199 research outputs found
Hydrologic and Water Quality Monitoring on Turkey Creek Watershed, Francis Marion National Forest, SC
2008 S.C. Water Resources Conference - Addressing Water Challenges Facing the State and Regio
IL-17 Signaling triggers degradation of the constitutive NF-κB inhibitor ABIN-1
IL-17 activates NF-κB and induces expression of proinflammatory genes. IL-17 drives disease in autoimmune conditions, and anti–IL-17 Abs have shown impressive success in the clinic. Although produced by lymphocytes, IL-17 predominantly signals in fibroblasts and epithelial cells. IL-17–driven inflammation is kept in check by negative feedback signaling molecules, including the ubiquitin editing enzyme A20, whose gene TNFAIP3 is linked to autoimmune disease susceptibility. The A20 binding inhibitor of NF-κB activation 1 (ABIN-1) is an A20-binding protein encoded by the TNIP1 gene, which is also linked to autoimmune disease susceptibility including psoriasis. Accordingly, we hypothesized that ABIN-1 might play a role in negatively regulating IL-17 signaling activity. Indeed, ABIN-1 enhanced both tonic and IL-17–dependent NF-κB signaling in IL-17–responsive fibroblast cells. Interestingly, the inhibitory activities of ABIN-1 on IL-17 signaling were independent of A20. ABIN-1 is a known NF-κB target gene, and we found that IL-17–induced activation of NF-κB led to enhanced ABIN-1 mRNA expression and promoter activity. Surprisingly, however, the ABIN-1 protein was inducibly degraded following IL-17 signaling in a proteasome-dependent manner. Thus, ABIN-1, acting independently of A20, restricts both baseline and IL-17–induced inflammatory gene expression. We conclude that IL-17–induced signals lead to degradation of ABIN-1, thereby releasing a constitutive cellular brake on NF-κB activation
Investigation of sex differences in delusion-associated cognitive biases
© 2018 Published by Elsevier Ltd. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/
This author accepted manuscript is made available following 12 month embargo from date of publication (December 2018) in accordance with the publisher’s archiving policyIn the past few decades, sex differences have been identified in a number of clinical, cognitive and functional outcomes in patients with schizophrenia spectrum disorders. However, to date, sex differences in higher-order cognitive biases have not been systematically studied. The present study aimed to examine sex differences in jumping-to-conclusions and evidence integration impairment based on data collected in two previous studies in patients with schizophrenia spectrum disorders and healthy controls. For this purpose, data from n = 58 patients and n = 60 healthy controls on the Fish Task (as a measure of jumping to conclusions) and bias against disconfirmatory evidence (BADE; as a measure of evidence integration) task were analyzed. Results indicated a lack of sex differences in jumping-to-conclusions and evidence integration impairment both in patients with schizophrenia spectrum disorders and healthy controls. Although the present study was adequately powered to detect sex differences of a low medium effect size, larger studies are warranted to exclude differences of a smaller magnitude between men and women regarding delusion-associated cognitive biases
Time for global scale-up, not randomized trials, of uterine balloon tamponade for postpartum hemorrhage.
Maternal death is the greatest health disparity globally, with postpartum hemorrhage the most common cause. As senior leaders in obstetrics and maternal health from Bolivia, Canada, Colombia, Côte d'Ivoire, Honduras, India, Kenya, Nepal, Niger, Norway, Peru, Tanzania, the UK, the USA, and Zambia, we are deeply disturbed by recent calls for randomized controlled trials (RCTs) of uterine balloon tamponade (UBT) in women with uncontrolled postpartum hemorrhage (PPH). Our collective experience, in combination with mounting evidence, unequivocally supports the effectiveness of commercial and condom UBTs in averting death and disability from PPH associated with atonic uterus. We believe it would be highly unethical to embark on an RCT of UBT, now or in the future, unless compared with a proven equivalent intervention. This article is protected by copyright. All rights reserved
Design of the Dhulikhel Heart Study (DHS): The epidemiology of emerging cardiovascular disease in Nepal
Elimination of wild-type P53 mRNA in glioblastomas showing heterozygous mutations of P53
We screened 50 glioblastomas for P53 mutations. Five glioblastomas showed heterozygous mutations, while three were putatively heterozygous. Six of these eight glioblastomas showed elimination of wild-type P53 mRNA. These results strongly suggest that some sort of mechanism(s) favouring mutated over wild-type P53 mRNA exists in glioblastoma cells with heterozygous mutations of this gene
Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy
BACKGROUND: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy with a high prevalence of ventricular arrhythmias. How the R14 deletion causes dilated cardiomyopathy is poorly understood, and there are no disease-specific therapies. METHODS: We used single-cell RNA sequencing to uncover PLN R14del disease mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We used both 2-dimensional and 3-dimensional functional contractility assays to evaluate the impact of modulating disease-relevant pathways in PLN R14del hiPSC-CMs. RESULTS: Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro. Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the 3 main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP (binding immunoglobulin protein) inducer X. PLN R14del hiPSC-CMs treated with BiP protein inducer X showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional engineered heart tissues without affecting calcium homeostasis. CONCLUSIONS: Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically
DNA methylation in glioblastoma: impact on gene expression and clinical outcome
International audienceBACKGROUND: Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies. RESULTS: We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04). CONCLUSIONS: This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions
What factors influence the choice of urban or rural location for future practice of Nepalese medical students? A cross-sectional descriptive study
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