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1.
Sci Adv ; 10(26): eadn5228, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38941469

RESUMO

Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.


Assuntos
Vesículas Extracelulares , Glicólise , Células Estreladas do Fígado , Cirrose Hepática , Animais , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/genética , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Vesículas Extracelulares/metabolismo , Camundongos , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Humanos , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Masculino
2.
ChemSusChem ; : e202400830, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38850522

RESUMO

Magnetite (Fe3O4) has a large theoretical reversible capacity and rich Earth abundance, making it a promising anode material for LIBs. However, it suffers from drastic volume changes during the lithiation process, which lead to poor cycle stability and low-rate performance. Hence, there is an urgent need for a solution to address the issue of volume expansion. Taking inspiration from how glycophyte cells mitigate excessive water uptake/loss through their cell wall to preserve the structural integrity of cells, we designed Fe3O4@PMMA multi-core capsules by microemulsion polymerization as a kind of anode materials, also proposed a new evaluation method for real-time repair effect of the battery capacity. The Fe3O4@PMMA anode shows a high reversible specific capacity (858.0 mAh g-1 at 0.1 C after 300 cycles) and an excellent cycle stability (450.99 mAh g-1 at 0.5 C after 450 cycles). Furthermore, the LiNi0.8Co0.1Mn0.1O2/Fe3O4@PMMA 200 mAh pouch cells exhibit a stable capacity (200.6 mAh) and high-capacity retention rate (95.5%) after 450 cycles at 0.5 C. Compared to the original battery, the capacity repair rate of this battery is as high as 93.4%. This kind of bionic capsules provide an innovative solution for improving the electrochemical performance of Fe3O4 anodes to promote their industrial applications.

3.
Plant Sci ; 344: 112089, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38640973

RESUMO

Accurate nucleocytoplasmic transport of signal molecules is essential for plant growth and development. Multiple studies have confirmed that nucleocytoplasmic transport and receptors are involved in regulating plant disease resistance responses, however, little is known about the regulatory mechanism in plants. In this study, we showed that the mutant of the importin beta-like protein SAD2 exhibited a more susceptible phenotype than wild-type Col-0 after treatment with Pseudomonas syringae pv tomato DC3000 (Pst DC3000). Coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) experiments demonstrated that SAD2 interacts with the hypersensitive response (HR)-positive transcriptional regulator MYB30. Subcellular localization showed that MYB30 was not fully localized in the nucleus in sad2-5 mutants, and western-blot experiments further indicated that SAD2 was required for MYB30 nuclear trafficking during the pathogen infection process. A phenotypic test of pathogen inoculation demonstrated that MYB30 partially rescued the disease symptoms of sad2-5 caused by Pst DC3000, and that MYB30 worked downstream of SAD2 in plant pathogen defense. These results suggested that SAD2 might be involved in plant pathogen defense by mediating MYB30 nuclear trafficking. Taken together, our results revealed the important function of SAD2 in plant pathogen defense and enriched understanding of the mechanism of nucleocytoplasmic transport-mediated plant pathogen defense.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Doenças das Plantas , Pseudomonas syringae , Fatores de Transcrição , Pseudomonas syringae/fisiologia , Arabidopsis/microbiologia , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Doenças das Plantas/microbiologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Resistência à Doença/genética , Núcleo Celular/metabolismo , Regulação da Expressão Gênica de Plantas
4.
J Transl Med ; 22(1): 224, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429799

RESUMO

BACKGROUND: In recent years, natural bone extracellular matrix (ECM)-inspired materials have found widespread application as scaffolds for bone tissue engineering. However, the challenge of creating scaffolds that mimic natural bone ECM's mechanical strength and hierarchical nano-micro-macro structures remains. The purposes of this study were to introduce an innovative bone ECM-inspired scaffold that integrates a 3D-printed framework with hydroxyapatite (HAp) mineralized graphene oxide-collagen (GO-Col) microscaffolds and find its application in the repair of mandibular bone defects. METHODS: Initially, a 3D-printed polycaprolactone (PCL) scaffold was designed with cubic disks and square pores to mimic the macrostructure of bone ECM. Subsequently, we developed multi-layer mineralized GO-Col-HAp microscaffolds (MLM GCH) to simulate natural bone ECM's nano- and microstructural features. Systematic in vitro and in vivo experiments were introduced to evaluate the ECM-inspired structure of the scaffold and to explore its effect on cell proliferation and its ability to repair rat bone defects. RESULTS: The resultant MLM GCH/PCL composite scaffolds exhibited robust mechanical strength and ample assembly space. Moreover, the ECM-inspired MLM GCH microscaffolds displayed favorable attributes such as water absorption and retention and demonstrated promising cell adsorption, proliferation, and osteogenic differentiation in vitro. The MLM GCH/PCL composite scaffolds exhibited successful bone regeneration within mandibular bone defects in vivo. CONCLUSIONS: This study presents a well-conceived strategy for fabricating ECM-inspired scaffolds by integrating 3D-printed PCL frameworks with multilayer mineralized porous microscaffolds, enhancing cell proliferation, osteogenic differentiation, and bone regeneration. This construction approach holds the potential for extension to various other biomaterial types.


Assuntos
Durapatita , Grafite , Osteogênese , Ratos , Animais , Durapatita/análise , Durapatita/metabolismo , Durapatita/farmacologia , Alicerces Teciduais/química , Regeneração Óssea , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Engenharia Tecidual , Poliésteres/química , Mandíbula , Impressão Tridimensional
5.
Support Care Cancer ; 32(4): 256, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38546900

RESUMO

BACKGROUND: For patients with nasopharyngeal carcinoma (NPC), the incidence of malnutrition is quite high, and malnutrition has severe effects on NPC patients. However, there is currently no recognized gold standard or specific nutritional assessment tool available to assess malnutrition in NPC patients. Our objective was to develop and verify a new nomogram model for NPC patients. METHODS: Data were collected from NPC patients. To evaluate risk factors for malnutrition, univariate and multivariate logistic regression analyses were used. Based on the risk factors, a new nomogram model was developed. The efficacy of the model was evaluated and validated. RESULTS: Logistic regression analysis showed that age ≥ 65 years, the number of chemotherapy cycles completed ≥ 1, a high total radiation dose received, low body mass index (BMI), low albumin, and low chloride were the risk factors. The assessment effect of the new model was good by evaluation and validation; it can be used as an assessment tool for malnutrition in NPC patients. CONCLUSIONS: Age ≥ 65 years, completing ≥ 1 chemotherapy cycles, a high total radiation dose received, low BMI, low albumin, and low chloride levels are risk factors for malnutrition in NPC patients. The assessment effect of the new model, developed based on these risk factors, is good, and it can be used as an assessment tool for malnutrition in NPC patients.


Assuntos
Desnutrição , Neoplasias Nasofaríngeas , Humanos , Idoso , Carcinoma Nasofaríngeo/patologia , Nomogramas , Neoplasias Nasofaríngeas/radioterapia , Cloretos/uso terapêutico , Fatores de Risco , Desnutrição/epidemiologia , Desnutrição/etiologia , Albuminas
6.
bioRxiv ; 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38293184

RESUMO

Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). Using RNAseq we identified target genes and found that siRNA against ATG9A phenocopied the effects of miR-29 and inhibited the initiation of PINK1-PRKN mitophagy. Furthermore, we discovered two rare, potentially deleterious, missense variants (p.R631W and p.S828L) in our EOPD cohort and tested them experimentally in cells. While expression of wild-type ATG9A was able to rescue the effects of miR-29a, the EOPD-associated variants behaved like loss-of-function mutations. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of mitophagy initiation. It further serves as proof-of-concept of finding novel, potentially disease-causing EOPD-linked variants specifically in mitophagy regulating genes. The nomination of genetic variants and biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPD.

7.
Mol Breed ; 43(4): 23, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37313528

RESUMO

As rice is a staple food for nearly half of the world's population, rice varieties with excellent agronomic traits as well as high flavor and nutritional quality such as fragrant rice and purple rice are naturally favored by the market. In the current study, we adopt a fast breeding strategy to improve the aroma and anthocyanin content in the excellent rice inbred line, F25. The strategy skillfully used the advantages of obtaining editing pure lines in T0 generation of CRISPR/Cas9 editing system and easy observation of purple character and grain shape, integrated the subsequent screening of non-transgenic lines, and the elimination of undesirable edited variants from gene-editing and cross-breeding at the same time as the separation of the progeny from the purple cross, thus expediting the breeding process. Compared with conventional breeding strategies, this strategy saves about 6-8 generations and reduces breeding costs. Firstly, we edited the OsBADH2 gene associated with rice flavor using an Agrobacterium-mediated CRISPR/Cas9 system to improve the aroma of F25. In the T0 generation, a homozygous OsBADH2-edited F25 line (F25B) containing more of the scented substance 2-AP was obtained. Then, we crossed F25B (♀) with a purple rice inbred line, P351 (♂), with high anthocyanin enrichment to improve the anthocyanin content of F25. After nearly 2.5 years of screening and identification over five generations, the undesirable variation characteristics caused by gene-editing and hybridization and the transgenic components were screened out. Finally, the improved F25 line with highly stable aroma component, 2-AP, increased anthocyanin content and no exogenous transgenic components were obtained. This study not only provides high-quality aromatic anthocyanin rice lines that meet the market demand, but also offers a reference for the comprehensive use of CRISPR/Cas9 editing technology, hybridization, and marker-assisted selection to accelerate multi-trait improvement and breeding process. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01369-1.

8.
Nutr Cancer ; 75(1): 61-72, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35903897

RESUMO

Early assessment of malnutrition in cancer patients is very important. The Mini Nutritional Assessment (MNA) is often used to assess malnutrition in adult cancer patients. However, the diagnostic values of MNA are controversial. We aimed to analyze the diagnostic values of MNA in assessing malnutrition in adult cancer patients. A systematic search was performed using Embase, Web of Science, PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, and China Science and Technology Journal Database (VIP). Studies comparing MNA with other tools or criteria in cancer patients were included. The quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The pooled sensitivity, specificity, the area under the receiver-operating characteristic curve (AUC), and the diagnostic odds ratio (DOR) were calculated using Stata 17.0 and Meta-DiSc1.4. In addition, sensitivity, subgroup, meta-regression, and publication bias analyses were conducted. In total, 11 studies involving 1367 patients involving MNA were included. The pooled sensitivity, specificity, ROC, and DOR were 0.84 (95% CI: 0.81-0.87), 0.66 (95% CI: 0.63-0.69), 0.84 (95% CI: 0.81-0.87), and 16.11 (95% CI: 7.16-36.27), respectively. In the assessment of malnutrition in adult cancer patients, MNA has high sensitivity and moderate specificity.


Assuntos
Desnutrição , Neoplasias , Humanos , Adulto , Avaliação Nutricional , Sensibilidade e Especificidade , Desnutrição/diagnóstico , Desnutrição/etiologia , Curva ROC , Neoplasias/complicações
9.
Physiol Rep ; 10(24): e15539, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36541258

RESUMO

Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well-studied. The purpose of this study was to investigate how obesity influences acute exercise responsiveness in skeletal muscle and circulating amino metabolites. Non-obese (NO; n = 19; 10F/9M; BMI = 25.1 ± 2.8 kg/m2 ) and Obese (O; n = 21; 14F/7M; BMI = 37.3 ± 4.6 kg/m2 ) adults performed 30 min of single-leg cycling at 70% of VO2 peak. 13 C6 -Phenylalanine was administered intravenously for muscle protein synthesis measurements. Serial muscle biopsies (vastus lateralis) were collected before exercise and 3.5- and 6.5-h post-exercise to measure protein synthesis and gene expression. Targeted plasma metabolomics was used to quantitate amino metabolites before and 30 and 90 min after exercise. The exercise-induced fold change in mixed muscle protein synthesis trended (p = 0.058) higher in NO (1.28 ± 0.54-fold) compared to O (0.95 ± 0.42-fold) and was inversely related to BMI (R2  = 0.140, p = 0.027). RNA sequencing revealed 331 and 280 genes that were differentially expressed after exercise in NO and O, respectively. Gene set enrichment analysis showed O had six blunted pathways related to metabolism, cell to cell communication, and protein turnover after exercise. The circulating amine response further highlighted dysregulations related to protein synthesis and metabolism in adults with obesity at the basal state and in response to the exercise bout. Collectively, these data highlight several unique pathways in individuals with obesity that resulted in a modestly blunted exercise response.


Assuntos
Perna (Membro) , Músculo Esquelético , Adulto , Humanos , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Músculo Quadríceps/metabolismo , Masculino , Feminino
10.
Appl Opt ; 61(21): 6158-6166, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-36256228

RESUMO

In the scattering environment, binocular stereo vision measurement technology produces large errors due to the change of refractive index of the imaging light path and the decrease in target image contrast. To address this problem, this paper proposes a method for improving the measurement accuracy of binocular stereo vision in a scattering environment combined with polarization imaging theory. First, scattering images with different polarization directions are obtained and filtered by a Gaussian low-pass filter to calculate the degree of polarization and angle of polarization. Then, the scattered light intensity is calculated by using polarization information to obtain images after removing the scattering. Second, feature extraction and matching are carried out for the images after scattering removal. Finally, the target is measured based on the binocular stereo vision measurement model. The experimental results show that when the scattering concentration is high enough, the conventional method can no longer perform measurement, but the method proposed in this paper can still obtain the target parameters at this time, and can also improve measurement accuracy by at least 46.30%. In conclusion, the proposed method provides a valuable reference to improve the accuracy of binocular stereo vision measurement in a scattering environment by reducing the interference of scattering light.

11.
BMC Med Genomics ; 15(1): 195, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114500

RESUMO

BACKGROUND: Formalin-fixed, paraffin-embedded (FFPE) tissues have many advantages for identification of risk biomarkers, including wide availability and potential for extended follow-up endpoints. However, RNA derived from archival FFPE samples has limited quality. Here we identified parameters that determine which FFPE samples have the potential for successful RNA extraction, library preparation, and generation of usable RNAseq data. METHODS: We optimized library preparation protocols designed for use with FFPE samples using seven FFPE and Fresh Frozen replicate pairs, and tested optimized protocols using a study set of 130 FFPE biopsies from women with benign breast disease. Metrics from RNA extraction and preparation procedures were collected and compared with bioinformatics sequencing summary statistics. Finally, a decision tree model was built to learn the relationship between pre-sequencing lab metrics and qc pass/fail status as determined by bioinformatics metrics. RESULTS: Samples that failed bioinformatics qc tended to have low median sample-wise correlation within the cohort (Spearman correlation < 0.75), low number of reads mapped to gene regions (< 25 million), or low number of detectable genes (11,400 # of detected genes with TPM > 4). The median RNA concentration and pre-capture library Qubit values for qc failed samples were 18.9 ng/ul and 2.08 ng/ul respectively, which were significantly lower than those of qc pass samples (40.8 ng/ul and 5.82 ng/ul). We built a decision tree model based on input RNA concentration, input library qubit values, and achieved an F score of 0.848 in predicting QC status (pass/fail) of FFPE samples. CONCLUSIONS: We provide a bioinformatics quality control recommendation for FFPE samples from breast tissue by evaluating bioinformatic and sample metrics. Our results suggest a minimum concentration of 25 ng/ul FFPE-extracted RNA for library preparation and 1.7 ng/ul pre-capture library output to achieve adequate RNA-seq data for downstream bioinformatics analysis.


Assuntos
Benchmarking , Biologia Computacional , Biomarcadores , Feminino , Formaldeído , Humanos , Inclusão em Parafina , Controle de Qualidade , RNA , Análise de Sequência de RNA/métodos , Fixação de Tecidos
12.
Proc Natl Acad Sci U S A ; 119(28): e2206415119, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35867768

RESUMO

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A2A receptor (A2AR) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A2AR inhibition by the Food and Drug Administration-approved A2AR antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin's antitumor activity. Collectively, our study identifies A2AR signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Antineoplásicos , Comprometimento Cognitivo Relacionado à Quimioterapia , Cisplatino , Neurogênese , Purinas , Receptor A2A de Adenosina , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Comprometimento Cognitivo Relacionado à Quimioterapia/prevenção & controle , Cisplatino/efeitos adversos , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Purinas/administração & dosagem , Purinas/uso terapêutico , Receptor A2A de Adenosina/metabolismo
13.
Materials (Basel) ; 15(12)2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35744288

RESUMO

The wafer backside grinding process has been a crucial technology to realize multi-layer stacking and chip performance improvement in the three dimension integrated circuits (3D IC) manufacturing. The total thickness variation (TTV) control is the bottleneck in the advanced process. However, the quantitative analysis theory model and adjustment strategy for TTV control are not currently available. This paper developed a comprehensive simulation model based on the optimized grinding tool configuration, and several typical TTV shapes were obtained. The relationship between the TTV feature components and the spindle posture was established. The linear superposition effect of TTV feature components and a new formation mechanism of TTV shape were revealed. It illustrated that the couple variation between the two TTV feature components could not be eliminated completely. To achieve the desired wafer thickness uniformity through a concise spindle posture adjustment operation, an effective strategy for TTV control was proposed. The experiments on TTV optimization were carried out, through which the developed model and TTV control strategy were verified to play a significant role in wafer thickness uniformity improvement. This work revealed a new insight into the fine control method to the TTV optimization, and provided a guidance for high-end grinding tool and advanced thinning process development.

15.
Front Physiol ; 13: 878389, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35600311

RESUMO

The heterogeneity of the human intestinal epithelium has hindered the understanding of the pathophysiology of distinct specialized cell types on a single-cell basis in disease states. Described here is a workflow for the cryopreservation of endoscopically obtained human intestinal mucosal biopsies, subsequent preparation of this tissue to yield highly viable fluorescence-activated cell sorting (FACS)isolated human intestinal epithelial cell (IEC) single-cell suspensions compatible with successful library preparation and deep single-cell RNA sequencing (scRNAseq). We validated this protocol in deep scRNAseq of 59,653 intestinal cells in 10 human participants. Furthermore, primary intestinal cultures were successfully generated from cryopreserved tissue, capable of surviving in short-term culture and suitable for physiological assays studying gut peptide secretion from rare hormone-producing enteroendocrine cells in humans. This study offers an accessible avenue for single-cell transcriptomics and ex vivo studies from cryopreserved intestinal mucosal biopsies. These techniques may be used in the future to dissect and define novel aberrations to the intestinal ecosystem that lead to the development and progression of disease states in humans, even in rare IEC populations.

16.
Front Genet ; 13: 836841, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35432445

RESUMO

Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with increased risk of prostate cancer (PrCa), and many of these risk loci is presumed to confer regulatory effects on gene expression. While eQTL studies of long RNAs has yielded many potential risk genes, the relationship between PrCa risk genetics and microRNA expression dysregulation is understudied. We performed an microRNA transcriptome-wide association study of PrCa risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate epithelium tissue samples along with N = 411 prostate adenocarcinoma tumor samples from the Cancer Genome Atlas (TCGA). Genetically regulated expression prediction models were trained for all expressed microRNAs using the FUSION TWAS software. TWAS for PrCa risk was performed with both sets of models using single-SNP summary statistics from the recent PRACTICAL consortium PrCa case-control OncoArray GWAS meta-analysis. A total of 613 and 571 distinct expressed microRNAs were identified in the normal and tumor tissue datasets, respectively (overlap: 480). Among these, 79 (13%) normal tissue microRNAs demonstrated significant cis-heritability (median cis-h2 = 0.15, range: 0.03-0.79) for model training. Similar results were obtained from TCGA tumor samples, with 48 (9%) microRNA expression models successfully trained (median cis-h2 = 0.14, range: 0.06-0.60). Using normal tissue models, we identified two significant TWAS microRNA associations with PrCa risk: over-expression of mir-941 family microRNAs (PTWAS = 2.9E-04) and reduced expression of miR-3617-5p (PTWAS = 1.0E-03). The TCGA tumor TWAS also identified a significant association with miR-941 overexpression (PTWAS = 9.7E-04). Subsequent finemapping of the TWAS results using a multi-tissue database indicated limited evidence of causal status for each microRNA with PrCa risk (posterior inclusion probabilities <0.05). Future work will examine downstream regulatory effects of microRNA dysregulation as well as microRNA-mediated risk mechanisms via competing endogenous RNA relationships.

17.
Obesity (Silver Spring) ; 30(5): 1091-1104, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35470975

RESUMO

OBJECTIVE: The health benefits of exercise are well documented, but several exercise-response parameters are attenuated in individuals with obesity. The goal of this pilot study was to identify molecular mechanisms that may influence exercise response with obesity. METHODS: A multi-omics comparison of the transcriptome, proteome, and phosphoproteome in muscle from a preliminary cohort of lean individuals (n = 4) and individuals with obesity (n = 4) was performed, before and after a single bout of 30 minutes of unilateral cycling at 70% maximal oxygen uptake (VO2 peak). Mass spectrometry and RNA sequencing were used to interrogate the proteome, phosphoproteome, and transcriptome from muscle biopsy tissue. RESULTS: The main findings are that individuals with obesity exhibited transcriptional and proteomic signatures consistent with reduced mitochondrial function, protein synthesis, and glycogen synthesis. Furthermore, individuals with obesity demonstrated markedly different transcriptional, proteomic, and phosphoproteomic responses to exercise, particularly biosynthetic pathways of glycogen synthesis and protein synthesis. Casein kinase II subunit alpha and glycogen synthase kinase-3ß signaling was identified as exercise-response pathways that were notably altered by obesity. CONCLUSIONS: Opportunities to enhance exercise responsiveness by targeting specific molecular pathways that are disrupted in skeletal muscle from individuals with obesity await a better understanding of the precise molecular mechanisms that may limit exercise-response pathways in obesity.


Assuntos
Proteoma , Proteômica , Glicogênio/metabolismo , Humanos , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Projetos Piloto , Proteoma/metabolismo
18.
BMC Oral Health ; 22(1): 126, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35428233

RESUMO

BACKGROUND: The role and mechanisms of lipid metabolism in oral squamous cell carcinomas (OSCC) metastasis have not been clarified. This study aims to identify lipid metabolism-related genes and transcription factors regulated by metastasis-associated enhancers (MAEs) in OSCC. METHODS: Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed for lipid metabolism enrichment. TCGA data were used to analyze the differentially expressed lipid metabolism-related genes. MAEs were analyzed using GSE120634. Overlapping analysis was used to screen the MAE-regulated lipid metabolism-related genes, and the prognosis of these genes was analyzed. Transcription factor prediction was performed for the MAE-regulated lipid metabolism-related genes with prognostic value. Validation of the metastatic specificity of MAEs at ACAT1, OXSM and VAPA locus was performed using GSE88976 and GSE120634. ChIP-qPCR, qRT-PCR and Western blotting were used to verify the regulation of ACAT1, OXSM and VAPA expression by CBFB. Effects of CBFB knockdown on proliferation, invasion and lipid synthesis in metastatic OSCC cells were analyzed. RESULTS: Lipid metabolism was significantly enhanced in metastatic OSCC compared to non-metastatic OSCC. The expression of 276 lipid metabolism-related genes was significantly upregulated in metastatic OSCC, which were functionally related to lipid uptake, triacylglycerols, phospholipids and sterols metabolism. A total of 6782 MAEs and 176 MAE-regulated lipid metabolism-related genes were filtered. Three MAE-regulated lipid metabolism-related genes, ACAT1, OXSM and VAPA, were associated with a poor prognosis in OSCC patients. Enhancers at ACAT1, OXSM and VAPA locus were metastasis-specific enhancers. CBFB regulated ACAT1, OXSM and VAPA expression by binding to the enhancers of these genes. Knockdown of CBFB inhibited proliferation, invasion and lipid synthesis in metastatic OSCC cells. CONCLUSION: The MAE-regulated lipid metabolism-related genes (ACAT1, OXSM and VAPA) and the key transcription factor (CBFB) were identified. CBFB knockdown inhibited proliferation, invasion and lipid synthesis of OSCC cells. These findings provide novel candidates for the development of therapeutic targets for OSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , Metabolismo dos Lipídeos , Neoplasias Bucais , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Bucais/patologia , Metástase Neoplásica , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Thromb Res ; 213: 34-42, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35279504

RESUMO

BACKGROUND: Totally implantable venous access ports (PORTs) and peripherally inserted central catheters (PICCs) are associated with an increased risk of venous thromboembolism (VTE). It is not known which type of catheter is most at risk of thrombosis. OBJECTIVE: We aimed to study the incidence of PORT-related VTE and PICC-related VTE in cancer patients by a meta-analysis. METHODS: A systematic search was performed using PubMed, Embase, Web of Science and the Cochrane Library. Cohort studies and randomized controlled trials (RCTs) comparing PORT-related VTE and PICC-related VTE in cancer patients were included. Quality was assessed using the Cochrane Collaboration tool for RCTs and the Newcastle-Ottawa Scale (NOS) for cohort studies. Random-effects meta-analysis was used to calculate odd ratio (OR). Sensitivity and subgroup analyses were conducted. RESULTS: In total, 22 studies comprising 11,940 patients were retrieved. Our meta-analysis of 22 studies suggested that the risk of PORT-related VTE was lower than that of PICC-related VTE in cancer patients (OR = 0.38, 95% CI: 0.25-0.58). The subgroup analysis showed that the risk of PORT-related VTE and PICC-related VTE is different in different regions. In the non-Asian countries, PORTs were associated with a decreased risk of VTE compared with PICCs. (OR = 0.41, 95%CI: 0.27-0.61). However, there was no significant difference in the risk of PORT-related VTE and PICC-related VTE in the Asian countries (OR = 0.23, 95% CI: 0.05-1.12). CONCLUSIONS: PORTs are associated with a lower risk of VTE than PICCs in cancer patients. The risk of VTE and benefits should be considered when selecting PORTs or PICCs for cancer patients.


Assuntos
Cateterismo Venoso Central , Cateterismo Periférico , Cateteres Venosos Centrais , Neoplasias , Tromboembolia Venosa , Cateterismo Venoso Central/efeitos adversos , Cateterismo Periférico/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Humanos , Neoplasias/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia
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