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3 bpm [95% confidence interval (CI) -4.6, -0.1] with tofogliflozin. Changes in resting heart rate were positively correlated with changes in Adipo-IR, whereas reductions in HbA1c , body weight and blood pressure were similar independent of changes in resting heart among quartiles of resting heart rate change. On multivariate analysis, higher baseline resting heart rates and Adipo-IR values were significantly associated with greater reductions in resting heart rate. CONCLUSIONS Tofogliflozin corrected resting heart rate levels in accordance with baseline levels. Correction of high resting heart rates may be attributed to improved adipose tissue insulin resistance, leading to correction of hyperinsulinaemia. © 2020 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.Gap junctions (GJs) are widely distributed in brains across the animal kingdom. To visualize the GJ- coupled networks of two major mechanosensory neurons in the ganglia of medicinal leeches, we injected these cells with the GJ-permeable tracer Neurobiotin. When diffusion time was limited to only 30 min, tracer coupling was highly variable for both cells, suggesting a possible modulation of GJ permeability. In invertebrates the innexins (homologs of vertebrate pannexins) form the GJs. Because extracellular adenosine triphosphate (ATP) modulates pannexin and leech innexin hemichannel permeability and is released by leech glial cells following injury, we tested the effects of bath application of ATP after the injection of Neurobiotin and observed a significant increase in the number of neurons tracer coupled to the sensory neurons. This effect required the elevation of intracellular Ca2+ and could be produced by bath application of caffeine. Conversely, scavenging endogenous extracellular ATP with the ATPase apyrase decreased the number of coupled cells. ATP also increased electrical conductance and tracer permeability between the bilateral Retzius neurons. This modulatory effect of ATP on GJ coupling was blocked by siRNA knockdown of a P1-like adenosine receptor. Finally, exposure of leech ganglia to extracellular ATP induced a characteristic low frequency ( less then 0.3 Hz) rhythmic bursting activity that was roughly synchronous among multiple neurons, a behavior that was significantly attenuated by the GJ blocker octanol. These findings highlight the mediation by ATP of a robust physiological mechanism for modifying neuronal circuits by rapidly recruiting neurons into active networks and entraining synchronized bursting activity. © 2020 Wiley Periodicals, Inc.This article is concerned about the test for the difference in the distributions of multigroup proportional data, which is motivated by the problem of comparing the distributions of quality of life (QoL) outcomes among different treatment groups in clinical trials. The proportional data, such as QoL outcomes assessed by answers to questions on a questionnaire, are bounded in a closed interval such as [0,1] with continuous observations in (0,1) and, in addition, excess observations taking the boundary values 0 and/or 1. Common statistical procedures used in practice, such as t- and rank-based tests, may not be very powerful since they ignore the specific feature of the proportional data. In this article, we propose a three-component mixture model for the proportional data and a density ratio model for the distributions of continuous observations in (0,1). A semiparametric test statistic for the homogeneity of distributions of multigroup proportional data is derived based on the empirical likelihood ratio principle and shown to be asymptotically distributed as a chi-squared random variable under null hypothesis. A nonparametric bootstrap procedure is proposed to further improve the performance of the semiparametric test. Simulation studies are performed to evaluate the empirical type I error and power of the proposed test procedure and compare it with likelihood ratio tests (LRTs) under parametric distribution assumptions, rank-based Kruskal-Wallis test, and Wald-type test. The proposed test procedure is also applied to the analysis of QoL outcomes from a clinical trial on colorectal cancer that motivated our study. © 2020 John Wiley & Sons, Ltd.Plants can enhance their defence against herbivorous insects by responding to insect egg depositions preceding larval feeding. The similarity of plant responses to insect eggs with those to phytopathogens gave rise to the hypothesis that egg-associated microbes might act as elicitors. We tested this hypothesis by investigating first if elimination of microbes in the butterfly Pieris brassicae changes the responses of Brassica nigra and Arabidopsis thaliana to eggs and larvae of this insect species. An antibiotic treatment of butterflies mitigated the plant transcriptional response to the eggs and the egg-mediated enhancement of the plant's defence against larvae. However, application of cultivated microbial isolates from the eggs onto A. thaliana did not enhance the plant's anti-herbivore defence. Instead, application of an egg-associated glandular secretion, which is attaching the eggs to the leaves, elicited the enhancing effect on the plant's defence against larvae. However, this effect was only achieved when the secretion was applied in similar quantities as released by control butterflies, but not when applied in the reduced quantity as released by antibiotic-treated butterflies. We conclude that glandular secretions rather than egg-associated microbes act in a dose-dependent manner as elicitor of the egg-mediated enhancement of the plant's defence against insect larvae. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Since December 2019, a series of unexplained pneumonia cases have been reported in Wuhan, China. On 12 January 2020, the World Health Organization (WHO) temporarily named this new virus as the 2019 novel coronavirus (2019-nCoV). On 11 February 2020, the WHO officially named the disease caused by the 2019-nCoV as coronavirus disease (COVID-19). The COVID-19 epidemic is spreading all over the world, especially in China. Based on the published evidence, we systematically discuss the characteristics of COVID-19 in the hope of providing a reference for future studies and help for the prevention and control of the COVID-19 epidemic. © 2020 Wiley Periodicals, Inc.To reconstruct the evolutionary dynamics of the 2019 novel-coronavirus recently causing an outbreak in Wuhan, China, 52 SARS-CoV-2 genomes available on 4 February 2020 at Global Initiative on Sharing All Influenza Data were analyzed. The two models used to estimate the reproduction number (coalescent-based exponential growth and a birth-death skyline method) indicated an estimated mean evolutionary rate of 7.8 × 10-4 subs/site/year (range, 1.1 × 10-4 -15 × 10-4 ) and a mean tMRCA of the tree root of 73 days. The estimated R value was 2.6 (range, 2.1-5.1), and increased from 0.8 to 2.4 in December 2019. The estimated mean doubling time of the epidemic was between 3.6 and 4.1 days. This study proves the usefulness of phylogeny in supporting the surveillance of emerging new infections even as the epidemic is growing. © 2020 Wiley Periodicals, Inc.Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated. Here, we discovered that CRLS1 was significantly downregulated in genetically obese and diet-induced mice models. In vitro studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas shRNA mediate CRLS1 knockdown aggravated these abnormalities. Moreover, high-fat diet (HFD) induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocyte-specific Crls1-knockout (Crls1-HKO) mice. It's worth noting that Crls1 depletion significantly aggravated high-fat and high-cholesterol (HFHC) diet induced inflammatory response and fibrosis during NASH development. RNA-sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder, inflammation and fibrosis resulted from Crls1-deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in Crls1-HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppressed ATF3 expression and inhibits its activity in palmitic acid-stimulated hepatocytes, while ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress. In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3. This article is protected by copyright. All rights reserved.During tissue and organ regeneration, cells initially detect damage and then alter nuclear transcription in favor of tissue/organ reconstruction. Until recently, studies of tissue regeneration have focused on the identification of relevant genes. These studies show that many developmental genes are reused during regeneration. Concurrently, comparative genomics studies have shown that the total number of genes does not vastly differ among vertebrate taxa. Moreover, functional analyses of developmental genes using various knockout/knockdown techniques demonstrated that the functions of these genes are conserved among vertebrates. Adavosertib Despite these data, the ability to regenerate damaged body parts varies widely between animals. Thus, it is important to determine how regenerative transcriptional programs are triggered and why animals with low regenerative potential fail to express developmental genes after injury. Recently, we discovered relevant enhancers and named them regeneration signal-response enhancers (RSREs) after identifying their activation mechanisms in a Xenopus laevis transgenic system. In this review, we summarize recent studies of injury/regeneration-associated enhancers and then discuss their mechanisms of activation. © 2020 Japanese Society of Developmental Biologists.Malaria is one of the most widespread human infectious diseases worldwide and a cause of mortality. It is difficult to induce immunological memory against the malarial parasite Plasmodium. The immunity to clinical malaria disease is acquired with multiple infection and treatment cycles, along with substantial reduction in parasite burden. However, the mechanism of the acquired immunity remains largely unclear. Conventional DCs (cDCs) play a pivotal role in orchestration of immune responses. The purpose of this study is to analyze the characterization of cDCs after the infection and cure treatment cycles. Mice were infected with the lethal rodent malarial parasite Plasmodium berghei ANKA, which was followed by cure treatment with the antimalarial drug pyrimethamine. This was then followed by a challenge with live parasites. The mice that went through infection cure cycles showed significant immune response, demonstrating robust immunological memory against malaria parasites. We investigated the cytokine production capacity of splenic cDCs in both naive and infection cure mice by stimulating purified splenic cDCs with LPS (TLR4 agonist) or CpG (TLR9 agonist).