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https://www.readbyqxmd.com/read/27914791/aberrant-developmental-titin-splicing-and-dysregulated-sarcomere-length-in-thymosin-%C3%AE-4-knockout-mice
#1
Nicola Smart, Johannes Riegler, Cameron W Turtle, Craig A Lygate, Debra J McAndrew, Katja Gehmlich, Karina N Dubé, Anthony N Price, Vivek Muthurangu, Andrew M Taylor, Mark F Lythgoe, Charles Redwood, Paul R Riley
Sarcomere assembly is a highly orchestrated and dynamic process which adapts, during perinatal development, to accommodate growth of the heart. Sarcomeric components, including titin, undergo an isoform transition to adjust ventricular filling. Many sarcomeric genes have been implicated in congenital cardiomyopathies, such that understanding developmental sarcomere transitions will inform the aetiology and treatment. We sought to determine whether Thymosin β4 (Tβ4), a peptide that regulates the availability of actin monomers for polymerization in non-muscle cells, plays a role in sarcomere assembly during cardiac morphogenesis and influences adult cardiac function...
November 30, 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/27889803/reducing-rbm20-activity-improves-diastolic-dysfunction-and-cardiac-atrophy
#2
Florian Hinze, Christoph Dieterich, Michael H Radke, Henk Granzier, Michael Gotthardt
: Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness...
November 26, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/27869827/titin-truncating-variants-affect-heart-function-in-disease-cohorts-and-the-general-population
#3
Sebastian Schafer, Antonio de Marvao, Eleonora Adami, Lorna R Fiedler, Benjamin Ng, Ester Khin, Owen J L Rackham, Sebastiaan van Heesch, Chee J Pua, Miao Kui, Roddy Walsh, Upasana Tayal, Sanjay K Prasad, Timothy J W Dawes, Nicole S J Ko, David Sim, Laura L H Chan, Calvin W L Chin, Francesco Mazzarotto, Paul J Barton, Franziska Kreuchwig, Dominique P V de Kleijn, Teresa Totman, Carlo Biffi, Nicole Tee, Daniel Rueckert, Valentin Schneider, Allison Faber, Vera Regitz-Zagrosek, Jonathan G Seidman, Christine E Seidman, Wolfgang A Linke, Jean-Paul Kovalik, Declan O'Regan, James S Ware, Norbert Hubner, Stuart A Cook
Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ∼1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism...
November 21, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27854229/increasing-role-of-titin-mutations-in-neuromuscular-disorders
#4
Marco Savarese, Jaakko Sarparanta, Anna Vihola, Bjarne Udd, Peter Hackman
The TTN gene with 363 coding exons encodes titin, a giant muscle protein spanning from the Z-disk to the M-band within the sarcomere. Mutations in the TTN gene have been associated with different genetic disorders, including hypertrophic and dilated cardiomyopathy and several skeletal muscle diseases.Before the introduction of next generation sequencing (NGS) methods, the molecular analysis of TTN has been laborious, expensive and not widely used, resulting in a limited number of mutations identified. Recent studies however, based on the use of NGS strategies, give evidence of an increasing number of rare and unique TTN variants...
August 30, 2016: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/27836965/exon-and-contraction-dependent-functions-of-titin-in-sarcomere-assembly
#5
Yu-Huan Shih, Alexey V Dvornikov, Ping Zhu, Xiao Ma, Maeng Jo Kim, Yonghe Ding, Xiaolei Xu
Truncating TTN variants (TTNtvs) are the major cause of dilated cardiomyopathy (DCM); however, allelic heterogeneity, i.e., TTNtvs in different exons, results in variable phenotypes, remains a major hurdle for disease diagnosis and therapy. Here, we generated a panel of ttn mutants in zebrafish. Four single deletion mutants in ttn.2 or ttn.1 resulted in 4 phenotypes, and 3 double ttn.2/ttn.1 mutants exhibited more severe phenotypes in somites. Protein analysis identified ttn(xu071) as a near-null mutant and the other 6 mutants as hypomorphic alleles...
November 11, 2016: Development
https://www.readbyqxmd.com/read/27824934/controlled-heat-stress-promotes-myofibrillogenesis-during-myogenesis
#6
Qiongyu Guo, Devin Miller, Hongying An, Howard Wang, Joseph Lopez, Denver Lough, Ling He, Anand Kumar
Hyperthermia therapy has recently emerged as a clinical modality used to finely tune heat stress inside the human body for various biomedical applications. Nevertheless, little is known regarding the optimal timing or temperature of heat stress that is needed to achieve favorable results following hyperthermia therapy for muscle regeneration purposes. The regeneration of skeletal muscle after injury is a highly complex and coordinated process that involves a multitude of cellular mechanisms. The main objective of this study was to characterize the effects of hyperthermal therapy on the overall behavior of myoblasts during myogenic differentiation...
2016: PloS One
https://www.readbyqxmd.com/read/27813826/huxleys-missing-filament-form-and-function-of-titin-in-vertebrate-striated-muscle
#7
Stan Lindstedt, Kiisa Nishikawa
Although superthin filaments were inferred from early experiments on muscle, decades passed before their existence was accepted. Phylogenetic analyses suggest that titin, the largest known protein, first appeared in the common ancestor of chordates and nematodes and evolved rapidly via duplication. Twitchin and projectin evolved later by truncation. Sallimus mutants in Drosophila exhibit disrupted sarcomere and chromosome structure, suggesting that giant proteins may have evolved as chromosomal scaffolds that were co-opted for a similar purpose in striated muscles...
October 28, 2016: Annual Review of Physiology
https://www.readbyqxmd.com/read/27813223/truncating-titin-mutations-are-associated-with-a-mild-and-treatable-form-of-dilated-cardiomyopathy
#8
Joeri A Jansweijer, Karin Nieuwhof, Francesco Russo, Edgar T Hoorntje, Jan D H Jongbloed, Ronald H Lekanne Deprez, Alex V Postma, Marieke Bronk, Ingrid A W van Rijsingen, Simone de Haij, Elena Biagini, Paul L van Haelst, Jan van Wijngaarden, Maarten P van den Berg, Arthur A M Wilde, Marcel M A M Mannens, Rudolf A de Boer, Karin Y van Spaendonck-Zwarts, J Peter van Tintelen, Yigal M Pinto
AIMS: Truncating titin mutations (tTTN) occur in 25% of dilated cardiomyopathy (DCM) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether tTTN variants are associated with a clinically distinguishable form of DCM. METHODS AND RESULTS: We compared clinical data on DCM probands and relatives with a tTTN mutation (n = 45, n = 73), LMNA mutation (n = 28, n = 29), and probands who tested negative for both genes [idiopathic DCM (iDCM); n = 60]...
November 3, 2016: European Journal of Heart Failure
https://www.readbyqxmd.com/read/27810862/dual-endothelin-a-endothelin-b-receptor-blockade-and-cardiac-remodeling-in-heart-failure-with-preserved-ejection-fraction
#9
Maria Valero-Munoz, Shanpeng Li, Richard M Wilson, Batbold Boldbaatar, Marc Iglarz, Flora Sam
BACKGROUND: Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension...
November 2016: Circulation. Heart Failure
https://www.readbyqxmd.com/read/27796757/targeted-next-generation-sequencing-reveals-novel-ttn-mutations-causing-recessive-distal-titinopathy
#10
Anni Evilä, Johanna Palmio, Anna Vihola, Marco Savarese, Giorgio Tasca, Sini Penttilä, Sara Lehtinen, Per Harald Jonson, Jan De Bleecker, Peter Rainer, Michaela Auer-Grumbach, Jean Pouget, Emmanuelle Salort-Campana, Juan J Vilchez, Nuria Muelas, Montse Olive, Peter Hackman, Bjarne Udd
Tibial muscular dystrophy (TMD) is the first described human titinopathy. It is a mild adult-onset slowly progressive myopathy causing weakness and atrophy in the anterior lower leg muscles. TMD is caused by mutations in the last two exons, Mex5 and Mex6, of the titin gene (TTN). The first reported TMD mutations were dominant, but the Finnish founder mutation FINmaj, an 11-bp insertion/deletion in Mex6, in homozygosity caused a completely different severe early-onset limb-girdle muscular dystrophy 2J (LGMD2J)...
October 29, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27790050/arrhythmogenic-right-ventricular-dysplasia-in-neuromuscular-disorders
#11
REVIEW
Josef Finsterer, Claudia Stöllberger
OBJECTIVES: Arrhythmogenic right ventricular dysplasia (ARVD) is a rare, genetic disorder predominantly affecting the right ventricle. There is increasing evidence that in some cases, ARVD is due to mutations in genes, which have also been implicated in primary myopathies. This review gives an overview about myopathy-associated ARVD and how these patients can be managed. METHODS: A literature review was done using appropriate search terms. RESULTS: The myopathy, which is most frequently associated with ARVD, is the myofibrillar myopathy due to desmin mutations...
2016: Clinical Medicine Insights. Cardiology
https://www.readbyqxmd.com/read/27768799/altered-protein-composition-and-gene-expression-in-strabismic-human-extraocular-muscles-and-tendons
#12
Andrea B Agarwal, Cheng-Yuan Feng, Amy L Altick, David R Quilici, Dan Wen, L Alan Johnson, Christopher S von Bartheld
Purpose: To determine whether structural protein composition and expression of key regulatory genes are altered in strabismic human extraocular muscles. Methods: Samples from strabismic horizontal extraocular muscles were obtained during strabismus surgery and compared with normal muscles from organ donors. We used proteomics, standard and customized PCR arrays, and microarrays to identify changes in major structural proteins and changes in gene expression. We focused on muscle and connective tissue and its control by enzymes, growth factors, and cytokines...
October 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27758811/left-atrial-remodeling-and-atrioventricular-coupling-in-a-canine-model-of-early-heart-failure-with-preserved-ejection-fraction
#13
Rosita Zakeri, Gilles Moulay, Qiang Chai, Ozgur Ogut, Saad Hussain, Hiroyuki Takahama, Tong Lu, Xiao-Li Wang, Wolfgang A Linke, Hon-Chi Lee, Margaret M Redfield
BACKGROUND: Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. METHODS AND RESULTS: Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13)...
October 2016: Circulation. Heart Failure
https://www.readbyqxmd.com/read/27756780/wrestling-the-giant-new-approaches-for-assessing-titin-variant-pathogenicity
#14
Emmi Helle, Victoria N Parikh
No abstract text is available yet for this article.
October 2016: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/27742555/the-insertion-sequence-of-the-n2a-region-of-titin-exists-in-an-extended-structure-with-helical-characteristics
#15
Holly Tiffany, Kanchan Sonkar, Matthew J Gage
The giant sarcomere protein titin is the third filament in muscle and is integral to maintaining sarcomere integrity as well as contributing to both active and passive tension. Titin is a multi-domain protein that contains regions of repeated structural elements. The N2A region sits at the boundary between the proximal Ig region of titin that is extended under low force and the PEVK region that is extended under high force. Multiple binding interactions have been associated with the N2A region and it has been proposed that this region acts as a mechanical stretch sensor...
October 11, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27737936/titin-forms-circles-regulation-by-heart-failure-and-the-rna-binding-protein-rbm20
#16
EDITORIAL
Nicolas Jaé, Stefanie Dimmeler
No abstract text is available yet for this article.
October 14, 2016: Circulation Research
https://www.readbyqxmd.com/read/27725266/complete-primary-structure-of-the-i-band-region-of-connectin-at-which-mechanical-property-is-modulated-in-zebrafish-heart-and-skeletal-muscle
#17
Akira Hanashima, Ken Hashimoto, Yoshihiro Ujihara, Takeshi Honda, Tomoko Yobimoto, Aya Kodama, Satoshi Mohri
Connectin, also called titin, is the largest protein with a critical function as a molecular spring during contraction and relaxation of striated muscle; its mutation leads to severe myopathy and cardiomyopathy. To uncover the cause of this pathogenesis, zebrafish have recently been used as disease models because they are easier to genetically modify than mice. Although the gene structures and putative primary structures of zebrafish connectin have been determined, the actual primary structures of zebrafish connectin in heart and skeletal muscles remain unclear because of its large size and the PCR amplification-associated difficulties...
October 7, 2016: Gene
https://www.readbyqxmd.com/read/27710886/developmental-effects-of-fipronil-on-japanese-medaka-oryzias-latipes-embryos
#18
Scott D Wagner, Tomofumi Kurobe, Bruce G Hammock, Chelsea H Lam, Gary Wu, Natalia Vasylieva, Shirley J Gee, Bruce D Hammock, Swee J Teh
Pesticides in urban runoff are a major source of pollutants in aquatic ecosystems. Fipronil, a phenylpyrazole insecticide, found in structural pest control products, turf grass control, and home pet flea medication, has recently increased in use and is commonly detected in urban runoff. However, little is known about the effects of fipronil on aquatic organisms at early developmental stages. Here, we evaluated toxicity of fipronil to embryos of Japanese Medaka (Oryzias latipes, Qurt strain) using a high-throughput 96-well plate toxicity test...
January 2017: Chemosphere
https://www.readbyqxmd.com/read/27698847/paraneoplastic-morvan-s-syndrome-following-surgical-treatment-of-recurrent-thymoma-a-case-report
#19
Edvina Galié, Rosaria Renna, Domenico Plantone, Andrea Pace, Mirella Marino, Bruno Jandolo, Tatiana Koudriavtseva
Morvan's syndrome (MoS) is a rare, complex neurological disorder characterized by neuromyotonia, neuropsychiatric features, dysautonomia and neuropathic pain. The majority of MoS cases have a paraneoplastic aetiology, usually occurring prior to the diagnosis of the underlying tumour and showing improvement following its treatment. The present study reports the case of a 35-year-old Caucasian male patient who was diagnosed with stage IVA thymoma. Thymectomy, lung resection, diaphragmatic pleurectomy and pericardio-phrenectomy were performed 6 months after neoadjuvant chemotherapy...
October 2016: Oncology Letters
https://www.readbyqxmd.com/read/27683155/exploration-of-pathomechanisms-triggered-by-a-single-nucleotide-polymorphism-in-titin-s-i-band-the-cardiomyopathy-linked-mutation-t2580i
#20
Julius Bogomolovas, Jennifer R Fleming, Brian R Anderson, Rhys Williams, Stephan Lange, Bernd Simon, Muzamil M Khan, Rüdiger Rudolf, Barbara Franke, Belinda Bullard, Daniel J Rigden, Henk Granzier, Siegfried Labeit, Olga Mayans
Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level...
September 2016: Open Biology
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