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关键词： binding orientation   cross-linking   epitope mapping   mass spectrometry   reverse binding   sulfo-SDA  

摘要： T cell receptors (TCRs) recognize specific peptides presented by human leukocyte antigens (HLAs) on the surface of antigenpresenting cells and are involved in fighting pathogens and cancer surveillance. Canonical docking orientation of TCRs to their target peptide-HLAs (pHLAs) is essential for T cell activation, with reverse binding TCRs lacking functionality. TCR binding geometry and molecular interaction footprint with pHLAs are typically obtained by determining the crystal structure. Here, we describe the use of a cross-linking tandem mass spectrometry (XL-MS/MS) method to decipher the binding orientation of several TCRs to their target pHLAs. Cross-linking sites were localized to specific residues and their molecular interactions showed differentiation between TCRs binding in canonical or reverse orientations. Structural prediction and crystal structure determination of two TCR-pHLA complexes validated these findings. The XL-MS/MS method described herein offers a faster and simpler approach for elucidating TCR-pHLA binding orientation and interactions.

关键词： Endocrinology and Metabolic Physiology  

摘要： The aim of the study. To investigate the relationship between the content of TNF-α in the blood of patients with diabetes and the development of diabetic neuropathy. Materials and Methods. Type 2 DM2 patients without complications and patients with diabetic neuropathy (DN) under inpatient treatment in RSSPMC of endocrinology of HM RUz participated in the study. Biochemical analysis and TNF-α cytokine were determined in blood. Results and discussion. The results of determining the content of TNF-α in the blood serum of the studied groups using ELISA showed that in patients with diabetes there is a significant increase in the content of TNF-α (3.05±0.44 pg/ml) relative to the values in the control group. In the group of patients with DN, an increase in the concentration of TNF-α in the blood serum was observed, which amounted to 5.2±0.44 pg/ml. A study of the concentration of TNF-α in patients without complications of diabetes and in patients with DN mild degree did not reveal statistically significant differences. In patients with DN mild degree, the average concentration of TNF-α was 3.62±0.89 pg/ml, and in DN severe degree -7.13±1.14 pg/ml, i.e. increased almost 2 times. Conclusion. It was found that the content of TNF-α in the serum of patients with diabetic neuropathy is in direct correlation with the degree of severity of the disease. Funding: by *** and WorldBank ФЗ-2020092959 (Ф-ОТ-2021-153) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

关键词： extracellular vesicles   non-structural protein 1   pro-inflammatory cytokines   tick-borne encephalitis virus  

摘要： Despite active research, so far the detailed mechanisms of TBEV pathogenesis have not been fully disclosed. Recently, extracellular vesicles, especially small-sized vesicles, which have been shown to play an important role in the pathogenesis of many viruses, have attracted the attention of scientists. In this study, we investigated the effect of the expression of nonstructural protein 1 (NS1) of tick-borne encephalitis virus on the release of extracellular vesicles by cells and assessed the possibility of these vesicles affecting other cells. NS1 expression by TBEV was found to increase the release of extracellular vesicles by HEK293T cells; however, no changes in the size profile of released vesicles were detected. In addition, NS1 is detected in both large and small vesicle size fractions. It was found that NS1 TBEV is not present inside the vesicles, but is associated with their outer surface. Small-sized vesicles derived from the culture medium of NS1-expressing HEK293T cells are able to induce an increase in the mRNA content and interleukin-1β(IL-1β) secretion in human neuroblastoma SHSY5Y cells. The results indicate the involvement of the NS1 protein and vesicles in the development of neuroinflammation and are important for understanding the mechanisms of pathogenesis of tick-borne encephalitis virus.

关键词： Esophageal squamous cell carcinoma   IL2RB   JAK1/STAT5   immune microenvironment   therapeutic target  

摘要： OBJECTIVE:Esophageal squamous cell carcinoma (ESCA) is a prevalent malignant tumor with poor prognosis. Interleukin 2 receptor beta (IL2RB) has been implicated in various cancers; however, its role in ESCC remains unclear. METHODS:We analyzed IL2RB expression in clinical samples and cell lines. The impact of IL2RB on tumor progression was assessed using gain- and loss-of-function approaches, along with in vivo tumor models. In addition, we explored the effect of IL2RB on the immune microenvironment and its potential to modulate the JAK1/STAT5 pathway. RESULTS:IL2RB was found to be significantly upregulated in ESCC tissues compared to normal tissues. Functional studies revealed that IL2RB knockdown inhibited tumor cell proliferation, migration, and invasion, as well as epithelial-mesenchymal transition (EMT). IL2RB was shown to reshape the tumor immune microenvironment by inducing CD8+T cell depletion. Mechanistic investigations indicated that IL2RB activates the JAK1/STAT5 pathway, thereby promoting ESCC progression. CONCLUSIONS:Our findings demonstrate that IL2RB plays a critical role in ESCC progression and immune evasion, suggesting its potential as a therapeutic target. Further studies are warranted to explore the clinical application of IL2RB targeting in ESCC treatment.

关键词： ulcerative colitis   transcriptomics   mitochondria   anti-TNF  

摘要： Background Recent studies hint at mitochondrial genes influencing UC patient response to anti-TNF treatment. We evaluated this hypothesis by following a targeted strategy to identify gene expression that captures the relationship between mitochondrial dysregulation and response to treatment. Our objective was to initially examine this relationship in colon samples and subsequently assess whether the resulting signal persists in the *** We analyzed the transcriptome of colon samples from an anti-TNF-treated murine model characterized by impaired mitochondrial activity and treatment resistance. We then transferred the findings that linked mitochondrial dysfunction and compromised treatment response to an anti-TNF-treated UC human cohort. We next matched differential expression in the blood using monocytes from the peripheral blood of controls and IBD patients, and we evaluated a classification process at baseline with whole blood samples from UC *** In human colon samples, the derived gene set from the murine model showed differential expression, primarily enriched metabolic pathways, and exhibited similar classification capacity as genes enriching inflammatory pathways. Moreover, the evaluation of the classification signal using blood samples from UC patients at baseline highlighted the involvement of mitochondrial homeostasis in treatment *** Our results highlight the involvement of metabolic pathways and mitochondrial homeostasis in determining treatment response and their ability to provide promising classification signals with detection levels in both the colon and the bloodstream. Research suggests mitochondrial dysfunction may compromise response to anti-TNF treatment in UC patients. Testing this, we induced mitochondrial dysregulation in a mouse model treated with anti-TNF and linked gene expression to non-response. The findings were then corroborated on human cohorts.

关键词： HLA   HLA-DPB1*104:01:08   novel allele   sequencing-based typing  

摘要： HLA-DPB1*104:01:08 differs from HLA-DPB1*104:01:01:04 by one nucleotide substitution in codon 199 in exon 4.