A structural phylogeny for understanding 2-oxoacid oxidoreductase function

2-Oxoacid:ferredoxin oxidoreductases (OFORs) are essential enzymes in microbial one-carbon metabolism. They use thiamine pyrophosphate to reversibly cleave carbon-carbon bonds, generating low potential (~-500 mV) electrons. Crystallographic analysis of a recently discovered OFOR, an oxalate oxidoreductase (OOR), has provided a second view of OFOR architecture and active site composition. Using these recent structural data along with the previously determined structures of pyruvate:ferredoxin oxidoreductase, structure-function relationships in this superfamily have been expanded and re-evaluated. Additionally, structural motifs have been defined that better serve to distinguish one OFOR subfamily from another and potentially uncover novel OFORs.National Institutes of Health (U.S.) (Grant GM069857)National Science Foundation (U.S.) (Grant 1122374

Mitochondrial ROS cause motor deficits induced by synaptic inactivity:implications for synapse pruning

Developmental synapse pruning refines burgeoning connectomes. The basic mechanisms of mitochondrial reactive oxygen species (ROS) production suggest they select inactive synapses for pruning: whether they do so is unknown. To begin to unravel whether mitochondrial ROS regulate pruning, we made the local consequences of neuromuscular junction (NMJ) pruning detectable as motor deficits by using disparate exogenous and endogenous models to induce synaptic inactivity en masse in developing Xenopus laevis tadpoles. We resolved whether: (1) synaptic inactivity increases mitochondrial ROS; and (2) antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bugarotoxin), nerve (α-latrotoxin) targeted neurotoxins or an endogenous pruning cue (SPARC), synaptic inactivity increased mitochondrial ROS in vivo. The manganese porphyrins MnTE-2-PyP5+ and/or MnTnBuOE-2-PyP5+ blocked mitochondrial ROS to significantly reduce neurotoxin and endogenous pruning cue induced motor deficits. Selectively inducing mitochondrial ROS—using mitochondria-targeted Paraquat (MitoPQ)—recapitulated synaptic inactivity induced motor deficits; which were significantly reduced by blocking mitochondrial ROS with MnTnBuOE-2-PyP5+. We unveil mitochondrial ROS as synaptic activity sentinels that regulate the phenotypical consequences of forced synaptic inactivity at the NMJ. Our novel results are relevant to pruning because synaptic inactivity is one of its defining features

Control of gag-pol gene expression in the Candida albicans retrotransposon Tca2

Non peer reviewedPublisher PD

A rabies lesson improves rabies knowledge amongst primary school children in Zomba, Malawi

<div><p>Rabies is an important neglected disease, which kills around 59,000 people a year. Over a third of these deaths are in children less than 15 years of age. Almost all human rabies deaths in Africa and Asia are due to bites from infected dogs. Despite the high efficacy of current rabies vaccines, awareness about rabies preventive healthcare is often low in endemic areas. It is therefore common for educational initiatives to be conducted in conjunction with other rabies control activities such as mass dog vaccination, however there are few examples where the efficacy of education activities has been assessed. Here, primary school children in Zomba, Malawi, were given a lesson on rabies biology and preventive healthcare. Subsequently, a mass dog vaccination programme was delivered in the same region. Knowledge and attitudes towards rabies were assessed by a questionnaire before the lesson, immediately after the lesson and 9 weeks later to assess the impact the lesson had on school children’s knowledge and attitudes. This assessment was also undertaken in children who were exposed to the mass dog vaccination programme but did not receive the lesson. Knowledge of rabies and how to be safe around dogs increased following the lesson (both p<0.001), and knowledge remained higher than baseline 9 weeks after the lesson (both p<0.001). Knowledge of rabies and how to be safe around dogs was greater amongst school children who had received the lesson compared to school children who had not received the lesson, but had been exposed to a rabies vaccination campaign in their community (both p<0.001) indicating that the lesson itself was critical in improving knowledge. In summary, we have shown that a short, focused classroom-based lesson on rabies can improve short and medium-term rabies knowledge and attitudes of Malawian schoolchildren.</p></div

Reduced Martian Carbon: Evidence from Martian Meteorites

Identification of indigenous reduced carbon species on Mars has been a challenge since the first hypotheses about life on Mars were proposed. Ranging from the early astronomical measurements to analyses of samples from the Martian surface in the form of Martian meteorites. The first direct attempt to analyze the carbon species on the surface was in 1976 with the Viking GC-MS in-situ experiment which gave inconclusive results at two sites on Mars [1]. With the recognition in 1983 that samples of the Martian surface were already present on Earth in the form of Martian meteorites by Bogard and Johnson [2] new opportunities became available for direct study of Mars's samples in te rlraesbtrioalratories. Carbon isotopic compositional information suggested a reduced carbon component was present in the Martian meteorites [3-5]. Polycyclic aromatic hydrocarbons associated with carbonate globules in ALH84001 were later identified [6,7]. Jull et al [8] noted that an insoluble component was present within Nakhla and more than 75% of its C lacked any 14C, which is modern-day carbon contaminant. This carbon fraction was believed to be either indigenous (i..e. Martian) or ancient meteoritic carbon phase. Within the fractures of Nakhla and ALH84001, Fisk et al [9,10] identified reduced carbon-enriched areas. Gibson et al. [11] using a combination of NanoSIMS, Focused Electron microscopy, Laser Raman Spectroscopy and Stepped-Combustion Static Mass Spectrometry analyses the presence of possible indigenous reduced carbon components within the 1.3 Ga old Nakhla

Friendships and Family Support Reduce Subsequent Depressive Symptoms in At-Risk Adolescents.

BACKGROUND: Early life stress (ELS) consists of child family adversities (CFA: negative experiences that happened within the family environment) and/or peer bullying. ELS plays an important role in the development of adolescent depressive symptoms and clinical disorders. Identifying factors that may reduce depressive symptoms in adolescents with ELS may have important public mental health implications. METHODS: We used structural equation modelling and examined the impact of adolescent friendships and/or family support at age 14 on depressive symptoms at age 17 in adolescents exposed to ELS before age 11. To this end, we used structural equation modelling in a community sample of 771 adolescents (322 boys and 477 girls) from a 3 year longitudinal study. Significant paths in the model were followed-up to test whether social support mediated or moderated the association between ELS and depressive symptoms at age 17. RESULTS: We found that adolescent social support in adolescence is negatively associated with subsequent depressive symptoms in boys and girls exposed to ELS. Specifically, we found evidence for two mediational pathways: In the first pathway family support mediated the link between CFA and depressive symptoms at age 17. Specifically, CFA was negatively associated with adolescent family support at age 14, which in turn was negatively associated with depressive symptoms at age 17. In the second pathway we found that adolescent friendships mediated the path between peer bullying and depressive symptoms. Specifically, relational bullying was negatively associated with adolescent friendships at age 14, which in turn were negatively associated with depressive symptoms at age 17. In contrast, we did not find a moderating effect of friendships and family support on the association between CFA and depressive symptoms. CONCLUSIONS: Friendships and/or family support in adolescence mediate the relationship between ELS and late adolescent depressive symptoms in boys and girls. Therefore, enhancing affiliate relationships and positive family environments may benefit the mental health of vulnerable youth that have experienced CFA and/or primary school bullying.AlvH was supported by a Rubicon Fellowship from the Netherlands Organization for Scientific Research. IMG was supported by a Wellcome Trust programme grant, and grants from the NIHR Collaboration for Leadership in Applied Health Research, and Care (CLAHRC) for Cambridgeshire and Peterborough; IMG, AlvH, and JLG were supported through a grant from Kidscompany UK; PBJ was supported by Wellcome Trust grants, and National Institute for Health Research grant; RAK is supported by a Wellcome grant; JLG reports grants from ESRC, grants from MRC, grants, and personal fees from Royal College of Speech, and Language therapists.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.015371

Implementation of a mass canine rabies vaccination campaign in both rural and urban regions in southern Malawi

Rabies is a devastating zoonotic disease causing nearly 60,000 deaths globally each year. The disease causes Malawi an economic loss of 13 million USD and kills almost 500 people annually. Domestic dogs are the main reservoir for rabies and vaccinating over 70% of the dog population is the most efficient method to reduce its incidence in both humans and canines. However, achieving such coverages is often difficult and depend on many geospatial factors. Rural and pastoral regions are considered difficult to vaccinate efficiently due to low dog densities, and reports of campaigns spanning large areas containing vastly different communities are lacking. This study describes a mass canine vaccination campaign covering rural and urban regions in southern Malawi. The campaign achieved an average vaccination coverage of 83.4% across 3 districts, and vaccinated over 89,000 dogs through a combined static point and door-to-door effort. A dog population of 107,574 dogs was estimated (dog:human ratio of 1:23). The canine population was found to be almost completely owned (99.2%) and mostly kept for security purposes (82.7%). The dogs were mainly adults, males, and not neutered. Regression analysis identified education level and proportion of young dogs as the only factors influencing (positively and negatively, respectively) whether vaccination coverage over 70% was achieved in a region, independently of variables such as population density or poverty. A second regression analysis was performed predicting absolute vaccination coverage. While education level and the proportion of confined dogs were associated with positive vaccination coverage, higher proportions of young animals and female dogs were associated with a decrease in coverage. This study confirms the feasibility of homogeneously vaccinating over 70% of the dogs in a large area including rural and urban communities. These findings can inform the logistics of future campaigns and might be used as a template to facilitate high-number, high-coverage vaccination campaigns to other regions in sub-Saharan Africa