Sedimentology and fossil-fuel potential of the Upper Carboniferous Barchois group, western Newfoundland

The coal-bearing Upper Carboniferous Barachois Group of western Newfoundland consists of the youngest known rocks in the St. George's Bay Lowlands. These lowlands are part of the Bay St. George Subbasin, which, in turn, is part of a network of Carboniferous depositional areas in eastern Canada. A detailed sedimentological study of the Barachois Group was undertaken as part of a more general study (involving geology and geophysics) to assess the fossil-fuel potential of the western Newfoundland Carboniferous subbasins. -- Cores and exposures of the Barachois Group in the St. George's Bay Lowlands define a lower coarse unit and an upper fine unit. The coarse unit consists of alternating red-brown mudstone-dominated units and grey sandstone and conglomerate-dominated units. The fine unit consists of thick grey or red-brown mudstone-dominated units with interspersed sandstone units. Eleven facies (A to K) are recognized in the two units. The facies are organized into three facies associations and eight subassociations. Facies association I includes fluvial channel sandstones and conglomerates found in outcrops and the BSG£1 core (subassociation IA) and channel and minor sheetflood deposits found in the FB2-76 core (subassociation IB). Facies association II comprises sandstones and mudstones deposited in proximal crevasse channel and levee environments (subassociation IIA), in undifferentiated crevasse splay, levee, and floodplain environments (subassociation IIB), and by progradation of crevasse splay, levee, and delta environments (subassociation IIC). Facies association III includes mudstone-dominated subassociations which represent the deposits of floodplain lakes (subassociation IIIA), poorly-drained swamps (subassociation IIIB), and well-drained swamps (subassociation IIIC). -- Sandstones of the Barachois Group are classified predominantly as arkose and subarkose, with up to 65% feldspar. The sandstones include a variety of authigenic minerals such as kaolinitie, chlorite, illite, calcite, and silica. Sandstone mineralogy does not identify any distinctive provenance. Potential sources of the arkoses could have included several of the presently exposed igneous intrusive complexes in the Long Range Mountains located southeast, east, and north of the study area. -- X-ray diffraction of the <2 micrometer fraction shows that mudstones contain illite, chlorite, kaolinite and mixed-layer clay minerals. Illite predominates in non-grey mudstone; chlorite is the most abundant clay mineral in grey mudstones. Variations in clay mineralogy are due to a combination of initial detrital mineralogy and relative stability of clay minerals through a variety of depositional and diagenetic environments. -- Kerogen types in the Barachois Group are dominated by woody (type III) kerogen with lesser amounts of amorphous and herbaceous types. Thermal maturation indices and kerogen type indicate that mudstones have a fair gas potential, but potential reservoir rocks exhibit poor to fair porosity. Oil shales are lean and coals exhibit considerable variation both between and within seams in terms of ash and sulfur contents. Oil shales and coals appear to be of limited lateral extent and coals are commonly faulted

Valsartan for attenuating disease evolution in early sarcomeric hypertrophic cardiomyopathy: the design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial

Background: Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype. Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained

Arctic Coastal Dynamics (ACD): an introduction

Background and rationale The coastal zone is the interface through which land-ocean exchanges in the Arctic are mediated and it is the site of most of the human activity that occurs at high latitudes. Arctic coastlines are highly variable and their dynamics are a function of environmental forcing (wind, waves, sea-level changes, sea-ice, etc.), geology, permafrost and its ground-ice content and coastline morphometry. Environmental forcing initiates coastal processes, such as the sediment transport by waves, currents and sea-ice and the degradation of coastal permafrost. The coastal response (erosion or accretion) results in land and habitat loss or gain and thus affects biological and human systems. Figure 1 schematically illustrates the major processes involved in Arctic coastal dynamics. Coastal processes in the Arctic are strongly controlled by Arctic-specific phenomena, i.e. the sea-ice cover and the existence of onshore and offshore permafrost. ... (Excerpt

Human Immunodeficiency Virus (HIV)-Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy.

BackgroundIdentifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy.MethodsCell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry.ResultsIntegrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines.ConclusionsHIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues

Comorbidity burden in axial spondyloarthritis: a cluster analysis

Objectives To examine how comorbidities cluster in axial spondyloarthritis (axSpA) and whether these clusters are associated with quality of life, global health and other outcome measures. Methods We conducted a cross-sectional study of consecutive patients meeting ASAS criteria for axSpA in Liverpool, UK. Outcome measures included quality of life (EQ5D), global health and disease activity (BASDAI). We used hierarchical cluster analysis to group patients according to 38 pre-specified comorbidities. In multivariable linear models, the associations between distinct comorbidity clusters and each outcome measure were compared, using axSpA patients with no comorbidities as the reference group. Analyses were adjusted for age, gender, symptom duration, BMI, deprivation, NSAID-use and smoking. Results We studied 419 patients (69% male, mean age 46 years). 255 patients (61%) had at least one comorbidity, among whom the median number was 1 (range 1–6). Common comorbidities were hypertension (19%) and depression (16%). Of 15 clusters identified, the most prevalent clusters were hypertension-coronary heart disease and depression-anxiety. Compared with patients with no comorbidities, the fibromyalgia-irritable bowel syndrome cluster was associated with adverse patient-reported outcome measures; these patients reported 1.5-unit poorer global health (95%CI 0.01, 2.9), reduced quality of life (0.25-unit lower EQ5D; 95%CI −0.37, −0.12) and 1.8-unit higher BASDAI (95% CI 0.4, 3.3). Similar effect estimates were found for patients in the depression-anxiety cluster. Conclusion Comorbidity is common among axSpA patients. The two most common comorbidities were hypertension and depression. Patients in the depression-anxiety and fibromyalgia-IBS clusters reported poorer health and increased axSpA severity

Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties.

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies

A Multidimensional Analytical Comparison of Remicade and the Biosimilar Remsima

In April 2016, the Food and Drug Administration approved the first biosimilar monoclonal antibody (mAb) – Inflectra/Remsima (Celltrion) based off the original product Remicade (infliximab, Janssen). Biosimilars promise significant cost savings for patients, but the unavoidable differences between innovator and copycat biologics raise questions regarding product interchangeability. In this study, Remicade and Remsima were examined by native mass spectrometry, ion mobility and quantitative peptide mapping. The levels of oxidation, deamidation and mutation of individual amino acids were remarkably similar. We found different levels of C-terminal truncation, soluble protein aggregates and glycation that all likely have a limited clinical impact. Importantly, we identified over 25 glycoforms for each product and observed glycoform population differences, with afucosylated glycans accounting for 19.7% of Remicade and 13,2% of Remsima glycoforms, which translated into a 2-fold reduction in FcγRIIIa binding for Remsima. While this difference was acknowledged in Remsima regulatory filings, our glycoform analysis and receptor binding results appear to be somewhat different from the published values, likely due to methodological differences between laboratories and improved glycoform identification by our laboratory using a peptide map-based method. Our mass spectrometry based analysis provides rapid and robust analytical information vital for biosimilar development. We have demonstrated the utility of our multiple attribute monitoring workflow using the model mAbs Remicade and Remsima, and have provided a template for analysis of future mAb biosimilars

Impact of animal strain on gene expression in a rat model of acute cardiac rejection

<p>Abstract</p> <p>Background</p> <p>The expression levels of many genes show wide natural variation among strains or populations. This study investigated the potential for animal strain-related genotypic differences to confound gene expression profiles in acute cellular rejection (ACR). Using a rat heart transplant model and 2 different rat strains (Dark Agouti, and Brown Norway), microarrays were performed on native hearts, transplanted hearts, and peripheral blood mononuclear cells (PBMC).</p> <p>Results</p> <p>In heart tissue, strain alone affected the expression of only 33 probesets while rejection affected the expression of 1368 probesets (FDR 10% and FC ≥ 3). Only 13 genes were affected by both strain and rejection, which was < 1% (13/1368) of all probesets differentially expressed in ACR. However, for PBMC, strain alone affected 265 probesets (FDR 10% and FC ≥ 3) and the addition of ACR had little further effect. Pathway analysis of these differentially expressed strain effect genes connected them with immune response, cell motility and cell death, functional themes that overlap with those related to ACR. After accounting for animal strain, additional analysis identified 30 PBMC candidate genes potentially associated with ACR.</p> <p>Conclusion</p> <p>In ACR, genetic background has a large impact on the transcriptome of immune cells, but not heart tissue. Gene expression studies of ACR should avoid study designs that require cross strain comparisons between leukocytes.</p