Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis

Defects in cilia formation and function result in a range of human skeletal and visceral abnormalities. Mutations in several genes have been identified to cause a proportion of these disorders, some of which display genetic (locus) heterogeneity. Mouse models are valuable for dissecting the function of these genes, as well as for more detailed analysis of the underlying developmental defects. The short-rib polydactyly (SRP) group of disorders are among the most severe human phenotypes caused by cilia dysfunction. We mapped the disease locus from two siblings affected by a severe form of SRP to 2p24, where we identified an in-frame homozygous deletion of exon 5 in WDR35. We subsequently found compound heterozygous missense and nonsense mutations in WDR35 in an independent second case with a similar, severe SRP phenotype. In a mouse mutation screen for developmental phenotypes, we identified a mutation in Wdr35 as the cause of midgestation lethality, with abnormalities characteristic of defects in the Hedgehog signaling pathway. We show that endogenous WDR35 localizes to cilia and centrosomes throughout the developing embryo and that human and mouse fibroblasts lacking the protein fail to produce cilia. Through structural modeling, we show that WDR35 has strong homology to the COPI coatamers involved in vesicular trafficking and that human SRP mutations affect key structural elements in WDR35. Our report expands, and sheds new light on, the pathogenesis of the SRP spectrum of ciliopathies.     

Anti-HIV siamycin I directly inhibits autophosphorylation activity of the bacterial FsrC quorum sensor and other ATP-dependent enzyme activities

Siamycin I disrupts growth and quorum sensing in Enterococcus faecalis. Using purified intact protein, we demonstrate here that quorum membrane sensor kinase FsrC is a direct target of siamycin I, reducing pheromone-stimulated autophosphorylation activity by up to 91%. Inhibition was non-competitive with ATP as substrate. Other ATP-binding enzymes were also inhibited, including nine other membrane sensor kinases of E. faecalis, Rhodobacter sphaeroides PrrB, porcine Na(+)-dependent ATPase and the catalytic subunit of bovine protein kinase A, but not bacterial β-galactosidase, confirming targeted inhibition of a wide range of ATP dependent reactions, and elucidating a likely mechanism underlying the lethality of the inhibitor.     

The hypervariable HIV-1 capsid protein residues comprise HLA-driven CD8+ T-cell escape mutations and covarying HLA-independent polymorphisms

One proposed HIV vaccine strategy is to induce Gag-specific CD8(+) T-cell responses that can corner the virus, through fitness cost of viral escape and unavailability of compensatory mutations. We show here that the most variable capsid residues principally comprise escape mutants driven by protective alleles HLA-B*57, -5801, and -8101 and covarying HLA-independent polymorphisms that arise in conjunction with these escape mutations. These covarying polymorphisms are potentially compensatory and are concentrated around three tropism-determining loops of p24, suggesting structural interdependencies. Our results demonstrate complex patterns of adaptation of HIV under immune selection pressure, the understanding of which should aid vaccine design.     

Interaction Between Nonviral Reprogrammed Fibroblast Stem Cells and Trophic Factors for Brain Repair

Diabetic encephalopathy is one of the most common complications of diabetes. Inflammatory events during diabetes may be an important mechanism of diabetic encephalopathy. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein (ASC), and caspase 1 or 5, which functions to switch on the inflammatory process and the release of inflammatory factors. The present study hypothesized that the formation and activation of NLRP1 inflammasome turns on neuroinflammation and neuron injury during hyperglycemia. The results demonstrated that the levels of interleukin-1 beta (IL-1β) were increased in the cortex of streptozocin (STZ)-induced diabetic rats. The levels of mature IL-1β and IL-18 were also elevated in culture medium of neurons treated with high glucose (50 mM). The expression of three essential components of the NLRP1 inflammasome complex, namely, NLRP1, ASC, and caspase 1, was also upregulated in vivo and in vitro under high glucose. Silencing the ASC gene prevented the caspase-1 activation, and inhibiting caspase 1 activity blocked hyperglycemia-induced release of inflammatory factors and neuron injury. Moreover, we found that pannexin 1 mediated the actvitation of NLRP1 inflammasome under high glucose. These results suggest that hyperglycemia induces neuroinflammation through activation of NLRP1 inflammasome, which represents a novel mechanism of diabetes-associated neuron injury.     

Do Interventions Designed to Support Shared Decision-Making Reduce Health Inequalities? A Systematic Review and Meta-Analysis

Background

Increasing patient engagement in healthcare has become a health policy priority. However, there has been concern that promoting supported shared decision-making could increase health inequalities.

Objective

To evaluate the impact of SDM interventions on disadvantaged groups and health inequalities.

Design

Systematic review and meta-analysis of randomised controlled trials and observational studies.

Data Sources

CINAHL, the Cochrane Register of Controlled Trials, the Cochrane Database of Systematic Reviews, EMBASE, HMIC, MEDLINE, the NHS Economic Evaluation Database, Open SIGLE, PsycINFO and Web of Knowledge were searched from inception until June 2012.

Study Eligibility Criteria

We included all studies, without language restriction, that met the following two criteria: (1) assess the effect of shared decision-making interventions on disadvantaged groups and/or health inequalities, (2) include at least 50% of people from disadvantaged groups, except if a separate analysis was conducted for this group.

Results

We included 19 studies and pooled 10 in a meta-analysis. The meta-analyses showed a moderate positive effect of shared decision-making interventions on disadvantaged patients. The narrative synthesis suggested that, overall, SDM interventions increased knowledge, informed choice, participation in decision-making, decision self-efficacy, preference for collaborative decision making and reduced decisional conflict among disadvantaged patients. Further, 7 out of 19 studies compared the intervention''s effect between high and low literacy groups. Overall, SDM interventions seemed to benefit disadvantaged groups (e.g. lower literacy) more than those with higher literacy, education and socioeconomic status. Interventions that were tailored to disadvantaged groups'' needs appeared most effective.

Conclusion

Results indicate that shared decision-making interventions significantly improve outcomes for disadvantaged patients. According to the narrative synthesis, SDM interventions may be more beneficial to disadvantaged groups than higher literacy/socioeconomic status patients. However, given the small sample sizes and variety in the intervention types, study design and quality, those findings should be interpreted with caution.     

The Moderating Effects of Sex and Age on the Association between Traumatic Brain Injury and Harmful Psychological Correlates among Adolescents

Background

Although it is well established that sex is a risk factor in acquiring a traumatic brain injury (TBI) among adolescents, it has not been established whether it also moderates the influence of other TBI psychological health correlates.

Methods and Findings

Data were derived from a 2011 population-based cross-sectional school survey, which included 9,288 Ontario 7th–12th graders who completed anonymous self-administered questionnaires in classrooms. Response rate was 62%. Preliminary analyses found no evidence of nonresponse bias in the reporting of TBI. TBI was defined as a hit or blow to the head that resulted in a 5 minutes loss of consciousness or at least one overnight hospitalization due to symptoms associated with it. Reports of lifetime TBI were more common among males than females (23.1%, 95% CI: 20.5, 25.8 vs. 17.1%, 95% CI: 14.7, 19.8). Thirteen correlates were examined and included cigarette smoking, elevated psychological distress, suicide ideation, bully victimization (at school, as well as cyber bullying), bullying others, cannabis use, cannabis dependence and drug use problems, physical injuries, daily smoking, drinking alcohol, binge drinking, use of cannabis, and poor academic performance. Among the outcomes examined, sex moderated the relationship between lifetime TBI and cigarette smoking. In addition, sex and age jointly moderated the relationship between lifetime TBI and daily smoking, alcohol use and physical injuries. Late adolescent males who reported lifetime TBI, relative to females, displayed elevated daily smoking and injuries, whereas their females counterparts displayed elevated past year drinking. Possible bias related to self-report procedures and the preclusion of causal inferences due to the cross-sectional nature of the data are limitations of this study.

Conclusions

TBI differences in outcomes need to be assessed for potential moderating effects of sex and age. Results have important implications for more tailored injury prevention efforts.