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关键词： SARS-CoV-2   Human leukocyte antigen   HLA evolutionary divergence  

摘要： Immunogenetic factors such as human leukocyte antigen (HLA) alleles, have yielded contrasting associations with protection or increased chances of hospitalization due to COVID-19 worldwide. This case-control study included 834 patients with confirmed COVID-19 diagnosis from five Brazilian states: Ceara (n = 110), Mato Grosso (n = 192), Para (n = 209), Rio de Janeiro (n = 211) and Rio Grande do Sul (n = 112). Genotyping was performed using the AxiomTM Human Genotyping SARS-CoV-2 array, targeting single nucleotide polymorphisms in HLA class I and II genes;HLA alleles were imputed for eight loci. Among the 15 preselected candidate alleles, only DQA1*05:01 (p = 0.015) in the state of Ceara remained significantly associated with hospitalization. The meta-analysis of the most frequent alleles in all states revealed that HLA-DPA1*01:03 (p = 0.0229, OR = 0.76, Pathogenesis 95 % CI = 0.60-0.96) and HLA-DPB1*04:01 (p = 0.0474, OR = 0.78, 95 % CI = 0.611.00) were associated with protection against hospitalization, whereas HLA-DPA1*02:01 (p = 0.0259, OR = 1.37, 95 % CI = 1.04-1.80), HLA-DQA1*05:01 (p = 0.0133, OR = 1.40, 95 % CI = 1.07-1.82), and HLA-DRB1*03:01 (p = 0.0276, OR: 1.59, 95 % CI: 1.05-2.40) associated with increased risk of hospitalization. HLA evolutionary divergence (HED) scores were significantly higher among the non-hospitalized group for the HLA-A locus, which has been shown to be a protective factor for the most severe forms and consequently hospitalization due to COVID-19.

关键词： HLA-A   NGS   novel allele  

摘要： Identification of five new HLA-A alleles by next-generation sequencing.

关键词： Tumor microenvironment   IL-35   iTr35   Immune evasion  

摘要： Dendrobium huoshanense has received special attention for its advantages in the treatment of lung cancer, but the underlying molecular mechanisms are not yet well understood. First, we obtained 8 active ingredients and 159 effective action targets of Dendrobium huoshanense using network pharmacology, and searching target interactions through STRING, constructing the PPI network and KEGG, GO and Hallmark enrichment analysis. Then, we combined target's enrichment analysis and GSEA enrichment analysis of IL-35, indicating the mechanism of cDHPs for non-small cell lung cancer (NSCLC) may be related to tight junction and NSCLC pathway. Further, FXR1 and ACTR3 were identified as core therapeutic targets, and high expression of FXR1 or ACTR3 was significantly associated with poor prognosis of patients. The analysis of single-cell data also indicated that the percentage of CD4-CTLA4-Treg cells may be increased by the expression of IL-35, resulting in a suppressive immune microenvironment. Next, In vivo experiment, we detected iTr35 by flow cytometry, detected IL-35 level by RT-PCR, Western blotting and ELISA, and detected NK cell activity to explore the immunomodulatory effects and anti-tumor mechanism of cDHPs. After cDHPs administration, the conversion of CD4+ T cells to iTr35 is inhibited, p35 and EBI3 in both protein and mRNA levels, the levels of IL-35 and IL-4 in serum decreased. The levels of IFN-gamma, while the activity of NK cells in mice increased, enhancing the anti-tumor immune effect of the organism. Finally, analysis of sequencing data from the immunotherapy cohort of tumor-bearing mice obtained from the TISMO database shows that the combination of cDHPs and PD-1/PD-L1 antibodies improves effector and thus PD-1/PD-L1 antibody efficacy. These findings suggest that cDHPs inhibit NSCLC proliferation and immune escape via the FXR1-IL-35 axis signaling pathway.

关键词： anti-TNF drug levels   transcriptomics   microRNA   Crohn's disease   gene regulation  

摘要： Background MicroRNAs (miRNAs) play a key role in regulating gene expression in Crohn's disease (CD). Although several studies have identified miRNAs with biomarker potential, an exhaustive characterization of the miRNAome in CD is still lacking. We performed the largest miRNA profiling effort to date to analyze miRNA variability across intestinal tissues, disease activity status, and infliximab treatment in *** We generated 119 transcriptomic profiles from the terminal ileum and left colon biopsies of 30 individuals (10 with active CD, 10 with quiescent CD, and 10 healthy controls). Half of the samples were cultured ex vivo with infliximab, and the remaining half with basal medium. Using variance analyses and linear mixed differential expression models, we explored the determinants of miRNAome variability in CD. We also generated infliximab response signatures to identify candidates and examine interactions between miRNAs and the coding *** Tissue location, and patient-specific effects, were the main factors in miRNA variability in CD, with some differentially expressed miRNAs involved in epithelial-mesenchymal transition (miR-200s, miR-429). We identified 9 miRNAs with treatment-responsive behaviour, particularly to the terminal ileum of active CD cases. Although the changes observed in active CD cases suggest that many alterations are not offset by infliximab incubation, we described 13 miRNAs-mRNA pairs with potential involvement in the anti-tumor necrosis factor (TNF) treatment, 7 of which have been already *** A comprehensive miRNA profiling revealed significant intestinal tissue-specific variability and identified key alterations in the miRNA-mRNA interactome that might be involved in therapeutic response to anti-TNF in CD. This article provides an extensive characterization of the miRNA variability in Crohn's Disease biopsies incubated ex vivo with infliximab, revealing tissue-specific regulatory programs and identif

关键词： 2′-MOE   2′-methoxyethyl   2’-O-Me   2′-O-methyl   AAV   adeno-associated virus   ACE2   angiotensin-converting enzyme 2   AD   Alzheimer's disease   Adv   adenovirus   AGO2   Argonaute2   AGSPR/ASGR-1   asialoglycoprotein receptor 1   ALA   aminolaevulinic acid   AMD   age-related macular degeneration   AML   acute myeloid leukemia   antimiR   anti-microRNAs   ApoB   apolipoprotein B   ASO   antisense oligonucleotide   BNA   bridged nucleic acid   CAR   chimeric antigen receptor   CDS   coding sequence   CFTR   cystic fibrosis transmembrane regulator   circRNA   circular RNA   ciRS-7   circRNA sponge for miR-7   CMV   cytomegalovirus   CPP   cell penetrating peptide   CRISPR   clustered regularly interspaced short palindromic repeat   csiRNA   circular small interfering RNA   DMD   Duchenne’s muscular dystrophy   DOPC   1,2-dioleoyl-sn-glycero-3-phosphocholine   DOPE   1,2-dioleoyl-sn-glycero-3-phosphoethanolamine   dsRNA   double-stranded RNA   dsiRNA   Dicer substrate RNAs   DSPC   2-Distearoyl-sn-glycero-3-phosphocholine   eIF-2α   eukaryotic initiation factor 2   EV   extracellular vesicle   FCS   familial chylomicronemia syndrome   FDA   Food and Drug Administration   GalNAc   N-acetylgalactosamine   GFP   green fluorescent protein   HBV   hepatitis B virus   HCC   hepatocellular carcinoma   HCV   hepatitis C virus   HIF-1α   hypoxia-inducible factor 1α   HSV   herpes simplex virus   HTT   Huntingtin   IFN   interferon   IL   interleukin   ITR   inverted terminal repeat   LDL   low-density lipoprotein   LDL-C   LDL-cholesterol   LNA   locked nucleic acid   LNP   lipid nanoparticle   5-m5C   methylcytidine   MDA-5   melanoma differentiation-associated protein 5   MDS   myelodysplastic syndrome   MI   myocardial infarction   miP   micropeptides   miR   microRNA   MV   microvesicles   nAbs   neutralizing antibodies   ncRNA   noncoding RNAs   nrHSV-1   nonreplicative “defective” vectors   nts   nucleotides   ORF   open reading frame   PCSK9   proprotein convertase subtilisin/kexin type 9   PD   Parkinson’s disease   PEG   polyethylene glycol   PEG2000-DMG   1,2-dimyristoyl-rac-glycero-3-methoxypolyethyleneglycol-2000   PEI   polyethyleneimine   PH1   primary hyperoxaluria type 1   PLGA   poly(lactic-co-glycolic acid)   PLL   poly-L-lysine   PMO   phosphorodiamidate morpholino oligonu  

摘要： Gene therapy has a pivotal role in treating new diseases. In addition to the recent mRNA-based COVID-19 vaccines produced by Pfizer-BioNTech and Moderna against severe acute respiratory syndrome corona virus 2, several new gene therapies have recently been approved as effective treatments for fatal genetic disorders such as Duchenne's muscular dystrophy, familial transthyretin amyloidosis, hemophilia A, hemophilia B, spinal muscle atrophy, early cerebral autoleukodystrophy, and b-thalassemia. This review provides novel insights into RNA therapeutics focusing on endogenous RNA species, RNA structure and function, and chemical modifications that improve the stability and distribution of RNAs. Furthermore, it includes updated knowledge on clinically approved gene therapies rendering a comprehensive understanding of the biochemical basis and clinical application of gene therapies. Significance Statement: There have recently been significant advances in clinical translation of RNA therapeutics. This review discusses the diverse types of RNA species, RNA structure and function, backbone and chemical modifications to RNAs, and every RNA therapeutic approved for clinical use at the time of writing. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： C*01:289   HLA-C   NGS   organ transplantation  

摘要： Full-length sequence of HLA-C*01:289 covers the 5 '-untranslated region (UTR), all exons and introns and the 3 ' UTR.

关键词： fetal growth restriction   gene polymorphisms   HLA-F   HLA-G   preeclampsia  

摘要： HLA-F and HLA-G may be involved in the pathogeneses of preeclampsia and fetal growth restriction (FGR). However, the functions of HLA-F and HLA-G in placental dysfunction remain unclear. The aim was to investigate differences in the prevalence of specific HLA-F and HLA-G gene allelic polymorphisms, genotypes, haplotypes, and diplotypes between controls and cases with preeclampsia or FGR. In total, blood samples from 365 pregnant females (controls, n = 192;preeclampsia, n = 164;FGR, n = 19) in their second and third trimester, and corresponding cordial blood samples (reflecting newborns, n = 160) were obtained after delivery. Genomic DNA was sequenced with a focus on the specific gene polymorphisms in the HLA-F gene locus, especially the single nucleotide polymorphisms (SNPs) rs1362126 (G/A), rs2523405 (T/G) and rs2523393 (A/G), as well as the rs371194629 (14-bp ins/del) in the 3 ' UTR of HLA-G. Haplotype and diplotype distributions were obtained using PHASE v2.1, and linkage disequilibrium analyses were performed. SNPs in the HLA-F gene locus and the 3 ' UTR of HLA-G were not associated with the risk of preeclampsia or FGR. The SNPs did not correlate with fetal-placental weight ratio, deviation of birth weight at gestational age, and placental weight. However, a trend towards an absence of certain HLA-F-HLA-G extended diplotypes in preeclampsia was observed. The current study does not support associations of the investigated HLA-F SNPs with preeclampsia or FGR. However, further studies are needed to evaluate the possible role of certain fetal HLA-F-HLA-G extended haplotypes and diplotypes in preeclampsia.

关键词： childhood Sjogren's disease   SUV3   monocytes   mitochondrial double-stranded RNAs   protein kinase R  

摘要： Objectives: This study investigates the molecular and functional implications of reduced Suv3-like RNA helicase (SUV3) expression in the interferon (IFN)-enriched subset of monocytes from childhood Sjogren's disease (cSjD). SUV3 is known to unwind double-stranded RNAs (dsRNAs) for homeostatic RNA decay within mitochondria. Methods: Using single-cell RNA sequencing, we analysed highly inflammatory IFN-enriched CD14+ monocytes from cSjD patients. To model SUV3 deficiency, we performed SUV3 knockdown in monocytic cells and studied the origin, localization and accumulation of dsRNAs in the cytosol. Formaldehyde crosslinking immunoprecipitation (fCLIP)-qPCR identified an intracellular sensor of dsRNAs. We further examined patient monocytes using J2 anti-dsRNA antibodies and transmission electron microscopy (TEM) for subcellular localization. In vitro assays assessed the impact of SUV3 knockdown on oxidative stress, ATP production, migration and phagocytosis. Results: SUV3 knockdown led to the accumulation of mitochondrial-dsRNAs (mt-dsRNAs) outside of the mitochondria, where they interacted with protein kinase R (PKR). This activated PKR, triggering a type I IFN signature and upregulating proinflammatory cytokines linked to fatigue. TEM revealed mt-dsRNAs in mitochondrial-derived vesicles and multi-vesicular bodies. Notably, cSjD monocytes had a significantly higher frequency of dsRNA-positive cells compared with controls (39% vs 0.08%, P < 0.002). SUV3 depletion also increased superoxide and ROS production, while impairing ATP synthesis, migration and phagocytosis, which are key innate immune functions. These defects were partially or fully reversed by co-knockdown of PKR. Conclusion: SUV3 is the key driver for defective innate immune functions through mt-dsRNA-mediated PKR activation, which enhances cellular stress, mitochondrial dysfunction and inflammatory signatures, uncovering a novel mechanism in cSjD pathogenesis.

关键词： Mitochondrial uncoupling proteins 1   TLR4/NLRP3/IL-1 beta signaling pathway   Aortic dissection/aneurysms   Inflammation   Phenotype switching  

摘要： Thoracic aortic aneurysms and dissection (TAAD) is a life-condition associated with high morbidity and mortality. Research has proven that inflammation contributes to the progression of TAAD. Mitochondrial uncoupling protein 1 (UCP1) can inhibit the release of inflammatory factors in perivascular adipose tissue (PVAT), regulate fat and inflammation, to confer vascular protection. However, whether UCP1 can ameliorate TAAD has not been clarified. In this study, aortas were harvested from organ donors and TAAD patients to explore the expression of UCP1 and Toll-like receptor 4 (TLR4)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/ interleukin-1(3 (IL-1(3) signaling pathway. Meanwhile, in vitro and in vivo models of TAAD were constructed to clarify the impact of UCP1 expression on VSMCs and TAAD. UCP1 expression was significantly downregulated and the TLR4/NLRP3/IL-1(3 signaling pathway was activated in TAAD in vivo. Moreover, UCP1 inhibited the migration, invasion, apoptosis, and phenotype switching of VSMCs in vitro. UCP1 significantly blocked the (3-aminopropionitrile (BAPN)-induced TAAD formation and rupture in mice, suppressed aortic dilation, elastic fiber fragmentation, and apoptosis in the aorta. It also activated the TLR4/NLRP3/IL-1(3 signaling pathway to alleviate aortic inflammation and prevent the degradation of systolic phenotype proteins and phenotype switching of VSMCs. These effects suggest that UCP1 may inhibit TAAD formation by blocking the TLR4/NLRP3/ IL-1(3 signaling pathway and VSMC phenotype switching.