Symptoms Of Depression Are Linked To Subsequent Recurrent Chest Pain In Patients Admitted To An Emergency Department Chest Pain Unit.

SYMPTOMS OF DEPRESSION ARE LINKED TO SUBSEQUENT RECURRENT CHEST PAIN IN PATIENTS ADMITTED TO AN EMERGENCY DEPARTMENT CHEST PAIN UNIT. Summer A. Paradise, Matt Naftilan, James Dziura, Aini Jelani, Morgan Soffler and Basmah Safdar. Department of Emergency Medicine, Yale University, School of Medicine, New Haven, CT. Prior studies suggest a high prevalence of depression in patients with chest pain, but few US studies have examined depression and recurrent chest pain in the emergency room setting. This study sought to compare symptoms of depression, socio-demographic features, and clinical features between low-moderate-risk emergency room (ER) chest pain center (CPC) patients with and without recurrent chest pain at one-month following enrollment. This study was a prospective cohort study using convenience sample at a tertiary care hospital emergency room in a semi-urban setting. Patients were recruited from the chest pain center (CPC), and completed baseline surveys that assessed depression, anxiety, stress and chest pain. A one-month follow-up assessed the recurrence of chest pain. Univariate and multivariate statistical analyses were conducted. Between July 30th 2013 to January 31st 2015 a total of 850 patients were invited to participate in our study, 442 (52.0%) agreed to do so, of which 327 (74.0%) were included in the final analysis. An overall 29% had some evidence of depression, be it high symptom scores or current treatment for depression. In addition, using the PHQ-8, we identified forty-one (12.5%) new patients with depressive symptoms. More than two-thirds of enrolled patients had chest pain on at least one occasion following discharge from the hospital (n=115; 35.2%). Patients with recurrent chest pain tended to be slightly younger (51 versus 55 years of age; p= .001), more female (64.3%; p= .023) and less Caucasian (63.5% versus 70.3%; p= .154). In general, women had higher rates of recurrent/persistent chest pain (n=74/184; 40.2%) than men (n=41/143; 28.7%). The overall burden of depression was 37.4% of patients with recurrent/persistent chest pain, compared to 24.5% of patients without (p= .018). Regression analysis revealed that for each single point increase in PHQ-8 score, there is an 7.5% increase in the odds of having recurrent chest pain (model 5: OR=1.075; 95% CI=1.005, 1.149; p= .035). Gender also had a significant effect in the regression model, and the overall burden of depression was highest among women with recurrent/persistent chest pain (43.2%), and differed significantly from women without recurrent/persistent chest pain (26.4%), (p= .023). The prevalence of depression is high in ER patients with chest pain, and this is particularly relevant for women with baseline depression and recurrent chest pain at one-month follow-up

Recruitment of Endophilin to Clathrin-Coated Pit Necks Is Required for Efficient Vesicle Uncoating after Fission

SummaryEndophilin is a membrane-binding protein with curvature-generating and -sensing properties that participates in clathrin-dependent endocytosis of synaptic vesicle membranes. Endophilin also binds the GTPase dynamin and the phosphoinositide phosphatase synaptojanin and is thought to coordinate constriction of coated pits with membrane fission (via dynamin) and subsequent uncoating (via synaptojanin). We show that although synaptojanin is recruited by endophilin at bud necks before fission, the knockout of all three mouse endophilins results in the accumulation of clathrin-coated vesicles, but not of clathrin-coated pits, at synapses. The absence of endophilin impairs but does not abolish synaptic transmission and results in perinatal lethality, whereas partial endophilin absence causes severe neurological defects, including epilepsy and neurodegeneration. Our data support a model in which endophilin recruitment to coated pit necks, because of its curvature-sensing properties, primes vesicle buds for subsequent uncoating after membrane fission, without being critically required for the fission reaction itself

Data from: A role of OCRL in clathrin-coated pit fission and uncoating revealed by studies of Lowe syndrome cells

Mutations in the inositol 5-phosphatase OCRL cause Lowe syndrome and Dent's disease. Although OCRL, a direct clathrin interactor, is recruited to late-stage clathrin-coated pits, clinical manifestations have been primarily attributed to intracellular sorting defects. Here we show that OCRL loss in Lowe syndrome patient fibroblasts impacts clathrin-mediated endocytosis and results in an endocytic defect. These cells exhibit an accumulation of clathrin-coated vesicles and an increase in U-shaped clathrin-coated pits, which may result from sequestration of coat components on uncoated vesicles. Endocytic vesicles that fail to lose their coat nucleate the majority of the numerous actin comets present in patient cells. SNX9, an adaptor that couples late-stage endocytic coated pits to actin polymerization and which we found to bind OCRL directly, remains associated with such vesicles. These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, an X-linked disorder characterized by bilateral cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome, and for Dent disease, another X-linked condition characterized by kidney reabsorption defects. We have previously described an interaction of OCRL with the endocytic adaptor APPL1 that links OCRL to protein networks involved in the disease phenotype. Here, we provide new evidence showing that among the interactions which target OCRL to membranes of the endocytic pathway, binding to APPL1 is the only one abolished by all known disease-causing missense mutations in the ASH-RhoGAP domains of the protein. Furthermore, we demonstrate that APPL1 and rab5 independently contribute to recruit OCRL to enlarged endosomes induced by the expression of constitutively active Rab5. Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease

Selective high-level expression of epsin 3 in gastric parietal cells, where it is localized at endocytic sites of apical canaliculi

Epsin is a ubiquitin-binding endocytic adaptor, which is highly concentrated at clathrin-coated pits and coordinates acquisition of bilayer curvature with coat recruitment and cargo selection. Epsin is encoded by three distinct genes in mammals. Epsin 1 and 2 have broad tissue distribution with high-level expression in the brain. In contrast, epsin 3 was reported to be expressed primarily in immature keratinocytes. Here, we show that epsin 3 is selectively expressed at high levels in the stomach (including the majority of gastric cancers), where it is concentrated in parietal cells. In these cells, epsin 3 is enriched and colocalized with clathrin around apical canaliculi, the sites that control acidification of the stomach lumen via the exo-endocytosis of vesicles containing the H/K ATPase. Deletion of the epsin 3 gene in mice did not result in obvious pathological phenotypes in either the stomach or other organs, possibly because of overlapping functions of the other two epsins. However, levels of EHD1 and EHD2, two membrane tubulating proteins with a role in endocytic recycling, were elevated in epsin 3 knock-out stomachs, pointing to a functional interplay of epsin 3 with EHD proteins in the endocytic pathway of parietal cells. We suggest that epsin 3 cooperates with other bilayer binding proteins with curvature sensing/generating properties in the specialized traffic and membrane remodeling processes typical of gastric parietal cells

A Role of the Lowe Syndrome Protein OCRL in Early Steps of the Endocytic Pathway

SummaryMutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, whose manifestations include mental retardation and renal Fanconi syndrome. OCRL has been implicated in membrane trafficking, but disease mechanisms remain unclear. We show that OCRL visits late-stage, endocytic clathrin-coated pits and binds the Rab5 effector APPL1 on peripheral early endosomes. The interaction with APPL1, which is mediated by the ASH-RhoGAP-like domains of OCRL and is abolished by disease mutations, provides a link to protein networks implicated in the reabsorptive function of the kidney and in the trafficking and signaling of growth factor receptors in the brain. Crystallographic studies reveal a role of the ASH-RhoGAP-like domains in positioning the phosphatase domain at the membrane interface and a clathrin box protruding from the RhoGAP-like domain. Our results support a role of OCRL in the early endocytic pathway, consistent with the predominant localization of its preferred substrates, PI(4,5)P2 and PI(3,4,5)P3, at the cell surface

OCRL interactors identified by label-free quantitative proteomics in immunoprecipitates from cell lines expressing GFP-OCRL at 5X endogenous levels

OCRL interactors identified by label-free quantitative proteomics in immunoprecipitates from cell lines expressing GFP-OCRL at 5X endogenous level

OCRL interactors identified by label-free quantitative proteomics from cell lines expressing GFP-OCRL near endogenous levels

OCRL interactors identified by label-free quantitative proteomics from cell lines expressing GFP-OCRL near endogenous level