Persistent Inflammation and Endothelial Activation in HIV-1 Infected Patients after 12 Years of Antiretroviral Therapy

Objective

The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART).

Methods

Inflammation and endothelial activation were assessed by measuring levels of immunoglobulins, β2-microglobulin, interleukin (IL) 8, tumor necrosis factor α (TNFα), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), sE-Selectin, and sP-Selectin.

Results

HIV infected patients had higher levels of β2-microglobulin, IL-8, TNFα, and sICAM-1 than uninfected controls, and HIV infected patients lacked correlation between platelet counts and sP-Selectin levels found in uninfected controls.

Conclusion

Discrete signs of systemic and vascular inflammation persist even after very long term cART.     

Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity

1. Download high-res image (174KB)
2. Download full-size image

     

Efficient Agrobacterium transformation of elite wheat germplasm without selection

A previously reported Agrobacterium tumefaciens transformation system that transformed wheat cultivar Fielder at high efficiency was shown to also transform eight out of nine Triticum aestivum (hexaploid wheat) cultivars tested and two Triticum turgidum (durum wheat) cultivars. Transformation efficiencies of these wheat lines ranged from 1.5 to 51 %. Included amongst this germplasm were elite Australian hexaploid wheat cultivars that are currently in commercial cultivation and two of these cultivars, Gladius and Westonia, were transformed at 32 and 45 % efficiency, respectively. Similar high transformation efficiencies were observed for durum wheat cultivars Kronos (51 %) and Stewart (26 %). This highly efficient transformation system was used to generate transgenic plants in the absence of selection and high heritability of unselected transgenes was observed. Selectable marker free transgenic wheat plants were produced at 3 % efficiency. These data demonstrate highly efficient Agrobacterium transformation of diverse wheat germplasm, including elite cultivars, which enables routine production of selectable marker free transgenics.     

Patterns of Mortality and Factors Influencing Survival of a Recently Restored Elk Population in Ontario,Canada

This study examined patterns of mortality and determinants of survival among elk recently restored to four sites in Ontario, Canada (1998–2005). We predicted that: (1) elk located in release sites closer to the core of their historic range would have higher survival; (2) survival would increase as an animal's time and experience on the landscape increased; and (3) survival rates would decline as animals moved farther away from the release site. During the study, 443 elk were radiocollared and released; 218 mortalities were documented. Predation by wolves was the most important proximate cause of mortality, followed by death due to injuries from translocation and/or capture myopathy, accidents, emaciation, poaching, and Parelaphostrongylus tenuis infection. Overall, annual survival of elk across Ontario ranged from 0.45 (0.37–0.53) to 0.81 (0.66–0.90), with rates being lowest in the years immediately following release and highest in the final years of the study; this pattern was due to high initial mortality from translocation injuries and/or capture myopathy and possibly lack of familiarity with novel habitat. Model‐averaged hazards further support this finding, as the most important factor influencing elk survival was the length of holding period, with elk released after limited holding being less likely to survive than those held for longer periods. Our results suggest that mortalities caused by capture myopathy and transportation‐related injuries are important sources of risk for translocated elk. The method of introduction to the novel landscape and behavior in the first year should be accommodated via soft‐release and appropriate release areas.     

Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A Genome-Wide Analysis of Individual-Level Data and a Meta-Analysis

Background

It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.

Methods and Findings

The NEWMEDS consortium, an academia–industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10⁻⁸). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10⁻⁸) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.

Conclusions

No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors'' Summary     

Structure and function of the transketolase from Mycobacterium tuberculosis and comparison with the human enzyme

The transketolase (TKT) enzyme in Mycobacterium tuberculosis represents a novel drug target for tuberculosis treatment and has low homology with the orthologous human enzyme. Here, we report on the structural and kinetic characterization of the transketolase from M. tuberculosis (TBTKT), a homodimer whose monomers each comprise 700 amino acids. We show that TBTKT catalyses the oxidation of donor sugars xylulose-5-phosphate and fructose-6-phosphate as well as the reduction of the acceptor sugar ribose-5-phosphate. An invariant residue of the TKT consensus sequence required for thiamine cofactor binding is mutated in TBTKT; yet its catalytic activities are unaffected, and the 2.5 Å resolution structure of full-length TBTKT provides an explanation for this. Key structural differences between the human and mycobacterial TKT enzymes that impact both substrate and cofactor recognition and binding were uncovered. These changes explain the kinetic differences between TBTKT and its human counterpart, and their differential inhibition by small molecules. The availability of a detailed structural model of TBTKT will enable differences between human and M. tuberculosis TKT structures to be exploited to design selective inhibitors with potential antitubercular activity.