In Vivo validation of a bioinformatics based tool to identify reduced replication capacity in HIV-1.

Although antiretroviral drug resistance is common in treated HIV infected individuals, it is not a consistent indicator of HIV morbidity and mortality. To the contrary, HIV resistance-associated mutations may lead to changes in viral fitness that are beneficial to infected individuals. Using a bioinformatics-based model to assess the effects of numerous drug resistance mutations, we determined that the D30N mutation in HIV-1 protease had the largest decrease in replication capacity among known protease resistance mutations. To test this in silico result in an in vivo environment, we constructed several drug-resistant mutant HIV-1 strains and compared their relative fitness utilizing the SCID-hu mouse model. We found HIV-1 containing the D30N mutation had a significant defect in vivo, showing impaired replication kinetics and a decreased ability to deplete CD4+ thymocytes, compared to the wild-type or virus without the D30N mutation. In comparison, virus containing the M184V mutation in reverse transcriptase, which shows decreased replication capacity in vitro, did not have an effect on viral fitness in vivo. Thus, in this study we have verified an in silico bioinformatics result with a biological assessment to identify a unique mutation in HIV-1 that has a significant fitness defect in vivo

Initial Virological and Immunologic Response to Highly Active Antiretroviral Therapy Predicts Long-Term Clinical Outcome

Little is known about the long-term clinical outcomes for human immunodeficiency virus (HIV)-infected patients who have received highly active antiretroviral therapy (HAART). Determining factors associated with long-term clinical outcomes early in the course of treatment may allow modifications to be made for patients who are at a greater risk of treatment failure. To evaluate these factors, we studied 213 HIV-infected patients who had received HAART for at least 115 weeks. In the univariate analysis, virological response, which was measured as the change in virus load from baseline at month 3 of treatment, was the single best predictor of clinical outcome (relative hazard, 0.722; P = .001), independent of virological suppression. In the multivariate analysis, virological response and immunologic response, which was measured as an increase in CD4 cell count of >200 cells/mm^3, resulted in better prediction of clinical outcomes than did use of either variable alone (P = .02). Our results indicate that changes in virus load and immunologic response together are good predictors of clinical outcome and can be assessed after the initiation of HAART, which would allow clinicians to identify patients early in the course of therapy who are at greater risk of negative outcome

Engineering Antigen-Specific T Cells from Genetically Modified Human Hematopoietic Stem Cells in Immunodeficient Mice

There is a desperate need for effective therapies to fight chronic viral infections. The immune response is normally fastidious at controlling the majority of viral infections and a therapeutic strategy aimed at reestablishing immune control represents a potentially powerful approach towards treating persistent viral infections. We examined the potential of genetically programming human hematopoietic stem cells to generate mature CD8+ cytotoxic T lymphocytes that express a molecularly cloned, “transgenic” human anti-HIV T cell receptor (TCR). Anti-HIV TCR transduction of human hematopoietic stem cells directed the maturation of a large population of polyfunctional, HIV-specific CD8+ cells capable of recognizing and killing viral antigen-presenting cells. Thus, through this proof-of-concept we propose that genetic engineering of human hematopoietic stem cells will allow the tailoring of effector T cell responses to fight HIV infection or other diseases that are characterized by the loss of immune control

LAGraph: Linear algebra, network analysis libraries, and the study of graph algorithms

Graph algorithms can be expressed in terms of linear algebra. GraphBLAS is a library of low-level building blocks for such algorithms that targets algorithm developers. LAGraph builds on top of the GraphBLAS to target users of graph algorithms with high-level algorithms common in network analysis. In this paper, we describe the first release of the LAGraph library, the design decisions behind the library, and performance using the GAP benchmark suite. LAGraph, however, is much more than a library. It is also a project to document and analyze the full range of algorithms enabled by the GraphBLAS. To that end, we have developed a compact and intuitive notation for describing these algorithms. In this paper, we present that notation with examples from the GAP benchmark suite

LAGraph: Linear algebra, network analysis libraries, and the study of graph algorithms

Graph algorithms can be expressed in terms of linear algebra. GraphBLAS is a library of low-level building blocks for such algorithms that targets algorithm developers. LAGraph builds on top of the GraphBLAS to target users of graph algorithms with high-level algorithms common in network analysis. In this paper, we describe the first release of the LAGraph library, the design decisions behind the library, and performance using the GAP benchmark suite. LAGraph, however, is much more than a library. It is also a project to document and analyze the full range of algorithms enabled by the GraphBLAS. To that end, we have developed a compact and intuitive notation for describing these algorithms. In this paper, we present that notation with examples from the GAP benchmark suite

Cryptic Distant Relatives Are Common in Both Isolated and Cosmopolitan Genetic Samples

Although a few hundred single nucleotide polymorphisms (SNPs) suffice to infer close familial relationships, high density genome-wide SNP data make possible the inference of more distant relationships such as 2nd to 9th cousinships. In order to characterize the relationship between genetic similarity and degree of kinship given a timeframe of 100–300 years, we analyzed the sharing of DNA inferred to be identical by descent (IBD) in a subset of individuals from the 23andMe customer database (n = 22,757) and from the Human Genome Diversity Panel (HGDP-CEPH, n = 952). With data from 121 populations, we show that the average amount of DNA shared IBD in most ethnolinguistically-defined populations, for example Native American groups, Finns and Ashkenazi Jews, differs from continentally-defined populations by several orders of magnitude. Via extensive pedigree-based simulations, we determined bounds for predicted degrees of relationship given the amount of genomic IBD sharing in both endogamous and ‘unrelated’ population samples. Using these bounds as a guide, we detected tens of thousands of 2nd to 9th degree cousin pairs within a heterogenous set of 5,000 Europeans. The ubiquity of distant relatives, detected via IBD segments, in both ethnolinguistic populations and in large ‘unrelated’ populations samples has important implications for genetic genealogy, forensics and genotype/phenotype mapping studies

Treatment outcomes in schizophrenia: qualitative study of the views of family carers

Background: Schizophrenia is a complex, heterogeneous disorder, with highly variable treatment outcomes, and relatively little is known about what is important to patients. The aim of the study was to understand treatment outcomes informal carers perceive to be important to people with schizophrenia. Method: Qualitative interview study with 34 individuals and 8 couples who care for a person with schizophrenia/ schizoaffective disorder. Interviews were transcribed verbatim and analysed by a thematic framework based approach. Results: Carers described well-recognised outcomes of importance, alongside more novel outcomes relating to: Safety (of the patient/others); insight (e.g. into non-reality of psychotic phenomena); respite from fear, distress or pain; socially acceptable behaviour; getting out of the house; attainment of life milestones; changes in personality and/or temperament; reduction of vulnerability to stress; and several aspects of physical health. Conclusions: These findings have the potential to inform the development of patient- or carer- focused outcome measures that take into account the full range of domains that carers feel are important for patients.EUFAM

Ecosystem resilience despite large-scale altered hydroclimatic conditions

Climate change is predicted to increase both drought frequency and duration, and when coupled with substantial warming, will establish a new hydroclimatological model for many regions. Large-scale, warm droughts have recently occurred in North America, Africa, Europe, Amazonia and Australia, resulting in major effects on terrestrial ecosystems, carbon balance and food security. Here we compare the functional response of above-ground net primary production to contrasting hydroclimatic periods in the late twentieth century (1975-1998), and drier, warmer conditions in the early twenty-first century (2000-2009) in the Northern and Southern Hemispheres. We find a common ecosystem water-use efficiency (WUE e: Above-ground net primary production/ evapotranspiration) across biomes ranging from grassland to forest that indicates an intrinsic system sensitivity to water availability across rainfall regimes, regardless of hydroclimatic conditions. We found higher WUE e in drier years that increased significantly with drought to a maximum WUE e across all biomes; and a minimum native state in wetter years that was common across hydroclimatic periods. This indicates biome-scale resilience to the interannual variability associated with the early twenty-first century drought - that is, the capacity to tolerate low, annual precipitation and to respond to subsequent periods of favourable water balance. These findings provide a conceptual model of ecosystem properties at the decadal scale applicable to the widespread altered hydroclimatic conditions that are predicted for later this century. Understanding the hydroclimatic threshold that will break down ecosystem resilience and alter maximum WUE e may allow us to predict land-surface consequences as large regions become more arid, starting with water-limited, low-productivity grasslands. © 2013 Macmillan Publishers Limited. All rights reserved