Evolutionary Toggling of Vpx/Vpr Specificity Results in Divergent Recognition of the Restriction Factor SAMHD1

SAMHD1 is a host restriction factor that blocks the ability of lentiviruses such as HIV-1 to undergo reverse transcription in myeloid cells and resting T-cells. This restriction is alleviated by expression of the lentiviral accessory proteins Vpx and Vpr (Vpx/Vpr), which target SAMHD1 for proteasome-mediated degradation. However, the precise determinants within SAMHD1 for recognition by Vpx/Vpr remain unclear. Here we show that evolution of Vpx/Vpr in primate lentiviruses has caused the interface between SAMHD1 and Vpx/Vpr to alter during primate lentiviral evolution. Using multiple HIV-2 and SIV Vpx proteins, we show that Vpx from the HIV-2 and SIVmac lineage, but not Vpx from the SIVmnd2 and SIVrcm lineage, require the C-terminus of SAMHD1 for interaction, ubiquitylation, and degradation. On the other hand, the N-terminus of SAMHD1 governs interactions with Vpx from SIVmnd2 and SIVrcm, but has little effect on Vpx from HIV-2 and SIVmac. Furthermore, we show here that this difference in SAMHD1 recognition is evolutionarily dynamic, with the importance of the N- and C-terminus for interaction of SAMHD1 with Vpx and Vpr toggling during lentiviral evolution. We present a model to explain how the head-to-tail conformation of SAMHD1 proteins favors toggling of the interaction sites by Vpx/Vpr during this virus-host arms race. Such drastic functional divergence within a lentiviral protein highlights a novel plasticity in the evolutionary dynamics of viral antagonists for restriction factors during lentiviral adaptation to its hosts. © 2013 Fregoso et al

Externalizing behavior in early childhood and body mass index from age 2 to 12 years: longitudinal analyses of a prospective cohort study

Background: Some evidence suggests that obesity and behavior problems are related in children, but studies have been conflicting and have rarely included children under age 4. An association between behavior problems in early childhood and risk for obesity could suggest that a common set of factors contribute to both. Our research objectives were to determine the extent to which externalizing behavior in early childhood is related to body mass index (BMI) in early childhood and through age 12, and to evaluate whether these associations differ by sex and race. Methods: Data from the NICHD Study of Early Child Care and Youth Development were analyzed. Externalizing behaviors at 24 months were assessed by mothers using the Child Behavior Checklist. BMI was calculated from measured height and weight assessed 7 times between age 2 and 12 years. Linear mixed effects models were used to assess associations between 24 month externalizing behavior and BMI from 2 to 12 years, calculate predicted differences in BMI, and evaluate effect modification. Results: Externalizing behavior at 24 months was associated with a higher BMI at 24 months and through age 12. Results from a linear mixed effects model, controlling for confounding variables and internalizing behavior, predicted a difference in BMI of approximately 3/4 of a unit at 24 months of age comparing children with high levels of externalizing behavior to children with low levels of externalizing behavior. There was some evidence of effect modification by race; among white children, the average BMI difference remained stable through age 12, but it doubled to 1.5 BMI units among children who were black or another race. Conclusions: Our analyses suggest that externalizing behaviors in early childhood are associated with children's weight status early in childhood and throughout the elementary school years, though the magnitude of the effect is modest.https://doi.org/10.1186/1471-2431-10-4

Use, acceptability and impact of booklets designed to support mental health self-management and help seeking in schools:Results of a large randomised controlled trial in England

Mental health booklets may provide a low-cost means of promoting mental health self-management and help seeking in schools. The aim of the study was to assess the (a) use, (b) acceptability and (c) impact of booklets for students in primary (10-11 years) and secondary school (12-13 years) alone and in conjunction with funding for targeted mental health support. This was a 2 × 2 factorial cluster randomized controlled trial, in which 846 schools in England were randomly allocated to receive/not receive: (1) booklets for students containing information on mental health self-management and help seeking, and (2) funding for mental health support as part of a national mental health initiative. 14,690 students (8139 primary, 6551 secondary) provided self-report on mental health, quality of life (baseline and 1 year follow-up) and help seeking (follow-up). (a) Approximately, 40 % primary school students and 20 % secondary school students reported seeing the booklets. (b) Of these, 87 % of primary school students reported that the booklet was 'very helpful' or 'quite helpful', compared with 73 % in secondary school. (c) There was no detectable impact of booklets on mental health, quality of life or help seeking, either alone or in conjunction with additional funding through the national mental health initiative. Lack of discernable impact of booklets underscores the need for caution in adopting such an approach. However, it is feasible that the impact was obscured by low uptake or that booklets may be more effective when used in a targeted way

Evolution records a Mx tape for anti-viral immunity

Viruses impose diverse and dynamic challenges on host defenses. Diversifying selection of codons and gene copy number variation are two hallmarks of genetic innovation in antiviral genes engaged in host-virus genetic conflicts. The myxovirus resistance (Mx) genes encode interferon-inducible GTPases that constitute a major arm of the cell-autonomous defense against viral infection. Unlike the broad antiviral activity of MxA, primate MxB was recently shown to specifically inhibit lentiviruses including HIV-1. We carried out detailed evolutionary analyses to investigate whether genetic conflict with lentiviruses has shaped MxB evolution in primates. We found strong evidence for diversifying selection in the MxB N-terminal tail, which contains molecular determinants of MxB anti-lentivirus specificity. However, we found no overlap between previously-mapped residues that dictate lentiviral restriction and those that have evolved under diversifying selection. Instead, our findings are consistent with MxB having a long-standing and important role in the interferon response to viral infection against a broader range of pathogens than is currently appreciated. Despite its critical role in host innate immunity, we also uncovered multiple functional losses of MxB during mammalian evolution, either by pseudogenization or by gene conversion from MxA genes. Thus, although the majority of mammalian genomes encode two Mx genes, this apparent stasis masks the dramatic effects that recombination and diversifying selection have played in shaping the evolutionary history of Mx genes. Discrepancies between our study and previous publications highlight the need to account for recombination in analyses of positive selection, as well as the importance of using sequence datasets with appropriate depth of divergence. Our study also illustrates that evolutionary analyses of antiviral gene families are critical towards understanding molecular principles that govern host-virus interactions and species-specific susceptibility to viral infection

Validity and usefulness of members reports of implementation progress in a quality improvement initiative: findings from the Team Check-up Tool (TCT)

<p>Abstract</p> <p>Background</p> <p>Team-based interventions are effective for improving safety and quality of healthcare. However, contextual factors, such as team functioning, leadership, and organizational support, can vary significantly across teams and affect the level of implementation success. Yet, the science for measuring context is immature. The goal of this study is to validate measures from a short instrument tailored to track dynamic context and progress for a team-based quality improvement (QI) intervention.</p> <p>Methods</p> <p>Design: Secondary cross-sectional and longitudinal analysis of data from a clustered randomized controlled trial (RCT) of a team-based quality improvement intervention to reduce central line-associated bloodstream infection (CLABSI) rates in intensive care units (ICUs).</p> <p>Setting: Forty-six ICUs located within 35 faith-based, not-for-profit community hospitals across 12 states in the U.S.</p> <p>Population: Team members participating in an ICU-based QI intervention.</p> <p>Measures: The primary measure is the Team Check-up Tool (TCT), an original instrument that assesses context and progress of a team-based QI intervention. The TCT is administered monthly. Validation measures include CLABSI rate, Team Functioning Survey (TFS) and Practice Environment Scale (PES) from the Nursing Work Index.</p> <p>Analysis: Temporal stability, responsiveness and validity of the TCT.</p> <p>Results</p> <p>We found evidence supporting the temporal stability, construct validity, and responsiveness of TCT measures of intervention activities, perceived group-level behaviors, and barriers to team progress.</p> <p>Conclusions</p> <p>The TCT demonstrates good measurement reliability, validity, and responsiveness. By having more validated measures on implementation context, researchers can more readily conduct rigorous studies to identify contextual variables linked to key intervention and patient outcomes and strengthen the evidence base on successful spread of efficacious team-based interventions. QI teams participating in an intervention should also find data from a validated tool useful for identifying opportunities to improve their own implementation.</p

Plant Vaccines: An Immunological Perspective.

The advent of technologies to express heterologous proteins in planta has led to the proposition that plants may be engineered to be safe, inexpensive vehicles for the production of vaccines and possibly even vectors for their delivery. The immunogenicity of a variety of antigens of relevance to vaccination expressed in different plants has been assessed. The purpose of this article is to examine the utility of plant-expression systems in vaccine development from an immunological perspective

Search for High Mass Photon Pairs in p-pbar --> gamma-gamma-jet-jet Events at sqrt(s)=1.8 TeV

A search has been carried out for events in the channel p-barp --> gamma gamma jet jet. Such a signature can characterize the production of a non-standard Higgs boson together with a W or Z boson. We refer to this non-standard Higgs, having standard model couplings to vector bosons but no coupling to fermions, as a "bosonic Higgs." With the requirement of two high transverse energy photons and two jets, the diphoton mass (m(gamma gamma)) distribution is consistent with expected background. A 90(95)% C.L. upper limit on the cross section as a function of mass is calculated, ranging from 0.60(0.80) pb for m(gamma gamma) = 65 GeV/c^2 to 0.26(0.34) pb for m(gamma gamma) = 150 GeV/c^2, corresponding to a 95% C.L. lower limit on the mass of a bosonic Higgs of 78.5 GeV/c^2.Comment: 9 pages, 3 figures. Replacement has new H->gamma gamma branching ratios and corresponding new mass limit

Batch and continuous removal of heavy metals from industrial effluents using microbial consortia

Bio-removal of heavy metals, using microbial biomass, increasingly attracting scientific attention due to their significant role in purification of different types of wastewaters making it reusable. Heavy metals were reported to have a significant hazardous effect on human health, and while the conventional methods of removal were found to be insufficient; microbial biosorption was found to be the most suitable alternative. In this work, an immobilized microbial consortium was generated using Statistical Design of Experiment (DOE) as a robust method to screen the efficiency of the microbial isolates in heavy metal removal process. This is the first report of applying Statistical DOE to screen the efficacy of microbial isolates to remove heavy metals instead of screening normal variables. A mixture of bacterial biomass and fungal spores was used both in batch and continuous modes to remove Chromium and Iron ions from industrial effluents. Bakery yeast was applied as a positive control, and all the obtained biosorbent isolates showed more significant efficiency in heavy metal removal. In batch mode, the immobilized biomass was enclosed in a hanged tea bag-like cellulose membrane to facilitate the separation of the biosorbent from the treated solutions, which is one of the main challenges in applying microbial biosorption at large scale. The continuous flow removal was performed using fixed bed mini-bioreactor, and the process was optimized in terms of pH (6) and flow rates (1 ml/min) using Response Surface Methodology. The most potential biosorbent microbes were identified and characterized. The generated microbial consortia and process succeeded in the total removal of Chromium ions and more than half of Iron ions both from standard solutions and industrial effluents