Connellcrowell8591

In Drosophila, dopamine signaling to the mushroom body intrinsic neurons, Kenyon cells (KCs), is critical to stabilize olfactory memory. Little is known about the downstream intracellular molecular signaling underlying memory stabilization. Here we address this question in the context of sugar-rewarded olfactory long-term memory (LTM). We show that associative conditioning increases the phosphorylation of MAPK in KCs, via Dop1R2 signaling. Consistently, the attenuation of Dop1R2, Raf or MAPK expression in KCs selectively impairs LTM but not short-term memory. Moreover, we show that the LTM deficit caused by the knockdown of Dop1R2 can be rescued by expressing active Raf in KCs. Thus, the Dop1R2/Raf/MAPK pathway is a pivotal downstream effector of dopamine signaling for stabilizing appetitive olfactory memory.SIGNIFICANCE STATEMENTDopaminergic input to the Kenyon cells (KCs) is pivotal to stabilize memory in Drosophila This process is mediated by dopamine receptors like Dop1R2. Nevertheless, little is known for its underlying molecular mechanism. Here we show that the Raf/MAPK pathway is specifically engaged in appetitive long term memory in KCs. With combined biochemical and behavioral experiments, we reveal that activation of the Raf/MAPK pathway is regulated through Dop1R2, shedding light on how dopamine modulates intracellular signaling for memory stabilization. Copyright © 2020 the authors.BACKGROUND Coil occlusion has become the standard treatment for many ruptured aneurysms. However, specific aneurysm structures pose technical difficulties and may require the use of adjunctive neck-bridging devices, which necessitate the use of dual antiplatelet therapy. The hydrophilic polymer coating (pHPC, phenox) is a surface modification that inhibits platelet adhesion. OBJECTIVE To present initial experience with the pCONUS HPC device as an adjunct to coil embolization for ruptured aneurysms using single antiplatelet therapy (SAPT). METHODS All patients who were treated with the pCONUS HPC for ruptured aneurysms using SAPT were retrospectively identified. The occurrence of thromboembolic and hemorrhagic complications was recorded together with the angiographic and clinical follow-up details. RESULTS Fifteen patients were identified (nine female) with a median age of 54 years (range 27-81). Six aneurysms were located at the anterior communicating artery, five at the middle cerebral artery bifurcation, tw (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. AG-1478 clinical trial CSTI-300 displayed selective high affinity for the human and rat 5-HT3 receptor (Ki approximately 2.0 nM) and acted as a partial agonist (approximately 30%-50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, t treatment with a suitable 5-HT3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy. Copyright © 2020 The Author(s).Transient receptor potential melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (Aδ-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (N-[(R)-3,3-difluoro-4-hydroxy-1-(2H-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious Experimental Therapeutics.Cholangiocarcinoma (CCA) is a malignant tumor that arises from the epithelial cells of the bile duct and is notorious for its poor prognosis. The clinical outcome remains disappointing and thus more effective therapeutic options are urgently required. Cordycepin, a traditional Chinese medicine, provides multiple pharmacological strategies in anti-tumors, but its mechanisms have not been fully elucidated. In this study, we reported that cordycepin inhibited the viability of CCA cells and induced apoptosis via ERK1/2 deactivation. Moreover, cordycepin significantly reduced the angiogenetic capabilities of CCA in vitro. We also found that cordycepin inhibited DEK expression, an oncogenic protein that is overexpressed in various gastrointestinal tumors. DEK silencing inhibited CCA cell viability and angiogenesis, but not apoptosis induction. Furthermore, cordycepin significantly inhibited tumor growth in a xenograft model by downregulating the expression of DEK and p-ERK1/2. Taken together, we demonstrated that cordycepin inhibited CCA cell proliferation and angiogenesis with a DEK interaction via downregulation in ERK signaling. These data indicate that cordycepin may be a novel agent to improve CCA clinical treatment and prognosis. SIGNIFICANCE STATEMENT Cordycepin provides multiple strategies in anti-tumors, but its mechanisms are not fully elucidated, especially on CCA. We reported that cordycepin inhibited the viability of CCA cells and induced apoptosis via ERK1/2 deactivation and DEK inhibition, reduced the angiogenetic capabilities of CCA both in vivo and in vitro. The American Society for Pharmacology and Experimental Therapeutics.OBJECTIVE To investigate whether aging differentially affects neural activity serving visuospatial processing in a large functional neuroimaging study of HIV-infected participants and to determine whether such aging effects are attributable to differences in the duration of HIV infection. METHODS A total of 170 participants, including 93 uninfected controls and 77 HIV-infected participants, underwent neuropsychological assessment followed by neuroimaging with magnetoencephalography (MEG). Time-frequency analysis of the MEG data followed by advanced image reconstruction of neural oscillatory activity and whole-brain statistical analyses were used to examine interactions between age, HIV infection, and cognitive status. Post hoc testing for a mediation effect of HIV infection duration on the relationship between age and neural activity was performed using a quasi-Bayesian approximation for significance testing. RESULTS Cognitively impaired HIV-infected participants were distinguished from unimpaired HIV-infectegy.Neurotoxic implications of the interactions between Cu(I/II) and amyloid-β (Aβ) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer's disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to Aβ utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)-Aβ was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)-Aβ was able to disrupt binding of Cu(II) to Aβ and result in chemically modified Aβ with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)-Aβ could stem from the molecule's ability to 1) interact with Cu(II)-Aβ and 2) foster copper-O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)-Aβ at a metal-binding amino acid residue and consequently alter Aβ's coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association among muscle nerves, IL-33+ mSCs, and Tregs has been reported, and invites a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors, and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down-tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell crosstalk in tissue repair, suggesting future therapeutic approaches.OBJECTIVE To examine associations between suicidal ideation and sexual and physical abuse among active and recently retired elite athletics (track and field) athletes. METHODS The study population consisted of all athletes (n=402) selected for a Swedish Athletics team between 2011 and 2017. Data on suicidal ideation, suicidal events (estimated through the 1 year non-sports injury prevalence), lifetime abuse experiences, sociodemographics, sense of coherence and coping strategies were collected using a cross-sectional survey. The data were analysed using binary logistic regression with suicidal ideation and non-sports injury as outcomes. RESULTS 192 athletes (47.8%) returned data. The prevalence of suicidal ideation was 15.6% (men 17.4%; women 14.2%) and the non-sports injury prevalence was 8.0% (men 11.6%; women 5.7%). Among women, suicidal ideation was associated with having been sexually abused (OR 5.94, 95% CI 1.42 to 24.90; p=0.015) and lower sense of coherence (OR 0.90, 95% CI 0.85 to 0.96; p=0.001) (Nagelkerke R2=0.33). Among men, suicidal ideation was only associated with use of behavioural disengagement for coping (OR 1.51, 95% CI 1.18 to 1.95; p=0.001) (R2 =0.25). Among women, non-sports injury prevalence was associated with having been sexually abused (OR 8.61, 95% CI 1.34 to 55.1; p=0.023) and participating in an endurance event (OR 7.37, 95% CI 1.11 to 48.9; p=0.039 (R2 =0.23), while among men, having immigrant parents (OR 5.67, 95% CI 1.31 to 24.5; p=0.020) (R2 =0.11) was associated with injury outside sports. CONCLUSIONS About one out of six international athletics athletes reported having experienced suicidal ideation. World Athletics and National Olympic Committees need to include suicide prevention in their athlete protection programmes. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.