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Moran Birk posted an update 6 months, 3 weeks ago
We present continuous T vector velocity (TVV) effect profiles as a new method for identifying drug effects on cardiac ventricular repolarization. TVV measures the temporal change in the myocardial action potential distribution during repolarization. The T vector dynamics were measured as the time required to reach p percent of the total T vector trajectory length, denoted as Tr(p), with p in 1, …, 100%. The Tr(p) values were individually corrected for heart rate at each trajectory length percentage p. Drug effects were measured by evaluating the placebo corrected changes from baseline of Tr(p)c jointly for all p using functional mixed effects models. The p-dependent model parameters were implemented as cubic splines, providing continuous drug effect profiles along the entire ventricular repolarization process. The effect profile distributions were approximated by bootstrap simulations. We applied this TVV-based analysis approach to ECGs available from three published studies that were conducted in the CiPA ity 0.99 and specificity 0.97. The TVV-based effect profile provides a detailed view of drug effects throughout the entire ventricular repolarization interval. It enables the evaluation of drug-induced blocks of multiple cardiac repolarization currents from clinical ECGs. The proposed pzero parameter enhances identification of the proarrhythmic risk of a drug beyond QT prolongation, and therefore constitutes an important tool for cardiac arrhythmia risk assessment.Corals’ obligate association with unicellular dinoflagellates, family Symbiodiniaceae form the foundation of coral reefs. For nearly a century, researchers have delved into understanding the coral-algal mutualism from multiple levels of resolution and perspectives, and the questions and scope have evolved with each iteration of new techniques. Advances in genetic technologies not only aided in distinguishing between the multitude of Symbiodiniaceae but also illuminated the existence and diversity of other organisms constituting the coral microbiome. The coral therefore is a meta-organism, often referred to as the coral holobiont. In this review, we address the importance of including a holistic perspective to understanding the coral holobiont. We also discuss the ramifications of how different genotypic combinations of the coral consortium affect the holobiont entity. We highlight the paucity of data on most of the coral microbiome. Using Symbiodiniaceae data, we present evidence that the holobiont properties are not necessarily the sum of its parts. We then discuss the consequences of the holobiont attributes to the fitness of the holobiont and the myriad of organisms that contribute to it. Considering the complexity of host-symbiont genotypic combinations will aid in our understanding of coral resilience, robustness, acclimation, and/or adaptation in the face of environmental change and increasing perturbations.Recently, we reported that Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) rats exhibit dyslipidemia and renal lipid accumulation independent of hyperglycemia that progresses to chronic kidney disease (CKD). Therefore, in the current study, we examined the effects of gemfibrozil, a lipid-lowering drug (200 mg/kg/day, orally), on the progression of renal injury in SS and SSLepRmutant rats for 4 weeks starting at 12 weeks of age. Plasma triglyceride levels were markedly elevated in the SSLepRmutant strain compared to SS rats (1193 ± 243 and 98 ± 16 mg/day, respectively). Gemfibrozil treatment only reduced plasma triglycerides in the SSLepRmutant strain (410 ± 79 mg/dL). MAP was significantly higher in the SSLepRmutant strain vs. SS rats at the end of the study (198 ± 7 vs. 165 ± 7 mmHg, respectively). Administration of gemfibrozil only lowered MAP in SSLepRmutant rats (163 ± 8 mmHg). During the course of the study, proteinuria increased to 125 ± 22 mg/day in SS rats. However, proteinuria did not change in the SSLepRmutant strain and remained near baseline (693 ± 58 mg/day). Interestingly, treatment with gemfibrozil increased the progression of proteinuria by 77% in the SSLepRmutant strain without affecting proteinuria in SS rats. The renal injury in the SSLepRmutant strain progressed to CKD. Moreover, the kidneys from SSLepRmutant rats displayed significant glomerular injury with mesangial expansion and increased renal lipid accumulation and fibrosis compared to SS rats. Treatment with gemfibrozil significantly reduced glomerular injury and lipid accumulation and improved renal function. These data indicate that reducing plasma triglyceride levels with gemfibrozil inhibits hypertension and CKD associated with obesity in SSLepRmutant rats.The Wnt pathway, which comprises the canonical and non-canonical pathways, is an evolutionarily conserved mechanism that regulates crucial biological aspects throughout the development and adulthood. Emergence and patterning of the nervous and vascular systems are intimately coordinated, a process in which Wnt pathway plays particularly important roles. mTOR inhibitor In the brain, Wnt ligands activate a cell-specific surface receptor complex to induce intracellular signaling cascades regulating neurogenesis, synaptogenesis, neuronal plasticity, synaptic plasticity, angiogenesis, vascular stabilization, and inflammation. The Wnt pathway is tightly regulated in the adult brain to maintain neurovascular functions. Historically, research in neuroscience has emphasized essentially on investigating the pathway in neurodegenerative disorders. Nonetheless, emerging findings have demonstrated that the pathway is deregulated in vascular- and traumatic-mediated brain injuries. These findings are suggesting that the pathway constitutes a promising target for the development of novel therapeutic protective and restorative interventions. Yet, targeting a complex multifunctional signal transduction pathway remains a major challenge. The review aims to summarize the current knowledge regarding the implication of Wnt pathway in the pathobiology of ischemic and hemorrhagic stroke, as well as traumatic brain injury (TBI). Furthermore, the review will present the strategies used so far to manipulate the pathway for therapeutic purposes as to highlight potential future directions.
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