CGP-37157 Inhibits the Sarcoplasmic Reticulum Ca 2ϩ ATPase and Activates Ryanodine Receptor Channels in Striated Muscle

ABSTRACT 7-Chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one ], a benzothiazepine derivative of clonazepam, is commonly used as a blocker of the mitochondrial Na ϩ /Ca 2ϩ exchanger. However, evidence suggests that CGP could also affect other targets, such as L-type Ca 2ϩ channels and plasmalemma Na ϩ /Ca 2ϩ exchanger. Here, we tested the possibility of a direct modulation of ryanodine receptor channels (RyRs) and/or sarco/endoplasmic reticulum Ca 2ϩ -stimulated ATPase (SERCA) by CGP. In the presence of ruthenium red (inhibitor of RyRs), CGP decreased SERCA-mediated Ca 2ϩ uptake of cardiac and skeletal sarcoplasmic reticulum (SR) microsomes (IC 50 values of 6.6 and 9.9 M, respectively). The CGP effects on SERCA activity correlated with a decreased V max of ATPase activity of SERCA-enriched skeletal SR fractions. CGP (Ն5 M) also increased RyR-mediated Ca 2ϩ leak from skeletal SR microsomes. Planar bilayer studies confirmed that both cardiac and skeletal RyRs are directly activated by CGP (EC 50 values of 9.4 and 12.0 M, respectively). In summary, we found that CGP inhibits SERCA and activates RyR channels. Hence, the action of CGP on cellular Ca 2ϩ homeostasis reported in the literature of cardiac, skeletal muscle, and other nonmuscle systems requires further analysis to take into account the contribution of all CGP-sensitive Ca 2ϩ transporters

Hepatic Transcriptome Analysis of Hepatitis C Virus Infection in Chimpanzees Defines Unique Gene Expression Patterns Associated with Viral Clearance

Hepatitis C virus infection leads to a high rate of chronicity. Mechanisms of viral clearance and persistence are still poorly understood. In this study, hepatic gene expression analysis was performed to identify any molecular signature associated with the outcome of hepatitis C virus (HCV) infection in chimpanzees. Acutely HCV-infected chimpanzees with self-limited infection or progression to chronicity were studied. Interferon stimulated genes were induced irrespective of the outcome of infection. Early induction of a set of genes associated with cell proliferation and immune activation was associated with subsequent viral clearance. Specifically, two of the genes: interleukin binding factor 3 (ILF3) and cytotoxic granule-associated RNA binding protein (TIA1), associated with robust T-cell response, were highly induced early in chimpanzees with self-limited infection. Up-regulation of genes associated with CD8+ T cell response was evident only during the clearance phase of the acute self-limited infection. The induction of these genes may represent an initial response of cellular injury and proliferation that successfully translates to a “danger signal” leading to induction of adaptive immunity to control viral infection. This primary difference in hepatic gene expression between self-limited and chronic infections supports the concept that successful activation of HCV-specific T-cell response is critical in clearance of acute HCV infection

Social network and dominance hierarchy analyses at Chimpanzee Sanctuary Northwest

Different aspects of sociality bear considerable weight on the individual- and group-level welfare of captive nonhuman primates. Social Network Analysis (SNA) is a useful tool for gaining a holistic understanding of the dynamic social relationships of captive primate groups. Gaining a greater understanding of captive chimpanzees through investigations of centrality, preferred and avoided relationships, dominance hierarchy, and social network diagrams can be useful in advising current management practices in sanctuaries and other captive settings. In this study, we investigated the dyadic social relationships, group-level social networks, and dominance hierarchy of seven chimpanzees (Pan troglodytes) at Chimpanzee Sanctuary Northwest. We used focal-animal and instantaneous scan sampling to collect 106.75 total hours of associative, affiliative, and agonistic data from June to September 2016. We analyzed our data using SOCPROG to derive dominance hierarchies and network statistics, and we diagrammed the group\u27s social networks in NetDraw. Three individuals were most central in the grooming network, while two others had little connection. Through agonistic networks, we found that group members reciprocally exhibited agonism, and the group\u27s dominance hierarchy was statistically non-linear. One chimpanzee emerged as the most dominant through agonism but was least connected to other group members across affiliative networks. Our results indicate that the conventional methods used to calculate individuals\u27 dominance rank may be inadequate to wholly depict a group\u27s social relationships in captive sanctuary populations. Our results have an applied component that can aid sanctuary staff in a variety of ways to best ensure the improvement of group welfare

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n(effective) = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (vertical bar r(g)vertical bar > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range vertical bar r(g)vertical bar = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.Peer reviewe

Global cerebral ischemia: synaptic and cognitive dysfunction

Cardiopulmonary arrest is one of the leading causes of death and disability, primarily occurring in the aged population. Numerous global cerebral ischemia animal models induce neuronal damage similar to cardiac arrest. These global cerebral ischemia models range from vessel occlusion to total cessation of cardiac function, both of which have allowed for the investigation of this multifaceted disease and detection of numerous agents that are neuroprotective. Synapses endure a variety of alterations after global cerebral ischemia from the resulting excitotoxicity and have been a major target for neuroprotection; however, neuroprotective agents have proven unsuccessful in clinical trials, as neurological outcomes have not displayed significant improvements in patients. A majority of these neuroprotective agents have specific neuronal targets, where the success of future neuroprotective agents may depend on non-specific targets and numerous cognitive improvements. This review focuses on the different models of global cerebral ischemia, neuronal synaptic alterations, synaptic neuroprotection and behavioral tests that can be used to determine deficits in cognitive function after global cerebral ischemia

Ischemic Preconditioning-Mediated Signaling Pathways Leading to Tolerance Against Cerebral Ischemia

Cerebral ischemia, most notably in the form of stroke, is the leading cause of morbidity and mortality resulting in long-term disability in the USA. Approximately 800,000 strokes occur each year in the USA, and 87 % of all strokes in the world are caused by embolism, thrombosis, or systemic hemorrhage/hypoperfusion, all of which are a form of cerebral ischemia (Roger et al. 2011). The medical cost for the treatment of stroke in the USA was estimated to be $25 billion in 2007 (Roger et al. 2011). Due to this great burden, a fundamental understanding of cerebral ischemia and the inciting cellular dysfunction is imperative for the development of new therapies to combat this growing epidemic

Neurovascular Mechanisms of Ischemia Tolerance Against Brain Injury

Traumatic brain injury (TBI) can result in secondary ischemia. This secondary ischemic insult is implicated in post-TBI pathophysiology. Pharmacological intervention to elevate cerebral blood flow can improve outcomes following TBI. The brain and other organ systems have an innate ability to induce protection against ischemic injury, limiting the severity of the ischemia-induced damage. This “self” protection can be initiated by exposing the brain to a stimulus before ischemia called “preconditioning,” such as exposure to a mild episode(s) of ischemia, hypoxia, anesthesia, or pharmacologically induced mild cell stressors. Current efforts to reduce ischemia-induced brain damage have been the focus in determining the mechanisms of preconditioning-induced ischemia tolerance as findings may help lower cerebral ischemia-induced brain damage in at-risk patients including TBI patients. Different preconditioning paradigms have been shown to lower TBI-induced damage. Although not all of the mechanisms of preconditioning are confirmed in models of TBI, basic mechanisms of preconditioning applies here as ischemia is a major part of TBI. Ischemic preconditioning, in part, confers protection by modulating regulators of cerebral blood flow, increase angiogenesis, and prevent cerebral ischemia-induced increase in blood–brain barrier permeability. This chapter highlights preconditioning-induced changes in components of the neurovascular system involved in ischemia tolerance. Understanding of these pathways may aid in the development of novel therapies to protect the brain from TBI-induced secondary ischemic insult