Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

Lipid-soluble Vitamins A, D, and E in HIV-Infected Pregnant women in Tanzania.

There is limited published research examining lipid-soluble vitamins in human immunodeficiency virus (HIV)-infected pregnant women, particularly in resource-limited settings. This is an observational analysis of 1078 HIV-infected pregnant women enrolled in a trial of vitamin supplementation in Tanzania. Baseline data on sociodemographic and anthropometric characteristics, clinical signs and symptoms, and laboratory parameters were used to identify correlates of low plasma vitamin A (<0.7 micromol/l), vitamin D (<80 nmol/l) and vitamin E (<9.7 micromol/l) status. Binomial regression was used to estimate risk ratios and 95% confidence intervals. Approximately 35, 39 and 51% of the women had low levels of vitamins A, D and E, respectively. Severe anemia (hemoglobin <85 g/l; P<0.01), plasma vitamin E (P=0.02), selenium (P=0.01) and vitamin D (P=0.02) concentrations were significant correlates of low vitamin A status in multivariate models. Erythrocyte Sedimentation Rate (ESR) was independently related to low vitamin A status in a nonlinear manner (P=0.01). The correlates of low vitamin D status were CD8 cell count (P=0.01), high ESR (ESR >81 mm/h; P<0.01), gestational age at enrollment (nonlinear; P=0.03) and plasma vitamins A (P=0.02) and E (P=0.01). For low vitamin E status, the correlates were money spent on food per household per day (P<0.01), plasma vitamin A concentration (nonlinear; P<0.01) and a gestational age <16 weeks at enrollment (P<0.01). Low concentrations of lipid-soluble vitamins are widely prevalent among HIV-infected women in Tanzania and are correlated with other nutritional insufficiencies. Identifying HIV-infected persons at greater risk of poor nutritional status and infections may help inform design and implementation of appropriate interventions

Varus distal femoral osteotomy in young adults with valgus knee

<p>Abstract</p> <p>Background</p> <p>Musculoskeletal disorders specially knee osteoarthritis are the most common causes of morbidity in old patients. Disturbance of the mechanical axis of the lower extremity is one of the most important causes in progression of knee osteoarthritis. The purpose of the present study was to analyze the surgical results of distal femoral varus osteotomy in patients with genu valgum.</p> <p>Methods</p> <p>In this study, after recording history and physical examination, appropriate radiographs were taken. We did varus distal femoral osteotomy by standard medial subvastus approach and 90-angle blade plate fixation then followed the patients clinically and radiographically.</p> <p>Results</p> <p>This study was done on 23 knees (16 patients) age 23.3 years (range, 17 to 41 years). The mean duration of following up was 16.3 months (range, 8 to 25 months). Based on paired T test, there were statistically significant difference between pre- and postoperative tibiofemoral and congruence angles (p < 0.001, t = 21.3 and p < 0.001, t = 10.1 respectively). Pearson correlation between the amount of tibiofemoral and congruence angle correction was also statistically significant (p = 0.02 and r = 0.46).</p> <p>Conclusion</p> <p>Distal femoral varus osteotomy with blade plate fixation can be a reliable procedure for the treatment of valgus knee deformity. In this procedure, with more tibiofemoral angle correction, more congruence angle correction can be achieved. Therefore, along with genu valgum correction, the patella should be stabilized simultaneously.</p

BSE can propagate in sheep co-infected or pre-infected with scrapie

To understand the possible role of mixed-prion infections in disease presentation, the current study reports the co-infection of sheep with bovine spongiform encephalopathy (BSE) and scrapie. The bovine BSE agent was inoculated subcutaneously into sheep with ARQ/ARQ or VRQ/ARQ PRNP genotypes either at the same time as subcutaneous challenge with scrapie, or three months later. In addition, VRQ/VRQ sheep naturally infected with scrapie after being born into a scrapie-affected flock were challenged subcutaneously with BSE at eight or twenty one months-of-age. Sheep were analysed by incubation period/attack rate, and western blot of brain tissue determined the presence of BSE or scrapie-like PrP Sc. Serial protein misfolding cyclic amplification (sPMCA) that can detect very low levels of BSE in the presence of an excess of scrapie agent was also applied to brain and lymphoreticular tissue. For VRQ/ARQ sheep challenged with mixed infections, scrapie-like incubation periods were produced, and no BSE agent was detected. However, whilst ARQ/ARQ sheep developed disease with BSE-like incubation periods, some animals had a dominant scrapie western blot phenotype in brain, but BSE was detected in these sheep by sPMCA. In addition, VRQ/VRQ animals challenged with BSE after natural exposure to scrapie had scrapie-like incubation periods and dominant scrapie PrP Sc in brain, but one sheep had BSE detectable by sPMCA in the brain. Overall, the study demonstrates for the first time that for scrapie/BSE mixed infections, VRQ/ARQ sheep with experimental scrapie did not propagate BSE but VRQ/VRQ sheep with natural scrapie could propagate low levels of BSE, and whilst BSE readily propagated in ARQ/ARQ sheep it was not always the dominant PrP Sc strain in brain tissue. Indeed, for several animals, a dominant scrapie biochemical phenotype in brain did not preclude the presence of BSE prion

Conserving the Stage: Climate Change and the Geophysical Underpinnings of Species Diversity

Conservationists have proposed methods for adapting to climate change that assume species distributions are primarily explained by climate variables. The key idea is to use the understanding of species-climate relationships to map corridors and to identify regions of faunal stability or high species turnover. An alternative approach is to adopt an evolutionary timescale and ask ultimately what factors control total diversity, so that over the long run the major drivers of total species richness can be protected. Within a single climatic region, the temperate area encompassing all of the Northeastern U.S. and Maritime Canada, we hypothesized that geologic factors may take precedence over climate in explaining diversity patterns. If geophysical diversity does drive regional diversity, then conserving geophysical settings may offer an approach to conservation that protects diversity under both current and future climates. Here we tested how well geology predicts the species diversity of 14 US states and three Canadian provinces, using a comprehensive new spatial dataset. Results of linear regressions of species diversity on all possible combinations of 23 geophysical and climatic variables indicated that four geophysical factors; the number of geological classes, latitude, elevation range and the amount of calcareous bedrock, predicted species diversity with certainty (adj. R2 = 0.94). To confirm the species-geology relationships we ran an independent test using 18,700 location points for 885 rare species and found that 40% of the species were restricted to a single geology. Moreover, each geology class supported 5–95 endemic species and chi-square tests confirmed that calcareous bedrock and extreme elevations had significantly more rare species than expected by chance (P<0.0001), strongly corroborating the regression model. Our results suggest that protecting geophysical settings will conserve the stage for current and future biodiversity and may be a robust alternative to species-level predictions

A Methodological Framework for the Evaluation of Syndromic Surveillance Systems: A Case Study of England

Background: Syndromic surveillance complements traditional public health surveillance by collecting and analysing health indicators in near real time. The rationale of syndromic surveillance is that it may detect health threats faster than traditional surveillance systems permitting more timely, and hence potentially more effective public health action. The effectiveness of syndromic surveillance largely relies on the methods used to detect aberrations. Very few studies have evaluated the performance of syndromic surveillance systems and consequently little is known about the types of events that such systems can and cannot detect. Methods: We introduce a framework for the evaluation of syndromic surveillance systems that can be used in any setting based upon the use of simulated scenarios. For a range of scenarios this allows the time and probability of to be determined and uncertainty is fully incorporated. In addition, we demonstrate how such a framework can model the benefits of increases in the number of centres reporting syndromic data and also determine the minimum size of outbreaks that can or cannot be detected. Here, we demonstrate its utility using simulations of national influenza outbreaks and localised outbreaks of cryptosporidiosis. Results: Influenza outbreaks are consistently detected with larger outbreaks being detected in a more timely manner. Small cryptosporidiosis outbreaks (<1000 symptomatic individuals) are unlikely to be detected. We also demonstrate the advantages of having multiple syndromic data streams (e.g. emergency attendance data, telephone helpline data, general practice consultation data) as different streams are able to detect different types outbreaks with different efficacy (e.g. emergency attendance data are useful for the detection of pandemic influenza but not for outbreaks of cryptosporidiosis). We also highlight that for any one disease, the utility of data streams may vary geographically, and that the detection ability of syndromic surveillance varies seasonally (e.g. an influenza outbreak starting in July is detected sooner than one starting later in the year). We argue that our framework constitutes a useful tool for public health emergency preparedness in multiple settings. Conclusions: The proposed framework allows the exhaustive evaluation of any syndromic surveillance system and constitutes a useful tool for emergency preparedness and response

Functional Analysis of a Breast Cancer-Associated FGFR2 Single Nucleotide Polymorphism Using Zinc Finger Mediated Genome Editing

The authors thank Barts Charity for funding and Breast Cancer Campaign for funding the Barts Breast Tissue Bank

Impact of individual-level social capital on quality of life among AIDS patients in China.

With growing recognition of the social determinants of health, social capital is an increasingly important construct in international health. However, the application of social capital discourse in response to HIV infection remains preliminary. The aim of this study was to assess the impact of social capital on quality of life (QoL) among adult patients with acquired immune deficiency syndrome (AIDS). A convenient sample of 283 patients receiving antiretroviral treatment (ART) was investigated in Anhui province, China. QoL data were collected using the Medical Outcomes Study HIV Survey (MOS-HIV) questionnaire. Social capital was measured using a self-developed questionnaire. Logistic regression models were used to explore associations between social capital and QoL. The study sample had a mean physical health summary (PHS) score of 50.13 ± 9.90 and a mean mental health summary (MHS) score of 41.64 ± 11.68. Cronbach's α coefficients of the five multi-item scales of social capital ranged from 0.44 to 0.79. When other variables were controlled for, lower individual levels of reciprocity and trust were associated with a greater likelihood of having a poor PHS score (odds ratio [OR] =2.02) or PHS score (OR=6.90). Additionally, the factors of social support and social networks and ties were associated positively with MHS score (OR=2.30, OR=4.17, respectively). This is the first report to explore the effects of social capital on QoL of AIDS patients in China. The results indicate that social capital is a promising avenue for developing strategies to improve the QoL of AIDS patients in China, suggesting that the contribution of social capital should be fully exploited, especially with enhancement of QoL through social participation. Social capital development policy may be worthy of consideration

Genome-Wide Analysis of Heteroduplex DNA in Mismatch Repair–Deficient Yeast Cells Reveals Novel Properties of Meiotic Recombination Pathways

Meiotic DNA double-strand breaks (DSBs) initiate crossover (CO) recombination, which is necessary for accurate chromosome segregation, but DSBs may also repair as non-crossovers (NCOs). Multiple recombination pathways with specific intermediates are expected to lead to COs and NCOs. We revisited the mechanisms of meiotic DSB repair and the regulation of CO formation, by conducting a genome-wide analysis of strand-transfer intermediates associated with recombination events. We performed this analysis in a SK1 × S288C Saccharomyces cerevisiae hybrid lacking the mismatch repair (MMR) protein Msh2, to allow efficient detection of heteroduplex DNAs (hDNAs). First, we observed that the anti-recombinogenic activity of MMR is responsible for a 20% drop in CO number, suggesting that in MMR–proficient cells some DSBs are repaired using the sister chromatid as a template when polymorphisms are present. Second, we observed that a large fraction of NCOs were associated with trans–hDNA tracts constrained to a single chromatid. This unexpected finding is compatible with dissolution of double Holliday junctions (dHJs) during repair, and it suggests the existence of a novel control point for CO formation at the level of the dHJ intermediate, in addition to the previously described control point before the dHJ formation step. Finally, we observed that COs are associated with complex hDNA patterns, confirming that the canonical double-strand break repair model is not sufficient to explain the formation of most COs. We propose that multiple factors contribute to the complexity of recombination intermediates. These factors include repair of nicks and double-stranded gaps, template switches between non-sister and sister chromatids, and HJ branch migration. Finally, the good correlation between the strand transfer properties observed in the absence of and in the presence of Msh2 suggests that the intermediates detected in the absence of Msh2 reflect normal intermediates

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente