Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US)

Effects of an Infectious Fungus, Batrachochytrium dendrobatidis, on Amphibian Predator-Prey Interactions

The effects of parasites and pathogens on host behaviors may be particularly important in predator-prey contexts, since few animal behaviors are more crucial for ensuring immediate survival than the avoidance of lethal predators in nature. We examined the effects of an emerging fungal pathogen of amphibians, Batrachochytrium dendrobatidis, on anti-predator behaviors of tadpoles of four frog species. We also investigated whether amphibian predators consumed infected prey, and whether B. dendrobatidis caused differences in predation rates among prey in laboratory feeding trials. We found differences in anti-predator behaviors among larvae of four amphibian species, and show that infected tadpoles of one species (Anaxyrus boreas) were more active and sought refuge more frequently when exposed to predator chemical cues. Salamander predators consumed infected and uninfected tadpoles of three other prey species at similar rates in feeding trials, and predation risk among prey was unaffected by B. dendrobatidis. Collectively, our results show that even sub-lethal exposure to B. dendrobatidis can alter fundamental anti-predator behaviors in some amphibian prey species, and suggest the unexplored possibility that indiscriminate predation between infected and uninfected prey (i.e., non-selective predation) could increase the prevalence of this widely distributed pathogen in amphibian populations. Because one of the most prominent types of predators in many amphibian systems is salamanders, and because salamanders are susceptible to B. dendrobatidis, our work suggests the importance of considering host susceptibility and behavioral changes that could arise from infection in both predators and prey

Successful Determination of Larval Dispersal Distances and Subsequent Settlement for Long-Lived Pelagic Larvae

Despite its importance, we still have a poor understanding of the level of connectivity between marine populations in most geographical locations. Taking advantage of the natural features of the southeast coast of New Zealand's North Island, we deployed a series of settlement stations and conducted plankton tows to capture recent settlers and planktonic larvae of the common intertidal gastropod Austrolittorina cincta (6–8 week larval period). Satellite image analysis and ground truthing surveys revealed the absence of suitable intertidal rocky shore habitat for A. cincta over a 100 km stretch of coastline between Kapiti Island to the south and Wanganui to the north. Fifteen settlement stations (3 replicates×5 sites), which were used to mimic intertidal habitat suitable for A. cincta, were deployed for two months around and north of Kapiti Island (at 0.5, 1, 5, 15, 50 km). In addition, we also conducted plankton tows at each settlement station when the stations were first deployed to collect A. cincta larvae in the water column. On collection, all newly settled gastropods and larvae in the plankton samples were individually isolated, and a species-specific microsatellite marker was used to positively identify A. cincta individuals. Most of the positively identified A. cincta settlers and larvae were collected at the first three sampling stations (<5 km). However, low numbers of A. cincta settlers and larvae were also recorded at the two more distant locations (15 and 50 km). Dispersal curves modeled from our data suggested that <1% of gastropod larvae would travel more than 100 km. While our data show that most larvae are retained close to their natal populations (<5 km), a small proportion of larvae are able to travel much larger geographic distances. Our estimates of larval dispersal and subsequent settlement are one of only a few for marine species with a long-lived larva

Recent methods for polygenic analysis of genome-wide data implicate an important effect of common variants on cardiovascular disease risk

<p>Abstract</p> <p>Background</p> <p>Traditional genome-wide association studies are generally limited in their ability explain a large portion of genetic risk for most common diseases. We sought to use both traditional GWAS methods, as well as more recently developed polygenic genome-wide analysis techniques to identify subsets of single-nucleotide polymorphisms (SNPs) that may be involved in risk of cardiovascular disease, as well as estimate the heritability explained by common SNPs.</p> <p>Methods</p> <p>Using data from the Framingham SNP Health Association Resource (SHARe), three complimentary methods were applied to examine the genetic factors associated with the Framingham Risk Score, a widely accepted indicator of underlying cardiovascular disease risk. The first method adopted a traditional GWAS approach - independently testing each SNP for association with the Framingham Risk Score. The second two approaches involved polygenic methods with the intention of providing estimates of aggregate genetic risk and heritability.</p> <p>Results</p> <p>While no SNPs were independently associated with the Framingham Risk Score based on the results of the traditional GWAS analysis, we were able to identify cardiovascular disease-related SNPs as reported by previous studies. A predictive polygenic analysis was only able to explain approximately 1% of the genetic variance when predicting the 10-year risk of general cardiovascular disease. However, 20% to 30% of the variation in the Framingham Risk Score was explained using a recently developed method that considers the joint effect of all SNPs simultaneously.</p> <p>Conclusion</p> <p>The results of this study imply that common SNPs explain a large amount of the variation in the Framingham Risk Score and suggest that future, better-powered genome-wide association studies, possibly informed by knowledge of gene-pathways, will uncover more risk variants that will help to elucidate the genetic architecture of cardiovascular disease.</p

Transient Ureteral Obstruction Prevents against Kidney Ischemia/Reperfusion Injury via Hypoxia-Inducible Factor (HIF)-2α Activation

Although the protective effect of transient ureteral obstruction (UO) prior to ischemia on subsequent renal ischemia/reperfusion (I/R) injury has been documented, the underlying molecular mechanism remains to be understood. We showed in the current study that 24 h of UO led to renal tubular hypoxia in the ipsilateral kidney in mice, with the accumulation of hypoxia-inducible factor (HIF)-2α, which lasted for a week after the release of UO. To address the functions of HIF-2α in UO-mediated protection of renal IRI, we utilized the Mx-Cre/loxP recombination system to knock out target genes. Inactivation of HIF-2α, but not HIF-1α blunted the renal protective effects of UO, as demonstrated by much higher serum creatinine level and severer histological damage. UO failed to prevent postischemic neutrophil infiltration and apoptosis induction in HIF-2α knockout mice, which also diminished the postobstructive up-regulation of the protective molecule, heat shock protein (HSP)-27. The renal protective effects of UO were associated with the improvement of the postischemic recovery of intra-renal microvascular blood flow, which was also dependent on the activation of HIF-2α. Our results demonstrated that UO protected the kidney via activation of HIF-2α, which reduced tubular damages via preservation of adequate renal microvascular perfusion after ischemia. Thus, preconditional HIF-2α activation might serve as a novel therapeutic strategy for the treatment of ischemic acute renal failure

Adaptation of mammalian host-pathogen interactions in a changing arctic environment

Many arctic mammals are adapted to live year-round in extreme environments with low winter temperatures and great seasonal variations in key variables (e.g. sunlight, food, temperature, moisture). The interaction between hosts and pathogens in high northern latitudes is not very well understood with respect to intra-annual cycles (seasons). The annual cycles of interacting pathogen and host biology is regulated in part by highly synchronized temperature and photoperiod changes during seasonal transitions (e.g., freezeup and breakup). With a warming climate, only one of these key biological cues will undergo drastic changes, while the other will remain fixed. This uncoupling can theoretically have drastic consequences on host-pathogen interactions. These poorly understood cues together with a changing climate by itself will challenge host populations that are adapted to pathogens under the historic and current climate regime. We will review adaptations of both host and pathogens to the extreme conditions at high latitudes and explore some potential consequences of rapid changes in the Arctic

Women's Preferences for Treatment of Perinatal Depression and Anxiety : A Discrete Choice Experiment

Perinatal depression and anxiety (PNDA) are an international healthcare priority, associated with significant short- and long-term problems for women, their children and families. Effective treatment is available but uptake is suboptimal: some women go untreated whilst others choose treatments without strong evidence of efficacy. Better understanding of women's preferences for treatment is needed to facilitate uptake of effective treatment. To address this issue, a discrete choice experiment (DCE) was administered to 217 pregnant or postnatal women in Australia, who were recruited through an online research company and had similar sociodemographic characteristics to Australian data for perinatal women. The DCE investigated preferences regarding cost, treatment type, availability of childcare, modality and efficacy. Data were analysed using logit-based models accounting for preference and scale heterogeneity. Predicted probability analysis was used to explore relative attribute importance and policy change scenarios, including how these differed by women's sociodemographic characteristics. Cost and treatment type had the greatest impact on choice, such that a policy of subsidising effective treatments was predicted to double their uptake compared with the base case. There were differences in predicted uptake associated with certain sociodemographic characteristics: for example, women with higher educational attainment were more likely to choose effective treatment. The findings suggest policy directions for decision makers whose goal is to reduce the burden of PNDA on women, their children and families

The effectiveness of mindfulness-based interventions in the perinatal period: a systematic review and meta-analysis

Perinatal mental health difficulties are associated with adverse consequences for parents and infants. However, the potential risks associated with the use of psychotropic medication for pregnant and breastfeeding women and the preferences expressed by women for non-pharmacological interventions mean it is important to ensure that effective psychological interventions are available. It has been argued that mindfulness-based interventions may offer a novel approach to treating perinatal mental health difficulties, but relatively little is known about their effectiveness with perinatal populations. This paper therefore presents a systematic review and meta-analysis of the effectiveness of mindfulness-based interventions for reducing depression, anxiety and stress and improving mindfulness skills in the perinatal period. A systematic review identified seventeen studies of mindfulness-based interventions in the perinatal period, including both controlled trials (n = 9) and pre-post uncontrolled studies (n = 8). Eight of these studies also included qualitative data. Hedge’s g was used to assess uncontrolled and controlled effect sizes in separate meta-analyses, and a narrative synthesis of qualitative data was produced. Pre- to post-analyses showed significant reductions in depression, anxiety and stress and significant increases in mindfulness skills post intervention, each with small to medium effect sizes. Completion of the mindfulness-based interventions was reasonable with around three quarters of participants meeting study-defined criteria for engagement or completion where this was recorded. Qualitative data suggested that participants viewed mindfulness interventions positively. However, between-group analyses failed to find any significant post-intervention benefits for depression, anxiety or stress of mindfulness-based interventions in comparison to control conditions: effect sizes were negligible and it was conspicuous that intervention group participants did not appear to improve significantly more than controls in their mindfulness skills. The interventions offered often deviated from traditional mindfulness-based cognitive therapy or mindfulness-based stress reduction programmes, and there was also a tendency for studies to focus on healthy rather than clinical populations, and on antenatal rather than postnatal populations. It is argued that these and other limitations with the included studies and their interventions may have been partly responsible for the lack of significant between-group effects. The implications of the findings and recommendations for future research are discussed

Changing Bee and Hoverfly Pollinator Assemblages along an Urban-Rural Gradient

The potential for reduced pollination ecosystem service due to global declines of bees and other pollinators is cause for considerable concern. Habitat degradation, destruction and fragmentation due to agricultural intensification have historically been the main causes of this pollinator decline. However, despite increasing and accelerating levels of global urbanization, very little research has investigated the effects of urbanization on pollinator assemblages. We assessed changes in the diversity, abundance and species composition of bee and hoverfly pollinator assemblages in urban, suburban, and rural sites across a UK city.Bees and hoverflies were trapped and netted at 24 sites of similar habitat character (churchyards and cemeteries) that varied in position along a gradient of urbanization. Local habitat quality (altitude, shelter from wind, diversity and abundance of flowers), and the broader-scale degree of urbanization (e.g. percentage of built landscape and gardens within 100 m, 250 m, 500 m, 1 km, and 2.5 km of the site) were assessed for each study site. The diversity and abundance of pollinators were both significantly negatively associated with higher levels of urbanization. Assemblage composition changed along the urbanization gradient with some species positively associated with urban and suburban land-use, but more species negatively so. Pollinator assemblages were positively affected by good site habitat quality, in particular the availability of flowering plants.Our results show that urban areas can support diverse pollinator assemblages, but that this capacity is strongly affected by local habitat quality. Nonetheless, in both urban and suburban areas of the city the assemblages had fewer individuals and lower diversity than similar rural habitats. The unique development histories of different urban areas, and the difficulty of assessing mobile pollinator assemblages in just part of their range, mean that complementary studies in different cities and urban habitats are required to discover if these findings are more widely applicable

Tuberculosis chemotherapy: current drug delivery approaches

Tuberculosis is a leading killer of young adults worldwide and the global scourge of multi-drug resistant tuberculosis is reaching epidemic proportions. It is endemic in most developing countries and resurgent in developed and developing countries with high rates of human immunodeficiency virus infection. This article reviews the current situation in terms of drug delivery approaches for tuberculosis chemotherapy. A number of novel implant-, microparticulate-, and various other carrier-based drug delivery systems incorporating the principal anti-tuberculosis agents have been fabricated that either target the site of tuberculosis infection or reduce the dosing frequency with the aim of improving patient outcomes. These developments in drug delivery represent attractive options with significant merit, however, there is a requisite to manufacture an oral system, which directly addresses issues of unacceptable rifampicin bioavailability in fixed-dose combinations. This is fostered by the need to deliver medications to patients more efficiently and with fewer side effects, especially in developing countries. The fabrication of a polymeric once-daily oral multiparticulate fixed-dose combination of the principal anti-tuberculosis drugs, which attains segregated delivery of rifampicin and isoniazid for improved rifampicin bioavailability, could be a step in the right direction in addressing issues of treatment failure due to patient non-compliance