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Backgrounds: Risk stratification for major adverse cardiovascular events (MACE) within one year in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) remains a challenge. Although several predictive models based on machine learning have emerged, they are difficult to understand. This study aimed to develop a machine learning prediction model that is easy to understand and trustworthy by lay people to assess the risk of MACE in ACS patients undergoing PCI within one year of the procedure. Methods: This retrospective cohort study used medical data from 1105 patients to construct a machine-learning model. To ensure thoroughness and multidimensionality of model parsing, Shapley Additive explanations (SHAP) analysis and Local interpretable model-agnostic explanations (LIME) interpretation techniques were used to systematically and deeply interpret the constructed models from a global to a detailed level. Results: The study assessed 12 machine learning methods' prediction models and found that the Random Forest model was the most effective in predicting the risk of MACE in ACS patients after undergoing PCI. The model achieved an AUC value of 0.807 in the validation set, with an accuracy of 0.82, and a stable F1 score of 0.51. SHAP analysis ranked eight key feature variables, such as LVEF, in global importance. The weights of each feature range in the prediction model were revealed using LIME analysis. Conclusion: The machine learning prediction model we developed is capable of accurately predicting the likelihood of patients with ACS experiencing a MACE within one year of surgery.
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Microbes play a crucial role in the arsenic biogeochemical cycle through specific metabolic pathways to adapt to arsenic toxicity. However, the different arsenic-detoxification strategies between prokaryotic and eukaryotic microbes are poorly understood. This hampers our comprehension of how microbe-arsenic interactions drive the arsenic cycle and the development of microbial methods for remediation. In this study, we utilized conserved protein domains from 16 arsenic biotransformation genes (ABGs) to search for homologous proteins in 670 microbial genomes. Prokaryotes exhibited a wider species distribution of arsenic reduction- and arsenic efflux-related genes than fungi, whereas arsenic oxidation-related genes were more prevalent in fungi than in prokaryotes. This was supported by significantly higher acr3 (arsenite efflux permease) expression in bacteria (upregulated 3.72-fold) than in fungi (upregulated 1.54-fold) and higher aoxA (arsenite oxidase) expression in fungi (upregulated 5.11-fold) than in bacteria (upregulated 2.05-fold) under arsenite stress. The average values of nonsynonymous substitutions per nonsynonymous site to synonymous substitutions per synonymous site (dN/dS) of homologous ABGs were higher in archaea (0.098) and bacteria (0.124) than in fungi (0.051). Significant negative correlations between the dN/dS of ABGs and species distribution breadth and gene expression levels in archaea, bacteria, and fungi indicated that microbes establish the distinct strength of purifying selection for homologous ABGs. These differences contribute to the distinct arsenic metabolism pathways in prokaryotic and eukaryotic microbes. These observations facilitate a significant shift from studying individual or several ABGs to characterizing the comprehensive microbial strategies of arsenic detoxification.
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In this paper, Ti3C2Tx MXene/Cu-Bi bimetallic sulfide (Ti3C2Tx/BiCuS2.5) composites were prepared by a simple in situ deposition method for electrocatalytic nitrogen reduction reaction (eNRR). Compared to Ti3C2Tx/Bi2S3 and Ti3C2Tx/CuS, the eNRR performance of Ti3C2Tx/BiCuS2.5 is significantly improved. The results show that Ti3C2Tx/BiCuS2.5 exhibits a NH3 yield of 62.57 µg h-1 mg-1cat. in 0.1 M Na2SO4 at -0.6 V vs reversible hydrogen electrode, and the Faradaic efficiency (FE) reaches 67.69%, which is better than that of Ti3C2Tx/CuS (NH3 yield: 52.26 µg h-1 mg-1cat., FE: 34.15%) and Ti3C2Tx/Bi2S3 (NH3 yield: 54.04 µg h-1 mg-1cat., FE: 37.38%). According to density functional theory calculations, the eNRR at the Ti3C2Tx/BiCuS2.5 surface is the alternating pathway. The 1H NMR experiment of 15N proves that the N of NH3 generated in the experiment originates from N2 passed during the experiment.
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Peritendinous adhesion that forms after tendon injury substantially limits daily life. The pathology of adhesion involves inflammation and the associated proliferation. However, the current studies on this condition are lacking, previous studies reveal that cyclooxygenase-2 (COX2) gene inhibitors have anti-adhesion effects through reducing prostaglandin E2 (PGE2) and the proliferation of fibroblasts, are contrary to the failure in anti-adhesion through deletion of EP4 (prostaglandin E receptor 4) gene in fibroblasts in mice of another study. In this study, single-cell RNA sequencing analysis of human and mouse specimens are combined with eight types of conditional knockout mice and further reveal that deletion of COX2 in myeloid cells and deletion of EP4 gene in sensory nerves decrease adhesion and impair the biomechanical properties of repaired tendons. Furthermore, the COX2 inhibitor parecoxib reduces PGE2 but impairs the biomechanical properties of repaired tendons. Interestingly, PGE2 local treatment improves the biomechanical properties of the repaired tendons. These findings clarify the complex role of PGE2 in peritendinous adhesion formation (PAF) and tendon repair.
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The concentrations of atmospheric pollutants PM2.5, O3, SO2, NO2, and CO together with the meteorological factors of temperature ï¼Tï¼, relative humidity ï¼RHï¼, wind speed, and other relevant data in Tangshan from 2015 to 2021 were collected to study the variation characteristics of PM2.5 and O3 at different periods in Tangshan City in the past seven years and their influencing factors, to discuss the contributions of air mass transport to PM2.5 and O3 pollution, and to reveal the synergistic influence mechanism of PM2.5 and O3 on atmospheric compound pollution by using correlation analysis and backward trajectory cluster analysis techniques. The results showed that PM2.5 concentrations in Tangshan decreased year by year from 2015 to 2021, whereas O3 concentration showed a unimodal trend, with the peak appearing in 2017. Both PM2.5 and O3 concentrations showed obvious seasonal variation trendsï¼ PM2.5 was characterized by the highest concentration in winter and the lowest concentration in summer, whereas O3 was characterized by the highest concentration in summer and the lowest concentration in winter. In addition, the diurnal variation in PM2.5 showed a bimodal distribution, with the peak occurring during the morning and evening on weekdays, and O3 showed a unimodal distribution, with the peak value appearing during the period with strong ultraviolet radiation in the afternoon. PM2.5 had a significant positive correlation with SO2, NO2, and CO, whereas O3 had a significant positive correlation with radiation and temperature. Under the different pollution conditions, PM2.5 and O3 were affected by air mass transports from different directions. Being impacted by various factors, the synergistic effect of PM2.5 and O3 on atmospheric compound pollution showed an obvious negative effect in winter, whereas there was an obvious positive effect in spring, summer, and autumn. Under the backgrounds of different pollutions, when the concentration of PM2.5 exceeded 150 µg·m-3, the synergistic effect of PM2.5 and O3 showed an obvious negative effect.
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Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammatory cell infiltration, which can lead to chronic disability, joint destruction and loss of function. At present, the pathogenesis of RA is still unclear. The purpose of this study is to explore the potential biomarkers and immune molecular mechanisms of rheumatoid arthritis through machine learning-assisted bioinformatics analysis, in order to provide reference for the early diagnosis and treatment of RA disease. Methods: RA gene chips were screened from the public gene GEO database, and batch correction of different groups of RA gene chips was performed using Strawberry Perl. DEGs were obtained using the limma package of R software, and functional enrichment analysis such as gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), disease ontology (DO), and gene set (GSEA) were performed. Three machine learning methods, least absolute shrinkage and selection operator regression (LASSO), support vector machine recursive feature elimination (SVM-RFE) and random forest tree (Random Forest), were used to identify potential biomarkers of RA. The validation group data set was used to verify and further confirm its expression and diagnostic value. In addition, CIBERSORT algorithm was used to evaluate the infiltration of immune cells in RA and control samples, and the correlation between confirmed RA diagnostic biomarkers and immune cells was analyzed. Results: Through feature screening, 79 key DEGs were obtained, mainly involving virus response, Parkinson's pathway, dermatitis and cell junction components. A total of 29 hub genes were screened by LASSO regression, 34 hub genes were screened by SVM-RFE, and 39 hub genes were screened by Random Forest. Combined with the three algorithms, a total of 12 hub genes were obtained. Through the expression and diagnostic value verification in the validation group data set, 7 genes that can be used as diagnostic biomarkers for RA were preliminarily confirmed. At the same time, the correlation analysis of immune cells found that γδT cells, CD4+ memory activated T cells, activated dendritic cells and other immune cells were positively correlated with multiple RA diagnostic biomarkers, CD4+ naive T cells, regulatory T cells and other immune cells were negatively correlated with multiple RA diagnostic biomarkers. Conclusions: The results of novel characteristic gene analysis of RA showed that KYNU, EVI2A, CD52, C1QB, BATF, AIM2 and NDC80 had good diagnostic and clinical value for the diagnosis of RA, and were closely related to immune cells. Therefore, these seven DEGs may become new diagnostic markers and immunotherapy markers for RA.
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Xanthogranulomatous cholecystitis (XGC) is a rare type of cholecystitis that, despite being benign poses diagnostic challenges due to its low prevalence and need for consensus on diagnostic criteria. Consequently, distinguishing XGC from gallbladder cancer (GBC) is challenging, leading to clinical misdiagnoses. This article presents a case where a patient initially diagnosed with GBC was later found to have XGC.
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Based on the heterogeneous composite design of C3N4 and TiO2, composite photocatalysts of C3N4@TiO2 (with varied molar ratios of C3N4 to TiO2) were synthesized by a water bath method to degrade RhB in wastewater. The composition, morphology, structure, and photocatalytic properties of the materials were assessed through a variety of characterization techniques. The results show that TiO2 nanoparticles are uniformly coated on two-dimensional g-C3N4 nanosheets, forming relatively dense heterostructures within the C3N4@TiO2 composite. Due to the synergistic effect derived from the heterogeneous component and appropriate proportion of C3N4 and TiO2, the light absorption range is extended, and the separation/transport performance of photon-generated carrier is improved. As a result, TCNT-3 (where the molar ratio of C3N4 to TiO2 is 1:1) presents remarkable photocatalytic performance, the degradation rate of which for 60 min is 99.8%, and the reaction rate constant is calculated to be 0.0872 min-1. Moreover, the degradation efficiency remains 94.4% after 5 cycles, indicating the superior cycle stability.
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ZnxCd1-xS photocatalysts have been widely investigated due to their diverse morphologies, suitable band gaps/band edge positions, and high electronic mobility. However, the sluggish charge separation and severe charge recombination impede the application of ZnxCd1-xS for hydrogen evolution reaction (HER). Herein, doping of phosphorus (P) atoms into Zn0.3Cd0.7S has been implemented to elevate S vacancies concentration as well as tune its Fermi level to be located near the impurity level of S vacancies, prolonging the lifetime of photogenerated electrons. Moreover, P doping induces a hybridized state in the bandgap, leading to an imbalanced charge distribution and a localized built-in electric field for effective separation of photogenerated charge carriers. Further construction of intimate heterojunctions between P-Zn0.3Cd0.7S and MoS2 accelerates surface redox reaction. Benefiting from the above merits, 1 % MoS2/P-Zn0.3Cd0.7S exhibits a high hydrogen production rate of 30.65 mmol·g-1·h-1 with AQE of 22.22 % under monochromatic light at 370 nm, exceeding most ZnxCd1-xS based photocatalysts reported so far. This work opens avenues to fabricate examplary photocatalysts for solar energy conversion and beyond.
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Atmospheric precipitation samples were collected in 2018, 2019, and 2021 in Beijing to study the concentrations and changes of the main metal elements and water-soluble ionsï¼ the wet deposition fluxes of heavy metals, water-soluble ions, dissolved inorganic nitrogen, and sulfur in the atmospheric precipitation and their impacts on the ecological environmentï¼ and the scavenging mechanisms of the typical precipitation to atmospheric pollutants during the study period. The results showed that the precipitation in Beijing during the study period was mostly neutral or alkaline, and the frequency of acid rain occurrence was very low, only accounting for 3.06%. The total concentrations of major metal elements in 2018, 2019, and 2021 were ï¼4 787.46 ±4 704.31ï¼, ï¼7 663.07 ±8 395.05ï¼, and ï¼2 629.13 ±2 369.51ï¼ µg·L-1, respectively. The total equivalent concentrations of ions in 2018, 2019, and 2021 were ï¼851.68 ±649.16ï¼, ï¼973.98 ±850.94ï¼, and ï¼644.31 ±531.16ï¼ µeq·L-1, respectively. The interannual changes in major metal elements and ions followed the order of 2019 > 2018 > 2021. The seasonal average total concentrations of major metal elements in spring, summer, autumn, and winter were ï¼9 624.25 ±7 327.92ï¼, ï¼4 088.67 ±5 710.14ï¼, ï¼3 357.68 ±3 995.64ï¼, and ï¼6 203.19 ±3 857.43ï¼ µg·L-1, respectively, and the seasonal average total equivalent concentrations of ions in spring, summer, autumn, and winter were ï¼1 014.71 ±512.21ï¼, ï¼729.83 ±589.90ï¼, ï¼724.35 ±681.40ï¼, and ï¼1 014.03 ±359.67ï¼ µeq·L-1, respectively, all presenting the order of spring > winter > summer > autumn. NO3- and SO42- were the main acid-causing ions in precipitation, whereas NH4+ and Ca2+ were the main acid-neutralizing ions. The wet deposition fluxes of the heavy metal Cd were very low [ï¼0.05 ±0.01ï¼ mg·ï¼m2·aï¼-1], only accounting for ï¼0.13 ±0.04ï¼% of the total wet deposition fluxes of main metal elementsï¼ however, its soil safety years were 291 years, significantly lower than those of other heavy metals, displaying that its ecological risk was relatively the highest. The total wet precipitation flux of water-soluble ions NH4+, Ca2+, NO3-, and SO42- accounted for ï¼85.72 ±2.18ï¼% of the wet precipitation flux of total ions, suggesting that their comprehensive impact on the ecological environment might have been higher. DIN wet deposition flux was mainly characterized by NH4+-N, which had a positive impact on the ecological environment in summer. SO42--S wet deposition flux was higher in summer, so its positive impact on the ecological environment was also greater. The scavenging effects of atmospheric precipitations to pollutants from the air were impacted by various factors, and the synergism effects of these factors could directly influence the scavenging mechanisms of precipitation to pollutants.
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We propose to improve the solar energy utilization by using InGaN inclined nanowire array photocathodes. We first study vertical nanowire array. On the basis of vertical nanowire array, we study inclined nanowires by changing the inclination angle of nanowires. The inclined nanowires exhibit higher quantum efficiency at larger period and larger inclination angle. However, the infinite expansion of period will cause its performance to degrade. The quantum efficiency of inclined nanowires with a period of 175 nm and an inclination angle of 5.35° is as high as 80.2% when the incident light angle is irradiated at 5°. In addition, applying an electric field can improve the collection efficiency of inclined nanowires and help them maintain a high collection efficiency over a longer wavelength range. The design principles proposed in this work will provide a theoretical reference for the performance improvement of InGaN photocathodes.
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Aim: The information assessing sex differences in outcomes of patients with three-vessel coronary disease (TVD) after different treatment strategies is sparse. This study aimed to investigate long-term outcomes of TVD among women compared with men after medical therapy (MT) alone, percutaneous coronary intervention (PCI), or coronary artery bypass grafting surgery (CABG). Methods: Consecutive 8943 patients with TVD were enrolled. Associations between sex and all-cause death and major adverse cardiac and cerebrovascular events (MACCE) (all-cause death, myocardial infarction, or stroke) were assessed. Results: Of the 8943 patients, 1821 (20.4%) were women. During a median follow-up of 6.6 years, women had comparable incidences of all-cause death (16.6% vs. 14.9%, P = 0.079) and MACCE (27.2% vs. 26.1%, P = 0.320) to men. After multivariable analysis, women showed lower adjusted risks of all-cause death (HR: 0.777; P = 0.001) and MACCE (HR: 0.870; P = 0.016) than men in the entire cohort. Subgroup analysis revealed that the less all-cause death risk of women relative to men was significant in PCI (HR: 0.702; P = 0.009), and CABG groups (HR: 0.708; P = 0.047), but not in MT alone group. Lower MACCE risk for women vs. men was significant only in PCI group (HR: 0.821; P = 0.037). However, no significant interaction between sex and three strategies was observed for all-cause death (P for interaction = 0.312) or MACCE (P for interaction = 0.228). Conclusions: The cardiovascular prognosis of TVD female patients is better than that of men, which has no interaction with the treatment strategies received (MT alone, PCI, or CABG).
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Puente de Arteria Coronaria , Enfermedad de la Arteria Coronaria , Intervención Coronaria Percutánea , Humanos , Femenino , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/métodos , Enfermedad de la Arteria Coronaria/cirugía , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/terapia , Factores Sexuales , Puente de Arteria Coronaria/estadística & datos numéricos , Anciano , Estudios de Seguimiento , Estudios Retrospectivos , Resultado del Tratamiento , Factores de Tiempo , Incidencia , Causas de Muerte/tendencias , Factores de Riesgo , Tasa de Supervivencia/tendenciasRESUMEN
The double-bag theory in modern anatomy suggests that structures with coatings are commonly found in human body at various length scales, such as osteocyte processes covered by pericellular matrix and bones covered by muscle tissue. To understand the mechanical behaviors and physiological responses of such biological structures, we develop an analytical model to quantify surface effects on the deformation of a coated cylindrical compressible liquid inclusion in an elastic matrix subjected to remote loading. Our analytical solution reveals that coating can either amplify or attenuate the volumetric strain of the inclusion, depending on the relative elastic moduli of inclusion, coating, and matrix. For illustration, we utilize this solution to explore amplification/attenuation of volumetric strain in musculoskeletal systems, nerve cells, and vascular tissues. We demonstrate that coating often plays a crucial role in mechanical regulation of the development and repair of human tissues and cells. Our model provides qualitative analysis of cross-scale mechanical response of coated liquid inclusions, helpful for constructing mechanical microenvironment of cells.
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Modelos Biológicos , Humanos , Fenómenos Biomecánicos , Estrés Mecánico , Módulo de Elasticidad , Fuerza CompresivaRESUMEN
The road passenger transportation enterprise is a complex system, requiring a clear understanding of their active safety situation (ASS), trends, and influencing factors. This facilitates transportation authorities to promptly receive signals and take effective measures. Through exploratory factor analysis and confirmatory factor analysis, we delved into potential factors for evaluating ASS and extracted an ASS index. To predict obtaining a higher ASS information rate, we compared multiple time series models, including GRU (gated recurrent unit), LSTM (long short-term memory), ARIMA, Prophet, Conv_LSTM, and TCN (temporal convolutional network). This paper proposed the WDA-DBN (water drop algorithm-Deep Belief Network) model and employed DEEPSHAP to identify factors with higher ASS information content. TCN and GRU performed well in the prediction. Compared to the other models, WDA-DBN exhibited the best performance in terms of MSE and MAE. Overall, deep learning models outperform econometric models in terms of information processing. The total time spent processing alarms positively influences ASS, while variables such as fatigue driving occurrences, abnormal driving occurrences, and nighttime driving alarm occurrences have a negative impact on ASS.
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BACKGROUND: Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers. METHODS: Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk. RESULTS: A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88-0.95, P = 2.92 × 10-7) and Europe (OR = 0.92, 95%CI 0.88-0.95, P = 4.61 × 10-6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field. CONCLUSION: Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.
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Elementos de Facilitación Genéticos , Neoplasias , Sitios de Carácter Cuantitativo , Humanos , Elementos de Facilitación Genéticos/genética , Neoplasias/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo/métodos , Neoplasias Colorrectales/genética , Estudios de Casos y Controles , ARN/genética , China , ARN PotenciadoresRESUMEN
Improving the separation efficiency of carriers is an important part of enhancing photocatalytic activity. Herein, we successfully decorated metallic 1T phase tungsten disulfide (1T-WS2) on the surface of zinc indium sulfide (ZnIn2S4) and investigated the synergistic effect of 1T-WS2 on ZnIn2S4. The characterization results show that 1T-WS2 improves the light absorption capacity and utilization efficiency, increases the catalytic active site, improves the photogenerated charge separation efficiency, and optimizes the reduction potential of ZnIn2S4. Theoretical calculations show that compared with ZnIn2S4, 1T-WS2/ZnIn2S4 has a smaller adsorption Gibbs free energy of the intermediate state H*, which is conducive to the catalytic reaction. Under simulated solar irradiation, the hydrogen (H2) production rate of 1T-WS2/ZnIn2S4 with a loading of 12 wt% reaches 30.90 mmol h-1 g-1, which is 3.38 times higher than that of single ZnIn2S4 (9.13 mmol h-1 g-1). In addition, the apparent quantum efficiency of 1T-WS2/ZnIn2S4 with a loading of 12 wt% reaches 21.14 % under monochromatic light at a wavelength of λ = 370 nm. This work analyzes the light absorption and carrier separation to the catalytic site, and elucidates the mechanism for the enhancement of the photocatalytic hydrogen production performance.
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The endoplasmic reticulum (ER) is connected to mitochondria through mitochondria-associated ER membranes (MAMs). MAMs provide a framework for crosstalk between the ER and mitochondria, playing a crucial role in regulating cellular calcium balance, lipid metabolism, and cell death. Dysregulation of MAMs is involved in the development of chronic liver disease (CLD). In CLD, changes in MAMs structure and function occur due to factors such as cellular stress, inflammation, and oxidative stress, leading to abnormal interactions between mitochondria and the ER, resulting in liver cell injury, fibrosis, and impaired liver function. Traditional Chinese medicine has shown some research progress in regulating MAMs signaling and treating CLD. This paper reviews the literature on the association between mitochondria and the ER, as well as the intervention of traditional Chinese medicine in regulating CLD.
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An efficient and sustainable electrochemical method for the synthesis of cyclic ethers and acyclic aldehydes from alkanols has been reported. This strategy has been successfully applied to cycloalkanols bearing different ring sizes and different types of nucleophiles. In addition, mechanistic investigations show that the reactions undergo sequential processes, including anodic oxidation, ß-scission, and nucleophilic addition. This method provides a new synthetic approach to constructing cyclic ethers and terminal aldehydes from cycloalkanols and nucleophiles.
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Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1-/- mice (Ackr1-/- chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.
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Movimiento Celular , Macrófagos , Regeneración , Humanos , Animales , Macrófagos/metabolismo , Ratones , Tendones/metabolismo , Tendones/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/genética , Proteómica , Femenino , MultiómicaRESUMEN
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. METHODS: This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. DISCUSSION: This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. TRIAL REGISTRATION: This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).