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1.
EMBO Mol Med ; : e13524, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33821572

RESUMO

Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. While pathways such as FoxM1 are involved in regulating compensatory beta cell proliferation, given the lack of therapeutics effectively targeting beta cell proliferation, other targetable pathways need to be identified. Herein, we show that Pbk, a serine/threonine protein kinase, is essential for high fat diet (HFD)-induced beta cell proliferation in vivo using a Pbk kinase deficiency knock-in mouse model. Mechanistically, JunD recruits menin and HDAC3 complex to the Pbk promoter to reduce histone H3 acetylation, leading to epigenetic repression of Pbk expression. Moreover, menin inhibitor (MI) disrupts the menin-JunD interaction and augments Pbk transcription. Importantly, MI administration increases beta cell proliferation, ameliorating hyperglycemia, and impaired glucose tolerance (IGT) in HFD-induced diabetic mice. Notably, Pbk is required for the MI-induced beta cell proliferation and improvement of IGT. Together, these results demonstrate the repressive role of the menin/JunD/Pbk axis in regulating HFD-induced compensatory beta cell proliferation and pharmacologically regulating this axis may serve as a novel strategy for type 2 diabetes therapy.

2.
Sports Health ; : 19417381211004937, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33813953

RESUMO

CONTEXT: Quadriceps dysfunction is common for patients after anterior cruciate ligament reconstruction (ACLR). Whole-body vibration (WBV) could effectively treat quadriceps dysfunction. OBJECTIVE: To summarize WBV protocols for patients with ACLR and to evaluate the effects of WBV on quadriceps function. DATA SOURCES: PubMed, CINAHL, SportDiscus, Web of Science, Medline, and Embase were searched from inception to January 2020. STUDY SELECTION: Randomized controlled trials recruiting patients with ACLR, using WBV as intervention, and reporting at least 1 of the following outcomes, strength, rate of torque development (RTD), and voluntary activation ratio of quadriceps, were included. STUDY DESIGN: Systematic review. EVIDENCE LEVEL: Level 3. METHODS: This systematic review was reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Quality of evidence was determined by PEDro criteria and GRADE system. Participant characteristics, interventions, and the relevant results of the included studies were extracted and synthesized in a narrative way. RESULTS: In total, 8 studies were included. Of these, 2 studies had serious risk of bias. Five of 8 studies implemented a series of WBV program ranging from 2 to 10 weeks in duration, while the other 3 studies implemented a single session of WBV. Eight WBV protocols were reported. The reported outcomes consisted of quadriceps strength, RTD, and central activation ratio. WBV protocols were heterogeneous. Low quality of evidence supported that exclusive conventional rehabilitation was more effective than exclusive WBV therapy in increasing quadriceps strength. Low quality of evidence supported that WBV combined with conventional rehabilitation was more beneficial in increasing quadriceps strength when compared with conventional rehabilitation alone. Very low quality of evidence supported the efficacy of a single session of WBV on quadriceps function. CONCLUSIONS: There is no standardized WBV protocol for patients with ACLR, and the effectiveness of WBV in rehabilitation on quadriceps function remains inconclusive.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33811273

RESUMO

BACKGROUND: Tetraspanin KAI1/CD82, a tumor metastasis suppressor, has emerged as a promising molecular target for the management of metastatic disease. However, the peptide mimicking small extracellular ring domain (EC1) of CD82 has not been fully investigated for the function of inhibiting cell migration in vitro and tumor metastasis in vivo. METHODS: Different cancer cells were treated with EC1 mimic peptide in order to detect migration and invasion by the healing assay and transwell. Cell aggregation and adhesion assays were used to investigate the function of homotypic cell-cell aggregation and adhesion to tissue culture plates. Then, we established syngeneic and xenograft animal models to assess the metastasis inhibitory effect of EC1 mimic peptide in vivo. RESULTS: In vitro studies, the EC1 mimic peptide had been showed to promote homotypic cell-cell aggregation, suppress cell migration, invasion and adherence in multiple tumor cell types. In vivo metastasis assays, the EC1 mimic peptide could strongly inhibit the pulmonary metastasis of LCC in syngeneic mice model and SW620 and H1299 in xenograft mice model. CONCLUSION: This novel finding will improve our understanding of the mechanism by which CD82 inhibits metastasis, and suggests that EC1 mimic peptide may be a promising candidate for developing anti-metastasis drugs.

4.
Brief Bioinform ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33791774

RESUMO

MOTIVATION: Rare variant-based analyses are beginning to identify risk genes for neuropsychiatric disorders and other diseases. However, the identified genes only account for a fraction of predicted causal genes. Recent studies have shown that rare damaging variants are significantly enriched in specific gene-sets. Methods which are able to jointly model rare variants and gene-sets to identify enriched gene-sets and use these enriched gene-sets to prioritize additional risk genes could improve understanding of the genetic architecture of diseases. RESULTS: We propose DECO (Integrated analysis of de novo mutations, rare case/control variants and omics information via gene-sets), an integrated method for rare-variant and gene-set analysis. The method can (i) test the enrichment of gene-sets directly within the statistical model, and (ii) use enriched gene-sets to rank existing genes and prioritize additional risk genes for tested disorders. In simulations, DECO performs better than a homologous method that uses only variant data. To demonstrate the application of the proposed protocol, we have applied this approach to rare-variant datasets of schizophrenia. Compared with a method which only uses variant information, DECO is able to prioritize additional risk genes. AVAILABILITY: DECO can be used to analyze rare-variants and biological pathways or cell types for any disease. The package is available on Github https://github.com/hoangtn/DECO.

5.
Int J Biol Macromol ; 180: 14-27, 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33722620

RESUMO

Phytochrome-interacting factors (PIFs) are members of basic helix-loop-helix (bHLH) transcription factors and the primary partners of phytochromes (PHY) in light signaling. PIFs interact with the Pfr forms of phytochrome to play an important role in the pathways of response to light and temperature in plants. In this study, 30, 12, and 16 potential PIF genes were identified in Brassica napus, Brassica rapa, Brassica oleracea, respectively, which could be divided into three subgroups. The Br/Bo/BnaPIF genes are intron-rich and similar to the PIF genes in Arabidopsis. However, unlike the AtPIFs that exist in multiple alternative-splicing forms, the majority of Br/Bo/BnaPIF genes have no alternative-splicing forms. A total of 52 Br/Bo/BnaPIF proteins have both the conserved active PHYB binding (APB) and bHLH domains. The Ka/Ks ratio revealed that most BnaPIFs underwent purifying selection. A promoter analysis found that light-related, abscisic acid-related and MYB-binding sites were the most abundant in the promoters of BnaPIFs. BnaPIF genes displayed different spatiotemporal patterns of expression and were regulated by light quality, circadian rhythms, cold, heat, and vernalization. Our results are useful for understanding the biological functions of PIF proteins in rapeseed.

6.
Org Lett ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33787274

RESUMO

A nickel-catalyzed C-H cyanation reaction of arenes has been developed using 2-cyanoisothiazolidine 1,1-dioxide as an electrophilic cyanation reagent. Many different directing groups can be used in this cyanation to obtain a series of cyanation products with good yields. Adopting this strategy to introduce a cyano group, natural alkaloid menisporphine was successfully synthesized through cyano group conversion that further proved the practicality of this cyanation method.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33787325

RESUMO

The distribution of fibrosis in idiopathic pulmonary fibrosis (IPF) is sub-pleural with basal predominance. Alveolar epithelial cell was considered as the key cell in the initial phase of IPF. However, the idea of activation and damage of alveolar epithelial cells is very difficult to explain why fibrosis distributes in the sub-pleural area. In this study, human pleural mesothelial cell (PMC) line and primary rat PMC was used as in vitro model. Intra-peritoneal injection of bleomycin was used for making a pulmonary fibrosis model. The integrity of cultured monolayer PMCs was determined by transepithelial electric resistance (TEER). Pleural permeability was estimated by measuring paracellular transport of fluorescein isothiocyanate (FITC)-conjugated dextran. Changes in lung tissue of IPF patients were analyzed by Masson's and immunofluorescence staining. We found bleomycin induced PMCs damage and increased PMCs permeability, increased PMCs permeability aggravated bleomycin-induced sub-pleural inflammation and pulmonary fibrosis. Moreover, bleomycin was found to activate VEGF/Src signaling which increased PMCs permeability. In vivo, inhibition of VEGF/Src signaling prevented bleomycin-induced sub-pleural pulmonary fibrosis. At last, activation of VEGF/Src signaling was confirmed in sub-pleural area in IPF patients. Taken together, our findings indicate that VEGF/Src signaling mediated pleural barrier damage and increased permeability which contributes to sub-pleural pulmonary fibrosis.

8.
Bioinformatics ; 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33647928

RESUMO

MOTIVATION: Trans-acting expression quantitative trait loci (eQTLs) collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are often individually weak. A large proportion of genetic effects on distal genes are mediated through cisgene expression. Cis-association (between SNP and cis-gene) and gene-gene correlation conditional on SNP genotype could establish trans-association (between SNP and trans-gene). Both cis-association and gene-gene conditional correlation have effects shared across relevant tissues and conditions, and transassociations mediated by cis-gene expression also have effects shared across relevant conditions. RESULTS: . We proposed a Cross-Condition Mediation analysis method (CCmed) for detecting cis-mediated trans-associations with replicable effects in relevant conditions/studies. CCmed integrates cis-association and gene-gene conditional correlation statistics from multiple tissues/studies. Motivated by the bimodal effect-sharing patterns of eQTLs, we proposed two variations of CCmed, CCmedmost and CCmedspec for detecting cross-tissue and tissue-specific trans-associations, respectively. We analyzed data of 13 brain tissues from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-mediated transassociations across brain tissues, many of which showed evidence of trans-association in two replication studies. We also identified trans-genes associated with schizophrenia loci in at least two brain tissues. AVAILABILITY AND IMPLEMENTATION: CCmed software is available at http://github.com/kjgleason/CCmed. SUPPLEMENTARY INFORMATION: Supplementary Material are available at Bioinformatics online.

9.
Cell Rep ; 34(12): 108882, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33761343

RESUMO

Microglia, brain-resident macrophages, require instruction from the CNS microenvironment to maintain their identity and morphology and regulate inflammatory responses, although what mediates this is unclear. Here, we show that neurons and astrocytes cooperate to promote microglial ramification, induce expression of microglial signature genes ordinarily lost in vitro and in age and disease in vivo, and repress infection- and injury-associated gene sets. The influence of neurons and astrocytes separately on microglia is weak, indicative of synergies between these cell types, which exert their effects via a mechanism involving transforming growth factor ß2 (TGF-ß2) signaling. Neurons and astrocytes also combine to provide immunomodulatory cues, repressing primed microglial responses to weak inflammatory stimuli (without affecting maximal responses) and consequently limiting the feedback effects of inflammation on the neurons and astrocytes themselves. These findings explain why microglia isolated ex vivo undergo de-differentiation and inflammatory deregulation and point to how disease- and age-associated changes may be counteracted.

10.
Food Funct ; 12(6): 2378-2388, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33645609

RESUMO

It is well known that fat dysfunction is the main driver of development of metabolic disorders. Changes in diet and lifestyle are particularly important to reverse the current global rise in obesity-related metabolic disorders. Seaweed has been consumed for thousands of years, and it is rich in bioactive compounds, especially unique polyphenols. The aim of the present review is to summarize the effects of different seaweed polyphenols on fat function in metabolic disorders and the related mechanisms. Seaweed polyphenols activate white adipose tissue to "brown" or "beige" adipose tissue to enhance energy consumption. In addition, the amelioration of fat factor imbalance and inflammatory response is also considered as an important reason for the regulation of lipid function with seaweed polyphenols. The present review provides an important basis for using seaweed polyphenols as potential dietary supplements to prevent metabolic disorders.

11.
Sci Prog ; 104(1): 368504211003762, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33788663

RESUMO

China is at a stage of rapid urbanization over the past decades, and the association of urbanization with cardiovascular disease has been confirmed by previous studies. However, few studies assessed the association of urbanization with cardiovascular risk factors, especially in Chinese population. We conducted a cross-sectional, populational-based study, using data from China Health and Nutrition Survey (CHNS) in 2009. The logistic regression was used to assess the association of urbanization measured by urban index with cardiovascular risk factors (diabetes mellitus, hypertension, dyslipidemia, obesity, smoking, physical activity and fruits and vegetables consumption), varied with sex. The current study included 18,887 participants enrolled (mean age 39.8 ± 19.8 years; 52.2% female) who live in China. In regression model, the urban index was significantly associated with the variations of cardiovascular risk factors for male, including diabetes (OR 1.34, 95% CI: 1.22-1.48), hypercholesterolemia (OR 1.15, 95% CI: 1.09-1.22), never smoking (OR 0.92, 95% CI: 0.89-0.96), higher fruits and vegetables consumptions (OR 0.93, 95% CI: 0.87-0.99), higher body mass index (BMI) (OR 1.16, 95% CI: 1.10-1.22), and higher physical activity (OR 0.69, 95% CI: 0.66-0.73). Compared with the male, the associations of urban index with cardiovascular risk factors for female were similar, but not for BMI (OR 1.00, 95% CI: 0.96-1.05). The present finding emphasizes the changes of cardiovascular risk factors associated with urbanization in China, and indicated that close attention should be paid to the risk of hypercholesterolemia, diabetes and men's obesity in the process of urbanization.

12.
Ann Surg Oncol ; 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33748895

RESUMO

INTRODUCTION: Tenosynovial giant cell tumor (TGCT) is a locally aggressive tumor with colony-stimulating factor 1 receptor (CSF1R) signal expression. However, there is a lack of better in vivo and ex vivo models for TGCT. This study aims to establish a favorable preclinical translational platform, which would enable the validation of efficient and personalized therapeutic candidates for TGCT. PATIENTS AND METHODS: Histological analyses were performed for the included patients. Fresh TGCT tumors were collected and sliced into 1.0-3.0 mm3 sections using a sterilized razor blade. The tumor grafts were surgically implanted into subrenal capsules of athymic mice to establish patient-derived tumor xenograft (PDTX) mouse models. Histological and response patterns to CSF1R inhibitors evaluations were analyzed. In addition, ex vivo cultures of patient-derived explants (PDEs) with endpoint analysis were used to validate TGCT graft response patterns to CSF1R inhibitors. RESULTS: The TGCT tumor grafts that were implanted into athymic mice subrenal capsules maintained their original morphological and histological features. The "take" rate of this model was 95% (19/20). Administration of CSF1R inhibitors (PLX3397, and a novel candidate, WXFL11420306) to TGCT-PDTX mice was shown to reduce tumor size while inducing intratumoral apoptosis. In addition, the CSF1R inhibitors suppressed circulating nonspecific monocyte levels and CD163-positive cells within tumors. These response patterns of engrafts to PDTX were validated by ex vivo PDE cultures. CONCLUSIONS: Subrenal capsule supports the growth of TGCT tumor grafts, maintaining their original morphology and histology. This TGCT-PDTX model plus ex vivo explant cultures is a potential preclinical translational platform for locally aggressive tumors, such as TGCT.

14.
Chembiochem ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33682991

RESUMO

The clustered regularly interspaced short palindromic repeats (CRISPR) technology has been widely applied for nucleic acid detection because of its high specificity. By using the highly specific and irreversible bond between HaloTag and its alkane chlorine ligand, we modified dCas9 (deactivated CRISPR/Cas9) with biotin as a biosensor to detect nucleic acids. The CRISPR biosensor was facilely prepared to adequately maintain its DNA-recognition capability. Furthermore, by coupling biolayer interferometry (BLI) with the CRISPR biosensor, a real-time, sensitive, and rapid digital system called CRISPR-BLI was established for the detection of double-stranded DNA. The CRISPR biosensor immobilised on the biolayer could recruit the target DNA onto the biosensor surface and change its optical thickness, resulting in a shift in the interference pattern and responding signal of the BLI. The CRISPR-BLI system was further applied to detect the ALP gene of Escherichia coli DH5α combined with a polymerase chain reaction, which demonstrated a linear range from 20 to 20 000 pg and a low detection limit (1.34 pg). The CRISPR-BLI system is a promising approach for rapid and sensitive detection of target DNA analytes.

15.
Twin Res Hum Genet ; : 1-8, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33645497

RESUMO

The objective of this study was to analyze differences in birth weight and overweight/obesity in a Shanghai twin cohort. We also wanted to study their association and explore possible risk factors for the discordance of overweight/obesity within twins. This was an internal case-control study designed for twins. The 2012 Shanghai Twin Registration System baseline survey data of a total of 3417 twin pairs were statistically analyzed using SPSS22 software. Results show that the body mass index (BMI) of the Shanghai twin population increased with age. Twins with a high birth weight had a higher BMI and a higher rate of overweight and obesity; 0- to 6-year-old twins, male twins and dizygotic (DZ) twins had higher rates of overweight/obesity than other groups. The greater the discordant birth weight rate of twins, the more obvious the difference in BMI (p < .05). There was a significant difference in overweight/obesity between twins with a relative difference of birth weight ≥15% in DZ twins (p < .05). DZ twins, male twins and 0- to 6-year-old twins were more likely to be discordant in overweight/obese than others. The discordant birth weight within twins was not a risk factor for discordant overweight/obesity. However, attention should be paid to childhood obesity, and appropriate interventions should be made at the appropriate time. Genetics may play an important role in the occurrence and development of overweight/obesity. In conclusion, discordant growth and development in the uterus early in life may not lead to discordant weight development in the future.

17.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760133

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the most debilitating and invasive tumors. Although previous reports have demonstrated the critical role microRNA­181a (miR­181a) serves in the progression of ESCC, how miR­181a induces epithelial­mesenchymal transition (EMT) remains to be elucidated. In the present study, the expression profiles of TGF­ß1 and Smad4 proteins in 88 patients with ESCC and 21 adjacent non­cancerous tissues were analyzed using immunohistochemistry. The expression of miR­181a in ESCC cells (ECA109 and TE­1) and HEEC was analyzed using reverse transcription­quantitative polymerase chain reaction (RT­qPCR). The role of miR­181a in ESCC was analyzed using miR­181a mimics and inhibitor in the same system. Migration, proliferation and apoptosis of cells were assessed using wound­healing assays and cell proliferation assays and flow cytometry, respectively. The expression levels of TGF­ß1 and Smad4 in ESCC cell lines transfected with miR­181a mimics and inhibitor were measured using RT­qPCR and western blotting. The expression of E­cadherin and vimentin was also assessed following transfection. The findings demonstrated that expression of TGF­ß1 was upregulated, in contrast to Smad4 expression which was downregulated. Expression levels of Smad4 affected the prognosis of patients with ESCC. Higher expression of miR­181a promoted migration and proliferation but inhibited apoptosis of ESCC cells. miR­181a promoted EMT by modulating Smad4 expression in ESCC cells. Overall, these findings revealed that miR­181a induced EMT in ESCC via the TGF­ß/Smad pathway in ESCC. Consequently, miR­181a is a potential novel target against ESCC.

18.
Sci Rep ; 11(1): 6965, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772036

RESUMO

The highly successful PBE functional and the modified Becke-Johnson exchange potential were used to calculate the structural, electronic, and optical properties of the vacancy-ordered double perovskites A2BX6 (A = Rb, Cs; B = Sn, Pd, Pt; X = Cl, Br, and I) using the density functional theory, a first principles approach. The convex hull approach was used to check the thermodynamic stability of the compounds. The calculated parameters (lattice constants, band gap, and bond lengths) are in tune with the available experimental and theoretical results. The compounds, Rb2PdBr6 and Cs2PtI6, exhibit band gaps within the optimal range of 0.9-1.6 eV, required for the single-junction photovoltaic applications. The photovoltaic efficiency of the studied materials was assessed using the spectroscopic-limited-maximum-efficiency (SLME) metric as well as the optical properties. The ideal band gap, high dielectric constants, and optimum light absorption of these perovskites make them suitable for high performance single and multi-junction perovskite solar cells.

19.
DNA Cell Biol ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33781092

RESUMO

The abnormal proliferation of vascular smooth muscle cells (VSMCs) is crucial in the atherosclerosis. Although long noncoding RNAs (lncRNAs) are implicated in a variety of diseases, their roles in activation of VSMCs proliferation and vascular disorder diseases are not well understood. In addition, heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) was reported to participate in lncRNAs-mediated function. Herein, we propose to investigate the role of lncRNA AC105942.1 and hnRNPA2/B1 in pathological VSMCs proliferation and the possible mechanisms in vitro. We have identified that lncRNA AC105942.1 was downregulated and hnRNPA2/B1 was upregulated in atherosclerotic plaques compared with normal artery tissues. Enhanced lncRNA AC105942.1 could noticeably inhibit Ang II-induced VSMCs proliferation. Further investigation suggested that lncRNA AC105942.1 could downregulate the expression of hnRNPA2/B1 and then regulate the level of CDK4 and p27. Taken together, our study indicated that lncRNA AC105942.1 downregulated hnRNPA2B1 to protect against the atherosclerosis by suppressing VSMCs proliferation. LncRNA AC105942.1 and hnRNPA2/B1 could represent potential therapeutic and diagnostic targets to atherosclerosis-related diseases.

20.
Theor Appl Genet ; 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33677638

RESUMO

KEY MESSAGE: Regional association analysis of 50 re-sequenced Chinese semi-winter rapeseed accessions in combination with co-expression analysis reveal candidate genes affecting oil accumulation in Brassica napus. One of the breeding goals in rapeseed production is to enhance the seed oil content to cater to the increased demand for vegetable oils due to a growing global population. To investigate the genetic basis of variation in seed oil content, we used 60 K Brassica Infinium SNP array along with phenotype data of 203 Chinese semi-winter rapeseed accessions to perform a genome-wide analysis of haplotype blocks associated with the oil content. Nine haplotype regions harbouring lipid synthesis/transport-, carbohydrate metabolism- and photosynthesis-related genes were identified as significantly associated with the oil content and were mapped to chromosomes A02, A04, A05, A07, C03, C04, C05, C08 and C09, respectively. Regional association analysis of 50 re-sequenced Chinese semi-winter rapeseed accessions combined with transcriptome datasets from 13 accessions was further performed on these nine haplotype regions. This revealed natural variation in the BnTGD3-A02 and BnSSE1-A05 gene regions correlated with the phenotypic variation of the oil content within the A02 and A04 chromosome haplotype regions, respectively. Moreover, co-expression network analysis revealed that BnTGD3-A02 and BnSSE1-A05 were directly linked with fatty acid beta-oxidation-related gene BnKAT2-C04, thus forming a molecular network involved in the potential regulation of seed oil accumulation. The results of this study could be used to combine favourable haplotype alleles for further improvement of the seed oil content in rapeseed.

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