The autism protein UBE3A/E6AP regulates remodeling of neuronal dendritic arborization

Autism spectrum disorders (ASDs) are clinically characterized by decreased communication abilities, impaired social interaction, and the occurrence of repetitive behaviors, with high genetic heritability. Ubiquitin protein ligase E3A (UBE3A) is a gene located on human chromosome 15q11-13, a region that has been the focus of genetic studies of susceptibility to ASD AND Angelman syndrome. An increased UBE3A gene dosage and thus an elevated amount of E6AP, the protein product of UBE3A, is associated with ASD. However, the underlying cellular and molecular details remain poorly understood. Normal development of neuronal structure is critical for intercellular connectivity and overall brain function, and abnormal brain development is a commonality amongst ASDs. These studies therefore investigated the role of increased dosage of Ube3A/E6AP in dendritic arborization and synapse maturation during brain development. Increased E6AP expression in vitro led to significant reduction in dendritic arborization by thinning and fragmentation of the distal tip, along with a decrease in spine density and an increase in immature spines in hippocampal neurons. This morphological remodeling effect was mediated by the ubiquitination and subsequent degradation of the X-linked inhibitor of apoptosis protein (XIAP) by E6AP, which led to activation of caspase-3. Furthermore, activated caspases cleaved tubulin, leading to retraction of microtubules from the distal tip of dendrites, dendritic thinning and eventual disappearance. In vivo studies investigated the role of E6AP in ASD-related neuronal development in Ube3A 2X transgenic mice and found that, consistent with our in vitro studies, increased E6AP in the brain lead to decreased XIAP levels, increased active caspase-3, and enhanced tubulin cleavage in hippocampal tissue in Ube3A 2X mice. In accord, Ube3A 2X mice showed a reduction in dendritic growth and branching and spine density. This work elucidated an important role of Ube3A/E6AP in dendritic pruning and identified XIAP as a novel ubiquitination target of E6AP. These findings provide a new insight into the molecular pathways underlying neurodevelopmental defects in Ube3A/E6AP-associated ASDs.2018-07-09T00:00:00

Synaptic Activity and Bioenergy Homeostasis: Implications in Brain Trauma and Neurodegenerative Diseases

Powered by glucose metabolism, the brain is the most energy-demanding organ in our body. Adequate ATP production and regulation of the metabolic processes are essential for the maintenance of synaptic transmission and neuronal function. Glutamatergic synaptic activity utilizes the largest portion of bioenergy for synaptic events including neurotransmitter synthesis, vesicle recycling, and most importantly, the postsynaptic activities leading to channel activation and rebalancing of ionic gradients. Bioenergy homeostasis is coupled with synaptic function via activities of the sodium pumps, glutamate transporters, glucose transport, and mitochondria translocation. Energy insufficiency is sensed by the AMP-activated protein kinase (AMPK), a master metabolic regulator that stimulates the catalytic process to enhance energy production. A decline in energy supply and a disruption in bioenergy homeostasis play a critical role in multiple neuropathological conditions including ischemia, stroke, and neurodegenerative diseases including Alzheimer’s disease and traumatic brain injuries

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

International audienc

Structural Diversity in 1,3-Bis(<i>m</i>‑cyanophenyl)urea

Hydrogen bonding between 1,3-bis ureas is a commonly used motif in the assembly of supramolecular structures such as gels, capsules and crystals. The title compound, 1,3-bis­(<i>m</i>-cyanophenyl)­urea (<b>mCyPU</b>), has previously been shown to crystallize in both an anhydrous and monohydrate phase (α and H–I). An expanded search for polymorphs and cocrystals of <b>mCyPU</b> revealed a much greater diversity of solid forms including three additional polymorphs (β, δ, ε), a second hydrate (H–II) and two cocrystal phases with dimethyl sulfoxide and triphenylphosphine oxide. Analysis of the single crystal structures obtained in this study shows that the typical 1-dimensional H-bonding between 1,3-bis urea groups is disrupted by the presence of other H-bond acceptors including cyano, water, sulfoxide and phosphine oxide functionalities. Re-examination of <b>α-mCyPU</b> additionally showed both blade and plate-like morphologies could be obtained from different growth solvents, with crystals of the latter morphology exhibiting a grain boundary migration prior to melting

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. These findings uncover a pivotal role for SMYD2 in promoting pancreatic cancer

A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors.

UnlabelledSmall cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.SignificanceOur work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells

Dose-dependent reduction of somatic expansions but not Htt aggregates by di-valent siRNA-mediated silencing of MSH3 in HdhQ111 mice

Abstract Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the HTT gene. In addition to germline CAG expansions, somatic repeat expansions in neurons also contribute to HD pathogenesis. The DNA mismatch repair gene, MSH3, identified as a genetic modifier of HD onset and progression, promotes somatic CAG expansions, and thus presents a potential therapeutic target. However, what extent of MSH3 protein reduction is needed to attenuate somatic CAG expansions and elicit therapeutic benefits in HD disease models is less clear. In our study, we employed potent di-siRNAs to silence mouse Msh3 mRNA expression in a dose-dependent manner in HdhQ111/+ mice and correlated somatic Htt CAG instability with MSH3 protein levels from simultaneously isolated DNA and protein after siRNA treatment. Our results reveal a linear correlation with a proportionality constant of ~ 1 between the prevention of somatic Htt CAG expansions and MSH3 protein expression in vivo, supporting MSH3 as a rate-limiting step in somatic expansions. Intriguingly, despite a 75% reduction in MSH3 protein levels, striatal nuclear HTT aggregates remained unchanged. We also note that evidence for nuclear Msh3 mRNA that is inaccessible to RNA interference was found, and that MSH6 protein in the striatum was upregulated following MSH3 knockdown in HdhQ111/+ mice. These results provide important clues to address critical questions for the development of therapeutic molecules targeting MSH3 as a potential therapeutic target for HD