A5080823164- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- 3D Printing in Biomedical Research
- Neuroscience and Neural Engineering
- Virus-based gene therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- Plant and animal studies
- Histone Deacetylase Inhibitors Research
- Heart Failure Treatment and Management
- Congenital heart defects research
- Cancer-related molecular mechanisms research
- Cardiomyopathy and Myosin Studies
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Cardiac electrophysiology and arrhythmias
- Animal Genetics and Reproduction
- Heat shock proteins research
- Evolution and Genetic Dynamics
- Cellular Mechanics and Interactions
- Tissue Engineering and Regenerative Medicine
- Plant Reproductive Biology
- Evolutionary Game Theory and Cooperation
- Renal and related cancers
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
Vital Therapies (United States)
2024-2025
Universidad Católica de Santa Fe
2023
Gladstone Institutes
2014-2020
Cincinnati Children's Hospital Medical Center
2018
University of California, San Francisco
2016-2017
Stanford University
2017
QB3
2017
Centre for Human Genetics
2010-2011
University of Oxford
2010-2011
Cambridge University Press
2010
A very focused function for lncRNAs The human genome generates many thousands of long noncoding RNAs (lncRNAs). small number have been shown to be functional. Liu et al. carried out a large-scale CRISPR-based screen assess the ∼17,000 in seven different cell lines. considerable (∼500) tested influenced growth, suggesting biological function. In almost all cases, though, was highly type—specific, often limited just one type. Science , this issue p. 10.1126/science.aah7111
Abstract Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety efficacy testing. A fundamental problem in this inefficient process is that cannot adequately represent human biology. Thus, there an urgent need for high-content vitro systems can better predict drug-induced toxicity. Systems cardiotoxicity of uppermost significance, as approximately one third safety-based pharmaceutical withdrawals due...
Contractile motion is the simplest metric of cardiomyocyte health in vitro, but unbiased quantification challenging. We describe a rapid automated method, requiring only standard video microscopy, to analyze contractility human-induced pluripotent stem cell-derived cardiomyocytes (iPS-CM). New algorithms for generating and filtering vectors combined with newly developed isogenic iPSC line harboring genetically encoded calcium indicator, GCaMP6f, allow simultaneous user-independent...
Abstract Tissue engineering approaches have the potential to increase physiologic relevance of human iPS-derived cells, such as cardiomyocytes (iPS-CM). However, forming Engineered Heart Muscle (EHM) typically requires >1 million cells per tissue. Existing miniaturization strategies involve complex not amenable mass production, limiting ability use EHM for iPS-based disease modeling and drug screening. Micro-scale cardiospheres are easily produced, but do facilitate assembly elongated...
Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6's role HFpEF their shared mechanisms inflammation and metabolism. Here, show inhibiting HDAC6 TYA-018 effectively reverses established heart its associated symptoms male mouse models. Additionally, mice lacking...
We present a non-invasive method to characterize the function of pluripotent stem-cell-derived cardiomyocytes based on video microscopy and image analysis. The platform, called Pulse, generates automated measurements beating frequency, beat duration, amplitude, beat-to-beat variation motion analysis phase-contrast images captured at fast frame rate. Using we demonstrate recapitulation drug effects in without use exogenous labels show that our platform can be used for high-throughput...
Despite a great deal of theoretical attention, we have limited empirical data about how ploidy influences the rate adaptation. We evolved isogenic haploid and diploid populations Saccharomyces cerevisiae for 200 generations in seven different environments. measured competitive fitness all ancestral lines against common competitor find that environments, adapted faster than diploids, significantly so three apply theory relates rates adaptation effective population sizes to properties...
Molecular chaperones regulate quality control in the human proteome, pathways that have been implicated many diseases, including heart failure. Mutations BAG3 gene, which encodes a co-chaperone protein, associated with failure due to both inherited and sporadic dilated cardiomyopathy. Familial mutations are autosomal dominant frequently cause truncation of coding sequence, suggesting heterozygous loss-of-function mechanism. However, knockout murine gene did not detectable phenotype. To model...
Abstract CRISPR/Cas technologies have transformed our ability to add functionality the genome by knock-in of payload via homology-directed repair (HDR). However, a systematic and quantitative profiling integration landscape is still lacking. Here, we present framework based on long-read sequencing an integrated computational pipeline (knock-knock) analyze outcomes across wide range experimental parameters. Our data uncover complex profiles, with perfect HDR often accounting for minority...
Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage attrition, pharmaceutical biotechnology industries need to establish biologically relevant models that use phenotypic screening detect drug-induced toxicity in vitro. In this study, we sought rapidly patterns using high-content image analysis with deep learning induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library 1280 bioactive compounds identified those...
Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards care do not target the underlying molecular mechanisms associated with genetic forms failure, driving a need develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)...
The ubiquity of sexual reproduction despite its cost has lead to an extensive body research on the evolution and maintenance reproduction. Previous work suggested that can substantially speed up rate adaptation in diploid populations, because populations are able produce fittest homozygous genotype by segregation mating heterozygous individuals. In contrast, asexual must wait for two rare mutational events, one producing a carrier second converting carrier, before beneficial mutation become...
Prolonged in vitro culture of human embryonic stem (hES) cells can result chromosomal abnormalities believed to confer a selective advantage. This potential occurrence has crucial implications for the appropriate use hES research and therapeutic purposes. In view this, time-point karyotypic evaluation assess genetic stability is recommended as necessary control test be carried out during extensive 'passaging'. Standard techniques currently used cytogenetic assessment ES include G-banding...
Morphogenesis involves interactions of asymmetric cell populations to form complex multicellular patterns and structures comprised distinct types. However, current methods model morphogenic events lack control over cell-type co-emergence offer little capability selectively perturb specific subpopulations. Our in vitro system interrogates cell-cell organization within human induced pluripotent stem (hiPSC) colonies. We examined effects mosaic knockdown molecular regulators cortical tension...
Cardiac and hepatic toxicity result from induced disruption of the functioning cardiomyocytes hepatocytes, respectively, which is tightly related to organization their subcellular structures. Cellular structure can be analyzed microscopy imaging data. However, subtle or complex structural changes that are not easily perceived may missed by conventional image-analysis techniques. Here we report evaluation PhenoTox, an image-based deep-learning method quantifying drug-induced using human...
Recombinant adeno-associated virus (rAAV) is a widely used viral vector for gene therapy. However, these vectors have limited availability due to manufacturing challenges with productivity and quality. These can be addressed by better understanding the mechanisms that influence cellular responses during rAAV production. In this study, we aimed identify targets may enhance production using transcriptomic analyses of five cell lines variable capacities Using an intersectional approach,...
Historically, explanations for the evolution of floral traits that reduce self-fertilization have tended to focus on selection avoid inbreeding depression. However, there is growing support hypothesis such also play a role in promoting efficient pollen dispersal by reducing anther-stigma interference. The relative importance these two selective pressures currently popular topic investigation. To date, has been no theoretical exploration contributions genetic costs and promote traits. We...
Abstract Advancing maturation of stem cell-derived cardiac muscle represents a major barrier to progress in regenerative medicine. Cardiac involves myriad gene, protein, and cell-based transitions, spanning across all aspects form function. We focused here on key developmentally controlled transition the sarcomere, functional unit heart. Using gene-editing platform, human induced pluripotent cell (hiPSCs) were engineered with drug-inducible expression cassette driving adult troponin I (cTnI)...