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In spite of extensive research and appreciable progress, in aqueous zinc-ion batteries, Zn metal anode is struggling with low Zn utility and poor cycling stability. In this study, a 3D "electrochemical welding" composite electrode is designed by introduction of ZnO/C nanofibers film to copper foils as an anode according to pre-electrodeposition active Zn (Zn@ZnO/C-Cu). The flow of Zn2+ through carbon fiber layer is regulated by zincophilic ZnO, promoting homogeneous diffusion of Zn2+ to Cu foil. In subsequent Zn deposition/stripping processes, the hydrophobicity of ZnO/C fiber layer reduces water at the interface of Zn@ZnO/C-Cu and results in uniform electric field significant suppressing growth of Zn dendritic and side reactions. Thus, pre-electrodeposition active Zn electrochemical welds ZnO/C nanofibers and Cu foil collectively provide stable charge/electron transfer and stripping/plating of Zn with low polarization and excellent cycling performance. The assembled symmetrical batteries exhibit stable cycling performance for over 470 h under 20% utilization of Zn at 5 mA cm-2, and an average coulombic efficiency of 99.9% at low negative/positive capacity ratio (N/P = 1) after 1000 cycles in the Zn@ZnO/C-Cu||Na2V6O16·1.5H2O full cell.
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In the field of microplastics (MPs) toxicity prediction, machine learning (ML) computer simulation techniques are showing great potential. In this study, six ML algorithms were utilized to predict the toxicity of MPs on BEAS-2B cells based on quantitative structure-activity relationship (QSAR) models. Comparing the models of different algorithms, the extreme gradient boosting model showed the best fit and prediction performance (R2tra = 0.9876, R2test = 0.9286). Additionally, Williams plot analysis showed that the six models developed were able to predict stably within their applicability domain, with few outliers. Finally, the three feature importance methods-Embedded Feature Importance (EFI), Recursive Feature Elimination (RFE), and SHapley Additive exPlanations (SHAP)-consistently identified particle size as the most critical feature affecting toxicity prediction. The proposed QSAR model can be utilized for preliminary environmental exposure assessments of MPs and to better understand the associated health risks.
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Age-related hearing loss (ARHL) is an auditory disease characterized by gradual loss of high-frequency hearing sensitivity. Excessive reactive oxygen species trigger NLRP3-inflammasome activation that may be crucial for ARHL pathogenesis. The antioxidant factor Sestrin2 (SESN2) has been reported to be involved in the remission of oxidative stress and ARHL. However, the mechanism by which SESN2 protects auditory cells in the aging mouse cochlea remains unknown. Here, we observed that ectopic overexpression of SESN2 delayed ARHL, whereas SESN2 knockdown accelerated it. Importantly, we elucidated that SESN2 exerts a hearing-protective effect by inhibiting the production of NLRP3 by acting as a mitophagy agonist. Our study proposes a new theoretical basis for SESN2 prevention of ARHL and provides a novel therapeutic strategy for maintaining SESN2 activity in the aging cochlea.
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BACKGROUND: Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. METHODS: RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE-/- mice, while EC-specific knockdown of Nrf2 was generated in Cdh5CreCas9floxed-stopApoE-/- mice. RESULTS: Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE-/- mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5CreCas9floxed-stopApoE-/- mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. CONCLUSIONS: Upon HCD feeding in ApoE-/- mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.
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Apolipoproteínas E , Aterosclerose , Células Endoteliais , Inflamação , Peroxidação de Lipídeos , Fator 2 Relacionado a NF-E2 , Animais , Humanos , Masculino , Camundongos , Apolipoproteínas E/genética , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Inflamação/metabolismo , Inflamação/genética , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse OxidativoRESUMO
BACKGROUND: This meta-analysis was dedicated to evaluating the effectiveness and safety of Atezolizumab plus Bevacizumab (Atez/Bev) and Lenvatinib (LEN) as first-line systematic therapy for unresectable hepatocellular carcinoma (u-HCC). METHODS: The prospective protocol for this study was registered with the PROSPERO (Registration number: CRD42022356874). Literature searches were conducted in PubMed, EMBASE database Cochrane Library, and Web Science to determine all clinical controlled studies that reported Atez/Bev and LEN for treating u-HCC. We. evaluated as primary end-point overall survival (OS) and progression-free survival (PFS), as well as other outcomes such as tumor response and adverse events (AEs).Quality assessment and data extraction of studies were conducted independently by three reviewers. Mean difference (MD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a fixed-effects or random-effects model. The meta-analysis was performed with RevMan 5.3 software. RESULTS: 12 retrospective cohort studies (RCSs) involving a total of 4948 patients were finally included. The results showed that compared with LEN, Atez/Bev can improve the patient's PFS (HR = 0.80, 95% CI: 0.72 ~ 0.88; p < 0.0001) and reduce the rate of overall AEs (OR = 0.46 95% CI: 0.38 ~ 0.55, p < 0.00001) and grade ≥ 3 AEs (OR = 0.43; 95% CI: 0.36 ~ 0.51, p < 0.00001), while there is no difference between OS and treatment responses rate (objective response rate, disease control rate, complete response, partial response, progressive disease, and stable disease) between two groups. In addition, the subgroup analysis shows that Atez/Bev can promote the OS of patients with viral hepatitis. (HR = 0.79, 95% CI: 0.67 ~ 0.95; p = 0.01), while LEN has an advantage in improving OS in patients with Child-Pugh grade B liver function (HR = 1.98, 95% CI: 1.50 ~ 2.63; p < 0.00001). CONCLUSION: Current evidence shows that compared with LEN, Atez/Bev has more advantages in PFS and safety in treating u-HCC and can improve the OS of patients with viral. LEN has advantages in improving the OS of patients with grade B liver function. However, more multicenter randomized controlled experiments are needed in the future to verify our results.
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In this paper, two flower-like magnesium silicate nanomaterials were prepared. These and another two commercial magnesium silicate materials were characterized using a scanning electron microscope, the N2 adsorption-desorption method, and other methods. The structure-activity relationship between the adsorption performance of these four magnesium silicate materials and their specific surface area, pore size distribution, and pore structure was compared. The results showed that the 3-FMS modified by sodium dodecyl sulfonate (SDS) had the largest specific surface area and pore size, the best adsorption performance, and the largest experimental equilibrium adsorption capacity (qe,exp) for Co2+, reaching 190.01 mg/g, and Cr3+, reaching 208.89 mg/g. The adsorption behavior of the four materials for Co2+ and Cr3+ both fitted the pseudo-second-order kinetic model and Langmuir adsorption model, indicating that chemical monolayer uniform adsorption was the dominant adsorption process. Among them, the theoretical adsorption capacity (qm) of 3-FMS was the highest, reaching 207.62 mg/g for Co2+ and 230.85 mg/g for Cr3+. Through further research, it was found that the four materials mainly removed Co2+ and Cr3+ through electrostatic adsorption, surface metal ions (Mg2+), and acidic groups (-OH and -SO3H) exchanging with ions in solution. The adsorption performance of two self-made flower-like magnesium silicate materials for Co2+ and Cr3+ was superior to that of two commercial magnesium silicates.
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Mustard gas, a representative of blister agents, poses a severe threat to human health. Although the structure of 2-chloroethyl ethyl sulfide (2-CEES) is similar to mustard gas, 2-CEES is non-toxic, rendering it a commonly employed simulant in related research. ZnFe2O4-based semiconductor gas sensors exhibit numerous advantages, including structural stability, high sensitivities, and easy miniaturization. However, they exhibit insufficient sensitivity at low concentrations and require high operating temperatures. Owing to the effect of electronic and chemical sensitization, the gas-sensing performance of a sensor may be remarkably enhanced via the sensitization method of noble metal loading. In this study, based on the morphologies of ZnFe2O4 hollow microspheres, a solvothermal method was adopted to realize different levels of Au loading. Toward 1 ppm of 2-CEES, the gas sensor based on 2 wt.% Au-loaded ZnFe2O4 hollow microspheres exhibited a response sensitivity twice that of the gas sensor based on pure ZnFe2O4; furthermore, the response/recovery times decreased. Additionally, the sensor displayed excellent linear response to low concentrations of 2-CEES, outstanding selectivity in the presence of several common volatile organic compounds, and good repeatability, as well as long-term stability. The Au-loaded ZnFe2O4-based sensor has considerable potential for use in detecting toxic chemical agents and their simulants.
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Homogeneous electrocatalysts can indirect oxidate the high overpotential substrates through single-electron transfer on the electrode surface, enabling efficient operation of organic electrosynthesis catalytic cycles. However, the problems of this chemistry still exist such as high dosage, difficult recovery, and low catalytic efficiency. Single-atom catalysts (SACs) exhibit high atom utilization and excellent catalytic activity, hold great promise in addressing the limitations of homogeneous catalysts. In view of this, we have employed Fe-SA@NC as an advanced redox mediator to try to change this situation. Fe-SA@NC was synthesized using an encapsulation-pyrolysis method, and it demonstrated remarkable performance as a redox mediator in a range of reported organic electrosynthesis reactions, and enabling the construction of various C-C/C-X bonds. Moreover, Fe-SA@NC demonstrated a great potential in exploring new synthetic method for organic electrosynthesis. We employed it to develop a new electro-oxidative ring-opening transformation of cyclopropyl amides. In this new reaction system, Fe-SA@NC showed good tolerance to drug molecules with complex structures, as well as enabling flow electrochemical syntheses and gram-scale transformations. This work highlights the great potential of SACs in organic electrosynthesis, thereby opening a new avenue in synthetic chemistry.
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BACKGROUND: Competitive endogenous RNA (ceRNA) is an innovative way of gene expression modulation, which plays a crucial part in neoplasia. However, the intricacy and behavioral characteristics of the ceRNA network in hepatocellular carcinoma (HCC) remain dismal. AIM: To establish a cyclin dependent kinase inhibitor 2A (CDKN2A)-related ceRNA network and recognize potential prognostic indicators for HCC. METHODS: The mutation landscape of CDKN2A in HCC was first explored using the cBioPortal database. Differential expression analysis was implemented between CDKN2Ahigh and CDKN2Alow expression HCC samples. The targeted microRNAs were predicted by lncBasev3.0, and the targeted mRNAs were predicted by miRDB, and Targetscan database. The univariate and multivariate analysis were utilized to identify independent prognostic indicators. RESULTS: CDKN2A was frequently mutated and deleted in HCC. The single-cell RNA-sequencing analysis revealed that CDKN2A participated in cell cycle pathways. The CDKN2A-related ceRNA network-growth arrest specific 5 (GAS5)/miR-25-3p/SRY-box transcription factor 11 (SOX11) was successfully established. GAS5 was recognized as an independent prognostic biomarker, whose overexpression was correlated with a poor prognosis in HCC patients. The association between GAS5 expression and methylation, immune infiltration was explored. Besides, traditional Chinese medicine effective components targeting GAS5 were obtained. CONCLUSION: This CDKN2A-related ceRNA network provides innovative insights into the molecular mechanism of HCC formation and progression. Moreover, GAS5 might be a significant prognostic biomarker and therapeutic target in HCC.
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Similar to GaN and SiC semiconductors, GaC may be a potential semiconductor because of the mixed elemental features of Ga and C. Unfortunately, the phase stability and mechanical and physical properties of GaC are unknown. To search for novel third-generation semiconductors, the present study delves into an in-depth analysis of the structural stability and electronic and optical properties of GaC by DFT calculations. Similar to GaN, three GaC phases are discussed. It is found that three GaC phases (two cubic phases and one hexagonal phase) are first predicted. The band gaps of Fm3Ì m, F4Ì 3m, and hexagonal GaC are 0.449, 2.733, and 3.340 eV, respectively. In particular, the band gap of F4Ì 3m GaC and hexagonal GaC is bigger than that of GaN. Compared to GaN semiconductors, the C-2p state is in the valence band region across the Fermi level, which is beneficial to electronic mobility and electronic transport capacity near the Fermi level. In addition, three GaC phases exhibit ultraviolet properties. The first peak of three GaC phases produces the right migration compared to the GaN semiconductor. Therefore, the author predicts that GaC is a potential third-generation semiconductor material which is potentially used in future third-generation semiconductor industries.
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Anti-cancer response of cell lines to drugs is in urgent need for individualized precision medical decision-making in the era of precision medicine. Measurements with wet-experiments is time-consuming and expensive and it is almost impossible for wide ranges of application. The design of computational models that can precisely predict the responses between drugs and cell lines could provide a credible reference for further research. Existing methods of response prediction based on matrix factorization or neural networks have revealed that both linear or nonlinear latent characteristics are applicable and effective for the precise prediction of drug responses. However, the majority of them consider only linear or nonlinear relationships for drug response prediction. Herein, we propose a Dual Branch Deep Neural Matrix Factorization (DBDNMF) method to address the above-mentioned issues. DBDNMF learns the latent representation of drugs and cell lines through flexible inputs and reconstructs the partially observed matrix through a series of hidden neural network layers. Experimental results on the datasets of Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) show that the accuracy of drug prediction exceeds state-of-the-art drug response prediction algorithms, demonstrating its reliability and stability. The hierarchical clustering results show that drugs with similar response levels tend to target similar signaling pathway, and cell lines coming from the same tissue subtype tend to share the same pattern of response, which are consistent with previously published studies.
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Algoritmos , Redes Neurais de Computação , Reprodutibilidade dos Testes , Medicina de Precisão/métodos , Linhagem Celular TumoralRESUMO
With the rapid progress in a power conversion efficiency reaching up to 26.1%, which is among the highest efficiency for single-junction solar cells, organic-inorganic hybrid perovskite solar cells have become a research focus in photovoltaic technology all over the world, while the instability of these perovskite solar cells, due to the decomposition of its unstable organic components, has restricted the development of all-inorganic perovskite solar cells. In recent years, Br-mixed halogen all-inorganic perovskites (CsPbI3-xBrx) have aroused great interests due to their ability to balance the band gap and phase stability of pure CsPbX3. However, the photoinduced phase segregation in lead mixed halide perovskites is still a big burden on their practical industrial production and commercialization. Here, we demonstrate inhibited photoinduced phase segregation all-inorganic CsPbI1.2Br1.8 films and their corresponding perovskite solar cells by incorporating a 1-butyl-1-methylpiperidinium tetrafluoroborate ([BMP]+[BF4]-) compound into the CsPbI1.2Br1.8 films. Then, its effect on the perovskite films and the corresponding hole transport layer-free CsPbI1.2Br1.8 solar cells with carbon electrodes under light is investigated. With a prolonged time added to the reduced phase segregation terminal, this additive shows an inhibitory effect on the photoinduced phase segregation phenomenon for perovskite films and devices with enhanced cell efficiency. Our study reveals an efficient and simple route that suppresses photoinduced phase segregation in cesium lead mixed halide perovskite solar cells with enhanced efficiency.
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BACKGROUND: Induction of beige fat for grafting is an emerging transplantation strategy. However, safety concerns associated with pharmaceutical interventions limit its wider application. Moreover, because beige fat is a special type of fat with strong metabolic functions, its effect on the metabolism of recipients after grafting has not been explored in the plastic surgery domain. OBJECTIVES: The aim of this study was to explore whether cold-induced inguinal white adipose tissue (iWAT) transplantation has a higher retention rate and beneficial effects on recipient metabolism. METHODS: C57/BL6 mice were subjected to cold stimulation for 48 hours to induce the browning of iWAT and harvested immediately. Subsequently, each mouse received a transplant of 0.2â mL cold-induced iWAT or normal iWAT. Fat grafts and recipients' iWAT, epididymal adipose tissue, and brown adipose tissue were harvested at 8 weeks after operation. Immunofluorescence staining, real-time polymerase chain reaction, and western blot were used for histological and molecular analysis. RESULTS: Cold-induced iWAT grafting had a higher mean [standard error of the mean] retention rate (67.33% [1.74%] vs 55.83% [2.94%], P < .01) and more satisfactory structural integrity than normal iWAT. Histological changes identified improved adipose tissue homeostasis after cold challenge, including abundant smaller adipocytes, higher levels of adipogenesis, angiogenesis, and proliferation, but lower levels of fibrosis. More importantly, cold-induced iWAT grafting suppressed the inflammation of epididymal adipose tissue caused by conventional fat grafting, and activated the glucose metabolism and thermogenic activity of recipients' adipose tissues. CONCLUSIONS: Cold-induced iWAT grafting is an effective nonpharmacological intervention strategy to improve the retention rate and homeostasis of grafts. Furthermore, it improves the adverse effects caused by traditional fat grafting, while also conferring metabolic benefits.
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Tecido Adiposo Marrom , Temperatura Baixa , Camundongos Endogâmicos C57BL , Gordura Subcutânea , Animais , Masculino , Gordura Subcutânea/transplante , Gordura Subcutânea/metabolismo , Camundongos , Tecido Adiposo Marrom/transplante , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/transplante , Tecido Adiposo Bege/metabolismo , Sobrevivência de EnxertoAssuntos
Carcinoma Hepatocelular , Ferroptose , Imunoterapia , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Ferroptose/genética , Prognóstico , Imunoterapia/métodos , Sistema y+ de Transporte de Aminoácidos/genética , MasculinoAssuntos
Povo Asiático , Carcinoma Hepatocelular , Depressão , Neoplasias Hepáticas , Análise da Randomização Mendeliana , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Depressão/epidemiologia , Depressão/genética , Povo Asiático/genética , Ásia Oriental/epidemiologia , População Branca/genética , Europa (Continente)/epidemiologia , Fatores de Risco , População do Leste AsiáticoRESUMO
Maintenance of intestinal barrier function contributes to gastrointestinal homeostasis and therefore cardiovascular diseases. A number of studies show that intestinal permeability is affected by excessive inflammatory responses. Krüppel-like factor (KLF) 4 is one of the critical transcriptional factors, which controls multiple immune responses. In this study we investigated the role of KLF4 in regulating intestinal inflammation and permeability during the atherosclerotic process. Atherosclerotic model was established in ApoE-/- mice by feeding a high fat high cholesterol (HFHC) diet. We showed that colon expression levels of KLF4 and tight junction proteins were significantly decreased whereas inflammatory responses increased in atherosclerotic mice. Overexpression of colon epithelial Klf4 decreased atherosclerotic plaque formation and vascular inflammation in atherosclerotic mice, accompanied by remarkable suppression of intestinal NF-κB activation. We found that overexpression of epithelial Klf4 in atherosclerotic mice significantly increased intestinal tight junction expression and ameliorated endotoxemia, whereas replenishment of LPS abolished these benefits. Overexpression of Klf4 reversed LPS-induced permeability and downregulation of ZO-1 and Occludin in Caco-2 cells in vitro. HFHC diet stimulated the expression of epithelial microRNA-34a, whereas silence of epithelial Klf4 abolished the benefits of microRNA-34a sponge, a specific miR-34a inhibitor, on intestinal permeability and atherosclerotic development. A clinical cohort of 24 atherosclerotic patients supported colon KLF4/NF-κB/tight junction protein axis mediated intestine/cardiovascular interaction in patients with atherosclerosis. Taken together, intestinal epithelial KLF4 protects against intestinal inflammation and barrier dysfunction, ameliorating atherosclerotic plaque formation.
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Aterosclerose , Endotoxemia , Mucosa Intestinal , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like , Camundongos Endogâmicos C57BL , MicroRNAs , NF-kappa B , Fator 4 Semelhante a Kruppel/metabolismo , Animais , Aterosclerose/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , NF-kappa B/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Humanos , Endotoxemia/metabolismo , Camundongos , Mucosa Intestinal/metabolismo , Masculino , Células CACO-2 , Permeabilidade , Lipopolissacarídeos , Função da Barreira IntestinalRESUMO
In this work, the major methods for implementing flexible sensing technology-flexible surface acoustic wave (SAW) sensors-are summarized; the working principles and device characteristics of the flexible SAW sensors are introduced; and the latest achievements of the flexible SAW sensors in the selection of the substrate materials, the development of the piezoelectric thin films, and the structural design of the interdigital transducers are discussed. This paper focuses on analyzing the research status of physical flexible SAW sensors such as temperature, humidity, and ultraviolet radiation, including the sensing mechanism, bending strain performance, device performance parameters, advantages and disadvantages, etc. It also looks forward to the development of future chemical flexible SAW sensors for gases, the optimization of the direction of the overall device design, and systematic research on acoustic sensing theory under strain. This will enable the manufacturing of multifunctional and diverse sensors that better meet human needs.
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The effective detection of isopropyl methylfluorophosphonate (GB, sarin), a type of organophosphine poisoning agent, is an urgent issue to address to maintain public safety. In this research, a gas-sensitive film material, poly (4-hydroxy-4,4-bis trifluoromethyl)-butyl-1-enyl)-siloxane (SXFA), with a structure of hexafluoroisopropyl (HFIP) functional group was synthesized by using methyl vinylpropyl dichlorosilane and hexafluoroacetone trihydrate as initial materials. The synthesis process products were characterized using FTIR. SXFA was prepared on a 200 MHz shear surface wave delay line using the spin-coating method for GB detection. A detection limit of <0.1 mg/m3 was achieved through conditional experiments. Meanwhile, we also obtained a maximum response of 2.168 mV at a 0.1 mg/m3 concentration, indicating the much lower detection limit of the SAW-SXFA sensor. Additionally, a maximum response standard deviation of 0.11 mV with a coefficient of variation of 0.01 and a maximum recovery standard deviation of 0.22 mV with a coefficient of variation of 0.02 were also obtained through five repeated experiments. The results show that the SAW-SXFA sensor has strong selectivity and reproducibility, good selectivity, positive detection ability, high sensitivity, and fast alarm performance for sarin detection.
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OBJECTIVE: To provide novel insights into the aetiology of non-syndromic cleft lip with or without cleft palate (NSCL/P) by integrating multi-omics data and exploring susceptibility genes associated with NSCL/P. METHODS: A two-stage genome-wide association study (GWAS) of NSCL/P was performed, involving a total of 1,069 cases and 1,724 controls. Using promoter capture Hi-C (pCHi-C) datasets in human embryonic stem cells (hESC) and chromatin immunoprecipitation sequencing (ChIP-seq) in craniofacial tissues, we filtered out single nucleotide polymorphisms (SNPs) with active cis-regulation and their target genes. Additionally, we employed expression quantitative trait loci (eQTL) analysis to identify candidate genes. RESULTS: Thirteen SNPs were identified as cis-regulation units associated with the risk of NSCL/P. Five of these were proven to be active in chromatin states in early human craniofacial development (rs7218002: odds ratio [OR] 1.50, P = 8.14E-08; rs835367: OR 0.78, P = 3.48E- 05; rs77022994: OR 0.55, P = 1.05E-04; rs961470: OR 0.73, P = 1.38E-04; rs17314727: OR 0.73, P = 1.85E-04). Additionally, pCHi-C and eQTL analysis prioritised three candidate genes (rs7218002: NTN1, rs835367: FGGY, LINC01135). NTN1 and FGGY were expressed in mouse orofacial development. Deficiencies in NTN1, FGGY and LINC01135 were associated with cleft palate and cleft lip, abnormal facial shape and bifid uvula, and abnormality of the face, respectively. CONCLUSION: Our study identified five SNPs (rs7218002, rs835367, rs77022994, rs961470 and rs17314727) and three susceptibility genes (NTN1, FGGY and LINC01135) associated with NSCL/P. These findings contribute to a better understanding of the genetic factors involved.
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Fenda Labial , Fissura Palatina , Ictiose Lamelar , Humanos , Animais , Camundongos , Fissura Palatina/genética , Fenda Labial/genética , Estudo de Associação Genômica Ampla , Multiômica , CromatinaRESUMO
Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H+-ATPase subunit Vod1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1AKO) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy. Methods and Results: Atp6v0d1AKO mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The Atp6v0d1AKO mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes-related cardiomyopathy. The Atp6v0d1AKO mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1AKO mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter. Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. In vivo, restoring myocardin expression specifically in Atp6v0d1AKO cardiomyocytes increased IRS-1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in Atp6v0d1AKO hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1AKO mice. Conclusion: Atp6v0d1AKO mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction-related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes-related cardiomyopathy.