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1.
Int J Obes (Lond) ; 43(8): 1556-1567, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31285522

RESUMO

BACKGROUND/OBJECTIVES: Short sleep is an obesity risk factor, however, little is known about its interplay with genetic predisposition and pathways involved in obesity pathogenesis, especially in the longitudinal setting. We aimed to investigate a possible sleep-gene interaction for childhood obesity risk, and whether the interaction in childhood longitudinally contributes to obesity risk at a 10-year follow-up and further to test if there is any mediation through the leptin pathway. SUBJECTS/METHODS: A total of 3211 children from China (6-18 years) at baseline and 848 participants at 10-year follow-up from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) cohort study were analyzed. Baseline leptin concentrations and 12 established adult body mass index (BMI) loci were examined for the associations with habitual sleep duration. RESULTS: After adjusting for covariates, including pubertal stages and behavioral factors, short sleep duration at baseline was significantly associated with increased overweight/obesity risk at both baseline and follow-up. Genetic predisposition scores (GPS), particularly consisting of leptin-related SNPs (GPSleptin), were robustly associated with baseline overweight/obesity in children who slept ≤8 h/day (P < 0.001), whereas the association was ablated in those who slept ≥10 h/day (P > 0.05). Comparable observations were made at follow-up. Mediation analysis revealed a modest direct effect of the GPSleptin-sleep interaction on BMI at baseline, while a significant indirect effect of this interaction was found to be mediated principally through elevated leptin (proportion: 52.6%); moreover, the mediation effect via leptin remained stable over 10 years. CONCLUSIONS: This study suggests that shorter sleep duration in children from China (< 8h/day), compared to longer sleep duration (≥10 h/day), has a long-term impact on the association of polygenic risk for obesity from childhood to young adulthood and leptin pathway explains a key mechanism via a modification effect. Therefore, adequate sleep duration during childhood is important for the early prevention of obesity, especially if there is a genetic predisposition to this trait.

2.
Nat Commun ; 10(1): 2760, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235787

RESUMO

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.


Assuntos
Redes Reguladoras de Genes/genética , Insuficiência Cardíaca/genética , Miócitos Cardíacos/patologia , Fosfoproteínas Fosfatases/metabolismo , Animais , Benzenoacetamidas , Células Cultivadas , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fosfoproteínas Fosfatases/genética , Cultura Primária de Células , Piridinas , Locos de Características Quantitativas/genética , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos
3.
Sensors (Basel) ; 19(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159240

RESUMO

For online sign language recognition (SLR) based on inertial measurement unit (IMU) and a surface electromyography (sEMG) sensor, achieving high-accuracy is a major challenge. The traditional method for that is the segmentation-recognition mechanism, which has two key challenges: (1) it is difficult to design a highly robust segmentation method for online data with inconspicuous segmentation information; and (2) the diversity of input data will increase the burden of the classification. The recognition-verification mechanism was proposed to improve the performance of online SLR. In the recognition stage, we used sliding windows to pull the data, and applied a convolutional neural network (CNN) to classify the sign language signal. In the verification stage, the confidence was evaluated by the Siamese network to judge the correctness of the classification results. The accuracy and rapidity of the classification model were discussed for 86 categories of Chinese sign language. In the experiments for online SLR, the superiority of the recognition-verification mechanism compared to the segmentation-recognition mechanism was verified.

4.
Blood ; 133(26): 2745-2752, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-30975639

RESUMO

Many genetic diseases, including hemophilia, require long-term therapeutic effects. Despite the initial success of liver-directed adeno-associated virus (AAV) gene therapy for hemophilia in clinical trials, long-term sustained therapeutic effects have yet to be seen. One explanation for the gradual decline of efficacy over time is that the nonintegrating AAV vector genome could be lost during cell division during hepatocyte turnover, albeit at a slow pace in adults. Readministering the same vector is challenging as a result of the AAV-neutralizing antibodies elicited by the initial treatment. Here, we investigated the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated homology-directed gene targeting for sustained treatment of hemophilia B. We developed a donor vector containing a promoterless partial human factor IX (FIX) complementary DNA carrying the hyperactive FIX Padua mutation. A single injection of dual AAV vectors in newborn and adult FIX-knockout (FIX-KO) mice led to stable expression of FIX at or above the normal levels for 8 months. Eight weeks after the vector treatment, we subjected a subgroup of newborn and adult treated FIX-KO mice to a two-thirds partial hepatectomy; all of these animals survived the procedure without any complications or interventions. FIX levels persisted at similar levels for 24 weeks after partial hepatectomy, indicating stable genomic targeting. Our results lend support for the use of a CRISPR/Cas9 approach to achieve lifelong expression of therapeutic proteins.

5.
Genes (Basel) ; 10(3)2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901858

RESUMO

Accurate prognosis of patients with cancer is important for the stratification of patients, the optimization of treatment strategies, and the design of clinical trials. Both clinical features and molecular data can be used for this purpose, for instance, to predict the survival of patients censored at specific time points. Multi-omics data, including genome-wide gene expression, methylation, protein expression, copy number alteration, and somatic mutation data, are becoming increasingly common in cancer studies. To harness the rich information in multi-omics data, we developed GDP (Group lass regularized Deep learning for cancer Prognosis), a computational tool for survival prediction using both clinical and multi-omics data. GDP integrated a deep learning framework and Cox proportional hazard model (CPH) together, and applied group lasso regularization to incorporate gene-level group prior knowledge into the model training process. We evaluated its performance in both simulated and real data from The Cancer Genome Atlas (TCGA) project. In simulated data, our results supported the importance of group prior information in the regularization of the model. Compared to the standard lasso regularization, we showed that group lasso achieved higher prediction accuracy when the group prior knowledge was provided. We also found that GDP performed better than CPH for complex survival data. Furthermore, analysis on real data demonstrated that GDP performed favorably against other methods in several cancers with large-scale omics data sets, such as glioblastoma multiforme, kidney renal clear cell carcinoma, and bladder urothelial carcinoma. In summary, we demonstrated that GDP is a powerful tool for prognosis of patients with cancer, especially when large-scale molecular features are available.

6.
Nat Commun ; 10(1): 380, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670690

RESUMO

Knowledge of cell type composition in disease relevant tissues is an important step towards the identification of cellular targets of disease. We present MuSiC, a method that utilizes cell-type specific gene expression from single-cell RNA sequencing (RNA-seq) data to characterize cell type compositions from bulk RNA-seq data in complex tissues. By appropriate weighting of genes showing cross-subject and cross-cell consistency, MuSiC enables the transfer of cell type-specific gene expression information from one dataset to another. When applied to pancreatic islet and whole kidney expression data in human, mouse, and rats, MuSiC outperformed existing methods, especially for tissues with closely related cell types. MuSiC enables the characterization of cellular heterogeneity of complex tissues for understanding of disease mechanisms. As bulk tissue data are more easily accessible than single-cell RNA-seq, MuSiC allows the utilization of the vast amounts of disease relevant bulk tissue RNA-seq data for elucidating cell type contributions in disease.


Assuntos
Perfilação da Expressão Gênica/métodos , Expressão Gênica , Teste de Histocompatibilidade/métodos , Análise de Célula Única/métodos , Animais , Doença , Humanos , Ilhotas Pancreáticas/citologia , Rim/citologia , Camundongos , Modelos Teóricos , Ratos , Análise de Sequência de RNA/métodos
7.
Stroke ; 50(3): 745-749, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30661491

RESUMO

Background and Purpose- We try to evaluate whether plaque features and perforator stroke after intracranial stenting is associated with the arterial remodeling patterns in patients with severe basilar artery stenosis. Methods- We studied patients with symptomatic intracranial arterial stenosis who underwent high-resolution magnetic resonance imaging from September 2014 to January 2017. Among them, patients with basilar artery stenosis underwent angioplasty and stenting were recruited. Arterial remodeling patterns were divided into negative or nonnegative remodeling. Plaque features were investigated by high-resolution magnetic resonance imaging, which includes plaque distribution, intraplaque hemorrhage, calcification, as well as enhancement patterns. Incidence of perforator strokes after intracranial stenting was recorded. Plaque features and incidence of poststenting perforator stroke were compared between negative and nonnegative remodeling. Results- Two hundred ninety-eight consecutive patients were enrolled. Among them, 30 patients fulfilled the inclusion criteria. There were 11 patients (36.7%) with negative remodeling and 19 (63.3%) with nonnegative remodeling. Twenty-six patients (86.7%) had diffuse distribution, 5 patients (16.7%) had intraplaque hemorrhage, 2 patients (6.7%) had calcification, and 17 patients (65.4%) had enhancement. Three patients had perforator stroke after stenting. Plaque features were similar between negative and nonnegative remodeling groups. Patients with negative remodeling were more likely to have perforator stroke after stenting comparing with patients with nonnegative remodeling (27.3% versus 0%, P=0.041). Conclusions- Perforator stroke after basilar artery stenting may be related to negative remodeling on high-resolution magnetic resonance imaging. The finding needs to be confirmed in future studies. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02705599.

8.
Circ Genom Precis Med ; 11(11): e001907, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30571184

RESUMO

BACKGROUND: Cytokine responses to activation of innate immunity differ between individuals, yet the genomic and tissue-specific transcriptomic determinants of inflammatory responsiveness are not well understood. We hypothesized that tissue-specific mRNA and long intergenic noncoding RNA (lincRNA) induction differs between individuals with divergent evoked inflammatory responses. METHODS: In the GENE Study (Genetics of Evoked Response to Niacin and Endotoxemia), we performed an inpatient endotoxin challenge (1 ng/kg lipopolysaccharide [LPS]) in healthy humans. We selected individuals in the top (high responders) and bottom (low responders) extremes of inflammatory responses and applied RNA sequencing to CD14 monocytes (N=15) and adipose tissue (N=25) before and after LPS administration. RESULTS: Although only a small number of genes were differentially expressed at baseline, there were clear differences in the magnitude of the transcriptional response post-LPS between high and low responders, with a far greater number of genes differentially expressed by endotoxemia in high responders. Furthermore, tissue responses differed during inflammation, and we found a number of tissue-specific differentially expressed lincRNAs post-LPS, which we validated. Relative to nondifferentially expressed lincRNAs, differentially expressed lincRNAs were equally likely to be nonconserved as conserved between human and mouse, indicating that conservation is not a predictor of lincRNAs associated with human inflammatory pathophysiology. Differentially expressed genes also were enriched for signals with inflammatory and cardiometabolic disease in published genome-wide association studies. CTB-41I6.2 ( AC002091.1), a nonconserved human-specific lincRNA, is one of the top lincRNAs regulated by endotoxemia in monocytes, but not in adipose tissue. Knockdown experiments in THP-1 monocytes suggest that this lincRNA enhances LPS-induced interleukin 6 ( IL6) expression in monocytes, and we now refer to this as monocyte LPS-induced lincRNA regulator of IL6 ( MOLRIL6). CONCLUSIONS: We highlight mRNAs and lincRNAs that represent novel candidates for modulation of innate immune and metabolic responses in humans. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00953667.


Assuntos
Tecido Adiposo/imunologia , Endotoxemia , Regulação da Expressão Gênica/imunologia , Monócitos/imunologia , RNA Longo não Codificante , RNA Mensageiro , Tecido Adiposo/patologia , Animais , Endotoxemia/genética , Endotoxemia/imunologia , Endotoxemia/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata/genética , Inflamação/genética , Inflamação/imunologia , Masculino , Camundongos , Monócitos/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Análise de Sequência de RNA
9.
J Am Heart Assoc ; 7(23): e009169, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30571596

RESUMO

Background The role of adipokine dysregulation in determining the metabolic fate of obesity is not well studied. We aimed to examine whether the matricellular protein osteonectin and the profiles of certain adipokines could differentiate metabolically healthy obese ( MHO ) versus metabolically unhealthy obese phenotypes in childhood. Methods and Results This study included 1137 obese children and 982 normal-weight healthy ( NWH ) controls recruited from the BCAMS (Beijing Child and Adolescent Metabolic Syndrome) study. MHO was defined by the absence of insulin resistance and/or any metabolic syndrome components. Six adipokines-osteonectin, leptin, adiponectin, resistin, FGF21 (fibroblast growth factor 21), and RBP-4 (retinol binding protein 4)-were assessed. Approximately 20% of obese children displayed the MHO phenotype. MHO children had a more favorable adipokine profile than metabolically unhealthy obese children, with lower osteonectin, leptin, and RBP -4 and higher adiponectin (all P<0.05). Compared with normal-weight healthy controls, MHO children displayed increased leptin, resistin, and RBP -4 levels and reduced adiponectin concentrations (all P<0.05) but similar osteonectin and FGF 21 levels. Among obese subjects, decreased osteonectin (odds ratio [OR]: 0.82; 95% confidence interval [CI] per standard deviation, 0.70-0.97), RBP -4 (OR: 0.77; 95% CI per standard deviation, 0.64-0.93), and leptin/adiponectin ratio (OR: 0.58; 95% CI per standard deviation, 0.43-0.77) were independent predictors of MHO . In addition, compared with children without abnormalities, those with any 3 adipokine abnormalities were 80% less likely to exhibit the MHO phenotype ( OR : 0.20; 95% CI , 0.10-0.43) and 3 times more likely to have metabolic syndrome ( OR : 2.77; 95% CI , 1.52-5.03). Conclusions These findings suggest that dysregulation of adipokines might govern the metabolic consequences of obesity in children. Low osteonectin levels, along with a healthy adipokine profile, might be used as an early marker of the MHO phenotype.

10.
Clin Cancer Res ; 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30181385

RESUMO

Purpose: Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3-ITD mutations might not guarantee effective clinical response. Motivated by the heterogeneity of FLT3-ITD mutations, we investigated the effects of FLT3-ITD structural features on the response of AML patients to treatment.Experimental Design: We developed the HeatITup (HEAT diffusion for Internal Tandem dUPlication) algorithm to identify and quantitate ITD structural features including nucleotide composition. Using HeatITup, we studied the impact of ITD structural features on the clinical response to FLT3i and induction chemotherapy in FLT3-ITD-positive AML patients.Results: HeatITup accurately identifies and classifies ITDs into newly defined categories of "typical" or "atypical" based on their nucleotide composition. A typical ITD's insert sequence completely matches the wild-type FLT3, whereas an atypical ITD's insert contains nucleotides exogenous to the wild-type FLT3 Our analysis shows marked divergence between typical and atypical ITD mutation features. Furthermore, our data suggest that AML patients carrying typical FLT3-ITDs benefited significantly more from both FLT3i and induction chemotherapy treatments than patients with atypical FLT3-ITDs.Conclusions: These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing toward personalized treatment of AML patients, and enable researchers and clinicians to unravel ITD complexity using the provided software. Clin Cancer Res; 1-11. ©2018 AACR.

11.
Cancer Res ; 78(21): 6171-6182, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30154145

RESUMO

Breast cancer brain metastases are a deadly sequela of primary breast tumors that overexpress human epidermal growth factor receptor 2 (HER2); median survival for patients with these tumors is 10 to 13 months from the time of diagnosis. Current treatments for HER2-positive breast cancer brain metastases are invasive, toxic, and largely ineffective. Here, we have developed an adeno-associated virus serotype 9 (AAV9) vector to express the anti-HER2 monoclonal antibody trastuzumab (Herceptin) in vivo A single prophylactic intrathecal administration of AAV9.trastuzumab vector in a novel orthotopic Rag1-/- murine xenograft model of HER2-positive breast cancer brain metastases significantly increased median survival, attenuated brain tumor growth, and preserved both the HER2 antigen specificity and the natural killer cell-associated mechanism of action of trastuzumab. When administered as a tumor treatment, AAV9.trastuzumab increased median survival. Dose-escalation studies revealed that higher doses of AAV9.trastuzumab resulted in smaller tumor volumes. Our results indicate that intrathecal AAV9.trastuzumab may provide significant antitumor activity in patients with HER2-positive breast cancer brain metastases.Significance: Intrathecal delivery of trastuzumab via adeno-associated virus has the potential to become a novel, integral part of adjuvant therapy for patients with HER2-positive breast cancer brain metastases. Cancer Res; 78(21); 6171-82. ©2018 AACR.

12.
Hum Gene Ther Methods ; 29(5): 201-211, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30051733

RESUMO

Sequence validation of plasmid DNA is a crucial quality control step that must occur prior to adeno-associated virus (AAV) vector packaging through plasmid transfection. AAV cis-plasmids present unique challenges to sequence analysis, as they contain inverted terminal repeats and are prone to sequence rearrangements. An accurate and rapid next-generation sequencing approach has been established to analyze full-length sequences of AAV cis-plasmids within 3.5 days. Here, a step-by-step protocol is described that can reliably detect and identify the location and frequency of sequence variants commonly observed in AAV cis-plasmids.

13.
Nat Biotechnol ; 36(8): 717-725, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29985478

RESUMO

Clinical translation of in vivo genome editing to treat human genetic diseases requires thorough preclinical studies in relevant animal models to assess safety and efficacy. A promising approach to treat hypercholesterolemia is inactivating the secreted protein PCSK9, an antagonist of the LDL receptor. Here we show that single infusions in six non-human primates of adeno-associated virus vector expressing an engineered meganuclease targeting PCSK9 results in dose-dependent disruption of PCSK9 in liver, as well as a stable reduction in circulating PCSK9 and serum cholesterol. Animals experienced transient, asymptomatic elevations of serum transaminases owing to the formation of T cells against the transgene product. Vector DNA and meganuclease expression declined rapidly, leaving stable populations of genome-edited hepatocytes. A second-generation PCSK9-specific meganuclease showed reduced off-target cleavage. These studies demonstrate efficient, physiologically relevant in vivo editing in non-human primates, and highlight safety considerations for clinical translation.

14.
Sci Transl Med ; 10(446)2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925637

RESUMO

Long intergenic noncoding RNAs (lincRNAs) have emerged as important modulators of cellular functions. Most lincRNAs are not conserved among mammals, raising the fundamental question of whether nonconserved adipose-expressed lincRNAs are functional. To address this, we performed deep RNA sequencing of gluteal subcutaneous adipose tissue from 25 healthy humans. We identified 1001 putative lincRNAs expressed in all samples through de novo reconstruction of noncoding transcriptomes and integration with existing lincRNA annotations. One hundred twenty lincRNAs had adipose-enriched expression, and 54 of these exhibited peroxisome proliferator-activated receptor γ (PPARγ) or CCAAT/enhancer binding protein α (C/EBPα) binding at their loci. Most of these adipose-enriched lincRNAs (~85%) were not conserved in mice, yet on average, they showed degrees of expression and binding of PPARγ and C/EBPα similar to those displayed by conserved lincRNAs. Most adipose lincRNAs differentially expressed (n = 53) in patients after bariatric surgery were nonconserved. The most abundant adipose-enriched lincRNA in our subcutaneous adipose data set, linc-ADAL, was nonconserved, up-regulated in adipose depots of obese individuals, and markedly induced during in vitro human adipocyte differentiation. We demonstrated that linc-ADAL interacts with heterogeneous nuclear ribonucleoprotein U (hnRNPU) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) at distinct subcellular locations to regulate adipocyte differentiation and lipogenesis.

15.
Eur Neuropsychopharmacol ; 28(8): 892-902, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29891216

RESUMO

The mechanisms by which obesity increases the risk of psychosocial disorders remain unclear. We aimed at exploring the association between obesity and self-concept in Chinese youths and the role of adipokines. Data for 559 participants (aged 14-28 years) were analyzed. Self-concept was assessed by utilizing the Self-Description Questionnaire II (SDQ-II). Subjects with obesity had higher leptin, FGF21 and lower adiponectin levels (all p < 0.001). They also had lower SDQ-II scores especially in the domains of general school, physical abilities, physical appearance and opposite-sex relations (all p < 0.001). Both elevated FGF21 and leptin were correlated with lower scores in math (p < 0.01), physical abilities (p < 0.01), and opposite-sex relations (p < 0.05), meanwhile FGF21 negatively correlated with the scores in general school and honesty/trustworthiness, and leptin negatively correlated with physical appearance (p < 0.01) but positively with verbal (p < 0.01). In contrast, decreased adiponectin was correlated with poorer physical abilities (p < 0.05), physical appearance (p < 0.05), and parent relations (p < 0.01). Moreover, these associations of leptin, FGF21 and adiponectin with certain domains remained significant after adjustment for BMI and other metabolic confounders. In conclusion, youths with obesity experienced poorly on self-concept, and these associations may be explained in part by adipokines leptin, FGF21 and adiponectin.

16.
Proc Natl Acad Sci U S A ; 115(28): E6437-E6446, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946020

RESUMO

Single-cell RNA sequencing (scRNA-seq) enables the quantification of each gene's expression distribution across cells, thus allowing the assessment of the dispersion, nonzero fraction, and other aspects of its distribution beyond the mean. These statistical characterizations of the gene expression distribution are critical for understanding expression variation and for selecting marker genes for population heterogeneity. However, scRNA-seq data are noisy, with each cell typically sequenced at low coverage, thus making it difficult to infer properties of the gene expression distribution from raw counts. Based on a reexamination of nine public datasets, we propose a simple technical noise model for scRNA-seq data with unique molecular identifiers (UMI). We develop deconvolution of single-cell expression distribution (DESCEND), a method that deconvolves the true cross-cell gene expression distribution from observed scRNA-seq counts, leading to improved estimates of properties of the distribution such as dispersion and nonzero fraction. DESCEND can adjust for cell-level covariates such as cell size, cell cycle, and batch effects. DESCEND's noise model and estimation accuracy are further evaluated through comparisons to RNA FISH data, through data splitting and simulations and through its effectiveness in removing known batch effects. We demonstrate how DESCEND can clarify and improve downstream analyses such as finding differentially expressed genes, identifying cell types, and selecting differentiation markers.


Assuntos
Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Modelos Genéticos , RNA/biossíntese , RNA/genética , Animais , Humanos
17.
Nat Methods ; 15(7): 539-542, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29941873

RESUMO

In single-cell RNA sequencing (scRNA-seq) studies, only a small fraction of the transcripts present in each cell are sequenced. This leads to unreliable quantification of genes with low or moderate expression, which hinders downstream analysis. To address this challenge, we developed SAVER (single-cell analysis via expression recovery), an expression recovery method for unique molecule index (UMI)-based scRNA-seq data that borrows information across genes and cells to provide accurate expression estimates for all genes.

18.
EBioMedicine ; 32: 164-171, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29903569

RESUMO

Left ventricular mass index (LVMI) provides a metric for cardiovascular disease risk. We aimed to assess the association of adiponectin-related genetic variants resulting from GWAS in East Asians (loci in/near CDH13, ADIPOQ, WDR11FGF, CMIP and PEPD) with LVMI, and to examine whether sleep duration modified these genetic associations in youth. The 559 subjects aged 15-28 years were recruited from the Beijing Child and Adolescent Metabolic Syndrome study. Among the six loci, CDH13 rs4783244 was significantly correlated with adiponectin levels (p = 8.07 × 10-7). The adiponectin-rising allele in rs4783244 locus was significantly associated with decreased LVMI (p = 6.99 × 10-4) after adjusting for classical cardiovascular risk factors, and further for adiponectin levels, while no significant association was found between the other loci and LVMI. Moreover, we observed a significant interaction effect between rs4783244 and sleep duration (p = .005) for LVMI; the genetic association was more evident in long sleep duration while lost in short sleep duration. Similar interaction was found in the subgroup analysis using longitudinal data (p = .025 for interaction). In this young Chinese population, CDH13 rs4783244 represents a key locus for cardiac structure, and confers stronger cardio-protection in longer sleep duration when contrasted with short sleep duration.


Assuntos
Caderinas/genética , Doenças Cardiovasculares/genética , Ventrículos do Coração/metabolismo , Síndrome Metabólica/genética , Adolescente , Adulto , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Feminino , Estudos de Associação Genética , Ventrículos do Coração/anatomia & histologia , Humanos , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Fatores de Risco , Sono/genética , Adulto Jovem
19.
Circ Res ; 122(12): 1632-1634, 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29880495
20.
Cardiovasc Diabetol ; 17(1): 69, 2018 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-29759068

RESUMO

BACKGROUND: Elevated retinol-binding protein 4 (RBP4) levels may contribute to the development of metabolic abnormalities, but prospective studies evaluating the association between childhood RBP4 levels and metabolic syndrome (MS) in adulthood are lacking. We investigated whether RBP4 levels during childhood predict cardiometabolic risk at 10-year follow-up. METHODS: The relationships between RBP4 levels, the established adipokines (leptin and adiponectin) and the components of MS were examined in 3445 school-aged children recruited in 2004 for the Beijing Child and Adolescent Metabolic Syndrome study. In 2015, 352 of these individuals completed an in-depth follow-up examination. RESULTS: Participants with higher childhood RBP4 levels had adverse cardiometabolic profiles at follow-up. Those with incident or persistent MS had higher baseline RBP4 levels than those who never exhibited the elements of MS. Moreover, baseline RBP4 predicted hyperglycemia (OR per SD increase = 1.48, P = 0.009), elevated triglyceride (OR = 1.54, P < 0.001), elevated blood pressures (OR = 1.46, P = 0.015), MS (OR = 1.68, P = 0.002) and insulin resistance (OR = 1.44, P = 0.015) in the 10-year follow-up phase, independent of baseline BMI. Significant improvements were seen for the net reclassification improvement and integrated discrimination index after adding childhood RBP4 levels into the risk models using conventional cardiometabolic risk factors in predicting MS at follow-up (P < 0.05). Leptin and adiponectin demonstrated the expected associations with metabolic disorders. CONCLUSIONS: Childhood RBP4 serves as a risk factor for subsequent development of MS and its components, independent of pediatric obesity. Incorporating childhood RBP4 into conventional cardiometabolic risk assessment models significantly improves the prediction of MS.

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