Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol

Introduction: Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12–15% of patients with SSc and accounts for 30– 40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc- PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. Methods and analysis: This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. Ethics and dissemination: Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals.Alicia Calderone, Wendy Stevens, David Prior, Harshal Nandurkar, Eli Gabbay, Susanna M Proudman, Trevor Williams, David Celermajer, Joanne Sahhar, Peter K K Wong, Vivek Thakkar, Nathan Dwyer, Jeremy Wrobel, Weng Chin, Danny Liew, Margaret Staples, Rachelle Buchbinder, Mandana Nikpou

Novel mutations in the voltage-gated sodium channel of pyrethroid-resistant Varroa destructor populations from the Southeastern USA

The parasitic mite Varroa destructor has a significant worldwide impact on bee colony health. In the absence of control measures, parasitized colonies invariably collapse within 3 years. The synthetic pyrethroids tau-fluvalinate and flumethrin have proven very effective at managing this mite within apiaries, but intensive control programs based mainly on one active ingredient have led to many reports of pyrethroid resistance. In Europe, a modification of leucine to valine at position 925 (L925V) of the V. destructor voltage-gated sodium channel was correlated with resistance, the mutation being found at high frequency exclusively in hives with a recent history of pyrethroid treatment. Here, we identify two novel mutations, L925M and L925I, in tau-fluvalinate resistant V. destructor collected at seven sites across Florida and Georgia in the Southeastern region of the USA. Using a multiplexed TaqMan® allelic discrimination assay, these mutations were found to be present in 98% of the mites surviving tau-fluvalinate treatment. The mutations were also found in 45% of the non-treated mites, suggesting a high potential for resistance evolution if selection pressure is applied. The results from a more extensive monitoring programme, using the Taqman® assay described here, would clearly help beekeepers with their decision making as to when to include or exclude pyrethroid control products and thereby facilitate more effective mite management programmes

Infrastructure for Detector Research and Development towards the International Linear Collider

The EUDET-project was launched to create an infrastructure for developing and testing new and advanced detector technologies to be used at a future linear collider. The aim was to make possible experimentation and analysis of data for institutes, which otherwise could not be realized due to lack of resources. The infrastructure comprised an analysis and software network, and instrumentation infrastructures for tracking detectors as well as for calorimetry.Comment: 54 pages, 48 picture

REST is a hypoxia-responsive transcriptional repressor

Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia

Host Sexual Dimorphism and Parasite Adaptation

Disease expression and prevalence often vary in the different sexes of the host. This is typically attributed to innate differences of the two sexes but specific adaptations by the parasite to one or other host sex may also contribute to these observations

Effect of acute pesticide exposure on bee spatial working memory using an analogue of the radial-arm maze

Pesticides, including neonicotinoids, typically target pest insects by being neurotoxic. Inadvertent exposure to foraging insect pollinators is usually sub-lethal, but may affect cognition. One cognitive trait, spatial working memory, may be important in avoiding previously-visited flowers and other spatial tasks such as navigation. To test this, we investigated the effect of acute thiamethoxam exposure on spatial working memory in the bumblebee Bombus terrestris, using an adaptation of the radial-arm maze (RAM). We first demonstrated that bumblebees use spatial working memory to solve the RAM by showing that untreated bees performed significantly better than would be expected if choices were random or governed by stereotyped visitation rules. We then exposed bees to either a high sub-lethal positive control thiamethoxam dose (2.5ng-1 bee), or one of two low doses (0.377 or 0.091ng-1) based on estimated field-realistic exposure. The high dose caused bees to make more and earlier spatial memory errors and take longer to complete the task than unexposed bees. For the low doses, the negative effects were smaller but statistically significant, and dependent on bee size. The spatial working memory impairment shown here has the potential to harm bees exposed to thiamethoxam, through possible impacts on foraging efficiency or homing

A Genome-Wide Screen for Genetic Variants That Modify the Recruitment of REST to Its Target Genes

Increasing numbers of human diseases are being linked to genetic variants, but our understanding of the mechanistic links leading from DNA sequence to disease phenotype is limited. The majority of disease-causing nucleotide variants fall within the non-protein-coding portion of the genome, making it likely that they act by altering gene regulatory sequences. We hypothesised that SNPs within the binding sites of the transcriptional repressor REST alter the degree of repression of target genes. Given that changes in the effective concentration of REST contribute to several pathologies—various cancers, Huntington's disease, cardiac hypertrophy, vascular smooth muscle proliferation—these SNPs should alter disease-susceptibility in carriers. We devised a strategy to identify SNPs that affect the recruitment of REST to target genes through the alteration of its DNA recognition element, the RE1. A multi-step screen combining genetic, genomic, and experimental filters yielded 56 polymorphic RE1 sequences with robust and statistically significant differences of affinity between alleles. These SNPs have a considerable effect on the the functional recruitment of REST to DNA in a range of in vitro, reporter gene, and in vivo analyses. Furthermore, we observe allele-specific biases in deeply sequenced chromatin immunoprecipitation data, consistent with predicted differenes in RE1 affinity. Amongst the targets of polymorphic RE1 elements are important disease genes including NPPA, PTPRT, and CDH4. Thus, considerable genetic variation exists in the DNA motifs that connect gene regulatory networks. Recently available ChIP–seq data allow the annotation of human genetic polymorphisms with regulatory information to generate prior hypotheses about their disease-causing mechanism

Identification of sumoylation targets, combined with inactivation of SMT3, reveals the impact of sumoylation upon growth, morphology, and stress resistance in the pathogen Candida albicans

Peer reviewedPublisher PD

CUBES: a UV spectrograph for the future

In spite of the advent of extremely large telescopes in the UV/optical/NIR range, the current generation of 8-10m facilities is likely to remain competitive at ground-UV wavelengths for the foreseeable future. The Cassegrain U-Band Efficient Spectrograph (CUBES) has been designed to provide high-efficiency (>40%) observations in the near UV (305-400 nm requirement, 300-420 nm goal) at a spectral resolving power of R>20,000, although a lower-resolution, sky-limited mode of R ~ 7,000 is also planned. CUBES will offer new possibilities in many fields of astrophysics, providing access to key lines of stellar spectra: a tremendous diversity of iron-peak and heavy elements, lighter elements (in particular Beryllium) and light-element molecules (CO, CN, OH), as well as Balmer lines and the Balmer jump (particularly important for young stellar objects). The UV range is also critical in extragalactic studies: the circumgalactic medium of distant galaxies, the contribution of different types of sources to the cosmic UV background, the measurement of H2 and primordial Deuterium in a regime of relatively transparent intergalactic medium, and follow-up of explosive transients. The CUBES project completed a Phase A conceptual design in June 2021 and has now entered the Phase B dedicated to detailed design and construction. First science operations are planned for 2028. In this paper, we briefly describe the CUBES project development and goals, the main science cases, the instrument design and the project organization and management