课程文献中心 更多>>

关键词： Autoantibodies   Diagnosis   Endotype   Genetics   Genotype   Heterogeneity   HLA   Immunologic   Phenotype   Precision medicine   Preclinical   Prediction   Screening   TrialNet   Type 1 diabetes  

摘要： Aims/hypothesis Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB1*04-DQA1*03-DQB1*0302 (HLA-DR4-DQ8) and/or HLA-DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes. Methods We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4;n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3;n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4;n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX;n=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A p value <0.01 was considered statistically significant. Results IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, p<0.001) and DR3/DR4 (44.8%, p<0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, p<0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, p<0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, p<0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all compa

关键词： Bioethics   illness severity   major depression   suicide   untreatable illness  

摘要： The debate on assisted suicide for patients suffering from severe depression raises complex issues spanning clinical, ethical, scientific, medico-legal, and cultural domains. This position paper asserts that such an option is unacceptable in the context of depressive illness, even in its most severe and treatment-resistant forms. Depression is not an irreversible or terminal condition: there are multiple therapeutic options available, including spontaneous and late remissions, and suicidal ideation must be seen as a core symptom of the disorder, not as a rational choice. Scientifically, there are no reliable biomarkers to define the "incurability" of depression, and prognosis is often uncertain. Ethically, the principle of non-maleficence prohibits physicians from contributing to a patient's death, while the vulnerability of individuals with severe depression impairs their decision-making capacity. From a medico-legal standpoint, it is extremely difficult to assess competence in such contexts with any degree of certainty. Culturally and symbolically, psychiatry must reaffirm its healing mandate and resist dangerous shifts that could legitimize stigma or suicidal contagion. In conclusion, psychiatrists cannot and must not adopt the role of facilitators of death. Instead, they are called to provide care, instil hope, and protect patients, even in the most challenging clinical scenarios.

关键词： HLA   HLA-C*04:534   novel allele   sequencing-based typing  

摘要： HLA-C*04:534 differs from HLA-C*04:01:01:01 by two nucleotide substitutions in codons 166 and 167 in exon 3.

关键词： Osteoarthritis   Inflammation   GUSBP11   miR-122-5p   Biomarker  

摘要： Studies have demonstrated that several lncRNAs exhibit abnormal expression levels in patients suffering from osteoarthritis, and in-depth investigation of these aberrantly expressed lncRNAs may pave the way for innovative therapeutic strategies targeting OA. The aim of this study was to examine the expression of glucuronidase beta pseudogene 11 (GUSBP11) in OA patients and to elucidate its potential molecular mechanism. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect GUSBP11 levels on cartilage tissues and serum samples obtained from OA patients. To establish an in vitro OA cell model, interleukin-1(3 (IL- 1(3) was utilized to induce CHON-001 and ATDC5 cell lines. Cell counting kit-8 (CCK-8) assay and flow cytometry were performed to evaluate cell viability and apoptosis, and enzyme-linked immunosorbent assay (ELISA) was employed to qualify the levels of inflammatory factors. StarBase database predicted that miR-122-5p was the target gene of GUSBP11. Subsequently, luciferase reporter genes were conducted to validate this interaction. Potential target genes of miR-122-5p were predicted, followed by gene function annotation and correlation analysis of these targets. Our findings revealed that GUSBP11 expression was markedly decreased in both the cartilage tissues and serum of OA patients. Diminished levels of GUSBP11 showed high diagnostic accuracy for OA. In the IL-1(3-induced OA cell model, GUSBP11 expression was notably reduced, leading to decreased cell viability, an increase in apoptotic cells, and elevated levels of inflammatory factors. Up-regulation of GUSBP11 significantly ameliorated these adverse effects. Luciferase reporter genes confirmed the interaction between GUSBP11 and miR-122-5p, indicating that an increase in miR-122-5p drastically inhibited cell viability while promoting apoptosis and inflammation. In conclusion, within the context of the in vitro OA cell model, GUSBP11 appears to exacerbate IL-1(3-induced

关键词： Heart failure   Mitochondrial permeability transition-driven   necrosis   Biomarkers   Predictive and diagnostic efficacy   Enrichment pathways   Regulatory networks  

摘要： Background: Heart failure is linked to increased hospitalization and mortality. Mitochondrial permeability transition-driven necrosis is associated with cardiovascular diseases, but its role in heart failure is unclear. This study aimed to identify and validate genes related to mitochondrial permeability transition-driven necrosis in heart failure, potentially leading to new drug targets and signaling pathways. Methods: We identified differentially expressed genes related to heart failure from the gene expression omnibus database and identified module genes related to mitochondrial permeability transition-driven necrosis from the gene set enrichment analysis database. Key genes were determined by intersecting these two gene groups using least absolute shrinkage and selection operator and support vector machine algorithms. Pathways, diagnostic efficacy, gene interactions, immune infiltration, and regulatory networks were analyzed. Small interfering RNAs were used for validation. Real-time-quantitative polymerase chain reaction, flow cytometry, and JC-1 assays were performed in vitro. Results: Forty-six differentially expressed genes, and 3439 module genes were identified. LYVE1, IL1RL1, and SERPINA3 were identified as significantly downregulated key genes, with IL1RL1 and SERPINA3 associated with heart failure risk. Benzo(a) pyrene, bisphenol A, estradiol, and particulate matter were found to simultaneously increase the expression of three key genes. In clinical samples, only LYVE1 and IL1RL1 were downregulated, as expected. Knockdown of these genes in cells led to increased necrosis and decreased mitochondrial membrane potential. Only estradiol reduced brain natriuretic peptide protein levels in hypertrophic cells. Conclusions: LYVE1 and IL1RL1 were validated as key genes linked to mitochondrial permeability transitiondriven necrosis in heart failure. Estradiol may have a therapeutic effect on heart failure.

关键词： Astragaloside IV   Retinal pigment epithelial cell   Cell senescence   FTO   m6A methylation   IL-1 beta  

摘要： Background: Resistance to senescence in retinal pigment epithelial (RPE) cells can delay the progression of agerelated macular degeneration (AMD). However, the mechanisms underlying RPE cell senescence remain inadequately understood, and effective therapeutic strategies are lacking. While astragaloside IV (Ast) has demonstrated anti-aging properties, its specific effects on RPE cell senescence and potential mechanisms are not yet fully clarified. Purpose: This study aimed to explore the impacts of Ast on RPE cell senescence and to uncover the molecular mechanisms involved. Methods: The therapeutic efficacy of Ast was assessed using sodium iodate (NaIO3)-induced adult retinal pigment epithelial cell line 19 (ARPE-19) cell models and an AMD mouse model. To investigate the mechanisms by which Ast mitigated RPE cell senescence, RNA sequencing (RNA-seq), drug affinity responsive target stability-mass spectrometry (DARTS-MS), cellular thermal shift assay (CETSA), reverse transcription quantitative PCR (RTqPCR), as well as western blotting were conducted. Results: Ast significantly inhibited NaIO3-treated ARPE-19 cell senescence and protected against NaIO3-induced AMD in mice. RNA-seq analysis revealed that Ast significantly attenuated inflammation-related signaling pathways and reduced the mRNA levels of interleukin-1 beta (IL-1f)). Specifically, Ast decreased the stability of IL-1f) mRNA while enhancing its N6-methyladenosine (m6A) methylation. Furthermore, Ast directly interacted with fat mass and obesity-associated protein (FTO). Knockdown or pharmacological inhibition of FTO mitigated the senescence and IL-1f) expression in NaIO3-treated ARPE-19 cells. FTO was essential for Ast to inhibit cellular senescence and IL-1f) expression. Additionally, inhibition or knockdown of FTO conferred also provided resistance to AMD in the murine model. Conclusion: Our results indicated that Ast significantly attenuated RPE cell senescence and showed anti-AMD properties. FTO was demon

摘要： Interleukin (IL)-18 functions primarily through its 18-kDa mature form produced from caspase-1 cleavage. However, IL-18 can also be processed by other proteases, leading to the generation of different fragments with less recognized functions. Here, we discover that, in cancer cells, caspase-3 cleavage of IL-18 generates a 15-kDa form of IL-18, referred to as short IL-18. Unlike mature IL-18, short IL-18 is not secreted, and does not bind IL-18R alpha;instead, it translocates into the nucleus, facilitating STAT1 phosphorylation at Ser727 via CDK8, and enhancing the expression and secretion of ISG15. This signaling cascade in cancer cells mobilizes natural killer cells with increased cytotoxicity to eliminate various syngeneic tumors and colitis-associated colorectal cancer in mice. Moreover, patients with colorectal cancer who have an abundance of short IL-18 in the nucleus have a better prognosis. This work highlights a distinct anti-tumor pathway driven by short IL-18.

关键词： Thalassemia   Alloimmunization   HLA-DRB1   HLA-DQB1   Transfusion reaction   Kell blood group system   Rh-hr blood group system  

摘要： Transfusion therapy is crucial for treating Transfusion-dependent thalassemia (TDT) patients. However, the production of Alloantibodies presents a substantial challenge for these individuals and impacts their quality of life. The Rh and Kell blood group antigens are particularly susceptible to alloantibody development. This study aims to establish the correlation between HLA-DRB1*04, HLA-DQB1*03, and HLA-DQB1*06 alleles and alloimmunzation in thalassemia patients from Iran. 98 thalassemic patients were recruited for this study (49 alloimmunized and 49 non-alloimmunized). Alloimmunized patients developed Rh and Kell specificities alloantibodies. The two groups were compared based on the results of HLA-DRB1 and HLA-DQB1 genotyping conducted using Sequence-Specific Primers (SSP-PCR). The findings from the antibody screening revealed that the predominant alloantibody detected was Anti-K (95.9%), Anti-E (65.3%), Anti-C (30.6%), Anti-D (28.6%), Anti-c (10.2%), Anti-e (2%), and Anti-k (2%). There was a notable difference in HLA-DQB1*03 between alloimmunized and non-alloimmunized groups, 41.8% vs. 58.2%, respectively. (iP = 0.001, OR = 0.135, CI = 0.036-0.499). There was not any notable relationship between HLA-DRB1*04 and HLA-DQB1*06 alleles and alloimmunization. Our findings indicate that HLA-DQB1*03 may have a protective role in preventing alloantibody production. Thus, HLA-typing, particularly focusing on DQB1*03, can significantly enhance the screening process, leading to improved blood transfusion management, reduced rejection of hematopoietic stem cell transplantation, and minimized blood transfusion complications.

关键词： neuroinflammation   circadian rhythms   depression-like behavior   mitochondria   RNA-seq  

摘要： Neuroinflammation is involved in the development of depression and may induce depression-like behaviors by affecting metabolism through interactions with circadian rhythms. As the hub of metabolism, mitochondria are regulated by various types of metabolism and release signals that regulate cellular functions. In this study, we performed transcriptomic analysis of the hippocampus of IL-33-overexpressing mice to provide new ideas to explore the pathogenesis of inflammation-mediated depression at the transcriptional level. Male C57BL/6J mice and IL-33-overexpressing mice were subjected to behavioral tests. The hippocampus was extracted during the light or dark period, and differential gene expression analysis was conducted using RNA sequencing. Differential gene enrichment analysis was performed, as well as multilayered analysis of mitochondrial transcriptional rhythms by integrating the regulatory networks and Mito 3.0 database. The results were further verified using RT-qPCR. IL-33-overexpressing mice exhibited depressive behaviors associated with rhythmic disorders and shortened circadian cycles. Differential KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis showed that the top 20 pathways with the lowest p-values included mood-related, immune-related, and circadian rhythm-related pathways. Differential gene GO (Gene Ontology) enrichment analysis showed that 20 of the top 30 pathways with the lowest p-values were related to metabolism. Transcriptome data from IL-33-overexpressing mice showed that the mitochondrial-encoded subunit of the oxidative respiratory complex showed predominantly increased expression during the light period. Metabolic disorders and disrupted mitochondrial transcriptional rhythm were also observed. Weighted gene correlation network analysis showed that the circadian cycle is associated with depression-like behavior disorders. Network analysis showed that circadian-related genes were enriched in mitochondrial pathways related t