Abstract:
:This study demonstrates that significantly shortened telomeres are a hallmark of cardiomyocytes (CMs) from individuals with end-stage hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) as a result of heritable defects in cardiac proteins critical to contractile function. Positioned at the ends of chromosomes, telomeres are DNA repeats that serve as protective caps that shorten with each cell division, a marker of aging. CMs are a known exception in which telomeres remain relatively stable throughout life in healthy individuals. We found that, relative to healthy controls, telomeres are significantly shorter in CMs of genetic HCM and DCM patient tissues harboring pathogenic mutations: TNNI3, MYBPC3, MYH7, DMD, TNNT2, and TTN Quantitative FISH (Q-FISH) of single cells revealed that telomeres were significantly reduced by 26% in HCM and 40% in DCM patient CMs in fixed tissue sections compared with CMs from age- and sex-matched healthy controls. In the cardiac tissues of the same patients, telomere shortening was not evident in vascular smooth muscle cells that do not express or require the contractile proteins, an important control. Telomere shortening was recapitulated in DCM and HCM CMs differentiated from patient-derived human-induced pluripotent stem cells (hiPSCs) measured by two independent assays. This study reveals telomere shortening as a hallmark of genetic HCM and DCM and demonstrates that this shortening can be modeled in vitro by using the hiPSC platform, enabling drug discovery.
journal_name
Proc Natl Acad Sci U S Aauthors
Chang ACY,Chang ACH,Kirillova A,Sasagawa K,Su W,Weber G,Lin J,Termglinchan V,Karakikes I,Seeger T,Dainis AM,Hinson JT,Seidman J,Seidman CE,Day JW,Ashley E,Wu JC,Blau HMdoi
10.1073/pnas.1714538115subject
Has Abstractpub_date
2018-09-11 00:00:00pages
9276-9281issue
37eissn
0027-8424issn
1091-6490pii
1714538115journal_volume
115pub_type
杂志文章abstract::Animal mitochondrial DNA (mtDNA) maintains a displacement loop (D loop) at the heavy strand origin of replication. These D loops represent sharply limited synthesis of heavy strands and provide a unique opportunity to examine the termination of DNA synthesis. Direct sizing at the nucleotide level indicates that the 3'...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.78.10.6116
更新日期:1981-10-01 00:00:00
abstract::During cell division, the mitotic spindle segregates the sister chromatids into two nascent cells, such that each daughter cell inherits one complete set of chromosomes. Errors in spindle formation can result in both chromosome missegregation and cytokinesis defects and hence lead to genomic instability. To ensure the...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0507066103
更新日期:2006-04-04 00:00:00
abstract::The AAA-ATPase thyroid hormone receptor interacting protein 13 (TRIP13), jointly with the Mad2-binding protein p31(comet), promotes the inactivation of the mitotic (spindle assembly) checkpoint by disassembling the mitotic checkpoint complex (MCC). This checkpoint system ensures the accuracy of chromosome segregation ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1515358112
更新日期:2015-09-15 00:00:00
abstract::Two prominent timekeeping systems, the cell cycle, which controls cell division, and the circadian system, which controls 24-h rhythms of physiology and behavior, are found in nearly all living organisms. A distinct feature of circadian rhythms is that they are temperature-compensated such that the period of the rhyth...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0914078107
更新日期:2010-05-25 00:00:00
abstract::Lod scores provide a method to unify linkage tests based on identity by descent and identity in marker state while permitting selection of the most informative individuals through their disease-related phenotypes and markers in relatives. After parametric lods are reviewed, a nonparametric approach that depends on a s...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.93.8.3471
更新日期:1996-04-16 00:00:00
abstract::Cajal-Retzius (CR) cells are early-generated transient neurons and are important in the regulation of cortical neuronal migration and cortical laminar formation. Molecular entities characterizing the CR cell identity, however, remain largely elusive. We purified mouse cortical CR cells expressing GFP to homogeneity by...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0406295101
更新日期:2004-10-05 00:00:00
abstract::Classification within the genus Pistacia has been based on leaf morphology and geographical distribution. Molecular genetic tools (PCR amplification followed by restriction analysis of a 3.2-kb region of variable chloroplast DNA, and restriction fragment length polymorphism analysis of the Pistacia cpDNA with tobacco ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.94.15.7987
更新日期:1997-07-22 00:00:00
abstract::The interaction between cells and nanostructured materials is attracting increasing interest, because of the possibility to open up novel concepts for the design of smart nanobiomaterials with active biological functionalities. In this frame we investigated the response of human neuroblastoma cell line (SH-SY5Y) to go...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0914456107
更新日期:2010-04-06 00:00:00
abstract::Metallic nanoscale structures are capable of supporting surface plasmon polaritons (SPPs), propagating collective electron oscillations with tight spatial confinement at the metal surface. SPPs represent one of the most promising structures to beat the diffraction limit imposed by conventional dielectric optics. Ag na...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0902064106
更新日期:2009-12-15 00:00:00
abstract::X-ray absorption spectra near the Kalpha edge have been measured in various iron group compounds using the intense synchrotron radiation at the Stanford Synchrotron Research Project. In the cubic compounds KMF3 where M = Mn+2, Fe+2, Co+2, Ni+2, and Zn+2, well resolved lines were observed and assigned to the 1s leads t...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.73.5.1384
更新日期:1976-05-01 00:00:00
abstract::We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in t...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0707291104
更新日期:2007-09-18 00:00:00
abstract::Graphene oxide (GO), the main precursor of graphene-based materials made by solution processing, is known to be very stiff. Indeed, it has a Young's modulus comparable to steel, on the order of 300 GPa. Despite its very high stiffness, we show here that GO is superflexible. We quantitatively measure the GO bending rig...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1605121113
更新日期:2016-10-04 00:00:00
abstract::By affinity chromatography on heparin-Sepharose, two classes of lipoproteins were separated from high density lipoproteins (HDL) isolated from patients with primary or secondary lecithin:cholesterol acyltransferase (LCATase; EC 2.3.1.43) deficiency and from normal subjects. The unretained fraction, HDL(A), was charact...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.77.5.2969
更新日期:1980-05-01 00:00:00
abstract::Cell membrane contact induces the de novo expression of choline O-acetyltransferase (CAT; acetyl-CoA: choline O-acetyltransferase, EC 2.3.1.6) activity in cultures of virtually pure neonatal rat dissociated sympathetic neurons. To identify molecular mechanisms underlying membrane-associated CAT induction, the responsi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.86.3.1080
更新日期:1989-02-01 00:00:00
abstract::Two high molecular weight heat shock proteins, HSP90 (Mr, 90,000) and HSP100 (Mr, 100,000), were separately purified from extracts of cultured cells of a mouse lymphoma cell line, L5178Y. Both of the HSPs exist in homodimeric form under physiological conditions. Their physicochemical properties are quite similar to ea...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.83.21.8054
更新日期:1986-11-01 00:00:00
abstract::Scientific cinematography using ultrafast optical imaging is a common tool to study motion. In opaque organisms or structures, X-ray radiography captures sequences of 2D projections to visualize morphological dynamics, but for many applications full four-dimensional (4D) spatiotemporal information is highly desirable....
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1308650111
更新日期:2014-03-18 00:00:00
abstract::The myocardin family proteins (myocardin, MRTF-A, and MRTF-B) are serum response factor (SRF) cofactors and potent transcription activators. Gene-ablation studies have indicated important developmental functions for myocardin family proteins primarily in regulation of cardiac and smooth muscle development. Using Xenop...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0703918105
更新日期:2008-02-05 00:00:00
abstract::SUMO, a small ubiquitin-related modifier, is known to covalently attach to a number of nuclear regulatory proteins such as p53, IkappaB, promyelocytic leukemia protein and c-Jun. The sumoylation reaction is catalyzed by the SUMO protease, which exposes the C-terminal active glycine residue of the nascent SUMO, the het...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0402889101
更新日期:2004-06-08 00:00:00
abstract::Ca(2+) signaling regulates cell function. This is subject to modulation by H(+) ions that are universal end-products of metabolism. Due to slow diffusion and common buffers, changes in cytoplasmic [Ca(2+)] ([Ca(2+)]i) or [H(+)] ([H(+)]i) can become compartmentalized, leading potentially to complex spatial Ca(2+)/H(+) ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1222433110
更新日期:2013-05-28 00:00:00
abstract::Fast axoplasmic transport was studied in dorsal root ganglion cells of the cat. Proteins carried in the fast axoplasmic flow were labeled after an intraganglionic injection of (L)-[4,5-(3)H]leucine. The rate of transport was 380 +/- 26 mm/day in both the central and peripheral branches of the bifurcating axons that ar...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.70.5.1521
更新日期:1973-05-01 00:00:00
abstract::Prenatal unilateral enucleation in mammals causes an extensive anatomical reorganization of visual pathways. The remaining eye innervates the entire extent of visual subcortical and cortical areas. Electrophysiological recordings have shown that the retino-geniculate connections are retinotopically organized and genic...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.90.23.11142
更新日期:1993-12-01 00:00:00
abstract::Neuropeptide B (NPB) and neuropeptide W (NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpre...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1518658113
更新日期:2016-05-24 00:00:00
abstract::Never before have individuals had to adapt to social environments defined by such magnitudes of ethnic diversity and cultural differentiation. However, neurobiological evidence informing about strategies to reduce xenophobic sentiment and foster altruistic cooperation with outsiders is scarce. In a series of experimen...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章,随机对照试验
doi:10.1073/pnas.1705853114
更新日期:2017-08-29 00:00:00
abstract::The activation of Janus kinases (JAKs) is crucial for propagation of the proliferative response initiated by many cytokines. The proliferation of various cell lines, particularly those of hematopoietic origin, is also modulated by mediators of oxidative stress such as nitric oxide and thiol redox reagents. Herein we d...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.1.126
更新日期:1998-01-06 00:00:00
abstract::Although the applicability of small subunit ribosomal RNA (16S rRNA) sequences for bacterial classification is now well accepted, the general use of these molecules has been hindered by the technical difficulty of obtaining their sequences. A protocol is described for rapidly generating large blocks of 16S rRNA sequen...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.20.6955
更新日期:1985-10-01 00:00:00
abstract::Directionality of signaling among brain regions provides essential information about human cognition and disease states. Assessing such effective connectivity (EC) across brain states using functional magnetic resonance imaging (fMRI) alone has proven difficult, however. We propose a novel measure of EC, termed metabo...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1513752113
更新日期:2016-01-12 00:00:00
abstract::The mitochondrial enzyme glutaminase C (GAC) catalyzes the hydrolysis of glutamine to glutamate plus ammonia, a key step in the metabolism of glutamine by cancer cells. Recently, we discovered a class of allosteric inhibitors of GAC that inhibit cancer cell growth without affecting their normal cellular counterparts, ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1414056112
更新日期:2015-01-13 00:00:00
abstract::The dansyl-conjugated (Dns) peptides Dns-Pro-Gly-Gly-Gln-Gln-Ile-Val and Dns-Ala-Gln-Gln-Ile-Val, patterned on the N-terminal sequence of fibronectin, were synthesized and used for the transglutaminase (protein-glutamine:amine gamma-glutamyltransferase, EC 2.3.2.13)-directed selective blocking of lens proteins that ot...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.1.82
更新日期:1991-01-01 00:00:00
abstract::Optical spectra of biological polymers contain important information about their structure and function in living organisms. This information can be accessed by extracting an optical interaction of monomers, i.e., their exciton coupling, from experimental data. This coupling is sensitive to molecular structure, geomet...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0808513106
更新日期:2009-01-27 00:00:00
abstract::Observations from human microbiome studies are often conflicting or inconclusive. Many factors likely contribute to these issues including small cohort sizes, sample collection, and handling and processing differences. The field of microbiome research is moving from 16S rDNA gene sequencing to a more comprehensive gen...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1519288112
更新日期:2015-11-10 00:00:00