Mesoscale Dynamics of Spectrin and Acto-Myosin Shape Membrane 2 Territories During Mechanoresponse
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Biomarkers in Tbi and Abi: Present, Future, and Going Nowhere
BIOMARKERS IN TBI AND ABI: PRESENT, FUTURE, AND GOING NOWHERE GABRIEL NEWMAN, PH.D., DIRECTOR: THE NEUROSCIENCE TEAM, TOWSON Disclosures: • No ties to drug companies, labs, or medical equipment companies • Studies being conducted by author at present are in area of Neuromoduation as an intervention in Autism, and Photobiomodulation as an intervention in TBI and ABI, not specifically in reliability of biomarkers for these conditions • Author of presentation is primarily a clinician in practice (70%), not researcher (30%) Lab assays: 1. MEG3 and Interluekin: Drops in MEG3 and rise in interleukin-1β (IL-1β), IL-6, and IL-8 correlate with poor prognosis in TBI. Thought to be specific to TBI, but research will tell… (Shao et al, May 2019, Eur Rev Med Pharmacol Sci). High likelihood for good use in future. Relatively easy to order. 2. S100β: calcium binding protein found in astrocytes, responsible for regulating intracellular levels of calcium; not brain specific, thus it shows up in injury not involving TBI. Must be considered along with trauma history. Also, must be taken an hour after concussion. Problem: Hard to obtain because of time limit. – probably going nowhere (Linda Papa, MD, MSc., Sports Med Arthrosc. 2016 Sep; 24(3): 108–115) 3. Glial Fibrillary Acid Protein (GFAP): Glial Fibrillary Acidic Protein (GFAP) is a promising, brain-specific glial-derived biomarker for MTBI in adults and children. GFAP is released in highly increased amounts into blood serum within an hour of an mTBI injury, and can remain elevated for several days after injury. More feasible, given extended detectability. Papa L, Mittal MK, Ramirez J, et al.; . -
Defining Functional Interactions During Biogenesis of Epithelial Junctions
ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Extraction of Dynamic Patterns from Static Rna Expression Data: an Application to Hematological Neoplasms
EXTRACTION OF DYNAMIC PATTERNS FROM STATIC RNA EXPRESSION DATA: AN APPLICATION TO HEMATOLOGICAL NEOPLASMS Relatore: Barbara Di Camillo Correlatore: Dott.ssa Alessandra Trojani Laureando: Giulia Bianchi ANNO ACCADEMICO 2012/2013 Nothing worth gaining was ever gained without effort. Theodore Roosevelt Index Section 1 INTRODUCTION 1 1.1. Extraction of temporal dynamics from gene expression data 2 1.2. Chronic Lymphocytic Leukemia 3 1.3. IgM Monoclonal Gammopathy of Undetermined Significance and Waldenstrӧm’s Macroglobulinemia 4 Section 2 DATA 7 2.1. CLL Data set 8 2.2. WM/MGUS Data set 8 Section 3 SAMPLE PROGRESSION DISCOVERY 10 3.1. Methods 10 3.2. SPD step by step 12 3.2.1. Input format 12 3.2.2. Gene filtering 12 3.2.3. Clustering 13 3.2.4. Construct MSTs – Compare modules and MSTs 14 3.2.5. Identify modules similar in terms of progression 16 3.3. Results and discussion 17 Section 4 PARAMETER SETTING 19 4.1. Input configuration 19 4.2. Result evaluation 20 4.3. Conclusions 26 Section 5 APPLICATION TO CHRONIC LYMPHOCYTIC LEUKEMIA 28 5.1. Gene selection 28 5.2. SPD results 29 Section 6 APPLICATION TO WALDENSTRÖM’S MACROGLOBULINEMIA AND IgM MGUS 39 6.1. Gene selection 39 6.2. SPD results 40 Section 7 DISCUSSION 45 Acknowledgements 49 Section 8 REFERENCES 51 Section 9 APPENDIX 55 i Section 1 INTRODUCTION Development and evolution of a disease are dynamic processes that, from a molecular point of view, involve changes in some gene expression levels in the involved organs and cells. A possible approach to study the behavior of such dynamic phenomena is to sample individuals, tissues or other relevant units at subsequent time-points throughout the progression. -
Protein Identities in Evs Isolated from U87-MG GBM Cells As Determined by NG LC-MS/MS
Protein identities in EVs isolated from U87-MG GBM cells as determined by NG LC-MS/MS. No. Accession Description Σ Coverage Σ# Proteins Σ# Unique Peptides Σ# Peptides Σ# PSMs # AAs MW [kDa] calc. pI 1 A8MS94 Putative golgin subfamily A member 2-like protein 5 OS=Homo sapiens PE=5 SV=2 - [GG2L5_HUMAN] 100 1 1 7 88 110 12,03704523 5,681152344 2 P60660 Myosin light polypeptide 6 OS=Homo sapiens GN=MYL6 PE=1 SV=2 - [MYL6_HUMAN] 100 3 5 17 173 151 16,91913397 4,652832031 3 Q6ZYL4 General transcription factor IIH subunit 5 OS=Homo sapiens GN=GTF2H5 PE=1 SV=1 - [TF2H5_HUMAN] 98,59 1 1 4 13 71 8,048185945 4,652832031 4 P60709 Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 - [ACTB_HUMAN] 97,6 5 5 35 917 375 41,70973209 5,478027344 5 P13489 Ribonuclease inhibitor OS=Homo sapiens GN=RNH1 PE=1 SV=2 - [RINI_HUMAN] 96,75 1 12 37 173 461 49,94108966 4,817871094 6 P09382 Galectin-1 OS=Homo sapiens GN=LGALS1 PE=1 SV=2 - [LEG1_HUMAN] 96,3 1 7 14 283 135 14,70620005 5,503417969 7 P60174 Triosephosphate isomerase OS=Homo sapiens GN=TPI1 PE=1 SV=3 - [TPIS_HUMAN] 95,1 3 16 25 375 286 30,77169764 5,922363281 8 P04406 Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 - [G3P_HUMAN] 94,63 2 13 31 509 335 36,03039959 8,455566406 9 Q15185 Prostaglandin E synthase 3 OS=Homo sapiens GN=PTGES3 PE=1 SV=1 - [TEBP_HUMAN] 93,13 1 5 12 74 160 18,68541938 4,538574219 10 P09417 Dihydropteridine reductase OS=Homo sapiens GN=QDPR PE=1 SV=2 - [DHPR_HUMAN] 93,03 1 1 17 69 244 25,77302971 7,371582031 11 P01911 HLA class II histocompatibility antigen, -
Transiently Structured Head Domains Control Intermediate Filament Assembly
Transiently structured head domains control intermediate filament assembly Xiaoming Zhoua, Yi Lina,1, Masato Katoa,b,c, Eiichiro Morid, Glen Liszczaka, Lillian Sutherlanda, Vasiliy O. Sysoeva, Dylan T. Murraye, Robert Tyckoc, and Steven L. McKnighta,2 aDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; bInstitute for Quantum Life Science, National Institutes for Quantum and Radiological Science and Technology, 263-8555 Chiba, Japan; cLaboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520; dDepartment of Future Basic Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, Japan; and eDepartment of Chemistry, University of California, Davis, CA 95616 Contributed by Steven L. McKnight, January 2, 2021 (sent for review October 30, 2020; reviewed by Lynette Cegelski, Tatyana Polenova, and Natasha Snider) Low complexity (LC) head domains 92 and 108 residues in length are, IF head domains might facilitate filament assembly in a manner respectively, required for assembly of neurofilament light (NFL) and analogous to LC domain function by RNA-binding proteins in the desmin intermediate filaments (IFs). As studied in isolation, these IF assembly of RNA granules. head domains interconvert between states of conformational disor- IFs are defined by centrally located α-helical segments 300 to der and labile, β-strand–enriched polymers. Solid-state NMR (ss-NMR) 350 residues in length. These central, α-helical segments are spectroscopic studies of NFL and desmin head domain polymers re- flanked on either end by head and tail domains thought to be veal spectral patterns consistent with structural order. -
Spectrin and Ankyrin Like Proteins in Spermatids and Spermatozoa of the Hamster and Some Other Mammals Ml Kann, La Pradel, J.-P
Spectrin and ankyrin like proteins in spermatids and spermatozoa of the hamster and some other mammals Ml Kann, La Pradel, J.-P. Fouquet To cite this version: Ml Kann, La Pradel, J.-P. Fouquet. Spectrin and ankyrin like proteins in spermatids and spermatozoa of the hamster and some other mammals. Reproduction Nutrition Development, EDP Sciences, 1993, 33 (1), pp.51-61. hal-00899573 HAL Id: hal-00899573 https://hal.archives-ouvertes.fr/hal-00899573 Submitted on 1 Jan 1993 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Original article Spectrin and ankyrin like proteins in spermatids and spermatozoa of the hamster and some other mammals ML Kann LA Pradel JP Fouquet1 1 UFR Biomédicale, Groupe d’Étude de la Formation et de la Maturation du Gamète mâle, 45 rue des Saints-Pères, 75270 Paris Cedex 06; 2 Institut de Biologie Physico-Chimique, Unité CNRS UA 1112 de Neurologie physico-chimique, 13 rue Pierre et Marie Curie, 75005 Paris, France (Received 7 July 1992; accepted 29 October 1992) Summary ― The presence of spectrin and ankyrin-like proteins was investigated during the differ- entiation and maturation of spermatozoa in mammalian species which have previously been studied for actin and calmodulin. -
Regulation of NMDA Receptor Activity by F-Actin and Myosin Light Chain Kinase
The Journal of Neuroscience, November 1, 2001, 21(21):8464–8472 Regulation of NMDA Receptor Activity by F-Actin and Myosin Light Chain Kinase Saobo Lei,1 Elzbieta Czerwinska,1 Waldemar Czerwinski,1 Michael P. Walsh,2 and John F. MacDonald1 1Canadian Institutes of Health Research Group “The Synapse,” Departments of Physiology and Pharmacology, University of Toronto, Toronto M5S 1A8, Canada, and 2Canadian Institutes of Health Research Group in Regulation of Vascular Contractility and The Smooth Muscle Research Group, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary T2N 4N1, Canada The postsynaptic density (PSD) at excitatory dendritic syn- This MLCK-dependent regulation was observed in cell- apses comprises a protein complex of glutamate receptors, attached patches but was lost after excision to inside-out scaffolding elements, and signaling enzymes. For example, patches. Furthermore, the enhancement induced by constitu- NMDA receptors (NMDARs) are linked to several proteins in the tively active MLCK and the depression of MLCK inhibitors were PSD, such as PSD-95, and are also tethered via binding pro- eliminated after depolymerization of the cytoskeleton. NMDARs teins such as ␣-actinin directly to filamentous actin of the and MLCK did not colocalize in clusters on the dendrites of cytoskeleton. Depolymerization of the cytoskeleton modulates cultured hippocampal neurons, further indicating that the ef- the activity of NMDARs, and, in turn, strong activation of fects of MLCK are mediated indirectly via actomyosin. Our NMDARs can trigger depolymerization of actin. Myosin, the results suggest that MLCK enhances actomyosin contractility motor protein of muscular contraction and nonmuscle motility, to either increase the membrane tension on NMDARs or to alter is also associated with NMDARs and the PSD. -
Nesprins: from the Nuclear Envelope and Beyond
expert reviews http://www.expertreviews.org/ in molecular medicine Nesprins: from the nuclear envelope and beyond Dipen Rajgor and Catherine M. Shanahan* Nuclear envelope spectrin-repeat proteins (Nesprins), are a novel family of nuclear and cytoskeletal proteins with rapidly expanding roles as intracellular scaffolds and linkers. Originally described as proteins that localise to the nuclear envelope (NE) and establish nuclear-cytoskeletal connections, nesprins have now been found to comprise a diverse spectrum of tissue specific isoforms that localise to multiple sub-cellular compartments. Here, we describe how nesprins are necessary in maintaining cellular architecture by acting as essential scaffolds and linkers at both the NE and other sub-cellular domains. More importantly, we speculate how nesprin mutations may disrupt tissue specific nesprin scaffolds and explain the tissue specific nature of many nesprin-associated diseases, including laminopathies. The eukaryotic cytoplasm contains three major composed of three α-helical bundles with a left- types of cytoskeletal filaments: Filamentous- handed twist, and its primary function is to actin (F-actin), microtubules (MTs) and provide docking sites for proteins and other intermediate filaments (IFs). These components higher order complexes (Refs 3, 4). Although are organised in a manner that provides the cell most SR proteins contain CHDs, some possess with an internal framework fundamental for motifs which can interact with other cytoskeletal many processes, such as controlling cellular components, allowing linkage of SR-associated shape, polarity, adhesion and migration, complexes to filamentous structures other than cytokinesis, inter- and intracellular F-actin. In addition, these motifs allow cross- Nesprins: from the nuclear envelope and beyond communication and trafficking of organelles, linking between different filaments and dynamic vesicles, proteins and RNA (Refs 1, 2). -
A Rhoa and Rnd3 Cycle Regulates Actin Reassembly During Membrane
A RhoA and Rnd3 cycle regulates actin reassembly PNAS PLUS during membrane blebbing Kana Aokia, Fumiyo Maedaa,1, Tomoya Nagasakob,1, Yuki Mochizukia, Seiichi Uchidab, and Junichi Ikenouchia,c,d,2 aDepartment of Biology, Faculty of Sciences, Kyushu University, Fukuoka 819-0395, Japan; bDepartment of Advanced Information Technology, Kyushu University, Fukuoka 819-0395, Japan; cPrecursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan; and dAMED-PRIME, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan Edited by Thomas D. Pollard, Yale University, New Haven, CT, and approved February 12, 2016 (received for review January 21, 2016) The actin cytoskeleton usually lies beneath the plasma membrane. membrane blebs is promoted by epidermal growth factor receptor When the membrane-associated actin cytoskeleton is transiently kinase substrate 8 (Eps8) and ezrin, and regulated by a RhoA– disrupted or the intracellular pressure is increased, the plasma Rho-associated protein kinase (ROCK)–Rnd3 feedback loop. membrane detaches from the cortex and protrudes. Such protruded membrane regions are called blebs. However, the molecular mech- Results and Discussion anisms underlying membrane blebbing are poorly understood. This Membrane Blebs Retract from Multiple Sites. We used the human study revealed that epidermal growth factor receptor kinase sub- colon carcinoma cell line DLD1 to observe membrane blebbing. strate 8 (Eps8) and ezrin are important regulators of rapid actin When cultured in 2D conditions, DLD1 cells did not exhibit reassembly for the initiation and retraction of protruded blebs. Live- membrane blebbing (Fig. 1A, Left). However, DLD1 cells ac- cell imaging of membrane blebbing revealed that local reassembly tively formed membrane blebs when embedded in a type I col- of actin filaments occurred at Eps8- and activated ezrin-positive foci lagen gel (Fig. -
Vaccinia Virus Strains Use Distinct Forms of Macropinocytosis for Host-Cell Entry
Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry Jason Mercer1, Stephan Knébel, Florian I. Schmidt, Josh Crouse, Christine Burkard, and Ari Helenius1 Eidgenössische Technische Hochschule Zurich, Institute of Biochemistry, Eidgenössische Technische Hochschule Hoenggerberg, 8093 Zurich, Switzerland Contributed by Ari Helenius, April 10, 2010 (sent for review January 20, 2010) To enter host cells, vaccinia virus, a prototype poxvirus, can induce Previous studies have suggested that entry of IHD-J MVs might transient macropinocytosis followed by endocytic internalization be different. Instead of blebs, they seem to induce narrow plasma and penetration through the limiting membrane of pinosomes by membrane protrusions (9). The IHD-J virus is also more de- membrane fusion. Although mature virions (MVs) of the Western pendent on glycosaminoglycan binding and does not require reserve (WR) strain do this in HeLa cells by activating transient acidic vacuolar pH (10). To determine whether the two strains of plasma membrane blebbing, MVs from the International Health VACV do, in fact, use different entry strategies, we compared Department-J strain were found to induce rapid formation (and their interaction with HeLa cells and found that the immediate lengthening) of filopodia. When the signaling pathways underly- cellular responses to the two strains were quite different. Clearly ing these responses were compared, differences were observed at the same host cells were capable of activating distinct forms the level of Rho GTPases. Key to the filopodial formation was the of macropinocytosis. virus-induced activation of Cdc42, and for the blebbing response the activation of Rac1. In addition, unlike WR, International Health Results Department-J MVs did not rely on genistein-sensitive tyrosine IHD-J MVs Induce Filopodia. -
Spectrin and Maladaptive Remodeling?
STAT3: a link between CaMKII–βIV-spectrin and maladaptive remodeling? Mohit Hulsurkar, … , Ann P. Quick, Xander H.T. Wehrens J Clin Invest. 2018;128(12):5219-5221. https://doi.org/10.1172/JCI124778. Commentary 2+ βIV-Spectrin, along with ankyrin and Ca /calmodulin-dependent kinase II (CaMKII), has been shown to form local signaling domains at the intercalated disc, while playing a key role in the regulation of Na+ and K+ channels in cardiomyocytes. In this issue of the JCI, Unudurthi et al. show that under chronic pressure overload conditions, CaMKII activation leads to βIV-spectrin degradation, resulting in the release of sequestered STAT3 from the intercalated discs. This in turn leads to dysregulation of STAT3-mediated gene transcription, maladaptive remodeling, fibrosis, and decreased cardiac function. Overall, this study presents interesting findings regarding the role of CaMKII and βIV-spectrin under physiological as well as pathological conditions. Find the latest version: https://jci.me/124778/pdf The Journal of Clinical Investigation COMMENTARY STAT3: a link between CaMKII–βIV-spectrin and maladaptive remodeling? Mohit Hulsurkar,1,2 Ann P. Quick,1,2 and Xander H.T. Wehrens1,2,3,4,5,6 1Cardiovascular Research Institute, 2Department of Molecular Physiology and Biophysics, 3Department of Medicine, 4Department of Pediatrics, 5Department of Neuroscience, and 6Center for Space Medicine, Baylor College of Medicine, Houston, Texas, USA. In addition to their physiological roles, β-spectrins may also contribute to patho- β -Spectrin, along with ankyrin and Ca2+/calmodulin-dependent kinase IV logical changes during pressure over- II (CaMKII), has been shown to form local signaling domains at the load that precipitate detrimental cardiac intercalated disc, while playing a key role in the regulation of Na+ and remodeling.