Mitochondria dysfunction is associated with long-term cognitive impairment in an animal sepsis mode

Background: Several different mechanisms have been proposed to explain long-term cognitive impairment in sepsis survivors. The role of persisting mitochondrial dysfunction is not known. We thus sought to determine whether stimulation of mitochondrial dynamics improves mitochondrial function and long-term cognitive impairment in an experimental model of sepsis. Methods: Sepsis was induced in adult Wistar rats by cecal ligation and perforation (CLP). Animals received intracerebroventricular injections of either rosiglitazone (biogenesis activator), rilmenidine, rapamycin (autophagy activators), or n-saline (sham control) once a day on days 7–9 after the septic insult. Cognitive impairment was assessed by inhibitory avoidance and object recognition tests. Animals were killed 24 h, 3 and 10 days after sepsis with the hippocampus and prefrontal cortex removed to determine mitochondrial function. Results: Sepsis was associated with both acute (24 h) and late (10 days) brain mitochondrial dysfunction. Markers of mitochondrial biogenesis, autophagy and mitophagy were not up-regulated during these time points. Activation of biogenesis (rosiglitazone) or autophagy (rapamycin and rilmenidine) improved brain ATP levels and ex vivo oxygen consumption and the long-term cognitive impairment observed in sepsis survivors. Conclusion: Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( P≤5×10-8 ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.Funding Agency Portuguese Foundation for Science and Technology CRESC ALGARVE 2020 European Union (EU) 303745 Maratona da Saude Award DL 57/2016/CP1361/CT0042 SFRH/BPD/99502/2014 CBMR-UID/BIM/04773/2013 POCI-01-0145-FEDER-022184info:eu-repo/semantics/publishedVersio

Clinical Value of Prognostic Instruments to Identify Patients with an Increased Risk for Osteoporotic Fractures: Systematic Review

There is a plethora of evidence available studying the association of risk profiles and the development of osteoporotic fractures. The small number of out-of-sample validations, the large variety of study characteristics, outcomes and follow-up periods impedes from deriving robust summaries and from conclusions regarding the clinical performance of many tools. First and foremost, future activity in this field should aim at reaching a consensus among clinical experts in respect to the existing instruments. Then we call for careful validations and expedient adaptations for local circumstances of the most promising candidates

Meteorologically estimated exposure but not distance predicts asthma symptoms in schoolchildren in the environs of a petrochemical refinery: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Community concern about asthma prompted an epidemiological study of children living near a petrochemical refinery in Cape Town, South Africa. Because of resource constraints and the complexity of refinery emissions, neither direct environmental measurements nor modelling of airborne pollutants was possible. Instead a meteorologically derived exposure metric was calculated with the refinery as the putative point source. The study aimed to determine whether (1) asthma symptom prevalences were elevated compared to comparable areas in Cape Town and (2) whether there was an association between asthma symptom prevalences and the derived exposure metric.</p> <p>Methods</p> <p>A cross-sectional study was carried out of all consenting school children aged 11 to 14 years attending schools in a defined area, utilizing the International Study of Asthma and Allergy in Childhood (ISAAC) written and video questionnaires. Information was collected on potential confounders, e.g. parental history of atopic disease, active and passive smoking by the participant, birth order, number of children in the home and distance from a major road. The exposure metric combined residential distance of each child from the refinery with a wind vector in the form of wind speed, wind direction and proportion of the year blown.</p> <p>Results</p> <p>A total of 2,361 children from 17 schools met the criteria for inclusion. In multivariate analysis, meteorologically estimated exposure (MEE), but not simple distance from the refinery, was positively associated with having to take an inhaler to school [odds ratio per interquartile range (OR) 1.22, 95% confidence interval (CI) 1.06-1.40], and with a number of video elicited asthma symptoms, including recent waking with wheezing (OR 1.33, 95% CI 1.06-1.66) and frequent wheezing at rest (OR 1.27, 95% CI 1.05 - 1.54). Symptom prevalences were higher than in other areas of the city, with frequent waking with wheezing being in great excess (OR 8.92, 95% CI 4.79-16.63).</p> <p>Conclusion</p> <p>The results support the hypothesis of an increased prevalence of asthma symptoms among children in the area as a result of refinery emissions and provide a substantive basis for community concern. The methodology also provides a low cost means of testing hypotheses about point source pollutant effects on surrounding populations of children.</p

Search for Charged Higgs Bosons in e+e- Collisions at \sqrt{s} = 189 GeV

A search for pair-produced charged Higgs bosons is performed with the L3 detector at LEP using data collected at a centre-of-mass energy of 188.6 GeV, corresponding to an integrated luminosity of 176.4 pb^-1. Higgs decays into a charm and a strange quark or into a tau lepton and its associated neutrino are considered. The observed events are consistent with the expectations from Standard Model background processes. A lower limit of 65.5 GeV on the charged Higgs mass is derived at 95 % confidence level, independent of the decay branching ratio Br(H^{+/-} -> tau nu)

Logging Affects Fledgling Sex Ratios and Baseline Corticosterone in a Forest Songbird

Silviculture (logging) creates a disturbance to forested environments. The degree to which forests are modified depends on the logging prescription and forest stand characteristics. In this study we compared the effects of two methods of group-selection (“moderate” and “heavy”) silviculture (GSS) and undisturbed reference stands on stress and offspring sex ratios of a forest interior species, the Ovenbird (Seiurus aurocapilla), in Algonquin Provincial Park, Canada. Blood samples were taken from nestlings for corticosterone and molecular sexing. We found that logging creates a disturbance that is stressful for nestling Ovenbirds, as illustrated by elevated baseline corticosterone in cut sites. Ovenbirds nesting in undisturbed reference forest produce fewer male offspring per brood (proportion male = 30%) while logging with progressively greater forest disturbance, shifted the offspring sex ratio towards males (proportion male: moderate = 50%, heavy = 70%). If Ovenbirds in undisturbed forests usually produce female-biased broods, then the production of males as a result of logging may disrupt population viability. We recommend a broad examination of nestling sex ratios in response to anthropogenic disturbance to determine the generality of our findings

Is there a subjective well-being premium in voluntary sector employment?

Previous studies have found that employment in the voluntary sector offers a so-called ‘job satisfaction premium’: despite lower salaries, voluntary sector employees are more satisfied with their jobs than workers in other sectors. This paper examines whether voluntary sector employees also experience a subjective well-being premium. Using data from the UK Annual Population Survey 2012/2013, we find that voluntary sector employees do have higher levels of subjective well-being but this subjective well-being premium is not evenly distributed between men and women. Men score higher on happiness and life satisfaction. However, women in the voluntary sector have lower levels of life satisfaction compared with their counterparts in the public sector. We discuss the implications of our findings for policy and practice in the voluntary sector in the UK

Targeting N-myristoylation for therapy of B-cell lymphomas

N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients