A coordinated DNA damage response promotes adult quiescent neural stem cell activation

Stem and differentiated cells frequently differ in their response to DNA damage, which can determine tissue sensitivity. By exploiting insight into the spatial arrangement of subdomains within the adult neural subventricular zone (SVZ) in vivo, we show distinct responses to ionising radiation (IR) between neural stem and progenitor cells. Further, we reveal different DNA damage responses between neonatal and adult neural stem cells (NSCs). Neural progenitors (transit amplifying cells and neuroblasts) but not NSCs (quiescent and activated) undergo apoptosis after 2 Gy IR. This response is cell type- rather than proliferationdependent and does not appear to be driven by distinctions in DNA damage induction or repair capacity. Moreover, exposure to 2 Gy IR promotes proliferation arrest and differentiation in the adult SVZ. These 3 responses are ataxia telangiectasia mutated (ATM)- dependent and promote quiescent NSC (qNSC) activation, which does not occur in the subdomains that lack progenitors. Neuroblasts arising post-IR derive from activated qNSCs rather than irradiated progenitors, minimising damage compounded by replication or mitosis. We propose that rather than conferring sensitive cell death, apoptosis is a form of rapid cell death that serves to remove damaged progenitors and promote qNSC activation. Significantly, analysis of the neonatal (P5) SVZ reveals that although progenitors remain sensitive to apoptosis, they fail to efficiently arrest proliferation. Consequently, their repopulation occurs rapidly from irradiated progenitors rather than via qNSC activation

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines

Domestic violence and decision-making power of married women in Myanmar: analysis of a nationally representative sample

BACKGROUND: Women in Myanmar are not considered decision makers in the community and the physical and psychological effect of violence makes them more vulnerable. There is a strong negative reaction, usually violent, to any economic activity generated by women among poorer and middle-class families in Myanmar because a woman's income is not considered necessary for basic survival. OBJECTIVE: Explore the relationship between domestic violence on the decision-making power of married women in Myanmar. DESIGN: Cross-sectional. SETTING: National, both urban and rural areas of Myanmar. PATIENTS AND METHODS: Data from the Myanmar Demographic and Health Survey 2015-16 were used in this analysis. In that survey, married women aged between 15 to 49 years were selected for interview using a multistage cluster sampling technique. The dependent variables were domestic violence and the decision-making power of women. Independent variables were age of the respondents, educational level, place of residence, employment status, number of children younger than 5 years of age and wealth index. MAIN OUTCOME MEASURES: Domestic violence and decision-making power of women. SAMPLE SIZE: 7870 currently married women. RESULTS: About 50% respondents were 35 to 49 years of age and the mean (SD) age was 35 (8.4) years. Women's place of residence and employment status had a significant impact on decision-making power whereas age group and decision-making power of women had a relationship with domestic violence. CONCLUSION: Giving women decision making power will be indispensable for the achievement of sustainable development goals. Government and other stakeholders should emphasize this to eliminate violence against women. LIMITATIONS: Use of secondary data analysis of cross-sectional study design and cross-sectional studies are not suitable design to assess this causality. Secondly the self-reported data on violence may be subject to recall bias. CONFLICT OF INTEREST: None

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Corporate Risk Disclosure: A Conventional and Islamic Bank Perspective

Focusing on the differences between conventional and Islamic banks, this paper examines the association between the extent of risk disclosure and banks’ risk governance, board structure and audit quality characteristics. Using 390 bank-year observations from 2006-2018, this paper uses content analysis to explore the extent of risk disclosure by conventional and Islamic banks. The results reveal that governance factors (e.g., risk committee, presence of a risk management unit, board independence, board size and Big4 auditor) are associated with the extent of risk disclosure more in conventional banks compared with their Islamic bank counterparts. The results support the notion that regulatory regimes for risk reporting within conventional banks emphasise risk governance characteristics and indicate a need for further improvement in an Islamic bank context. The results also support the notion that more strongly governed banks are likely to provide a higher level of risk disclosure and they provide a foundation for further research in this area. This paper adds to the limited existing literature on risk disclosure and is distinctive in examining risk governance characteristics in both conventional and Islamic banks within a developing country context where risk disclosure is effectively voluntary.Full Tex

Brain hemodynamic activity during viewing and re-viewing of comedy movies explained by experienced humor

Humor is crucial in human social interactions. To study the underlying neural processes, three comedy clips were shown twice to 20 volunteers during functional magnetic resonance imaging (fMRI). Inter-subject similarities in humor ratings, obtained immediately after fMRI, explained inter-subject correlation of hemodynamic activity in right frontal pole and in a number of other brain regions. General linear model analysis also indicated activity in right frontal pole, as well as in additional cortical areas and subcortically in striatum, explained by humorousness. The association of the right frontal pole with experienced humorousness is a novel finding, which might be related to humor unfolding over longer time scales in the movie clips. Specifically, frontal pole has been shown to exhibit longer temporal receptive windows than, e.g., sensory areas, which might have enabled processing of humor in the clips based on holding information and reinterpreting that in light of new information several (even tens of) seconds later. As another novel finding, medial and lateral prefrontal areas, frontal pole, posterior-inferior temporal areas, posterior parietal areas, posterior cingulate, striatal structures and amygdala showed reduced activity upon re-viewing of the clips, suggesting involvement in processing of humor related to novelty of the comedic events.publishedVersionPeer reviewe