Abstract:
:The ability to generate patient-specific human induced pluripotent stem cells (iPSCs) offers a new paradigm for modelling human disease and for individualizing drug testing. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies.
journal_name
Naturejournal_title
Natureauthors
Itzhaki I,Maizels L,Huber I,Zwi-Dantsis L,Caspi O,Winterstern A,Feldman O,Gepstein A,Arbel G,Hammerman H,Boulos M,Gepstein Ldoi
10.1038/nature09747subject
Has Abstractpub_date
2011-03-10 00:00:00pages
225-9issue
7337eissn
0028-0836issn
1476-4687pii
nature09747journal_volume
471pub_type
杂志文章相关文献
NATURE文献大全abstract::Chronic myelogenous leukaemia (CML) is a clonal disease arising from malignant transformation of pluripotent hematopoietic stem cells. In most cases, it is characterized by the presence of the Philadelphia (Ph1) chromosome (22q-) which results from a reciprocal translocation between chromosomes 9 and 22 (refs 1-3). In...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/319331a0
更新日期:1986-01-23 00:00:00
abstract::The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes1,2 has stimulated efforts towards their streamlined synthesis3-9. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination3, which compr...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2213-0
更新日期:2020-05-01 00:00:00
abstract::Cell competition-the sensing and elimination of less fit 'loser' cells by neighbouring 'winner' cells-was first described in Drosophila. Although cell competition has been proposed as a selection mechanism to optimize tissue and organ development, its evolutionary generality remains unclear. Here, by using live imagin...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-019-1199-y
更新日期:2019-05-01 00:00:00
abstract::One simple, widely accepted mechanism for generating an aberrant chromosome number, or aneuploidy, is through nondisjunction--a chromosome distribution error that occurs during mitosis when both copies of a duplicated chromosome are deposited into one daughter cell and none into the other. Shi and King challenge this ...
journal_title:Nature
pub_type: 评论,杂志文章
doi:10.1038/nature05139
更新日期:2006-08-17 00:00:00
abstract::The global mid-ocean ridge system is the most extensive magmatic system on our planet and is the site of 75 per cent of Earth's volcanism1. The vertical extent of mid-ocean-ridge magmatic systems has been considered to be restricted: even at the ultraslow-spreading Gakkel mid-ocean ridge under the Arctic Ocean, where ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-019-1448-0
更新日期:2019-08-01 00:00:00
abstract::The germ-cell lineage ensures the continuity of life through the generation of male and female gametes, which unite to form a totipotent zygote. We have previously demonstrated that, by using cytokines, embryonic stem cells and induced pluripotent stem cells can be induced into epiblast-like cells (EpiLCs) and then in...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature12417
更新日期:2013-09-12 00:00:00
abstract::Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature22393
更新日期:2017-07-06 00:00:00
abstract::We have investigated age-related reactivation of the X chromosome by devising a model in which reactivation of a single gene in one cell among many can be identified. We have used mice with an X-autosomal translocation giving consistent non-random inactivation of the normal X (as judged by biochemical and cytogenetic ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/327725a0
更新日期:1987-06-25 00:00:00
abstract::The dispute among federal agencies over regulation of commercial biotechnology has been addressed in the Federal Register by the Office of Science and Technology Policy (OSTP), which says the Recombinant DNA Advisory Committee of the National Institutes of Health should continue to oversee biomedical research in this ...
journal_title:Nature
pub_type: 新闻
doi:10.1038/313085b0
更新日期:1985-01-10 00:00:00
abstract::The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death l...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature24302
更新日期:2017-11-16 00:00:00
abstract::In 2001 the Intergovernmental Panel on Climate Change projected the contribution to sea level rise from the Greenland ice sheet to be between -0.02 and +0.09 m from 1990 to 2100 (ref. 1). However, recent work has suggested that the ice sheet responds more quickly to climate perturbations than previously thought, parti...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature05168
更新日期:2006-09-21 00:00:00
abstract::Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcome...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-018-0768-9
更新日期:2019-01-01 00:00:00
abstract::Constructing agents with planning capabilities has long been one of the main challenges in the pursuit of artificial intelligence. Tree-based planning methods have enjoyed huge success in challenging domains, such as chess1 and Go2, where a perfect simulator is available. However, in real-world problems, the dynamics ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-03051-4
更新日期:2020-12-01 00:00:00
abstract::Structural fluctuations in proteins on the picosecond timescale have been studied in considerable detail by theoretical methods such as molecular dynamics simulation, but there exist very few experimental data with which to test the conclusions. We have used the technique of inelastic neutron scattering to investigate...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/337754a0
更新日期:1989-02-23 00:00:00
abstract::In this Letter, owing to a copying error in Illustrator, the two centre panels in Extended Data Fig. 7a were identical. This error has been corrected online. The old, incorrect Extended Data Fig. 7 is shown in the Supplementary Information to this Amendment for transparency. Some typos ('occurence') in Figs. 1, 2 and ...
journal_title:Nature
pub_type: 杂志文章,已发布勘误
doi:10.1038/s41586-018-0231-y
更新日期:2018-07-01 00:00:00
abstract::Certain bacteria promote the formation of ice in super-cooled water by means of ice nucleators which contain a unique protein associated with the cell membrane. Ice nucleators in general are believed to act by mimicking the structure of an ice crystal surface, thus imposing an ice-like arrangement on the water molecul...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/333782a0
更新日期:1988-06-23 00:00:00
abstract::Mice of the AKR strain are characterised by a high incidence of spontaneous thymic lymphomas. AKR chromosomes contain the genomes of ecotropic murine leukaemia virus (MuLV) at two loci, termed Akv-1 and Akv-2 (refs 2-6). Shortly after birth, the normal tissues of AKR mice begin to produce high levels of this XC-positi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/282753a0
更新日期:1979-12-13 00:00:00
abstract::Materials are said to show a shape-memory effect if they can be deformed and fixed into a temporary shape, and recover their original, permanent shape only on exposure to an external stimulus. Shape-memory polymers have received increasing attention because of their scientific and technological significance. In princi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature03496
更新日期:2005-04-14 00:00:00
abstract::The human gene for the hepatic enzyme phenylalanine hydroxylase has been cloned and used to analyse the phenylalanine hydroxylase locus in the human genome. The detection of polymorphisms in this locus by several restriction enzymes has allowed feasibility studies of prenatal diagnosis of classical phenylketonuria and...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/306151a0
更新日期:1983-11-10 00:00:00
abstract::Polymeric matrices can be used to grow new tissues and organs, and the delivery of growth factors from these matrices is one method to regenerate tissues. A problem with engineering tissues that exist in a mechanically dynamic environment, such as bone, muscle and blood vessels, is that most drug delivery systems have...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35050141
更新日期:2000-12-21 00:00:00
abstract::Time-of-flight mass spectrometry-most notably matrix-assisted laser-desorption-ionization time-of-flight (MALDI-TOF) spectrometry-is an important class of techniques for the study of proteins and other biomolecules. Although these techniques provide excellent performance for masses up to about 20,000 daltons, there ha...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35582
更新日期:1998-02-12 00:00:00
abstract::More than 99 per cent of the roughly 58,000 living vertebrate species have jaws. This major clade, whose members are collectively known as gnathostomes ('jawed mouths'), made its earliest definitive appearance in the Silurian period, 444-416 million years (Myr) ago, with both the origin of the modern (crown-group) rad...
journal_title:Nature
pub_type: 历史文章,杂志文章
doi:10.1038/nature10207
更新日期:2011-07-06 00:00:00
abstract::Vitreoscilla, a filamentous bacterium in the Beggiatoa family, synthesizes a soluble haem-protein which has two identical subunits of relative molecular mass 15,775 and two b haems per molecule. It is synthesized in relatively large quantities when the organism, a strict aerobe, is grown under hypoxic conditions. It f...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/322481a0
更新日期:1986-07-31 00:00:00
abstract::Comprehensive protein protein interaction maps promise to reveal many aspects of the complex regulatory network underlying cellular function. Recently, large-scale approaches have predicted many new protein interactions in yeast. To measure their accuracy and potential as well as to identify biases, strengths and weak...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature750
更新日期:2002-05-23 00:00:00
abstract::Resolving current concerns about the role of biodiversity on ecosystems calls for understanding the separate roles of changes in species numbers and of composition. Recent work shows that primary productivity often, but not always, saturates with species richness within single trophic levels. However, any interpretati...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/416837a
更新日期:2002-04-25 00:00:00
abstract::A combination of biochemistry in animal cell-free systems and genetics in yeast is revealing the molecular machinery of the secretory pathway of eukaryotes. Transporting vesicles have a simple coat structure and employ a general mechanism for fusion that is conserved in evolution. ...
journal_title:Nature
pub_type: 杂志文章,评审
doi:10.1038/355409a0
更新日期:1992-01-30 00:00:00
abstract::Considerable evidence points to a role for G1 cyclin-dependent kinase (CDK) in allowing the accumulation of E2F transcription factor activity and induction of the S phase of the cell cycle. Numerous experiments have also demonstrated a critical role for both Myc and Ras activities in allowing cell-cycle progression. H...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/387422a0
更新日期:1997-05-22 00:00:00
abstract::Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in princi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10334
更新日期:2011-08-03 00:00:00
abstract::The balance between stem cell self-renewal and differentiation is controlled by intrinsic factors and niche signals. In the Drosophila melanogaster ovary, some intrinsic factors promote germline stem cell (GSC) self-renewal, whereas others stimulate differentiation. However, it remains poorly understood how the balanc...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature13562
更新日期:2014-10-09 00:00:00
abstract::Elucidation of the molecular contacts between actin and myosin is central to understanding the force-generating process in muscle and other cells. Actin, a highly conserved globular protein found in all eukaryotes, polymerizes into filaments (F-actin) for most of its biological functions. Myosins, which are more diver...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/364171a0
更新日期:1993-07-08 00:00:00