collection
https://read.qxmd.com/read/28536302/a-cryo-em-based-model-of-phosphorylation-and-fkbp12-6-mediated-allosterism-of-the-cardiac-ryanodine-receptor
#1
JOURNAL ARTICLE
Sonali Dhindwal, Joshua Lobo, Vanessa Cabra, Demetrio J Santiago, Ashok R Nayak, Kelly Dryden, Montserrat Samsó
Type 2 ryanodine receptors (RyR2s) are calcium channels that play a vital role in triggering cardiac muscle contraction by releasing calcium from the sarcoplasmic reticulum into the cytoplasm. Several cardiomyopathies are associated with the abnormal functioning of RyR2. We determined the three-dimensional structure of rabbit RyR2 in complex with the regulatory protein FKBP12.6 in the closed state at 11.8 Å resolution using cryo-electron microscopy and built an atomic model of RyR2. The heterogeneity in the data set revealed two RyR2 conformations that we proposed to be related to the extent of phosphorylation of the P2 domain...
May 23, 2017: Science Signaling
https://read.qxmd.com/read/28408455/cell-therapy-trials-in-congenital-heart-disease
#2
REVIEW
Hidemasa Oh
Dramatic evolution in medical and catheter interventions and complex surgeries to treat children with congenital heart disease (CHD) has led to a growing number of patients with a multitude of long-term complications associated with morbidity and mortality. Heart failure in patients with hypoplastic left heart syndrome predicated by functional single ventricle lesions is associated with an increase in CHD prevalence and remains a significant challenge. Pathophysiological mechanisms contributing to the progression of CHD, including single ventricle lesions and dilated cardiomyopathy, and adult heart disease may inevitably differ...
April 14, 2017: Circulation Research
https://read.qxmd.com/read/28360271/science-funders-plunge-into-publishing
#3
JOURNAL ARTICLE
Martin Enserink
No abstract text is available yet for this article.
March 31, 2017: Science
https://read.qxmd.com/read/28360277/circular-rnas-hint-at-new-realm-of-genetics
#4
JOURNAL ARTICLE
Kelly Servick
No abstract text is available yet for this article.
March 31, 2017: Science
https://read.qxmd.com/read/28337273/t-box-family-of-transcription-factor-tbx5-insights-in-development-and-disease
#5
JOURNAL ARTICLE
Ting Zhu, Longwei Qiao, Qian Wang, Rui Mi, Jinnan Chen, Yaojuan Lu, Junxia Gu, Qiping Zheng
The T-box gene family refers to a group of transcription factors that share a highly conserved, sequence-specific DNA-binding domain (T-box) containing around 180-amino acids. According to HUGO gene nomenclature committee (HGNC), there are 18 T-box family members. These T-box genes have been implicated essential roles during embryogenesis and cardiac development, given their specific expression pattern in developing mammalian heart for several T-box genes, including TBX5 . TBX5 is consisted of three transcriptional variants which cover 9 exons and encode two distinct isoforms that differ in N-terminus...
2017: American Journal of Translational Research
https://read.qxmd.com/read/28356340/analysis-of-cardiac-myocyte-maturation-using-casaav-a-platform-for-rapid-dissection-of-cardiac-myocyte-gene-function-in-vivo
#6
REVIEW
Yuxuan Guo, Nathan J VanDusen, Lina Zhang, Weiliang Gu, Isha Sethi, Silvia Guatimosim, Qing Ma, Blake D Jardin, Yulan Ai, Donghui Zhang, Biyi Chen, Ang Guo, Guo-Cheng Yuan, Long-Sheng Song, William T Pu
RATIONALE: Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly understood. Previous studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation. OBJECTIVE: To develop a new technical platform to rapidly characterize cell-autonomous gene function in postnatal murine CMs and apply it to identify genes that regulate transverse tubules (T-tubules), a hallmark of mature CMs...
June 9, 2017: Circulation Research
https://read.qxmd.com/read/28266538/profiling-analysis-of-long-non-coding-rnas-in-early-postnatal-mouse-hearts
#7
JOURNAL ARTICLE
Xiongshan Sun, Qi Han, Hongqin Luo, Xiaodong Pan, Yan Ji, Yao Yang, Hanying Chen, Fangjie Wang, Wenjing Lai, Xiao Guan, Qi Zhang, Yuan Tang, Jianhong Chu, Jianhua Yu, Weinian Shou, Youcai Deng, Xiaohui Li
Mammalian cardiomyocytes undergo a critical hyperplastic-to-hypertrophic growth transition at early postnatal age, which is important in establishing normal physiological function of postnatal hearts. In the current study, we intended to explore the role of long non-coding (lnc) RNAs in this transitional stage. We analyzed lncRNA expression profiles in mouse hearts at postnatal day (P) 1, P7 and P28 via microarray. We identified 1,146 differentially expressed lncRNAs with more than 2.0-fold change when compared the expression profiles of P1 to P7, P1 to P28, and P7 to P28...
March 7, 2017: Scientific Reports
https://read.qxmd.com/read/28241135/an-atlas-of-human-long-non-coding-rnas-with-accurate-5-ends
#8
JOURNAL ARTICLE
Chung-Chau Hon, Jordan A Ramilowski, Jayson Harshbarger, Nicolas Bertin, Owen J L Rackham, Julian Gough, Elena Denisenko, Sebastian Schmeier, Thomas M Poulsen, Jessica Severin, Marina Lizio, Hideya Kawaji, Takeya Kasukawa, Masayoshi Itoh, A Maxwell Burroughs, Shohei Noma, Sarah Djebali, Tanvir Alam, Yulia A Medvedeva, Alison C Testa, Leonard Lipovich, Chi-Wai Yip, Imad Abugessaisa, Mickaël Mendez, Akira Hasegawa, Dave Tang, Timo Lassmann, Peter Heutink, Magda Babina, Christine A Wells, Soichi Kojima, Yukio Nakamura, Harukazu Suzuki, Carsten O Daub, Michiel J L de Hoon, Erik Arner, Yoshihide Hayashizaki, Piero Carninci, Alistair R R Forrest
Long non-coding RNAs (lncRNAs) are largely heterogeneous and functionally uncharacterized. Here, using FANTOM5 cap analysis of gene expression (CAGE) data, we integrate multiple transcript collections to generate a comprehensive atlas of 27,919 human lncRNA genes with high-confidence 5' ends and expression profiles across 1,829 samples from the major human primary cell types and tissues. Genomic and epigenomic classification of these lncRNAs reveals that most intergenic lncRNAs originate from enhancers rather than from promoters...
March 9, 2017: Nature
https://read.qxmd.com/read/28183995/structure-of-a-eukaryotic-voltage-gated-sodium-channel-at-near-atomic-resolution
#9
JOURNAL ARTICLE
Huaizong Shen, Qiang Zhou, Xiaojing Pan, Zhangqiang Li, Jianping Wu, Nieng Yan
Voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. They are associated with a variety of channelopathies and are targeted by multiple pharmaceutical drugs and natural toxins. Here, we report the cryogenic electron microscopy structure of a putative Nav channel from American cockroach (designated NavPaS) at 3.8 angstrom resolution. The voltage-sensing domains (VSDs) of the four repeats exhibit distinct conformations. The entrance to the asymmetric selectivity filter vestibule is guarded by heavily glycosylated and disulfide bond-stabilized extracellular loops...
March 3, 2017: Science
https://read.qxmd.com/read/28096424/%C3%AE-actinin-titin-interaction-a-dynamic-and-mechanically-stable-cluster-of-bonds-in-the-muscle-z-disk
#10
JOURNAL ARTICLE
Marco Grison, Ulrich Merkel, Julius Kostan, Kristina Djinović-Carugo, Matthias Rief
Stable anchoring of titin within the muscle Z-disk is essential for preserving muscle integrity during passive stretching. One of the main candidates for anchoring titin in the Z-disk is the actin cross-linker α-actinin. The calmodulin-like domain of α-actinin binds to the Z-repeats of titin. However, the mechanical and kinetic properties of this important interaction are still unknown. Here, we use a dual-beam optical tweezers assay to study the mechanics of this interaction at the single-molecule level...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/28097712/force-generation-by-titin-folding
#11
JOURNAL ARTICLE
Zsolt Mártonfalvi, Pasquale Bianco, Katalin Naftz, György G Ferenczy, Miklós Kellermayer
Titin is a giant protein that provides elasticity to muscle. As the sarcomere is stretched, titin extends hierarchically according to the mechanics of its segments. Whether titin's globular domains unfold during this process and how such unfolded domains might contribute to muscle contractility are strongly debated. To explore the force-dependent folding mechanisms, here we manipulated skeletal-muscle titin molecules with high-resolution optical tweezers. In force-clamp mode, after quenching the force (<10 pN), extension fluctuated without resolvable discrete events...
July 2017: Protein Science
https://read.qxmd.com/read/28076345/structure-of-a-spliceosome-remodelled-for-exon-ligation
#12
JOURNAL ARTICLE
Sebastian M Fica, Chris Oubridge, Wojciech P Galej, Max E Wilkinson, Xiao-Chen Bai, Andrew J Newman, Kiyoshi Nagai
The spliceosome excises introns from pre-mRNAs in two sequential transesterifications-branching and exon ligation-catalysed at a single catalytic metal site in U6 small nuclear RNA (snRNA). Recently reported structures of the spliceosomal C complex with the cleaved 5' exon and lariat-3'-exon bound to the catalytic centre revealed that branching-specific factors such as Cwc25 lock the branch helix into position for nucleophilic attack of the branch adenosine at the 5' splice site. Furthermore, the ATPase Prp16 is positioned to bind and translocate the intron downstream of the branch point to destabilize branching-specific factors and release the branch helix from the active site...
February 16, 2017: Nature
https://read.qxmd.com/read/28076346/cryo-em-structure-of-a-human-spliceosome-activated-for-step-2-of-splicing
#13
JOURNAL ARTICLE
Karl Bertram, Dmitry E Agafonov, Wen-Ti Liu, Olexandr Dybkov, Cindy L Will, Klaus Hartmuth, Henning Urlaub, Berthold Kastner, Holger Stark, Reinhard Lührmann
Spliceosome rearrangements facilitated by RNA helicase PRP16 before catalytic step two of splicing are poorly understood. Here we report a 3D cryo-electron microscopy structure of the human spliceosomal C complex stalled directly after PRP16 action (C*). The architecture of the catalytic U2-U6 ribonucleoprotein (RNP) core of the human C* spliceosome is very similar to that of the yeast pre-Prp16 C complex. However, in C* the branched intron region is separated from the catalytic centre by approximately 20 Å, and its position close to the U6 small nuclear RNA ACAGA box is stabilized by interactions with the PRP8 RNase H-like and PRP17 WD40 domains...
February 16, 2017: Nature
https://read.qxmd.com/read/27861123/tecrl-a-new-life-threatening-inherited-arrhythmia-gene-associated-with-overlapping-clinical-features-of-both-lqts-and-cpvt
#14
JOURNAL ARTICLE
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 2016: EMBO Molecular Medicine
https://read.qxmd.com/read/27864509/loss-of-%C3%AE-adrenergic-stimulated-phosphorylation-of-cav1-2-channels-on-ser1700-leads-to-heart-failure
#15
JOURNAL ARTICLE
Linghai Yang, Dao-Fu Dai, Can Yuan, Ruth E Westenbroek, Haijie Yu, Nastassya West, Horacio O de la Iglesia, William A Catterall
L-type Ca2+ currents conducted by voltage-gated calcium channel 1.2 (CaV 1.2) initiate excitation-contraction coupling in the heart, and altered expression of CaV 1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of CaV 1.2 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 CaV 1.2 protein in the mutant mice (SA mice)...
December 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/27869827/titin-truncating-variants-affect-heart-function-in-disease-cohorts-and-the-general-population
#16
COMPARATIVE STUDY
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...
January 2017: Nature Genetics
https://read.qxmd.com/read/27802169/junctophilin-2-in-the-nanoscale-organisation-and-functional-signalling-of-ryanodine-receptor-clusters-in-cardiomyocytes
#17
JOURNAL ARTICLE
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://read.qxmd.com/read/27786225/young-scientists-under-pressure-what-the-data-show
#18
JOURNAL ARTICLE
Brendan Maher, Miquel Sureda Anfres
No abstract text is available yet for this article.
October 27, 2016: Nature
https://read.qxmd.com/read/27783597/transcription-of-the-non-coding-rna-upperhand-controls-hand2-expression-and-heart-development
#19
JOURNAL ARTICLE
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...
November 17, 2016: Nature
https://read.qxmd.com/read/27698420/pore-architecture-of-tric-channels-and-insights-into-their-gating-mechanism
#20
JOURNAL ARTICLE
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 27, 2016: Nature
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