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Basic Science

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29 papers 0 to 25 followers
https://www.readbyqxmd.com/read/27861123/tecrl-a-new-life-threatening-inherited-arrhythmia-gene-associated-with-overlapping-clinical-features-of-both-lqts-and-cpvt
#1
Harsha D Devalla, Roselle Gélinas, Elhadi H Aburawi, Abdelaziz Beqqali, Philippe Goyette, Christian Freund, Marie-A Chaix, Rafik Tadros, Hui Jiang, Antony Le Béchec, Jantine J Monshouwer-Kloots, Tom Zwetsloot, Georgios Kosmidis, Frédéric Latour, Azadeh Alikashani, Maaike Hoekstra, Jurg Schlaepfer, Christine L Mummery, Brian Stevenson, Zoltan Kutalik, Antoine Af de Vries, Léna Rivard, Arthur Am Wilde, Mario Talajic, Arie O Verkerk, Lihadh Al-Gazali, John D Rioux, Zahurul A Bhuiyan, Robert Passier
Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation...
December 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27798624/identification-of-genomic-loci-associated-with-resting-heart-rate-and-shared-genetic-predictors-with-all-cause-mortality
#2
Ruben N Eppinga, Yanick Hagemeijer, Stephen Burgess, David A Hinds, Kari Stefansson, Daniel F Gudbjartsson, Dirk J van Veldhuisen, Patricia B Munroe, Niek Verweij, Pim van der Harst
Resting heart rate is a heritable trait correlated with life span. Little is known about the genetic contribution to resting heart rate and its relationship with mortality. We performed a genome-wide association discovery and replication analysis starting with 19.9 million genetic variants and studying up to 265,046 individuals to identify 64 loci associated with resting heart rate (P < 5 × 10(-8)); 46 of these were novel. We then used the genetic variants identified to study the association between resting heart rate and all-cause mortality...
October 31, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27864509/loss-of-%C3%AE-adrenergic-stimulated-phosphorylation-of-cav1-2-channels-on-ser1700-leads-to-heart-failure
#3
Linghai Yang, Dao-Fu Dai, Can Yuan, Ruth E Westenbroek, Haijie Yu, Nastassya West, Horacio O de la Iglesia, William A Catterall
L-type Ca(2+) currents conducted by voltage-gated calcium channel 1.2 (CaV1.2) initiate excitation-contraction coupling in the heart, and altered expression of CaV1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of CaV1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the CaV1.2 protein in the mutant mice (SA mice)...
November 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27869827/titin-truncating-variants-affect-heart-function-in-disease-cohorts-and-the-general-population
#4
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/27791149/cardiac-arrhythmia-in-a-mouse-model-of-sodium-channel-scn8a-epileptic-encephalopathy
#5
Chad R Frasier, Jacy L Wagnon, Yangyang Oliver Bao, Luke G McVeigh, Luis F Lopez-Santiago, Miriam H Meisler, Lori L Isom
: Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel gene SCN8A, encoding the sodium channel Nav1.6, result in EIEE13 (OMIM 614558), which has a 10% risk of SUDEP. Here, we investigated the cardiac phenotype of a mouse model expressing the gain of function EIEE13 patient mutation p.Asn1768Asp in Scn8a (Nav1.6-N1768D). We tested Scn8a(N1768D/+) mice for alterations in cardiac excitability...
October 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25561044/basic-concepts-and-potential-applications-of-genetics-and-genomics-for-cardiovascular-and-stroke-clinicians-a-scientific-statement-from-the-american-heart-association
#6
REVIEW
Kiran Musunuru, Kathleen T Hickey, Sana M Al-Khatib, Christian Delles, Myriam Fornage, Caroline S Fox, Lorraine Frazier, Bruce D Gelb, David M Herrington, David E Lanfear, Jonathan Rosand
No abstract text is available yet for this article.
February 2015: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/27802169/junctophilin-2-in-the-nanoscale-organisation-and-functional-signalling-of-ryanodine-receptor-clusters-in-cardiomyocytes
#7
Michelle L Munro, Isuru D Jayasinghe, Qiongling Wang, Ann Quick, Wei Wang, David Baddeley, Xander H T Wehrens, Christian Soeller
Signalling nanodomains requiring close contact between the plasma membrane and internal compartments, known as 'junctions', are fast communication hubs within excitable cells such as neurones and muscle. Here, we have examined two transgenic murine models probing the role of junctophilin-2, a membrane-tethering protein crucial for the formation and molecular organisation of sub-microscopic junctions in ventricular muscle cells of the heart. Quantitative single-molecule localisation microscopy showed that junctions in animals producing above-normal levels of junctophilin-2 were enlarged, allowing the re-organisation of the primary functional protein within it, the ryanodine receptor (RyR; in this paper, we use RyR to refer to the myocardial isoform RyR2)...
December 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27786225/young-scientists-under-pressure-what-the-data-show
#8
Brendan Maher, Miquel Sureda Anfres
No abstract text is available yet for this article.
October 26, 2016: Nature
https://www.readbyqxmd.com/read/27783597/transcription-of-the-non-coding-rna-upperhand-controls-hand2-expression-and-heart-development
#9
Kelly M Anderson, Douglas M Anderson, John R McAnally, John M Shelton, Rhonda Bassel-Duby, Eric N Olson
HAND2 is an ancestral regulator of heart development and one of four transcription factors that control the reprogramming of fibroblasts into cardiomyocytes. Deletion of Hand2 in mice results in right ventricle hypoplasia and embryonic lethality. Hand2 expression is tightly regulated by upstream enhancers that reside within a super-enhancer delineated by histone H3 acetyl Lys27 (H3K27ac) modifications. Here we show that transcription of a Hand2-associated long non-coding RNA, which we named upperhand (Uph), is required to maintain the super-enhancer signature and elongation of RNA polymerase II through the Hand2 enhancer locus...
October 26, 2016: Nature
https://www.readbyqxmd.com/read/27756708/a-type-2-ryanodine-receptor-variant-associated-with-reduced-ca-2-release-and-short-coupled-torsade-de-pointe-ventricular-arrhythmia
#10
Yusuke Fujii, Hideki Itoh, Seiko Ohno, Takashi Murayama, Nagomi Kurebayashi, Hisaaki Aoki, Malorie Blancard, Yoshihisa Nakagawa, Satoshi Yamamoto, Yumie Matsui, Mari Ichikawa, Keiko Sonoda, Tomoya Ozawa, Kimie Ohkubo, Ichiro Watanabe, Pascale Guicheney, Minoru Horie
BACKGROUND: Ventricular fibrillation (VF) may be caused by premature ventricular contractions (PVCs) whose coupling intervals are under 300ms, a characteristic of scTdP. OBJECTIVE: The purpose of this study is to analyze the underlying RyR2 variants in patients with the short-coupled variant of torsade de pointes (scTdP). METHODS: Seven patients with scTdP (34±12 years old, 3 females) were enrolled in this study. The RyR2 gene was screened by targeted gene sequencing methods, and variant minor allele frequency (MAF) was confirmed in three databases, and the pathogenicity was investigated in multiple in silico tools...
October 15, 2016: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/27698420/pore-architecture-of-tric-channels-and-insights-into-their-gating-mechanism
#11
Hanting Yang, Miaohui Hu, Jianli Guo, Xiaomin Ou, Tanxi Cai, Zhenfeng Liu
Intracellular Ca(2+) signalling processes are fundamental to muscle contraction, neurotransmitter release, cell growth and apoptosis. Release of Ca(2+) from the intracellular stores is supported by a series of ion channels in sarcoplasmic or endoplasmic reticulum (SR/ER). Among them, two isoforms of the trimeric intracellular cation (TRIC) channel family, named TRIC-A and TRIC-B, modulate the release of Ca(2+) through the ryanodine receptor or inositol triphosphate receptor, and maintain the homeostasis of ions within SR/ER lumen...
October 3, 2016: Nature
https://www.readbyqxmd.com/read/27688314/genotype-dependent-and-independent-calcium-signaling-dysregulation-in-human-hypertrophic-cardiomyopathy
#12
Adam S Helms, Francisco J Alvarado, Jaime Yob, Vi T Tang, Francis Pagani, Mark W Russell, Héctor H Valdivia, Sharlene M Day
BACKGROUND: Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. METHODS: We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). RESULTS: Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban, calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM samples compared with controls...
November 29, 2016: Circulation
https://www.readbyqxmd.com/read/27654912/the-simons-genome-diversity-project-300-genomes-from-142-diverse-populations
#13
Swapan Mallick, Heng Li, Mark Lipson, Iain Mathieson, Melissa Gymrek, Fernando Racimo, Mengyao Zhao, Niru Chennagiri, Susanne Nordenfelt, Arti Tandon, Pontus Skoglund, Iosif Lazaridis, Sriram Sankararaman, Qiaomei Fu, Nadin Rohland, Gabriel Renaud, Yaniv Erlich, Thomas Willems, Carla Gallo, Jeffrey P Spence, Yun S Song, Giovanni Poletti, Francois Balloux, George van Driem, Peter de Knijff, Irene Gallego Romero, Aashish R Jha, Doron M Behar, Claudio M Bravi, Cristian Capelli, Tor Hervig, Andres Moreno-Estrada, Olga L Posukh, Elena Balanovska, Oleg Balanovsky, Sena Karachanak-Yankova, Hovhannes Sahakyan, Draga Toncheva, Levon Yepiskoposyan, Chris Tyler-Smith, Yali Xue, M Syafiq Abdullah, Andres Ruiz-Linares, Cynthia M Beall, Anna Di Rienzo, Choongwon Jeong, Elena B Starikovskaya, Ene Metspalu, Jüri Parik, Richard Villems, Brenna M Henn, Ugur Hodoglugil, Robert Mahley, Antti Sajantila, George Stamatoyannopoulos, Joseph T S Wee, Rita Khusainova, Elza Khusnutdinova, Sergey Litvinov, George Ayodo, David Comas, Michael F Hammer, Toomas Kivisild, William Klitz, Cheryl A Winkler, Damian Labuda, Michael Bamshad, Lynn B Jorde, Sarah A Tishkoff, W Scott Watkins, Mait Metspalu, Stanislav Dryomov, Rem Sukernik, Lalji Singh, Kumarasamy Thangaraj, Svante Pääbo, Janet Kelso, Nick Patterson, David Reich
Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity...
September 21, 2016: Nature
https://www.readbyqxmd.com/read/27639456/developmental-changes-in-electrophysiological-characteristics-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#14
Meital Ben-Ari, Shulamit Naor, Naama Zeevi-Levin, Revital Schick, Ronen Ben Jehuda, Irina Reiter, Amit Raveh, Inna Grijnevitch, Omri Barak, Michael R Rosen, Amir Weissman, Ofer Binah
BACKGROUND: Previous studies proposed that throughout differentiation of human induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs), only 3 types of action potentials (APs) exist: nodal-, atrial-, and ventricular-like. OBJECTIVES: To investigate whether there are precisely 3 phenotypes or a continuum exists among them, we tested 2 hypotheses: (1) During culture development a cardiac precursor cell is present that-depending on age-can evolve into the 3 phenotypes...
September 14, 2016: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/27630136/experimentally-increasing-the-compliance-of-titin-through-rna-binding-motif-20-rbm20-inhibition-improves-diastolic-function-in-a-mouse-model-of-heart-failure-with-preserved-ejection-fraction
#15
Mei Methawasin, Joshua G Strom, Rebecca E Slater, Vanessa Fernandez, Chandra Saripalli, Henk Granzier
BACKGROUND: Left ventricular (LV) stiffening contributes to heart failure with preserved ejection fraction (HFpEF), a syndrome with no effective treatment options. Increasing the compliance of titin in the heart has become possible recently through inhibition of the splicing factor RNA binding motif-20. Here, we investigated the effects of increasing the compliance of titin in mice with diastolic dysfunction. METHODS: Mice in which the RNA recognition motif (RRM) of one of the RNA binding motif-20 alleles was floxed and that expressed the MerCreMer transgene under control of the αMHC promoter (referred to as cRbm20(ΔRRM) mice) were used...
October 11, 2016: Circulation
https://www.readbyqxmd.com/read/27357797/coordinating-cardiomyocyte-interactions-to-direct-ventricular-chamber-morphogenesis
#16
Peidong Han, Joshua Bloomekatz, Jie Ren, Ruilin Zhang, Jonathan D Grinstein, Long Zhao, C Geoffrey Burns, Caroline E Burns, Ryan M Anderson, Neil C Chi
Many organs are composed of complex tissue walls that are structurally organized to optimize organ function. In particular, the ventricular myocardial wall of the heart comprises an outer compact layer that concentrically encircles the ridge-like inner trabecular layer. Although disruption in the morphogenesis of this myocardial wall can lead to various forms of congenital heart disease and non-compaction cardiomyopathies, it remains unclear how embryonic cardiomyocytes assemble to form ventricular wall layers of appropriate spatial dimensions and myocardial mass...
June 29, 2016: Nature
https://www.readbyqxmd.com/read/26301497/genetic-association-analyses-highlight-biological-pathways-underlying-mitral-valve-prolapse
#17
Christian Dina, Nabila Bouatia-Naji, Nathan Tucker, Francesca N Delling, Katelynn Toomer, Ronen Durst, Maelle Perrocheau, Leticia Fernandez-Friera, Jorge Solis, Thierry Le Tourneau, Ming-Huei Chen, Vincent Probst, Yohan Bosse, Philippe Pibarot, Diana Zelenika, Mark Lathrop, Serge Hercberg, Ronan Roussel, Emelia J Benjamin, Fabrice Bonnet, Su Hao Lo, Elena Dolmatova, Floriane Simonet, Simon Lecointe, Florence Kyndt, Richard Redon, Hervé Le Marec, Philippe Froguel, Patrick T Ellinor, Ramachandran S Vasan, Patrick Bruneval, Roger R Markwald, Russell A Norris, David J Milan, Susan A Slaugenhaupt, Robert A Levine, Jean-Jacques Schott, Albert A Hagege, Xavier Jeunemaitre
Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation...
October 2015: Nature Genetics
https://www.readbyqxmd.com/read/27313038/translational-control-by-5-untranslated-regions-of-eukaryotic-mrnas
#18
REVIEW
Alan G Hinnebusch, Ivaylo P Ivanov, Nahum Sonenberg
The eukaryotic 5' untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control of translation efficiency and shaping the cellular proteome. The ribosomal initiation complex is assembled on the mRNA via a cap-dependent or cap-independent mechanism. We describe various mechanisms controlling ribosome scanning and initiation codon selection by 5' upstream open reading frames, translation initiation factors, and primary and secondary structures of the 5'UTR, including particular sequence motifs...
June 17, 2016: Science
https://www.readbyqxmd.com/read/26424448/stim1-ca2-signaling-modulates-automaticity-of-the-mouse-sinoatrial-node
#19
Hengtao Zhang, Albert Y Sun, Jong J Kim, Victoria Graham, Elizabeth A Finch, Igor Nepliouev, Guiling Zhao, Tianyu Li, W J Lederer, Jonathan A Stiber, Geoffrey S Pitt, Nenad Bursac, Paul B Rosenberg
Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca(2+) release from internal Ca(2+) stores (Ca(2+) clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca(2+) entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca(2+) stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling...
October 13, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25505419/role-of-sinoatrial-node-architecture-in-maintaining-a-balanced-source-sink-relationship-and-synchronous-cardiac-pacemaking
#20
REVIEW
Sathya D Unudurthi, Roseanne M Wolf, Thomas J Hund
Normal heart rhythm (sinus rhythm) depends on regular activity of the sinoatrial node (SAN), a heterogeneous collection of specialized myocytes in the right atrium. SAN cells, in general, possess a unique electrophysiological profile that promotes spontaneous electrical activity (automaticity). However, while automaticity is required for normal pacemaking, it is not necessarily sufficient. Less appreciated is the importance of the elaborate structure of the SAN complex for proper pacemaker function. Here, we review the important structural features of the SAN with a focus on how these elements help manage a precarious balance between electrical charge generated by the SAN ("source") and the charge needed to excite the surrounding atrial tissue ("sink")...
2014: Frontiers in Physiology
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