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  • 1
    Online Resource
    Online Resource
    Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 145, No. 16 ( 2022-04-19), p. 1205-1217
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 145, No. 16 ( 2022-04-19), p. 1205-1217
    Abstract: Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. Methods: We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis -protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis. Results: Forty-four of ninety proteins were positively associated with risk of incident HF ( P 〈 6.0×10 –4 ). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1. Conclusions: We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.121.056663
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 2
    Online Resource
    Online Resource
    The relationship between cardiac endothelium and fibroblasts: it’s complicated
    American Society for Clinical Investigation ; 2017
    In:  Journal of Clinical Investigation Vol. 127, No. 8 ( 2017-6-26), p. 2892-2894
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 127, No. 8 ( 2017-6-26), p. 2892-2894
    Type of Medium: Online Resource
    ISSN: 0021-9738 , 1558-8238
    URL: Article
    DOI: 10.1172/JCI95492
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2017
    detail.hit.zdb_id: 2018375-6
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  • 3
    Online Resource
    Online Resource
    The (Pluri)Potential of Cell Therapy for Heart Failure
    Elsevier BV ; 2023
    In:  Journal of Cardiac Failure Vol. 29, No. 4 ( 2023-04), p. 514-516
    Details
    In: Journal of Cardiac Failure, Elsevier BV, Vol. 29, No. 4 ( 2023-04), p. 514-516
    Type of Medium: Online Resource
    ISSN: 1071-9164
    URL: Article
    DOI: 10.1016/j.cardfail.2023.01.008
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2048826-9
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  • 4
    Online Resource
    Online Resource
    Unmet needs in the management of functional impairment in patients with chronic pain: a multinational survey
    Future Medicine Ltd ; 2021
    In:  Pain Management Vol. 11, No. 3 ( 2021-05), p. 303-314
    Details
    In: Pain Management, Future Medicine Ltd, Vol. 11, No. 3 ( 2021-05), p. 303-314
    Abstract: Lay abstract Chronic pain is one of the most common and complex conditions. It can lead to disability in some patients and significantly affect their ability to function. Patients with chronic pain often have difficulty performing routine household tasks, working productively, engaging in social activities and sleeping. When individuals seek treatment for chronic pain they should be able to have an honest conversation with their doctor about all of the disabling aspects of their pain and agree on achievable goals of treatment (e.g., the ability to perform routine household chores). We asked a group of delegates attending the European Pain Federation pain congress what they thought may impede doctors’ ability to accurately assess and alleviate functional disability associated with chronic pain. According to these survey respondents, general practitioners (GPs) do not have sufficient knowledge, time or resources to properly manage patients with chronic pain. When asked what would help to improve this situation, the survey respondents suggested more training for GPs, better techniques for assessing disability that focus on measurable indicators of disability, such as activity levels, time off work and sleep quality. They also recommend consulting with a number of different healthcare professionals, including physiotherapists and psychologists, who should work collaboratively with GPs to provide comprehensive, holistic care to patients with chronic pain.
    Type of Medium: Online Resource
    ISSN: 1758-1869 , 1758-1877
    URL: Article
    DOI: 10.2217/pmt-2020-0098
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2021
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  • 5
    Online Resource
    Online Resource
    Clonal Analysis of the Neonatal Mouse Heart using Nearest Neighbor Modeling
    MyJove Corporation ; 2020
    In:  Journal of Visualized Experiments , No. 162 ( 2020-08-22)
    Details
    In: Journal of Visualized Experiments, MyJove Corporation, , No. 162 ( 2020-08-22)
    Type of Medium: Online Resource
    ISSN: 1940-087X
    URL: Article
    DOI: 10.3791/61656
    Language: English
    Publisher: MyJove Corporation
    Publication Date: 2020
    detail.hit.zdb_id: 2259946-0
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  • 6
    Online Resource
    Online Resource
    Abstract 15756: Vascular Guidance of Cardiomyocyte Proliferation During Growth and Regeneration
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. Suppl_3 ( 2020-11-17)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
    Abstract: Introduction: Stimulating cardiomyocyte (CM) proliferation is a major strategy for achieving therapeutic heart regeneration. However, heart regeneration requires coordinated interactions of multiple cell types. Because a hallmark of advanced heart failure is vascular rarefaction, the requirement of cardiac endothelial cells (CECs) for cardiac growth and regeneration is of particular importance. Hypothesis: We hypothesized that CECs are required for CM proliferation during growth and regeneration. Methods and Results: We performed a large-scale histologic assessment of neonatal mouse hearts and found the rate of CEC proliferation to shadow CM proliferation over the first 10 days of life. Using a nearest neighbor analysis, we found the fraction of proliferating CECs to be significantly enriched around cycling CMs compared to non-cycling CMs, suggesting that CEC and CM expansion are coupled within a myovascular niche. Single cell sequencing of neonatal mouse hearts after cryoinjury revealed that a majority of these proliferating CECs also express Vegfr2 . To functionally link CEC and CM proliferation, we generated Cdh5-CreER T2 ; Vefgr2 flox/flox mice to genetically delete Vegfr2 from CECs. Compared to mice with intact Vegfr2 , loss of Vegfr2 from CECs in neonatal mice leads to loss of CECs and severely dampens CM proliferation by 4 days (7.01±0.88% vs 0.39±0.35%, p = 7.4x10-4, n = 9),. Interestingly, CM proliferation is attenuated when Vegfr2 is deleted from CECs despite an increase of hypoxia indicators in CMs, signifying that hypoxia-induced CM proliferation is dependent on CECs. In contrast to CEC depletion, treatment of cryoinjured neonatal hearts with AAV encoding the master angiogenic factor, Vegfa can enhance heart regeneration with increased CM cycling in the borderzone (12.6±2.2% vs 5.4±0.4%, p = 0.02, n = 8), reduced scarring of the left ventricle (3.4±1.4% vs 7.6±1.2%, p = 03, n = 16), and improved fractional shortening (51.7±2.5% vs 36.7±4.3%, p = 0.007, n = 14). Conclusions: CEC and CM expansion are spatiotemporally coupled in a myovascular niche during cardiac growth. CECs play a critical role to support CM proliferation and are likely to provide instructive cues that may be leveraged for therapeutic heart regeneration.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.142.suppl_3.15756
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1466401-X
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  • 7
    Online Resource
    Online Resource
    Essential and Unexpected Role of Yin Yang 1 to Promote Mesodermal Cardiac Differentiation
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Circulation Research Vol. 112, No. 6 ( 2013-03-15), p. 900-910
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 112, No. 6 ( 2013-03-15), p. 900-910
    Abstract: Cardiogenesis is regulated by a complex interplay between transcription factors. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). Objective: To identify novel regulators of mesodermal cardiac lineage commitment. Methods and Results: We performed a bioinformatic-based transcription factor binding site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell–derived CPCs. From 32 candidate transcription factors screened, we found that Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays, in vivo chromatin immunoprecipitation, and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4 at a nearby chromatin. Cardiac mesoderm–specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by embryonic stem cell–based assays in which we showed that the overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs. Conclusions: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.113.259259
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467838-X
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  • 8
    Online Resource
    Online Resource
    Abstract 12781: NF-κB Activity is Required for Heart Regeneration
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Circulation Vol. 130, No. suppl_2 ( 2014-11-25)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)
    Abstract: Objectives: In contrast to humans, zebrafish recover from cardiac injury through a robust regenerative response. Recent work suggests that the mammalian heart is able to undergo low-grade cardiomyocyte turnover in response to injury. However, this level of turnover in not sufficient for cardiac recovery. A better understanding of the mechanisms that contribute to zebrafish heart regeneration can instruct approaches to achieve therapeutic heart regeneration in humans. Methods and Results: We performed expression profiling of regenerating zebrafish hearts by RNA-Seq to identify factors that modify heart regeneration. Expression levels for members of the NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) pathway were significantly enriched in regenerating hearts. Using a transgenic reporter strain for NF-κB activity, we found NF-κB to be induced in cardiomyocytes following injury. Moreover, NF-κB activity overlaps with the activation of gata4 regulatory sequences that are induced in regenerating cardiomyocytes. We subsequently developed a transgenic zebrafish strain to conditionally inhibit NF-κB signaling in cardiomyocytes by expression of mutant IκBα. Zebrafish hearts with loss of NF-κB activity scar following injury, indicative of impaired regeneration. Conclusions: NF-κB mediates an early transcriptional response to injury in cardiomyocytes that is required for heart regeneration.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.130.suppl_2.12781
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1466401-X
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  • 9
    Online Resource
    Online Resource
    A Metagenomics Analysis on B-Carotene Synthesis in Neurospora Crassa
    Nepal Journals Online (JOL) ; 2015
    In:  International Journal of Applied Sciences and Biotechnology Vol. 3, No. 3 ( 2015-09-25), p. 490-503
    Details
    In: International Journal of Applied Sciences and Biotechnology, Nepal Journals Online (JOL), Vol. 3, No. 3 ( 2015-09-25), p. 490-503
    Abstract: We have studied insilico on evolutionary uniqueness of phytoene synthase, which is one of the regulatory enzymes of ?-carotene synthesis in Neurospora crassa.  This study reveals multiple sequence alignments showed high sequences with similarity within a species of bacteria, fungi and higher plants.  This results designate interestingly between species of bacteria-fungi, fungi-plant, and among the species of bacteria-fungi-plant, showed tremendously less sequence with similarity, except bacteria-plant (high sequence with similarity) respectively.  In Phylogenetics tree analysis showed within species of bacteria, fungi and plant 91%, 92% and 99% homology.  Whereas in between species of bacteria-fungi, bacteria-plant, fungi-plant, and among the species bacteria-fungi-plant showed 99%, 96%, 100%, and 91%-99% homology respectively.  N. crassa phytoene synthase enzyme encode (Isoprenoid Biosynthesis enzymes, Class 1) protein size 610aa, Cyanobacteria phytoene encode (Isoprenoid Biosynthesis enzymes, Class 1) protein size 310aa, and Oryza sativa Indica phytoene synthase 1 (chloroplast), (Isoprenoid Biosynthesis enzymes, Class 1) encode protein size 421aa (e- value 0.0, 0.0 and 0.0; identity 100%, 100% and 100%; Max.score:1238, 644 and 870) respectively.  We studied insilico on basis of an evolutionary Endosymbiotic theory; a bacterium is the ancestors to eukaryotes. Int J Appl Sci Biotechnol, Vol 3(3): 490-503
    Type of Medium: Online Resource
    ISSN: 2091-2609
    URL: Article
    DOI: 10.3126/ijasbt.v3i3.13306
    Language: Unknown
    Publisher: Nepal Journals Online (JOL)
    Publication Date: 2015
    detail.hit.zdb_id: 2733295-0
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  • 10
    Online Resource
    Online Resource
    A Roadmap to Heart Regeneration Through Conserved Mechanisms in Zebrafish and Mammals
    Springer Science and Business Media LLC ; 2021
    In:  Current Cardiology Reports Vol. 23, No. 4 ( 2021-04)
    Details
    In: Current Cardiology Reports, Springer Science and Business Media LLC, Vol. 23, No. 4 ( 2021-04)
    Type of Medium: Online Resource
    ISSN: 1523-3782 , 1534-3170
    URL: Article
    DOI: 10.1007/s11886-021-01459-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2094155-9
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