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https://www.readbyqxmd.com/read/27910042/direct-cardiac-reprogramming-as-a-novel-therapeutic-strategy-for-treatment-of-myocardial-infarction
#1
Hong Ma, Li Wang, Jiandong Liu, Li Qian
Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds great promise as a novel therapy for the treatment of heart failure, a common and morbid disease that is usually caused by irreversible loss of functional cardiomyocytes (CMs). Recently, we and others showed that in a murine model of acute myocardial infarction, delivery of three transcription factors, Gata4, Mef2c, and Tbx5 converted endogenous cardiac fibroblasts into functional iCMs. These iCMs integrated electrically and mechanically with surrounding myocardium, resulting in a reduction in scar size and an improvement in heart function...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27834668/chemical-enhancement-of-in-vitro-and-in-vivo-direct-cardiac-reprogramming
#2
Tamer M A Mohamed, Nicole R Stone, Emily C Berry, Ethan Radzinsky, Yu Huang, Karishma Pratt, Yen-Sin Ang, Pengzhi Yu, Haixia Wang, Shibing Tang, Sergey Magnitsky, Sheng Ding, Kathryn N Ivey, Deepak Srivastava
BACKGROUND: -Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells (iCMs) in situ represents a promising strategy for cardiac regeneration. A combination of three cardiac transcription factors, Gata4, Mef2c and Tbx5 (GMT), can convert fibroblasts into iCMs, albeit with low efficiency in vitro METHODS: -We screened 5,500 compounds in primary cardiac fibroblasts to identify the pathways that can be modulated to enhance cardiomyocyte reprogramming. RESULTS: -We found that a combination of the transforming growth factor (TGF)-β inhibitor SB431542 and the WNT inhibitor XAV939 increased reprogramming efficiency eight-fold when added to GMT-overexpressing cardiac fibroblasts...
November 10, 2016: Circulation
https://www.readbyqxmd.com/read/27833996/expression-of-t-box-transcription-factors-2-4-and-5-is-decreased-in-the-branching-airway-mesenchyme-of-nitrofen-induced-hypoplastic-lungs
#3
Toshiaki Takahashi, Florian Friedmacher, Julia Zimmer, Prem Puri
PURPOSE: Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major therapeutic challenge in newborns with congenital diaphragmatic hernia (CDH). T-box transcription factors (Tbx) have been identified as key components of the gene network that regulates fetal lung development. Tbx2, Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung, regulating the process of lung branching morphogenesis. Furthermore, lungs of Tbx2-, Tbx4- and Tbx5-deficient mice are hypoplastic and exhibit decreased lung branching, similar to PH in human CDH...
November 11, 2016: Pediatric Surgery International
https://www.readbyqxmd.com/read/27819261/sirt1-deacetylates-the-cardiac-transcription-factor-nkx2-5-and-inhibits-its-transcriptional-activity
#4
Xiaoqiang Tang, Han Ma, Lei Han, Wei Zheng, Yun-Biao Lu, Xiao-Feng Chen, Shu-Ting Liang, Gong-Hong Wei, Zhu-Qin Zhang, Hou-Zao Chen, De-Pei Liu
The homeodomain transcription factor Nkx2.5/Csx is critically essential for heart specification, morphogenesis, and homeostasis. Acetylation/deacetylation is important for the localization, stability and activation of transcription factors. It remains unknown how Nkx2.5 is deacetylated and how Nkx2.5 acetylation determines its activity. In this study, we provide evidence that the NAD(+)-dependent class III protein deacetylase SIRT1 deacetylates Nkx2.5 in cardiomyocytes and represses the transcriptional activity of Nkx2...
November 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27818139/cited2-cooperates-with-isl1-and-promotes-cardiac-differentiation-of-mouse-embryonic-stem-cells
#5
Ivette Pacheco-Leyva, Ana Catarina Matias, Daniel V Oliveira, João M A Santos, Rita Nascimento, Eduarda Guerreiro, Anna C Michell, Annebel M van De Vrugt, Gisela Machado-Oliveira, Guilherme Ferreira, Ibrahim Domian, José Bragança
The transcriptional regulator CITED2 is essential for heart development. Here, we investigated the role of CITED2 in the specification of cardiac cell fate from mouse embryonic stem cells (ESC). The overexpression of CITED2 in undifferentiated ESC was sufficient to promote cardiac cell emergence upon differentiation. Conversely, the depletion of Cited2 at the onset of differentiation resulted in a decline of ESC ability to generate cardiac cells. Moreover, loss of Cited2 expression impairs the expression of early mesoderm markers and cardiogenic transcription factors (Isl1, Gata4, Tbx5)...
October 31, 2016: Stem Cell Reports
https://www.readbyqxmd.com/read/27773576/in-situ-reprogramming-to-transdifferentiate-fibroblasts-into-cardiomyocytes-using-adenoviral-vectors-implications-for-clinical-myocardial-regeneration
#6
Megumi Mathison, Vivek P Singh, Maria J Chiuchiolo, Deepthi Sanagasetti, Yun Mao, Vivekkumar B Patel, Jianchang Yang, Stephen M Kaminsky, Ronald G Crystal, Todd K Rosengart
OBJECTIVE: The reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells improves ventricular function in myocardial infarction models. Only integrating persistent expression vectors have thus far been used to induce reprogramming, potentially limiting its clinical applicability. We therefore tested the reprogramming potential of nonintegrating, acute expression adenoviral (Ad) vectors. METHODS: Ad or lentivirus vectors encoding Gata4 (G), Mef2c (M), and Tbx5 (T) were validated in vitro...
September 23, 2016: Journal of Thoracic and Cardiovascular Surgery
https://www.readbyqxmd.com/read/27722056/life-threatening-cardiac-episode-in-a-polish-patient-carrying-contiguous-gene-microdeletion-of-the-tbx5-and-the-tbx3-genes
#7
Katarzyna Iwanicka-Pronicka, Magdalena Socha, Maria Jędrzejowska, Małgorzata Krajewska-Walasek, Aleksander Jamsheer
Holt-Oram syndrome (HOS) features radial ray hypoplasia, heart defect and cardiac conduction impairment. Ulnar-mammary syndrome (UMS) characterizes congenital defects of the ulnar side of the upper limbs, underdevelopment of apocrine glands including hypoplasia and the dysfunction of mammary glands, hypogonadism and obesity. Inheritance of both conditions is autosomal dominant, mutations or deletions are found in the TBX5 and TBX3 gene, respectively. The Polish patient presented short stature, obesity, congenital malformation of the radial and ulnar side of the upper limbs, heart block, hypogonadism and dysmorphic features...
2016: SpringerPlus
https://www.readbyqxmd.com/read/27652283/a-novel-de-novo-tbx5-mutation-in-a-patient-with-holt-oram-syndrome-leading-to-a-dramatically-reduced-biological-function
#8
Martina Dreßen, Harald Lahm, Armin Lahm, Klaudia Wolf, Stefanie Doppler, Marcus-André Deutsch, Julie Cleuziou, Jelena Pabst von Ohain, Patric Schön, Peter Ewert, Ivan Malcic, Rüdiger Lange, Markus Krane
BACKGROUND: The Holt-Oram syndrome (HOS) is an autosomal dominant disorder affecting 1/100.000 live births. It is defined by upper limb anomalies and congenital heart defects with variable severity. We describe a dramatic phenotype of a male, 15-month-old patient being investigated for strict diagnostic criteria of HOS. METHODS AND RESULTS: Genetic analysis revealed a so far unpublished TBX5 mutation, which occurs de novo in the patient with healthy parents. TBX5 belongs to the large family of T-box transcription factors playing major roles in morphogenesis and cell-type specification...
September 2016: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/27633992/emergence-of-dorsal-ventral-polarity-in-esc-derived-retinal-tissue
#9
Yuiko Hasegawa, Nozomu Takata, Satoru Okuda, Masako Kawada, Mototsugu Eiraku, Yoshiki Sasai
We previously demonstrated that mouse embryonic stem cell (mESC)-derived retinal epithelium self-forms an optic cup-like structure. In the developing retina, the dorsal and ventral sides differ in terms of local gene expression and morphological features. This aspect has not yet been shown in vitro Here, we demonstrate that mESC-derived retinal tissue spontaneously acquires polarity reminiscent of the dorsal-ventral (D-V) patterning of the embryonic retina. Tbx5 and Vax2 were expressed in a mutually exclusive manner, as seen in vivo Three-dimensional morphometric analysis showed that the in vitro-formed optic cup often contains cleft structures resembling the embryonic optic fissure...
November 1, 2016: Development
https://www.readbyqxmd.com/read/27582060/pitx2-modulates-a-tbx5-dependent-gene-regulatory-network-to-maintain-atrial-rhythm
#10
Rangarajan D Nadadur, Michael T Broman, Bastiaan Boukens, Stefan R Mazurek, Xinan Yang, Malou van den Boogaard, Jenna Bekeny, Margaret Gadek, Tarsha Ward, Min Zhang, Yun Qiao, James F Martin, Christine E Seidman, Jon Seidman, Vincent Christoffels, Igor R Efimov, Elizabeth M McNally, Christopher R Weber, Ivan P Moskowitz
Cardiac rhythm is extremely robust, generating 2 billion contraction cycles during the average human life span. Transcriptional control of cardiac rhythm is poorly understood. We found that removal of the transcription factor gene Tbx5 from the adult mouse caused primary spontaneous and sustained atrial fibrillation (AF). Atrial cardiomyocytes from the Tbx5-mutant mice exhibited action potential abnormalities, including spontaneous depolarizations, which were rescued by chelating free calcium. We identified a multitiered transcriptional network that linked seven previously defined AF risk loci: TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2 In addition, reduced Tbx5 dose by adult-specific haploinsufficiency caused decreased target gene expression, myocardial automaticity, and AF inducibility, which were all rescued by Pitx2 haploinsufficiency in mice...
August 31, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27579918/meta-analysis-of-transcriptome-regulation-during-induction-to-cardiac-myocyte-fate-from-mouse-and-human-fibroblasts
#11
Shima Rastegar-Pouyani, Niusha Khazaei, Ping Wee, Moein Yaqubi, Abdulshakour Mohammadnia
Ectopic expression of a defined set of transcription factors (TFs) can directly convert fibroblasts into a cardiac myocyte cell fate. Beside inefficiency in generating induced cardiomyocytes (iCMs), the molecular mechanisms that regulate this process remained to be well defined. The main purpose of this study was to provide better insight on the transcriptome regulation and to introduce a new strategy for candidating TFs for the transdifferentiation process. Eight mouse and three human high quality microarray data sets were analyzed to find differentially expressed genes (DEGs), which we integrated with TF-binding sites and protein-protein interactions to construct gene regulatory and protein-protein interaction networks...
August 31, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27577874/fine-mapping-novel-loci-identification-and-snp-association-transferability-in-a-genome-wide-association-study-of-qrs-duration-in-african-americans
#12
Daniel S Evans, Christy L Avery, Mike A Nalls, Guo Li, John Barnard, Erin N Smith, Toshiko Tanaka, Anne M Butler, Sarah G Buxbaum, Alvaro Alonso, Dan E Arking, Gerald S Berenson, Joshua C Bis, Steven Buyske, Cara L Carty, Wei Chen, Mina K Chung, Steven R Cummings, Rajat Deo, Charles B Eaton, Ervin R Fox, Susan R Heckbert, Gerardo Heiss, Lucia A Hindorff, Wen-Chi Hsueh, Aaron Isaacs, Yalda Jamshidi, Kathleen F Kerr, Felix Liu, Yongmei Liu, Kurt K Lohman, Jared W Magnani, Joseph F Maher, Reena Mehra, Yan A Meng, Solomon K Musani, Christopher Newton-Cheh, Kari E North, Bruce M Psaty, Susan Redline, Jerome I Rotter, Renate B Schnabel, Nicholas J Schork, Ralph V Shohet, Andrew B Singleton, Jonathan D Smith, Elsayed Z Soliman, Sathanur R Srinivasan, Herman A Taylor, David R Van Wagoner, James G Wilson, Taylor Young, Zhu-Ming Zhang, Alan B Zonderman, Michele K Evans, Luigi Ferrucci, Sarah S Murray, Gregory J Tranah, Eric A Whitsel, Alex P Reiner, Nona Sotoodehnia
The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with QRS duration at 22 loci among those of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a GWAS meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent...
August 29, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27573776/common-variants-confer-susceptibility-to-barrett-s-esophagus-insights-from-the-first-genome-wide-association-studies
#13
Claire Palles, John M Findlay, Ian Tomlinson
Eight loci have been identified by the two genome-wide association studies of Barrett's esophagus that have been conducted to date. Esophageal adenocarcinoma cases were included in the second study following evidence that predisposing genetic variants for this cancer overlap with those for Barrett's esophagus. Genes with roles in embryonic development of the foregut are adjacent to 6 of the loci identified (FOXF1, BARX1, FOXP1, GDF7, TBX5, and ALDH1A2). An additional locus maps to a gene with known oncogenic potential (CREB-regulated transcription coactivator 1), but expression quantitative trait data implicates yet another gene involved in esophageal development (PBX4)...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27569213/ablation-of-mir-10b-suppresses-oncogene-induced-mammary-tumorigenesis-and-metastasis-and-reactivates-tumor-suppressive-pathways
#14
Jongchan Kim, Ashley N Siverly, Dahu Chen, Min Wang, Yuan Yuan, Yumeng Wang, Hyemin Lee, Jinsong Zhang, William J Muller, Han Liang, Boyi Gan, Xianbin Yang, Yutong Sun, M James You, Li Ma
The invasive and metastatic properties of many human tumors have been associated with upregulation of the miRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here, we report the generation of miR-10b-deficient mice, in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR-10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial-mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27553283/a-long-lasting-cardiomyogenic-gene-expression-by-pei-based-transfection-induces-endogenous-cardiac-mrnas-in-human-adipose-derived-stem-cells
#15
Eulsoon Park, Koichi Takimoto
Our previous work revealed that a polyethyleneimine (PEI)-based gene delivery causes robust and sustained expression of exogenous genes in human adipose-derived stem cells (hADSCs). Here we use this method to test whether a single introduction of cDNAs for the three cardiomyogenic reprogramming genes (GATA4, MEF2C, and TBX5) might be sufficient to induce transdifferentiation of hADSCs towards the cardiomyogenic lineage. A single transfection results in sustained expression of the introduced genes for more than two weeks...
October 7, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27552067/holt-oram-syndrome-because-of-the-novel-tbx5-mutation-c-481a-c
#16
Hatice Koçak Eker, Umut Altunoglu, Güven Toksoy, Hülya Kayserili
No abstract text is available yet for this article.
October 2016: Clinical Dysmorphology
https://www.readbyqxmd.com/read/27503876/regulatory-evolution-of-tbx5-and-the-origin-of-paired-appendages
#17
Noritaka Adachi, Molly Robinson, Aden Goolsbee, Neil H Shubin
The diversification of paired appendages has been a major factor in the evolutionary radiation of vertebrates. Despite its importance, an understanding of the origin of paired appendages has remained elusive. To address this problem, we focused on T-box transcription factor 5 (Tbx5), a gene indispensable for pectoral appendage initiation and development. Comparison of gene expression in jawless and jawed vertebrates reveals that the Tbx5 expression in jawed vertebrates is derived in having an expression domain that extends caudal to the heart and gills...
September 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27484899/brg1-interacts-with-gli2-and-binds-mef2c-gene-in-a-hedgehog-signalling-dependent-manner-during-in-vitro-cardiomyogenesis
#18
Joel Vincent Fair, Anastassia Voronova, Neven Bosiljcic, Rashida Rajgara, Alexandre Blais, Ilona Sylvia Skerjanc
BACKGROUND: The Hedgehog (HH) signalling pathway regulates cardiomyogenesis in vivo and in differentiating P19 embryonal carcinoma (EC) cells, a mouse embryonic stem (mES) cell model. To further assess the transcriptional role of HH signalling during cardiomyogenesis in stem cells, we studied the effects of overexpressing GLI2, a primary transducer of the HH signalling pathway, in mES cells. RESULTS: Stable GLI2 overexpression resulted in an enhancement of cardiac progenitor-enriched genes, Mef2c, Nkx2-5, and Tbx5 during mES cell differentiation...
2016: BMC Developmental Biology
https://www.readbyqxmd.com/read/27479212/common-variants-in-the-tbx5-gene-associated-with-atrial-fibrillation-in-a-chinese-han-population
#19
Rongfeng Zhang, Xiaochen Tian, Lianjun Gao, Huihua Li, Xiaomeng Yin, Yingxue Dong, Yanzong Yang, Yunlong Xia
BACKGROUND: PR interval variations have recently been associated with an increased risk of long-term atrial fibrillation (AF), heart block and all-cause mortality. Genome-wide association studies have linked the PR interval with several common variants in the TBX5 gene. Several variants in the TBX5 gene, including rs7312625 and rs883079, have been associated with AF. The purpose of this study was to determine the association of single-nucleotide polymorphisms (SNPs) in the TBX5 gene, rs7312625 and rs883079, with AF in Chinese Han patients...
2016: PloS One
https://www.readbyqxmd.com/read/27477082/genome-wide-dna-methylation-pattern-in-visceral-adipose-tissue-differentiates-insulin-resistant-from-insulin-sensitive-obese-subjects
#20
A B Crujeiras, A Diaz-Lagares, J M Moreno-Navarrete, J Sandoval, D Hervas, A Gomez, W Ricart, F F Casanueva, M Esteller, J M Fernandez-Real
Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples...
July 15, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
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