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21.
Robert W. Buckheit III Maria Salgado Karen O. Martins Joel N. Blankson 《Cellular and molecular life sciences : CMLS》2013,70(6):1009-1019
The mechanisms by which a small percentage of HIV-1 infected individuals known as elite suppressors or controllers are able to control viral replication are not fully understood. Early cases of viremic control were attributed to infection with defective virus, but subsequent work has demonstrated that infection with a defective virus is not the exclusive cause of control. Replication-competent virus has been isolated from patients who control viral replication, and studies have demonstrated that evolution occurs in plasma virus but not in virus isolates from the latent reservoir. Additionally, transmission pair studies have demonstrated that patients infected with similar viruses can have dramatically different outcomes of infection. An increased understanding of the viral factors associated with control is important to understand the interplay between viral replication and host control, and has implications for the design of an effective therapeutic vaccine that can lead to a functional cure of HIV-1 infection. 相似文献
22.
Campbell CD Ogburn EL Lunetta KL Lyon HN Freedman ML Groop LC Altshuler D Ardlie KG Hirschhorn JN 《Nature genetics》2005,37(8):868-872
Population stratification occurs in case-control association studies when allele frequencies differ between cases and controls because of ancestry. Stratification may lead to false positive associations, although this issue remains controversial. Empirical studies have found little evidence of stratification in European-derived populations, but potentially significant levels of stratification could not be ruled out. We studied a European American panel discordant for height, a heritable trait that varies widely across Europe. Genotyping 178 SNPs and applying standard analytical methods yielded no evidence of stratification. But a SNP in the gene LCT that varies widely in frequency across Europe was strongly associated with height (P < 10(-6)). This apparent association was largely or completely due to stratification; rematching individuals on the basis of European ancestry greatly reduced the apparent association, and no association was observed in Polish or Scandinavian individuals. The failure of standard methods to detect this stratification indicates that new methods may be required. 相似文献
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Genome sequencing in microfabricated high-density picolitre reactors 总被引:21,自引:0,他引:21
Margulies M Egholm M Altman WE Attiya S Bader JS Bemben LA Berka J Braverman MS Chen YJ Chen Z Dewell SB Du L Fierro JM Gomes XV Godwin BC He W Helgesen S Ho CH Ho CH Irzyk GP Jando SC Alenquer ML Jarvie TP Jirage KB Kim JB Knight JR Lanza JR Leamon JH Lefkowitz SM Lei M Li J Lohman KL Lu H Makhijani VB McDade KE McKenna MP Myers EW Nickerson E Nobile JR Plant R Puc BP Ronan MT Roth GT Sarkis GJ Simons JF Simpson JW Srinivasan M Tartaro KR Tomasz A Vogt KA Volkmer GA Wang SH Wang Y Weiner MP 《Nature》2005,437(7057):376-380
The proliferation of large-scale DNA-sequencing projects in recent years has driven a search for alternative methods to reduce time and cost. Here we describe a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, we have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. Here we show the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembly of the Mycoplasma genitalium genome with 96% coverage at 99.96% accuracy in one run of the machine. 相似文献
26.
Joel S. Schwartz 《Annals of science》2013,70(6):631-637
While Charles Darwin wrote his Observations on South America, he often sought the advice and help of other scientists in solving specific problems. Three letters that the Cambridge geologist and mathematician William Hopkins wrote to Darwin exemplify such aid. In these letters Hopkins was able to show Darwin how he could calculate the position of the sedimentary beds on the Chonos Archipelago, which Darwin had visited. In his first letter Hopkins sent a solution, part of which eluded Darwin. Darwin's letters to Hopkins have not yet been found, but two additional letters gave Darwin the solution he was looking for. 相似文献
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Andrew Brighouse Joel B. Dacks Mark C. Field 《Cellular and molecular life sciences : CMLS》2010,67(20):3449-3465
Spectacular increases in the quantity of sequence data genome have facilitated major advances in eukaryotic comparative genomics.
By exploiting homology with classical model organisms, this makes possible predictions of pathways and cellular functions
currently impossible to address in intractable organisms. Echoing realization that core metabolic processes were established
very early following evolution of life on earth, it is now emerging that many eukaryotic cellular features, including the
endomembrane system, are ancient and organized around near-universal principles. Rab proteins are key mediators of vesicle
transport and specificity, and via the presence of multiple paralogues, alterations in interaction specificity and modification
of pathways, contribute greatly to the evolution of complexity of membrane transport. Understanding system-level contributions
of Rab proteins to evolutionary history provides insight into the multiple processes sculpting cellular transport pathways
and the exciting challenges that we face in delving further into the origins of membrane trafficking specificity. 相似文献
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At some point during the 1950s, mainstream American philosophy of science began increasingly to avoid questions about the role of non-cognitive values in science and, accordingly, increasingly to avoid active engagement with social, political and moral concerns. Such questions and engagement eventually ceased to be part of the mainstream. Here we show that the eventual dominance of ‘value-free’ philosophy of science can be attributed, at least in part, to the policies of the U.S. National Science Foundation's “History and Philosophy of Science” sub-program. In turn, the sub-program's policies were set by logical empiricists who espoused value-free philosophy of science; these philosophers' actions, we also point out, fit a broad pattern, one in which analytic philosophers used institutional control to marginalize rival approaches to philosophy. We go on to draw on existing knowledge of this pattern to suggest two further, similar, contributors to the withdrawal from value-laden philosophy of science, namely decisions by the editors of Philosophy of Science and by the editors of The Journal of Philosophy. Political climate was, we argue, at most an indirect contributor to the withdrawal and was neither a factor that decided whether it occurred nor one that was sufficient to bring it about. Moreover, we argue that the actions at the National Science Foundation went beyond what was required by its senior administrators and are better viewed as part of what drove, rather than as what was being driven by, the adoption of logical empiricism by the philosophy of science community. 相似文献
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The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in beta-cells in vivo are not understood. Here we show that mice with a beta-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased beta-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, beta-cells lacking Cnb1 have a reduced expression of established regulators of beta-cell proliferation. Conditional expression of active NFATc1 in Cnb1-deficient beta-cells rescues these defects and prevents diabetes. In normal adult beta-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases beta-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for beta-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark beta-cell functions, revealing unique models for the pathogenesis and therapy of diabetes. 相似文献