Synaptotagmin 1 clamps synaptic vesicle fusion in mammalian neurons independent of complexin.

Synaptic vesicle (SV) exocytosis is mediated by SNARE proteins. Reconstituted SNAREs are constitutively active, so a major focus has been to identify fusion clamps that regulate their activity in synapses: the primary candidates are synaptotagmin (syt) 1 and complexin I/II. Syt1 is a Ca sensor for SV release that binds Ca via tandem C2-domains, C2A and C2B.

Persistent symptoms after endovenous thermal ablation may suggest proximal venous outflow obstruction.

Objective: Proximal venous outflow obstruction (PVOO) in the iliac veins and superficial venous disease are inter-related in ways not fully understood. We observed among our patients undergoing vein stent placement for PVOO a significant number having had prior endovenous thermal ablations (EVTA) in their history. This study was undertaken to better characterize these patients and develop an algorithm in their management.

Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation.

The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation.

Synaptotagmin 17 controls neurite outgrowth and synaptic physiology via distinct cellular pathways.

The synaptotagmin (syt) proteins have been widely studied for their role in regulating fusion of intracellular vesicles with the plasma membrane. Here we report that syt-17, an unusual isoform of unknown function, plays no role in exocytosis, and instead plays multiple roles in intracellular membrane trafficking. Syt-17 is localized to the Golgi complex in hippocampal neurons, where it coordinates import of vesicles from the endoplasmic reticulum to support neurite outgrowth and facilitate axon regrowth after injury.

Making Power Visible: "Slow Activism" to Address Staff Sexual Misconduct in Higher Education.

This article examines activism to address staff-to-student sexual misconduct in higher education in the United Kingdom from our perspective as founders and members of the research and lobby organization The 1752 Group. We argue that in order to tackle staff sexual misconduct in higher education, the problem has first to be made visible. We theorize this as "slow activism" and outline the activities that we and others have been engaged in toward this end: conducting research, using complaints processes within institutions, naming the experiences of staff sexual misconduct and/or institutions and perpetrators, and carrying out discipline-led and sector-level initiatives.

Changes in Reported Injection Behaviors Following the Public Health Response to an HIV Outbreak Among People Who Inject Drugs: Indiana, 2016.

A syringe services program (SSP) was established following the Indiana HIV outbreak among persons who inject drugs (PWID) in Scott County. Among Indiana-based PWID, we examined injection behaviors associated with HIV status, SSP use after its establishment, and changes in injection behaviors after the outbreak response. During 2016, we interviewed 200 PWID and assessed injection behaviors before the response by HIV status.

An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol.

A library of natural products and their derivatives was screened for inhibition of protein tyrosine phosphatase (PTP) 1B, which is a validated drug target for the treatment of obesity and type II diabetes. Of those active in the preliminary assay, the most promising was compound containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol () with hydrazine. This nitrogen-atom augmented radicicol derivative was found to be PTP1B selective relative to other highly homologous nonreceptor PTPs.

Mycobacterium chimaera Encephalitis Following Cardiac Surgery: A New Syndrome.

We report the cases of 3 patients with fatal, disseminated Mycobacterium chimaera infections following cardiac surgeries. Progressive neurocognitive decline and death were explained by active granulomatous encephalitis, with widespread involvement of other organs. This syndrome is clinically elusive and, thus, may have caused deaths in prior reported series.

Vestibular neurons with direct projections to the solitary nucleus in the rat.

Anterograde and retrograde tract tracing were combined with neurotransmitter and modulator immunolabeling to identify the chemical anatomy of vestibular nuclear neurons with direct projections to the solitary nucleus in rats. Direct, sparsely branched but highly varicose axonal projections from neurons in the caudal vestibular nuclei to the solitary nucleus were observed. The vestibular neurons giving rise to these projections were predominantly located in ipsilateral medial vestibular nucleus.

Malignant Hyperthermia During Translabyrinthine Acoustic Neuroma Surgery After Previous Uneventful Surgery.

Objective: Review current literature and guidelines for malignant hyperthermia in the context of neurotologic surgery.

Patient: A case of malignant hyperthermia during vestibular schwannoma surgery, in a patient previously exposed to anesthesia.

Interventions: Excision of vestibular schwannoma, acute management of malignant hyperthermia.

Phosphatidylinositol 4,5-bisphosphate drives Ca-independent membrane penetration by the tandem C2 domain proteins synaptotagmin-1 and Doc2β.

Exocytosis mediates the release of neurotransmitters and hormones from neurons and neuroendocrine cells. Tandem C2 domain proteins in the synaptotagmin (syt) and double C2 domain (Doc2) families regulate exocytotic membrane fusion via direct interactions with Ca and phospholipid bilayers. Syt1 is a fast-acting, low-affinity Ca sensor that penetrates membranes upon binding Ca to trigger synchronous vesicle fusion.

A high throughput substrate binding assay reveals hexachlorophene as an inhibitor of the ER-resident HSP70 chaperone GRP78.

Glucose-regulated protein 78 (GRP78) is the ER resident 70 kDa heat shock protein 70 (HSP70) and has been hypothesized to be a therapeutic target for various forms of cancer due to its role in mitigating proteotoxic stress in the ER, its elevated expression in some cancers, and the correlation between high levels for GRP78 and a poor prognosis. Herein we report the development and use of a high throughput fluorescence polarization-based peptide binding assay as an initial step toward the discovery and development of GRP78 inhibitors. This assay was used in a pilot screen to discover the anti-infective agent, hexachlorophene, as an inhibitor of GRP78.

Functional cooperation of α-synuclein and VAMP2 in synaptic vesicle recycling.

The function of α-synuclein (α-syn) has been long debated, and two seemingly divergent views have emerged. In one, α-syn binds to VAMP2, acting as a SNARE chaperone-but with no effect on neurotransmission-while another posits that α-syn attenuates neurotransmitter release by restricting synaptic vesicle mobilization and recycling. Here, we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation.

Risk factors for chronic kidney disease of non-traditional causes: a systematic review.

Objectives: To evaluate the potential associations between chronic kidney disease of uncertain or non-traditional etiology (CKDnT) and agrochemicals, heat stress, heavy metals, and other factors identified in the literature in any region of the world and at any time.

Methods: This was a systematic review of the most frequent exposures suspected to be possible causes of CKDnT. A search was conducted of PubMed, LILACS, World Wide Science electronic databases, among other sources.

Virchow's triad in "silent" deep vein thrombosis.

Objective: While determining the incidence of chronic deep vein thrombosis (DVT) and the hypercoagulation profiles of patients who underwent venous stenting for symptomatic venous insufficiency, we assessed the significance of Virchow's triad in the setting of proximal venous outflow obstruction and DVT.

Methods: Within our registry of 500 patients who underwent venous stenting for proximal venous outflow obstruction between 2013 and 2016, we selected the first 152 consecutive patients who had routine hypercoagulation profile testing performed preoperatively. Statistical analysis was performed using independent t-tests, χ tests, and multiple logistic regressions.

Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections.

Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of care. One strategy is to target protein homeostasis pathways by inhibiting molecular chaperones such as GroEL/ES (HSP60/10) chaperonin systems.

Structural Basis for the Distinct Membrane Binding Activity of the Homologous C2A Domains of Myoferlin and Dysferlin.

Dysferlin has been implicated in acute membrane repair processes, whereas myoferlin's activity is maximal during the myoblast fusion stage of early skeletal muscle cell development. Both proteins are similar in size and domain structure; however, despite the overall similarity, myoferlin's known physiological functions do not overlap with those of dysferlin. Here we present for the first time the X-ray crystal structure of human myoferlin C2A to 1.

A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis.

Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism.

MiR-35 buffers apoptosis thresholds in the C. elegans germline by antagonizing both MAPK and core apoptosis pathways.

Apoptosis is a genetically programmed cell death process with profound roles in development and disease. MicroRNAs modulate the expression of many proteins and are often deregulated in human diseases, such as cancer. C.

Desensitization in patients with hypersensitivity to haem arginate: A case report.

Background: Porphyria comprises a group of metabolic disorders caused by the irregular activities of enzymes within the haem biosynthetic pathway. This disease can provoke a large variety of symptoms. Acute porphyria attacks need to be treated urgently to avoid prolonged illness and fatal complications.

Caught in a Trap? Proteomic Analysis of Neutrophil Extracellular Traps in Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Neutrophil Extracellular Traps (NETs) are implicated in the development of auto-immunity in diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) through the externalization of intracellular neoepitopes e.g., dsDNA and nuclear proteins in SLE and citrullinated peptides in RA.

Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S-Mediated Noncanonical Mechanism.

Spermidine (SPD), a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of SPD protects against liver fibrosis and hepatocarcinogenesis through activation of microtubule associated protein 1S (MAP1S)-mediated autophagy. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance.

HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.

All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy.