Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes

OBJECTIVE - Recently we have shown that calpain-1 activation contributes to cardiomyocyte apoptosis induced by hyperglycemia. This study was undertaken to investigate whether targeted disruption of calpain would reduce myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes. RESEARCH DESIGN AND METHODS - Diabetes in mice was induced by injection of streptozotocin (STZ), and OVE26 mice were also used as a type 1 diabetic model. The function of calpain was genetically manipulated by cardiomyocyte-specific knockout Capn4 in mice and the use of calpastatin transgenic mice. Myocardial hypertrophy and fibrosis were investigated 2 and 5 months after STZ injection or in OVE26 diabetic mice at the age of 5 months. Cultured isolated adult mouse cardiac fibroblast cells were also investigated under high glucose conditions. RESULTS - Calpain activity, cardiomyocyte cross-sectional areas, and myocardial collagen deposition were significantly increased in both STZ-induced and OVE26 diabetic hearts, and these were accompanied by elevated expression of hypertrophic and fibrotic collagen genes. Deficiency of Capn4 or overexpression of calpastatin reduced myocardial hypertrophy and fibrosis in both diabetic models, leading to the improvement of myocardial function. These effects were associated with a normalization of the nuclear factor of activated T-cell nuclear factor-kB and matrix metalloproteinase (MMP) activities in diabetic hearts. In cultured cardiac fibroblasts, high glucose-induced proliferation and MMP activities were prevented by calpain inhibition. CONCLUSIONS - Myocardial hypertrophy and fibrosis in diabetic mice are attenuated by reduction of calpain function. Thus targeted inhibition of calpain represents a potential novel therapeutic strategy for reversing diabetic cardiomyopathy. © 2011 by the American Diabetes Association

An evaluation of operational and research weather forecasts for Southern West Africa using observations from the DACCIWA field campaign in June‐July 2016

Reliable and accurate weather forecasts have the potential to improve living conditions in densely populated southern West Africa (SWA), in particularly those of rainfall and its extremes. A limited availability of observations has long impeded a rigorous evaluation of current state‐of‐the‐art forecast models. The field campaign of the Dynamics‐Aerosol‐Chemistry‐Cloud Interactions in West Africa (DACCIWA) project in June‐July 2016 has created an unprecedentedly dense set of measurements from surface stations and radiosondes. Here we present results from a comprehensive evaluation of both numerical model forecasts and satellite products using these data on a regional and local level. Results reveal a substantial observational uncertainty showing considerable underestimations in satellite estimates of rainfall and low‐cloud cover with little correlation at the local scale. Models have a dry bias of 0.1–1.9 mmday−1 in rainfall and too low column relative humidity. They tend to underestimate low clouds, leading to excess surface solar radiation of 43 Wm−2. Remarkably, most models show some skill in representing regional modulations of rainfall related to synoptic‐scale disturbances, while local variations in rainfall and cloudiness are hardly captured. Slightly better results are found with respect to temperature and for the post‐onset rather than for the pre‐onset period. Delicate local features such as the Maritime Inflow phenomenon are also rather poorly represented, leading to too cool, dry and cloudy conditions at the coast. Differences between forecast days 1 and 2 are relatively small and hardly systematic, suggesting a relatively quick error saturation. Using explicit convection leads to more realistic spatial variability in rainfall, but otherwise no marked improvement. Future work should aim at improving the subtle balance between the diurnal cycles of low clouds, surface radiation, the boundary layer and convection. Further efforts are also needed to improve the observational system beyond field campaign periods

Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance.

BACKGROUND: Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. METHODS: In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. RESULTS: We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. CONCLUSIONS: We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response

Measuring the capability to raise revenue process and output dimensions and their application to the Zambia revenue authority

The worldwide diffusion of the good governance agenda and new public management has triggered a renewed focus on state capability and, more specifically, on the capability to raise revenue in developing countries. However, the analytical tools for a comprehensive understanding of the capability to raise revenue remain underdeveloped. This article aims at filling this gap and presents a model consisting of the three process dimensions ‘information collection and processing’, ‘merit orientation’ and ‘administrative accountability’. ‘Revenue performance’ constitutes the fourth capability dimension which assesses tax administration’s output. This model is applied to the case of the Zambia Revenue Authority. The dimensions prove to be valuable not only for assessing the how much but also the how of collecting taxes. They can be a useful tool for future comparative analyses of tax administrations’ capabilities in developing countries.Die weltweite Verbreitung der Good-Governance- und New-Public-Management-Konzepte hat zu einer zunehmenden Konzentration auf staatliche Leistungsfähigkeit und, im Besonderen, auf die Leistungsfähigkeit der Steuererhebung in Entwicklungsländern geführt. Allerdings bleiben die analytischen Werkzeuge für ein umfassendes Verständnis von Leistungsfähigkeit unterentwickelt. Dieser Artikel stellt hierfür ein Modell vor, das die drei Prozess-Dimensionen „Sammeln und Verarbeiten von Informationen“, „Leistungsorientierung der Mitarbeiter“ und „Verantwortlichkeit der Verwaltung“ beinhaltet. „Einnahmeperformanz“ ist die vierte Dimension und erfasst den Output der Steuerverwaltung. Das mehrdimensionale Modell wird für die Analyse der Leistungsfähigkeit der Steuerbehörde Zambias (Zambia Revenue Authority) genutzt. Es erweist sich nicht nur für die Untersuchung des Wieviel, sondern auch des Wie des Erhebens von Steuern als wertvoll. Die vier Dimensionen können in Zukunft zur umfassenden und vergleichenden Analyse der Leistungsfähigkeit verschiedener Steuerverwaltungen in Entwicklungsländern genutzt werden

Reconstruction of Family-Level Phylogenetic Relationships within Demospongiae (Porifera) Using Nuclear Encoded Housekeeping Genes

Background: Demosponges are challenging for phylogenetic systematics because of their plastic and relatively simple morphologies and many deep divergences between major clades. To improve understanding of the phylogenetic relationships within Demospongiae, we sequenced and analyzed seven nuclear housekeeping genes involved in a variety of cellular functions from a diverse group of sponges. Methodology/Principal Findings: We generated data from each of the four sponge classes (i.e., Calcarea, Demospongiae, Hexactinellida, and Homoscleromorpha), but focused on family-level relationships within demosponges. With data for 21 newly sampled families, our Maximum Likelihood and Bayesian-based approaches recovered previously phylogenetically defined taxa: Keratosap, Myxospongiaep, Spongillidap, Haploscleromorphap (the marine haplosclerids) and Democlaviap. We found conflicting results concerning the relationships of Keratosap and Myxospongiaep to the remaining demosponges, but our results strongly supported a clade of Haploscleromorphap+Spongillidap+Democlaviap. In contrast to hypotheses based on mitochondrial genome and ribosomal data, nuclear housekeeping gene data suggested that freshwater sponges (Spongillidap) are sister to Haploscleromorphap rather than part of Democlaviap. Within Keratosap, we found equivocal results as to the monophyly of Dictyoceratida. Within Myxospongiaep, Chondrosida and Verongida were monophyletic. A well supported clade within Democlaviap, Tetractinellidap, composed of all sampled members of Astrophorina and Spirophorina (including the only lithistid in our analysis), was consistently revealed as the sister group to all other members of Democlaviap. Within Tetractinellidap, we did not recover monophyletic Astrophorina or Spirophorina. Our results also reaffirmed the monophyly of order Poecilosclerida (excluding Desmacellidae and Raspailiidae), and polyphyly of Hadromerida and Halichondrida. Conclusions/Significance: These results, using an independent nuclear gene set, confirmed many hypotheses based on ribosomal and/or mitochondrial genes, and they also identified clades with low statistical support or clades that conflicted with traditional morphological classification. Our results will serve as a basis for future exploration of these outstanding questions using more taxon- and gene-rich datasets

Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4

Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-gamma (IFN gamma) production in stimulated natural killer cells, and decreased circulating IFN gamma concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFN gamma-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.Peer reviewe

Conducting robust ecological analyses with climate data

Although the number of studies discerning the impact of climate change on ecological systems continues to increase, there has been relatively little sharing of the lessons learnt when accumulating this evidence. At a recent workshop entitled ‘Using climate data in ecological research’ held at the UK Met Office, ecologists and climate scientists came together to discuss the robust analysis of climate data in ecology. The discussions identified three common pitfalls encountered by ecologists: 1) selection of inappropriate spatial resolutions for analysis; 2) improper use of publically available data or code; and 3) insufficient representation of the uncertainties behind the adopted approach. Here, we discuss how these pitfalls can be avoided, before suggesting ways that both ecology and climate science can move forward. Our main recommendation is that ecologists and climate scientists collaborate more closely, on grant proposals and scientific publications, and informally through online media and workshops. More sharing of data and code (e.g. via online repositories), lessons and guidance would help to reconcile differing approaches to the robust handling of data. We call on ecologists to think critically about which aspects of the climate are relevant to their study system, and to acknowledge and actively explore uncertainty in all types of climate data. And we call on climate scientists to make simple estimates of uncertainty available to the wider research community. Through steps such as these, we will improve our ability to robustly attribute observed ecological changes to climate or other factors, while providing the sort of influential, comprehensive analyses that efforts to mitigate and adapt to climate change so urgently require

A Model Analysis of Arterial Oxygen Desaturation during Apnea in Preterm Infants

Rapid arterial O2 desaturation during apnea in the preterm infant has obvious clinical implications but to date no adequate explanation for why it exists. Understanding the factors influencing the rate of arterial O2 desaturation during apnea () is complicated by the non-linear O2 dissociation curve, falling pulmonary O2 uptake, and by the fact that O2 desaturation is biphasic, exhibiting a rapid phase (stage 1) followed by a slower phase when severe desaturation develops (stage 2). Using a mathematical model incorporating pulmonary uptake dynamics, we found that elevated metabolic O2 consumption accelerates throughout the entire desaturation process. By contrast, the remaining factors have a restricted temporal influence: low pre-apneic alveolar causes an early onset of desaturation, but thereafter has little impact; reduced lung volume, hemoglobin content or cardiac output, accelerates during stage 1, and finally, total blood O2 capacity (blood volume and hemoglobin content) alone determines during stage 2. Preterm infants with elevated metabolic rate, respiratory depression, low lung volume, impaired cardiac reserve, anemia, or hypovolemia, are at risk for rapid and profound apneic hypoxemia. Our insights provide a basic physiological framework that may guide clinical interpretation and design of interventions for preventing sudden apneic hypoxemia