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  • Female  (1,864)
  • Protein Binding  (474)
  • Protein Structure, Tertiary  (376)
  • Nature Publishing Group (NPG)  (2,536)
  • Blackwell Publishing Ltd
  • 1
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    Sex bias blights drug studies (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-03-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Check Hayden, Erika -- England -- Nature. 2010 Mar 18;464(7287):332-3. doi: 10.1038/464332b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20237530" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bias (Epidemiology) ; Biomedical Research/*methods ; Clinical Trials as Topic/methods ; Drug Evaluation/*methods ; Female ; Humans ; Male ; Patient Selection ; Prejudice ; *Sex Characteristics ; Sex Distribution
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    The structural basis for autonomous dimerization of the pre-T-cell antigen receptor (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-15
    Description: The pre-T-cell antigen receptor (pre-TCR), expressed by immature thymocytes, has a pivotal role in early T-cell development, including TCR beta-selection, survival and proliferation of CD4(-)CD8(-) double-negative thymocytes, and subsequent alphabeta T-cell lineage differentiation. Whereas alphabetaTCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling, pre-TCR-induced signalling occurs by means of a ligand-independent dimerization event. The pre-TCR comprises an invariant alpha-chain (pre-Talpha) that pairs with any TCR beta-chain (TCRbeta) following successful TCR beta-gene rearrangement. Here we provide the basis of pre-Talpha-TCRbeta assembly and pre-TCR dimerization. The pre-Talpha chain comprised a single immunoglobulin-like domain that is structurally distinct from the constant (C) domain of the TCR alpha-chain; nevertheless, the mode of association between pre-Talpha and TCRbeta mirrored that mediated by the Calpha-Cbeta domains of the alphabetaTCR. The pre-TCR had a propensity to dimerize in solution, and the molecular envelope of the pre-TCR dimer correlated well with the observed head-to-tail pre-TCR dimer. This mode of pre-TCR dimerization enabled the pre-Talpha domain to interact with the variable (V) beta domain through residues that are highly conserved across the Vbeta and joining (J) beta gene families, thus mimicking the interactions at the core of the alphabetaTCR's Valpha-Vbeta interface. Disruption of this pre-Talpha-Vbeta dimer interface abrogated pre-TCR dimerization in solution and impaired pre-TCR expression on the cell surface. Accordingly, we provide a mechanism of pre-TCR self-association that allows the pre-Talpha chain to simultaneously 'sample' the correct folding of both the V and C domains of any TCR beta-chain, regardless of its ultimate specificity, which represents a critical checkpoint in T-cell development. This unusual dual-chaperone-like sensing function of pre-Talpha represents a unique mechanism in nature whereby developmental quality control regulates the expression and signalling of an integral membrane receptor complex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pang, Siew Siew -- Berry, Richard -- Chen, Zhenjun -- Kjer-Nielsen, Lars -- Perugini, Matthew A -- King, Glenn F -- Wang, Christina -- Chew, Sock Hui -- La Gruta, Nicole L -- Williams, Neal K -- Beddoe, Travis -- Tiganis, Tony -- Cowieson, Nathan P -- Godfrey, Dale I -- Purcell, Anthony W -- Wilce, Matthew C J -- McCluskey, James -- Rossjohn, Jamie -- England -- Nature. 2010 Oct 14;467(7317):844-8. doi: 10.1038/nature09448.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944746" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Gene Rearrangement, T-Lymphocyte/genetics ; Humans ; Models, Molecular ; Mutation ; Protein Folding ; *Protein Multimerization ; Protein Structure, Tertiary ; Receptors, Antigen, T-Cell/*chemistry/genetics/*metabolism ; Receptors, Antigen, T-Cell, alpha-beta/chemistry/metabolism ; Signal Transduction ; Solutions ; T-Lymphocytes/cytology/immunology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    The primate connection (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trivedi, Bijal -- England -- Nature. 2010 Jul 15;466(7304):S5. doi: 10.1038/nature09236.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20631704" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/immunology ; Animals ; Chronic Disease ; Disease Models, Animal ; Disease Progression ; Female ; Genome, Viral/genetics ; HIV Infections/*immunology/physiopathology/virology ; HIV-1/genetics/growth & development/immunology ; Host-Pathogen Interactions/immunology ; Immunity, Innate/immunology ; Inflammation/immunology/pathology ; Interleukin-17/immunology ; Macaca/immunology/virology ; Male ; Physiology, Comparative/methods ; Primates/*immunology/metabolism/*virology ; Receptors, HIV/metabolism ; Simian Acquired Immunodeficiency Syndrome/*immunology/metabolism/virology ; Simian Immunodeficiency Virus/classification/genetics/pathogenicity/*physiology ; T-Lymphocytes, Helper-Inducer/immunology/pathology ; Viral Load
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Males still dominate animal studies (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-06-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zucker, Irving -- Beery, Annaliese K -- England -- Nature. 2010 Jun 10;465(7299):690. doi: 10.1038/465690a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departmentsof Psychology, Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA. irvzuck@berkeley.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535186" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bias (Epidemiology) ; Biomedical Research/ethics/*methods/trends ; *Disease Models, Animal ; Female ; Humans ; Male ; Prevalence ; *Sex Characteristics ; Sex Distribution ; Sex Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Single-molecule imaging reveals mechanisms of protein disruption by a DNA translocase (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-11-26
    Description: In physiological settings, nucleic-acid translocases must act on substrates occupied by other proteins, and an increasingly appreciated role of translocases is to catalyse protein displacement from RNA and DNA. However, little is known regarding the inevitable collisions that must occur, and the fate of protein obstacles and the mechanisms by which they are evicted from DNA remain unexplored. Here we sought to establish the mechanistic basis for protein displacement from DNA using RecBCD as a model system. Using nanofabricated curtains of DNA and multicolour single-molecule microscopy, we visualized collisions between a model translocase and different DNA-bound proteins in real time. We show that the DNA translocase RecBCD can disrupt core RNA polymerase, holoenzymes, stalled elongation complexes and transcribing RNA polymerases in either head-to-head or head-to-tail orientations, as well as EcoRI(E111Q), lac repressor and even nucleosomes. RecBCD did not pause during collisions and often pushed proteins thousands of base pairs before evicting them from DNA. We conclude that RecBCD overwhelms obstacles through direct transduction of chemomechanical force with no need for specific protein-protein interactions, and that proteins can be removed from DNA through active disruption mechanisms that act on a transition state intermediate as they are pushed from one nonspecific site to the next.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230117/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230117/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Finkelstein, Ilya J -- Visnapuu, Mari-Liis -- Greene, Eric C -- F32GM80864/GM/NIGMS NIH HHS/ -- GM074739/GM/NIGMS NIH HHS/ -- GM082848/GM/NIGMS NIH HHS/ -- R01 CA146940/CA/NCI NIH HHS/ -- R01 GM074739/GM/NIGMS NIH HHS/ -- R01 GM074739-01A1/GM/NIGMS NIH HHS/ -- R01 GM074739-05/GM/NIGMS NIH HHS/ -- R01 GM082848/GM/NIGMS NIH HHS/ -- R01 GM082848-01A1/GM/NIGMS NIH HHS/ -- R01 GM082848-04/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Dec 16;468(7326):983-7. doi: 10.1038/nature09561. Epub 2010 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107319" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophage lambda/genetics ; Biocatalysis ; DNA/genetics/*metabolism ; DNA, Viral/genetics/metabolism ; DNA-Binding Proteins/*metabolism ; DNA-Directed RNA Polymerases/chemistry/metabolism ; Deoxyribonuclease EcoRI/metabolism ; Escherichia coli/enzymology ; Exodeoxyribonuclease V/*metabolism ; Holoenzymes/chemistry/metabolism ; Lac Repressors/metabolism ; Microscopy, Fluorescence ; *Movement ; Nucleosomes/metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding ; Quantum Dots ; Time Factors
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Foot strike patterns and collision forces in habitually barefoot versus shod runners (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-30
    Description: Humans have engaged in endurance running for millions of years, but the modern running shoe was not invented until the 1970s. For most of human evolutionary history, runners were either barefoot or wore minimal footwear such as sandals or moccasins with smaller heels and little cushioning relative to modern running shoes. We wondered how runners coped with the impact caused by the foot colliding with the ground before the invention of the modern shoe. Here we show that habitually barefoot endurance runners often land on the fore-foot (fore-foot strike) before bringing down the heel, but they sometimes land with a flat foot (mid-foot strike) or, less often, on the heel (rear-foot strike). In contrast, habitually shod runners mostly rear-foot strike, facilitated by the elevated and cushioned heel of the modern running shoe. Kinematic and kinetic analyses show that even on hard surfaces, barefoot runners who fore-foot strike generate smaller collision forces than shod rear-foot strikers. This difference results primarily from a more plantarflexed foot at landing and more ankle compliance during impact, decreasing the effective mass of the body that collides with the ground. Fore-foot- and mid-foot-strike gaits were probably more common when humans ran barefoot or in minimal shoes, and may protect the feet and lower limbs from some of the impact-related injuries now experienced by a high percentage of runners.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lieberman, Daniel E -- Venkadesan, Madhusudhan -- Werbel, William A -- Daoud, Adam I -- D'Andrea, Susan -- Davis, Irene S -- Mang'eni, Robert Ojiambo -- Pitsiladis, Yannis -- England -- Nature. 2010 Jan 28;463(7280):531-5. doi: 10.1038/nature08723.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Human Evolutionary Biology, 11 Divinity Avenue, Harvard University, Cambridge, Massachusetts 02138, USA. danlieb@fas.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20111000" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Biomechanical Phenomena ; Child ; Female ; Foot/*physiology ; Forefoot, Human/physiology ; Gait/physiology ; Humans ; Kenya ; Male ; Running/*physiology ; *Shoes/standards ; *Stress, Mechanical ; United States ; Weight-Bearing/physiology ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Amygdalar and hippocampal substrates of anxious temperament differ in their heritability (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-08-13
    Description: Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution (18)F-labelled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oler, Jonathan A -- Fox, Andrew S -- Shelton, Steven E -- Rogers, Jeffrey -- Dyer, Thomas D -- Davidson, Richard J -- Shelledy, Wendy -- Oakes, Terrence R -- Blangero, John -- Kalin, Ned H -- MH018931/MH/NIMH NIH HHS/ -- MH046729/MH/NIMH NIH HHS/ -- MH059490/MH/NIMH NIH HHS/ -- MH081884/MH/NIMH NIH HHS/ -- MH084051/MH/NIMH NIH HHS/ -- P50 MH084051/MH/NIMH NIH HHS/ -- P50 MH084051-030001/MH/NIMH NIH HHS/ -- R01 MH046729/MH/NIMH NIH HHS/ -- R01 MH046729-17/MH/NIMH NIH HHS/ -- R01 MH081884/MH/NIMH NIH HHS/ -- R01 MH081884-04/MH/NIMH NIH HHS/ -- R37 MH059490/MH/NIMH NIH HHS/ -- R37 MH059490-13/MH/NIMH NIH HHS/ -- England -- Nature. 2010 Aug 12;466(7308):864-8. doi: 10.1038/nature09282.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin 53719, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20703306" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/*metabolism ; Animals ; Anxiety/*genetics/*physiopathology ; Depression/genetics ; Female ; Freezing Reaction, Cataleptic ; Genetic Predisposition to Disease/*genetics ; Glucose/metabolism ; *Heredity ; Hippocampus/*metabolism ; Macaca mulatta/genetics/physiology ; Male ; Models, Animal ; Neural Pathways/physiology ; Pedigree ; Phenotype ; Positron-Emission Tomography ; Stress, Psychological ; Temperament/*physiology ; Temporal Lobe/metabolism ; Vocalization, Animal
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Forgotten lessons (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Basu, Paroma -- England -- Nature. 2010 Jul 15;466(7304):S14-5. doi: 10.1038/nature09241.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20631697" target="_blank"〉PubMed〈/a〉
    Keywords: Acquired Immunodeficiency Syndrome/drug therapy/epidemiology/prevention & ; control/psychology/transmission ; Adult ; Child ; Chronic Disease/drug therapy/epidemiology/prevention & control/psychology ; Community-Institutional Relations ; Developed Countries/*statistics & numerical data ; Female ; HIV Infections/drug therapy/*epidemiology/prevention & ; control/*psychology/transmission ; Health Education ; Humans ; Incidence ; Male ; Patient Compliance/psychology/statistics & numerical data ; Risk-Taking ; Safe Sex/*psychology/*statistics & numerical data ; Viral Load/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-05-21
    Description: MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88-IRAK4-IRAK2 complex provides a template for Toll signalling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888693/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888693/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Su-Chang -- Lo, Yu-Chih -- Wu, Hao -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 AI050872/AI/NIAID NIH HHS/ -- R01 AI050872-09/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Jun 17;465(7300):885-90. doi: 10.1038/nature09121. Epub 2010 May 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Weill Cornell Medical College, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485341" target="_blank"〉PubMed〈/a〉
    Keywords: Humans ; *Interleukin-1 Receptor-Associated Kinases/chemistry/metabolism ; *Models, Molecular ; *Myeloid Differentiation Factor 88/chemistry/metabolism ; Protein Structure, Tertiary ; Receptors, Interleukin-1/metabolism/*physiology ; *Signal Transduction ; Toll-Like Receptors/metabolism/*physiology
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    Competition drives cooperation among closely related sperm of deer mice (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-22
    Description: Among the extraordinary adaptations driven by sperm competition is the cooperative behaviour of spermatozoa. By forming cooperative groups, sperm can increase their swimming velocity and thereby gain an advantage in intermale sperm competition. Accordingly, selection should favour cooperation of the most closely related sperm to maximize fitness. Here we show that sperm of deer mice (genus Peromyscus) form motile aggregations, then we use this system to test predictions of sperm cooperation. We find that sperm aggregate more often with conspecific than heterospecific sperm, suggesting that individual sperm can discriminate on the basis of genetic relatedness. Next, we provide evidence that the cooperative behaviour of closely related sperm is driven by sperm competition. In a monogamous species lacking sperm competition, Peromyscus polionotus, sperm indiscriminately group with unrelated conspecific sperm. In contrast, in the highly promiscuous deer mouse, Peromyscus maniculatus, sperm are significantly more likely to aggregate with those obtained from the same male than with sperm from an unrelated conspecific donor. Even when we test sperm from sibling males, we continue to see preferential aggregations of related sperm in P. maniculatus. These results suggest that sperm from promiscuous deer mice discriminate among relatives and thereby cooperate with the most closely related sperm, an adaptation likely to have been driven by sperm competition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824558/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824558/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fisher, Heidi S -- Hoekstra, Hopi E -- F32 GM084719/GM/NIGMS NIH HHS/ -- F32 GM084719-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Feb 11;463(7282):801-3. doi: 10.1038/nature08736. Epub 2010 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Cambridge, Massachusetts 02138, USA. hfisher@oeb.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20090679" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Aggregation ; Competitive Behavior/*physiology ; *Cooperative Behavior ; Copulation/physiology ; Female ; Male ; Peromyscus/*classification/*physiology ; Sexual Behavior, Animal/*physiology ; Species Specificity ; Sperm Motility/physiology ; Spermatozoa/*physiology
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    A systems approach (2010)
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    Publication Date: 2010-05-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chi, Kelly Rae -- England -- Nature. 2010 Apr 15;464(7291):1090-1.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20503480" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/genetics/metabolism/pathology/therapy ; Computational Biology/education/manpower/trends ; Female ; Genetic Heterogeneity ; Humans ; Models, Biological ; Neoplasms/genetics/*metabolism/*pathology/therapy ; Research Personnel/education ; Systems Biology/education/manpower/*trends
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    Neuroscience: Sexy circuits (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-12-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Benton, Richard -- England -- Nature. 2010 Dec 2;468(7324):638-40. doi: 10.1038/468638a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21124442" target="_blank"〉PubMed〈/a〉
    Keywords: Acetates/pharmacology ; Animals ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/anatomy & histology/*cytology/*drug effects/physiology ; Female ; Gene Expression Regulation ; Male ; Nerve Tissue Proteins/genetics/metabolism ; Neuroanatomical Tract-Tracing Techniques/methods ; Oleic Acids/pharmacology ; Olfactory Pathways/anatomy & histology/cytology/*drug effects ; Olfactory Perception/drug effects/physiology ; Pheromones/*pharmacology ; Sensory Receptor Cells/drug effects/physiology ; *Sex Characteristics ; Sexual Behavior, Animal/physiology ; Transcription Factors/genetics/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells (2010)
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    Publication Date: 2010-12-03
    Description: The capacity to fine-tune cellular bioenergetics with the demands of stem-cell maintenance and regeneration is central to normal development and ageing, and to organismal survival during periods of acute stress. How energy metabolism and stem-cell homeostatic processes are coordinated is not well understood. Lkb1 acts as an evolutionarily conserved regulator of cellular energy metabolism in eukaryotic cells and functions as the major upstream kinase to phosphorylate AMP-activated protein kinase (AMPK) and 12 other AMPK-related kinases. Whether Lkb1 regulates stem-cell maintenance remains unknown. Here we show that Lkb1 has an essential role in haematopoietic stem cell (HSC) homeostasis. We demonstrate that ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality. Loss of Lkb1 leads to impaired survival and escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. Lkb1 deletion has an impact on cell proliferation in HSCs, but not on more committed compartments, pointing to context-specific functions for Lkb1 in haematopoiesis. The adverse impact of Lkb1 deletion on haematopoiesis was predominantly cell-autonomous and mTOR complex 1 (mTORC1)-independent, and involves multiple mechanisms converging on mitochondrial apoptosis and possibly downregulation of PGC-1 coactivators and their transcriptional network, which have critical roles in mitochondrial biogenesis and function. Thus, Lkb1 serves as an essential regulator of HSCs and haematopoiesis, and more generally, points to the critical importance of coupling energy metabolism and stem-cell homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058342/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058342/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gan, Boyi -- Hu, Jian -- Jiang, Shan -- Liu, Yingchun -- Sahin, Ergun -- Zhuang, Li -- Fletcher-Sananikone, Eliot -- Colla, Simona -- Wang, Y Alan -- Chin, Lynda -- Depinho, Ronald A -- 01CA141508/CA/NCI NIH HHS/ -- R21 CA135057/CA/NCI NIH HHS/ -- R21 CA135057-01/CA/NCI NIH HHS/ -- R21CA135057/CA/NCI NIH HHS/ -- U01 CA141508/CA/NCI NIH HHS/ -- U01 CA141508-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 2;468(7324):701-4. doi: 10.1038/nature09595.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21124456" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Cell Cycle/*physiology ; Cell Proliferation ; Cell Survival ; *Energy Metabolism ; Female ; Gene Deletion ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/*metabolism/pathology ; *Homeostasis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism/pathology ; Multiprotein Complexes ; Pancytopenia/genetics ; Phenotype ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Proteins/metabolism ; Survival Analysis ; TOR Serine-Threonine Kinases ; Transcription Factors/metabolism
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    Coupled chaperone action in folding and assembly of hexadecameric Rubisco (2010)
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    Publication Date: 2010-01-16
    Description: Form I Rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase), a complex of eight large (RbcL) and eight small (RbcS) subunits, catalyses the fixation of atmospheric CO(2) in photosynthesis. The limited catalytic efficiency of Rubisco has sparked extensive efforts to re-engineer the enzyme with the goal of enhancing agricultural productivity. To facilitate such efforts we analysed the formation of cyanobacterial form I Rubisco by in vitro reconstitution and cryo-electron microscopy. We show that RbcL subunit folding by the GroEL/GroES chaperonin is tightly coupled with assembly mediated by the chaperone RbcX(2). RbcL monomers remain partially unstable and retain high affinity for GroEL until captured by RbcX(2). As revealed by the structure of a RbcL(8)-(RbcX(2))(8) assembly intermediate, RbcX(2) acts as a molecular staple in stabilizing the RbcL subunits as dimers and facilitates RbcL(8) core assembly. Finally, addition of RbcS results in RbcX(2) release and holoenzyme formation. Specific assembly chaperones may be required more generally in the formation of complex oligomeric structures when folding is closely coupled to assembly.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Cuimin -- Young, Anna L -- Starling-Windhof, Amanda -- Bracher, Andreas -- Saschenbrecker, Sandra -- Rao, Bharathi Vasudeva -- Rao, Karnam Vasudeva -- Berninghausen, Otto -- Mielke, Thorsten -- Hartl, F Ulrich -- Beckmann, Roland -- Hayer-Hartl, Manajit -- England -- Nature. 2010 Jan 14;463(7278):197-202. doi: 10.1038/nature08651.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20075914" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/chemistry/metabolism ; Chaperonin 10/metabolism ; Chaperonin 60/metabolism ; Cryoelectron Microscopy ; Holoenzymes/chemistry/metabolism ; Models, Molecular ; Molecular Chaperones/chemistry/*metabolism ; Protein Binding ; *Protein Folding ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Ribulose-Bisphosphate Carboxylase/*chemistry/*metabolism/ultrastructure ; Synechococcus/*chemistry/metabolism
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    The folding cooperativity of a protein is controlled by its chain topology (2010)
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    Publication Date: 2010-05-25
    Description: The three-dimensional structures of proteins often show a modular architecture comprised of discrete structural regions or domains. Cooperative communication between these regions is important for catalysis, regulation and efficient folding; lack of coupling has been implicated in the formation of fibrils and other misfolding pathologies. How different structural regions of a protein communicate and contribute to a protein's overall energetics and folding, however, is still poorly understood. Here we use a single-molecule optical tweezers approach to induce the selective unfolding of particular regions of T4 lysozyme and monitor the effect on other regions not directly acted on by force. We investigate how the topological organization of a protein (the order of structural elements along the sequence) affects the coupling and folding cooperativity between its domains. To probe the status of the regions not directly subjected to force, we determine the free energy changes during mechanical unfolding using Crooks' fluctuation theorem. We pull on topological variants (circular permutants) and find that the topological organization of the polypeptide chain critically determines the folding cooperativity between domains and thus what parts of the folding/unfolding landscape are explored. We speculate that proteins may have evolved to select certain topologies that increase coupling between regions to avoid areas of the landscape that lead to kinetic trapping and misfolding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911970/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911970/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shank, Elizabeth A -- Cecconi, Ciro -- Dill, Jesse W -- Marqusee, Susan -- Bustamante, Carlos -- GM 32543/GM/NIGMS NIH HHS/ -- GM 50945/GM/NIGMS NIH HHS/ -- R01 GM050945/GM/NIGMS NIH HHS/ -- R01 GM050945-17/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jun 3;465(7298):637-40. doi: 10.1038/nature09021. Epub 2010 May 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular & Cell Biology, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20495548" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Bacteriophage T4/*enzymology ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Optical Tweezers ; Probability ; Protein Denaturation ; *Protein Folding ; Protein Structure, Tertiary ; Viral Proteins/*chemistry/genetics/*metabolism
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    Secrets of the shaking palsy (2010)
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    Publication Date: 2010-08-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schnabel, Jim -- England -- Nature. 2010 Aug 26;466(7310):S2-5. doi: 10.1038/466S2b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20739933" target="_blank"〉PubMed〈/a〉
    Keywords: Amyloid/metabolism ; Female ; Humans ; Male ; Mitochondria/pathology ; Neurons/*pathology ; Parkinson Disease/diagnosis/genetics/*pathology ; alpha-Synuclein/genetics/metabolism
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    NINJA connects the co-repressor TOPLESS to jasmonate signalling (2010)
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    Publication Date: 2010-04-03
    Description: Jasmonoyl-isoleucine (JA-Ile) is a plant hormone that regulates a broad array of plant defence and developmental processes. JA-Ile-responsive gene expression is regulated by the transcriptional activator MYC2 that interacts physically with the jasmonate ZIM-domain (JAZ) repressor proteins. On perception of JA-Ile, JAZ proteins are degraded and JA-Ile-dependent gene expression is activated. The molecular mechanisms by which JAZ proteins repress gene expression remain unknown. Here we show that the Arabidopsis JAZ proteins recruit the Groucho/Tup1-type co-repressor TOPLESS (TPL) and TPL-related proteins (TPRs) through a previously uncharacterized adaptor protein, designated Novel Interactor of JAZ (NINJA). NINJA acts as a transcriptional repressor whose activity is mediated by a functional TPL-binding EAR repression motif. Accordingly, both NINJA and TPL proteins function as negative regulators of jasmonate responses. Our results point to TPL proteins as general co-repressors that affect multiple signalling pathways through the interaction with specific adaptor proteins. This new insight reveals how stress-related and growth-related signalling cascades use common molecular mechanisms to regulate gene expression in plants.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849182/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849182/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pauwels, Laurens -- Barbero, Gemma Fernandez -- Geerinck, Jan -- Tilleman, Sofie -- Grunewald, Wim -- Perez, Amparo Cuellar -- Chico, Jose Manuel -- Bossche, Robin Vanden -- Sewell, Jared -- Gil, Eduardo -- Garcia-Casado, Gloria -- Witters, Erwin -- Inze, Dirk -- Long, Jeff A -- De Jaeger, Geert -- Solano, Roberto -- Goossens, Alain -- R01 GM072764/GM/NIGMS NIH HHS/ -- R01 GM072764-06/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Apr 1;464(7289):788-91. doi: 10.1038/nature08854.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB), Technologiepark 927, B-9052 Gent, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20360743" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/cytology/*drug effects/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cyclopentanes/antagonists & inhibitors/*pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Plant ; Models, Biological ; Oxylipins/antagonists & inhibitors/*pharmacology ; Plants, Genetically Modified ; Protein Binding ; Repressor Proteins/genetics/*metabolism ; Signal Transduction/*drug effects ; Two-Hybrid System Techniques
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    Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin (2010)
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    Publication Date: 2010-02-09
    Description: Ca(2+) channels and calmodulin (CaM) are two prominent signalling hubs that synergistically affect functions as diverse as cardiac excitability, synaptic plasticity and gene transcription. It is therefore fitting that these hubs are in some sense coordinated, as the opening of Ca(V)1-2 Ca(2+) channels are regulated by a single CaM constitutively complexed with channels. The Ca(2+)-free form of CaM (apoCaM) is already pre-associated with the isoleucine-glutamine (IQ) domain on the channel carboxy terminus, and subsequent Ca(2+) binding to this 'resident' CaM drives conformational changes that then trigger regulation of channel opening. Another potential avenue for channel-CaM coordination could arise from the absence of Ca(2+) regulation in channels lacking a pre-associated CaM. Natural fluctuations in CaM concentrations might then influence the fraction of regulable channels and, thereby, the overall strength of Ca(2+) feedback. However, the prevailing view has been that the ultrastrong affinity of channels for apoCaM ensures their saturation with CaM, yielding a significant form of concentration independence between Ca(2+) channels and CaM. Here we show that significant exceptions to this autonomy exist, by combining electrophysiology (to characterize channel regulation) with optical fluorescence resonance energy transfer (FRET) sensor determination of free-apoCaM concentration in live cells. This approach translates quantitative CaM biochemistry from the traditional test-tube context into the realm of functioning holochannels within intact cells. From this perspective, we find that long splice forms of Ca(V)1.3 and Ca(V)1.4 channels include a distal carboxy tail that resembles an enzyme competitive inhibitor that retunes channel affinity for apoCaM such that natural CaM variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels, the connection between ambient CaM levels and Ca(2+) entry through channels is broadly significant for Ca(2+) homeostasis. Strategies such as ours promise key advances for the in situ analysis of signalling molecules resistant to in vitro reconstitution, such as Ca(2+) channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553577/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553577/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Xiaodong -- Yang, Philemon S -- Yang, Wanjun -- Yue, David T -- P30 DC005211/DC/NIDCD NIH HHS/ -- R01 DC000276/DC/NIDCD NIH HHS/ -- England -- Nature. 2010 Feb 18;463(7283):968-72. doi: 10.1038/nature08766. Epub 2010 Feb 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Calcium Signals Laboratory, Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20139964" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Animals ; Apoproteins/analysis/metabolism ; Binding, Competitive/drug effects ; Calcium/analysis/metabolism/pharmacology ; Calcium Channel Blockers/*chemistry/*metabolism ; Calcium Channels/*chemistry/genetics/*metabolism ; Calmodulin/analysis/*metabolism ; Cell Line ; Cell Survival ; Electrophysiology ; *Feedback, Physiological ; Fluorescence Resonance Energy Transfer ; Humans ; Protein Structure, Tertiary ; Rats ; Recombinant Fusion Proteins/chemistry/genetics/metabolism
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    Sister chromosome pairing maintains heterozygosity in parthenogenetic lizards (2010)
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    Publication Date: 2010-02-23
    Description: Although bisexual reproduction has proven to be highly successful, parthenogenetic all-female populations occur frequently in certain taxa, including the whiptail lizards of the genus Aspidoscelis. Allozyme analysis revealed a high degree of fixed heterozygosity in these parthenogenetic species, supporting the view that they originated from hybridization events between related sexual species. It has remained unclear how the meiotic program is altered to produce diploid eggs while maintaining heterozygosity. Here we show that meiosis commences with twice the number of chromosomes in parthenogenetic versus sexual species, a mechanism that provides the basis for generating gametes with unreduced chromosome content without fundamental deviation from the classic meiotic program. Our observation of synaptonemal complexes and chiasmata demonstrate that a typical meiotic program occurs and that heterozygosity is not maintained by bypassing recombination. Instead, fluorescent in situ hybridization probes that distinguish between homologues reveal that bivalents form between sister chromosomes, the genetically identical products of the first of two premeiotic replication cycles. Sister chromosome pairing provides a mechanism for the maintenance of heterozygosity, which is critical for offsetting the reduced fitness associated with the lack of genetic diversity in parthenogenetic species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840635/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840635/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lutes, Aracely A -- Neaves, William B -- Baumann, Diana P -- Wiegraebe, Winfried -- Baumann, Peter -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Mar 11;464(7286):283-6. doi: 10.1038/nature08818. Epub 2010 Feb 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20173738" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromosome Pairing/*genetics ; Chromosomes/*genetics ; Crossing Over, Genetic/genetics ; Female ; *Heterozygote ; Lizards/*genetics ; Meiosis/genetics ; Microscopy, Electron, Transmission ; Oocytes/cytology/physiology/ultrastructure ; Telomere/genetics
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    Structural biology: Proteins in dynamic equilibrium (2010)
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    Publication Date: 2010-12-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bernado, Pau -- Blackledge, Martin -- England -- Nature. 2010 Dec 23;468(7327):1046-8. doi: 10.1038/4681046a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21179158" target="_blank"〉PubMed〈/a〉
    Keywords: *Biochemistry/methods ; Models, Chemical ; Protein Structure, Tertiary ; Proteins/*chemistry ; Proto-Oncogene Proteins c-hck/chemistry
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    Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect (2010)
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    Publication Date: 2010-04-23
    Description: The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Min -- Nettles, Richard E -- Belema, Makonen -- Snyder, Lawrence B -- Nguyen, Van N -- Fridell, Robert A -- Serrano-Wu, Michael H -- Langley, David R -- Sun, Jin-Hua -- O'Boyle, Donald R 2nd -- Lemm, Julie A -- Wang, Chunfu -- Knipe, Jay O -- Chien, Caly -- Colonno, Richard J -- Grasela, Dennis M -- Meanwell, Nicholas A -- Hamann, Lawrence G -- England -- Nature. 2010 May 6;465(7294):96-100. doi: 10.1038/nature08960. Epub 2010 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20410884" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Animals ; Antiviral Agents/blood/chemistry/*pharmacology/therapeutic use ; Cell Line ; Cercopithecus aethiops ; Drug Resistance, Viral ; Female ; Genotype ; HeLa Cells ; Hepacivirus/*drug effects ; Hepatitis C/drug therapy/virology ; Humans ; Imidazoles/blood/chemistry/*pharmacology ; Inhibitory Concentration 50 ; Male ; Middle Aged ; Time Factors ; Vero Cells ; Viral Load/drug effects ; Viral Nonstructural Proteins/*antagonists & inhibitors ; Young Adult
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    Evolutionary biology: Oh sibling, who art thou? (2010)
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    Publication Date: 2010-08-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cockburn, Andrew -- England -- Nature. 2010 Aug 19;466(7309):930-1. doi: 10.1038/466930a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20725030" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Birds/classification/genetics/*physiology ; *Cooperative Behavior ; Fathers ; Female ; Male ; Models, Biological ; Mothers ; Phylogeny ; Reproduction/genetics/physiology ; Sexual Behavior, Animal/*physiology ; *Siblings
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    Long shadow of the stem-cell ruling (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Oct 28;467(7319):1031-3. doi: 10.1038/4671031a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20981069" target="_blank"〉PubMed〈/a〉
    Keywords: *Embryonic Stem Cells ; Female ; HeLa Cells ; Humans ; *Policy Making ; Politics ; Public Policy/legislation & jurisprudence/trends ; Research Personnel/economics/ethics/psychology ; Stem Cell Research/*economics/ethics/*legislation & jurisprudence ; United States
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    Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-12
    Description: Jasmonates are a family of plant hormones that regulate plant growth, development and responses to stress. The F-box protein CORONATINE INSENSITIVE 1 (COI1) mediates jasmonate signalling by promoting hormone-dependent ubiquitylation and degradation of transcriptional repressor JAZ proteins. Despite its importance, the mechanism of jasmonate perception remains unclear. Here we present structural and pharmacological data to show that the true Arabidopsis jasmonate receptor is a complex of both COI1 and JAZ. COI1 contains an open pocket that recognizes the bioactive hormone (3R,7S)-jasmonoyl-l-isoleucine (JA-Ile) with high specificity. High-affinity hormone binding requires a bipartite JAZ degron sequence consisting of a conserved alpha-helix for COI1 docking and a loop region to trap the hormone in its binding pocket. In addition, we identify a third critical component of the jasmonate co-receptor complex, inositol pentakisphosphate, which interacts with both COI1 and JAZ adjacent to the ligand. Our results unravel the mechanism of jasmonate perception and highlight the ability of F-box proteins to evolve as multi-component signalling hubs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988090/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988090/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sheard, Laura B -- Tan, Xu -- Mao, Haibin -- Withers, John -- Ben-Nissan, Gili -- Hinds, Thomas R -- Kobayashi, Yuichi -- Hsu, Fong-Fu -- Sharon, Michal -- Browse, John -- He, Sheng Yang -- Rizo, Josep -- Howe, Gregg A -- Zheng, Ning -- P30 DK056341/DK/NIDDK NIH HHS/ -- P30 DK056341-10/DK/NIDDK NIH HHS/ -- R01 AI068718/AI/NIAID NIH HHS/ -- R01 AI068718-04/AI/NIAID NIH HHS/ -- R01 CA107134/CA/NCI NIH HHS/ -- R01 CA107134-07/CA/NCI NIH HHS/ -- R01 GM057795/GM/NIGMS NIH HHS/ -- R01 GM057795-12/GM/NIGMS NIH HHS/ -- R01AI068718/AI/NIAID NIH HHS/ -- R01GM57795/GM/NIGMS NIH HHS/ -- T32 GM07270/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Nov 18;468(7322):400-5. doi: 10.1038/nature09430. Epub 2010 Oct 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20927106" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acids/chemistry/metabolism ; Arabidopsis/chemistry/metabolism ; Arabidopsis Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Cyclopentanes/chemistry/*metabolism ; F-Box Proteins/chemistry/metabolism ; Indenes/chemistry/metabolism ; Inositol Phosphates/*metabolism ; Isoleucine/analogs & derivatives/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Oxylipins/chemistry/*metabolism ; Peptide Fragments/chemistry/metabolism ; Plant Growth Regulators/chemistry/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/*chemistry/*metabolism ; Signal Transduction
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    Stem cells: Cues from steroid hormones (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-06-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lydon, John P -- England -- Nature. 2010 Jun 10;465(7299):695-6. doi: 10.1038/465695a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535190" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/pathology ; Cell Division ; Estrogens/*metabolism ; Estrous Cycle/physiology ; Female ; Humans ; Lactation/physiology ; Mammary Glands, Animal/*cytology ; Mice ; Paracrine Communication ; Pregnancy ; Pregnancy, Animal/physiology ; Progesterone/*metabolism ; RANK Ligand/metabolism ; Receptors, Estrogen/deficiency ; Receptors, Progesterone/deficiency ; Stem Cell Niche/cytology/metabolism ; Stem Cells/*cytology/drug effects/*metabolism
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    RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-25
    Description: Tumours with mutant BRAF are dependent on the RAF-MEK-ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178447/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178447/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poulikakos, Poulikos I -- Zhang, Chao -- Bollag, Gideon -- Shokat, Kevan M -- Rosen, Neal -- 1P01CA129243-02/CA/NCI NIH HHS/ -- 2R01EB001987/EB/NIBIB NIH HHS/ -- P01 CA129243-010002/CA/NCI NIH HHS/ -- R01 EB001987/EB/NIBIB NIH HHS/ -- U01 CA091178/CA/NCI NIH HHS/ -- U01 CA091178-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Mar 18;464(7287):427-30. doi: 10.1038/nature08902.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20179705" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Catalytic Domain ; Cell Line ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Indoles/pharmacology ; MAP Kinase Signaling System/*drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Models, Biological ; Neoplasms/drug therapy/enzymology/genetics/metabolism ; Phosphorylation ; Protein Binding ; Protein Kinase Inhibitors/metabolism/*pharmacology/therapeutic use ; Protein Multimerization ; Proto-Oncogene Proteins B-raf/antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Sulfonamides/pharmacology ; Transcriptional Activation/*drug effects ; raf Kinases/*antagonists & inhibitors/chemistry/genetics/*metabolism ; ras Proteins/genetics/metabolism
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    Higher rates of sex evolve in spatially heterogeneous environments (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-15
    Description: The evolution and maintenance of sexual reproduction has puzzled biologists for decades. Although this field is rich in hypotheses, experimental evidence is scarce. Some important experiments have demonstrated differences in evolutionary rates between sexual and asexual populations; other experiments have documented evolutionary changes in phenomena related to genetic mixing, such as recombination and selfing. However, direct experiments of the evolution of sex within populations are extremely rare (but see ref. 12). Here we use the rotifer, Brachionus calyciflorus, which is capable of both sexual and asexual reproduction, to test recent theory predicting that there is more opportunity for sex to evolve in spatially heterogeneous environments. Replicated experimental populations of rotifers were maintained in homogeneous environments, composed of either high- or low-quality food habitats, or in heterogeneous environments that consisted of a mix of the two habitats. For populations maintained in either type of homogeneous environment, the rate of sex evolves rapidly towards zero. In contrast, higher rates of sex evolve in populations experiencing spatially heterogeneous environments. The data indicate that the higher level of sex observed under heterogeneity is not due to sex being less costly or selection against sex being less efficient; rather sex is sufficiently advantageous in heterogeneous environments to overwhelm its inherent costs. Counter to some alternative theories for the evolution of sex, there is no evidence that genetic drift plays any part in the evolution of sex in these populations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Becks, Lutz -- Agrawal, Aneil F -- England -- Nature. 2010 Nov 4;468(7320):89-92. doi: 10.1038/nature09449. Epub 2010 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, Ontario M5S 3B2, Canada. lutz.becks@utoronto.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944628" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Migration/physiology ; Animals ; *Biological Evolution ; Diet/veterinary ; *Ecosystem ; Female ; *Food ; Genetic Drift ; Male ; Meiosis/genetics ; Models, Biological ; Ovum/physiology ; Population Density ; Reproduction/physiology ; Reproduction, Asexual/physiology ; Rotifera/cytology/genetics/*physiology ; Selection, Genetic ; *Sex
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    Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells (2010)
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    Publication Date: 2010-08-06
    Description: Long interspersed element-1 (LINE-1 or L1) retrotransposition continues to affect human genome evolution. L1s can retrotranspose in the germline, during early development and in select somatic cells; however, the host response to L1 retrotransposition remains largely unexplored. Here we show that reporter genes introduced into the genome of various human embryonic carcinoma-derived cell lines (ECs) by L1 retrotransposition are rapidly and efficiently silenced either during or immediately after their integration. Treating ECs with histone deacetylase inhibitors rapidly reverses this silencing, and chromatin immunoprecipitation experiments revealed that reactivation of the reporter gene was correlated with changes in chromatin status at the L1 integration site. Under our assay conditions, rapid silencing was also observed when reporter genes were delivered into ECs by mouse L1s and a zebrafish LINE-2 element, but not when similar reporter genes were delivered into ECs by Moloney murine leukaemia virus or human immunodeficiency virus, suggesting that these integration events are silenced by distinct mechanisms. Finally, we demonstrate that subjecting ECs to culture conditions that promote differentiation attenuates the silencing of reporter genes delivered by L1 retrotransposition, but that differentiation, in itself, is not sufficient to reactivate previously silenced reporter genes. Thus, our data indicate that ECs differ from many differentiated cells in their ability to silence reporter genes delivered by L1 retrotransposition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034402/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034402/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garcia-Perez, Jose L -- Morell, Maria -- Scheys, Joshua O -- Kulpa, Deanna A -- Morell, Santiago -- Carter, Christoph C -- Hammer, Gary D -- Collins, Kathleen L -- O'Shea, K Sue -- Menendez, Pablo -- Moran, John V -- 5 P30 CA46592/CA/NCI NIH HHS/ -- GM-069985/GM/NIGMS NIH HHS/ -- GM060518/GM/NIGMS NIH HHS/ -- GM082970/GM/NIGMS NIH HHS/ -- NS-048187/NS/NINDS NIH HHS/ -- R01 DK62027/DK/NIDDK NIH HHS/ -- R01 GM060518/GM/NIGMS NIH HHS/ -- R01 GM060518-12/GM/NIGMS NIH HHS/ -- R01 GM082970/GM/NIGMS NIH HHS/ -- R01 GM082970-04/GM/NIGMS NIH HHS/ -- R01AI051198/AI/NIAID NIH HHS/ -- T32-GM08322/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Aug 5;466(7307):769-73. doi: 10.1038/nature09209.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Human Genetics, 1241 East Catherine Street, University of Michigan Medical School, Ann Arbor, Michigan 48109-5618, USA. josel.garcia.perez@juntadeandalucia.es〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686575" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/genetics/physiology ; Cell Line, Tumor ; Chromatin/drug effects/genetics/metabolism ; Chromatin Immunoprecipitation ; Embryonal Carcinoma Stem Cells/*metabolism/pathology ; Epigenesis, Genetic/drug effects/*genetics ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; *Gene Silencing/drug effects ; Genes, Reporter/genetics ; Genetic Engineering ; Genetic Vectors/genetics ; Genome, Human/genetics ; HIV/genetics ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Long Interspersed Nucleotide Elements/genetics ; Male ; Mice ; Models, Genetic ; Moloney murine leukemia virus/genetics ; Retroelements/*genetics ; Zebrafish/genetics
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    Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-01
    Description: Breast cancer is one of the most common cancers in humans and will on average affect up to one in eight women in their lifetime in the United States and Europe. The Women's Health Initiative and the Million Women Study have shown that hormone replacement therapy is associated with an increased risk of incident and fatal breast cancer. In particular, synthetic progesterone derivatives (progestins) such as medroxyprogesterone acetate (MPA), used in millions of women for hormone replacement therapy and contraceptives, markedly increase the risk of developing breast cancer. Here we show that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-kappaB ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49f(hi) stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084017/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084017/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schramek, Daniel -- Leibbrandt, Andreas -- Sigl, Verena -- Kenner, Lukas -- Pospisilik, John A -- Lee, Heather J -- Hanada, Reiko -- Joshi, Purna A -- Aliprantis, Antonios -- Glimcher, Laurie -- Pasparakis, Manolis -- Khokha, Rama -- Ormandy, Christopher J -- Widschwendter, Martin -- Schett, Georg -- Penninger, Josef M -- HD055601/HD/NICHD NIH HHS/ -- R01 HD055601/HD/NICHD NIH HHS/ -- R01 HD055601-04/HD/NICHD NIH HHS/ -- England -- Nature. 2010 Nov 4;468(7320):98-102. doi: 10.1038/nature09387. Epub 2010 Sep 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20881962" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/radiation effects ; Cell Differentiation ; Cell Proliferation/drug effects ; DNA Damage ; Epithelial Cells/cytology/drug effects/metabolism/radiation effects ; Female ; Gamma Rays ; Integrin alpha6/metabolism ; Mammary Neoplasms, Experimental/*chemically ; induced/genetics/metabolism/*pathology ; Medroxyprogesterone Acetate/administration & dosage/adverse effects ; Mice ; NF-kappa B/metabolism ; Osteoclasts/cytology ; Phosphoproteins/analysis/immunology ; Progestins/administration & dosage/*adverse effects ; RANK Ligand/deficiency/genetics/*metabolism ; Receptor Activator of Nuclear Factor-kappa B/deficiency/genetics/metabolism ; Signal Transduction ; Stem Cells/cytology/drug effects/metabolism
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    Structural basis for the suppression of skin cancers by DNA polymerase eta (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-06-26
    Description: DNA polymerase eta (Poleta) is unique among eukaryotic polymerases in its proficient ability for error-free replication through ultraviolet-induced cyclobutane pyrimidine dimers, and inactivation of Poleta (also known as POLH) in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of Saccharomyces cerevisiae Poleta (also known as RAD30) in ternary complex with a cis-syn thymine-thymine (T-T) dimer and with undamaged DNA. The structures reveal that the ability of Poleta to replicate efficiently through the ultraviolet-induced lesion derives from a simple and yet elegant mechanism, wherein the two Ts of the T-T dimer are accommodated in an active site cleft that is much more open than in other polymerases. We also show by structural, biochemical and genetic analysis that the two Ts are maintained in a stable configuration in the active site via interactions with Gln 55, Arg 73 and Met 74. Together, these features define the basis for Poleta's action on ultraviolet-damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, thereby reducing the incidence of skin cancers in humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030469/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030469/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Silverstein, Timothy D -- Johnson, Robert E -- Jain, Rinku -- Prakash, Louise -- Prakash, Satya -- Aggarwal, Aneel K -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 CA107650/CA/NCI NIH HHS/ -- R01 CA107650-39/CA/NCI NIH HHS/ -- R01 ES017767/ES/NIEHS NIH HHS/ -- R01 ES017767-01/ES/NIEHS NIH HHS/ -- England -- Nature. 2010 Jun 24;465(7301):1039-43. doi: 10.1038/nature09104.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20577207" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA Damage ; DNA-Directed DNA Polymerase/*chemistry/genetics/*metabolism ; Humans ; Kinetics ; Models, Molecular ; Mutation, Missense ; Nucleic Acid Conformation ; Protein Structure, Tertiary ; Pyrimidine Dimers/chemistry/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Skin Neoplasms/*enzymology/genetics ; Structure-Activity Relationship ; Xeroderma Pigmentosum/enzymology/genetics
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    RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-01
    Description: RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. Mammary glands of RANK- and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis, and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed. However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzalez-Suarez, Eva -- Jacob, Allison P -- Jones, Jon -- Miller, Robert -- Roudier-Meyer, Martine P -- Erwert, Ryan -- Pinkas, Jan -- Branstetter, Dan -- Dougall, William C -- England -- Nature. 2010 Nov 4;468(7320):103-7. doi: 10.1038/nature09495. Epub 2010 Sep 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Hematology/Oncology Research, Amgen Inc, Seattle, Washington 98119, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20881963" target="_blank"〉PubMed〈/a〉
    Keywords: 9,10-Dimethyl-1,2-benzanthracene/administration & dosage/adverse effects ; Animals ; Breast Neoplasms/metabolism/pathology ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/*chemically induced/*drug effects/pathology ; Disease Models, Animal ; Epithelial Cells/drug effects/metabolism/pathology ; Female ; Humans ; Lung Neoplasms/secondary ; Mammary Neoplasms, Experimental/*chemically ; induced/genetics/metabolism/*pathology ; Mammary Tumor Virus, Mouse/genetics/physiology ; Medroxyprogesterone Acetate/administration & dosage/adverse effects ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasm Invasiveness ; Precancerous Conditions/pathology/prevention & control ; Progesterone/administration & dosage/adverse effects ; Progestins/administration & dosage/*adverse effects ; RANK Ligand/antagonists & inhibitors/genetics/*metabolism ; Receptor Activator of Nuclear Factor-kappa B/genetics/metabolism
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    A population-specific HTR2B stop codon predisposes to severe impulsivity (2010)
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    Publication Date: 2010-12-24
    Description: Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency 〉 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183507/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183507/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bevilacqua, Laura -- Doly, Stephane -- Kaprio, Jaakko -- Yuan, Qiaoping -- Tikkanen, Roope -- Paunio, Tiina -- Zhou, Zhifeng -- Wedenoja, Juho -- Maroteaux, Luc -- Diaz, Silvina -- Belmer, Arnaud -- Hodgkinson, Colin A -- Dell'osso, Liliana -- Suvisaari, Jaana -- Coccaro, Emil -- Rose, Richard J -- Peltonen, Leena -- Virkkunen, Matti -- Goldman, David -- AA-09203/AA/NIAAA NIH HHS/ -- AA-12502/AA/NIAAA NIH HHS/ -- Z01 AA000301-09/Intramural NIH HHS/ -- Z01 AA000301-10/Intramural NIH HHS/ -- Z99 AA999999/Intramural NIH HHS/ -- England -- Nature. 2010 Dec 23;468(7327):1061-6. doi: 10.1038/nature09629.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland 20852, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21179162" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/metabolism ; Case-Control Studies ; Cell Line ; Female ; Finland ; Founder Effect ; Gene Expression Regulation ; Gene Knockout Techniques ; Genotype ; Humans ; Impulsive Behavior/*genetics ; Male ; Mental Disorders/genetics ; Mice ; Mice, 129 Strain ; Mice, Knockout ; Pedigree ; Polymorphism, Single Nucleotide/genetics ; Receptor, Serotonin, 5-HT2B/*genetics/*metabolism ; Testosterone/blood/cerebrospinal fluid
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    MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake (2010)
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    Publication Date: 2010-08-10
    Description: Mitochondrial calcium uptake has a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here we use an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics and organelle proteomics. RNA interference against 13 top candidates highlighted one gene, CBARA1, that we call hereafter mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the mitochondrial inner membrane and has two canonical EF hands that are essential for its activity, indicating a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high-capacity mitochondrial calcium uptake. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2977980/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2977980/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perocchi, Fabiana -- Gohil, Vishal M -- Girgis, Hany S -- Bao, X Robert -- McCombs, Janet E -- Palmer, Amy E -- Mootha, Vamsi K -- DK080261/DK/NIDDK NIH HHS/ -- GM0077465/GM/NIGMS NIH HHS/ -- GM084027/GM/NIGMS NIH HHS/ -- R01 GM077465/GM/NIGMS NIH HHS/ -- R01 GM077465-01A1/GM/NIGMS NIH HHS/ -- R01 GM077465-02/GM/NIGMS NIH HHS/ -- R01 GM077465-03/GM/NIGMS NIH HHS/ -- R01 GM077465-04/GM/NIGMS NIH HHS/ -- R01 GM077465-05/GM/NIGMS NIH HHS/ -- R01 GM077465-06/GM/NIGMS NIH HHS/ -- R01 GM084027/GM/NIGMS NIH HHS/ -- R24 DK080261/DK/NIDDK NIH HHS/ -- R24 DK080261-04/DK/NIDDK NIH HHS/ -- TR2 GM08759/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Sep 16;467(7313):291-6. doi: 10.1038/nature09358. Epub 2010 Aug 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20693986" target="_blank"〉PubMed〈/a〉
    Keywords: Allergens/*chemistry/genetics/*metabolism ; Amino Acid Sequence ; Antigens, Plant ; Calcium/*metabolism ; *Calcium Signaling ; Calcium-Binding Proteins/*chemistry/deficiency/genetics/*metabolism ; Cation Transport Proteins ; Cell Respiration ; Cytoplasm/metabolism ; DNA, Mitochondrial/analysis ; *EF Hand Motifs ; Endoplasmic Reticulum/metabolism ; Gene Knockdown Techniques ; HeLa Cells ; Homeostasis ; Humans ; Membrane Potentials ; Mitochondria/*metabolism ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; NAD/metabolism ; NADP/metabolism ; Oxidative Phosphorylation ; Protein Structure, Tertiary ; Protein Transport ; RNA Interference
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    Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia (2010)
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    Publication Date: 2010-03-23
    Description: Mesenchymal cells contribute to the 'stroma' of most normal and malignant tissues, with specific mesenchymal cells participating in the regulatory niches of stem cells. By examining how mesenchymal osteolineage cells modulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors, but not in mature osteoblasts, disrupts the integrity of haematopoiesis. Myelodysplasia resulted and acute myelogenous leukaemia emerged that had acquired several genetic abnormalities while having intact Dicer1. Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletion showed reduced expression of Sbds, the gene mutated in Schwachman-Bodian-Diamond syndrome-a human bone marrow failure and leukaemia pre-disposition condition. Deletion of Sbds in mouse osteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, perturbation of specific mesenchymal subsets of stromal cells can disorder differentiation, proliferation and apoptosis of heterologous cells, and disrupt tissue homeostasis. Furthermore, primary stromal dysfunction can result in secondary neoplastic disease, supporting the concept of niche-induced oncogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422863/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422863/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raaijmakers, Marc H G P -- Mukherjee, Siddhartha -- Guo, Shangqin -- Zhang, Siyi -- Kobayashi, Tatsuya -- Schoonmaker, Jesse A -- Ebert, Benjamin L -- Al-Shahrour, Fatima -- Hasserjian, Robert P -- Scadden, Edward O -- Aung, Zinmar -- Matza, Marc -- Merkenschlager, Matthias -- Lin, Charles -- Rommens, Johanna M -- Scadden, David T -- MC_U120027516/Medical Research Council/United Kingdom -- R01 DK050234/DK/NIDDK NIH HHS/ -- R01 HL044851/HL/NHLBI NIH HHS/ -- R01 HL097794/HL/NHLBI NIH HHS/ -- U01 HL100402/HL/NHLBI NIH HHS/ -- U54 HL081030/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Apr 8;464(7290):852-7. doi: 10.1038/nature08851. Epub 2010 Mar 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School CPZN, USA. hraaijmakers@partners.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20305640" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow/metabolism/pathology ; Bone and Bones/metabolism/*pathology ; Cell Differentiation ; Cell Lineage ; Female ; Gene Deletion ; Hematopoiesis/genetics ; Leukemia, Myeloid, Acute/genetics/metabolism/*pathology ; Male ; Mesoderm/cytology ; Mice ; Myelodysplastic Syndromes/genetics/metabolism/*pathology ; Osteoblasts/metabolism/pathology ; Phenotype ; Proteins/genetics/metabolism ; Ribonuclease III/deficiency/genetics/metabolism ; Sarcoma, Myeloid/genetics/metabolism/pathology ; Stem Cell Niche/metabolism/pathology ; Stem Cells/metabolism/*pathology ; Stromal Cells/metabolism/pathology
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    The evolution of eusociality (2010)
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    Publication Date: 2010-08-27
    Description: Eusociality, in which some individuals reduce their own lifetime reproductive potential to raise the offspring of others, underlies the most advanced forms of social organization and the ecologically dominant role of social insects and humans. For the past four decades kin selection theory, based on the concept of inclusive fitness, has been the major theoretical attempt to explain the evolution of eusociality. Here we show the limitations of this approach. We argue that standard natural selection theory in the context of precise models of population structure represents a simpler and superior approach, allows the evaluation of multiple competing hypotheses, and provides an exact framework for interpreting empirical observations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279739/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279739/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nowak, Martin A -- Tarnita, Corina E -- Wilson, Edward O -- R01 GM078986/GM/NIGMS NIH HHS/ -- R01 GM078986-04/GM/NIGMS NIH HHS/ -- R01GM078986/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Aug 26;466(7310):1057-62. doi: 10.1038/nature09205.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program for Evolutionary Dynamics, Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA. martin_nowak@harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20740005" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Behavior, Animal/*physiology ; *Biological Evolution ; Female ; Humans ; Insects/physiology ; Male ; Models, Biological ; Selection, Genetic ; *Social Behavior
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    Structure of a bacterial homologue of vitamin K epoxide reductase (2010)
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    Publication Date: 2010-01-30
    Description: Vitamin K epoxide reductase (VKOR) generates vitamin K hydroquinone to sustain gamma-carboxylation of many blood coagulation factors. Here, we report the 3.6 A crystal structure of a bacterial homologue of VKOR from Synechococcus sp. The structure shows VKOR in complex with its naturally fused redox partner, a thioredoxin-like domain, and corresponds to an arrested state of electron transfer. The catalytic core of VKOR is a four transmembrane helix bundle that surrounds a quinone, connected through an additional transmembrane segment with the periplasmic thioredoxin-like domain. We propose a pathway for how VKOR uses electrons from cysteines of newly synthesized proteins to reduce a quinone, a mechanism confirmed by in vitro reconstitution of vitamin K-dependent disulphide bridge formation. Our results have implications for the mechanism of the mammalian VKOR and explain how mutations can cause resistance to the VKOR inhibitor warfarin, the most commonly used oral anticoagulant.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919313/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919313/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Weikai -- Schulman, Sol -- Dutton, Rachel J -- Boyd, Dana -- Beckwith, Jon -- Rapoport, Tom A -- GMO41883/PHS HHS/ -- K99 HL097083/HL/NHLBI NIH HHS/ -- K99 HL097083-01/HL/NHLBI NIH HHS/ -- K991K99HL097083/HL/NHLBI NIH HHS/ -- R00 HL097083/HL/NHLBI NIH HHS/ -- R01 GM041883/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jan 28;463(7280):507-12. doi: 10.1038/nature08720.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. weikai@crystal.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20110994" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anticoagulants ; Bacterial Proteins/chemistry ; Catalytic Domain ; Disulfides/chemistry ; Drug Resistance/genetics ; Electron Transport ; Humans ; Membrane Proteins/chemistry ; Mixed Function Oxygenases/*chemistry/genetics ; *Models, Molecular ; Protein Structure, Tertiary ; Synechococcus/*enzymology ; Vitamin K Epoxide Reductases ; Warfarin
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    A redox switch in angiotensinogen modulates angiotensin release (2010)
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    Publication Date: 2010-10-12
    Description: Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 A resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 A structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024006/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024006/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Aiwu -- Carrell, Robin W -- Murphy, Michael P -- Wei, Zhenquan -- Yan, Yahui -- Stanley, Peter L D -- Stein, Penelope E -- Broughton Pipkin, Fiona -- Read, Randy J -- 082961/Wellcome Trust/United Kingdom -- BS/05/002/18361/British Heart Foundation/United Kingdom -- MC_U105663142/Medical Research Council/United Kingdom -- PG/08/041/24818/British Heart Foundation/United Kingdom -- PG/09/072/27945/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Nov 4;468(7320):108-11. doi: 10.1038/nature09505. Epub 2010 Oct 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK. awz20@cam.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20927107" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Angiotensinogen/blood/*chemistry/*metabolism ; Angiotensins/chemistry/*metabolism/secretion ; Blood Pressure ; Crystallography, X-Ray ; Disulfides/chemistry/metabolism ; Female ; Humans ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Oxidation-Reduction ; Oxidative Stress ; Pre-Eclampsia/blood/metabolism ; Pregnancy ; Protein Conformation ; *Protein Processing, Post-Translational ; Renin/chemistry/metabolism
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    The sequence and de novo assembly of the giant panda genome (2009)
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    Publication Date: 2009-12-17
    Description: Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951497/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951497/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ruiqiang -- Fan, Wei -- Tian, Geng -- Zhu, Hongmei -- He, Lin -- Cai, Jing -- Huang, Quanfei -- Cai, Qingle -- Li, Bo -- Bai, Yinqi -- Zhang, Zhihe -- Zhang, Yaping -- Wang, Wen -- Li, Jun -- Wei, Fuwen -- Li, Heng -- Jian, Min -- Li, Jianwen -- Zhang, Zhaolei -- Nielsen, Rasmus -- Li, Dawei -- Gu, Wanjun -- Yang, Zhentao -- Xuan, Zhaoling -- Ryder, Oliver A -- Leung, Frederick Chi-Ching -- Zhou, Yan -- Cao, Jianjun -- Sun, Xiao -- Fu, Yonggui -- Fang, Xiaodong -- Guo, Xiaosen -- Wang, Bo -- Hou, Rong -- Shen, Fujun -- Mu, Bo -- Ni, Peixiang -- Lin, Runmao -- Qian, Wubin -- Wang, Guodong -- Yu, Chang -- Nie, Wenhui -- Wang, Jinhuan -- Wu, Zhigang -- Liang, Huiqing -- Min, Jiumeng -- Wu, Qi -- Cheng, Shifeng -- Ruan, Jue -- Wang, Mingwei -- Shi, Zhongbin -- Wen, Ming -- Liu, Binghang -- Ren, Xiaoli -- Zheng, Huisong -- Dong, Dong -- Cook, Kathleen -- Shan, Gao -- Zhang, Hao -- Kosiol, Carolin -- Xie, Xueying -- Lu, Zuhong -- Zheng, Hancheng -- Li, Yingrui -- Steiner, Cynthia C -- Lam, Tommy Tsan-Yuk -- Lin, Siyuan -- Zhang, Qinghui -- Li, Guoqing -- Tian, Jing -- Gong, Timing -- Liu, Hongde -- Zhang, Dejin -- Fang, Lin -- Ye, Chen -- Zhang, Juanbin -- Hu, Wenbo -- Xu, Anlong -- Ren, Yuanyuan -- Zhang, Guojie -- Bruford, Michael W -- Li, Qibin -- Ma, Lijia -- Guo, Yiran -- An, Na -- Hu, Yujie -- Zheng, Yang -- Shi, Yongyong -- Li, Zhiqiang -- Liu, Qing -- Chen, Yanling -- Zhao, Jing -- Qu, Ning -- Zhao, Shancen -- Tian, Feng -- Wang, Xiaoling -- Wang, Haiyin -- Xu, Lizhi -- Liu, Xiao -- Vinar, Tomas -- Wang, Yajun -- Lam, Tak-Wah -- Yiu, Siu-Ming -- Liu, Shiping -- Zhang, Hemin -- Li, Desheng -- Huang, Yan -- Wang, Xia -- Yang, Guohua -- Jiang, Zhi -- Wang, Junyi -- Qin, Nan -- Li, Li -- Li, Jingxiang -- Bolund, Lars -- Kristiansen, Karsten -- Wong, Gane Ka-Shu -- Olson, Maynard -- Zhang, Xiuqing -- Li, Songgang -- Yang, Huanming -- Wang, Jian -- Wang, Jun -- R01 HG003229/HG/NHGRI NIH HHS/ -- R01 HG003229-05/HG/NHGRI NIH HHS/ -- England -- Nature. 2010 Jan 21;463(7279):311-7. doi: 10.1038/nature08696. Epub 2009 Dec 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉BGI-Shenzhen, Shenzhen 518083, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010809" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Animals ; China ; Conserved Sequence/genetics ; Contig Mapping ; Diet/veterinary ; Dogs ; Evolution, Molecular ; Female ; Fertility/genetics/physiology ; Genome/*genetics ; *Genomics ; Heterozygote ; Humans ; Multigene Family/genetics ; Polymorphism, Single Nucleotide/genetics ; Receptors, G-Protein-Coupled/genetics ; Sequence Alignment ; Sequence Analysis, DNA ; Synteny/genetics ; Ursidae/classification/*genetics/physiology
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    Affinity gradients drive copper to cellular destinations (2010)
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    Publication Date: 2010-05-14
    Description: Copper is an essential trace element for eukaryotes and most prokaryotes. However, intracellular free copper must be strictly limited because of its toxic side effects. Complex systems for copper trafficking evolved to satisfy cellular requirements while minimizing toxicity. The factors driving the copper transfer between protein partners along cellular copper routes are, however, not fully rationalized. Until now, inconsistent, scattered and incomparable data on the copper-binding affinities of copper proteins have been reported. Here we determine, through a unified electrospray ionization mass spectrometry (ESI-MS)-based strategy, in an environment that mimics the cellular redox milieu, the apparent Cu(I)-binding affinities for a representative set of intracellular copper proteins involved in enzymatic redox catalysis, in copper trafficking to and within various cellular compartments, and in copper storage. The resulting thermodynamic data show that copper is drawn to the enzymes that require it by passing from one copper protein site to another, exploiting gradients of increasing copper-binding affinity. This result complements the finding that fast copper-transfer pathways require metal-mediated protein-protein interactions and therefore protein-protein specific recognition. Together with Cu,Zn-SOD1, metallothioneins have the highest affinity for copper(I), and may play special roles in the regulation of cellular copper distribution; however, for kinetic reasons they cannot demetallate copper enzymes. Our study provides the thermodynamic basis for the kinetic processes that lead to the distribution of cellular copper.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banci, Lucia -- Bertini, Ivano -- Ciofi-Baffoni, Simone -- Kozyreva, Tatiana -- Zovo, Kairit -- Palumaa, Peep -- England -- Nature. 2010 Jun 3;465(7298):645-8. doi: 10.1038/nature09018. Epub 2010 May 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Magnetic Resonance Center CERM and Department of Chemistry, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, Florence, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20463663" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Carrier Proteins/*metabolism ; Cations, Monovalent/metabolism ; Copper/isolation & purification/*metabolism ; Cyclooxygenase 2/chemistry/metabolism ; Dithiothreitol/metabolism ; Glutathione/metabolism ; Humans ; Intracellular Space/*metabolism ; Ion Transport ; Kinetics ; Ligands ; Metallothionein/metabolism ; Mitochondria, Liver ; Oxidation-Reduction ; Protein Binding ; Rats ; Spectrometry, Mass, Electrospray Ionization ; Thermodynamics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport (2010)
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    Publication Date: 2010-09-25
    Description: Gram-negative bacteria, such as Escherichia coli, frequently use tripartite efflux complexes in the resistance-nodulation-cell division (RND) family to expel various toxic compounds from the cell. The efflux system CusCBA is responsible for extruding biocidal Cu(I) and Ag(I) ions. No previous structural information was available for the heavy-metal efflux (HME) subfamily of the RND efflux pumps. Here we describe the crystal structures of the inner-membrane transporter CusA in the absence and presence of bound Cu(I) or Ag(I). These CusA structures provide new structural information about the HME subfamily of RND efflux pumps. The structures suggest that the metal-binding sites, formed by a three-methionine cluster, are located within the cleft region of the periplasmic domain. This cleft is closed in the apo-CusA form but open in the CusA-Cu(I) and CusA-Ag(I) structures, which directly suggests a plausible pathway for ion export. Binding of Cu(I) and Ag(I) triggers significant conformational changes in both the periplasmic and transmembrane domains. The crystal structure indicates that CusA has, in addition to the three-methionine metal-binding site, four methionine pairs-three located in the transmembrane region and one in the periplasmic domain. Genetic analysis and transport assays suggest that CusA is capable of actively picking up metal ions from the cytosol, using these methionine pairs or clusters to bind and export metal ions. These structures suggest a stepwise shuttle mechanism for transport between these sites.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946090/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946090/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Long, Feng -- Su, Chih-Chia -- Zimmermann, Michael T -- Boyken, Scott E -- Rajashankar, Kanagalaghatta R -- Jernigan, Robert L -- Yu, Edward W -- GM 072014/GM/NIGMS NIH HHS/ -- GM 074027/GM/NIGMS NIH HHS/ -- GM 081680/GM/NIGMS NIH HHS/ -- GM 086431/GM/NIGMS NIH HHS/ -- R01 GM072014/GM/NIGMS NIH HHS/ -- R01 GM074027/GM/NIGMS NIH HHS/ -- R01 GM074027-05/GM/NIGMS NIH HHS/ -- R01 GM086431/GM/NIGMS NIH HHS/ -- R01 GM086431-01A2/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Sep 23;467(7314):484-8. doi: 10.1038/nature09395.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular, Cellular and Developmental Biology Interdepartmental Graduate Program, Iowa State University, Iowa 50011, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20865003" target="_blank"〉PubMed〈/a〉
    Keywords: Apoproteins/chemistry/metabolism ; Binding Sites ; Cell Membrane/metabolism ; Copper/chemistry/*metabolism ; Crystallography, X-Ray ; Cytosol/metabolism ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Ion Transport ; Membrane Transport Proteins/*chemistry/*metabolism ; Methionine/*metabolism ; Models, Biological ; Models, Molecular ; Periplasm/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Silver/chemistry/*metabolism ; Structure-Activity Relationship
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structural basis of semaphorin-plexin signalling (2010)
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    Publication Date: 2010-09-30
    Description: Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1(1-2)-SEMA4D(ecto) and murine PlxnA2(1-4)-Sema6A(ecto)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto). These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed beta-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin-plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587840/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587840/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Janssen, Bert J C -- Robinson, Ross A -- Perez-Branguli, Francesc -- Bell, Christian H -- Mitchell, Kevin J -- Siebold, Christian -- Jones, E Yvonne -- 082301/Wellcome Trust/United Kingdom -- 083111/Wellcome Trust/United Kingdom -- 10976/Cancer Research UK/United Kingdom -- A10976/Cancer Research UK/United Kingdom -- A3964/Cancer Research UK/United Kingdom -- A5261/Cancer Research UK/United Kingdom -- G0700232/Medical Research Council/United Kingdom -- G0700232(82098)/Medical Research Council/United Kingdom -- G0900084/Medical Research Council/United Kingdom -- G9900061/Medical Research Council/United Kingdom -- G9900061(69203)/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Oct 28;467(7319):1118-22. doi: 10.1038/nature09468. Epub 2010 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20877282" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/chemistry/genetics/metabolism ; Binding Sites ; Cell Adhesion Molecules/*chemistry/genetics/*metabolism ; Cell Communication ; Crystallography, X-Ray ; Humans ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; NIH 3T3 Cells ; Nerve Tissue Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Cell Surface/chemistry/genetics/metabolism ; Semaphorins/*chemistry/genetics/*metabolism ; *Signal Transduction ; Structure-Activity Relationship
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    CD95 promotes tumour growth (2010)
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    Publication Date: 2010-05-28
    Description: CD95 (also called Fas and APO-1) is a prototypical death receptor that regulates tissue homeostasis mainly in the immune system through the induction of apoptosis. During cancer progression CD95 is frequently downregulated or cells are rendered apoptosis resistant, raising the possibility that loss of CD95 is part of a mechanism for tumour evasion. However, complete loss of CD95 is rarely seen in human cancers and many cancer cells express large quantities of CD95 and are highly sensitive to CD95-mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for CD95, CD95L. These data raise the possibility that CD95 could actually promote the growth of tumours through its non-apoptotic activities. Here we show that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by cancer-produced CD95L, for optimal growth. Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumours. The tumorigenic activity of CD95 is mediated by a pathway involving JNK and Jun. These results demonstrate that CD95 has a growth-promoting role during tumorigenesis and indicate that efforts to inhibit its activity rather than to enhance it should be considered during cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879093/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879093/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Lina -- Park, Sun-Mi -- Tumanov, Alexei V -- Hau, Annika -- Sawada, Kenjiro -- Feig, Christine -- Turner, Jerrold R -- Fu, Yang-Xin -- Romero, Iris L -- Lengyel, Ernst -- Peter, Marcus E -- CA112240/CA/NCI NIH HHS/ -- K12 HD000849/HD/NICHD NIH HHS/ -- L30 CA153336/CA/NCI NIH HHS/ -- R01 CA095319/CA/NCI NIH HHS/ -- R01 CA11182/CA/NCI NIH HHS/ -- R01 CA112240/CA/NCI NIH HHS/ -- R01 CA112240-01A1/CA/NCI NIH HHS/ -- R01 CA112240-02/CA/NCI NIH HHS/ -- R01 CA112240-03/CA/NCI NIH HHS/ -- R01 CA112240-04/CA/NCI NIH HHS/ -- R01 CA112240-05/CA/NCI NIH HHS/ -- England -- Nature. 2010 May 27;465(7297):492-6. doi: 10.1038/nature09075.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Ben May Department for Cancer Research, The University of Chicago, 924 E 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20505730" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD95/deficiency/genetics/*metabolism ; Apoptosis ; Carcinoma, Endometrioid/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation ; Fas Ligand Protein/antagonists & inhibitors/immunology/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Hepatocytes/enzymology/metabolism/pathology ; Humans ; Liver Neoplasms/enzymology/metabolism/pathology ; Male ; Mice ; Mitogen-Activated Protein Kinase 8/deficiency/genetics/metabolism ; Neoplasms/*metabolism/*pathology ; Ovarian Neoplasms/metabolism/pathology
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    Migrastatin analogues target fascin to block tumour metastasis (2010)
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    Publication Date: 2010-04-16
    Description: Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857318/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857318/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Lin -- Yang, Shengyu -- Jakoncic, Jean -- Zhang, J Jillian -- Huang, Xin-Yun -- CA136837/CA/NCI NIH HHS/ -- R01 CA136837/CA/NCI NIH HHS/ -- R01 CA136837-01A1/CA/NCI NIH HHS/ -- England -- Nature. 2010 Apr 15;464(7291):1062-6. doi: 10.1038/nature08978.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, Cornell University Weill Medical College, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20393565" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Animals ; Antineoplastic Agents/chemistry/metabolism/pharmacology/therapeutic use ; Binding Sites/drug effects ; Breast Neoplasms/drug therapy/pathology ; Carrier Proteins/*antagonists & inhibitors/chemistry/genetics/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Crystallography, X-Ray ; Drug Resistance, Neoplasm/genetics ; Female ; Humans ; Lung Neoplasms/prevention & control/secondary ; Macrolides/*chemistry/metabolism/*pharmacology/therapeutic use ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, SCID ; Microfilament Proteins/*antagonists & inhibitors/chemistry/genetics/metabolism ; Models, Molecular ; Mutation/genetics ; Neoplasm Invasiveness/pathology/prevention & control ; Neoplasm Metastasis/drug therapy/pathology/*prevention & control ; Piperidones/*chemistry/metabolism/*pharmacology/therapeutic use ; Protein Conformation
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    Altruism researchers must cooperate (2010)
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    Publication Date: 2010-10-12
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okasha, Samir -- England -- Nature. 2010 Oct 7;467(7316):653-5. doi: 10.1038/467653a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Philosophy, University of Bristol, Bristol BS8 1TB, UK. Samir.Okasha@bristol.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20930821" target="_blank"〉PubMed〈/a〉
    Keywords: *Altruism ; Animals ; Biological Evolution ; *Cooperative Behavior ; Female ; Group Processes ; Male ; Models, Biological ; *Research Personnel ; Selection, Genetic ; Social Behavior
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    Sex determination: An avian sexual revolution (2010)
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    Publication Date: 2010-03-12
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barske, Lindsey A -- Capel, Blanche -- England -- Nature. 2010 Mar 11;464(7286):171-2. doi: 10.1038/464171a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20220830" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Birds/genetics/*physiology ; Chick Embryo ; Chickens ; Female ; Genotype ; Humans ; Male ; Mice ; Mosaicism ; Phenotype ; Sex Characteristics ; Sex Chromosomes/genetics ; *Sex Determination Processes
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    Role of a ribosome-associated E3 ubiquitin ligase in protein quality control (2010)
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    Publication Date: 2010-09-14
    Description: Messenger RNA lacking stop codons ('non-stop mRNA') can arise from errors in gene expression, and encode aberrant proteins whose accumulation could be deleterious to cellular function. In bacteria, these 'non-stop proteins' become co-translationally tagged with a peptide encoded by ssrA/tmRNA (transfer-messenger RNA), which signals their degradation by energy-dependent proteases. How eukaryotic cells eliminate non-stop proteins has remained unknown. Here we show that the Saccharomyces cerevisiae Ltn1 RING-domain-type E3 ubiquitin ligase acts in the quality control of non-stop proteins, in a process that is mechanistically distinct but conceptually analogous to that performed by ssrA: Ltn1 is predominantly associated with ribosomes, and it marks nascent non-stop proteins with ubiquitin to signal their proteasomal degradation. Ltn1-mediated ubiquitylation of non-stop proteins seems to be triggered by their stalling in ribosomes on translation through the poly(A) tail. The biological relevance of this process is underscored by the finding that loss of Ltn1 function confers sensitivity to stress caused by increased non-stop protein production. We speculate that defective protein quality control may underlie the neurodegenerative phenotype that results from mutation of the mouse Ltn1 homologue Listerin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988496/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988496/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bengtson, Mario H -- Joazeiro, Claudio A P -- R01 GM083060/GM/NIGMS NIH HHS/ -- R01 GM083060-03/GM/NIGMS NIH HHS/ -- R01GM083060/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Sep 23;467(7314):470-3. doi: 10.1038/nature09371. Epub 2010 Sep 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, The Scripps Research Institute, CB168, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20835226" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Codon, Terminator/genetics ; Mice ; Models, Biological ; Peptide Chain Termination, Translational ; Polylysine/biosynthesis/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Protein Biosynthesis/*physiology ; Ribosomes/*enzymology/*metabolism ; Saccharomyces cerevisiae/cytology/enzymology/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Stress, Physiological ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; *Ubiquitination
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    Blindsight depends on the lateral geniculate nucleus (2010)
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    Publication Date: 2010-06-25
    Description: Injury to the primary visual cortex (V1) leads to the loss of visual experience. Nonetheless, careful testing shows that certain visually guided behaviours can persist even in the absence of visual awareness. The neural circuits supporting this phenomenon, which is often termed blindsight, remain uncertain. Here we demonstrate that the thalamic lateral geniculate nucleus (LGN) has a causal role in V1-independent processing of visual information. By comparing functional magnetic resonance imaging (fMRI) and behavioural measures with and without temporary LGN inactivation, we assessed the contribution of the LGN to visual functions of macaque monkeys (Macaca mulatta) with chronic V1 lesions. Before LGN inactivation, high-contrast stimuli presented to the lesion-affected visual field (scotoma) produced significant V1-independent fMRI activation in the extrastriate cortical areas V2, V3, V4, V5/middle temporal (MT), fundus of the superior temporal sulcus (FST) and lateral intraparietal area (LIP) and the animals correctly located the stimuli in a detection task. However, following reversible inactivation of the LGN in the V1-lesioned hemisphere, fMRI responses and behavioural detection were abolished. These results demonstrate that direct LGN projections to the extrastriate cortex have a critical functional contribution to blindsight. They suggest a viable pathway to mediate fast detection during normal vision.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904843/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904843/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmid, Michael C -- Mrowka, Sylwia W -- Turchi, Janita -- Saunders, Richard C -- Wilke, Melanie -- Peters, Andrew J -- Ye, Frank Q -- Leopold, David A -- Z01 MH002838-05/Intramural NIH HHS/ -- England -- Nature. 2010 Jul 15;466(7304):373-7. doi: 10.1038/nature09179. Epub 2010 Jun 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neuropsychology, National Institute of Mental Health (NIMH), 49 Convent Drive, Bethesda, Maryland 20892, USA. schmidmicha@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20574422" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Female ; Geniculate Bodies/*physiology/physiopathology ; Macaca mulatta/*physiology ; Male ; Models, Neurological ; Photic Stimulation ; Visual Cortex/physiology/physiopathology ; Visual Pathways/*physiology/physiopathology ; Visual Perception/*physiology
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    The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule (2010)
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    Publication Date: 2010-11-05
    Description: Many physiological events require transient increases in cytosolic Ca(2+) concentrations. Ryanodine receptors (RyRs) are ion channels that govern the release of Ca(2+) from the endoplasmic and sarcoplasmic reticulum. Mutations in RyRs can lead to severe genetic conditions that affect both cardiac and skeletal muscle, but locating the mutated residues in the full-length channel structure has been difficult. Here we show the 2.5 A resolution crystal structure of a region spanning three domains of RyR type 1 (RyR1), encompassing amino acid residues 1-559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kDa cytoplasmic vestibule around the four-fold symmetry axis. We pinpoint the exact locations of more than 50 disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into three groups: those that destabilize the interfaces between the three amino-terminal domains, disturb the folding of individual domains or affect one of six interfaces with other parts of the receptor. We propose a model whereby the opening of a RyR coincides with allosterically coupled motions within the N-terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. The crystal structure provides a framework to understand the many disease-associated mutations in RyRs that have been studied using functional methods, and will be useful for developing new strategies to modulate RyR function in disease states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tung, Ching-Chieh -- Lobo, Paolo A -- Kimlicka, Lynn -- Van Petegem, Filip -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2010 Nov 25;468(7323):585-8. doi: 10.1038/nature09471. Epub 2010 Nov 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21048710" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Models, Molecular ; Mutation/genetics ; Protein Structure, Tertiary ; Rabbits ; Ryanodine Receptor Calcium Release Channel/*chemistry/*genetics/metabolism
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    Animal behaviour: An ill wind for finches (2010)
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    Publication Date: 2010-02-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lincoln, Tim -- England -- Nature. 2010 Feb 18;463(7283):888. doi: 10.1038/463888a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164914" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bird Diseases/*epidemiology/microbiology/transmission ; Cues ; Feeding Behavior/*physiology ; Female ; Finches/*physiology ; Male ; Mycoplasma Infections/epidemiology/microbiology/transmission/*veterinary ; *Mycoplasma gallisepticum/pathogenicity ; Sex Factors
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    Two enzymes bound to one transfer RNA assume alternative conformations for consecutive reactions (2010)
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    Publication Date: 2010-10-01
    Description: In most bacteria and all archaea, glutamyl-tRNA synthetase (GluRS) glutamylates both tRNA(Glu) and tRNA(Gln), and then Glu-tRNA(Gln) is selectively converted to Gln-tRNA(Gln) by a tRNA-dependent amidotransferase. The mechanisms by which the two enzymes recognize their substrate tRNA(s), and how they cooperate with each other in Gln-tRNA(Gln) synthesis, remain to be determined. Here we report the formation of the 'glutamine transamidosome' from the bacterium Thermotoga maritima, consisting of tRNA(Gln), GluRS and the heterotrimeric amidotransferase GatCAB, and its crystal structure at 3.35 A resolution. The anticodon-binding body of GluRS recognizes the common features of tRNA(Gln) and tRNA(Glu), whereas the tail body of GatCAB recognizes the outer corner of the L-shaped tRNA(Gln) in a tRNA(Gln)-specific manner. GluRS is in the productive form, as its catalytic body binds to the amino-acid-acceptor arm of tRNA(Gln). In contrast, GatCAB is in the non-productive form: the catalytic body of GatCAB contacts that of GluRS and is located near the acceptor stem of tRNA(Gln), in an appropriate site to wait for the completion of Glu-tRNA(Gln) formation by GluRS. We identified the hinges between the catalytic and anticodon-binding bodies of GluRS and between the catalytic and tail bodies of GatCAB, which allow both GluRS and GatCAB to adopt the productive and non-productive forms. The catalytic bodies of the two enzymes compete for the acceptor arm of tRNA(Gln) and therefore cannot assume their productive forms simultaneously. The transition from the present glutamylation state, with the productive GluRS and the non-productive GatCAB, to the putative amidation state, with the non-productive GluRS and the productive GatCAB, requires an intermediate state with the two enzymes in their non-productive forms, for steric reasons. The proposed mechanism explains how the transamidosome efficiently performs the two consecutive steps of Gln-tRNA(Gln) formation, with a low risk of releasing the unstable intermediate Glu-tRNA(Gln).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Takuhiro -- Yokoyama, Shigeyuki -- England -- Nature. 2010 Sep 30;467(7315):612-6. doi: 10.1038/nature09411.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20882017" target="_blank"〉PubMed〈/a〉
    Keywords: Anticodon/genetics ; Biocatalysis ; Crystallography, X-Ray ; Electrophoretic Mobility Shift Assay ; Glutamate-tRNA Ligase/*chemistry/*metabolism ; Models, Molecular ; Molecular Conformation ; Nitrogenous Group Transferases/*chemistry/*metabolism ; Protein Binding ; RNA, Transfer, Gln/biosynthesis/*chemistry/*metabolism ; RNA, Transfer, Glu/chemistry/metabolism ; Staphylococcus aureus/enzymology ; Substrate Specificity ; Thermotoga maritima/*enzymology
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    Multiple personal genomes await (2010)
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    Publication Date: 2010-04-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venter, J Craig -- England -- Nature. 2010 Apr 1;464(7289):676-7. doi: 10.1038/464676a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉J. Craig Venter Institute, La Jolla, California 92121, USA. jcventer@jcvi.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20360717" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Continental Population Groups/genetics ; Diploidy ; Female ; Genetic Predisposition to Disease/genetics ; Genetic Variation/genetics ; Genetics, Medical/*trends ; Genome, Human/*genetics ; Genomics/economics/history/*trends ; Haploidy ; Haplotypes/genetics ; History, 20th Century ; History, 21st Century ; Human Genome Project/economics/history ; Humans ; Male ; Phenotype ; Precision Medicine/*trends ; Sequence Analysis, DNA/economics/history/instrumentation/methods
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    In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium (2010)
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    Publication Date: 2010-02-16
    Description: Haematopoietic stem cells (HSCs), responsible for blood production in the adult mouse, are first detected in the dorsal aorta starting at embryonic day 10.5 (E10.5). Immunohistological analysis of fixed embryo sections has revealed the presence of haematopoietic cell clusters attached to the aortic endothelium where HSCs might localize. The origin of HSCs has long been controversial and several candidates of the direct HSC precursors have been proposed (for review see ref. 7), including a specialized endothelial cell population with a haemogenic potential. Such cells have been described both in vitro in the embryonic stem cell (ESC) culture system and retrospectively in vivo by endothelial lineage tracing and conditional deletion experiments. Whether the transition from haemogenic endothelium to HSC actually occurs in the mouse embryonic aorta is still unclear and requires direct and real-time in vivo observation. To address this issue we used time-lapse confocal imaging and a new dissection procedure to visualize the deeply located aorta. Here we show the dynamic de novo emergence of phenotypically defined HSCs (Sca1(+), c-kit(+), CD41(+)) directly from ventral aortic haemogenic endothelial cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boisset, Jean-Charles -- van Cappellen, Wiggert -- Andrieu-Soler, Charlotte -- Galjart, Niels -- Dzierzak, Elaine -- Robin, Catherine -- R37 DKO54077/PHS HHS/ -- England -- Nature. 2010 Mar 4;464(7285):116-20. doi: 10.1038/nature08764. Epub 2010 Feb 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Erasmus Medical Center, Department of Cell Biology, CA Rotterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20154729" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aorta/*cytology/embryology/surgery ; *Cell Differentiation ; *Cell Lineage ; Core Binding Factor Alpha 2 Subunit/deficiency/genetics/metabolism ; Dissection ; Embryo, Mammalian/cytology ; Endothelial Cells/cytology ; Endothelium, Vascular/*cytology/embryology ; Female ; Hematopoietic Stem Cells/*cytology ; Male ; Mice ; Microscopy, Confocal ; Phenotype ; Pregnancy
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    A novel pathway regulates memory and plasticity via SIRT1 and miR-134 (2010)
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    Publication Date: 2010-07-14
    Description: The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928875/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928875/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Jun -- Wang, Wen-Yuan -- Mao, Ying-Wei -- Graff, Johannes -- Guan, Ji-Song -- Pan, Ling -- Mak, Gloria -- Kim, Dohoon -- Su, Susan C -- Tsai, Li-Huei -- P01 AG027916/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Aug 26;466(7310):1105-9. doi: 10.1038/nature09271. Epub 2010 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20622856" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain-Derived Neurotrophic Factor/metabolism ; CREB-Binding Protein/metabolism ; Electrical Synapses/genetics/pathology ; Gene Expression Regulation ; Gene Knockdown Techniques ; Long-Term Potentiation/genetics ; Male ; Memory/*physiology ; Memory Disorders/genetics/physiopathology ; Mice ; MicroRNAs/*genetics/*metabolism ; Neuronal Plasticity/*genetics ; Protein Binding ; Sequence Deletion ; Sirtuin 1/*genetics/*metabolism
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    PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression (2010)
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    Publication Date: 2010-07-14
    Description: While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while using multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1-S transition in conjunction with E2F1, HCF-1 (also known as HCFC1) and SET1A (also known as SETD1A), at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the condensin II loading process. Accordingly, the HEAT repeat clusters in two non-structural maintenance of chromosomes (SMC) condensin II subunits, N-CAPD3 and N-CAPG2 (also known as NCAPD3 and NCAPG2, respectively), are capable of recognizing H4K20me1, and ChIP-Seq analysis demonstrates a significant overlap of condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059551/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Wen -- Tanasa, Bogdan -- Tyurina, Oksana V -- Zhou, Tian Yuan -- Gassmann, Reto -- Liu, Wei Ting -- Ohgi, Kenneth A -- Benner, Chris -- Garcia-Bassets, Ivan -- Aggarwal, Aneel K -- Desai, Arshad -- Dorrestein, Pieter C -- Glass, Christopher K -- Rosenfeld, Michael G -- R01 CA097134/CA/NCI NIH HHS/ -- R01 CA097134-09/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK018477-35/DK/NIDDK NIH HHS/ -- R01 DK039949/DK/NIDDK NIH HHS/ -- R01 DK039949-18/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS034934-21/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 22;466(7305):508-12. doi: 10.1038/nature09272. Epub 2010 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20622854" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Cell Cycle/*physiology ; Cell Line ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/chemistry/deficiency/genetics/*metabolism ; DNA-Binding Proteins/chemistry/metabolism ; HeLa Cells ; Histone Demethylases/chemistry/genetics/*metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/*metabolism ; Host Cell Factor C1/genetics/metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Multiprotein Complexes/chemistry/metabolism ; Phosphorylation ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Transcription Factors/chemistry/deficiency/genetics/*metabolism
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    Coupled dynamics of body mass and population growth in response to environmental change (2010)
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    Publication Date: 2010-07-24
    Description: Environmental change has altered the phenology, morphological traits and population dynamics of many species. However, the links underlying these joint responses remain largely unknown owing to a paucity of long-term data and the lack of an appropriate analytical framework. Here we investigate the link between phenotypic and demographic responses to environmental change using a new methodology and a long-term (1976-2008) data set from a hibernating mammal (the yellow-bellied marmot) inhabiting a dynamic subalpine habitat. We demonstrate how earlier emergence from hibernation and earlier weaning of young has led to a longer growing season and larger body masses before hibernation. The resulting shift in both the phenotype and the relationship between phenotype and fitness components led to a decline in adult mortality, which in turn triggered an abrupt increase in population size in recent years. Direct and trait-mediated effects of environmental change made comparable contributions to the observed marked increase in population growth. Our results help explain how a shift in phenology can cause simultaneous phenotypic and demographic changes, and highlight the need for a theory integrating ecological and evolutionary dynamics in stochastic environments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ozgul, Arpat -- Childs, Dylan Z -- Oli, Madan K -- Armitage, Kenneth B -- Blumstein, Daniel T -- Olson, Lucretia E -- Tuljapurkar, Shripad -- Coulson, Tim -- P01 AG022500/AG/NIA NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Jul 22;466(7305):482-5. doi: 10.1038/nature09210.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Life Sciences, Imperial College London, Ascot, Berkshire SL5 7PY, UK. a.ozgul@imperial.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20651690" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Evolution ; Body Weight/*physiology ; Colorado ; Female ; *Global Warming ; Hibernation/*physiology ; Marmota/*anatomy & histology/growth & development/*physiology ; Phenotype ; Population Dynamics ; Reproduction/physiology ; Survival Rate ; Time Factors ; Weaning
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    Gender agenda: sex bias can be justified in animal research (2010)
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    Details
    Publication Date: 2010-07-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bolon, Brad -- England -- Nature. 2010 Jul 1;466(7302):28. doi: 10.1038/466028d.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20595991" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Experimentation/standards ; Animals ; Animals, Laboratory ; *Bias (Epidemiology) ; Clinical Trials as Topic ; Editorial Policies ; Female ; Humans ; Male ; *Models, Animal ; *Research Design ; *Sex Characteristics
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    NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-30
    Description: The post-translational methylation of alpha-amino groups was first discovered over 30 years ago on the bacterial ribosomal proteins L16 and L33 (refs 1, 2), but almost nothing is known about the function or enzymology of this modification. Several other bacterial and eukaryotic proteins have since been shown to be alpha-N-methylated. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of alpha-N-methylation has been identified. Methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects, but further characterization of this modification has been hindered by ignorance of the responsible methyltransferase. All fungal and animal N-terminally methylated proteins contain a unique N-terminal motif, Met-(Ala/Pro/Ser)-Pro-Lys, indicating that they may be targets of the same, unknown enzyme. The initiating Met is cleaved, and the exposed alpha-amino group is mono-, di- or trimethylated. Here we report the discovery of the first alpha-N-methyltransferase, which we named N-terminal RCC1 methyltransferase (NRMT). Substrate docking and mutational analysis of RCC1 defined the NRMT recognition sequence and enabled the identification of numerous new methylation targets, including SET (also known as TAF-I or PHAPII) and the retinoblastoma protein, RB. Knockdown of NRMT recapitulates the multi-spindle phenotype seen with methylation-defective RCC1 mutants, demonstrating the importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939154/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tooley, Christine E Schaner -- Petkowski, Janusz J -- Muratore-Schroeder, Tara L -- Balsbaugh, Jeremy L -- Shabanowitz, Jeffrey -- Sabat, Michal -- Minor, Wladek -- Hunt, Donald F -- Macara, Ian G -- R01 GM050526/GM/NIGMS NIH HHS/ -- R01 GM050526-17/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Aug 26;466(7310):1125-8. doi: 10.1038/nature09343.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA. ces5g@virginia.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20668449" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/*metabolism ; Cell Line ; Chromosome Segregation ; Gene Knockdown Techniques ; Guanine Nucleotide Exchange Factors/*metabolism ; HeLa Cells ; Histone Chaperones/metabolism ; Humans ; Methyltransferases/chemistry/genetics/*metabolism ; Models, Molecular ; Mutation/genetics ; Nuclear Proteins/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Retinoblastoma Protein/*metabolism ; Spindle Apparatus/metabolism ; Transcription Factors/metabolism
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    Climate-driven population divergence in sex-determining systems (2010)
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    Publication Date: 2010-10-29
    Description: Sex determination is a fundamental biological process, yet its mechanisms are remarkably diverse. In vertebrates, sex can be determined by inherited genetic factors or by the temperature experienced during embryonic development. However, the evolutionary causes of this diversity remain unknown. Here we show that live-bearing lizards at different climatic extremes of the species' distribution differ in their sex-determining mechanisms, with temperature-dependent sex determination in lowlands and genotypic sex determination in highlands. A theoretical model parameterized with field data accurately predicts this divergence in sex-determining systems and the consequence thereof for variation in cohort sex ratios among years. Furthermore, we show that divergent natural selection on sex determination across altitudes is caused by climatic effects on lizard life history and variation in the magnitude of between-year temperature fluctuations. Our results establish an adaptive explanation for intra-specific divergence in sex-determining systems driven by phenotypic plasticity and ecological selection, thereby providing a unifying framework for integrating the developmental, ecological and evolutionary basis for variation in vertebrate sex determination.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pen, Ido -- Uller, Tobias -- Feldmeyer, Barbara -- Harts, Anna -- While, Geoffrey M -- Wapstra, Erik -- England -- Nature. 2010 Nov 18;468(7322):436-8. doi: 10.1038/nature09512. Epub 2010 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Theoretical Biology Group, University of Groningen, PO Box 14, 9750 AA Haren, the Netherlands. i.r.pen@rug.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20981009" target="_blank"〉PubMed〈/a〉
    Keywords: Altitude ; Animals ; Biological Evolution ; *Climate ; Female ; Genotype ; Lizards/*genetics/*physiology ; Male ; Models, Biological ; Phenotype ; Selection, Genetic ; Sex Chromosomes ; *Sex Determination Processes/genetics/physiology ; *Sex Differentiation/genetics/physiology ; Sex Ratio ; *Temperature ; Time Factors ; Viviparity, Nonmammalian/physiology
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    Protein-protein interactions: Real-time analysis (2010)
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    Publication Date: 2010-12-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonetta, Laura -- England -- Nature. 2010 Dec 9;468(7325):854. doi: 10.1038/468854a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21151000" target="_blank"〉PubMed〈/a〉
    Keywords: California ; Protein Binding ; Protein Interaction Mapping/*methods ; RNA, Transfer/metabolism ; Ribosomes/metabolism ; Sequence Analysis, DNA/methods ; Time Factors
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    Physiology: The bones of contention (2010)
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    Publication Date: 2010-08-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Katsnelson, Alla -- England -- Nature. 2010 Aug 19;466(7309):914-5. doi: 10.1038/466914a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20725014" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Remodeling ; Bone and Bones/*physiology ; Diabetes Mellitus/metabolism/therapy ; *Energy Metabolism ; Female ; Glucose/*metabolism ; Humans ; Insulin/metabolism/secretion ; Islets of Langerhans/secretion ; Leptin/deficiency/genetics/metabolism ; Mice ; Obesity/metabolism ; Osteocalcin/blood/deficiency/genetics/metabolism ; Osteoporosis/metabolism ; Receptor, Insulin/deficiency/genetics/metabolism
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    Neuroscience: A mine of imprinted genes (2010)
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    Publication Date: 2010-08-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keverne, Eric B -- England -- Nature. 2010 Aug 12;466(7308):823-4. doi: 10.1038/466823a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20703293" target="_blank"〉PubMed〈/a〉
    Keywords: *Alleles ; Animals ; Bias (Epidemiology) ; Brain/cytology/*metabolism ; Fathers ; Female ; Genomic Imprinting/*genetics ; Male ; Mice ; Models, Genetic ; Mothers ; X Chromosome/genetics
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    Strange lesions after stem-cell therapy (2010)
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    Publication Date: 2010-06-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2010 Jun 24;465(7301):997. doi: 10.1038/465997a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20577182" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Child ; Fatal Outcome ; Female ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Lupus Nephritis/*complications/*therapy ; Male ; Thailand
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    What will get sick from the slick? (2010)
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    Publication Date: 2010-07-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gaskill, Melissa -- England -- Nature. 2010 Jul 1;466(7302):14-5. doi: 10.1038/466014a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20595980" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Identification Systems/utilization ; Animal Migration ; Animals ; *Disasters ; *Ecosystem ; Female ; Food Chain ; Larva/drug effects/growth & development ; Marine Biology ; Mexico ; Oceans and Seas ; Petroleum/analysis/*poisoning/*toxicity ; Seawater/*chemistry ; Sharks/physiology ; Survival Rate ; Tuna/physiology ; Turtles/physiology ; Whales/physiology
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    Toxicology: The big test for bisphenol A (2010)
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    Publication Date: 2010-04-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Borrell, Brendan -- England -- Nature. 2010 Apr 22;464(7292):1122-4. doi: 10.1038/4641122a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20414285" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzhydryl Compounds ; Chemical Industry/methods/standards ; Endocrine Disruptors/adverse effects/toxicity ; Estrogens, Non-Steroidal/adverse effects/toxicity ; Female ; Guidelines as Topic ; Humans ; Infant ; Male ; Mice ; National Institute of Environmental Health Sciences (U.S.) ; Neoplasms/chemically induced/etiology ; Phenols/adverse effects/*toxicity ; Rats ; Toxicity Tests/methods/standards ; Toxicology/economics/*methods/*standards ; United States ; United States Environmental Protection Agency ; Validation Studies as Topic
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    Orm family proteins mediate sphingolipid homeostasis (2010)
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    Publication Date: 2010-02-26
    Description: Despite the essential roles of sphingolipids both as structural components of membranes and critical signalling molecules, we have a limited understanding of how cells sense and regulate their levels. Here we reveal the function in sphingolipid metabolism of the ORM genes (known as ORMDL genes in humans)-a conserved gene family that includes ORMDL3, which has recently been identified as a potential risk factor for childhood asthma. Starting from an unbiased functional genomic approach in Saccharomyces cerevisiae, we identify Orm proteins as negative regulators of sphingolipid synthesis that form a conserved complex with serine palmitoyltransferase, the first and rate-limiting enzyme in sphingolipid production. We also define a regulatory pathway in which phosphorylation of Orm proteins relieves their inhibitory activity when sphingolipid production is disrupted. Changes in ORM gene expression or mutations to their phosphorylation sites cause dysregulation of sphingolipid metabolism. Our work identifies the Orm proteins as critical mediators of sphingolipid homeostasis and raises the possibility that sphingolipid misregulation contributes to the development of childhood asthma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877384/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877384/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Breslow, David K -- Collins, Sean R -- Bodenmiller, Bernd -- Aebersold, Ruedi -- Simons, Kai -- Shevchenko, Andrej -- Ejsing, Christer S -- Weissman, Jonathan S -- N01-HV-28179/HV/NHLBI NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- P50 GM073210-06/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Feb 25;463(7284):1048-53. doi: 10.1038/nature08787.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 1700 4th Street, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20182505" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Asthma/metabolism ; Cell Line ; Conserved Sequence ; Fatty Acids, Monounsaturated/pharmacology ; HeLa Cells ; *Homeostasis ; Humans ; Molecular Sequence Data ; *Multigene Family ; Multiprotein Complexes/chemistry/metabolism ; Phosphoric Monoester Hydrolases/genetics/metabolism ; Phosphorylation ; Protein Binding ; Saccharomyces cerevisiae/drug effects/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/classification/genetics/*metabolism ; Serine C-Palmitoyltransferase/genetics/metabolism ; Sphingolipids/biosynthesis/*metabolism
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    Sex bias in trials and treatment must end (2010)
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    Publication Date: 2010-06-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Alison M -- Tingen, Candace M -- Woodruff, Teresa K -- England -- Nature. 2010 Jun 10;465(7299):688-9. doi: 10.1038/465688a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535184" target="_blank"〉PubMed〈/a〉
    Keywords: Bias (Epidemiology) ; Biomedical Research/methods/*trends ; Clinical Trials as Topic/methods/*trends ; Drug Dosage Calculations ; Female ; Genomic Imprinting ; Humans ; Male ; Precision Medicine/trends ; *Sex Characteristics ; Sex Distribution ; Sex Factors
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    A conserved spider silk domain acts as a molecular switch that controls fibre assembly (2010)
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    Publication Date: 2010-05-14
    Description: A huge variety of proteins are able to form fibrillar structures, especially at high protein concentrations. Hence, it is surprising that spider silk proteins can be stored in a soluble form at high concentrations and transformed into extremely stable fibres on demand. Silk proteins are reminiscent of amphiphilic block copolymers containing stretches of polyalanine and glycine-rich polar elements forming a repetitive core flanked by highly conserved non-repetitive amino-terminal and carboxy-terminal domains. The N-terminal domain comprises a secretion signal, but further functions remain unassigned. The C-terminal domain was implicated in the control of solubility and fibre formation initiated by changes in ionic composition and mechanical stimuli known to align the repetitive sequence elements and promote beta-sheet formation. However, despite recent structural data, little is known about this remarkable behaviour in molecular detail. Here we present the solution structure of the C-terminal domain of a spider dragline silk protein and provide evidence that the structural state of this domain is essential for controlled switching between the storage and assembly forms of silk proteins. In addition, the C-terminal domain also has a role in the alignment of secondary structural features formed by the repetitive elements in the backbone of spider silk proteins, which is known to be important for the mechanical properties of the fibre.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hagn, Franz -- Eisoldt, Lukas -- Hardy, John G -- Vendrely, Charlotte -- Coles, Murray -- Scheibel, Thomas -- Kessler, Horst -- England -- Nature. 2010 May 13;465(7295):239-42. doi: 10.1038/nature08936.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Integrated Protein Science (CIPSM), Technische Universitat Munchen, 85747 Garching, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20463741" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calorimetry, Differential Scanning ; Circular Dichroism ; *Conserved Sequence ; Hydrophobic and Hydrophilic Interactions ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Protein Structure, Tertiary ; Silk/*chemistry/*metabolism ; Spectrometry, Fluorescence ; Spectroscopy, Fourier Transform Infrared ; Spiders/*chemistry
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    Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate (2010)
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    Publication Date: 2010-01-15
    Description: Immune homeostasis is dependent on tight control over the size of a population of regulatory T (T(reg)) cells capable of suppressing over-exuberant immune responses. The T(reg) cell subset is comprised of cells that commit to the T(reg) lineage by upregulating the transcription factor Foxp3 either in the thymus (tT(reg)) or in the periphery (iT(reg)). Considering a central role for Foxp3 in T(reg) cell differentiation and function, we proposed that conserved non-coding DNA sequence (CNS) elements at the Foxp3 locus encode information defining the size, composition and stability of the T(reg) cell population. Here we describe the function of three Foxp3 CNS elements (CNS1-3) in T(reg) cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T(reg) cells generated in the thymus and the periphery, binds c-Rel in in vitro assays. In contrast, CNS1, which contains a TGF-beta-NFAT response element, is superfluous for tT(reg) cell differentiation, but has a prominent role in iT(reg) cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T(reg) cells. Foxp3 binds to CNS2 in a Cbf-beta-Runx1 and CpG DNA demethylation-dependent manner, suggesting that Foxp3 recruitment to this 'cellular memory module' facilitates the heritable maintenance of the active state of the Foxp3 locus and, therefore, T(reg) lineage stability. Together, our studies demonstrate that the composition, size and maintenance of the T(reg) cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884187/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884187/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Ye -- Josefowicz, Steven -- Chaudhry, Ashutosh -- Peng, Xiao P -- Forbush, Katherine -- Rudensky, Alexander Y -- R37 AI034206/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Feb 11;463(7282):808-12. doi: 10.1038/nature08750. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Immunology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072126" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Lineage/*genetics ; Chromatin Assembly and Disassembly ; Conserved Sequence/*genetics ; CpG Islands/genetics ; DNA Methylation ; Female ; Forkhead Transcription Factors/*genetics/metabolism ; Gene Expression Regulation ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-rel/metabolism ; Regulatory Sequences, Nucleic Acid/*genetics ; Response Elements/genetics ; T-Lymphocytes, Regulatory/*cytology/immunology/*metabolism ; Thymus Gland/cytology/immunology/metabolism
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    Science in court: head case (2010)
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    Publication Date: 2010-03-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hughes, Virginia -- England -- Nature. 2010 Mar 18;464(7287):340-2. doi: 10.1038/464340a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20237536" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Antisocial Personality Disorder/physiopathology/psychology ; Child ; Female ; Forensic Sciences/ethics/*methods/trends ; Homicide/*legislation & jurisprudence/*psychology ; Humans ; Insanity Defense ; Magnetic Resonance Imaging/standards/*utilization ; Male ; *Neurosciences ; Positron-Emission Tomography/utilization ; Rape/legislation & jurisprudence/psychology ; Reproducibility of Results
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    DNMT1 maintains progenitor function in self-renewing somatic tissue (2010)
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    Publication Date: 2010-01-19
    Description: Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation. DNA methylation provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1) maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance, the role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unclear. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. Genome-wide analysis showed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, UHRF1 (refs 9, 10), a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A and B, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050546/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050546/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sen, George L -- Reuter, Jason A -- Webster, Daniel E -- Zhu, Lilly -- Khavari, Paul A -- AR055849/AR/NIAMS NIH HHS/ -- AR45192/AR/NIAMS NIH HHS/ -- F32 AR055849/AR/NIAMS NIH HHS/ -- F32 AR055849-02/AR/NIAMS NIH HHS/ -- K01 AR057828/AR/NIAMS NIH HHS/ -- R01 AR045192/AR/NIAMS NIH HHS/ -- R01 AR045192-11A2/AR/NIAMS NIH HHS/ -- R01 AR049737/AR/NIAMS NIH HHS/ -- R01 AR049737-05/AR/NIAMS NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jan 28;463(7280):563-7. doi: 10.1038/nature08683. Epub 2010 Jan 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Programs in Epithelial Biology and Cancer Biology and the Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20081831" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; DNA Methylation ; Down-Regulation ; Epidermis/*cytology/*metabolism ; Female ; Gene Silencing ; Humans ; Mice ; Mice, SCID ; Repressor Proteins/deficiency/genetics/*metabolism ; Stem Cells/*cytology/*metabolism
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    Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-04-30
    Description: Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862593/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862593/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baranzini, Sergio E -- Mudge, Joann -- van Velkinburgh, Jennifer C -- Khankhanian, Pouya -- Khrebtukova, Irina -- Miller, Neil A -- Zhang, Lu -- Farmer, Andrew D -- Bell, Callum J -- Kim, Ryan W -- May, Gregory D -- Woodward, Jimmy E -- Caillier, Stacy J -- McElroy, Joseph P -- Gomez, Refujia -- Pando, Marcelo J -- Clendenen, Leonda E -- Ganusova, Elena E -- Schilkey, Faye D -- Ramaraj, Thiruvarangan -- Khan, Omar A -- Huntley, Jim J -- Luo, Shujun -- Kwok, Pui-Yan -- Wu, Thomas D -- Schroth, Gary P -- Oksenberg, Jorge R -- Hauser, Stephen L -- Kingsmore, Stephen F -- P20 RR016480/RR/NCRR NIH HHS/ -- P20 RR016480-09/RR/NCRR NIH HHS/ -- R01 NS026799/NS/NINDS NIH HHS/ -- R01 NS026799-20A1/NS/NINDS NIH HHS/ -- R01 NS046297/NS/NINDS NIH HHS/ -- R01 NS046297-06/NS/NINDS NIH HHS/ -- R01NS26799/NS/NINDS NIH HHS/ -- R01NS46297/NS/NINDS NIH HHS/ -- RR016480/RR/NCRR NIH HHS/ -- U01 AI066569/AI/NIAID NIH HHS/ -- U01 AI066569-05/AI/NIAID NIH HHS/ -- U19 HD077693/HD/NICHD NIH HHS/ -- England -- Nature. 2010 Apr 29;464(7293):1351-6. doi: 10.1038/nature08990.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, University of California at San Francisco, San Francisco, California 94143, USA. sebaran@cgl.ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20428171" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Allelic Imbalance/genetics ; Breast/metabolism ; Breast Neoplasms/genetics ; CD4-Positive T-Lymphocytes/metabolism ; Case-Control Studies ; CpG Islands/genetics ; DNA Copy Number Variations/genetics ; DNA Methylation/genetics ; Epigenesis, Genetic/*genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genome, Human/*genetics ; Haplotypes/genetics ; Heterozygote ; Humans ; INDEL Mutation/genetics ; Lung/metabolism ; Lung Neoplasms/genetics ; Male ; Multiple Sclerosis/*genetics ; Polymorphism, Genetic/genetics ; Quantitative Trait Loci/genetics ; RNA, Messenger/analysis/*genetics/metabolism ; Twins, Monozygotic/*genetics
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    Selective inhibition of BET bromodomains (2010)
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    Publication Date: 2010-09-28
    Description: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010259/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010259/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Filippakopoulos, Panagis -- Qi, Jun -- Picaud, Sarah -- Shen, Yao -- Smith, William B -- Fedorov, Oleg -- Morse, Elizabeth M -- Keates, Tracey -- Hickman, Tyler T -- Felletar, Ildiko -- Philpott, Martin -- Munro, Shonagh -- McKeown, Michael R -- Wang, Yuchuan -- Christie, Amanda L -- West, Nathan -- Cameron, Michael J -- Schwartz, Brian -- Heightman, Tom D -- La Thangue, Nicholas -- French, Christopher A -- Wiest, Olaf -- Kung, Andrew L -- Knapp, Stefan -- Bradner, James E -- 13058/Cancer Research UK/United Kingdom -- G0500905/Medical Research Council/United Kingdom -- G1000807/Medical Research Council/United Kingdom -- G9400953/Medical Research Council/United Kingdom -- K08 CA128972/CA/NCI NIH HHS/ -- K08 CA128972-03/CA/NCI NIH HHS/ -- T32-075762/PHS HHS/ -- Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Dec 23;468(7327):1067-73. doi: 10.1038/nature09504. Epub 2010 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20871596" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Azirines/chemical synthesis/chemistry/*pharmacology ; Binding Sites ; Carcinoma, Squamous Cell/physiopathology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatin/metabolism ; Dihydropyridines/chemical synthesis/chemistry/*pharmacology ; Female ; Humans ; Mice ; Mice, Nude ; *Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/*antagonists & inhibitors/*metabolism ; Protein Binding/drug effects ; Protein Structure, Tertiary ; Recombinant Proteins/metabolism ; Sequence Alignment ; Skin Neoplasms/physiopathology ; Stereoisomerism ; Transcription Factors/*antagonists & inhibitors/*metabolism
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    Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition (2010)
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    Publication Date: 2010-07-14
    Description: In birds, as in mammals, one pair of chromosomes differs between the sexes. In birds, males are ZZ and females ZW. In mammals, males are XY and females XX. Like the mammalian XY pair, the avian ZW pair is believed to have evolved from autosomes, with most change occurring in the chromosomes found in only one sex--the W and Y chromosomes. By contrast, the sex chromosomes found in both sexes--the Z and X chromosomes--are assumed to have diverged little from their autosomal progenitors. Here we report findings that challenge this assumption for both the chicken Z chromosome and the human X chromosome. The chicken Z chromosome, which we sequenced essentially to completion, is less gene-dense than chicken autosomes but contains a massive tandem array containing hundreds of duplicated genes expressed in testes. A comprehensive comparison of the chicken Z chromosome with the finished sequence of the human X chromosome demonstrates that each evolved independently from different portions of the ancestral genome. Despite this independence, the chicken Z and human X chromosomes share features that distinguish them from autosomes: the acquisition and amplification of testis-expressed genes, and a low gene density resulting from an expansion of intergenic regions. These features were not present on the autosomes from which the Z and X chromosomes originated but were instead acquired during the evolution of Z and X as sex chromosomes. We conclude that the avian Z and mammalian X chromosomes followed convergent evolutionary trajectories, despite their evolving with opposite (female versus male) systems of heterogamety. More broadly, in birds and mammals, sex chromosome evolution involved not only gene loss in sex-specific chromosomes, but also marked expansion and gene acquisition in sex chromosomes common to males and females.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943333/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943333/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bellott, Daniel W -- Skaletsky, Helen -- Pyntikova, Tatyana -- Mardis, Elaine R -- Graves, Tina -- Kremitzki, Colin -- Brown, Laura G -- Rozen, Steve -- Warren, Wesley C -- Wilson, Richard K -- Page, David C -- R01 HG000257/HG/NHGRI NIH HHS/ -- R01 HG000257-21/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 29;466(7306):612-6. doi: 10.1038/nature09172. Epub 2010 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20622855" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chickens/*genetics ; Chromosomes, Human, X/*genetics ; *Evolution, Molecular ; Female ; Gene Deletion ; Genes/*genetics ; Genome/genetics ; Humans ; Male ; Multigene Family/genetics ; Sex Characteristics ; Sex Chromosomes/*genetics ; Testis/metabolism
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    eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation (2010)
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    Publication Date: 2010-05-21
    Description: In protein synthesis initiation, the eukaryotic translation initiation factor (eIF) 2 (a G protein) functions in its GTP-bound state to deliver initiator methionyl-tRNA (tRNA(i)(Met)) to the small ribosomal subunit and is necessary for protein synthesis in all cells. Phosphorylation of eIF2 [eIF2(alphaP)] is critical for translational control in diverse settings including nutrient deprivation, viral infection and memory formation. eIF5 functions in start site selection as a GTPase accelerating protein (GAP) for the eIF2.GTP.tRNA(i)(Met) ternary complex within the ribosome-bound pre-initiation complex. Here we define new regulatory functions of eIF5 in the recycling of eIF2 from its inactive eIF2.GDP state between successive rounds of translation initiation. First we show that eIF5 stabilizes the binding of GDP to eIF2 and is therefore a bi-functional protein that acts as a GDP dissociation inhibitor (GDI). We find that this activity is independent of the GAP function and identify conserved residues within eIF5 that are necessary for this role. Second we show that eIF5 is a critical component of the eIF2(alphaP) regulatory complex that inhibits the activity of the guanine-nucleotide exchange factor (GEF) eIF2B. Together our studies define a new step in the translation initiation pathway, one that is critical for normal translational controls.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875157/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875157/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jennings, Martin D -- Pavitt, Graham D -- BB/E002005/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/H010599/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BBE0020051/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2010 May 20;465(7296):378-81. doi: 10.1038/nature09003.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485439" target="_blank"〉PubMed〈/a〉
    Keywords: Basic-Leucine Zipper Transcription Factors/metabolism ; Eukaryotic Initiation Factor-2/antagonists & inhibitors/chemistry/*metabolism ; GTPase-Activating Proteins/metabolism ; Guanine Nucleotide Dissociation Inhibitors/chemistry/*metabolism ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; *Peptide Chain Initiation, Translational ; Peptide Initiation Factors/chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Protein Subunits/chemistry/metabolism ; RNA, Transfer, Met/metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism
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    Network organization of the human autophagy system (2010)
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    Publication Date: 2010-06-22
    Description: Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. Although conserved protein kinase, lipid kinase and ubiquitin-like protein conjugation subnetworks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here we report a proteomic analysis of the autophagy interaction network in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 409 candidate interacting proteins with extensive connectivity among subnetworks. Many new autophagy interaction network components have roles in vesicle trafficking, protein or lipid phosphorylation and protein ubiquitination, and affect autophagosome number or flux when depleted by RNA interference. The six ATG8 orthologues in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901998/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Behrends, Christian -- Sowa, Mathew E -- Gygi, Steven P -- Harper, J Wade -- R01 AG011085/AG/NIA NIH HHS/ -- R01 AG011085-18/AG/NIA NIH HHS/ -- R01 GM054137/GM/NIGMS NIH HHS/ -- R01 GM054137-14/GM/NIGMS NIH HHS/ -- R01 GM054137-14S1/GM/NIGMS NIH HHS/ -- R01 GM054137-15/GM/NIGMS NIH HHS/ -- R01 GM070565/GM/NIGMS NIH HHS/ -- R01 GM070565-05S1/GM/NIGMS NIH HHS/ -- R01 GM095567/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jul 1;466(7302):68-76. doi: 10.1038/nature09204. Epub 2010 Jun 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20562859" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Autophagy/genetics/*physiology ; Homeostasis ; Humans ; Microfilament Proteins/genetics/metabolism ; Phagosomes ; Phosphorylation ; Protein Binding ; *Protein Interaction Mapping ; Proteomics ; RNA Interference ; Reproducibility of Results ; Ubiquitination
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    TFIIA and the transactivator Rap1 cooperate to commit TFIID for transcription initiation (2010)
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    Publication Date: 2010-06-19
    Description: Transcription of eukaryotic messenger RNA (mRNA) encoding genes by RNA polymerase II (Pol II) is triggered by the binding of transactivating proteins to enhancer DNA, which stimulates the recruitment of general transcription factors (TFIIA, B, D, E, F, H) and Pol II on the cis-linked promoter, leading to pre-initiation complex formation and transcription. In TFIID-dependent activation pathways, this general transcription factor containing TATA-box-binding protein is first recruited on the promoter through interaction with activators and cooperates with TFIIA to form a committed pre-initiation complex. However, neither the mechanisms by which activation signals are communicated between these factors nor the structural organization of the activated pre-initiation complex are known. Here we used cryo-electron microscopy to determine the architecture of nucleoprotein complexes composed of TFIID, TFIIA, the transcriptional activator Rap1 and yeast enhancer-promoter DNA. These structures revealed the mode of binding of Rap1 and TFIIA to TFIID, as well as a reorganization of TFIIA induced by its interaction with Rap1. We propose that this change in position increases the exposure of TATA-box-binding protein within TFIID, consequently enhancing its ability to interact with the promoter. A large Rap1-dependent DNA loop forms between the activator-binding site and the proximal promoter region. This loop is topologically locked by a TFIIA-Rap1 protein bridge that folds over the DNA. These results highlight the role of TFIIA in transcriptional activation, define a molecular mechanism for enhancer-promoter communication and provide structural insights into the pathways of intramolecular communication that convey transcription activation signals through the TFIID complex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900199/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900199/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Papai, Gabor -- Tripathi, Manish K -- Ruhlmann, Christine -- Layer, Justin H -- Weil, P Anthony -- Schultz, Patrick -- GM52461/GM/NIGMS NIH HHS/ -- R01 GM052461/GM/NIGMS NIH HHS/ -- R01 GM052461-14/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jun 17;465(7300):956-60. doi: 10.1038/nature09080.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology and Genomics, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, BP10142, 67404 Illkirch, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20559389" target="_blank"〉PubMed〈/a〉
    Keywords: Cryoelectron Microscopy ; *Models, Molecular ; Nucleoproteins/chemistry/ultrastructure ; Protein Structure, Tertiary ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism/ultrastructure ; Telomere-Binding Proteins/chemistry/*metabolism/ultrastructure ; Transcription Factor TFIIA/chemistry/*metabolism ; Transcription Factor TFIID/chemistry/*metabolism ; Transcription Factors/chemistry/*metabolism/ultrastructure ; *Transcriptional Activation
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    Learning from the elite (2010)
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    Publication Date: 2010-07-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trivedi, Bijal -- England -- Nature. 2010 Jul 15;466(7304):S4. doi: 10.1038/nature09235.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20631703" target="_blank"〉PubMed〈/a〉
    Keywords: Acquired Immunodeficiency Syndrome/genetics/*immunology/prevention & ; control/virology ; Alleles ; *Disease Progression ; Female ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; HIV/genetics/immunology ; HIV Infections/genetics/*immunology/prevention & control/virology ; *HIV Long-Term Survivors/statistics & numerical data ; HLA-B Antigens/genetics/immunology ; Humans ; Immunity, Innate/genetics/*immunology ; Major Histocompatibility Complex/genetics ; Male ; Polymorphism, Single Nucleotide/genetics ; RNA, Viral/blood
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    TRIM24 links a non-canonical histone signature to breast cancer (2010)
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    Publication Date: 2010-12-18
    Description: Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058826/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsai, Wen-Wei -- Wang, Zhanxin -- Yiu, Teresa T -- Akdemir, Kadir C -- Xia, Weiya -- Winter, Stefan -- Tsai, Cheng-Yu -- Shi, Xiaobing -- Schwarzer, Dirk -- Plunkett, William -- Aronow, Bruce -- Gozani, Or -- Fischle, Wolfgang -- Hung, Mien-Chie -- Patel, Dinshaw J -- Barton, Michelle Craig -- GM079641/GM/NIGMS NIH HHS/ -- GM081627/GM/NIGMS NIH HHS/ -- P01 GM081627/GM/NIGMS NIH HHS/ -- P01 GM081627-010003/GM/NIGMS NIH HHS/ -- P01 GM081627-020003/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- P30DK078392-01/DK/NIDDK NIH HHS/ -- T32 HD07325/HD/NICHD NIH HHS/ -- U54 RR025216/RR/NCRR NIH HHS/ -- UL1 TR000077/TR/NCATS NIH HHS/ -- England -- Nature. 2010 Dec 16;468(7326):927-32. doi: 10.1038/nature09542.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biomedical Sciences, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21164480" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Breast Neoplasms/*genetics/*metabolism/pathology ; Carrier Proteins/chemistry/genetics/*metabolism ; Cell Line, Tumor ; Chromatin/metabolism ; Chromatin Assembly and Disassembly ; Crystallography, X-Ray ; Estrogen Receptor alpha/metabolism ; Estrogens/metabolism ; *Gene Expression Regulation, Neoplastic/genetics ; HEK293 Cells ; Histones/chemistry/*metabolism ; Humans ; Methylation ; Protein Array Analysis ; Protein Binding ; Protein Structure, Tertiary ; Substrate Specificity ; Survival Rate
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    Putting gender on the agenda (2010)
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    Publication Date: 2010-06-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Jun 10;465(7299):665. doi: 10.1038/465665a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535156" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bias (Epidemiology) ; Biomedical Research/*methods/*trends ; Clinical Trials as Topic/*methods/*trends ; Evidence-Based Medicine/methods/trends ; Female ; Humans ; Male ; Precision Medicine/methods/trends ; Pregnancy ; *Sex Characteristics ; Sex Factors
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    Chagas disease: pushing through the pipeline (2010)
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    Publication Date: 2010-06-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clayton, Julie -- England -- Nature. 2010 Jun 24;465(7301):S12-5. doi: 10.1038/nature09224.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20571548" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Chagas Disease/complications/diagnosis/*drug therapy/parasitology ; Child ; Chronic Disease ; Clinical Trials as Topic ; Drug Evaluation, Preclinical/*trends ; Female ; Humans ; Infant, Newborn ; Lupus Erythematosus, Systemic/complications/drug therapy/immunology ; Molecular Targeted Therapy/trends ; Nitroimidazoles/therapeutic use ; Triazoles/pharmacology/therapeutic use ; *Trypanocidal Agents/economics/pharmacology/therapeutic use ; Trypanosoma cruzi/drug effects/enzymology/genetics/metabolism ; Young Adult
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    Evolutionary biology: pregnant fathers in charge (2010)
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    Publication Date: 2010-03-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berglund, Anders -- England -- Nature. 2010 Mar 18;464(7287):364-5. doi: 10.1038/464364a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20237558" target="_blank"〉PubMed〈/a〉
    Keywords: Abortion, Eugenic/veterinary ; Animals ; *Biological Evolution ; Body Size/physiology ; *Conflict (Psychology) ; Embryo, Nonmammalian/embryology/physiology ; Embryonic Development/*physiology ; Female ; Male ; Mating Preference, Animal/*physiology ; Paternal Behavior ; Selection, Genetic ; *Sex ; Sex Characteristics ; Smegmamorpha/anatomy & histology/embryology/*physiology ; Survival Rate
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    Pregnant women deserve better (2010)
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    Publication Date: 2010-06-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baylis, Francoise -- England -- Nature. 2010 Jun 10;465(7299):689-90. doi: 10.1038/465689a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioethics, Dalhousie University, Halifax, Nova Scotia B3H 3P7, Canada. francoise.baylis@dal.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535185" target="_blank"〉PubMed〈/a〉
    Keywords: Bias (Epidemiology) ; Clinical Trials as Topic/ethics/*methods ; Evidence-Based Medicine/ethics/trends ; Female ; Humans ; Pregnancy ; *Sex Characteristics ; Sex Distribution ; Sex Factors ; Uncertainty
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    Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint (2010)
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    Publication Date: 2010-09-08
    Description: Cell cycle checkpoints are implemented to safeguard the genome, avoiding the accumulation of genetic errors. Checkpoint loss results in genomic instability and contributes to the evolution of cancer. Among G1-, S-, G2- and M-phase checkpoints, genetic studies indicate the role of an intact S-phase checkpoint in maintaining genome integrity. Although the basic framework of the S-phase checkpoint in multicellular organisms has been outlined, the mechanistic details remain to be elucidated. Human chromosome-11 band-q23 translocations disrupting the MLL gene lead to poor prognostic leukaemias. Here we assign MLL as a novel effector in the mammalian S-phase checkpoint network and identify checkpoint dysfunction as an underlying mechanism of MLL leukaemias. MLL is phosphorylated at serine 516 by ATR in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) E3 ligase, leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine 4 at late replication origins and inhibits the loading of CDC45 to delay DNA replication. Cells deficient in MLL showed radioresistant DNA synthesis and chromatid-type genomic abnormalities, indicative of S-phase checkpoint dysfunction. Reconstitution of Mll(-/-) (Mll also known as Mll1) mouse embryonic fibroblasts with wild-type but not S516A or DeltaSET mutant MLL rescues the S-phase checkpoint defects. Moreover, murine myeloid progenitor cells carrying an Mll-CBP knock-in allele that mimics human t(11;16) leukaemia show a severe radioresistant DNA synthesis phenotype. MLL fusions function as dominant negative mutants that abrogate the ATR-mediated phosphorylation/stabilization of wild-type MLL on damage to DNA, and thus compromise the S-phase checkpoint. Together, our results identify MLL as a key constituent of the mammalian DNA damage response pathway and show that deregulation of the S-phase checkpoint incurred by MLL translocations probably contributes to the pathogenesis of human MLL leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940944/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Han -- Takeda, Shugaku -- Kumar, Rakesh -- Westergard, Todd D -- Brown, Eric J -- Pandita, Tej K -- Cheng, Emily H-Y -- Hsieh, James J-D -- CA119008/CA/NCI NIH HHS/ -- CA123232/CA/NCI NIH HHS/ -- CA129537/CA/NCI NIH HHS/ -- R01 CA119008/CA/NCI NIH HHS/ -- R01 CA119008-01/CA/NCI NIH HHS/ -- R01 CA119008-02/CA/NCI NIH HHS/ -- R01 CA119008-03/CA/NCI NIH HHS/ -- R01 CA119008-04/CA/NCI NIH HHS/ -- R01 CA119008-05/CA/NCI NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):343-6. doi: 10.1038/nature09350. Epub 2010 Sep 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20818375" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line ; Chromatin/metabolism ; DNA Damage ; DNA Replication/physiology ; Genes, Dominant/genetics ; Genomic Instability/physiology ; Histone-Lysine N-Methyltransferase ; Histones/chemistry/metabolism ; Humans ; Leukemia/genetics ; Lysine/metabolism ; Methylation ; Mice ; Myeloid Progenitor Cells/metabolism ; Myeloid-Lymphoid Leukemia Protein/chemistry/deficiency/genetics/*metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/*metabolism ; S Phase/*physiology ; S-Phase Kinase-Associated Proteins/metabolism ; Signal Transduction ; Translocation, Genetic/genetics
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    Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization (2010)
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    Publication Date: 2010-05-21
    Description: Commensal bacteria are known to inhibit pathogen colonization; however, complex host-microbe and microbe-microbe interactions have made it difficult to gain a detailed understanding of the mechanisms involved in the inhibition of colonization. Here we show that the serine protease Esp secreted by a subset of Staphylococcus epidermidis, a commensal bacterium, inhibits biofilm formation and nasal colonization by Staphylococcus aureus, a human pathogen. Epidemiological studies have demonstrated that the presence of Esp-secreting S. epidermidis in the nasal cavities of human volunteers correlates with the absence of S. aureus. Purified Esp inhibits biofilm formation and destroys pre-existing S. aureus biofilms. Furthermore, Esp enhances the susceptibility of S. aureus in biofilms to immune system components. In vivo studies have shown that Esp-secreting S. epidermidis eliminates S. aureus nasal colonization. These findings indicate that Esp hinders S. aureus colonization in vivo through a novel mechanism of bacterial interference, which could lead to the development of novel therapeutics to prevent S. aureus colonization and infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Iwase, Tadayuki -- Uehara, Yoshio -- Shinji, Hitomi -- Tajima, Akiko -- Seo, Hiromi -- Takada, Koji -- Agata, Toshihiko -- Mizunoe, Yoshimitsu -- England -- Nature. 2010 May 20;465(7296):346-9. doi: 10.1038/nature09074.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bacteriology, The Jikei University School of Medicine, Tokyo, 105-8461 Japan. iwase.tadayuki@jikei.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485435" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/chemistry/isolation & purification/*metabolism/pharmacology ; Biofilms/*growth & development ; Female ; Humans ; Male ; Nose/*microbiology ; Odds Ratio ; Serine Proteases/chemistry/deficiency/isolation & purification/*metabolism ; Staphylococcal Infections/microbiology/prevention & control/therapy ; Staphylococcus aureus/*growth & development/immunology ; Staphylococcus epidermidis/*enzymology/genetics/*physiology ; Superinfection/immunology/microbiology/prevention & control/therapy ; Young Adult ; beta-Defensins/immunology/pharmacology
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    Korean deaths spark inquiry (2010)
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    Publication Date: 2010-11-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2010 Nov 25;468(7323):485. doi: 10.1038/468485a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107396" target="_blank"〉PubMed〈/a〉
    Keywords: Female ; Humans ; Male ; *Medical Tourism/economics/ethics/legislation & jurisprudence ; Republic of Korea ; Stem Cell Transplantation/*ethics/*legislation & jurisprudence/mortality ; *Travel
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    Production of p53 gene knockout rats by homologous recombination in embryonic stem cells (2010)
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    Publication Date: 2010-08-13
    Description: The use of homologous recombination to modify genes in embryonic stem (ES) cells provides a powerful means to elucidate gene function and create disease models. Application of this technology to engineer genes in rats has not previously been possible because of the absence of germline-competent ES cells in this species. We have recently established authentic rat ES cells. Here we report the generation of gene knockout rats using the ES-cell-based gene targeting technology. We designed a targeting vector to disrupt the tumour suppressor gene p53 (also known as Tp53) in rat ES cells by means of homologous recombination. p53 gene-targeted rat ES cells can be routinely generated. Furthermore, the p53 gene-targeted mutation in the rat ES-cell genome can transmit through the germ line via ES-cell rat chimaeras to create p53 gene knockout rats. The rat is the most widely used animal model in biological research. The establishment of gene targeting technology in rat ES cells, in combination with advances in genomics and the vast amount of research data on physiology and pharmacology in this species, now provide a powerful new platform for the study of human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tong, Chang -- Li, Ping -- Wu, Nancy L -- Yan, Youzhen -- Ying, Qi-Long -- 1R01 RR025881/RR/NCRR NIH HHS/ -- R01 OD010926/OD/NIH HHS/ -- R01 RR025881/RR/NCRR NIH HHS/ -- R01 RR025881-01A2/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Sep 9;467(7312):211-3. doi: 10.1038/nature09368. Epub 2010 Aug 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20703227" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Culture Techniques ; Embryo, Mammalian/cytology ; Embryonic Stem Cells/*cytology ; Female ; Gene Knockout Techniques/*methods ; *Genes, p53 ; Germ-Line Mutation ; Male ; Mice ; Molecular Sequence Data ; Rats/*genetics ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Recombination, Genetic
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    ON and OFF pathways in Drosophila motion vision (2010)
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    Publication Date: 2010-11-12
    Description: Motion vision is a major function of all visual systems, yet the underlying neural mechanisms and circuits are still elusive. In the lamina, the first optic neuropile of Drosophila melanogaster, photoreceptor signals split into five parallel pathways, L1-L5. Here we examine how these pathways contribute to visual motion detection by combining genetic block and reconstitution of neural activity in different lamina cell types with whole-cell recordings from downstream motion-sensitive neurons. We find reduced responses to moving gratings if L1 or L2 is blocked; however, reconstitution of photoreceptor input to only L1 or L2 results in wild-type responses. Thus, the first experiment indicates the necessity of both pathways, whereas the second indicates sufficiency of each single pathway. This contradiction can be explained by electrical coupling between L1 and L2, allowing for activation of both pathways even when only one of them receives photoreceptor input. A fundamental difference between the L1 pathway and the L2 pathway is uncovered when blocking L1 or L2 output while presenting moving edges of positive (ON) or negative (OFF) contrast polarity: blocking L1 eliminates the response to moving ON edges, whereas blocking L2 eliminates the response to moving OFF edges. Thus, similar to the segregation of photoreceptor signals in ON and OFF bipolar cell pathways in the vertebrate retina, photoreceptor signals segregate into ON-L1 and OFF-L2 channels in the lamina of Drosophila.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joesch, Maximilian -- Schnell, Bettina -- Raghu, Shamprasad Varija -- Reiff, Dierk F -- Borst, Alexander -- England -- Nature. 2010 Nov 11;468(7321):300-4. doi: 10.1038/nature09545.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MPI for Neurobiology, Department of Systems and Computational Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21068841" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium Signaling/radiation effects ; Drosophila melanogaster/cytology/metabolism/*physiology/radiation effects ; Female ; Gap Junctions/metabolism/radiation effects ; Light ; Models, Neurological ; *Motion ; Motion Perception/*physiology/radiation effects ; Optic Lobe, Nonmammalian/cytology/physiology/radiation effects ; Photoreceptor Cells, Invertebrate/metabolism/radiation effects ; Vision, Ocular/*physiology/radiation effects ; Visual Pathways/cytology/*physiology/radiation effects
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    Protein-protein interactions: Interactome under construction (2010)
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    Publication Date: 2010-12-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonetta, Laura -- England -- Nature. 2010 Dec 9;468(7325):851-4. doi: 10.1038/468851a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21150998" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/diagnosis/metabolism/pathology ; Computational Biology ; Databases, Factual/trends ; False Negative Reactions ; False Positive Reactions ; Genes, Reporter ; Humans ; Immunoprecipitation ; Mass Spectrometry ; Protein Array Analysis ; Protein Binding ; Protein Interaction Mapping/*methods/*trends ; Proteome/genetics/metabolism ; Two-Hybrid System Techniques
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    The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4 (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-08
    Description: Eukaryotic DNA replication uses kinase regulatory pathways to facilitate coordination with other processes during cell division cycles and response to environmental cues. At least two cell cycle-regulated protein kinase systems, the S-phase-specific cyclin-dependent protein kinases (S-CDKs) and the Dbf4-Cdc7 kinase (DDK, Dbf4-dependent protein kinase) are essential activators for initiation of DNA replication. Although the essential mechanism of CDK activation of DNA replication in Saccharomyces cerevisiae has been established, exactly how DDK acts has been unclear. Here we show that the amino terminal serine/threonine-rich domain (NSD) of Mcm4 has both inhibitory and facilitating roles in DNA replication control and that the sole essential function of DDK is to relieve an inhibitory activity residing within the NSD. By combining an mcm4 mutant lacking the inhibitory activity with mutations that bypass the requirement for CDKs for initiation of DNA replication, we show that DNA synthesis can occur in G1 phase when CDKs and DDK are limited. However, DDK is still required for efficient S phase progression. In the absence of DDK, CDK phosphorylation at the distal part of the Mcm4 NSD becomes crucial. Moreover, DDK-null cells fail to activate the intra-S-phase checkpoint in the presence of hydroxyurea-induced DNA damage and are unable to survive this challenge. Our studies establish that the eukaryote-specific NSD of Mcm4 has evolved to integrate several protein kinase regulatory signals for progression through S phase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805463/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805463/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sheu, Yi-Jun -- Stillman, Bruce -- R01 GM045436/GM/NIGMS NIH HHS/ -- R01 GM045436-18/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jan 7;463(7277):113-7. doi: 10.1038/nature08647.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20054399" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/antagonists & inhibitors/chemistry/genetics/*metabolism ; Cell Proliferation/drug effects ; DNA Damage ; DNA-Binding Proteins/antagonists & inhibitors/chemistry/genetics/*metabolism ; G1 Phase/drug effects ; Genes, Essential ; Hydroxyurea/pharmacology ; Microbial Viability/drug effects ; Minichromosome Maintenance Complex Component 4 ; Phosphorylation ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; S Phase/drug effects/*physiology ; Saccharomyces cerevisiae/*cytology/enzymology/growth & development/*metabolism ; Saccharomyces cerevisiae Proteins/antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Sequence Deletion ; Substrate Specificity
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    Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-22
    Description: Two forms of X-chromosome inactivation (XCI) ensure the selective silencing of female sex chromosomes during mouse embryogenesis. Imprinted XCI begins with the detection of Xist RNA expression on the paternal X chromosome (Xp) at about the four-cell stage of embryonic development. In the embryonic tissues of the inner cell mass, a random form of XCI occurs in blastocysts that inactivates either Xp or the maternal X chromosome (Xm). Both forms of XCI require the non-coding Xist RNA that coats the inactive X chromosome from which it is expressed. Xist has crucial functions in the silencing of X-linked genes, including Rnf12 (refs 3, 4) encoding the ubiquitin ligase RLIM (RING finger LIM-domain-interacting protein). Here we show, by targeting a conditional knockout of Rnf12 to oocytes where RLIM accumulates to high levels, that the maternal transmission of the mutant X chromosome (Deltam) leads to lethality in female embryos as a result of defective imprinted XCI. We provide evidence that in Deltam female embryos the initial formation of Xist clouds and Xp silencing are inhibited. In contrast, embryonic stem cells lacking RLIM are able to form Xist clouds and silence at least some X-linked genes during random XCI. These results assign crucial functions to the maternal deposit of Rnf12/RLIM for the initiation of imprinted XCI.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967734/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967734/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shin, Jongdae -- Bossenz, Michael -- Chung, Young -- Ma, Hong -- Byron, Meg -- Taniguchi-Ishigaki, Naoko -- Zhu, Xiaochun -- Jiao, Baowei -- Hall, Lisa L -- Green, Michael R -- Jones, Stephen N -- Hermans-Borgmeyer, Irm -- Lawrence, Jeanne B -- Bach, Ingolf -- 5 P30 DK32520/DK/NIDDK NIH HHS/ -- DK32520/DK/NIDDK NIH HHS/ -- GM053234/GM/NIGMS NIH HHS/ -- R01 CA131158/CA/NCI NIH HHS/ -- R01 CA131158-04/CA/NCI NIH HHS/ -- R01 GM033977/GM/NIGMS NIH HHS/ -- R01 GM053234/GM/NIGMS NIH HHS/ -- R01CA131158/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Oct 21;467(7318):977-81. doi: 10.1038/nature09457.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Gene Function and Expression, University of Massachusetts Medical School (UMMS), Worcester, Massachusetts 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20962847" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Congenic ; Blastocyst/metabolism ; Cell Line ; Chromosomes, Mammalian/*genetics ; Embryo Loss/genetics ; Fathers ; Female ; Gene Silencing ; *Genomic Imprinting ; Male ; Mice ; Mice, Transgenic ; *Mothers ; RNA, Long Noncoding ; RNA, Untranslated/genetics ; Repressor Proteins/deficiency/genetics/*metabolism ; Ubiquitin-Protein Ligases ; X Chromosome/*genetics ; X Chromosome Inactivation/*genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Haematopoietic stem cells derive directly from aortic endothelium during development (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-16
    Description: A major goal of regenerative medicine is to instruct formation of multipotent, tissue-specific stem cells from induced pluripotent stem cells (iPSCs) for cell replacement therapies. Generation of haematopoietic stem cells (HSCs) from iPSCs or embryonic stem cells (ESCs) is not currently possible, however, necessitating a better understanding of how HSCs normally arise during embryonic development. We previously showed that haematopoiesis occurs through four distinct waves during zebrafish development, with HSCs arising in the final wave in close association with the dorsal aorta. Recent reports have suggested that murine HSCs derive from haemogenic endothelial cells (ECs) lining the aortic floor. Additional in vitro studies have similarly indicated that the haematopoietic progeny of ESCs arise through intermediates with endothelial potential. Here we have used the unique strengths of the zebrafish embryo to image directly the generation of HSCs from the ventral wall of the dorsal aorta. Using combinations of fluorescent reporter transgenes, confocal time-lapse microscopy and flow cytometry, we have identified and isolated the stepwise intermediates as aortic haemogenic endothelium transitions to nascent HSCs. Finally, using a permanent lineage tracing strategy, we demonstrate that the HSCs generated from haemogenic endothelium are the lineal founders of the adult haematopoietic system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858358/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858358/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bertrand, Julien Y -- Chi, Neil C -- Santoso, Buyung -- Teng, Shutian -- Stainier, Didier Y R -- Traver, David -- DK074482/DK/NIDDK NIH HHS/ -- F32DK752433/DK/NIDDK NIH HHS/ -- HL074891/HL/NHLBI NIH HHS/ -- HL54737/HL/NHLBI NIH HHS/ -- R01 DK074482/DK/NIDDK NIH HHS/ -- R01 DK074482-04/DK/NIDDK NIH HHS/ -- England -- Nature. 2010 Mar 4;464(7285):108-11. doi: 10.1038/nature08738. Epub 2010 Feb 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0380, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20154733" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Aorta/*cytology/*embryology ; *Cell Differentiation ; *Cell Lineage ; Cell Separation ; Endothelial Cells/cytology ; Endothelium, Vascular/*cytology/embryology ; Female ; Flow Cytometry ; Genes, Reporter/genetics ; Hematopoietic Stem Cells/*cytology ; Male ; Microscopy, Confocal ; Microscopy, Fluorescence ; Transgenes/genetics ; Zebrafish/blood/*embryology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Twin study surveys genome for cause of multiple sclerosis (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-04-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Katsnelson, Alla -- England -- Nature. 2010 Apr 29;464(7293):1259. doi: 10.1038/4641259a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20428135" target="_blank"〉PubMed〈/a〉
    Keywords: Diseases in Twins/*genetics ; *Environment ; Epigenesis, Genetic/genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genome, Human/*genetics ; Humans ; Multiple Sclerosis/*etiology/*genetics ; Sequence Analysis, DNA ; *Twin Studies as Topic
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Metabolic disorders: Fathers' nutritional legacy (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Skinner, Michael K -- England -- Nature. 2010 Oct 21;467(7318):922-3. doi: 10.1038/467922a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20962833" target="_blank"〉PubMed〈/a〉
    Keywords: Adiposity/drug effects ; Animals ; Body Weight/drug effects ; DNA Methylation ; Diabetes Mellitus, Type 2/etiology/genetics/pathology/physiopathology ; Diet/*adverse effects ; Dietary Fats/*administration & dosage/*adverse effects ; Epigenesis, Genetic/drug effects ; *Fathers ; Female ; Gene Expression Profiling ; Glucose Intolerance/etiology/pathology/physiopathology ; Insulin/secretion ; Insulin-Secreting Cells/metabolism/*pathology/secretion ; Male ; Obesity/etiology/genetics/pathology/physiopathology ; Paternal Exposure/*adverse effects ; Rats ; Spermatozoa/drug effects/metabolism
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    Drug discovery: Pulled from a protein's embrace (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jorgensen, William L -- England -- Nature. 2010 Jul 1;466(7302):42-3. doi: 10.1038/466042a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20596009" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; *Computer-Aided Design ; Drug Design ; Drug Discovery/*methods ; Enzyme Inhibitors/*chemistry/*metabolism ; Flavonoids/chemistry/metabolism ; Ligands ; Luteolin/chemistry/metabolism ; Molecular Dynamics Simulation ; Plasmodium falciparum ; Protein Binding ; Protozoan Proteins/chemistry/metabolism ; Thermodynamics
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    Promiscuity and the evolutionary transition to complex societies (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-08-21
    Description: Theory predicts that the evolution of cooperative behaviour is favoured by low levels of promiscuity leading to high within-group relatedness. However, in vertebrates, cooperation often occurs between non-relatives and promiscuity rates are among the highest recorded. Here we resolve this apparent inconsistency with a phylogenetic analysis of 267 bird species, demonstrating that cooperative breeding is associated with low promiscuity; that in cooperative species, helping is more common when promiscuity is low; and that intermediate levels of promiscuity favour kin discrimination. Overall, these results suggest that promiscuity is a unifying feature across taxa in explaining transitions to and from cooperative societies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cornwallis, Charlie K -- West, Stuart A -- Davis, Katie E -- Griffin, Ashleigh S -- England -- Nature. 2010 Aug 19;466(7309):969-72. doi: 10.1038/nature09335.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Edward Grey Institute, Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20725039" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Birds/classification/genetics/*physiology ; *Cooperative Behavior ; Fathers ; Female ; Male ; Models, Biological ; Mothers ; Phylogeny ; Reproduction/genetics/physiology ; Sexual Behavior, Animal/*physiology ; *Siblings
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    Ageing: rushed decisions (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-03-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shadan, Sadaf -- England -- Nature. 2008 Mar 6;452(7183):39. doi: 10.1038/452039a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18322520" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Cell Differentiation ; Cell Lineage ; Child, Preschool ; Female ; Humans ; Lamin Type A ; Mesenchymal Stromal Cells/pathology ; Nuclear Proteins/genetics/metabolism ; Progeria/metabolism/*pathology/*physiopathology ; Protein Precursors/genetics/metabolism
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    Live birth in the Devonian period (2008)
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    Publication Date: 2008-05-30
    Description: The extinct placoderm fishes were the dominant group of vertebrates throughout the Middle Palaeozoic era, yet controversy about their relationships within the gnathostomes (jawed vertebrates) is partly due to different interpretations of their reproductive biology. Here we document the oldest record of a live-bearing vertebrate in a new ptyctodontid placoderm, Materpiscis attenboroughi gen. et sp. nov., from the Late Devonian Gogo Formation of Australia (approximately 380 million years ago). The new specimen, remarkably preserved in three dimensions, contains a single, intra-uterine embryo connected by a permineralized umbilical cord. An amorphous crystalline mass near the umbilical cord possibly represents the recrystallized yolk sac. Another ptyctodont from the Gogo Formation, Austroptyctodus gardineri, also shows three small embryos inside it in the same position. Ptyctodontids have already provided the oldest definite evidence for vertebrate copulation, and the new specimens confirm that some placoderms had a remarkably advanced reproductive biology, comparable to that of some modern sharks and rays. The new discovery points to internal fertilization and viviparity in vertebrates as originating earliest within placoderms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Long, John A -- Trinajstic, Kate -- Young, Gavin C -- Senden, Tim -- England -- Nature. 2008 May 29;453(7195):650-2. doi: 10.1038/nature06966.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Museum Victoria, Melbourne, PO Box 666, Melbourne 3001, Australia. jlong@museum.vic.gov.au〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18509443" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Australia ; Biological Evolution ; Female ; Fishes/classification/*embryology/*physiology ; *Fossils ; History, Ancient ; Microscopy, Electron, Scanning ; Viviparity, Nonmammalian/*physiology
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    Pyruvate kinase M2 is a phosphotyrosine-binding protein (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-03-14
    Description: Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Christofk, Heather R -- Vander Heiden, Matthew G -- Wu, Ning -- Asara, John M -- Cantley, Lewis C -- R01 GM056203/GM/NIGMS NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- England -- Nature. 2008 Mar 13;452(7184):181-6. doi: 10.1038/nature06667.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337815" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Site ; Animals ; Catalysis ; Cell Line ; Cell Proliferation/drug effects ; Cells/drug effects/metabolism ; HeLa Cells ; Humans ; Lysine/metabolism ; Models, Molecular ; Peptide Library ; Phosphotyrosine/*metabolism ; Protein Binding ; Proteomics ; Pyruvate Kinase/antagonists & inhibitors/*metabolism ; Substrate Specificity
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    Stem cells: stuck in New Jersey (2008)
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    Publication Date: 2008-02-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wadman, Meredith -- England -- Nature. 2008 Feb 7;451(7179):622-6. doi: 10.1038/451622a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18256640" target="_blank"〉PubMed〈/a〉
    Keywords: Academies and Institutes/economics/legislation & jurisprudence ; Female ; Humans ; New Jersey ; *Politics ; Research Embryo Creation/economics/legislation & jurisprudence ; *State Government ; *Stem Cells
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    The cost of silence? (2008)
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    Publication Date: 2008-12-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Dec 4;456(7222):545. doi: 10.1038/456545a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052574" target="_blank"〉PubMed〈/a〉
    Keywords: Acquired Immunodeficiency Syndrome/drug therapy/*epidemiology/*mortality ; Anti-HIV Agents/*supply & distribution ; Child ; *Federal Government ; Female ; Humans ; Politics ; Pregnancy ; *Public Policy ; South Africa/epidemiology
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