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1.
Anim Genet ; 55(3): 471-474, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38618678

RESUMO

This work aimed to identify markers and candidate genes underlying porcine digestive traits. In total, 331 pigs were genotyped by 80 K Chip data or 50 K Chip data. For apparent neutral detergent fiber digestibility, a total of 19 and 21 candidate single nucleotide polymorphisms (SNP) were respectively identified using a genome-wide efficient mixed-model association algorithm and linkage-disequilibrium adjusted kinship. Among them, three quantitative trait locus (QTL) regions were identified. For apparent acid detergent fiber digestibility, a total of 16 and 17 SNPs were identified by these two methods, respectively. Of these, three QTL regions were also identified. Moreover, two candidate genes (MST1 and LATS1), which are functionally related to intestinal homeostasis and health, were detected near these significant SNPs. Taken together, our results could provide a basis for deeper research on digestive traits in pigs.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Sus scrofa , Animais , Sus scrofa/genética , Estudo de Associação Genômica Ampla/veterinária , Digestão/genética , Desequilíbrio de Ligação , Genótipo
2.
Int J Mol Sci ; 25(2)2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38256277

RESUMO

The introduction of single-cell RNA sequencing (scRNA-seq) technology has spurred additional advancements in analyzing the cellular composition of tissues. The longissimus dorsi (LD) in pigs serves as the primary skeletal muscle for studying meat quality in the pig industry. However, the single-cell profile of porcine LD is still in its infancy stage. In this study, we profiled the transcriptomes of 16,018 cells in the LD of a newborn Suhuai pig at single-cell resolution. Subsequently, we constructed a cellular atlas of the LD, identifying 11 distinct cell populations, including endothelial cells (24.39%), myotubes (18.82%), fibro-adipogenic progenitors (FAPs, 18.11%), satellite cells (16.74%), myoblasts (3.99%), myocytes (5.74%), Schwann cells (3.81%), smooth muscle cells (3.22%), dendritic cells (2.99%), pericytes (1.86%), and neutrophils (0.33%). CellChat was employed to deduce the cell-cell interactions by evaluating the gene expression of receptor-ligand pairs across different cell types. The results show that FAPs and pericytes are the primary signal contributors in LD. In addition, we delineated the developmental trajectory of myogenic cells and examined alterations in the expression of various marker genes and molecular events throughout various stages of differentiation. Moreover, we found that FAPs can be divided into three subclusters (NR2F2-FAPs, LPL-FAPs, and TNMD-FAPs) according to their biological functions, suggesting that the FAPs could be associated with the differentiation of tendon cell. Taken together, we constructed the cellular atlas and cell communication network in LD of a newborn Suhuai pig, and analyzed the developmental trajectory of myogenic cells and the heterogeneity of FAPs subpopulation cells. This enhances our comprehension of the molecular features involved in skeletal muscle development and the meat quality control in pigs.


Assuntos
Células Endoteliais , Fibras Musculares Esqueléticas , Suínos , Animais , Diferenciação Celular , Pericitos , Análise de Sequência de RNA
3.
BMC Genomics ; 24(1): 733, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38049711

RESUMO

BACKGROUND: Eurasian pigs have undergone lineage admixture throughout history. It has been confirmed that the genes of indigenous pig breeds in China have been introduced into Western commercial pigs, providing genetic materials for breeding Western pigs. Pigs in Taihu Lake region (TL), such as the Meishan pig and Erhualian pig, serve as typical representatives of indigenous pig breeds in China due to their high reproductive performances. These pigs have also been imported into European countries in 1970 and 1980 s. They have played a positive role in improving the reproductive performances in European commercial pigs such as French Large White pigs (FLW). However, it is currently unclear if the lineage of TL pigs have been introgressed into the Danish Large White pigs (DLW), which are also known for their high reproductive performances in European pigs. To systematically identify genomic regions in which TL pigs have introgressed into DLW pigs and their physiological functions, we collected the re-sequencing data from 304 Eurasian pigs, to identify shared haplotypes between DLW and TL pigs. RESULTS: The findings revealed the presence of introgressed genomic regions from TL pigs in the genome of DLW pigs indeed. The genes annotated within these regions were found to be mainly enriched in neurodevelopmental pathways. Furthermore, we found that the 115 kb region located in SSC16 exhibited highly shared haplotypes between TL and DLW pigs. The major haplotype of TL pigs in this region could significantly improve reproductive performances in various pig populations. Around this genomic region, NDUFS4 gene was highly expressed and showed differential expression in multiple reproductive tissues between extremely high and low farrowing Erhualian pigs. This suggested that NDUFS4 gene could be an important candidate causal gene responsible for affecting the reproductive performances of DLW pigs. CONCLUSIONS: Our study has furthered our knowledge of the pattern of introgression from TL into DLW pigs and the potential effects on the fertility of DLW pigs.


Assuntos
Lagos , Sus scrofa , Suínos/genética , Animais , Sus scrofa/genética , Genoma , Fertilidade/genética , Polimorfismo de Nucleotídeo Único , Dinamarca
4.
Anim Genet ; 54(3): 295-306, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36727217

RESUMO

Meat color is an attractive trait that influences consumers' purchase decisions at the point of sale. To decipher the genetic basis of meat color traits, we performed a genome-wide association study based on low-coverage whole-genome sequencing. In total, 669 (Pietrain × Duroc) × (Landrace × Yorkshire) pigs were genotyped using low-coverage whole-genome sequencing. Single nucleotide polymorphism (SNP) calling and genotype imputation were performed using the BaseVar + STITCH channel. Six individuals with an average depth of 12.05× whole-genome resequencing were randomly selected to assess the accuracy of imputation. Heritability evaluation and genome-wide association study for meat color traits were conducted. Functional enrichment analysis of the candidate genes from genome-wide association study and integration analysis with our previous transcriptome data were conducted. The imputation accuracy parameters, allele frequency R2 , concordance rate, and dosage R2 were 0.959, 0.952, and 0.933, respectively. The heritability values of a*45 min , b*45 min , L*45 min , C*, and H0 were 0.19, 0.11, 0.06, 0.16, and 0.26, respectively. In total, 3884 significant SNPs and 15 QTL, corresponding to 382 genes, were associated with meat color traits. Functional enrichment analysis revealed that 10 genes were the potential candidates for regulating meat color. Moreover, integration analysis revealed that DMRT2, EFNA5, FGF10, and COL11A2 were the most promising candidates affecting meat color. In summary, this study provides new insights into the molecular basis of meat color traits, and provides a new theoretical basis for the molecular breeding of meat color traits in pigs.


Assuntos
Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Suínos , Animais , Carne/análise , Genótipo , Fenótipo , Polimorfismo de Nucleotídeo Único , Perfilação da Expressão Gênica , Sequenciamento Completo do Genoma
5.
Anim Genet ; 54(4): 435-445, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36911996

RESUMO

The number of ribs (NR) and carcass length (CL) are important economic traits in pig breeding programs. Pigs with a higher NR and longer CL produce greater pork yields. In the present study, Suhuai pigs with NR and CL phenotypes were genotyped using the Neogen® GGP Porcine 80 K SNP array to identify the QTL affecting NR and CL and dissect the candidate genes for the two traits. The SNP-chip data was imputed to the whole-genome sequence (iWGS) to increase the probability of identifying causal variants. Through genome-wide association studies (GWAS) based on both chip and iWGS data, significant SNPs were detected on Sus scrofa chromosome (SSC) 1, SSC4 and SSC7 for NR and on SSC5, SSC16 and SSC17 for CL. Moreover, two SNPs (H3GA0022644 and WU_10.2_7_103460706) on SSC7 detected in chip-based GWAS were significantly associated with both NR and CL. Through Bayes fine mapping, one reported QTL for NR on SSC7 and two reported QTL for CL on SSC17 were verified, and two new QTL (SSC1: 14.05-15.84 Mb and SSC4: 64.83-66.59 Mb) affecting NR and two new QTL (SSC5: 58.31-59.84 Mb and SSC16: 22.98-23.43 Mb) affecting CL were detected. According to the biological functions of genes, MTHFD1L on SSC1 and SULF1 on SSC4 are novel functional candidate genes for NR, and EMP1 on SSC5 and EGFLAM on SSC16 are novel functional candidate genes for CL. Overall, our findings provide a basis for identifying new causal genes and mutations affecting NR and CL.


Assuntos
Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Animais , Suínos/genética , Estudo de Associação Genômica Ampla/veterinária , Teorema de Bayes , Genótipo , Fenótipo , Costelas , Polimorfismo de Nucleotídeo Único , Sus scrofa/genética
6.
Clin Exp Hypertens ; 45(1): 2253381, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37652577

RESUMO

BACKGROUND: The impacts and mechanisms of morning hypertension (MHT) on the risk of new-onset atrial fibrillation (AF) in the elderly have not been clarified. We aimed to investigate an association between MHT and new-onset AF and explore a mediating effect of subclinical inflammation on this association. METHODS: From 2008 to 2010, 1789 older adults aged ≥60 years were recruited in Shandong area, China. Morning blood pressure (BP) was assessed using 24-hour ambulatory BP monitoring. MHT was defined as BP ≥ 135/85 mm Hg during the period from wake time to 0900 a.m. Subclinical inflammation was assessed by hypersensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and galectin-3. New-onset AF was rated during the follow-up period. RESULTS: Over an average 129.0 [standard deviation (SD): 21.58] months of follow-up, the hazard ratio of new-onset AF in MHT patients was 1.39 (95% confidence interval: 1.01 to 1.91) compared with non-MHT participants (Padjusted = 0.027). The risk of new-onset AF was 1.17-fold with one-SD increment of morning systolic BP. Subclinical inflammation was significantly associated with new-onset AF. The hazard ratios of new-onset AF were 2.29, 2.04, 2.08, 2.08, 2.03, and 3.25 for one-SD increment in hsCRP, TNF-α, SII, NLR, PLR, and galectin-3, respectively (Padjusted < 0.001). The analysis showed that hsCRP, TNF-α, SII, NLR, PLR, and galectin-3 separately mediated the process of MHT inducing new-onset AF (Padjusted < 0.05). CONCLUSIONS: MHT is associated with an increased risk of new-onset AF. The subclinical inflammation might play a mediating role in this association.


Assuntos
Fibrilação Atrial , Hipertensão , Idoso , Humanos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Proteína C-Reativa , Galectina 3 , Fator de Necrose Tumoral alfa , Inflamação/complicações , Hipertensão/complicações
7.
J Biol Chem ; 296: 100170, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33298525

RESUMO

Elongin is an RNA polymerase II (RNAPII)-associated factor that has been shown to stimulate transcriptional elongation in vitro. The Elongin complex is thought to be required for transcriptional induction in response to cellular stimuli and to ubiquitinate RNAPII in response to DNA damage. Yet, the impact of the Elongin complex on transcription in vivo has not been well studied. Here, we performed comprehensive studies of the role of Elongin A, the largest subunit of the Elongin complex, on RNAPII transcription genome-wide. Our results suggest that Elongin A localizes to actively transcribed regions and potential enhancers, and the level of recruitment correlated with transcription levels. We also identified a large group of factors involved in transcription as Elongin A-associated factors. In addition, we found that loss of Elongin A leads to dramatically reduced levels of serine2-phosphorylated, but not total, RNAPII, and cells depleted of Elongin A show stronger promoter RNAPII pausing, suggesting that Elongin A may be involved in the release of paused RNAPII. Our RNA-seq studies suggest that loss of Elongin A did not alter global transcription, and unlike prior in vitro studies, we did not observe a dramatic impact on RNAPII elongation rates in our cell-based nascent RNA-seq experiments upon Elongin A depletion. Taken together, our studies provide the first comprehensive analysis of the role of Elongin A in regulating transcription in vivo. Our studies also revealed that unlike prior in vitro findings, depletion of Elongin A has little impact on global transcription profiles and transcription elongation in vivo.


Assuntos
Cromatina/metabolismo , Elonguina/genética , RNA Polimerase II/genética , RNA Mensageiro/genética , Elongação da Transcrição Genética , Linhagem Celular Tumoral , Cromatina/química , Biologia Computacional/métodos , Elonguina/antagonistas & inibidores , Elonguina/metabolismo , Elementos Facilitadores Genéticos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Fosforilação , RNA Polimerase II/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Análise de Sequência de RNA , Serina/metabolismo , Transdução de Sinais
8.
FASEB J ; 35(2): e21308, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33481304

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) is a master regulator of adipogenesis and lipogenesis. To understand its roles in fiber formation and fat deposition in skeletal muscle, we successfully generated muscle-specific overexpression of PPARγ in two pig models by random insertion and CRISPR/Cas9 transgenic cloning procedures. The content of intramuscular fat was significantly increased in PPARγ pigs while had no changes on lean meat ratio. PPARγ could promote adipocyte differentiation by activating adipocyte differentiating regulators such as FABP4 and CCAAT/enhancer-binding protein (C/EBP), along with enhanced expression of LPL, FABP4, and PLIN1 to proceed fat deposition. Proteomics analyses demonstrated that oxidative metabolism of fatty acids and respiratory chain were activated in PPARγ pigs, thus, gathered more Ca2+ in PPARγ pigs. Raising of Ca2+ could result in increased phosphorylation of CAMKII and p38 MAPK in PPARγ pigs, which can stimulate MEF2 and PGC1α to affect fiber type and oxidative capacity. These results support that skeletal muscle-specific overexpression of PPARγ can promote oxidative fiber formation and intramuscular fat deposition in pigs.


Assuntos
DNA Mitocondrial/metabolismo , Músculo Esquelético/metabolismo , PPAR gama/metabolismo , Adipócitos/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Animais , Southern Blotting , Western Blotting , Proteína alfa Estimuladora de Ligação a CCAAT , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Oxirredução , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Perilipina-1/genética , Perilipina-1/metabolismo , Proteômica , Reação em Cadeia da Polimerase em Tempo Real , Suínos
9.
Biochem J ; 478(7): 1471-1484, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33769438

RESUMO

Tau pathology initiates in defined brain regions and is known to spread along neuronal connections as symptoms progress in Alzheimer's disease (AD) and other tauopathies. This spread requires the release of tau from donor cells, but the underlying molecular mechanisms remained unknown. Here, we established the interactome of the C-terminal tail region of tau and identified syntaxin 8 (STX8) as a mediator of tau release from cells. Similarly, we showed the syntaxin 6 (STX6), part of the same SNARE family as STX8 also facilitated tau release. STX6 was previously genetically linked to progressive supranuclear palsy (PSP), a tauopathy. Finally, we demonstrated that the transmembrane domain of STX6 is required and sufficient to mediate tau secretion. The differential role of STX6 and STX8 in alternative secretory pathways suggests the association of tau with different secretory processes. Taken together, both syntaxins, STX6 and STX8, may contribute to AD and PSP pathogenesis by mediating release of tau from cells and facilitating pathology spreading.


Assuntos
Doença de Alzheimer/patologia , Domínios e Motivos de Interação entre Proteínas , Proteínas Qa-SNARE/metabolismo , Via Secretória , Tauopatias/patologia , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Ligação Proteica , Proteínas Qa-SNARE/genética , Tauopatias/genética , Tauopatias/metabolismo , Proteínas tau/genética
10.
Proc Natl Acad Sci U S A ; 116(29): 14583-14592, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31249142

RESUMO

Elongation factor Paf1C regulates several stages of the RNA polymerase II (Pol II) transcription cycle, although it is unclear how it modulates Pol II distribution and progression in mammalian cells. We found that conditional ablation of Paf1 resulted in the accumulation of unphosphorylated and Ser5 phosphorylated Pol II around promoter-proximal regions and within the first 20 to 30 kb of gene bodies, respectively. Paf1 ablation did not impact the recruitment of other key elongation factors, namely, Spt5, Spt6, and the FACT complex, suggesting that Paf1 function may be mechanistically distinguishable from each of these factors. Moreover, loss of Paf1 triggered an increase in TSS-proximal nucleosome occupancy, which could impose a considerable barrier to Pol II elongation past TSS-proximal regions. Remarkably, accumulation of Ser5P in the first 20 to 30 kb coincided with reductions in histone H2B ubiquitylation within this region. Furthermore, we show that nascent RNA species accumulate within this window, suggesting a mechanism whereby Paf1 loss leads to aberrant, prematurely terminated transcripts and diminution of full-length transcripts. Importantly, we found that loss of Paf1 results in Pol II elongation rate defects with significant rate compression. Our findings suggest that Paf1C is critical for modulating Pol II elongation rates by functioning beyond the pause-release step as an "accelerator" over specific early gene body regions.


Assuntos
Proteínas de Transporte/metabolismo , RNA Polimerase II/metabolismo , Elongação da Transcrição Genética , Terminação da Transcrição Genética , Animais , Sistemas CRISPR-Cas/genética , Proteínas de Transporte/genética , Linhagem Celular , Técnicas de Inativação de Genes , Histonas/metabolismo , Camundongos , Mioblastos , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/metabolismo , Ubiquitinação/genética
11.
BMC Nurs ; 21(1): 256, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123689

RESUMO

BACKGROUND: Due to the high nursing pressure of patients with cerebral hemorrhage and the general shortage of clinical nurses, nursing support workers often participate in clinical nursing work, but the influence of nursing support workers' participation on the negative emotion, quality of life and life satisfaction of patients with intracerebral hemorrhage is unknown. METHODS: This quasi-experimental study was conducted with a pretest-posttest design. A total of 181 ICH patients admitted to our hospital from January 2022 to April 2022 were enrolled, including 81 patients receiving conventional care (CG control group) and 80 patients receiving nursing support worker participation (RG research group). All patients were recorded with self-perceived Burden Scale (SPBS), Hamilton Depression Scale (HAMD), Quality of Life Scale (SF-36), Somatic Self rating Scale (SSS), Patient self-care ability assessment scale (Barthel) and Satisfaction with life scale (SWLS) scores. RESULTS: Patients with high negative emotion were more willing to participate in clinical nursing work (p < 0.05). Nursing support workers involved in cerebral hemorrhage patients can alleviate negative emotions, improve life quality, improve life satisfaction (p < 0.05). CONCLUSION: The participation of nursing support workers can alleviate the negative emotions of ICH patients, enhance their self-management ability, and improve their life quality.

12.
FASEB J ; 33(7): 8479-8489, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30970222

RESUMO

Apolipoprotein A-I (apoA-I), the main protein constituent of HDLs, increases insulin synthesis and insulin secretion in pancreatic ß cells. ApoA-I also accepts cholesterol that effluxes from cells expressing ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1). Mice with conditional deletion of ABCA1 and ABCG1 in ß cells [ß-double knockout (DKO) mice] have increased islet cholesterol levels and reduced glucose-stimulated insulin secretion (GSIS). The project asks whether metabolic pathways are dysregulated in ß-DKO mouse islets and whether this can be corrected, and GSIS improved, by treatment with apoA-I. ß-DKO mice were treated with apoA-I or PBS, and islets were isolated for determination of GSIS. Total RNA was extracted from ß-DKO and control mouse islets for microarray analysis. Metabolic pathways were interrogated by functional enrichment analysis. ApoA-I treatment improved GSIS in ß-DKO but not control mouse islets. Plasma lipid and lipoprotein levels and islet cholesterol levels were also unaffected by treatment with apoA-I. Cholesterol metabolism, glucose metabolism, and inflammation pathways were dysregulated in ß-DKO mouse islets. This was not corrected by treatment with apoA-I. In summary, apoA-I treatment improves GSIS by a cholesterol-independent mechanism, but it does not correct metabolic dysregulation in ß-DKO mouse islets.-Hou, L., Tang, S., Wu, B. J., Ong, K.-L., Westerterp, M., Barter, P. J., Cochran, B. J., Tabet, F., Rye, K.-A. Apolipoprotein A-I improves pancreatic ß-cell function independent of the ATP-binding cassette transporters ABCA1 and ABCG1.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Apolipoproteína A-I/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Transporte Biológico/fisiologia , Colesterol/metabolismo , Glucose/metabolismo , Humanos , Inflamação/metabolismo , Insulina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipoproteínas/metabolismo , Lipoproteínas HDL/metabolismo , Masculino , Camundongos
13.
Nephrol Dial Transplant ; 34(6): 1009-1016, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29771383

RESUMO

BACKGROUND: Fibroblast growth factor 21 (FGF21) may play a role in the development of chronic kidney disease (CKD). We therefore investigated the relationship of plasma FGF21 levels with kidney function and albuminuria in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: The analysis included 5724 MESA participants ages 45-84 years between 2000 and 2002, free of clinically apparent cardiovascular disease (CVD). Participants were followed up in person at four additional clinic visits over 10 years. Plasma FGF21 levels were measured at baseline examination by enzyme-linked immunosorbent assay. Kidney function was assessed by estimated glomerular filtration rate (eGFR). Outcomes were urinary albumin:creatinine ratio (UACR) progression, incident CKD by eGFR (reaching eGFR <60 mL/min/1.73 m2 with eGFR loss rate ≥1 mL/min/1.73 m2 per year) and rapid kidney function decline (eGFR decline >5%/year). RESULTS: At baseline, higher FGF21 levels, assessed as both continuous and categorical quartile variables, were significantly associated with lower eGFR and higher UACR, after adjusting for demographic, socioeconomic and other confounding factors [adjusted mean differences of -2.63 mL/min/1.73 m2 in eGFR and 0.134 in log normally transformed UACR (mg/g) for the highest FGF21 quartile compared with the lowest quartile, all P < 0.001]. However, in longitudinal analyses, baseline FGF21 levels did not predict incident CKD by eGFR, rapid kidney function decline or UACR progression. No significant interaction with sex and race/ethnicity was found (all P > 0.05). CONCLUSIONS: Our study does not support a role of FGF21 as a biomarker for predicting kidney function decline or albuminuria in adults free of clinically apparent CVD at baseline.


Assuntos
Albuminúria/sangue , Fatores de Crescimento de Fibroblastos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/complicações , Albuminúria/etnologia , Aterosclerose/sangue , Aterosclerose/complicações , Aterosclerose/etnologia , Biomarcadores/sangue , Doenças Cardiovasculares , Progressão da Doença , Etnicidade , Feminino , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/etnologia , Urinálise
14.
PLoS Genet ; 12(1): e1005794, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26765774

RESUMO

The PAF complex (Paf1C) has been shown to regulate chromatin modifications, gene transcription, and RNA polymerase II (PolII) elongation. Here, we provide the first genome-wide profiles for the distribution of the entire complex in mammalian cells using chromatin immunoprecipitation and high throughput sequencing. We show that Paf1C is recruited not only to promoters and gene bodies, but also to regions downstream of cleavage/polyadenylation (pA) sites at 3' ends, a profile that sharply contrasted with the yeast complex. Remarkably, we identified novel, subunit-specific links between Paf1C and regulation of alternative cleavage and polyadenylation (APA) and upstream antisense transcription using RNAi coupled with deep sequencing of the 3' ends of transcripts. Moreover, we found that depletion of Paf1C subunits resulted in the accumulation of PolII over gene bodies, which coincided with APA. Depletion of specific Paf1C subunits led to global loss of histone H2B ubiquitylation, although there was little impact of Paf1C depletion on other histone modifications, including tri-methylation of histone H3 on lysines 4 and 36 (H3K4me3 and H3K36me3), previously associated with this complex. Our results provide surprising differences with yeast, while unifying observations that link Paf1C with PolII elongation and RNA processing, and indicate that Paf1C subunits could play roles in controlling transcript length through suppression of PolII accumulation at transcription start site (TSS)-proximal pA sites and regulating pA site choice in 3'UTRs.


Assuntos
Proteínas de Transporte/genética , Poliadenilação/genética , RNA Polimerase II/genética , Transcrição Gênica , Animais , Cromatina/genética , Citocinese , Metilação de DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/genética , Camundongos , Sítio de Iniciação de Transcrição , Ubiquitinação
15.
Chem Res Toxicol ; 31(12): 1332-1338, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30456946

RESUMO

Chloride channels represent a group of potential drug targets; their blockers showed significant protecting effect on impaired cells by modulating apoptosis, autophagy, and other cell signals. However, clinical drugs with chloride channel inhibitory properties have not yet been developed. Natural product extract becomes an underlying candidate satisfied the clinical requirements for its low toxicity, low cost, and abundant sources. Here, a fluorescence-based EYFP-H148Q/I153L-HeLa cell line model was constructed by molecular cloning and verified by real-time polymerase chain reaction and Western blotting assay. By using this chloride channel blocker screening model, seven hit compounds chosen from 6988 natural compounds showed the channel blocking activity. Then the hit compounds were further validated by electrophysiological patch-clamp analysis. Our study preliminarily identified PC-4 as a new chloride channel inhibitor and demonstrated the reliability and sensitivity of fluorescence-based high throughput screening technologies for discovery of biologically active compounds from natural herbal compounds.


Assuntos
Canais de Cloreto/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Potenciais de Ação/efeitos dos fármacos , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Mutagênese Sítio-Dirigida , Técnicas de Patch-Clamp , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
16.
Arterioscler Thromb Vasc Biol ; 37(12): 2333-2341, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29025709

RESUMO

OBJECTIVE: Angioplasty and stent implantation, the most common treatment for atherosclerotic lesions, have a significant failure rate because of restenosis. This study asks whether increasing plasma high-density lipoprotein (HDL) levels by inhibiting cholesteryl ester transfer protein activity with the anacetrapib analog, des-fluoro-anacetrapib, prevents stent-induced neointimal hyperplasia. APPROACH AND RESULTS: New Zealand White rabbits received normal chow or chow supplemented with 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Iliac artery endothelial denudation and bare metal steel stent deployment were performed after 2 weeks of des-fluoro-anacetrapib treatment. The animals were euthanized 4 weeks poststent deployment. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma cholesteryl ester transfer protein activity and increased plasma apolipoprotein A-I and HDL cholesterol levels by 53±6.3% and 120±19%, respectively. Non-HDL cholesterol levels were unaffected. Des-fluoro-anacetrapib treatment reduced the intimal area of the stented arteries by 43±5.6% (P<0.001), the media area was unchanged, and the arterial lumen area increased by 12±2.4% (P<0.05). Des-fluoro-anacetrapib treatment inhibited vascular smooth muscle cell proliferation by 41±4.5% (P<0.001). Incubation of isolated HDLs from des-fluoro-anacetrapib-treated animals with human aortic smooth muscle cells at apolipoprotein A-I concentrations comparable to their plasma levels inhibited cell proliferation and migration. These effects were dependent on scavenger receptor-B1, the adaptor protein PDZ domain-containing protein 1, and phosphatidylinositol-3-kinase/Akt activation. HDLs from des-fluoro-anacetrapib-treated animals also inhibited proinflammatory cytokine-induced human aortic smooth muscle cell proliferation and stent-induced vascular inflammation. CONCLUSIONS: Inhibiting cholesteryl ester transfer protein activity in New Zealand White rabbits with iliac artery balloon injury and stent deployment increases HDL levels, inhibits vascular smooth muscle cell proliferation, and reduces neointimal hyperplasia in an scavenger receptor-B1, PDZ domain-containing protein 1- and phosphatidylinositol-3-kinase/Akt-dependent manner.


Assuntos
Angioplastia com Balão/instrumentação , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima , Oxazolidinonas/farmacologia , Stents , Lesões do Sistema Vascular/prevenção & controle , Angioplastia com Balão/efeitos adversos , Animais , Apolipoproteína A-I/sangue , Proteínas de Transporte/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangue , Modelos Animais de Doenças , Humanos , Hiperplasia , Artéria Ilíaca/efeitos dos fármacos , Artéria Ilíaca/lesões , Artéria Ilíaca/metabolismo , Artéria Ilíaca/patologia , Proteínas de Membrana , Metais , Músculo Liso Vascular/lesões , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Desenho de Prótese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coelhos , Receptores Depuradores Classe B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Lesões do Sistema Vascular/etiologia , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/patologia
17.
Sensors (Basel) ; 18(7)2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30013017

RESUMO

The existing multi-sensor control algorithms for multi-target tracking (MTT) within the random finite set (RFS) framework are all based on the distributed processing architecture, so the rule of generalized covariance intersection (GCI) has to be used to obtain the multi-sensor posterior density. However, there has still been no reliable basis for setting the normalized fusion weight of each sensor in GCI until now. Therefore, to avoid the GCI rule, the paper proposes a new constrained multi-sensor control algorithm based on the centralized processing architecture. A multi-target mean-square error (MSE) bound defined in our paper is served as cost function and the multi-sensor control commands are just the solutions that minimize the bound. In order to derive the bound by using the generalized information inequality to RFS observation, the error between state set and its estimation is measured by the second-order optimal sub-pattern assignment metric while the multi-target Bayes recursion is performed by using a δ-generalized labeled multi-Bernoulli filter. An additional benefit of our method is that the proposed bound can provide an online indication of the achievable limit for MTT precision after the sensor control. Two suboptimal algorithms, which are mixed penalty function (MPF) method and complex method, are used to reduce the computation cost of solving the constrained optimization problem. Simulation results show that for the constrained multi-sensor control system with different observation performance, our method significantly outperforms the GCI-based Cauchy-Schwarz divergence method in MTT precision. Besides, when the number of sensors is relatively large, the computation time of the MPF and complex methods is much shorter than that of the exhaustive search method at the expense of completely acceptable loss of tracking accuracy.

18.
Sensors (Basel) ; 18(12)2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30477185

RESUMO

A new optimization algorithm of sensor selection is proposed in this paper for decentralized large-scale multi-target tracking (MTT) network within a labeled random finite set (RFS) framework. The method is performed based on a marginalized δ-generalized labeled multi-Bernoulli RFS. The rule of weighted Kullback-Leibler average (KLA) is used to fuse local multi-target densities. A new metric, named as the label assignment (LA) metric, is proposed to measure the distance for two labeled sets. The lower bound of LA metric based mean square error between the labeled multi-target state set and its estimate is taken as the optimized objective function of sensor selection. The proposed bound is obtained by the information inequality to RFS measurement. Then, we present the sequential Monte Carlo and Gaussian mixture implementations for the bound. Another advantage of the bound is that it provides a basis for setting the weights of KLA. The coordinate descent method is proposed to compromise the computational cost of sensor selection and the accuracy of MTT. Simulations verify the effectiveness of our method under different signal-to- noise ratio scenarios.

19.
J Cell Physiol ; 232(7): 1893-1906, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27966786

RESUMO

Fibroblast growth factor 21(FGF21) is a pivotal regulator of energy metabolism, which is currently being assessed as a potential drug target for the treatment of insulin-resistant conditions. However, the cellular mechanisms by which FGF21 affects myogenesis remain unclear. In this study, we explored the function of FGF21 in myogenesis both in vitro and in vivo. Our experiments showed for the first time that FGF21 promotes myoblast differentiation and serves as a switch of molecular transformation from anaerobic myofibers to aerobic myofibers via the FGF21-SIRT1-AMPK-PGC1α axis. Furthermore, we employed the Dual-Luciferase Reporter Assay System and Electrophoretic Mobility Shift Assay (EMSA) and demonstrated that MYOD, a major myogenic transcription factor, binds directly to the promoter region of Fgf21, leading to the activation of Fgf21 expression in mouse C2C12 myoblasts. Our study revealed a novel mechanism of myogenesis and muscle fiber transformation and indicated that FGF21 serves as a vital regulator of muscle development and important contributor to the pathogenesis of myopathy. J. Cell. Physiol. 232: 1893-1906, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Aerobiose , Animais , Sequência de Bases , Biomarcadores/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Metabolismo Energético/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos C57BL , Modelos Biológicos , Desenvolvimento Muscular/genética , Proteína MyoD/metabolismo , Transdução de Sinais/genética
20.
FASEB J ; 30(12): 4239-4255, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27630170

RESUMO

Apolipoprotein A-I (apoA-I) is the major component of HDL and central to the ability of HDL to stimulate ATP-binding cassette transporter A1 (ABCA1)-dependent, antiatherogenic export of cholesterol from macrophage foam cells, a key player in the pathology of atherosclerosis. Cell-mediated modifications of apoA-I, such as chlorination, nitration, oxidation, and proteolysis, can impair its antiatherogenic function, although it is unknown whether macrophages themselves contribute to such modifications. To investigate this, human monocyte-derived macrophages (HMDMs) were incubated with human apoA-I under conditions used to induce cholesterol export. Two-dimensional gel electrophoresis and Western blot analysis identified that apoA-I is cleaved (∼20-80%) by HMDMs in a time-dependent manner, generating apoA-I of lower MW and isoelectric point. Mass spectrometry analysis identified a novel C-terminal cleavage site of apoA-I between Ser228-Phe229 Recombinant apoA-I truncated at Ser228 demonstrated profound loss of capacity to solubilize lipid and to promote ABCA1-dependent cholesterol efflux. Protease inhibitors, small interfering RNA knockdown in HMDMs, mass spectrometry analysis, and cathepsin B activity assays identified secreted cathepsin B as responsible for apoA-I cleavage at Ser228 Importantly, C-terminal cleavage of apoA-I was also detected in human carotid plaque. Cleavage at Ser228 is a novel, functionally important post-translational modification of apoA-I mediated by HMDMs that limits the antiatherogenic properties of apoA-I.-Dinnes, D. L. M., White, M. Y., Kockx, M., Traini, M., Hsieh, V., Kim, M.-J., Hou, L., Jessup, W., Rye, K.-A., Thaysen-Andersen, M., Cordwell, S. J., Kritharides, L. Human macrophage cathepsin B-mediated C-terminal cleavage of apolipoprotein A-I at Ser228 severely impairs antiatherogenic capacity.


Assuntos
Apolipoproteína A-I/metabolismo , Aterosclerose/metabolismo , Catepsina B/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transporte Biológico/fisiologia , Células Espumosas/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/fisiologia , Proteólise , Serina/metabolismo
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