Dapagliflozin Ameliorates Lipopolysaccharide Related Acute Kidney Injury in Mice with Streptozotocin-induced Diabetes Mellitus

Sepsis, which is a serious medical condition induced by infection, has been the most common cause of acute kidney injury (AKI) and is associated with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new oral antidiabetic drug that has greatly improved the cardiovascular and renal outcomes in patients with type 2 diabetes independent of its sugar lowering effect, possibly by attenuation of the inflammatory process. We investigated the effect of the SGLT2 inhibitor dapagliflozin on lipopolysaccharide (LPS)-induced endotoxic shock with AKI in streptozotocin-induced diabetic mice. Endotoxin shock with AKI was induced by intravenous injection of 10 mg/kg LPS in C57BL6 mice with streptozotocin-induced diabetic mellitus with or without dapagliflozin treatment. Observation was done for 48 hours thereafter. In addition, NRK-52E cells incubated with LPS or dapagliflozin were evaluated for the possible mechanism. Treatment with dapagliflozin attenuated LPS-induced endotoxic shock associated AKI and decreased the inflammatory cytokines in diabetic mice. In the in vitro study, dapagliflozin decreased the expression of inflammatory cytokines and reactive oxygen species and increased the expressions of AMP-activated protein kinase (AMPK), nuclear factor erythroid-2-related factor, and heme oxygenase 1. These results demonstrated that dapagliflozin can attenuate LPS-induced endotoxic shock associated with AKI; this was possibly mediated by activation of the AMPK pathway.     

Visfatin Polymorphisms,Lifestyle Risk Factors and Risk of Oral Squamous Cell Carcinoma in a Cohort of Taiwanese Males

Oral cancer is the eighth greatest generally diagnosed cancer amongst males worldwide and the fourth most generally malignancy amongst Taiwanese males. The pro-inflammatory adipocytokine visfatin promotes tumor growth. Elevated plasma visfatin levels have been identified in patients with oral squamous cell carcinoma (OSCC), although the biological mechanisms underlying the involvement of visfatin in the pathogenesis of OSCC are not well understood. Moreover, no information is available regarding associations between visfatin polymorphisms and carcinogenic lifestyle factors with OSCC. This study, therefore, investigated the effects of four visfatin gene polymorphisms (rs11977021, rs61330082, rs2110385, and rs4730153) and carcinogenic lifestyle factors (betel nut chewing, alcohol consumption and cigarette smoking) on the risk of developing OSCC in 1,275 Taiwanese males with OSCC, and 1,195 healthy males (controls). We also examined the associations between these visfatin genotypes and OSCC histopathological prognostic factors (pathological stage, tumor status, lymph node status, and metastasis). We found that compared with subjects with the CC genotype of SNP rs11977021, those with the CT+TT genotype were less likely to progress OSCC. In addition, an association was found between the rs4730153 variant and lymph node metastasis in the OSCC cohort.     

Extensive sampling of Saccharomyces cerevisiae in Taiwan reveals ecology and evolution of predomesticated lineages

The ecology and genetic diversity of the model yeast Saccharomyces cerevisiae before human domestication remain poorly understood. Taiwan is regarded as part of this yeast''s geographic birthplace, where the most divergent natural lineage was discovered. Here, we extensively sampled the broadleaf forests across this continental island to probe the ancestral species’ diversity. We found that S. cerevisiae is distributed ubiquitously at low abundance in the forests. Whole-genome sequencing of 121 isolates revealed nine distinct lineages that diverged from Asian lineages during the Pleistocene, when a transient continental shelf land bridge connected Taiwan to other major landmasses. Three lineages are endemic to Taiwan and six are widespread in Asia, making this region a focal biodiversity hotspot. Both ancient and recent admixture events were detected between the natural lineages, and a genetic ancestry component associated with isolates from fruits was detected in most admixed isolates. Collectively, Taiwanese isolates harbor genetic diversity comparable to that of the whole Asia continent, and different lineages have coexisted at a fine spatial scale even on the same tree. Patterns of variations within each lineage revealed that S. cerevisiae is highly clonal and predominantly reproduces asexually in nature. We identified different selection patterns shaping the coding sequences of natural lineages and found fewer gene family expansion and contractions that contrast with domesticated lineages. This study establishes that S. cerevisiae has rich natural diversity sheltered from human influences, making it a powerful model system in microbial ecology.

The yeast genus Saccharomyces, which includes S. cerevisiae, is a powerful model system for revealing patterns of genomic variation underlying reproductive isolation and adaptation in eukaryotic microorganisms. Surveys of population genetic data have been used in S. cerevisiae to date the origin of key domestication events (Gallone et al. 2016; Duan et al. 2018; Peter et al. 2018), to determine life cycle frequencies in nature (Tsai et al. 2008), to determine the genomic basis of adaptation at continental scale (Duan et al. 2018; Peter et al. 2018), and, more recently, to establish its geographical origin and dispersal history (Xia et al. 2017). Phylogenomic analyses of the Saccharomyces sensu stricto complex and extensive sequencing of collections across the world suggest that S. cerevisiae originated in East Asia (Duan et al. 2018; Peter et al. 2018). The 1011 Genome Project—the most broad large-scale yeast population genomic study—discovered that three wild isolates from Taiwan showed an unprecedented high genetic diversity compared with populations from the rest of the world (Peter et al. 2018). Population genomics of 266 domestic and wild isolates in China revealed six wild lineages from primeval forests. The newly identified CHN-IX group represents the most diverged lineage (Duan et al. 2018). Isolates from this group and the three Taiwanese isolates were grouped into a single lineage that showed a disjunct geographic distribution (Bendixsen et al. 2021). Although considerable knowledge is available on the biogeography and population genetics of plants and animals across continents (Whittaker et al. 2017), little is known about how eukaryotic microorganisms such as S. cerevisiae disperse, establish, reproduce, and persist in nature (Liti 2015).Most S. cerevisiae biology has been based on experiments on a handful of laboratory domesticated strains, but comprehensive analyses of the ecology and evolutionary biology of S. cerevisiae in the wild are still unavailable. In nature, S. cerevisiae have been isolated from the bark, fruits, surrounding soil, and leaves of plants belonging to several different families (Naumov et al. 2013), with early reports suggesting that the yeast is most successfully isolated from the oak family Fagaceae (Sniegowski et al. 2002; Sampaio and Gonçalves 2008; Wang et al. 2012). S. cerevisiae contains high genetic diversity in certain populations, including lineage-specific variants that display clear population structures (Barnett 1992; Wang et al. 2012; Cromie et al. 2013; Strope et al. 2015; Gallone et al. 2016; Gonçalves et al. 2016; Zhu et al. 2016; Duan et al. 2018; Legras et al. 2018; Peter et al. 2018) and explain phenotypic variance similar to common variants (Fournier et al. 2019). Samples from natural habitats tend to be homozygous diploids forming unique populations with minimal genetic admixture, whereas lineages associated with human activities were likely heterozygous, containing higher ploidy and greater genetic admixture leading to a mosaic genome makeup (Diezmann and Dietrich 2009; Liti et al. 2009; Wang et al. 2012; Almeida et al. 2015). The diverse natural lineages of S. cerevisiae present in East Asia provide an excellent opportunity to study the natural diversity of this species, which was previously believed to be fully domesticated (Fay and Benavides 2005).Taiwan is a continental shelf island with the fifth highest tree density in the world (Crowther et al. 2015). Among the 13 climate-related forests types in Taiwan, five are Fagaceae-dominated natural forests on low- and mid-elevation mountains (Li et al. 2013), thus a potentially ideal natural habitat for S. cerevisiae. Taiwan also harbors a high phylogenetic diversity of flowering plants (53 out of 64 angiosperm orders present under the APG IV classification system) (Lin and Chung 2017) and endemism compared with other oceanic islands (Hsieh 2002), raising the possibility that the associated microbial populations are genetically different from their continental counterparts. Here, we set out to characterize the intra-genetic diversity, relative abundance, and distribution of S. cerevisiae in Taiwanese forests over 4 yr of broad sampling. Our study provides novel insights of the predomestication phase of S. cerevisiae and broadens our understanding of the ecological and biogeographic implications before anthropogenic impacts.     

Viral co‐infections are associated with increased rates of hospitalization in those with influenza

BackgroundInfluenza causes significant morbidity and mortality in the United States. Among patients infected with influenza, the presence of bacterial co‐infection is associated with worse clinical outcomes; less is known regarding the clinical importance of viral co‐infections. The objective of this study was to determine rates of viral co‐infections in emergency department (ED) patients with confirmed influenza and association of co‐infection with disease severity.MethodsSecondary analysis of a biorepository and clinical database from a parent study where rapid influenza testing was implemented in four U.S. academic EDs, during the 2014–2015 influenza season. Patients were systematically tested for influenza virus using a validated clinical decision guideline. Demographic and clinical data were extracted from medical records; nasopharyngeal specimens from influenza‐positive patients were tested for viral co‐infections (ePlex, Genmark Diagnostics). Patterns of viral co‐infections were evaluated using chi‐square analysis. The association of viral co‐infection with hospital admission was assessed using univariate and multivariate regression.ResultsThe overall influenza A/B positivity rate was 18.1% (1071/5919). Of the 999 samples with ePlex results, the prevalence of viral co‐infections was 7.9% (79/999). The most common viral co‐infection was rhinovirus/enterovirus (RhV/EV), at 3.9% (39/999). The odds of hospital admission (OR 2.33, 95% CI: 1.01–5.34) increased significantly for those with viral co‐infections (other than RhV/EV) versus those with influenza A infection only.ConclusionPresence of viral co‐infection (other than RhV/EV) in ED influenza A/B positive patients was independently associated with increased risk of hospital admission. Further research is needed to determine clinical utility of ED multiplex testing.     

Analysis of accelerated failure time data with dependent censoring using auxiliary variables via nonparametric multiple imputation

We consider the situation of estimating the marginal survival distribution from censored data subject to dependent censoring using auxiliary variables. We had previously developed a nonparametric multiple imputation approach. The method used two working proportional hazards (PH) models, one for the event times and the other for the censoring times, to define a nearest neighbor imputing risk set. This risk set was then used to impute failure times for censored observations. Here, we adapt the method to the situation where the event and censoring times follow accelerated failure time models and propose to use the Buckley–James estimator as the two working models. Besides studying the performances of the proposed method, we also compare the proposed method with two popular methods for handling dependent censoring through the use of auxiliary variables, inverse probability of censoring weighted and parametric multiple imputation methods, to shed light on the use of them. In a simulation study with time‐independent auxiliary variables, we show that all approaches can reduce bias due to dependent censoring. The proposed method is robust to misspecification of either one of the two working models and their link function. This indicates that a working proportional hazards model is preferred because it is more cumbersome to fit an accelerated failure time model. In contrast, the inverse probability of censoring weighted method is not robust to misspecification of the link function of the censoring time model. The parametric imputation methods rely on the specification of the event time model. The approaches are applied to a prostate cancer dataset. Copyright © 2015 John Wiley & Sons, Ltd.     

从基础研究中探寻前列腺癌新的治疗靶向

Since 1990, prostate cancer （PCa） has been the most common non-skin cancer in American men, even snrpassing lung cancer. Because the mean age of the American population continues to increase while mortality from other causes continues to decrease, the incidence and mortality of PCa are likely to slay relative high level because the incidence of PCa rises significantly in men over 50-55 years old.[第一段]     

Detecting spontaneous deception in the brain

Deception detection can be of great value during the juristic investigation. Although the neural signatures of deception have been widely documented, most prior studies were biased by difficulty levels. That is, deceptive behavior typically required more effort, making deception detection possibly effort detection. Furthermore, no study has examined the generalizability across instructed and spontaneous responses and across participants. To explore these issues, we used a dual‐task paradigm, where the difficulty level was balanced between truth‐telling and lying, and the instructed and spontaneous truth‐telling and lying were collected independently. Using Multivoxel pattern analysis, we were able to decode truth‐telling versus lying with a balanced difficulty level. Results showed that the angular gyrus (AG), inferior frontal gyrus (IFG), and postcentral gyrus could differentiate lying from truth‐telling. Critically, linear classifiers trained to distinguish instructed truthful and deceptive responses could correctly differentiate spontaneous truthful and deceptive responses in AG and IFG with above‐chance accuracy. In addition, with a leave‐one‐participant‐out analysis, multivoxel neural patterns from AG could classify if the left‐out participant was lying or not in a trial. These results indicate the commonality of neural responses subserved instructed and spontaneous deceptive behavior as well as the feasibility of cross‐participant deception validation.     

Pregnancy estriol,estradiol, progesterone and prolactin in relation to birth weight and other birth size variables (United States)

Objective: Because birth weight has been positively associated with adult life breast cancer risk and pregnancy estrogens have been hypothesized to affect breast cancer risk in the offspring, we have evaluated the association of pregnancy estriol (E3), estradiol (E2), progesterone and prolactin in maternal serum samples collected during the 16th and 27th gestational week with birth size parameters. Methods: Prospective study of 230 Caucasian women who delivered a live singleton after 37–42 weeks of gestation. Results: E3 at the 27th gestational week was significantly positively associated with birth weight, birth length and placental weight. Progesterone at the 27th gestational week was also significantly positively associated with birth weight and placental weight but, after mutual adjustment among the studied pregnancy hormones, these associations weakened considerably. There was also inconsistent evidence that SHBG and prolactin at the 27th gestational week may be respectively positively and inversely related with birth size parameters. Measurements during the 16th gestational week were generally unrelated to birth size parameters. Conclusions: Because E3 is a dominant estrogen during pregnancy, the positive association of it with birth weight allows the use of the latter as a proxy of in utero exposure to estrogens in breast cancer investigations.