Unraveling the immunogenic cell death pathways in gastric adenocarcinoma: A multi-omics study.

BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal (GI) system. However, the lack of reliable biomarkers has made its diagnosis, prognosis, and treatment challenging. Immunogenic cell death (ICD) is a type of programmed cell death that is strongly related to the immune system. However, its function in GC requires further investigation. METHOD: We used multi-omics and multi-angle approaches to comprehensively explore the prognostic features of ICD in patients with stomach adenocarcinoma (STAD). At the single-cell level, we screened genes associated with ICD at the transcriptome level, selected prognostic genes related to ICD using weighted gene co-expression network analysis (WGCNA) and machine learning, and constructed a prognostic model. In addition, we constructed nomograms that incorporated pertinent clinical features and provided effective tools for prognostic prediction in clinical settings. We also investigated the sensitivity of the risk subgroups to both immunotherapy and drugs. Finally, in addition to quantitative real-time polymerase chain reaction, immunofluorescence was used to validate the expression of ICD-linked genes. RESULTS: Based on single-cell and transcriptome WGCNA analyses, we identified 34 ICD-related genes, of which 11 were related to prognosis. We established a prognostic model using the least absolute shrinkage and selection operator (LASSO) algorithm and identified dissimilarities in overall survival (OS) and progression-free survival (PFS) in risk subgroups. The nomograms associated with the ICD-related signature (ICDRS) demonstrated a good predictive value for clinical applications. Moreover, we detected changes in the tumor microenvironment (TME), including biological functions, mutation landscapes, and immune cell infiltration, between the high- and low-risk groups. CONCLUSION: We constructed an ICD-related prognostic model that incorporated features related to cell death. This model can serve as a useful tool for predicting the prognosis of GC, targeted prevention, and personalized medicine.

Machine learning-based prediction model and visual interpretation for prostate cancer.

BACKGROUND: Most prostate cancers(PCa) rely on serum prostate-specific antigen (PSA) testing for biopsy confirmation, but the accuracy needs to be further improved. We need to continue to develop PCa prediction model with high clinical application value. METHODS: Benign prostatic hyperplasia (BPH) and prostate cancer data were obtained from the Chinese National Clinical Medical Science Data Center for retrospective analysis. The model was constructed using the XGBoost algorithm, and patients' age, body mass index (BMI), PSA-related parameters and serum biochemical parameters were used as model variables. Using decision analysis curve (DCA) to evaluate the clinical utility of the models. The shapley additive explanation (SHAP) framework was used to analyze the importance ranking and risk threshold of the variables. RESULTS: A total of 1915 patients were included in this study, including 823 (43.0%) were BPH patients and 1092 (57.0%) were PCa patients. The XGBoost model provided better performance (AUC 0.82) compared with f/tPSA (AUC 0.75),tPSA (AUC 0.68) and fPSA (AUC 0.61), respectively. Based on SHAP values, f/tPSA was the most important variable, and the top five most important biochemical parameter variables were inorganic phosphorus (P), potassium (K), creatine kinase MB isoenzyme (CKMB), low-density lipoprotein cholesterol (LDL-C), and creatinine (Cre). PCa risk thresholds for these risk markers were f/tPSA (0.13), P (1.29 mmol/L), K (4.29 mmol/L), CKMB ( 11.6U/L), LDL-C (3.05mmol/L) and Cre (74.5-99.1umol/L). CONCLUSION: The present model has advantages of wide-spread availability and high net benefit, especially for underdeveloped countries and regions. Furthermore, these risk thresholds can assist in the diagnosis and screening of prostate cancer in clinical practice.

[Association of ventricular septal defect with rare variations of the HAND2 gene]. / 室间隔缺损与HAND2åŸºå› ç½•è§å˜å¼‚çš„å ³è”åˆ†æž.

OBJECTIVES: To study the association of ventricular septal defect (VSD) with rare variations in the promoter region of HAND2 gene, as well as related molecular mechanisms. METHODS: Blood samples were collected from 349 children with VSD and 345 healthy controls. The target fragments were amplified by polymerase chain reaction and sequenced to identify the rare variation sites in the promoter region of the HAND2 gene. Dual-luciferase reporter assay was used to perform a functional analysis of the variation sites. Electrophoretic mobility shift assay (EMSA) was used to investigate related molecular mechanisms. TRANSFAC and JASPAR databases were used to predict transcription factors. RESULTS: Sequencing revealed that three variation sites (g.173530852A>G, g.173531173A>G, and g.173531213C>G) were only observed in the promoter region of the HAND2 gene in 10 children with VSD, among whom 4 children had only one variation site. The dual-luciferase reporter assay revealed that g.173531213C>G reduced the transcriptional activity of the HAND2 gene promoter. EMSA and transcription factor prediction revealed that g.173531213C>G created a binding site for transcription factor. CONCLUSIONS: The rare variation, g.173531213C>G, in the promoter region of the HAND2 gene participates in the development and progression of VSD possibly by affecting the binding of transcription factors.

Ultra-narrow-linewidth DFB laser array based on dual-cavity feedback.

Herein, we propose a structure to simultaneously compress the distributed feedback (DFB) laser array's linewidth. The proposed structure is meticulously designed to ensure single longitudinal mode operation via the interference phenomenon between the laser's primary cavity and the dual-cavity feedback. Given the weak feedback effect for each wavelength in the laser array, the proposed structure could realize the intense compression of the laser linewidths. The study results show that the side-mode suppression ratios of each DFB laser are over 40 dB, and the linewidths have been compressed from 3 MHz to ∼800 Hz. Thus, we believe the idea of an overall compression linewidth scheme in the present study can be adopted for integrated laser arrays.

A support vector regression model to predict nitrate-nitrogen isotopic composition using hydro-chemical variables.

Nitrate is a prominent pollutant in surface and groundwater bodies worldwide. Isotopes in nitrate provide a powerful approach for tracing nitrate sources and transformations in waters. Given that analytical techniques for determining isotopic compositions are generally time-consuming, laborious and expensive, alternative methods are warranted to supplement and enhance existing approaches. Hence, we developed a support vector regression (SVR) model and explored its feasibility to predict nitrogen isotopic composition of nitrate (δ15N-NO3-) in a rural-urban river system in Southeastern China. A total of 16 easily obtained hydro-chemical variables were measured in the wet season (September 2019) and dry season (January 2020) and used to develop the SVR prediction model. The grading method utilized ~75% (35) of the samples for model building while the remaining 11 samples assessed model performance. Principal component analysis (PCA) extracted 7 principal components for SVR model inputs as PCA reduces superfluous variables. We optimized tuning parameters in the SVR model using a grid search technique coupled with V-fold cross-validation. The optimized SVR model provided accurate δ15N-NO3- predictions with a determination coefficient (R2) of 0.88, Nash-Sutcliffe (NS) of 0.87, and mean square error (MSE) of 0.53‰ in the testing step, and performed much better than the corresponding multivariate linear regression model (R2 = 0.60, NS = 0.58 and MSE = 1.76‰) and general regression neural network model (R2 = 0.66, NS = 0.65 and MSE = 1.45‰). Overall, the SVR model provides a potential indirect method to predict environmental isotope values for water quality management that will complement and enhance the interpretation of direct measurements of δ15N-NO3-.

Protein-Based Artificial Nanosystems in Cancer Therapy.

Proteins, like actors, play different roles in specific applications. In the past decade, significant achievements have been made in protein-engineered biomedicine for cancer therapy. Certain proteins such as human serum albumin, working as carriers for drug/photosensitizer delivery, have entered clinical use due to their long half-life, biocompatibility, biodegradability, and inherent nonimmunogenicity. Proteins with catalytic abilities are promising as adjuvant agents for other therapeutic modalities or as anticancer drugs themselves. These catalytic proteins are usually defined as enzymes with high biological activity and substrate specificity. However, clinical applications of these kinds of proteins remain rare due to protease-induced denaturation and weak cellular permeability. Based on the characteristics of different proteins, tailor-made protein-based nanosystems could make up for their individual deficiencies. Therefore, elaborately designed protein-based nanosystems, where proteins serve as drug carriers, adjuvant agents, or therapeutic drugs to make full use of their intrinsic advantages in cancer therapy, are reviewed. Up-to-date progress on research in the field of protein-based nanomedicine is provided.

Molecularly Imprinted Materials for Selective Biological Recognition.

Molecular imprinting is an approach of generating imprinting cavities in polymer structures that are compatible with the target molecules. The cavities have memory for shape and chemical recognition, similar to the recognition mechanism of antigen-antibody in organisms. Their structures are also called biomimetic receptors or synthetic receptors. Owing to the excellent selectivity and unique structural predictability of molecularly imprinted materials (MIMs), practical MIMs have become a rapidly evolving research area providing key factors for understanding separation, recognition, and regenerative properties toward biological small molecules to biomacromolecules, even cell and microorganism. In this review, the characteristics, morphologies, and applicability of currently popular carrier materials for molecular imprinting, especially the fundamental role of hydrogels, porous materials, hierarchical nanoparticles, and 2D materials in the separation and recognition of biological templates are discussed. Moreover, through a series of case studies, emphasis is given on introducing imprinting strategies for biological templates with different molecular scales. In particular, the differences and connections between small molecular imprinting (bulk imprinting, "dummy" template imprinting, etc.), large molecular imprinting (surface imprinting, interfacial imprinting, etc.), and cell imprinting strategies are demonstrated in detail. Finally, future research directions are provided.

Fractal MTW Zeolite Crystals: Hidden Dimensions in Nanoporous Materials.

Screw dislocation structures in crystals are an origin of symmetry breaking in a wide range of dense-phase crystals. Preparation of such analogous structures in framework-phase crystals is of great importance in zeolites but is still a challenge. On the basis of crystal-structure solving and model building, it was found that the two specific intergrowths in MTW zeolite produce this complex fractal and spiral structure. With the structurally determined parameters (spiral pitch h, screw angle θ, and spatial angle ψ) of Burgers circuit, the screw dislocation structure can be constructed by two different dimensional intergrowth sections. Thus the reported complexity of various dimensions in diverse crystals can be unified.

Two novel reassortants of avian influenza A (H5N6) virus in China.

Eight avian influenza A (H5N6) viruses were isolated from live poultry markets (LPMs) in Sichuan and Jiangxi Provinces in China in 2014, including those close to the county where the human H5N6 infection occurred. Genetic and phylogenetic analyses revealed that these H5N6 viruses were novel reassortants between H5N1 clade 2.3.4 and H6N6 viruses, and had evolved into two distinct lineages (Sichuan and Jiangxi). Moreover, the human H5N6 virus was closely related to the avian-source viruses of Sichuan lineage. Notably, H5N6 viruses contained a T160A substitution in the haemagglutinin protein and an 11 aa deletion in the neuraminidase stalk, which may aid in enhancing viral affinity for human-like receptors and virulence in mammals. As the H5N1 virus infects humans through direct contact, infection with the novel H5N6 virus raised significant concerns that the H5 subtype was a likely candidate for a pandemic. Therefore, extensive and long-term surveillance of avian influenza viruses in LPMs is essential.

Age-related DNA methylation changes for forensic age-prediction.

There is no available method of age-prediction for biological samples. The accumulating evidences indicate that DNA methylation patterns change with age. Aging resembles a developmentally regulated process that is tightly controlled by specific epigenetic modifications and age-associated methylation changes exist in human genome. In this study, three age-related methylation fragments were isolated and identified in blood of 40 donors. Age-related methylation changes with each fragment was validated and replicated in a general population sample of 65 donors over a wide age range (11-72 years). Methylation of these fragments is linearly correlated with age over a range of six decades (r = 0.80-0.88). Using average methylation of CpG sites of three fragments, a regression model that explained 95 % of the variance in age was built and is able to predict an individual's age with great accuracy (R (2 )= 0.93). The predicted value is highly correlated with the observed age in the sample (r = 0.96) and has great accuracy of average 4 years difference between predicted age and true age. This study implicates that DNA methylation can be an available biological marker of age-prediction. Further measurement of relevant markers in the genome could be a tool in routine screening to predict age of forensic biological samples.

An efficient one-pot four-segment condensation method for protein chemical synthesis.

Successive peptide ligation using a one-pot method can improve the efficiency of protein chemical synthesis. Although one-pot three-segment ligation has enjoyed widespread application, a robust method for one-pot four-segment ligation had to date remained undeveloped. Herein we report a new one-pot multisegment peptide ligation method that can be used to condense up to four segments with operational simplicity and high efficiency. Its practicality is demonstrated by the one-pot four-segment synthesis of a plant protein, crambin, and a human chemokine, hCCL21.

An inverse causal relationship between serum 25-hydroxyvitamin D levels and pulmonary hypertension: A two-sample Mendelian randomization study.

Observational studies have confirmed that 25-hydroxyvitamin D (25(OH)D) is associated with pulmonary hypertension (PH), but the causal association between each other is unclear. Therefore, Mendelian randomization (MR) method was performed to validate the causal association between PH and serum 25(OH)D levels. The summary data for 25(OH)D and PH were from the National Human Genome Research Institute-European Bioinformatics Institute. Catalog of human genome-wide association studies and FinnGen biobank consortium. MR analysis was utilized to explore the potential causal association between PH and 25(OH)D. To evaluate this association, inverse variance weighting was considered as the primary method. Cochran's Q test, MR-Egger intercept test, and "leave-one-out" sensitivity analyses were utilized to control the pleiotropy and heterogeneity in the study. Two-sample MR analysis revealed an inverse causal relationship between 25(OH)D and PH (odds ratio: 0.376, 95% confidence interval: 0.162-0.876, p = 2.334 × 10-2). There was no significant heterogeneity and pleiotropy. The present study confirmed the inverse causal relationship between 25(OH)D and PH. This pathway may provide another treatment pathway in PH. Further studies to elucidate this pathway is indicated.

Whole exome sequencing and proteomics-based investigation of the pathogenesis of coronary artery disease with diffuse long lesion.

OBJECTIVES: The long-term prognosis of patients with coronary artery disease (CAD) with diffuse long lesion underwent coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) remains worse. Here, we aimed to identify distinctive genes involved and offer novel insights into the pathogenesis of diffuse long lesion. MATERIALS AND METHODS: Whole exome sequencing was performed on peripheral blood samples from 20 CAD patients with diffuse long lesion (CAD-DLL) and from 10 controls with focal lesion (CAD-FL) through a uniform pipeline. Proteomics analysis was conducted on the serum samples from 10 CAD-DLL patients and from 10 controls with CAD-FL by mass spectrometry. Bioinformatics analysis was performed to elucidate the involved genes, including functional annotation and protein-protein interaction analysis. RESULTS: A total of 742 shared variant genes were found in CAD-DLL patients but not in controls. Of these, 46 genes were identified as high-frequency variant genes (≥ 4/20) distinctive genes. According to the consensus variant site, 148 shared variant sites were found in the CAD-DLL group. The lysosome and cellular senescence-related pathway may be the most significant pathway in diffuse long lesion. Following the DNA-protein combined analysis, eight genes were screened whose expression levels were altered at both DNA and protein levels. Among these genes, the MAN2A2 gene, the only one that was highly expressed at the protein level, was associated with metabolic and immune-inflammatory dysregulation. CONCLUSIONS: Compared to individuals with CAD-FL, patients with CAD-DLL show additional variants. These findings contribute to the understanding of the mechanism of CAD-DLL and provide potential targets for the diagnosis and treatment of CAD-DLL.

Research progress of porcine epidemic diarrhea virus S protein.

Porcine epidemic diarrhea virus (PEDV) is a single-stranded RNA virus with a capsid membrane that causes acute infectious gastrointestinal disease characterized by vomiting, diarrhea, and dehydration in swine. Piglets are more susceptible to PEDV than adults, with an infection rate reaching 90% and a fatality rate as high as 100%. Moreover, PEDV has a rapid transmission rate and broad transmission range. Consequently, PEDV has caused considerable economic losses and negatively impacted the sustainability of the pig industry. The surface spike (S) glycoprotein is the largest structural protein in PEDV virions and is closely associated with host cell fusion and virus invasion. As such, the S protein is an important target for vaccine development. In this article, we review the genetic variation, immunity, apoptosis-induction function, virulence, vaccine potential, and other aspects of the PEDV S protein. This review provides a theoretical foundation for preventing and controlling PEDV infection and serves as a valuable resource for further research and development of PEDV vaccines.

Blood-brain barrier permeable carbon nano-assemblies for amyloid-ß clearance and neurotoxic attenuation.

Abnormal amyloid ß-protein (Aß42) fibrillation is a key event in Alzheimer's disease (AD), and photodynamic therapy (PDT) possesses great potential in modulating Aß42 self-assembly. However, the poor blood-brain barrier (BBB) penetration, low biocompatibility, and limited tissue penetration depth of existing photosensitizers limit the progress of photo-oxidation strategies. In this paper, novel indocyanine green-modified graphene quantum dot nano-assemblies (NBGQDs-ICGs) were synthesized based on a molecular assembly strategy of electrostatic interactions for PDT inhibition of Aß42 self-assembly process and decomposition of preformed fibrils under near-infrared light. Combining the small-size structure of graphene quantum dots and the near-infrared light-responsive properties of ICGs, the NBGQDs-ICGs could achieve BBB penetration under 808 nm irradiation. More importantly, the neuroprotective mechanism of NBGQDs-ICG was studied for the first time by AFM, which effectively weakened the adhesion of Aß42 aggregates to the cell surface by blocking the interaction between Aß42 and the cell membrane, and restored the mechanical stability and adhesion of the neuron membrane. Meanwhile, NBGQDs-ICG promoted phagocytosis of Aß42 by microglia. In addition, the good biocompatibility and stability ensured the biosafety of NBGQDs-ICG in future clinical applications. We anticipate that such multifunctional nanocomponents may provide promising avenues for the development of novel AD inhibitors.

Identification, pathological, and genomic characterization of novel goose reovirus associated with liver necrosis in geese, China.

Since 2021, a novel strain of goose reovirus (GRV) has emerged within the goose farming industry in Guangdong province, China. This particular viral variant is distinguished by the presence of white necrotic foci primarily localized in the liver and spleen, leading to substantial economic losses for the poultry industry. However, the etiology, prevalence and genomic characteristics of the causative agent have not been thoroughly investigated. In this study, we conducted an epidemiological inquiry employing suspected GRV samples collected from May 2021 to September 2022. The macroscopic pathological and histopathological lesions associated with GRV-infected clinical specimens were examined. Moreover, we successfully isolated the GRV strain and elucidated the complete genome sequence of the isolate GD21/88. Through phylogenetic and recombination analysis, we unveiled that the GRV strains represent a novel variant resulting from multiple reassortment events. Specifically, the µNS, λC, and σNS genes of GRV were found to have originated from chicken reovirus, while the σA gene of GRV exhibited a higher degree of similarity with a novel duck reovirus. The remaining genes of GRV were traced back to Muscovy duck reovirus. Collectively, our findings underscore the significance of GRV as a pathogenic agent impacting the goose farming industry. The insights gleaned from this study contribute to a more comprehensive understanding of the epidemiology of GRV in Southern China and shed light on the genetic reassortment events exhibited by the virus.

Biodegradation of 3-methylpyridine by an isolated strain, Gordonia rubripertincta ZJJ.

Methylpyridines are a class of highly toxic pyridine derivatives. In this study, a novel degrading bacterium was isolated for 3-methylpyridine (3-MP) degradation (Gordonia rubripertincta ZJJ, GenBank accession NO. OP430847.1; CCTCC M 2022975). The maximum specific degradation rate, half-saturation constant and inhibition constant were fitted to be 0.48 h-1, 88.3 mg L-1 and 924.0 mg L-1, respectively. During 3-MP biodegradation, the lost total organic carbon was transformed into CO2 (67.4 %) and biomass (32.6 %), and ammonia nitrogen was almost the sole inorganic species with a conversion rate of 36.3 %. Three metabolic pathways were possibly involved in 3-MP degradation: I) methyl oxidation followed by ring hydroxylation and hydrogenation; II) rupture of C=C and C-N bonds after ring reduction; III) initial ring hydroxylation. The study not only provides a novel strain for the high-efficient degradation of 3-MP, but also contributes to an in-depth understanding of 3-MP biotransformation.

Analysis of the distribution characteristics of prostate cancer and its environmental factors in China.

The high incidence and mortality and the increasing trend of prostate cancer has been one of the public health issues in many countries and regions. Meanwhile, the spatio-temporal heterogeneity of prostate cancer implies that lifestyle and ecological changes may be associated with prostate cancer, however, sufficient evidence is still lacking. This paper tried to reveal the spatial and temporal distribution characteristics of prostate cancer in China and explore the potential associations with related socioeconomic and natural condition factors. Data on prostate cancer incidence and mortality in 182 counties (districts) in mainland China from 2014-2016 were collected, and the distribution characteristics of prostate cancer were analyzed using spatiotemporal scan statistic. Spatial regression models and geodetector method were used to analyze the potential associations between meteorological conditions, socioeconomic development, and prostate cancer incidence and mortality. SaTScan, GeoDa, and GeoDetector were used for the above statistical analyses. The high-risk clusters for prostate cancer incidence and mortality were located in southeastern China, and the low-risk clusters were located in north-central China. Spatial regression models showed that the number of industrial enterprises/km2 (incidence: ß = 0.322, P < 0.001; mortality: ß = 0.179, P < 0.001), GDP (incidence:ß = 0.553, P < 0.001; mortality: ß = 0.324, P < 0.001), number of beds in medical and health institutions/1000 persons (incidence: ß = 0.111, P = 0.005; mortality: ß = 0.068, P = 0.021), and urbanization rate (incidence: ß = 0.156, P < 0.001; mortality: ß = 0.100, P < 0.001) were positively associated with the incidence and mortality of prostate cancer. The urbanization rate (incidence: q = 0.185, P < 0.001; mortality: q = 0.182, P < 0.001) has the greatest explanatory power, and the interaction of all factors was bivariate enhanced or nonlinearly enhanced. The distribution of prostate cancer in China has obvious spatial heterogeneity. The incidence and mortality rate of prostate cancer are on the rise, and special plans should be formulated in each region according to local conditions.

Photooxidative inhibition and decomposition of ß-amyloid in Alzheimer's by nano-assemblies of transferrin and indocyanine green.

Photoinduced modulation of Aß42 aggregation has emerged as a therapeutic option for treating Alzheimer's disease (AD) due to its high spatiotemporal controllability, noninvasive nature, and low systemic toxicity. However, existing photo-oxidants have the poor affinity for Aß42, low depolymerization efficiency, and difficulty in crossing the blood-brain barrier (BBB), hindering their application in the treatment of AD. Here, through hydrophobic interactions and hydrogen bonding, we integrated the near-infrared (NIR) photosensitizer indocyanine green with transferrin (denoted as TF-ICG), a protein with a high affinity for Aß42, and demonstrated its anti-amyloid activity in vitro. TF-ICG was shown to bind to Aß42 residues via hydrophobic interaction, impeding π-π stacking of Aß42 peptide monomers and disassembling mature Aß42 protofibrils in a concentration-dependent manner. More importantly, under NIR (808 nm, 0.6w/cm2) irradiation, TF-ICG completely inhibited the fibrillation process of Aß42 to generate amorphous aggregates, with an inhibition rate of 96 % at only 65 nM. Meanwhile, TF-ICG could photo-oxidize rigid Aß42 aggregates and break them down into small amorphous structures. Tyrosine fluorescence assay further demonstrated the intrinsic affinity and targeting of TF-ICG to Aß42 fibrils. In vitro studies validated the anti-amyloid activity of TF-ICG, which provided a theoretical basis for further in vivo application as a BBB-penetrating nanotherapeutic platform.

Rheumatoid arthritis increases the risk of heart failure-current evidence from genome-wide association studies.

Background: Numerous studies have demonstrated that rheumatoid arthritis (RA) is related to increased incidence of heart failure (HF), but the underlying association remains unclear. In this study, the potential association of RA and HF was clarified using Mendelian randomization analysis. Methods: Genetic tools for RA, HF, autoimmune disease (AD), and NT-proBNP were acquired from genome-wide studies without population overlap. The inverse variance weighting method was employed for MR analysis. Meanwhile, the results were verified in terms of reliability by using a series of analyses and assessments. Results: According to MR analysis, its genetic susceptibility to RA may lead to increased risk of heart failure (OR=1.02226, 95%CI [1.005495-1.039304], P=0.009067), but RA was not associated with NT-proBNP. In addition, RA was a type of AD, and the genetic susceptibility of AD had a close relation to increased risk of heart failure (OR=1.045157, 95%CI [1.010249-1.081272], P=0.010825), while AD was not associated with NT-proBNP. In addition, the MR Steiger test revealed that RA was causal for HF and not the opposite (P = 0.000). Conclusion: The causal role of RA in HF was explored to recognize the underlying mechanisms of RA and facilitate comprehensive HF evaluation and treatment of RA.