Friedrichsenhurst0061

AIMS The effects of vericiguat vs. placebo on high-sensitivity C-reactive protein (hsCRP) and serum uric acid (SUA) were assessed in patients with heart failure with reduced ejection fraction (HFrEF) in the Phase 2 SOCRATES-REDUCED study (NCT01951625). METHODS AND RESULTS Changes from baseline hsCRP and SUA values at 12 weeks with placebo and vericiguat (1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg, respectively) were assessed. The probability of achieving an hsCRP value of ≤3.0 mg/L or SUA value of less then 7.0 mg/dL at week 12 was tested. Median baseline hsCRP and SUA levels were 3.68 mg/L [interquartile range (IQR) 1.41-8.41; n = 335] and 7.80 mg/dL (IQR 6.40-9.33; n = 348), respectively. Baseline-adjusted mean percentage changes in hsCRP were 0.2%, -19.5%, -24.3%, -25.7% and -31.9% in the placebo and vericiguat 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg groups, respectively; significance vs. placebo was observed in the vericiguat 10.0 mg group (P = 0.035). Baseline-adjusted mean percentage changes in SUA were 5.0%, -1.3%, -1.1%, -3.5% and -5.3% in the placebo, and vericiguat 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg groups, respectively; significance vs. placebo was observed in the 5.0 mg and 10.0 mg groups (P = 0.0202 and P = 0.004, respectively). Estimated probability for an end-of-treatment hsCRP value of ≤3.0 mg/L and SUA value of less then 7.0 mg/dL was higher with vericiguat compared with placebo. The effect was dose-dependent, with the greatest effect observed in the 10.0 mg group. CONCLUSIONS Vericiguat treatment for 12 weeks was associated with reductions in hsCRP and SUA, and a higher likelihood of achieving an hsCRP value of ≤3.0 mg/L and SUA value of less then 7.0 mg/dL. © 2020 Bayer AG Pharmaceuticals. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.Secondary metabolites (SMs) are crucial for fungi and vary in function from beneficial antibiotics to pathogenicity factors. To generate diversified SMs that enable different functions, SM-coding regions rapidly evolve in fungal genomes. However, the driving force and genetic mechanism of fungal SM diversification in the context of host-pathogen interactions remain largely unknown. Previously, we grouped field populations of the rice blast fungus Magnaporthe oryzae (syn Pyricularia oryzae) into three major globally distributed clades based on population genomic analyses. Here, we characterize a recent duplication of an avirulent gene-containing SM cluster, ACE1, in a clonal M. oryzae population (Clade 2). We demonstrate that the ACE1 cluster is specifically duplicated in Clade 2, a dominant clade in indica rice-growing areas. With long-read sequencing, we obtained chromosome-level genome sequences of four Clade 2 isolates, which displayed differences in genomic organization of the ACE1 duplication process. Comparative genomic analyses suggested that the original ACE1 cluster experienced frequent rearrangement in Clade 2 isolates and revealed that the new ACE1 cluster is located in a newly formed and transposable element-rich region. Taken together, these results highlight the frequent mutation and expansion of an avirulent gene-containing SM cluster through transposable element-mediated whole-cluster duplication in the context of host-pathogen interactions. © 2020 Society for Applied Microbiology and John Wiley & Sons Ltd.An outbreak of a novel coronavirus (2019-nCoV) that emerged in Wuhan has rapidly spread throughout China and has now become a global public health concern. As of the early March, a total of 100,000 cases have been confirmed in multiple countries. Clinical characteristics of 2019-nCoV that respiratory symptoms, such as cough, are the most common.[1] This is consistent with the finding that the majority of patients are virus-positive in nasopharyngeal and oropharyngeal swabs suggesting it mainly invades and infects the respiratory system, a hypothesis supported by pathological data.[2] In addition, it has been reported that patients' stool has tested positive for 2019-nCoV, indicating that the virus could spread from the respiratory tract to the digestive tract, or that individuals could be infected via the faecal-oral route. However, the neuroinvasive potential of 2019-nCoV remains poorly understood. This article is protected by copyright. All rights reserved.BACKGROUND Given the potentially additive risk from using donor livers that are both steatotic and from a donation after circulatory death(DCD) donor, there is a paucity of data on the outcome of DCD liver transplantation(LT) utilizing livers with macrosteatosis. METHODS All DCD LT performed at Mayo Clinic-Florida, Mayo Clinic-Arizona and Mayo Clinic-Rochester from 1999-2019 were included(N=714). Recipients of DCD LT were divided into 3 groups those with Moderate Macrosteatosis(30-60%), Mild Macrosteatosis(5-30%) and No Steatosis. RESULTS Patients with Moderate Macrosteatosis had a higher rate of post-reperfusion syndrome (PRS)(53.9% vs. 26.2%;p=0.002), post-reperfusion cardiac arrest(7.7% vs.0.3%;p less then 0.001), primary non-function(PNF)(7.7%vs.1.0%;p=0.003), early allograft dysfunction(EAD)(70.8%vs.45.6% and 8.3%;p=0.02) and acute kidney injury (AKI)(39.1%vs.19.4%; p=0.02) than patients with No Steatosis. No difference in any of the peri-operative complications was seen between the Mild Macrosteatosis and the No Steatosis groups except for the rate of EAD(56.8%vs.45.6%;p=0.04). No difference in ischemic cholangiopathy(IC), vascular thrombosis/stenosis or graft and patient survival was seen between the three groups. CONCLUSION DCD donors with mild macrosteatosis less then 30% can be utilized with no increase in peri-operative complications and similar patient and graft survival compared to DCD donors with no steatosis. When utilizing DCD donors with moderate macrosteatosis higher rates of PRS, PNF, post-reperfusion cardiac arrest, EAD and AKI should be anticipated. This article is protected by copyright. All rights reserved.Demographic compensation arises when vital rates change in opposite directions across populations, buffering the variation in population growth rates, and is a mechanism often invoked to explain the stability of species geographic ranges. However, studies on demographic compensation have disregarded the effects of temporal variation in vital rates and their temporal correlations, despite theoretical evidence that stochastic dynamics can affect population persistence in temporally varying environments. We carried out a seven-year-long demographic study on the perennial plant Arabis alpina (L.) across six populations encompassing most of its elevational range. We discovered demographic compensation in the form of negative correlations between the means of plant vital rates, but also between their temporal coefficients of variation, correlations and elasticities. Even if their contribution to demographic compensation was small, this highlights a previously overlooked, but potentially important, role of stochastic processes in stabilising population dynamics at range margins. © 2020 John Wiley & Sons Ltd/CNRS.Hepatitis B virus (HBV) is a leading cause of cirrhosis and hepatocellular carcinoma worldwide, with 250 million individuals chronically infected. Many stages of the HBV infectious cycle have been elucidated, but the mechanisms of HBV entry remain poorly understood. The identification of the sodium taurocholate cotransporting polypeptide (NTCP) as an HBV receptor and the establishment of NTCP-overexpressing hepatoma cell lines susceptible to HBV infection opens up new possibilities for investigating these mechanisms. We used HepG2-NTCP cells, and various chemical inhibitors and RNA interference (RNAi) approaches to investigate the host cell factors involved in HBV entry. We found that HBV uptake into these cells was dependent on the actin cytoskeleton and did not involve macropinocytosis or caveolae-mediated endocytosis. Instead, entry occurred via the clathrin-mediated endocytosis pathway. HBV internalisation was inhibited by pitstop-2 treatment and RNA-mediated silencing (siRNA) of the clathrin heavy chain, adaptor protein AP-2 and dynamin-2. We were able to visualise HBV entry in clathrin-coated pits and vesicles by electron microscopy (EM) and cryo-EM with immunogold labelling. These data demonstrating that HBV uses a clathrin-mediated endocytosis pathway to enter HepG2-NTCP cells increase our understanding of the complete HBV life cycle. © 2020 John Wiley & Sons Ltd.The inside walls of a nanopipette tip are decorated by a Pt deposit that is used as an open bipolar electrochemiluminescence (ECL) device to achieve intracellular wireless electroanalysis . The synergetic actions of nanopipette and of bipolar ECL lead to the spatial confinement of the voltage drop at the level of the Pt deposit, which generates ECL emission from luminol. The porous structure of Pt deposit permits the electrochemical transport of intracellular molecules into the nanopipette that is coupled with enzymatic reactions. Thus the intracellular concentrations of hydrogen peroxide or glucose are measured in vivo as well as the intracellular sphingomyelinase activity. In comparison with the classic bipolar ECL, the remarkably low potential applied in our approach is restricted inside the nanopipette and it minimizes the potential bias of the voltage on the cellular activity. Accordingly, this wireless ECL approach provides a new direction for analysis of single living cells. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.OBJECTIVES Alzheimer's disease (AD) is the most common neurodegenerative disease which is characterized by the formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. signaling pathway These abnormal proteins induce disturbance in mitochondrial dynamics and defect in autophagy system. Since presenilin-1 (PS1) is a core component in γ-secretase complex, the mutations of PS1 gene cause the interference of γ-secretase activity and lead to the increased Aβ42 secretion. We aimed to characterize the patient-specific induced pluripotent stem cell (iPSC) line carrying PS1-S170F mutation. Furthermore, we tested whether disease-modifying drug can reduce AD pathology in the AD iPSC-derived neurons. MATERIALS AND METHODS Mononuclear cells (MNCs) were isolated freshly from the peripheral blood of an autosomal dominant AD (ADAD) patient carrying presenilin-1 (PS1) mutation (Ser170Phe; PS1-S170F) and a cognitively normal control. We generated induced pluripotent stem cell (iPSC) lines, which were differentiated into functional coTau can be dramatically reduced by the treatment of LY-2886721, a BACE1 inhibitor. CONCLUSIONS Taken together, we have established and characterized the pathological features of an AD patient carrying PS1-S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future. © 2020 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.OBJECTIVES Loss-of-function mutations in the gene encoding the calcium-calmodulin (Ca2+ -CaM) dependent protein kinase kinase-2 (CaMKK2) enzyme are linked to bipolar disorder. Recently, a de novo arginine to cysteine (R311C) mutation in CaMKK2 was identified from a whole exome sequencing study of bipolar patients and their unaffected parents. The aim of the present study was to determine the functional consequences of the R311C mutation on CaMKK2 activity and regulation by Ca2+ -CaM. METHODS The effects of the R311C mutation on CaMKK2 activity and Ca2+ -CaM activation were examined using a radiolabeled adenosine triphosphate (ATP) kinase assay. We performed immunoblot analysis to determine whether the R311C mutation impacts threonine-85 (T85) autophosphorylation, an activating phosphorylation site on CaMKK2 that has also been implicated in bipolar disorder. We also expressed the R311C mutant in CaMKK2 knockout HAP1 cells and used immunoblot analysis and an MTS reduction assay to study its effects on Ca2+ -dependent downstream signaling and cell viability, respectively.