Li Wang
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Publication
Journal: Nature
May/7/2012
Abstract
The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
Publication
Journal: Nature
May/9/2011
Abstract
Chromatin profiling has emerged as a powerful means of genome annotation and detection of regulatory activity. The approach is especially well suited to the characterization of non-coding portions of the genome, which critically contribute to cellular phenotypes yet remain largely uncharted. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions. Focusing on cell-type-specific patterns of promoters and enhancers, we define multicell activity profiles for chromatin state, gene expression, regulatory motif enrichment and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell-type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for the interpretation of genome-wide association studies. Top-scoring disease single nucleotide polymorphisms are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus suggesting a mechanism for the association. Our study presents a general framework for deciphering cis-regulatory connections and their roles in disease.
Publication
Journal: Nucleic Acids Research
September/8/2011
Abstract
TALENs are important new tools for genome engineering. Fusions of transcription activator-like (TAL) effectors of plant pathogenic Xanthomonas spp. to the FokI nuclease, TALENs bind and cleave DNA in pairs. Binding specificity is determined by customizable arrays of polymorphic amino acid repeats in the TAL effectors. We present a method and reagents for efficiently assembling TALEN constructs with custom repeat arrays. We also describe design guidelines based on naturally occurring TAL effectors and their binding sites. Using software that applies these guidelines, in nine genes from plants, animals and protists, we found candidate cleavage sites on average every 35 bp. Each of 15 sites selected from this set was cleaved in a yeast-based assay with TALEN pairs constructed with our reagents. We used two of the TALEN pairs to mutate HPRT1 in human cells and ADH1 in Arabidopsis thaliana protoplasts. Our reagents include a plasmid construct for making custom TAL effectors and one for TAL effector fusions to additional proteins of interest. Using the former, we constructed de novo a functional analog of AvrHah1 of Xanthomonas gardneri. The complete plasmid set is available through the non-profit repository AddGene and a web-based version of our software is freely accessible online.
Publication
Journal: Nature Genetics
November/20/2011
Abstract
We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops.
Publication
Journal: The Lancet
March/11/2012
Abstract
BACKGROUND
The prevalence of chronic kidney disease is high in developing countries. However, no national survey of chronic kidney disease has been done incorporating both estimated glomerular filtration rate (eGFR) and albuminuria in a developing country with the economic diversity of China. We aimed to measure the prevalence of chronic kidney disease in China with such a survey.
METHODS
We did a cross-sectional survey of a nationally representative sample of Chinese adults. Chronic kidney disease was defined as eGFR less than 60 mL/min per 1·73 m(2) or the presence of albuminuria. Participants completed a lifestyle and medical history questionnaire and had their blood pressure measured, and blood and urine samples taken. Serum creatinine was measured and used to estimate glomerular filtration rate. Urinary albumin and creatinine were tested to assess albuminuria. The crude and adjusted prevalence of indicators of kidney damage were calculated and factors associated with the presence of chronic kidney disease analysed by logistic regression.
RESULTS
50,550 people were invited to participate, of whom 47,204 agreed. The adjusted prevalence of eGFR less than 60 mL/min per 1·73 m(2) was 1·7% (95% CI 1·5-1·9) and of albuminuria was 9·4% (8·9-10·0). The overall prevalence of chronic kidney disease was 10·8% (10·2-11·3); therefore the number of patients with chronic kidney disease in China is estimated to be about 119·5 million (112·9-125·0 million). In rural areas, economic development was independently associated with the presence of albuminuria. The prevalence of chronic kidney disease was high in north (16·9% [15·1-18·7]) and southwest (18·3% [16·4-20·4]) regions compared with other regions. Other factors independently associated with kidney damage were age, sex, hypertension, diabetes, history of cardiovascular disease, hyperuricaemia, area of residence, and economic status.
CONCLUSIONS
Chronic kidney disease has become an important public health problem in China. Special attention should be paid to residents in economically improving rural areas and specific geographical regions in China.
BACKGROUND
The Ministry of Science and Technology (China); the Science and Technology Commission of Shanghai; the National Natural Science Foundation of China; the Department of Health, Jiangsu Province; the Sichuan Science and Technology Department; the Ministry of Education (China); the International Society of Nephrology Research Committee; and the China Health and Medical Development Foundation.
Publication
Journal: Annals of Internal Medicine
January/23/2006
Abstract
BACKGROUND
Alzheimer disease and other dementing disorders are major sources of morbidity and mortality in aging societies. Proven strategies to delay onset or reduce risk for dementing disorders would be greatly beneficial.
OBJECTIVE
To determine whether regular exercise is associated with a reduced risk for dementia and Alzheimer disease.
METHODS
Prospective cohort study.
METHODS
Group Health Cooperative, Seattle, Washington.
METHODS
1740 persons older than age 65 years without cognitive impairment who scored above the 25th percentile on the Cognitive Ability Screening Instrument (CASI) in the Adult Changes in Thought study and who were followed biennially to identify incident dementia.
METHODS
Baseline measurements, including exercise frequency, cognitive function, physical function, depression, health conditions, lifestyle characteristics, and other potential risk factors for dementia (for example, apolipoprotein E epsilon4); biennial assessment for dementia.
RESULTS
During a mean follow-up of 6.2 years (SD, 2.0), 158 participants developed dementia (107 developed Alzheimer disease). The incidence rate of dementia was 13.0 per 1000 person-years for participants who exercised 3 or more times per week compared with 19.7 per 1000 person-years for those who exercised fewer than 3 times per week. The age- and sex-adjusted hazard ratio of dementia was 0.62 (95% CI, 0.44 to 0.86; P = 0.004). The interaction between exercise and performance-based physical function was statistically significant (P = 0.013). The risk reduction associated with exercise was greater in those with lower performance levels. Similar results were observed in analyses restricted to participants with incident Alzheimer disease.
CONCLUSIONS
Exercise was measured by self-reported frequency. The study population had a relatively high proportion of regular exercisers at baseline.
CONCLUSIONS
These results suggest that regular exercise is associated with a delay in onset of dementia and Alzheimer disease, further supporting its value for elderly persons.
Publication
Journal: Journal of Clinical Investigation
June/16/2004
Abstract
We explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of molecular, cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the molecular level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) alpha and beta, we demonstrate the critical dependence of the reduction of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXR alpha and LXR beta. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.
Publication
Journal: Cell
October/18/2010
Abstract
We report the generation and comparative analysis of genome-wide chromatin state maps, PPARγ and CTCF localization maps, and gene expression profiles from murine and human models of adipogenesis. The data provide high-resolution views of chromatin remodeling during cellular differentiation and allow identification of thousands of putative preadipocyte- and adipocyte-specific cis-regulatory elements based on dynamic chromatin signatures. We find that the specific locations of most such elements differ between the two models, including at orthologous loci with similar expression patterns. Based on sequence analysis and reporter assays, we show that these differences are determined, in part, by evolutionary turnover of transcription factor motifs in the genome sequences and that this turnover may be facilitated by the presence of multiple distal regulatory elements at adipogenesis-dependent loci. We also utilize the close relationship between open chromatin marks and transcription factor motifs to identify and validate PLZF and SRF as regulators of adipogenesis.
Publication
Journal: Molecular Carcinogenesis
February/10/2011
Abstract
Numerous studies have shown that aberrant microRNA (miRNA) expression is associated with the development and progression of various types of human cancer and serum miRNAs are potential biomarkers. This study examined whether some commonly deregulated miRNAs in hepatocellular carcinoma (HCC) are presented in serum of patients with HCC and can serve as diagnostic markers. Serum miRNAs (miR-21, miR-122, and miR-223) were quantified by real-time quantitative RT-PCR in 101 patients with HCC and 89 healthy controls. In addition, 48 patients with chronic type B hepatitis were also analyzed for comparison. We found that the median levels of miR-21, miR-122, and miR-223 were significantly higher in patients with HCC than those in healthy controls (P = 7.48 x 10⁻¹³, P = 6.93 x 10⁻⁹, and P = 3.90 x 10⁻¹², respectively). However, these elevated serum miRNAs were also detected in patients with chronic hepatitis (P = 2.05 x 10⁻¹², P = 4.52 x 10⁻¹⁶, and P = 1.65 x 10⁻¹¹, respectively). Moreover, serum miR-21 and miR-122 in patients with chronic hepatitis were higher than in patients with HCC (P = 3.99 x 10⁻⁴ and P = 4.97 x 10⁻⁸), although no such significant difference was found for miR-223. Receiver-operator characteristic (ROC) curve analyses suggest that these serum miRNAs may be useful markers for discriminating patients with HCC or chronic hepatitis from healthy controls, but not patients with HCC from patients with chronic hepatitis. Our results indicate that serum miR-21, miR-122 and miR-223 are elevated in patients with HCC or chronic hepatitis and these miRNAs have strong potential to serve as novel biomarkers for liver injury but not specifically for HCC.
Publication
Journal: Nature Communications
October/26/2015
Abstract
Polyploidization has provided much genetic variation for plant adaptive evolution, but the mechanisms by which the molecular evolution of polyploid genomes establishes genetic architecture underlying species differentiation are unclear. Brassica is an ideal model to increase knowledge of polyploid evolution. Here we describe a draft genome sequence of Brassica oleracea, comparing it with that of its sister species B. rapa to reveal numerous chromosome rearrangements and asymmetrical gene loss in duplicated genomic blocks, asymmetrical amplification of transposable elements, differential gene co-retention for specific pathways and variation in gene expression, including alternative splicing, among a large number of paralogous and orthologous genes. Genes related to the production of anticancer phytochemicals and morphological variations illustrate consequences of genome duplication and gene divergence, imparting biochemical and morphological variation to B. oleracea. This study provides insights into Brassica genome evolution and will underpin research into the many important crops in this genus.
Publication
Journal: Science Translational Medicine
August/8/2012
Abstract
Characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure, dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy in patients. DCM is the most common diagnosis leading to heart transplantation and places a significant burden on healthcare worldwide. The advent of induced pluripotent stem cells (iPSCs) offers an exceptional opportunity for creating disease-specific cellular models, investigating underlying mechanisms, and optimizing therapy. Here, we generated cardiomyocytes from iPSCs derived from patients in a DCM family carrying a point mutation (R173W) in the gene encoding sarcomeric protein cardiac troponin T. Compared to control healthy individuals in the same family cohort, cardiomyocytes derived from iPSCs from DCM patients exhibited altered regulation of calcium ion (Ca(2+)), decreased contractility, and abnormal distribution of sarcomeric α-actinin. When stimulated with a β-adrenergic agonist, DCM iPSC-derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric α-actinin distribution. Treatment with β-adrenergic blockers or overexpression of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (Serca2a) improved the function of iPSC-derived cardiomyocytes from DCM patients. Thus, iPSC-derived cardiomyocytes from DCM patients recapitulate to some extent the morphological and functional phenotypes of DCM and may serve as a useful platform for exploring disease mechanisms and for drug screening.
Publication
Journal: JAMA - Journal of the American Medical Association
March/5/2009
Abstract
BACKGROUND
Prior mechanistic studies reported that omeprazole decreases the platelet inhibitory effects of clopidogrel, yet the clinical significance of these findings is not clear.
OBJECTIVE
To assess outcomes of patients taking clopidogrel with or without a proton pump inhibitor (PPI) after hospitalization for acute coronary syndrome (ACS).
METHODS
Retrospective cohort study of 8205 patients with ACS taking clopidogrel after discharge from 127 Veterans Affairs hospitals between October 1, 2003, and January 31, 2006. Vital status information was available for all patients through September 30, 2006.
METHODS
All-cause mortality or rehospitalization for ACS.
RESULTS
Of 8205 patients taking clopidogrel after discharge, 63.9% (n = 5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n = 2961) were not prescribed PPI. Death or rehospitalization for ACS occurred in 20.8% (n = 615) of patients taking clopidogrel without PPI and 29.8% (n = 1561) of patients taking clopidogrel plus PPI. In multivariable analyses, use of clopidogrel plus PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95% confidence interval [CI], 1.11-1.41). Among patients taking clopidogrel after hospital discharge and prescribed PPI at any point during follow-up (n = 5244), periods of use of clopidogrel plus PPI (compared with periods of use of clopidogrel without PPI) were associated with a higher risk of death or rehospitalization for ACS (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). In analyses of secondary outcomes, patients taking clopidogrel plus PPI had a higher risk of hospitalizations for recurrent ACS compared with patients taking clopidogrel without PPI (14.6% vs 6.9%; AOR, 1.86 [95% CI, 1.57-2.20]) and revascularization procedures (15.5% vs 11.9%; AOR, 1.49 [95% CI, 1.30-1.71]), but not for all-cause mortality (19.9% vs 16.6%; AOR, 0.91 [95% CI, 0.80-1.05]). The association between use of clopidogrel plus PPI and increased risk of adverse outcomes also was consistent using a nested case-control study design (AOR, 1.32; 95% CI, 1.14-1.54). In addition, use of PPI without clopidogrel was not associated with death or rehospitalization for ACS among patients not taking clopidogrel after hospital discharge (n = 6450) (AOR, 0.98; 95% CI, 0.85-1.13).
CONCLUSIONS
Concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS.
Publication
Journal: Nature Biotechnology
June/17/2012
Abstract
Learning to read and write the transcriptional regulatory code is of central importance to progress in genetic analysis and engineering. Here we describe a massively parallel reporter assay (MPRA) that facilitates the systematic dissection of transcriptional regulatory elements. In MPRA, microarray-synthesized DNA regulatory elements and unique sequence tags are cloned into plasmids to generate a library of reporter constructs. These constructs are transfected into cells and tag expression is assayed by high-throughput sequencing. We apply MPRA to compare >27,000 variants of two inducible enhancers in human cells: a synthetic cAMP-regulated enhancer and the virus-inducible interferon-β enhancer. We first show that the resulting data define accurate maps of functional transcription factor binding sites in both enhancers at single-nucleotide resolution. We then use the data to train quantitative sequence-activity models (QSAMs) of the two enhancers. We show that QSAMs from two cellular states can be combined to design enhancer variants that optimize potentially conflicting objectives, such as maximizing induced activity while minimizing basal activity.
Publication
Journal: Nature Medicine
November/3/2015
Abstract
We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
August/7/2008
Abstract
Although mature dendritic cells (DCs) are potent initiators of adaptive immune response, immature steady-state DCs contribute to immune tolerance. In this study, we show that ex vivo splenic DCs are capable of inducing conversion of naïve CD4(+) T cells to adaptive Foxp3(+)CD4(+) regulatory T cells (aTreg) in the presence of TGF-beta. In particular, when compared with splenic CD8alpha(-) DCs, the CD8alpha(+) DC subset were superior in inducing higher frequencies of conversion. This was not attributable to the difference in basal level of costimulation, because deficiency of CD40 or CD80/86 signaling did not diminish the differential induction of Foxp3. Conversion was regulated by DC maturation status. Further insights into the molecular mechanisms of conversion were gained by analyzing the contribution of several costimulatory and coinhibitory receptors. Costimulatory signals through GITR suppressed conversion, whereas coinhibitory signaling via programmed death 1 ligand (PD-L1) but not PD-L2 was required for conversion. Ex vivo PD-L1(-/-) DCs failed to support Foxp3 induction in the presence of TGF-beta. In vivo blocking PD-L1 signaling abolished conversion in a tumor-induced aTreg conversion model. Collectively, this study highlights the cellular and molecular parameters that might be exploited to control the de novo generation of aTregs and peripheral tolerance.
Publication
Journal: Developmental Cell
July/21/2002
Abstract
The orphan nuclear hormone receptor SHP has been proposed to have a key role in the negative feedback regulation of bile acid production. Consistent with this, mice lacking the SHP gene exhibit mild defects in bile acid homeostasis and fail to repress cholesterol 7-alpha-hydroxylase expression in response to a specific agonist for the bile acid receptor FXR. However, this repression is retained in SHP null mice fed bile acids, demonstrating the existence of compensatory repression pathways of bile acid signaling. We provide evidence for two such pathways, based on activation of the xenobiotic receptor PXR or the c-Jun N-terminal kinase JNK. We conclude that redundant mechanisms regulate this critical aspect of cholesterol homeostasis.
Publication
Journal: Cell Stem Cell
June/6/2013
Abstract
Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca(2+)) imaging indicated dysregulation of Ca(2+) cycling and elevation in intracellular Ca(2+) ([Ca(2+)](i)) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca(2+) homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
January/30/2006
Abstract
The PIK3CA gene encoding the p110alpha subunit of Class IA phosphatidylinositol 3-kinases (PI3Ks) is frequently mutated in human tumors. Mutations in the PIK3CB gene encoding p110beta, the only other widely expressed Class IA PI3K, have not been reported. We compared the biochemical activity and transforming potential of mutant forms of p110alpha and p110beta in a human mammary epithelial cell system. The two most common tumor-derived alleles of p110alpha, H1047R and E545K, potently activated PI3K signaling. Human mammary epithelial cells expressing these alleles grew efficiently in soft agar and as orthotopic tumors in nude mice. We also examined a third class of mutations in p110alpha, those in the p85-binding domain. A representative tumor-derived p85-binding-domain mutant R38H showed modestly reduced p85 binding and weakly activated PI3K/Akt signaling. In contrast, a deletion mutant lacking the entire p85-binding domain efficiently activated PI3K signaling. When we constructed in p110beta a mutation homologous to the E545K allele of p110alpha, the resulting p110beta mutant was only weakly activated and allowed minimal soft-agar growth. However, a gene fusion of p110beta with the membrane anchor from c-Src was highly active and transforming in both soft-agar and orthotopic nude mouse assays. Thus, although introduction of activating mutations from p110alpha at the corresponding sites in p110beta failed to render the enzyme oncogenic in human cells, the possibility remains that other mutations might activate the beta isoform.
Publication
Journal: Nature Medicine
December/26/2007
Abstract
Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.
Publication
Journal: Circulation
February/13/2006
Abstract
BACKGROUND
Patients with heart failure are frequently hospitalized for fluid overload. A reliable method for chronic monitoring of fluid status is therefore desirable. We evaluated an implantable system capable of measuring intrathoracic impedance to identify potential fluid overload before heart failure hospitalization and to determine the correlation between intrathoracic impedance and standard measures of fluid status during hospitalization.
RESULTS
Thirty-three patients with NYHA class III and IV heart failure were implanted with a special pacemaker in the left pectoral region and a defibrillation lead in the right ventricle. Intrathoracic impedance was regularly measured and recorded between the lead and the pacemaker case. During hospitalizations, pulmonary capillary wedge pressure and fluid status were monitored. Ten patients were hospitalized for fluid overload 25 times over 20.7+/-8.4 months. Intrathoracic impedance decreased before each admission by an average of 12.3+/-5.3% (P<0.001) over an average of 18.3+/-10.1 days. Impedance reduction began 15.3+/-10.6 days (P<0.001) before the onset of worsening symptoms. There was an inverse correlation between intrathoracic impedance and pulmonary capillary wedge pressure (r=-0.61, P<0.001) and between intrathoracic impedance and net fluid loss (r=-0.70, P<0.001) during hospitalization. Automated detection of impedance decreases was 76.9% sensitive in detecting hospitalization for fluid overload, with 1.5 false-positive (threshold crossing without hospitalization) detections per patient-year of follow-up.
CONCLUSIONS
Intrathoracic impedance is inversely correlated with pulmonary capillary wedge pressure and fluid balance and decreased before the onset of patient symptoms and before hospital admission for fluid overload. Regular monitoring of impedance may provide early warning of impending decompensation and diagnostic information for titration of medication.
Publication
Journal: Circulation Research
August/27/2012
Abstract
BACKGROUND
Direct reprogramming of fibroblasts into cardiomyocytes is a novel strategy for cardiac regeneration. However, the key determinants involved in this process are unknown.
OBJECTIVE
To assess the efficiency of direct fibroblast reprogramming via viral overexpression of GATA4, Mef2c, and Tbx5 (GMT).
RESULTS
We induced GMT overexpression in murine tail tip fibroblasts (TTFs) and cardiac fibroblasts (CFs) from multiple lines of transgenic mice carrying different cardiomyocyte lineage reporters. We found that the induction of GMT overexpression in TTFs and CFs is inefficient at inducing molecular and electrophysiological phenotypes of mature cardiomyocytes. In addition, transplantation of GMT infected CFs into injured mouse hearts resulted in decreased cell survival with minimal induction of cardiomyocyte genes.
CONCLUSIONS
Significant challenges remain in our ability to convert fibroblasts into cardiomyocyte-like cells and a greater understanding of cardiovascular epigenetics is needed to increase the translational potential of this strategy.
Publication
Journal: Parasitology Research
March/21/2013
Abstract
Since praziquantel was developed in 1970s, it has replaced other antischistosomal drugs to become the only drug of choice for treatment of human schistosomiases, due to high efficacy, excellent tolerability, few and transient side effects, simple administration, and competitive cost. Praziquantel-based chemotherapy has been involved in the global control strategy of the disease and led to the control strategy shifting from disease control to morbidity control, which has greatly reduced the prevalence and intensity of infections. Given that the drug has been widely used for morbidity control in endemic areas for more than three decades, the emergence of resistance of Schistosoma to praziquantel under drug selection pressure has been paid much attention. It is possible to induce resistance of Schistosoma mansoni and Schistosoma japonicum to praziquantel in mice under laboratorial conditions, and a reduced susceptibility to praziquantel in the field isolates of S. mansoni has been found in many foci. In addition, there are several schistosomiasis cases caused by Schistosoma haematobium infections in which repeated standard treatment fails to clear the infection. However, in the absence of exact mechanisms of action of praziquantel, the mechanisms of drug resistance in schistosomes remain unclear. The present review mainly demonstrates the evidence of drug resistance in the laboratory and field and the mechanism of praziquantel resistance and proposes some strategies for control of praziquantel resistance in schistosomes.
Publication
Journal: Cell
March/4/2002
Abstract
Three membrane microdomains can be identified on docked vacuoles: "outside" membrane, not in contact with other vacuoles, "boundary" membrane that contacts adjacent vacuoles, and "vertices," where boundary and outside membrane meet. In living cells and in vitro, vacuole fusion occurs at vertices rather than from a central pore expanding radially. Vertex fusion leaves boundary membrane within the fused organelle and is an unexpected pathway for the formation of intralumenal membranes. Proteins that regulate docking and fusion (Vac8p, the GTPase Ypt7p, its HOPS/Vps-C effector complex, the t-SNARE Vam3p, and protein phosphatase 1) accumulate at these vertices during docking. Their vertex enrichment requires cis-SNARE complex disassembly and is thus part of the normal fusion pathway.
Publication
Journal: DNA Research
October/20/2004
Abstract
Genomics provides an unprecedented opportunity to probe in minute detail into the genomes of the world's most deadly pathogenic bacteria- Yersinia pestis. Here we report the complete genome sequence of Y. pestis strain 91001, a human-avirulent strain isolated from the rodent Brandt's vole-Microtus brandti. The genome of strain 91001 consists of one chromosome and four plasmids (pPCP1, pCD1, pMT1 and pCRY). The 9609-bp pPCP1 plasmid of strain 91001 is almost identical to the counterparts from reference strains (CO92 and KIM). There are 98 genes in the 70,159-bp range of plasmid pCD1. The 106,642-bp plasmid pMT1 has slightly different architecture compared with the reference ones. pCRY is a novel plasmid discovered in this work. It is 21,742 bp long and harbors a cryptic type IV secretory system. The chromosome of 91001 is 4,595,065 bp in length. Among the 4037 predicted genes, 141 are possible pseudo-genes. Due to the rearrangements mediated by insertion elements, the structure of the 91001 chromosome shows dramatic differences compared with CO92 and KIM. Based on the analysis of plasmids and chromosome architectures, pseudogene distribution, nitrate reduction negative mechanism and gene comparison, we conclude that strain 91001 and other strains isolated from M. brandti might have evolved from ancestral Y. pestis in a different lineage. The large genome fragment deletions in the 91001 chromosome and some pseudogenes may contribute to its unique nonpathogenicity to humans and host-specificity.
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