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1.
EMBO J ; 40(5): e106309, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33459381

RESUMO

The N6-methyladenosine (m6 A) RNA modification serves crucial functions in RNA metabolism; however, the molecular mechanisms underlying the regulation of m6 A are not well understood. Here, we establish arginine methylation of METTL14, a component of the m6 A methyltransferase complex, as a novel pathway that controls m6 A deposition in mammalian cells. Specifically, protein arginine methyltransferase 1 (PRMT1) interacts with, and methylates the intrinsically disordered C terminus of METTL14, which promotes its interaction with RNA substrates, enhances its RNA methylation activity, and is crucial for its interaction with RNA polymerase II (RNAPII). Mouse embryonic stem cells (mESCs) expressing arginine methylation-deficient METTL14 exhibit significantly reduced global m6 A levels. Transcriptome-wide m6 A analysis identified 1,701 METTL14 arginine methylation-dependent m6 A sites located in 1,290 genes involved in various cellular processes, including stem cell maintenance and DNA repair. These arginine methylation-dependent m6 A sites are associated with enhanced translation of genes essential for the repair of DNA interstrand crosslinks; thus, METTL14 arginine methylation-deficient mESCs are hypersensitive to DNA crosslinking agents. Collectively, these findings reveal important aspects of m6 A regulation and new functions of arginine methylation in RNA metabolism.


Assuntos
Adenosina/análogos & derivados , Arginina/química , Metiltransferases/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/metabolismo , RNA Polimerase II/metabolismo , Adenosina/química , Animais , Citoplasma , Metiltransferases/química , Metiltransferases/genética , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Proteína-Arginina N-Metiltransferases/genética , RNA Polimerase II/genética , Transcriptoma
2.
Genome Res ; 31(6): 1106-1119, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33832989

RESUMO

Steps of mRNA maturation are important gene regulatory events that occur in distinct cellular locations. However, transcriptomic analyses often lose information on the subcellular distribution of processed and unprocessed transcripts. We generated extensive RNA-seq data sets to track mRNA maturation across subcellular locations in mouse embryonic stem cells, neuronal progenitor cells, and postmitotic neurons. We find disparate patterns of RNA enrichment between the cytoplasmic, nucleoplasmic, and chromatin fractions, with some genes maintaining more polyadenylated RNA in chromatin than in the cytoplasm. We bioinformatically defined four regulatory groups for intron retention, including complete cotranscriptional splicing, complete intron retention in the cytoplasmic RNA, and two intron groups present in nuclear and chromatin transcripts but fully excised in cytoplasm. We found that introns switch their regulatory group between cell types, including neuronally excised introns repressed by polypyrimidine track binding protein 1 (PTBP1). Transcripts for the neuronal gamma-aminobutyric acid (GABA) B receptor, 1 (Gabbr1) are highly expressed in mESCs but are absent from the cytoplasm. Instead, incompletely spliced Gabbr1 RNA remains sequestered on chromatin, where it is bound by PTBP1, similar to certain long noncoding RNAs. Upon neuronal differentiation, Gabbr1 RNA becomes fully processed and exported for translation. Thus, splicing repression and chromatin anchoring of RNA combine to allow posttranscriptional regulation of Gabbr1 over development. For this and other genes, polyadenylated RNA abundance does not indicate functional gene expression. Our data sets provide a rich resource for analyzing many other aspects of mRNA maturation in subcellular locations and across development.


Assuntos
Precursores de RNA , Splicing de RNA , Animais , Núcleo Celular/genética , Núcleo Celular/metabolismo , Genes Controladores do Desenvolvimento , Íntrons/genética , Camundongos , Precursores de RNA/genética , Precursores de RNA/metabolismo
3.
Molecules ; 29(16)2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39202799

RESUMO

Single-atom catalysts (SACs) have attracted extensive attention due to their unique catalytic properties and wide range of applications. Advanced characterization techniques, such as energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, scanning electron microscopy, and X-ray absorption fine-structure spectroscopy, have been used to investigate the elemental compositions, structural morphologies, and chemical bonding states of SACs in detail, aiming at unraveling the catalytic mechanism. Meanwhile, theoretical calculations, such as quantum chemical calculations and kinetic simulations, were used to predict the catalytic reaction pathways, active sites, and reaction kinetic behaviors of SACs, providing theoretical guidance for the design and optimization of SACs. This review overviews advanced characterization techniques and theoretical calculations for SACs in Fenton-like chemistry. Moreover, this work highlights the importance of advanced characterization techniques and theoretical calculations in the study of SACs and provides perspectives on the potential applications of SACs in the field of environmental remediation and the challenges of practical engineering.

4.
Molecules ; 29(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38474463

RESUMO

Developing a green, low-carbon, and circular economic system is the key to achieving carbon neutrality. This study investigated the organics removal efficiency in a three-dimensional electrode reactor (3DER) constructed from repurposed industrial solid waste, i.e., Mn-loaded steel slag, as the catalytic particle electrodes (CPE). The CPE, a micron-grade material consisting primarily of transition metals, including Fe and Mn, exhibited excellent electric conductivity, catalytic ability, and recyclability. High rhodamine B (RhB) removal efficiency in the 3DER was observed through a physical modelling experiment. The optimal operating condition was determined through a single-factor experiment in which 5.0 g·L-1 CPE and 3 mM peroxymonosulfate (PMS) were added to a 200 mL solution of 10 mM RhB under a current intensity of 0.5 A and a 1.5 to 2.0 cm distance between the 2D electrodes. When the initial pH value of the simulated solution was 3 to 9, the RhB removal rate exceeded 96% after 20 min reaction. In addition, the main reactive oxidation species in the 3DER were determined. The results illustrated that HO• and SO4•- both existed, but that the contribution of SO4•- to RhB removal was much lower than that of HO• in the 3DER. In summary, this research provides information on the potential of the 3DER for removing refractory organics from water.

5.
Eur J Orthop Surg Traumatol ; 34(6): 3215-3216, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39209983

RESUMO

PURPOSE: To improve the scientificity and accuracy of this study. METHOD: We studied the research methods of the article by carefully reading the author 's article and consulting the relevant literature. RESULT: The authors performed an excellent and meaningful work, finding that FNS appeared advantageous over CCS in Harris Hip Scores (HHS), operative time, and reoperation rates, providing clinicians with a basis for selecting internal fixation methods. It is a useful reference, but there are still some problems. CONCLUSION: In order to improve the scientific nature of the study, we believe that some aspects may need to be improved.


Assuntos
Parafusos Ósseos , Fraturas do Colo Femoral , Fixação Interna de Fraturas , Reoperação , Fraturas do Colo Femoral/cirurgia , Humanos , Fixação Interna de Fraturas/instrumentação , Fixação Interna de Fraturas/métodos , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Duração da Cirurgia , Feminino , Masculino
6.
Am J Hum Genet ; 107(2): 196-210, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32589925

RESUMO

A major question in human genetics is how sequence variants of broadly expressed genes produce tissue- and cell type-specific molecular phenotypes. Genetic variation of alternative splicing is a prevalent source of transcriptomic and proteomic diversity in human populations. We investigated splicing quantitative trait loci (sQTLs) in 1,209 samples from 13 human brain regions, using RNA sequencing (RNA-seq) and genotype data from the Genotype-Tissue Expression (GTEx) project. Hundreds of sQTLs were identified in each brain region. Some sQTLs were shared across brain regions, whereas others displayed regional specificity. These "regionally ubiquitous" and "regionally specific" sQTLs showed distinct positional distributions of single-nucleotide polymorphisms (SNPs) within and outside essential splice sites, respectively, suggesting their regulation by distinct molecular mechanisms. Integrating the binding motifs and expression patterns of RNA binding proteins with exon splicing profiles, we uncovered likely causal variants underlying brain region-specific sQTLs. Notably, SNP rs17651213 created a putative binding site for the splicing factor RBFOX2 and was associated with increased splicing of MAPT exon 3 in cerebellar tissues, where RBFOX2 was highly expressed. Overall, our study reveals a more comprehensive spectrum and regional variation of sQTLs in human brain and demonstrates that such regional variation can be used to fine map potential causal variants of sQTLs and their associated neurological diseases.


Assuntos
Encéfalo/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Splicing de RNA/genética , Éxons/genética , Humanos , Proteômica/métodos , Proteínas de Ligação a RNA/genética , Transcriptoma/genética
7.
Nat Methods ; 16(4): 307-310, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30923373

RESUMO

A major limitation of RNA sequencing (RNA-seq) analysis of alternative splicing is its reliance on high sequencing coverage. We report DARTS (https://github.com/Xinglab/DARTS), a computational framework that integrates deep-learning-based predictions with empirical RNA-seq evidence to infer differential alternative splicing between biological samples. DARTS leverages public RNA-seq big data to provide a knowledge base of splicing regulation via deep learning, thereby helping researchers better characterize alternative splicing using RNA-seq datasets even with modest coverage.


Assuntos
Aprendizado Profundo , Splicing de RNA , RNA/análise , Análise de Sequência de RNA , Algoritmos , Processamento Alternativo , Teorema de Bayes , Epigenômica , Éxons , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células Hep G2 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células K562 , Modelos Estatísticos , RNA/genética , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador
8.
J Environ Manage ; 302(Pt A): 114020, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731713

RESUMO

Wastewater treatment based on the activated sludge process is complex process, which is easily affected by influent quality, aeration time and other factors, leading to unstable effluent. Facing increasingly stringent sewage discharge standards in China, it is necessary to build a prediction model for early warning of effluent quality. In this study, nine machine learning algorithms were adopted to construct models for the prediction of effluent Chemical Oxygen Demand (COD). In order to improve the prediction accuracy of the models, model optimization was conducted by introducing the hysteresis condition [Hydraulic Retention Time (HRT) of 18 h], data processing method (K-FOLD) and process parameters [dissolved oxygen (DO), sludge return ratio (SRR) and mixed liquid suspended solids (MLSS)]. Results showed that both K-Nearest Neighbour (KNN) and Gradient Boosting Decision Tree (GBDT) displayed excellent prediction effects, the best results of MAPE, RMSE and R2 were 7.34%/1.29/0.92(COD, KNN). The optimized models were further applied to the prediction of effluent total phosphorus (TP), total nitrogen (TN) and pH. The MAPE/RMSE/R2 were 7.43%/0.92/0.93(TN, GBDT), 17.81%/0.19/0.99(TP, KNN), 0.53%/0.16/0.99 (pH, KNN) respectively, indicating high prediction accuracy. The change and comparison of modeling conditions provide a new insight to wastewater prediction models. In addition, this study is close to the actual application scenario of WWTPs operation and management, also laying a foundation for the reverse regulation of energy saving and consumption reduction of wastewater treatment plants (WWTPs).


Assuntos
Eliminação de Resíduos Líquidos , Purificação da Água , Análise da Demanda Biológica de Oxigênio , Reatores Biológicos , Nitrogênio , Esgotos/análise , Águas Residuárias
9.
Am J Hum Genet ; 102(1): 11-26, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29304370

RESUMO

Alternative splicing is a tightly regulated biological process by which the number of gene products for any given gene can be greatly expanded. Genomic variants in splicing regulatory sequences can disrupt splicing and cause disease. Recent developments in sequencing technologies and computational biology have allowed researchers to investigate alternative splicing at an unprecedented scale and resolution. Population-scale transcriptome studies have revealed many naturally occurring genetic variants that modulate alternative splicing and consequently influence phenotypic variability and disease susceptibility in human populations. Innovations in experimental and computational tools such as massively parallel reporter assays and deep learning have enabled the rapid screening of genomic variants for their causal impacts on splicing. In this review, we describe technological advances that have greatly increased the speed and scale at which discoveries are made about the genetic variation of alternative splicing. We summarize major findings from population transcriptomic studies of alternative splicing and discuss the implications of these findings for human genetics and medicine.


Assuntos
Processamento Alternativo/genética , Variação Genética , Genética Populacional , Doença/genética , Estudos de Associação Genética , Humanos , Aprendizado de Máquina , Fenótipo , Locos de Características Quantitativas/genética , Análise de Sequência de RNA , Transcriptoma/genética
10.
Int J Med Sci ; 17(15): 2328-2337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922198

RESUMO

Background: Dilated cardiomyopathy (DCM) is considered as the most common form of non-ischemic cardiomyopathy with a high mortality worldwide. Cytoskeleton protein Cypher plays an important role in maintaining cardiac function. Genetic studies in human and animal models revealed that Cypher is involved in the development of DCM. However, the underlying molecular mechanism is not fully understood. Accumulating evidences suggest that apoptosis in myocytes may contribute to DCM. Thus, the purpose of this study is to define whether lack of Cypher in cardiomyocytes can elevate apoptosis signaling and lead to DCM eventually. Methods and Results: Cypher-siRNA sufficiently inhibited Cypher expression in cardiomyocytes. TUNEL-positive cardiomyocytes were increased in both Cypher knockdown neonatal rat cardiomyocytes and Cypher knockout mice hearts, which were rare in the control group. Flow cytometry further confirmed that downregulation of Cypher significantly increased myocytes apoptosis in vitro. Cell counting kit-8 assay revealed that Cypher knockdown in H9c2 cells significantly reduced cell viability. Cypher knockdown was found to increase cleaved caspase-3 expression and suppress p21, ratio of bcl-2 to Bax. Cypher-deficiency induced apoptosis was linked to downregulation of Akt activation and elevated p-p38 MAPK accumulation. Pharmacological activation of Akt with SC79 attenuated apoptosis with enhanced phosphorylation of Akt and reduced p-p38 MAPK and Bax expression. Conclusions: Downregulation of Cypher participates in the promotion of cardiomyocytes apoptosis through inhibiting Akt dependent pathway and enhancing p38 MAPK phosphorylation. These findings may provide a new potential therapeutic strategy for the treatment of DCM.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Cardiomiopatia Dilatada/patologia , Proteínas com Domínio LIM/deficiência , Miócitos Cardíacos/patologia , Acetatos/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Benzopiranos/farmacologia , Cardiomiopatia Dilatada/genética , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Proteínas com Domínio LIM/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miocárdio/citologia , Miocárdio/patologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/agonistas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(1): 113-117, 2020 05 25.
Artigo em Zh | MEDLINE | ID: mdl-32621415

RESUMO

Atherosclerosis is an important pathological basis for coronary artery disease. ANRIL is an antisense non-coding RNA located in Chr9p21 locus, which was identified as the most significant risk locus associated with atherosclerosis. ANRIL can produce multiple transcripts including linear and circular transcripts after various transcript splicing. It has been illustrated that ANRIL plays important roles in the pathology of atherosclerosis by regulating the proliferation and apoptosis of vascular cells. Linear ANRIL can regulate the proliferation of vascular smooth muscle cells (VSMCs) in plaques by chromatin modification, as well as influence the proliferation and the apoptosis of macrophages in post transcription; circular ANRIL can affect the proliferation and apoptosis of VSMCs by chromatin modification as well as interfering with rRNA maturation. In this review, we describe the ANRIL evolution, different transcripts characteristics, and their roles in the proliferation and apoptosis of vascular cells to participate in the process of atherosclerosis, for further understanding the pathogenesis of atherosclerosis and finding potential targets for diagnosis and treatment of atherosclerosis.


Assuntos
Aterosclerose , RNA Longo não Codificante , Apoptose/genética , Aterosclerose/genética , Proliferação de Células/genética , Humanos , Miócitos de Músculo Liso/patologia , RNA Longo não Codificante/metabolismo
12.
J Cell Mol Med ; 23(10): 7054-7062, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31424159

RESUMO

Idiopathic dilated cardiomyopathy (IDCM), characterized by ventricular dilation and impaired systolic function, is a primary cardiomyopathy resulting in heart failure. During heart contraction, the Z-line is responsible for transmitting force between sarcomeres and is also a hot spot for muscle cell signalling. Mutations in Z-line proteins have been linked to cardiomyopathies in both humans and mice. Actinin-associated LIM protein (ALP) and enigma homolog protein (ENH), encoded by PDLIM3 and PDLIM5, are components of the muscle cytoskeleton and localize to the Z-line. A PDLIM3 or PDLIM5 deficiency in mice leads to dilated cardiomyopathy. Since PDLIM3 and PDLIM5 are candidate IDCM susceptibility genes, the current study aims to investigate whether polymorphisms within PDLIM3 and PDLIM5 could be correlated with IDCM. We designed a case-control study, and exons of the PDLIM3 and PDLIM5 were amplified by polymerase chain reactions in 111 IDCM patients and 137 healthy controls. We found that five synonymous polymorphisms had statistical distribution differences between IDCM patients and controls, including rs4861669, rs4862543, c.731 + 131 T > G, c.1789-3 C > T and rs7690296, according to genotype and allele distribution. Haplotype G-C-C-C and A-T-C-T (rs2306705, rs10866276, rs12644280 and rs4635850 synthesized) were regarded as risk factors for IDCM patients when compared with carriers of other haplotypes (all P < .05). Furthermore, IDCM patients with two novel polymorphisms (c.731 + 131 T > G and c.1789-3 C > T) had lower systolic blood pressure. In conclusion, these five synonymous polymorphisms might constitute a genetic background that increases the risk of the development of IDCM in the Chinese Han population.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cardiomiopatia Dilatada/genética , Predisposição Genética para Doença , Proteínas com Domínio LIM/genética , Proteínas dos Microfilamentos/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Pressão Sanguínea/genética , Cardiomiopatia Dilatada/fisiopatologia , Estudos de Casos e Controles , Etnicidade/genética , Feminino , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sístole/genética
14.
Nucleic Acids Res ; 45(9): e75, 2017 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-28115622

RESUMO

Whole genome sequencing (WGS) is a promising strategy to unravel variants or genes responsible for human diseases and traits. However, there is a lack of robust platforms for a comprehensive downstream analysis. In the present study, we first proposed three novel algorithms, sequence gap-filled gene feature annotation, bit-block encoded genotypes and sectional fast access to text lines to address three fundamental problems. The three algorithms then formed the infrastructure of a robust parallel computing framework, KGGSeq, for integrating downstream analysis functions for whole genome sequencing data. KGGSeq has been equipped with a comprehensive set of analysis functions for quality control, filtration, annotation, pathogenic prediction and statistical tests. In the tests with whole genome sequencing data from 1000 Genomes Project, KGGSeq annotated several thousand more reliable non-synonymous variants than other widely used tools (e.g. ANNOVAR and SNPEff). It took only around half an hour on a small server with 10 CPUs to access genotypes of ∼60 million variants of 2504 subjects, while a popular alternative tool required around one day. KGGSeq's bit-block genotype format used 1.5% or less space to flexibly represent phased or unphased genotypes with multiple alleles and achieved a speed of over 1000 times faster to calculate genotypic correlation.


Assuntos
Algoritmos , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Humanos
15.
Cell Physiol Biochem ; 46(6): 2271-2283, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29734192

RESUMO

BACKGROUND/AIMS: Skeletal muscle plays an essential role in the body movement. However, injuries to the skeletal muscle are common. Lifelong maintenance of skeletal muscle function largely depends on preserving the regenerative capacity of muscle. Muscle satellite cells proliferation, differentiation, and myoblast fusion play an important role in muscle regeneration after injury. Therefore, understanding of the mechanisms associated with muscle development during muscle regeneration is essential for devising the alternative treatments for muscle injury in the future. METHODS: Edu staining, qRT-PCR and western blot were used to evaluate the miR-27b effects on pig muscle satellite cells (PSCs) proliferation and differentiation in vitro. Then, we used bioinformatics analysis and dual-luciferase reporter assay to predict and confirm the miR-27b target gene. Finally, we elucidate the target gene function on muscle development in vitro and in vivo through Edu staining, qRT-PCR, western blot, H&E staining and morphological observation. RESULT: miR-27b inhibits PSCs proliferation and promotes PSCs differentiation. And the miR-27b target gene, MDFI, promotes PSCs proliferation and inhibits PSCs differentiation in vitro. Furthermore, interfering MDFI expression promotes mice muscle regeneration after injury. CONCLUSION: our results conclude that miR-27b promotes PSCs myogenesis by targeting MDFI. These results expand our understanding of muscle development mechanism in which miRNAs and genes work collaboratively in regulating skeletal muscle development. Furthermore, this finding has implications for obtaining the alternative treatments for patients with the muscle injury.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Desenvolvimento Muscular , Fatores de Regulação Miogênica/genética , Células Satélites de Músculo Esquelético/citologia , Suínos/genética , Animais , Proliferação de Células , Células Cultivadas , Masculino , Células Satélites de Músculo Esquelético/metabolismo , Suínos/fisiologia
16.
Mol Cell Biochem ; 437(1-2): 45-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28653238

RESUMO

Endothelial inflammation and monocyte plays an essential role in the initiation and progression of atherosclerosis. Ghrelin is beneficial for atherosclerosis progression. However, the detailed and precise molecular mechanisms of how ghrelin regulates endothelial inflammation are not clear. In this study, we investigated the regulation mechanism of ghrelin on TNF-α-activated endothelial inflammation and monocyte adhesion. It was found that TNF-α-induced monocyte adhesion on HUVEC was significantly attenuated by ghrelin. Furthermore, we found that ghrelin effectively suppressed TNF-α-induced inflammatory factors' (including ICAM-1, VCAM-1, MCP-1, and IL-1ß) expression through inhibiting AMPK phosphorylation and p65 expression both in HUVEC and THP-1. This phenomenon was further demonstrated by using AMPK agonist AICAR and inhibitor compound C, respectively. Our findings suggest that ghrelin may mediate TNF-α-induced endothelial inflammation and monocyte adhesion, in part via AMPK/NF-κB signaling pathway. These novel anti-inflammatory and immunoregulatory actions of ghrelin may play a certain role in understanding the formation and development of atherosclerosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Grelina/farmacologia , Mediadores da Inflamação/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Citocinas/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/metabolismo , Inflamação/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Células THP-1 , Molécula 1 de Adesão de Célula Vascular/metabolismo
17.
Bioinformatics ; 32(20): 3065-3071, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27354691

RESUMO

MOTIVATION: Exome sequencing studies have facilitated the detection of causal genetic variants in yet-unsolved Mendelian diseases. However, the identification of disease causal genes among a list of candidates in an exome sequencing study is still not fully settled, and it is often difficult to prioritize candidate genes for follow-up studies. The inheritance mode provides crucial information for understanding Mendelian diseases, but none of the existing gene prioritization tools fully utilize this information. RESULTS: We examined the characteristics of Mendelian disease genes under different inheritance modes. The results suggest that Mendelian disease genes with autosomal dominant (AD) inheritance mode are more haploinsufficiency and de novo mutation sensitive, whereas those autosomal recessive (AR) genes have significantly more non-synonymous variants and regulatory transcript isoforms. In addition, the X-linked (XL) Mendelian disease genes have fewer non-synonymous and synonymous variants. As a result, we derived a new scoring system for prioritizing candidate genes for Mendelian diseases according to the inheritance mode. Our scoring system assigned to each annotated protein-coding gene (N = 18 859) three pathogenic scores according to the inheritance mode (AD, AR and XL). This inheritance mode-specific framework achieved higher accuracy (area under curve = 0.84) in XL mode. CONCLUSION: The inheritance-mode specific pathogenicity prioritization (ISPP) outperformed other well-known methods including Haploinsufficiency, Recessive, Network centrality, Genic Intolerance, Gene Damage Index and Gene Constraint scores. This systematic study suggests that genes manifesting disease inheritance modes tend to have unique characteristics. AVAILABILITY AND IMPLEMENTATION: ISPP is included in KGGSeq v1.0 (http://grass.cgs.hku.hk/limx/kggseq/), and source code is available from (https://github.com/jacobhsu35/ISPP.git). CONTACT: mxli@hku.hkSupplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Genes Dominantes , Genes Recessivos , Mutação , Proteínas/genética , Área Sob a Curva , Bases de Dados Genéticas , Variação Genética , Humanos
18.
Bioinformatics ; 32(18): 2729-36, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27273672

RESUMO

MOTIVATION: Prediction and prioritization of human non-coding regulatory variants is critical for understanding the regulatory mechanisms of disease pathogenesis and promoting personalized medicine. Existing tools utilize functional genomics data and evolutionary information to evaluate the pathogenicity or regulatory functions of non-coding variants. However, different algorithms lead to inconsistent and even conflicting predictions. Combining multiple methods may increase accuracy in regulatory variant prediction. RESULTS: Here, we compiled an integrative resource for predictions from eight different tools on functional annotation of non-coding variants. We further developed a composite strategy to integrate multiple predictions and computed the composite likelihood of a given variant being regulatory variant. Benchmarked by multiple independent causal variants datasets, we demonstrated that our composite model significantly improves the prediction performance. AVAILABILITY AND IMPLEMENTATION: We implemented our model and scoring procedure as a tool, named PRVCS, which is freely available to academic and non-profit usage at http://jjwanglab.org/PRVCS CONTACT: wang.junwen@mayo.edu, jliu@stat.harvard.edu, or limx54@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Modelos Teóricos , Anotação de Sequência Molecular , Software , Evolução Biológica , Variação Genética , Humanos , RNA não Traduzido
19.
Nucleic Acids Res ; 43(Database issue): D328-34, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25392421

RESUMO

We reported an updated database of MiCroKiTS 4.0 (http://microkit.biocuckoo.org) for proteins temporally and spatially localized in distinct subcellular positions including midbody, centrosome, kinetochore, telomere and mitotic spindle during cell division/mitosis. The database was updated from our previously developed database of MiCroKit 3.0, which contained 1489 proteins mostly forming super-complexes at midbody, centrosome and kinetochore from seven eukaryotes. Since the telomere and spindle apparatus are critical for cell division, the proteins localized at the two positions were also integrated. From the scientific literature, we curated 1872 experimentally identified proteins which at least locate in one of the five positions from eight species. Then the ortholog detection was performed to identify potential MiCroKiTS proteins from 144 eukaryotic organisms, which contains 66, 45 and 33 species of animals, fungi and plants, respectively. In total, 87,983 unique proteins with corresponding localization information were integrated into the database. The primary references of experimentally identified localizations were provided and the fluorescence microscope figures for the localizations of human proteins were shown. The orthologous relations between predicted and experimental localizations were also present. Taken together, we anticipate the database can serve as a useful resource for further analyzing the molecular mechanisms during cell division.


Assuntos
Divisão Celular , Centrossomo/química , Bases de Dados de Proteínas , Cinetocoros/química , Fuso Acromático/química , Telômero/química , Animais , Humanos , Internet , Camundongos , Proteínas/análise
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