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Abstract Background Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly defined condition encompassing hepatic steatosis and metabolic dysfunction. However, the relationship between MAFLD and multi-system diseases remains unclear, and the time-dependent sequence of these diseases requires further clarification. Methods After propensity score matching, 163,303 MAFLD subjects and 163,303 matched subjects were included in the community-based UK Biobank study. The International Classification of Diseases, Tenth Revision (ICD-10), was used to reclassify medical conditions into 490 and 16 specific causes of death. We conducted a disease trajectory analysis to map the key pathways linking MAFLD to various health conditions, providing an overview of their interconnections. Results Participants aged 59 (51–64) years, predominantly males (62.5%), were included in the study. During the 12.9-year follow-up period, MAFLD participants were found to have a higher risk of 113 medical conditions and eight causes of death, determined through phenome-wide association analysis using Cox regression models. Temporal disease trajectories of MAFLD were established using disease pairing, revealing intermediary diseases such as asthma, diabetes, hypertension, hypothyroid conditions, tobacco abuse, diverticulosis, chronic ischemic heart disease, obesity, benign tumors, and inflammatory arthritis. These trajectories primarily resulted in acute myocardial infarction, disorders of fluid, electrolyte, and acid–base balance, infectious gastroenteritis and colitis, and functional intestinal disorders. Regarding death trajectories of MAFLD, malignant neoplasms, cardiovascular diseases, and respiratory system deaths were the main causes, and organ failure, infective disease, and internal environment disorder were the primary end-stage conditions. Disease trajectory analysis based on the level of genetic susceptibility to MAFLD yielded consistent results. Conclusions Individuals with MAFLD have a risk of a number of different medical conditions and causes of death. Notably, these diseases and potential causes of death constitute many pathways that may be promising targets for preventing general health decline in patients with MAFLD.

Objective To report the clinical and pathological features of 4 patients with oculopharyngodistal myopathy type 1 (OPDM1) caused by CGG repeat expansion in the 5'untranslated region (5'UTR) of LRP12 gene. Methods and Results This study included 4 patients with OPDM1 who were admitted to Peking University First Hospital from January 2008 to August 2023. All 4 patients presented with weakness of eyes closed, dysarthria, dysphagia, facial muscle weakness and muscle weakness mainly involving distal muscles. None of 4 patients had restricted eye movements. Two of the patients had ptosis (Case 1 and Case 2). Serum creatine kinase (CK) levels were mildly to moderately elevated (190- 1211 U/L) in 4 patients. Three patients (Case 1, Case 2 and Case 3) underwent lower extremity muscle MRI which showed varying degrees of fatty infiltration, with the soleus and tibialis anterior muscles being worst affected. Skeletal muscle biopsies in all 4 patients showed rimmed vacuoles with muscular dystrophy‑like pathological changes. Immunofluorescence staining revealed p62 ‑ positive and ubiquitin ‑ positive intranuclear inclusions in all 4 patients. Genetic testing revealed that all 4 patients carried CGG repeat expansion in the 5'UTR of the LRP12 gene. Conclusions Most OPDM1 patients start with weakness in the distal extremities of both limbs and dysarthria. The involvement of muscles in the lower extremities is asymmetrical, and the involvement of tissues and organs other than muscles is not obvious. The remaining clinical phenotype and pathological features are consistent with other subtypes of OPDM.

Short tandem repeat (STR) is a component of the human genome, the number of repeats of STR is prone to change during DNA replication, and when it exceeds a certain threshold, it will lead to the occurrence of diseases, most of which involve the nervous system. With the rapid development and wide application of the third generation long read long sequencing technology, more and more neuromuscular diseases have been confirmed to be related to STR variation. This article reviews the clinical and mechanism research progress on STR‑related neuromuscular diseases, so as to provide guidance for clinical research.

Abstract Objective SNRPA1, a subunit of spliceosome complex, has been implicated in diverse cancers, while its biological effect in LUAD remains elusive. Therefore, we sought to decipher the relationship between SNRPA1 expression and the prognosis of patients with LUAD and reveal the underlying molecular mechanism. Materials and methods Based on the clinical data from TCGA databases, the multivariate Cox model was constructed to screen the prognostic value of SNRPA1. qRT‐PCR and immunohistochemical staining were used to examine SNRPA1 mRNA and protein expression in LUAD. The effect of SNRPA1 on LUAD cell proliferation, migration, and epithelial mesenchymal transformation were examined using colony formation assays, wound healing, and western blot assays, respectively. Finally, the influence of SNRPA1 on LUAD immune microenvironment were validated from the Tumor Immune Estimation Resource database. Results SNRPA1 was significantly upregulated in both LUAD tissues and cell lines, and highly expressed SNRPA1 contributed to poor prognosis of LUAD patients. In vitro, SNRPA1 knockdown inhibited the proliferation and migration, as well as delayed the EMT differentiation of LUAD cells. Lastly, SNRPA1 was found to be positively associated with immune infiltration and some immune‐check‐point markers. Conclusions Our findings indicate that SNRPA1 may be a new biomarker for prognostic prediction and a potential therapeutic target in the treatment of LUAD.

Abstract Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis.

Abstract Background Cellular senescence plays an essential role in the development and progression of end-stage renal disease (ESRD). However, the detailed mechanisms phenomenon remains unclear. Methods The mRNA expression profiling dataset GSE37171 was taken from the Gene Expression Omnibus (GEO) database. The cell senescence-associated hub genes were selected by applying protein–protein interaction (PPI), followed by correlation analysis, gene interaction analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We next explored the relationships of hub genes with miRNAs, TFs, and diseases. The absolute abundance of eight immune cells and two stromal cells were calculated by MCPcount and the correlation of hub genes with these ten cells was analyzed. Lasso was used to selecting for trait genes. ROC curves and DCA decision curves were used to assess the accuracy and predictive power of the trait genes. Results A total of 65 cellular senescence signature genes were identified among patients and controls. The PPI network screened out ten hub genes. GO and KEGG indicated that ten hub genes were associated with ESRD progression. Transcription factor gene interactions and common regulatory networks of miRNAs were also identified in the datasets. The hub genes were significantly correlated with immune cells and stromal cells. Then the lasso model was constructed to screen out the five most relevant signature genes (FOS, FOXO3, SIRT1, TP53, SMARCA4). The area under the ROC curve (AUC) showed that these five characteristic genes have good resolving power for the diagnostic model. Conclusions Our findings suggested that cellular senescence-associated genes played an important role in the development of ESRD and immune regulation.

Abstract Background Malnutrition is associated with a high risk of mortality in adults with ischemic stroke (IS). This study aimed to investigate the relationship between malnutrition and the risk of stroke-associated pneumonia (SAP) as only a few studies examined the relationship between malnutrition and the risk of SAP in IS. Methods Patients were included from emergency departments of five tertiary hospitals in the REtrospective Multicenter study for Ischemic Stroke Evaluation (REMISE) study from January 2020 to December 2020. Malnutrition was defined according to the Controlling Nutritional Status (CONUT), Geriatric Nutritional Risk Index (GNRI), and Prognostic Nutritional Index (PNI) systems. Multivariable logistic regression analysis was used to explore the association between malnutrition and risk of SAP. Results We enrolled 915 patients with IS, 193 (14.75%), 495 (54.1%), and 148 (16.2%) of whom were malnourished according to the PNI, CONUT, and GNRI scores, respectively. SAP occurred in 294 (32.1%) patients. After adjusting for confounding influencing factors in the logistic regression analysis, malnutrition (moderate and severe risk vs. absent malnutrition) was independently associated with an increased risk of SAP based on the PNI (odds ratio [OR], 5.038; 95% confidence interval [CI] 2.435–10.421, P

This study introduces a deep neural network approach that utilizes radial basis functions (RBFs) to solve forward and inverse problems in the process of diffusion. The input layer incorporates multiquadric (MQ) RBFs, symbolizing the radial distance between the boundary points on the spacetime boundary and the source points positioned outside the spacetime boundary. The output layer is the initial and boundary data given by analytical solutions of the diffusion equation. Utilizing the concept of the spacetime coordinates, the approximations for forward and backward diffusion problems involve assigning initial data on the bottom or top spacetime boundaries, respectively. As the need for discretization of the governing equation is eliminated, our straightforward approach uses only the provided boundary data and MQ RBFs. To validate the proposed method, various diffusion scenarios, including forward, backward, and inverse problems with noise, are examined. Results indicate that the method can achieve high-precision numerical solutions for solving diffusion problems. Notably, only 1/4 of the initial and boundary conditions are known, yet the method still yields precise results.