147 research outputs found

    Extreme genetic fragility of the HIV-1 capsid

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    Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

    Search for Kaluza-Klein Graviton Emission in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV using the Missing Energy Signature

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    We report on a search for direct Kaluza-Klein graviton production in a data sample of 84 pb1{pb}^{-1} of \ppb collisions at s\sqrt{s} = 1.8 TeV, recorded by the Collider Detector at Fermilab. We investigate the final state of large missing transverse energy and one or two high energy jets. We compare the data with the predictions from a 3+1+n3+1+n-dimensional Kaluza-Klein scenario in which gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for nn=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71 TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure

    Measurement of the average time-integrated mixing probability of b-flavored hadrons produced at the Tevatron

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    We have measured the number of like-sign (LS) and opposite-sign (OS) lepton pairs arising from double semileptonic decays of bb and bˉ\bar{b}-hadrons, pair-produced at the Fermilab Tevatron collider. The data samples were collected with the Collider Detector at Fermilab (CDF) during the 1992-1995 collider run by triggering on the existence of μμ\mu \mu and eμe \mu candidates in an event. The observed ratio of LS to OS dileptons leads to a measurement of the average time-integrated mixing probability of all produced bb-flavored hadrons which decay weakly, χˉ=0.152±0.007\bar{\chi} = 0.152 \pm 0.007 (stat.) ±0.011\pm 0.011 (syst.), that is significantly larger than the world average χˉ=0.118±0.005\bar{\chi} = 0.118 \pm 0.005.Comment: 47 pages, 10 figures, 15 tables Submitted to Phys. Rev.

    The Steady State Great Ape? Long Term Isotopic Records Reveal the Effects of Season, Social Rank and Reproductive Status on Bonobo Feeding Behavior

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    Dietary ecology of extant great apes is known to respond to environmental conditions such as climate and food availability, but also to vary depending on social status and life history characteristics. Bonobos (Pan paniscus) live under comparatively steady ecological conditions in the evergreen rainforests of the Congo Basin. Bonobos are an ideal species for investigating influences of sociodemographic and physiological factors, such as female reproductive status, on diet. We investigate the long term dietary pattern in wild but fully habituated bonobos by stable isotope analysis in hair and integrating a variety of long-term sociodemographic information obtained through observations. We analyzed carbon and nitrogen stable isotopes in 432 hair sections obtained from 101 non-invasively collected hair samples. These samples represented the dietary behavior of 23 adult bonobos from 2008 through 2010. By including isotope and crude protein data from plants we could establish an isotope baseline and interpret the results of several general linear mixed models using the predictors climate, sex, social rank, reproductive state of females, adult age and age of infants. We found that low canopy foliage is a useful isotopic tracer for tropical rainforest settings, and consumption of terrestrial herbs best explains the temporal isotope patterns we found in carbon isotope values of bonobo hair. Only the diet of male bonobos was affected by social rank, with lower nitrogen isotope values in low-ranking young males. Female isotope values mainly differed between different stages of reproduction (cycling, pregnancy, lactation). These isotopic differences appear to be related to changes in dietary preference during pregnancy (high protein diet) and lactation (high energy diet), which allow to compensate for different nutritional needs during maternal investment

    Gene targeting in adult rhesus macaque fibroblasts

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    <p>Abstract</p> <p>Background</p> <p>Gene targeting in nonhuman primates has the potential to produce critical animal models for translational studies related to human diseases. Successful gene targeting in fibroblasts followed by somatic cell nuclear transfer (SCNT) has been achieved in several species of large mammals but not yet in primates. Our goal was to establish the protocols necessary to achieve gene targeting in primary culture of adult rhesus macaque fibroblasts as a first step in creating nonhuman primate models of genetic disease using nuclear transfer technology.</p> <p>Results</p> <p>A primary culture of adult male fibroblasts was transfected with hTERT to overcome senescence and allow long term <it>in vitro </it>manipulations. Successful gene targeting of the HPRT locus in rhesus macaques was achieved by electroporating S-phase synchronized cells with a construct containing a SV40 enhancer.</p> <p>Conclusion</p> <p>The cell lines reported here could be used for the production of null mutant rhesus macaque models of human genetic disease using SCNT technology. In addition, given the close evolutionary relationship and biological similarity between rhesus macaques and humans, the protocols described here may prove useful in the genetic engineering of human somatic cells.</p

    Ulnar-sided wrist pain. Part I: anatomy and physical examination

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    Ulnar-sided wrist pain is a common complaint, and it presents a diagnostic challenge for hand surgeons and radiologists. The complex anatomy of this region, combined with the small size of structures and subtle imaging findings, compound this problem. A thorough understanding of ulnar-sided wrist anatomy and a systematic clinical examination of this region are essential in arriving at an accurate diagnosis. In part I of this review, ulnar-sided wrist anatomy and clinical examination are discussed for a more comprehensive understanding of ulnar-sided wrist pain

    Molecular Evolution of the Primate Antiviral Restriction Factor Tetherin

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    Background: Tetherin is a recently identified antiviral restriction factor that restricts HIV-1 particle release in the absence of the HIV-1 viral protein U (Vpu). It is reminiscent of APOBEC3G and TRIM5a that also antagonize HIV. APOBEC3G and TRIM5a have been demonstrated to evolve under pervasive positive selection throughout primate evolution, supporting the redqueen hypothesis. Therefore, one naturally presumes that Tetherin also evolves under pervasive positive selection throughout primate evolution and supports the red-queen hypothesis. Here, we performed a detailed evolutionary analysis to address this presumption. Methodology/Principal Findings: Results of non-synonymous and synonymous substitution rates reveal that Tetherin as a whole experiences neutral evolution rather than pervasive positive selection throughout primate evolution, as well as in non-primate mammal evolution. Sliding-window analyses show that the regions of the primate Tetherin that interact with viral proteins are under positive selection or relaxed purifying selection. In particular, the sites identified under positive selection generally focus on these regions, indicating that the main selective pressure acting on the primate Tetherin comes from virus infection. The branch-site model detected positive selection acting on the ancestral branch of the New World Monkey lineage, suggesting an episodic adaptive evolution. The positive selection was also found in duplicated Tetherins in ruminants. Moreover, there is no bias in the alterations of amino acids in the evolution of the primate Tetherin, implyin
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