeding behaviors. This finding demonstrates that feather-feeding behaviors of insects originated at least in mid-Cretaceous, accompanying the radiation of feathered dinosaurs including early birds (461).

 

Theis Z. T. Jensen (DK), Jonas Niemann (DK), Katrine Højholt Iversen (DK), Anna K. Fotakis (DK), Shyam Gopalakrishnan (DK), Åshild J. Vågene (DK), Mikkel Winther Pedersen (DK), Mikkel-Holger S. Sinding (DK), Martin R. Ellegaard (DK), Morten E. Allentoft (DK), Liam T. Lanigan (DK), Alberto J. Taurozzi (DK), Sofie Holtsmark Nielsen (DK), Michael W. Dee (DK), Martin N. Mortensen (DK), Mads C. Christensen (DK), Søren A. Sørensen (DK), Matthew J. Collins (DK), M. Thomas P. Gilbert (DK), Martin Sikora (DK), Simon Rasmussen (DK), and Hannes Schroeder (DK) presented a complete ancient human genome and oral microbiome sequenced from a 5700 year-old piece of chewed birch pitch from Denmark. They sequenced the human genome to an average depth of 2.3× and find that the individual who chewed the pitch was female and that she was genetically more closely related to western hunter-gatherers from mainland Europe than hunter-gatherers from central Scandinavia. They also found that she likely had dark skin, dark brown hair and blue eyes. In addition, they identified DNA fragments from several bacterial and viral taxa, including Epstein-Barr virus, as well as animal and plant DNA, which may have derived from a recent meal (705).

 

Bettina Schulz Paulsson (SE) analyzed 2,410 radiocarbon dates and highly precise chronologies for megalithic sites and related contexts. The results argue for a maritime mobility and intercultural exchange from 4.5K B.C.E. to 2.5K B.C.E. favoring the transfer of the megalithic concept over sea routes emanating from northwest France, and for advanced maritime technology and seafaring in the megalithic Age (1137).

 

2020

The Nobel Prize in Physiology or Medicine was awarded to Harvey J. Alter (US), Michael Houghton (GB) and Charles M. Rice (US) for the discovery of Hepatitis C virus. Viral infection is the leading cause of hepatitis, with some forms persisting without symptoms for many years before life-threatening complications develop.

 

Guojing Shen (CN), Nian Liu (CN), Jingxiong Zhang (CN), Yuxing Xu (CN), Ian T. Baldwin (GB), Jianqiang Wu (CN) showed that host-synthesized FLOWERING LOCUS T (FT) protein is able to move into Cuscuta australis (dodder) stems, where FT physically interacts with dodder FD transcription factor, activating flowering of dodder. This specific manner of flowering allows dodder to synchronize its flowering time with that of the host plant, and this is likely a trait that is beneficial for dodder’s reproductive success (1331).

 

Caleb A. Dawson (AU), Bhupinder Pal (AU), François Vaillant (AU), Luke C. Gandolfo (AU), Zhaoyuan Liu (SG), Camille Bleriot (SG), Florent Ginhoux (SG), Gordon K. Smyth (AU), Geoffrey J. Lindeman (AU), Scott N. Mueller (AU), Anne C. Rios (AU), and Jane E. Visvader (AU) discovered a new population of specialised immune cells that maintain the health of breast ducts. The cells, called ductal macrophages, eat up dying milk-producing cells that need to be cleared away after milk production stops (321).

 

Jack P. Antel (CA), Burkhard Becher (CH), Samuel K. Ludwin (CA), Alexandre Prat (CA), and Francisco J. Quintana (US) reported results obtained with microglia isolated from the adult human brain which contributed to recognizing the dynamic properties of endogenous glial cells in the central nervous system (CNS) and how the state of such cells regulate and mediate immune responses within the CNS. Their multitude of interactions with locally and systemically derived signals leads to a complex spectrum of phenotypes in these cells (43).

 

Stephen T. Ferris (US), Vivek Durai (US), Renee Wu (US), Derek J. Theisen (US), Jeffrey P. Ward (US), Michael D. Bern (US), Jesse T. Davidson IV (US), Prachi Bagadia (US), Tiantian Liu (US), Carlos G. Briseño (US), Lijin Li (US), William E. Gillanders (US), Gregory F. Wu (US), Wayne M. Yokoyama (US), Theresa L. Murphy (US), Robert D. Schreiber (US), and Kenneth M. Murphy (US) report that in the setting of tumor-derived antigens, conventional type 1 dendritic cells (cDC1) function as an autonomous platform capable of antigen processing and priming for both CD4+ and CD8+ T cells and of the direct orchestration of their cross-talk that is required for optimal anti-tumor immunity (408).

 

Jonathan M. Stokes (US), Kevin Yang (US), Kyle Swanson (US) , Wengong Jin (US), Andres Cubillos-Ruiz (US), Nina M. Donghia (US), Craig R. MacNair (CA), Shawn French (CA), Lindsey A. Carfrae (CA), Zohar Bloom-Ackermann (US), Victoria M. Tran (US), Anush Chiappino-Pepe (US), Ahmed H. Badran (US), Ian W. Andrews (US), Emma J. Chory (US), George M. Church (US), Eric D. Brown (CA), Tommi S. Jaakkola (US), Regina Barzilay (US), and James J. Collins (US) trained a machine-learning algorithm to predict molecules with antibacterial activity. They performed predictions using multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub-halicin-that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules (1404). Note: Halicin worked against every species that they tested, with the exception of Pseudomonas aeruginosa, a difficult-to-treat lung pathogen.

 

Minetta C. Liu (US), Geoffrey R. Oxnard (US), Eric A. Klein (US), Charles Swanton (UK), Michael V. Seiden (US), and the CCGA Consortium used cell-free DNA sequencing (leveraging informative methylation patterns) to detect more than 50 cancer types across stages. Cancers were detected across all stages (stage I–III sensitivity: 43.9%; stage I–IV sensitivity: 54.9%) at a specificity of >99% and a single false positive rate of <1%. This targeted methylation approach localized the tissue of origin with >90% accuracy, which will be critical for directing follow-up care (888). Note: This is named the Galleri test. It is a Multi-Cancer Early Detection (MCED) test.

 

Ivan Djordjevic (SG), Oleksandr Pokholenko (SG), Ankur Harish Shah (SG), Gautama Wicaksono (SG), Lluis Blancafort (ES), John V. Hanna (GB), Samuel J. Page (GB), Himansu Sekhar Nanda (IN-SG), Chee Bing Ong (SG), Sze Ryn Chung (SG), Andrew Yuan Hui Chin (SG), Duncan McGrouther (SG), Muntasir Mannan Choudhury (SG), Fang Li (SG), Jonathan Shunming Teo (SG), Lui Shiong Lee (SG), and Terry W.J. Steele (SG) developed a new type of surgical glue that can help join blood vessels and close wounds faster. Known as CaproGlu, the glue can bond soft tissues, including muscle and blood vessels, even when their surfaces are wet (342).

 

Chi-Fen Chiu (TW), Li-Wei Chu (TW), I-Chen Liao (TW),Yogy Simanjuntak (TW), Yi-Ling Lin (TW), Chi-Chang Juan (TW), and Yueh-Hsin Ping (TW) showed that the Zika virus (ZIKV) uses a cell-type specific paracellular pathway to cross the placenta monolayer barrier by disrupting cellular tight junctions. In addition, the ZIKV can also cross both the placenta barrier and the BBB by transcytosis. Their study provided new insights into on the mechanism of the cellular barrier penetration of ZIKV particles (246).

 

Hiroyuki J. Kanaya (JP), Sungeon Park (KR), Ji-hyung Kim (KR), Junko Kusumi (JP), Sofian Krenenou (FR), Etsuko Sawatari (JP), Aya Sato (JP), Jongbin Lee (KR), Hyunwoo Bang (KR), Yoshitaka Kobayakawa (JP), Chunghun Lim (KR), and Taichi Q. Itoh (JP) reported a sleep-like state in the cnidarian Hydra vulgaris with a primitive nervous organization. Hydra sleep was shaped by homeostasis and necessary for cell proliferation, but it lacked free-running circadian rhythms. Instead, they detected 4-hour rhythms that might be generated by ultradian oscillators underlying Hydra sleep. Sleep-relevant physiology and sleep-regulatory components may have already been acquired at molecular levels in a brain-less metazoan phylum and reprogrammed accordingly (732).

 

Peter A. McCullough (US), Ronan J. Kelly (US), Gaetano Ruocco (IT), Edgar Lerma (US), James Tumlin (US), Kevin R. Wheelan (US), Nevin Katz (US), Norman E. Lepor (US), Kris Vijay (US), Harvey Carter (US), Bhupinder Singh (US), Sean P. McCullough (US), Brijesh K. Bhambi (US), Alberto Palazzuoli (IT), Gaetano M. De Ferrari (IT), Gregory P. Milligan (US), Taimur Safder (US), Kristen M. Tecson (US), Dee Dee Wang (US), John E. McKinnon (US), William W. O'Neill (US), Marcus Zervos (US), and Harvey A. Risch (US) reported that in the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of SARS-CoV-2 (COVID-19) with the aim of preventing hospitalization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine (969). Note: This article was first published online 2020 Aug 6.

 

Jonathas Souza Bittencourt (BR), Tiago Rodrigues Simões (US), Michael Wayne Caldwell (CA), and Max Cardoso Langer (BR) described a new lizard species that represents the oldest (early Cretaceous) fossil squamate from South America, demonstrating that squamates were present on that continent at least 20 million years earlier than previously recorded. They named it Neokotus sanfranciscanus. The new species represents the first occurrence of the extinct squamate family Paramacellodidae in South America and displays an unusual limb morphology. Finally, their findings suggest early South American squamates were part of a much broader distribution of their respective clades, in sharp contrast to the high levels of endemicity characteristic of modern faunas (129).

 

Lara M. Cassidy (IE), Ros Ó Maoldúin (IE), Thomas Kador (GB), Ann Lynch (IE), Carleton Jones (IE), Peter C. Woodman (IE), Eileen Murphy (GB), Greer Ramsey (GB), Marion Dowd (IE), Alice Noonan (IE), Ciarán Campbell (IE), Eppie R. Jones (GB), Valeria Mattiangeli (IE), and Daniel G. Bradley (IE), from their survey of ancient Irish genomes, suggested a man who had been buried in Newgrange passage tomb in Ireland (c. 3K B.C.E.) belonged to a dynastic elite. Their analyses allowed them to confirm that his parents were first-degree relatives. Matings of this type (e.g. brother-sister unions) are a near universal taboo for entwined cultural and biological reasons. The only confirmed social acceptances of first-degree incest are found among the elites— typically within a deified royal family. By breaking the rules, the elite separates itself from the general population, intensifying hierarchy and legitimizing power. Public ritual and extravagant monumental architecture often co-occur with dynastic incest, to achieve the same ends (215).

 

Lu Chen (US) , Aaron B. Wolf (US) , Wenqing Fu (US) , Liming Li (US) , and Joshua M. Akey (US) detailed a new computational method for detecting Neanderthal ancestry in the human genome. Their method, called IBDmix, enabled them for the first time to search for Neanderthal ancestry in African populations as well as non-African ones. African individuals carry a stronger signal of Neanderthal ancestry than previously thought. This can be explained by genuine Neanderthal ancestry due to migrations back to Africa, predominately from ancestral Europeans, and gene flow into Neanderthals from an early dispersing group of humans out of Africa. Their results refine our understanding of Neanderthal ancestry in African and non-African populations and demonstrate that remnants of Neanderthal genomes survive in every modern human population studied to date (235).

 

2021

"The COVID-19 pandemic has clearly demonstrated that there are real catastrophes caused by microscopic viral agents, and that even this has been somewhat overplayed in an overly risk-averse society. Hopefully this will help bring the fake catastrophes into perspective. People are not dying by the tens of thousands from climate change. Species are not going extinct by the tens of thousands either. And genetically modified food has not been known to cause a single illness, never mind thousands of deaths." Patrick Albert Moore (CA) (1014).

 

Ryan G. Gaudet (US), Shiwei Zhu (US), Anushka Halder (US), Bae-Hoon Kim (US), Clinton J. Bradfield (US), Shuai Huang (US), Dijin Xu (US), Ngoc Nguyen (AU), Michael Lazarou (AU), Erdem Karatekin (FR), Kallol Gupta (US), and John D. MacMicking (US) discovered human apolipoprotein L (APOL3) with detergent-like activity that kills intracellular pathogens. It appears that humans have harnessed the detergent-like properties of extracellular apolipoproteins to fashion an intracellular lysin, thereby endowing resident nonimmune cells with a mechanism to achieve sterilizing immunity (474).

 

Yuko Sato (JP), Koji Atarashi (JP), Damian R Plichta (US), Yasumichi Arai (JP), Satoshi Sasajima (JP), Sean M Kearney (JP), Wataru Suda (JP), Kozue Takeshita (JP), Takahiro Sasaki (JP), Shoki Okamoto (JP), Ashwin N Skelly (JP), Yuki Okamura (JP), Hera Vlamakis (US), Youxian Li (JP), Takeshi Tanoue (JP), Hajime Takei (JP), Hiroshi Nittono (JP), Seiko Narushima (JP), Junichiro Irie (JP), Hiroshi Itoh (JP), Kyoji Moriya (JP), Yuki Sugiura (JP), Makoto Suematsu (JP), Nobuko Moritoki (JP), Shinsuke Shibata (JP), Dan R Littman (US), Michael A Fischbach (US), Yoshifumi Uwamino (JP), Takashi Inoue (JP), Akira Honda (JP), Masahira Hattori (JP), Tsuyoshi Murai (JP), Ramnik J Xavier (US), Nobuyoshi Hirose (JP), and Kenya Honda (JP) showed that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the fecal microbiota of a centenarian, they identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, they found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against gram-positive (but not gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis (1280).

Note: Centenarians have a decreased susceptibility to aging-associated illnesses, chronic inflammation and infectious diseases.

 

Lindsay S. Cahill (CA), Greg Stortz (CA), Anjana Ravi Chandran (CA), Natasha Milligan (CA), Shiri Shinar (CA), Clare L. Whitehead (AU), Sebastian R. Hobson (CA), Viji Ayyathurai (CA), Anum Rahman (CA), Rojan Saghian (CA), Karl J. Jobst (CA), Cyrethia McShane (US),Dana Block-Abraham (US), Viola Seravalli (US), Melissa Laurie (US), Sarah Millard (US), Cassandra Delp (US), Denise Wolfson (US), Ahmet A. Baschat (US), Kellie E. Murphy (CA), Lena Serghides (CA), Eric Morgen (CA), Christopher K. Macgowan (CA), W. Tony Parks (CA), John C. Kingdom (CA), and John G. Sled (CA) developed a new ultrasound technique to monitor the placenta for impaired fetal blood flow early in pregnancy. The technique, which uses conventional ultrasound equipment, relies on subtle differences in the pulsation of fetal blood through the arteries at the fetal and placental ends of the umbilical cord, potentially enabling physicians to identify placental abnormalities that impair fetal blood flow and, if necessary, deliver the fetus early. Like current ultrasound techniques, the new technique can also detect impaired flow of maternal blood through the placenta (193).

 

Mirna Kramar (DE) and Karen Alim (DE) found that the slime mold Physarum polycephalum records important details of its surroundings by changing the diameter of outstretched feeding tubes. They observed the tubes to become thicker when they encountered food and thinner when they found none (800).

 

Nina Helt Nielsen (DK), Peter Steen Henriksen (DK), Renée Enevold (DK), Cartsten Scavenius (DK), Morten Fischer Mortensen (DK), Martin Nordvig Mortensen (DK), and Jan J. Enghild (DK) described the last meal of "Tollund Man", a bog body from Early Iron Age Denmark, his bowl contents were reexamined using new analyses of plant macrofossils, pollen, non-pollen palynomorphs, steroid markers and proteins found in his gut. Some 12-24 hours before he was killed, he ate a porridge containing barley, pale persicaria and flax, and probably some fish. Proteins and eggs from intestinal worms—whipworms, tapeworms, and mawworms—indicate that he was infected with parasites (1079). Note: "Tollund Man", a naturally mummified corpse of a man who lived during the 5th century B.C.E., during the period characterised in Scandinavia as the Pre-Roman Iron Age. He was found in 1950, preserved as a bog body, on the Jutland peninsula, in Denmark and remains the best preserved of the bog people. Common to them is that they show signs of untimely and very violent deaths and that they received an extraordinary burial in a watery place.

 

Jamie Hodgkins (US), Caley M. Orr (US), Claudine Gravel-Miguel (US-CA), Julien Riel-Salvatore (CA), Christopher E. Miller (DE-NO), Luca Bondioli (IT), Alessia Nava (GB-IT), Federico Lugli (IT), Sahra Talamo (IT-DE), Mateja Hajdinjak (GB), Emanuela Cristiani (IT), Matteo Romandini (IT), Dominique Meyer (US), Danylo Drohobytsky (US), Falko Kuester (US), Geneviève Pothier-Bouchard (GB), Michael Buckley (GB), Lucia Mancini (IT), Fabio Baruffaldi (IT), Sara Silvestrini (IT), Simona Arrighi (IT), Hannah M. Keller (US), Rocío Belén Griggs (US), Marco Peresani (IT), David S. Strait (ZA), Stefano Benazzi (IT-DE), and Fabio Negrino (IT) reported a richly-decorated young infant burial (AVH-1) from Arma Veirana (Liguria, northwestern Italy) that is directly dated to 10,211–9910 cal BP (95.4% probability), placing it within the early Holocene and therefore attributable to the early Mesolithic. The Arma Veirana burial provides insight into sex/gender-based social status, funerary treatment, and the attribution of personhood to the youngest individuals among prehistoric hunter-gatherer groups and adds substantially to the scant data on mortuary practices from an important period in prehistory shortly following the end of the last Ice Age (635).

 

Mateja Hajdinjak (DE), Fabrizio Mafessoni (DE), Laurits Skov (DE), Benjamin Vernot (DE), Alexander Hübner (DE), Qiaomei Fu (CN), Elena Essel (DE), Sarah Nagel (DE), Birgit Nickel (DE), Julia Richter (DE), Oana Teodora Moldovan (RO), Silviu Constantin (RO) ,Elena Endarova (BG) ,Nikolay Zahariev (BG) ,Rosen Spasov (BG) ,Frido Welker (DE) ,Geoff M Smith (DE) ,Virginie Sinet-Mathiot (DE) ,Lindsey Paskulin (GB) ,Helen Fewlass (DE) ,Sahra Talamo (DE) ,Zeljko Rezek (DE) ,Svoboda Sirakova (BG) ,Nikolay Sirakov (BG) ,Shannon P McPherron (DE) ,Tsenka Tsanova (DE) ,Jean-Jacques Hublin (DE) ,Benjamin M Peter (DE) ,Matthias Meyer (DE) ,Pontus Skoglund (GB) ,Janet Kelso (DE) , and Svante Pääbo (DE) present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artifact assemblage. These individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, they found that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common (577).

Ludovic Slimak (FR), Clément Zanolli (FR), Tom Higham (GB), Marine Frouin (GB), Jean-Luc Schwenninger (GB), Lee J. Arnold (AU), Martina Demuro (AU), Katerina Douka (AT), Norbert Mercier (FR), Gilles Guérin (FR), Hélène Valladas (FR),Pascale Yvorra(FR), Yves Giraud (FR), Andaine Seguin-Orlando (FR), Jason E. Lewis (US), Xavier Muth (CH), Hubert Camus(FR), Ségolène Vandevelde (FR), Mike Buckley (GB), Carolina Mallol (ES), Chris Stringer (GB), and Laure Metz (FR) reported hominin fossils from Grotte Mandrin in France that reveal the earliest known presence of modern humans in Europe between 56,800 and 51,700 years ago. This early modern human incursion in the Rhône Valley is associated with technologies unknown in any industry of that age outside Africa or the Levant. Mandrin documents the first alternating occupation of Neanderthals and modern humans, with a modern human fossil and associated Neronian lithic industry found stratigraphically between layers containing Neanderthal remains associated with Mousterian industries (1355).

 

2022

Jian Zhou(US), Junpeng Lai (US), Gil Menda (US), Jay A. Stafstrom (US), Carol I. MIles (US), Ronald R. Hoy (US), and Ronald N. Niles (US) discovered that by outsourcing its acoustic sensors to its web, the spider is released from body size constraints and permits the araneid spider to increase its sound-sensitive surface area enormously, up to 10,000 times greater than the spider itself (1633).

 

Maria C. Basil (US), Fabian L. Cardenas-Diaz (US), Jaymin J. Kathiriya (US), Michael P. Morley (US), Justine Carl (US), Alexis N. Brumwell (US), Jeremy Katzen (US), Katherine J. Slovik (US), Apoorva Babu (US), Su Zhou (US), Madison M. Kremp (US), Katherine B. McCauley (US), Shanru Li (US), Joseph D. Planer (US), Shah S. Hussain (US), Xiaoming Liu (US), Rebecca Windmueller (US), Yun Ying (US), Kathleen M. Stewart (US), Michelle Oyster (US), Jason D. Christie (US), Joshua M. Diamond (US), John F. Engelhardt (US), Edward Cantu (US), Steven M. Rowe (US), Darrell N. Kotton (US), Harold A. Chapman (US), and Edward E. Morrisey (US) identified a distinct secretory cell lineage deep within human lungs that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease. The newly-identified lung cells, named respiratory airway secretory cells (RASCs), line tiny airway branches near the alveoli structures where oxygen is exchanged for carbon dioxide. They have stem-cell-like properties enabling them to regenerate other cells that are essential for the normal functioning of alveoli (91).

 

Tralokinumab (tralokinumab-ldrm) [Adbry() (USA); Adtralza() (EU)], a human IgG4 monoclonal antibody that binds specifically to interleukin (IL)-13, is an effective and generally well tolerated treatment option for adult patients with moderate to severe atopic dermatitis (131).

 

Zhiyu Wang (CA), Junbo Huang (CA), Seung-Pil Yang (CA), and Donald F. Weaver (CA) discovered that an anti-inflammatory anthranilate analog enhances autophagy through mTOR and promotes endoplasmic-reticulum-turnover through TEX264 during Alzheimer-associated neuroinflammation (1539). Note: This work suggests that Alzheimer's disease may be an auto-immune disease.

 

Andrea Cercek (US), Melissa Lumish (US), Jenna Sinopoli (US), Jill Weiss (US), Jinru Shia (US), Michelle Lamendola-Essel (US), Imane H. El Dika (US), Neil Segal (US), Marina Shcherba (US), Ryan Sugarman (US), Zsofia Stadler (US), Rona Yaeger (US), J. Joshua Smith (US), Benoit Rousseau (US), Guillem Argiles (US), Miteshkumar Patel (US), Avni Desai (US), Leonard B. Saltz (US), Maria Widmar (US), Krishna Iyer (US), Janie Zhang (US), Nicole Gianino (US), Christopher Crane (US), Paul B. Romesser (US), Emmanouil P. Pappou (US), Philip Paty (US), Julio Garcia-Aguilar (US), Mithat Gonen (US), Marc Gollub (US), Martin R. Weiser (US), Kurt A. Schalper (US), and Luis A. Diaz, Jr. (US) initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. A total of 12 patients completed treatment with dostarlimab and underwent at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, ¹⁸F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy (221). This appears to be the first-time in the history of cancer treatment that an anti-cancer agent has been 100% efficient. Note: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum was a standard treatment for locally advanced rectal cancer at that time.

 

Evan Xu (US), Yan Xie (US), and Zyad Al-Aly (US) undertook a comprehensive evaluation of neurologic sequelae 1 year following acute COVID-19 infection. Results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis or encephalopathy. They provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19 (1601).

 

Kurt H. Kjær (DK), Mikkel Winther Pedersen (DK), Bianca De Sanctis (GB), Binia De Cahsan (DK), Thorfinn S. Korneliussen (DK), Christian S. Michelsen (DK), Karina K. Sand (DK), Stanislav Jelavić (DK), Anthony H. Ruter (DK), Astrid M. A. Schmidt (DK), Kristian K. Kjeldsen (DK), Alexey S. Tesakov (RU), Ian Snowball (SE), John C. Gosse (CA), Inger G. Alsos (NO), Yucheng Wang (DK), Christoph Dockter (DK), Magnus Rasmussen (DK), Morten E. Jørgensen (DK), Birgitte Skadhauge (DK), Ana Prohaska (DK), Jeppe Å. Kristensen (GB), Morten Bjerager (DK), Morten E. Allentoft (DK-AU), Eric Coissac (NO-FR), PhyloNorway Consortium (NO-FR), Alexandra Rouillard (DK-NO), Alexandra Simakova (DK), Antonio Fernandez-Guerra (DK), Chris Bowler (FR), Marc Macias-Fauria (GB), Lasse Vinner (DK), John J. Welch (GB), Alan J. Hidy (US), Martin Sikora (DK), Matthew J. Collins (DK), Richard Durbin (GB), Nicolaj K. Larsen (DK), and Eske Willerslev (DK-GB-DE) reported an ancient environmental DNA (eDNA) record describing the rich plant and animal assemblages of the Kap København Formation in North Greenland, dated to around two million years ago. The record shows an open boreal forest ecosystem with mixed vegetation of poplar, birch and thuja trees, as well as a variety of Arctic and boreal shrubs and herbs, many of which had not previously been detected at the site from macrofossil and pollen records. The DNA record confirms the presence of hare and mitochondrial DNA from animals including mastodons, reindeer, rodents and geese, all ancestral to their present-day and late Pleistocene relatives. The presence of marine species including horseshoe crab and green algae support a warmer climate than today (773).

 

English country names and code elements taken from the International Organization for Standardization:

DZ = Algerian; US = American; AR = Argentinian; AU = Australian; AT = Austrian; AT/HU = Austro/Hungarian; BA = Bosnian-Herzegovinian; BE = Belgian; BW = a Motswana (Botswana); BR = Brazilian; GB = British; BG = Bulgarian; CM = Cameroonian; CA = Canadian; TD = Chadian; CL = Chilean; CN = Chinese; CO = Colombian; CR = Costa Rican; HR = Croatian; CU = Cuban; CY = Cypriot; CZ = Czechoslovakian; DK = Danish; NL = Dutch; EC = Ecuadorian; EG = Egyptian; EE = Estonian; ET = Ethiopian; FI = Finnish; FR = French; GA = Gabon; DE = German; GR = Greek; GT = Guatemalan; GU = Guamanian; GN = Guinean; HU = Hungarian; IS = Icelander; IN = Indian; ID = Indonesian; IR = Iranian; IQ = Iraqi; IL = Israeli; IE = Irish; IT = Italian; JM = Jamaican; JP = Japanese; KE = Kenyan; KR = South Korean; KW = Kuwaiti; KZ = Kazakhstanean; LV = Latvian; LB = Lebanese; LT = Lithuanian; LU = Luxembourgian; MK= Macedonian; MG = Malagasy; MW = Malawian; BW ML = Malian; MT = Maltese; MY = Malaysian; MX = Mexican; MA = Moroccan; NA = Namibian; NZ = New Zealander; NG = Nigerian; NO = Norwegian; PK = Pakistani; PA = Panamanian; PE = Peruvian; PH = Filipino; PL = Polish; PT = Portuguese; PR = Puerto Rican; RO = Romanian; RU = Russian; SA = Saudi Arabian; SN = Senegalese; CS = Serbian-Montenegrin; SG = Singaporean; SK = Slovakian; SI = Slovenian; ZA = South African; ES = Spanish; LK = Sri Lankan; SE = Swedish; CH = Swiss; SY = Syrian; TW = Taiwanese; TH = Thai; TN = Tunisian; TR = Turkish; UG = Ugandan; UA = Ukrainian; UY = Uruguayan; VE = Venezuelan; ZW = Zimbabwean

 

 

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