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https://www.readbyqxmd.com/read/29905796/heart-failure-with-preserved-ejection-fraction-from-mechanisms-to-therapies
#1
Carolyn S P Lam, Adriaan A Voors, Rudolf A de Boer, Scott D Solomon, Dirk J van Veldhuisen
This review aims to provide a translational perspective on recent developments in heart failure with preserved ejection fraction (HFpEF), linking mechanistic insights to potential therapies. A key concept in this review is that HFpEF is a haemodynamic condition wherein the heart fails to keep up with the circulatory demands of the body, or does so at the expense of raised left ventricular filling pressures. We, therefore, propose that the 'final common pathway' for development of congestion, i.e. basic haemodynamic mechanisms of increased left ventricular end-diastolic pressure, left atrial hypertension, pulmonary venous congestion, and plasma volume expansion, represents important initial targets for therapy in HFpEF...
June 13, 2018: European Heart Journal
https://www.readbyqxmd.com/read/29897447/a-spatially-explicit-model-shows-how-titin-stiffness-modulates-muscle-mechanics-and-energetics
#2
Joseph Powers, Charles Williams, Michael Regnier, Thomas Daniel
In striated muscle, the giant protein titin spans the entire length of a half-sarcomere and extends from the backbone of the thick filament, reversibly attaches to the thin filaments, and anchors to the dense protein network of the z-disk capping the end of the half-sarcomere. However, little is known about the relationship between the basic mechanical properties of titin and muscle contractility. Here, we build upon our previous multi-filament, spatially explicit computational model of the half-sarcomere by incorporating the nonlinear mechanics of titin filaments in the I-band...
June 12, 2018: Integrative and Comparative Biology
https://www.readbyqxmd.com/read/29895960/phosphorylation-of-the-rsrsp-stretch-is-critical-for-splicing-regulation-by-rna-binding-motif-protein-20-rbm20-through-nuclear-localization
#3
Rie Murayama, Mariko Kimura-Asami, Marina Togo-Ohno, Yumiko Yamasaki-Kato, Taeko K Naruse, Takeshi Yamamoto, Takeharu Hayashi, Tomohiko Ai, Katherine G Spoonamore, Richard J Kovacs, Matteo Vatta, Mai Iizuka, Masumi Saito, Shotaro Wani, Yuichi Hiraoka, Akinori Kimura, Hidehito Kuroyanagi
RBM20 is a major regulator of heart-specific alternative pre-mRNA splicing of TTN encoding a giant sarcomeric protein titin. Mutation in RBM20 is linked to autosomal-dominant familial dilated cardiomyopathy (DCM), yet most of the RBM20 missense mutations in familial and sporadic cases were mapped to an RSRSP stretch in an arginine/serine-rich region of which function remains unknown. In the present study, we identified an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients...
June 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29889873/drug-discovery-with-an-rbm20-dependent-titin-splice-reporter-identifies-cardenolides-as-lead-structures-to-improve-cardiac-filling
#4
Martin Liss, Michael H Radke, Jamina Eckhard, Martin Neuenschwander, Vita Dauksaite, Jens-Peter von Kries, Michael Gotthardt
Diastolic dysfunction is increasingly prevalent in our ageing society and an important contributor to heart failure. The giant protein titin could serve as a therapeutic target, as its elastic properties are a main determinant of cardiac filling in diastole. This study aimed to develop a high throughput pharmacological screen to identify small molecules that affect titin isoform expression through differential inclusion of exons encoding the elastic PEVK domains. We used a dual luciferase splice reporter assay that builds on the titin splice factor RBM20 to screen ~34,000 small molecules and identified several compounds that inhibit the exclusion of PEVK exons...
2018: PloS One
https://www.readbyqxmd.com/read/29870683/urinary-n-terminal-fragment-of-titin-is-a-marker-to-diagnose-muscular-dystrophy-in-patients-with-cardiomyopathy
#5
Akiomi Yoshihisa, Takatoyo Kiko, Takamasa Sato, Masayoshi Oikawa, Atsushi Kobayashi, Yasuchika Takeishi
The differential diagnosis of cardiomyopathy is important. It has been recently reported that urinary titin N (U-TN) is increased in patients with muscular dystrophy (MD), and is associated with muscular damage. We aimed to clarify whether U-TN is useful as a diagnostic tool for distinguishing MD from various cardiomyopathies [e.g. dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM)]. We measured and compared the U-TN/creatinine ratio (U-TN/Cr; pmol/mg/dl) in 278 control subjects and 331 patients with various cardiomyopathies (DCM, n = 199; sarcoidosis, n = 18; HCM, n = 86; amyloidosis, n = 15; Fabry disease, n = 6; MD, n = 7)...
June 2, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29850810/muscle-function-from-organisms-to-molecules
#6
Kiisa C Nishikawa, Jenna A Monroy, Uzma Tahir
Gaps in our understanding of muscle contraction at the molecular level limit the ability to predict in vivo muscle forces in humans and animals during natural movements. Because muscles function as motors, springs, brakes, or struts, it is not surprising that uncertainties remain as to how sarcomeres produce these different behaviors. Current theories fail to explain why a single extra stimulus, added shortly after the onset of a train of stimuli, doubles the rate of force development. When stretch and doublet stimulation are combined in a work loop, muscle force doubles and work increases by 50% per cycle, yet no theory explains why this occurs...
May 29, 2018: Integrative and Comparative Biology
https://www.readbyqxmd.com/read/29846170/a-transcriptomics-resource-reveals-a-transcriptional-transition-during-ordered-sarcomere-morphogenesis-in-flight-muscle
#7
Maria L Spletter, Christiane Barz, Assa Yeroslaviz, Xu Zhang, Sandra B Lemke, Adrien Bonnard, Erich Brunner, Giovanni Cardone, Konrad Basler, Bianca H Habermann, Frank Schnorrer
Muscles organise pseudo-crystalline arrays of actin, myosin and titin filaments to build force-producing sarcomeres. To study sarcomerogenesis, we have generated a transcriptomics resource of developing Drosophila flight muscles and identified 40 distinct expression profile clusters. Strikingly, most sarcomeric components group in two clusters, which are strongly induced after all myofibrils have been assembled, indicating a transcriptional transition during myofibrillogenesis. Following myofibril assembly, many short sarcomeres are added to each myofibril...
May 30, 2018: ELife
https://www.readbyqxmd.com/read/29792937/a-reliable-targeted-next-generation-sequencing-strategy-for-diagnosis-of-myopathies-and-muscular-dystrophies-especially-for-the-giant-titin-and-nebulin-genes
#8
Reda Zenagui, Delphine Lacourt, Henri Pegeot, Kevin Yauy, Raul Juntas Morales, Corine Theze, François Rivier, Claude Cances, Guilhem Sole, Dimitri Renard, Ulrike Walther-Louvier, Xavier Ferrer-Monasterio, Caroline Espil, Marie-Christine Arné-Bes, Pascal Cintas, Emmanuelle Uro-Coste, Marie-Laure Martin Negrier, Valérie Rigau, Eric Bieth, Cyril Goizet, Mireille Claustres, Michel Koenig, Mireille Cossée
Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with more than 100 identified genes, including the giant and complex titin (TTN) and nebulin (NEB) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTN and NEB variants. We developed a next-generation sequencing diagnostic strategy targeted on the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library capture kit (Roche-Nimblegen) and Nextera Rapid Capture Custom Enrichment kit (Illumina)) and of two whole exome sequencing kits (SureSelect V5 (Agilent) and TruSeq RapidExome capture (Illumina)) revealed best coverage with the SeqCap EZ Choice protocol...
May 21, 2018: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29783952/differences-between-fast-and-slow-muscles-in-scallops-revealed-through-proteomics-and-transcriptomics
#9
Xiujun Sun, Zhihong Liu, Biao Wu, Liqing Zhou, Qi Wang, Wei Wu, Aiguo Yang
BACKGROUND: Scallops possess striated and catch adductor muscles, which have different structure and contractile properties. The striated muscle contracts very quickly for swimming, whereas the smooth catch muscle can keep the shells closed for long periods with little expenditure of energy. In this study, we performed proteomic and transcriptomic analyses of differences between the striated (fast) and catch (slow) adductor muscles in Yesso scallop Patinopecten yessoensis. RESULTS: Transcriptomic analysis reveals 1316 upregulated and 8239 downregulated genes in slow compared to fast adductor muscle...
May 22, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29773157/genetic-etiology-for-alcohol-induced-cardiac-toxicity
#10
James S Ware, Almudena Amor-Salamanca, Upasana Tayal, Risha Govind, Isabel Serrano, Joel Salazar-Mendiguchía, Jose Manuel García-Pinilla, Domingo A Pascual-Figal, Julio Nuñez, Gonzalo Guzzo-Merello, Emiliano Gonzalez-Vioque, Alfredo Bardaji, Nicolas Manito, Miguel A López-Garrido, Laura Padron-Barthe, Elizabeth Edwards, Nicola Whiffin, Roddy Walsh, Rachel J Buchan, William Midwinter, Alicja Wilk, Sanjay Prasad, Antonis Pantazis, John Baski, Declan P O'Regan, Luis Alonso-Pulpon, Stuart A Cook, Enrique Lara-Pezzi, Paul J Barton, Pablo Garcia-Pavia
BACKGROUND: Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown which factors determine cardiac toxicity on exposure to alcohol. OBJECTIVES: This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity. METHODS: The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers...
May 22, 2018: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/29768046/does-partial-titin-degradation-affect-sarcomere-length-non-uniformities-and-force-in-active-and-passive-myofibrils
#11
Venus Joumaa, Fanny Bertrand, Shuyue Liu, Sophia Poscente, Walter Herzog
The aim of this study was to determine the role of titin in preventing the development of sarcomere length non-uniformities following activation and after active and passive stretch, by determining the effect of partial titin degradation on sarcomere length non-uniformities and force in passive and active myofibrils. Selective partial titin degradation was performed using a low dose of trypsin. Myofibrils were set at a sarcomere length of 2.4 µm and then passively stretched to sarcomere lengths of 3.4 µm and 4...
May 16, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29763733/in-depth-profiling-of-mirna-regulation-in-the-body-wall-of-sea-cucumber-apostichopus-japonicus-during-skin-ulceration-syndrome-progression
#12
Hongjuan Sun, Zunchun Zhou, Ying Dong, Aifu Yang, Yongjia Pan, Jingwei Jiang, Zhong Chen, Xiaoyan Guan, Bai Wang, Shan Gao, Bei Jiang
MicroRNAs (miRNAs) are small non-coding RNAs that mediate mRNA degradation or translation repression. Previous study showed that the expression of miRNAs was significantly changed in the body wall of sea cucumber Apostichopus japonicus after skin ulceration syndrome (SUS) infection, which is a dynamic process. However, the critical miRNAs from body wall that involved in different infection stages of SUS remain unknown. In this study, four cDNA libraries were constructed with the body wall from healthy and three SUS-infected stages of A...
May 12, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29760016/diabetes-induced-cardiomyocyte-passive-stiffening-is-caused-by-impaired-insulin-dependent-titin-modification-and-can-be-modulated-by-neuregulin-1
#13
Anna-Eliane Hopf, Christian Andresen, Sebastian Kötter, Malgorzata Isic, Kamila Ulrich, Senem Sahin, Sabine Bongardt, Wilhelm Roell, Felicitas Drove, Nina Scheerer, Leni Vandekerckhove, Gilles W De Keulenaer, Nazha Hamdani, Wolfgang A Linke, Martina Krüger
<u>Rationale:</u> Increased titin-dependent cardiomyocyte tension is a hallmark of heart failure with preserved ejection fraction (HFpEF) associated with type-2 diabetes mellitus (T2DM). However, the insulin-related signaling pathways that modify titin-based cardiomyocyte tension, thereby contributing to modulation of diastolic function, are largely unknown. <u>Objective:</u> We aimed to determine how impaired insulin signaling affects titin expression and phosphorylation and thus increases passive cardiomyocyte tension, and whether metformin or neuregulin-1 can correct disturbed titin modifications and increased titin-based stiffness...
May 14, 2018: Circulation Research
https://www.readbyqxmd.com/read/29738832/topology-of-interaction-between-titin-and-myosin-thick-filaments
#14
Miklós Kellermayer, Dominik Sziklai, Zsombor Papp, Brennan Decker, Eszter Lakatos, Zsolt Mártonfalvi
Titin is a giant protein spanning between the Z- and M-lines of the sarcomere. In the A-band titin is associated with the myosin thick filament. It has been speculated that titin may serve as a blueprint for thick-filament formation due to the super-repeat structure of its A-band domains. Accordingly, titin might provide a template that determines the length and structural periodicity of the thick filament. Here we tested the titin ruler hypothesis by mixing titin and myosin at in situ stoichiometric ratios (300 myosins per 12 titins) in buffers of different ionic strength (KCl concentration range 100-300 mM)...
May 5, 2018: Journal of Structural Biology
https://www.readbyqxmd.com/read/29727215/acute-stimulation-of-the-soluble-guanylate-cyclase-does-not-impact-on-left-ventricular-capacitance-in-normal-and-hypertrophied-porcine-hearts-in-vivo
#15
Alessio Alogna, Michael Schwarzl, Martin Manninger, Nazha Hamdani, Birgit Zirngast, Benjamin Kloth, Paul Steendijk, Jochen Verderber, David Zweiker, Dirk Westermann, Stefan Blankenberg, Heinrich Maechler, Carsten Tschöpe, Wolfgang A Linke, Gunther Marsche, Burkert M Pieske, Heiner Post
Experimental data indicate that stimulation of the nitric oxide (NO) - soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) - protein kinase G (PKG) pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy, landrace pigs and seven pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume-relationships (EDPVR) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 μg/kg/min for 30 min, respectively)...
May 4, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29725258/splicing-factor-rbm20-regulates-transcriptional-network-of-titin-associated-and-calcium-handling-genes-in-the-heart
#16
Wei Guo, Chaoqun Zhu, Zhiyong Yin, Qiurong Wang, Mingming Sun, Huojun Cao, Marion L Greaser
RNA binding motif 20 (RBM20) regulates pre-mRNA splicing of over thirty genes, among which titin is a major target. With RBM20 expression, titin expresses a larger isoform at fetal stage to a smaller isoform at adult resulting from alternative splicing, while, without RBM20, titin expresses exclusively a larger isoform throughout all ages. In addition to splicing regulation, it is unknown whether RBM20 also regulates gene expression. In this study, we employed Rbm20 knockout rats to investigate gene expression profile using Affymetrix expression array...
2018: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29718870/ctla-4-methylation-regulates-the-pathogenesis-of-myasthenia-gravis-and-the-expression-of-related-cytokines
#17
Ti-Kun Fang, Cheng-Jun Yan, Juan Du
BACKGROUND: Myasthenia gravis (MG) is a progressive autoimmune disease that occurs as a result of the failure of neuromuscular transmission and is characterized by muscle weakness. There has been evidence on the correlations between the genetic predisposition of cytotoxic T lymphocyte and the antigen-4 (CTLA-4) and MG. Thus, the present study was conducted to study is designed to examine the effects of CTLA-4 methylation on the pathogenesis of MG and the expressions of related cytokines...
May 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29715185/darapladib-inhibits-atherosclerosis-development-in-type-2-diabetes-mellitus-sprague-dawley-rat-model
#18
Titin Andri Wihastuti, Teuku Heriansyah, Hanifa Hanifa, Sri Andarini, Zuhrotus Sholichah, Yuni Hendrati Sulfia, Aditya Angela Adam, Jeki Refialdinata, Nurul Cholifah Lutfiana
OBJECTIVE: Increase in the low-density lipoprotein (LDL) level in diabetes mellitus and atherosclerosis is related to lipoprotein associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is an enzyme that produces lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (oxNEFA). LysoPC regulates inflammation mediators, including intra-cellular adhesion molecule-1 (ICAM-1). Darapladib is known as a Lp-PLA2 specific inhibitor. The aim of this study was to reveal the effect of darapladib on the foam cell number, inducible nitric oxide synthase (iNOS), and ICAM-1 expression in aorta at early stages of the atherosclerosis in type 2 diabetes mellitus Sprague-Dawley rat model...
April 1, 2018: Endocrine Regulations
https://www.readbyqxmd.com/read/29702642/polarization-resolved-microscopy-reveals-a-muscle-myosin-motor-independent-mechanism-of-molecular-actin-ordering-during-sarcomere-maturation
#19
Olivier Loison, Manuela Weitkunat, Aynur Kaya-Çopur, Camila Nascimento Alves, Till Matzat, Maria L Spletter, Stefan Luschnig, Sophie Brasselet, Pierre-François Lenne, Frank Schnorrer
Sarcomeres are stereotyped force-producing mini-machines of striated muscles. Each sarcomere contains a pseudocrystalline order of bipolar actin and myosin filaments, which are linked by titin filaments. During muscle development, these three filament types need to assemble into long periodic chains of sarcomeres called myofibrils. Initially, myofibrils contain immature sarcomeres, which gradually mature into their pseudocrystalline order. Despite the general importance, our understanding of myofibril assembly and sarcomere maturation in vivo is limited, in large part because determining the molecular order of protein components during muscle development remains challenging...
April 27, 2018: PLoS Biology
https://www.readbyqxmd.com/read/29691892/congenital-titinopathy-comprehensive-characterisation-and-pathogenic-insights
#20
Emily C Oates, Kristi J Jones, Sandra Donkervoort, Amanda Charlton, Susan Brammah, John E Smith, James S Ware, Kyle S Yau, Lindsay C Swanson, Nicola Whiffin, Anthony J Peduto, Adam Bournazos, Leigh B Waddell, Michelle A Farrar, Hugo A Sampaio, Hooi Ling Teoh, Phillipa J Lamont, David Mowat, Robin B Fitzsimons, Alastair J Corbett, Monique M Ryan, Gina L O'Grady, Sarah A Sandaradura, Roula Ghaoui, Himanshu B Joshi, Jamie L Marshall, Melinda A Nolan, Simranpreet Kaur, Jaya Punetha, Ana Töpf, Elizabeth Harris, Madhura Bakshi, Casie A Genetti, Minttu Marttila, Ulla Werlauff, Nathalie Streichenberger, Alan Pestronk, Ingrid Mazanti, Jason R Pinner, Carole Vuillerot, Carla Grosmann, Ana Camacho, Payam Mohassel, Meganne E Leach, A Reghan Foley, Diana Bharucha-Goebel, James Collins, Anne M Connolly, Heather R Gilbreath, Susan T Iannaccone, Diana Castro, Beryl B Cummings, Richard I Webster, Leïla Lazaro, John Vissing, Sandra Coppens, Nicolas Deconinck, Ho-Ming Luk, Neil H Thomas, Nicola C Foulds, Marjorie A Illingworth, Sian Ellard, Catriona A McLean, Rahul Phadke, Gianina Ravenscroft, Nanna Witting, Peter Hackman, Isabelle Richard, Sandra T Cooper, Erik-Jan Kamsteeg, Eric P Hoffman, Kate Bushby, Volker Straub, Bjarne Udd, Ana Ferreiro, Kathryn N North, Nigel F Clarke, Monkol Lek, Alan H Beggs, Carsten G Bönnemann, Daniel G MacArthur, Henk Granzier, Mark R Davis, Nigel G Laing
OBJECTIVE: Comprehensive clinical characterisation of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with two pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathology and imaging features of these patients. RESULTS: All patients had prenatal- or early-onset hypotonia and/or congenital contractures...
April 25, 2018: Annals of Neurology
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