Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study

OBJECTIVES: We conducted a genome-wide association study to explore whether common host genetic variants (>5% frequency) were associated with presence of virus able to use CXCR4 for entry. METHODS: Phenotypic determination of human immunodeficiency virus (HIV)-1 coreceptor usage was performed on pretreatment plasma HIV-1 samples from treatment-naive participants in AIDS Clinical Trials Group A5095, a study of initial antiretroviral regimens. Associations between genome-wide single-nucleotide polymorphisms (SNPs), CCR5 Δ32 genotype, and human leukocyte antigen (HLA) class I alleles and viral coreceptor usage were explored. RESULTS: Viral phenotypes were obtained from 593 patients with available genome-wide SNP data. Forty-four percent of subjects had virus capable of using CXCR4 for entry as determined by phenotyping. Overall, no associations, including those between polymorphisms in genes encoding viral coreceptors and their promoter regions or in HLA genes previously associated with HIV-1 disease progression, passed the statistical threshold for genome-wide significance (P < 5.0 × 10(-8)) in any comparison. However, the presence of viruses able to use CXCR4 for entry was marginally associated with the CCR5 Δ32 genotype in the nongenome-wide analysis. CONCLUSIONS: No human genetic variants were significantly associated with virus able to use CXCR4 for entry at the genome-wide level. Although the sample size had limited power to definitively exclude genetic associations, these results suggest that host genetic factors, including those that influence coreceptor expression or the immune pressures leading to viral envelope diversity, are either rare or have only modest effects in determining HIV-1 coreceptor usage

Ice sheets as a missing source of silica to the polar oceans

Ice sheets play a more important role in the global silicon cycle than previously appreciated. Input of dissolved and amorphous particulate silica into natural waters stimulates the growth of diatoms. Here we measure dissolved and amorphous silica in Greenland Ice Sheet meltwaters and icebergs, demonstrating the potential for high ice sheet export. Our dissolved and amorphous silica flux is 0.20 (0.06-0.79) Tmol year(-1), ∼50% of the input from Arctic rivers. Amorphous silica comprises >95% of this flux and is highly soluble in sea water, as indicated by a significant increase in dissolved silica across a fjord salinity gradient. Retreating palaeo ice sheets were therefore likely responsible for high dissolved and amorphous silica fluxes into the ocean during the last deglaciation, reaching values of ∼5.5 Tmol year(-1), similar to the estimated export from palaeo rivers. These elevated silica fluxes may explain high diatom productivity observed during the last glacial-interglacial period

Effects of Alcohol on the Acquisition and Expression of Fear Potentiated Startle in Mouse Lines Selectively Bred for High and Low Alcohol Preference

Rationale: Anxiety disorders and alcohol-use disorders frequently co-occur in humans perhaps because alcohol relieves anxiety. Studies in humans and rats indicate that alcohol may have greater anxiolytic effects in organisms with increased genetic propensity for high alcohol consumption. Objectives and Methods: The purpose of this study was to investigate the effects of moderate doses of alcohol (0.5, 1.0, 1.5 g/kg) on the acquisition and expression of anxiety-related behavior using a fear-potentiated startle (FPS) procedure. Experiments were conducted in two replicate pairs of mouse lines selectively bred for high- (HAP1 and HAP2) and low- (LAP1 and LAP2) alcohol preference; these lines have previously shown a genetic correlation between alcohol preference and FPS (HAP\u3eLAP; Barrenha and Chester 2007). In a control experiment, the effect of diazepam (4.0 mg/kg) on the expression of FPS was tested in HAP2 and LAP2 mice. Results: The 1.5 g/kg alcohol dose moderately decreased the expression of FPS in both HAP lines but not LAP lines. Alcohol had no effect on the acquisition of FPS in any line. Diazepam reduced FPS to a similar extent in both HAP2 and LAP2 mice. Conclusions: HAP mice may be more sensitive to the anxiolytic effects of alcohol than LAP mice when alcohol is given prior to the expression of FPS. These data collected in two pairs of HAP/LAP mouse lines suggest that the anxiolytic response to alcohol in HAP mice may be genetically correlated with their propensity toward high alcohol preference and robust FPS

Genome-wide gene expression analysis supports a developmental model of low temperature tolerance gene regulation in wheat (Triticum aestivum L.)

<p>Abstract</p> <p>Background</p> <p>To identify the genes involved in the development of low temperature (LT) tolerance in hexaploid wheat, we examined the global changes in expression in response to cold of the 55,052 potentially unique genes represented in the Affymetrix Wheat Genome microarray. We compared the expression of genes in winter-habit (winter Norstar and winter Manitou) and spring-habit (spring Manitou and spring Norstar)) cultivars, wherein the locus for the vernalization gene <it>Vrn-A1 </it>was swapped between the parental winter Norstar and spring Manitou in the derived near-isogenic lines winter Manitou and spring Norstar. Global expression of genes in the crowns of 3-leaf stage plants cold-acclimated at 6°C for 0, 2, 14, 21, 38, 42, 56 and 70 days was examined.</p> <p>Results</p> <p>Analysis of variance of gene expression separated the samples by genetic background and by the developmental stage before or after vernalization saturation was reached. Using gene-specific ANOVA we identified 12,901 genes (at <it>p </it>< 0.001) that change in expression with respect to both genotype and the duration of cold-treatment. We examined in more detail a subset of these genes (2,771) where expression was highly influenced by the interaction between these two main factors. Functional assignments using GO annotations showed that genes involved in transport, oxidation-reduction, and stress response were highly represented. Clustering based on the pattern of transcript accumulation identified genes that were up or down-regulated by cold-treatment. Our data indicate that the cold-sensitive lines can up-regulate known cold-responsive genes comparable to that of cold-hardy lines. The levels of expression of these genes were highly influenced by the initial rate and the duration of the gene's response to cold. We show that the <it>Vrn-A1 </it>locus controls the duration of gene expression but not its initial rate of response to cold treatment. Furthermore, we provide evidence that <it>Ta.Vrn-A1 </it>and <it>Ta.Vrt1 </it>originally hypothesized to encode for the same gene showed different patterns of expression and therefore are distinct.</p> <p>Conclusion</p> <p>This study provides novel insight into the underlying mechanisms that regulate the expression of cold-responsive genes in wheat. The results support the developmental model of LT tolerance gene regulation and demonstrate the complex genotype by environment interactions that determine LT adaptation in winter annual cereals.</p

Development of a Model System to Identify Differences in Spring and Winter Oat

Our long-term goal is to develop a Swedish winter oat (Avena sativa). To identify molecular differences that correlate with winter hardiness, a winter oat model comprising of both non-hardy spring lines and winter hardy lines is needed. To achieve this, we selected 294 oat breeding lines, originating from various Russian, German, and American winter oat breeding programs and tested them in the field in south- and western Sweden. By assaying for winter survival and agricultural properties during four consecutive seasons, we identified 14 breeding lines of different origins that not only survived the winter but also were agronomically better than the rest. Laboratory tests including electrolytic leakage, controlled crown freezing assay, expression analysis of the AsVrn1 gene and monitoring of flowering time suggested that the American lines had the highest freezing tolerance, although the German lines performed better in the field. Finally, six lines constituting the two most freezing tolerant lines, two intermediate lines and two spring cultivars were chosen to build a winter oat model system. Metabolic profiling of non-acclimated and cold acclimated leaf tissue samples isolated from the six selected lines revealed differential expression patterns of 245 metabolites including several sugars, amino acids, organic acids and 181 hitherto unknown metabolites. The expression patterns of 107 metabolites showed significant interactions with either a cultivar or a time-point. Further identification, characterisation and validation of these metabolites will lead to an increased understanding of the cold acclimation process in oats. Furthermore, by using the winter oat model system, differential sequencing of crown mRNA populations would lead to identification of various biomarkers to facilitate winter oat breeding

The impact of regular physical activity on fatigue, depression and quality of life in persons with multiple sclerosis

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to compare fatigue, depression and quality of life scores in persons with multiple sclerosis who do (Exercisers) and do not (Non-exercisers) regularly participate in physical activity.</p> <p>Methods</p> <p>A cross-sectional questionnaire study of 121 patients with MS (age 25–65 yr) living in Queensland, Australia was conducted. Physical activity level, depression, fatigue and quality of life were assessed using the International Physical Activity Questionnaire, Health Status Questionnaire Short Form 36, Becks Depression Inventory and Modified Fatigue Impact Scale.</p> <p>Results</p> <p>52 participants performed at least two 30-min exercise sessions·wk^-1(Exercisers) and 69 did not participate in regular physical activity (Non-exercisers). Exercisers reported favourable fatigue, depression and quality of life scores when compared to Non-exercisers. Significant weak correlations were found between both leisure-time and overall reported physical activity levels and some subscales of the quality of life and fatigue questionnaires. Additionally, some quality of life subscale scores indicated that regular physical activity had a greater benefit in subjects with moderate MS.</p> <p>Conclusion</p> <p>Favourable fatigue, depression and quality of life scores were reported by persons with MS who regularly participated in physical activity, when compared to persons with MS who were classified as Non-exercisers.</p

SHIV-162P3 Infection of Rhesus Macaques Given Maraviroc Gel Vaginally Does Not Involve Resistant Viruses

Maraviroc (MVC) gels are effective at protecting rhesus macaques from vaginal SHIV transmission, but breakthrough infections can occur. To determine the effects of a vaginal MVC gel on infecting SHIV populations in a macaque model, we analyzed plasma samples from three rhesus macaques that received a MVC vaginal gel (day 0) but became infected after high-dose SHIV-162P3 vaginal challenge. Two infected macaques that received a placebo gel served as controls. The infecting SHIV-162P3 stock had an overall mean genetic distance of 0.294±0.027%; limited entropy changes were noted across the envelope (gp160). No envelope mutations were observed consistently in viruses isolated from infected macaques at days 14–21, the time of first detectable viremia, nor selected at later time points, days 42–70. No statistically significant differences in MVC susceptibilities were observed between the SHIV inoculum (50% inhibitory concentration [IC50] 1.87 nM) and virus isolated from the three MVC-treated macaques (MVC IC50 1.18 nM, 1.69 nM, and 1.53 nM, respectively). Highlighter plot analyses suggested that infection was established in each MVC-treated animal by one founder virus genotype. The expected Poisson distribution of pairwise Hamming Distance frequency counts was observed and a phylogenetic analysis did not identify infections with distinct lineages from the challenge stock. These data suggest that breakthrough infections most likely result from incomplete viral inhibition and not the selection of MVC-resistant variants

Natural anti-CCR5 antibodies in HIV-infection and -exposure

Natural antibodies constitute a first-line of defence against pathogens; they may also play other roles in immune regulation and homeostasis, through their ability to bind host antigens, surface molecules and receptors. Natural anti-CCR5 antibodies can be decisive in preventing HIV infection in mucosal tissues and offer prompt and effective protection just at major sites of virus entry. Among natural anti-CCR5 antibodies, IgG and IgA to the ECL1 domain have been shown to block HIV effectively and durably without causing harm to the host. Their biological properties and their uncommon generation in subsets of HIV-infected and HIV-exposed individuals (so called ESN) will be introduced and discussed, with the aim at exploiting their potential in therapy and prevention

Heavy and light roles: myosin in the morphogenesis of the heart

Myosin is an essential component of cardiac muscle, from the onset of cardiogenesis through to the adult heart. Although traditionally known for its role in energy transduction and force development, recent studies suggest that both myosin heavy-chain and myosin lightchain proteins are required for a correctly formed heart. Myosins are structural proteins that are not only expressed from early stages of heart development, but when mutated in humans they may give rise to congenital heart defects. This review will discuss the roles of myosin, specifically with regards to the developing heart. The expression of each myosin protein will be described, and the effects that altering expression has on the heart in embryogenesis in different animal models will be discussed. The human molecular genetics of the myosins will also be reviewed

Interaction of Temperature and Light in the Development of Freezing Tolerance in Plants

Abstract Freezing tolerance is the result of a wide range of physical and biochemical processes, such as the induction of antifreeze proteins, changes in membrane composition, the accumulation of osmoprotectants, and changes in the redox status, which allow plants to function at low temperatures. Even in frost-tolerant species, a certain period of growth at low but nonfreezing temperatures, known as frost or cold hardening, is required for the development of a high level of frost hardiness. It has long been known that frost hardening at low temperature under low light intensity is much less effective than under normal light conditions; it has also been shown that elevated light intensity at normal temperatures may partly replace the cold-hardening period. Earlier results indicated that cold acclimation reflects a response to a chloroplastic redox signal while the effects of excitation pressure extend beyond photosynthetic acclimation, influencing plant morphology and the expression of certain nuclear genes involved in cold acclimation. Recent results have shown that not only are parameters closely linked to the photosynthetic electron transport processes affected by light during hardening at low temperature, but light may also have an influence on the expression level of several other cold-related genes; several cold-acclimation processes can function efficiently only in the presence of light. The present review provides an overview of mechanisms that may explain how light improves the freezing tolerance of plants during the cold-hardening period