Mcgrawgentry3150

Intra-tumor heterogeneity (ITH) was a potential mechanism of progression and drug resistance in bladder cancer (BCa). However, the understanding of ITH in BCa remains insufficient. Single-cell RNA sequencing (scRNA-seq) profiles of 2075 cells were analyzed, and 2940 cell markers were screened. The ITH of 396 cases was evaluated, and 96 ITH-related genes were identified. Based on the gene-pair strategy, 96 genes were cyclically paired, and an 8-gene-pair model was successfully established to evaluate the overall survival of BCa through Lasso and multivariate Cox regressions. The risk model showed high predictive value in the training dataset (n = 396, p = 0) and external validation datasets (n = 165, p = 2.497e-02; n = 224, p = 3.423e-02). The model was also valuable for the prediction of clinical treatment outcomes. Totally, a prognostic model based on scRNA-seq and ITH was successfully constructed and validated in large cohorts, providing novel clues for ITH study of BCa.Parkinson's disease (PD), the typical neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). However, no therapeutic agent used currently could slow down neuronal cell loss so as to decelerate or halt the progression of PD. Traditional Chinese medicine (TCM) has been utilized to treat the dysfunction of the autonomic nervous system. Wen-Shen-Yang-Gan decoction (WSYGD) has a good effect on the clinical treatment of PD with constipation. However, it is not clear which ingredients and what mechanism are responsible for the therapeutic effect. In this study, the pharmacodynamic study of WSYGD in PD mice was applied. Concurrently, a novel method for the identification of metabolic profiles of WSYGD has been developed. Finally, we found that WSYGD could protect the PD mice induced by rotenone. The underlying mechanism of the protective effect may be related to the reduction of the DA neurons apoptosis via reducing inflammatory reaction. By virtue of UPLC-MS and chemoinformatics method, 35 prototype compounds and 27 metabolites were filtered out and tentatively characterized. In conclusion, this study provides an insight into the metabolism of WSYGD in vivo to enable understanding of the metabolic process and therapeutic mechanism of PD.Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene polymorphisms may be involved in the risk of Rheumatoid arthritis (RA). However, evidence for the association remains controversial. Therefore, we performed a meta-analysis to confirm the relationship between CTLA-4 gene polymorphisms and RA. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association. Stratified analysis was conducted by ethnicity. In total, 66 case-control studies including 21681 cases and 23457 controls were obtained. For rs3087243 polymorphism, significant association was detected in Asians (A vs. G OR=0.77, 95%CI=0.65-0.90, P=0.001; AA vs. GG OR=0.67, 95%CI=0.48-0.94, P=0.02) and Caucasians (A vs. G OR=0.89, 95%CI=0.86-0.93, P less then 0.00001; AA vs. GG OR=0.81, 95%CI=0.75-0.88, P less then 0.00001). For rs231775 polymorphism, significant association was observed in the overall (G vs. A OR =1.16, 95%CI=1.08-1.25, P less then 0.0001; GG vs. AA OR=1.29, 95%CI=1.12-1.50, P=0.0006), and in Asians (G vs. A OR=1.27, 95%CI=1.10-1.47, P=0.001; GG vs. AA OR=1.58, 95%CI=1.24-2.01, P=0.0002), but not in Caucasians. However, there was no association between rs5742909 polymorphism and RA. This meta-analysis confirmed that rs3087243 and rs231775 polymorphism were associated with the risk of RA in both overall population and ethnic-specific analysis, but there was no association between rs5742909 polymorphism and RA risk.The turnover of the epidermis beginning with the progenitor cells in the basal layer to the fully differentiated corneocytes is tightly regulated by calcium. Calcium more than anything else promotes the differentiation of keratinocytes which implies the need for a calcium gradient with low concentrations in the stratum basale and high concentrations in the stratum granulosum. One of the hallmarks of skin aging is a collapse of this gradient that has a direct impact on the epidermal fitness. The rise of calcium in the stratum basale reduces cell proliferation, whereas the drop of calcium in the stratum granulosum leads to a changed composition of the cornified envelope. We showed that keratinocytes respond to the calcium induced block of cell division by a large increase of the expression of several miRNAs (hsa-mir542-5p, hsa-mir125a, hsa-mir135a-5p, hsa-mir196a-5p, hsa-mir491-5p and hsa-mir552-5p). The pitfall of this rescue mechanism is a dramatic change in gene expression which causes a further impairment of the epidermal barrier. This effect is attenuated by a pseudogene (SPRR2C) that gives rise to a lncRNA. SPRR2C specifically resides in the stratum granulosum/corneum thus acting as a sponge for miRNAs.CC16 is almost exclusively expressed in non-ciliated epithelial Clara cells, and widely used as a Clara cell marker. Diesel exhaust particles (DEPs), the fine particulate matters produced by diesel engines, cause or exacerbate airway-related diseases. Our previous study documented that DEP inhibits the CC16 expression in the immortalized mouse Clara cell line through methylation of C/EBPα promoter. However, the molecular mechanism by which DEP regulates CC16 secretion is unclear. Here, we isolated CC16 containing Clara cells (CC16+) from human distal lung, and found that DEP inhibited CC16 secretion from CC16+ cells via methylation of C/EBPα and inhibition of Munc18b transcription. CC16+ cell conditioned media containing different concentrations of CC16 was prepared and used for culture of airway epithelial cells BEAS-2B with no expression of CC16. A positive correlation was observed between CC16 level and DEP-induced autophagy activity, and a negative correlation between CC16 level and DEP-induced pro-inflammatory cytokine TNF-α, IL-6, and IL-8 level, suggesting that CC16 might mitigate DEP-induced inflammation via promoting autophagy in BEAS-2B cells. This result was further confirmed by adding recombinant CC16 to BEAS-2B cells exposed to DEP. Moreover, CC16 level was significantly increased when CC16+ cells were cultured in BEAS-2B cell conditioned medium containing TNF-α or the normal medium supplemented with recombinant TNF-α, suggesting that TNF-α induced CC16 production and secretion from CC16+ cells. Collectively, these data point that CC16 and TNF-α form a negative feedback loop, and this negative feedback loop between Clara cells and normal airway epithelial cells protects against DEP exposure-induced inflammation.Aedes aegypti, the mosquito that transmits arboviral diseases such as dengue (DENV), chikungunya (CHIKV), and Zika viruses (ZIKV), is present in tropical and subtropical regions of the world. Individuals at risk of mosquito-borne disease (MBD) in the urban tropics face daily challenges linked to their socio-environment conditions, such as poor infrastructure, poverty, crowding, and limited access to adequate healthcare. These daily demands induce chronic stress events and dysregulated immune responses. We sought to investigate the role of socio-ecologic risk factors in distress symptoms and their impact on biological responses to MBD in Machala, Ecuador. Between 2017 and 2019, individuals (≥ 18 years) with suspected arbovirus illness (DENV, ZIKV, and CHIKV) from sentinel clinics were enrolled (index cases, N = 28). Cluster investigations of the index case households and people from four houses within a 200-m radius of index home (associate cases, N = 144) were conducted (total N = 172). Hair samples were collected to measure hair cortisol concentration (HCC) as a stress biomarker. Blood samples were collected to measure serum cytokines concentrations of IL-10, IL-8, TNF-α, and TGF-β. Univariate analyses were used to determine the association of socio-health metrics related to perceived stress scores (PSS), HCC, and immune responses. We found that housing conditions influence PSS and HCC levels in individuals at risk of MBD. Taurocholicacid Inflammatory cytokine distribution was associated with the restorative phase of immune responses in individuals with low-moderate HCC. These data suggest that cortisol may dampen pro-inflammatory responses and influence activation of the restorative phase of immune responses to arboviral infections.Ivermectin (IVM) is a widely used anthelmintic. However, with widespread use comes the risk of the emergence of IVM resistance, particularly in strongyloidiasis. Adenosine triphosphate (ATP)-binding cassette (ABC) transporter genes play an important role in the IVM-resistance mechanism. Here, we aimed to establish an animal experimental model of IVM resistance by frequent treatment of Strongyloides ratti with subtherapeutic doses of IVM, resistance being evaluated by the expression levels of ABC transporter genes. Rats infected with S. ratti were placed in experimental groups as follows 1) untreated control (control); 2) treated with the mutagen ethyl methanesulfonate (EMS); 3) injected with 100 µg/kg body weight of IVM (IVM); 4) treated with a combination of EMS and IVM (IVM+EMS). Parasites were evaluated after four generations. Extent of IVM resistance was assessed using IVM sensitivity, larval development, and expression of ABC genes. By the F4 generation, S. ratti in the IVM group exhibited significantly higher levels of IVM resistance than did other groups according to in vitro drug-sensitivity tests and inhibition of larval development (IC50 = 36.60 ng/mL; 95% CI 31.6, 42.01). Expression levels of ABC isoform genes (ABCA, ABCF, and ABCG) were statistically significantly higher in the IVM-resistant line compared with the susceptible line. In conclusion, IVM subtherapeutic doses induced IVM resistance in S. ratti by the F4 generation with corresponding upregulation of some ABC isoform genes. The study provides a model for inducing and assessing drug resistance in Strongyloides.In northwestern Kenya, Turkana County has been historically considered unsuitable for stable malaria transmission because of its unfavorable climate and predominantly semi-nomadic population; consequently, it is overlooked during malaria control planning. However, the area is changing, with substantial development, an upsurge in travel associated with resource extraction, and more populated settlements forming. Recently, numerous malaria outbreaks have highlighted the need to characterize malaria transmission and its associated risk factors in the region to inform control strategies. Reactive case detection of confirmed malaria cases at six health facilities across central Turkana was conducted from 2018 to 2019. Infections in household members of index cases were detected by malaria rapid diagnostic tests (RDTs) and PCR tests, and they were grouped according household and individual characteristics. The relationships between putative risk factors and infection were quantified by multilevel logistic regression models. Of the 3,189 household members analyzed, 33.6% had positive RDT results and/or PCR test results. RDT-detected infections were more prevalent in children; however, PCR-detected infections were similarly prevalent across age groups. Recent travel was rarely reported and not significantly associated with infection. Bed net coverage was low and net crowding was associated with increased risks of household infections. Infections were present year-round, and fluctuations in prevalence were not associated with rainfall. These findings indicate year-round, endemic transmission with moderate population immunity. This is in stark contrast to recent estimates in this area. Therefore, further investigations to design effective intervention approaches to address malaria in this rapidly changing region and other similar settings across the Horn of Africa are warranted.