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关键词： brain fog   cognitive decline   executive functions   inflammation   post-COVID syndrome  

摘要： Beyond the immediate impact of the COVID-19 pandemic, survivors often grapple with incapacitating post-infection symptoms, referred to as Post-Acute Sequelae of COVID (PASC) when persistent beyond 90 days. Cognitive manifestations, encompassing attention, memory, and executive functions (EF), collectively termed brain fog, contribute to functional challenges in PASC. This infection also elicits a long-lasting pro-inflammatory response that persists even after viral clearance, potentially correlated with brain fog. However, it is unclear whether pro-inflammatory responses and cognitive sequelae persist beyond 1 year after the onset of infection. Thus, this study sought to investigate the long-term consequences of PASC on EFs as well as a potential association with markers of inflammation. Forty individuals with PASC who passed performance validity testing (PVT) and 40 matched healthy controls (HC) underwent neuropsychological assessments, including the Montreal Cognitive Assessment to assess global cognition, Victoria Stroop Test to assess inhibitory control, Wisconsin Card Sorting Test to assess cognitive flexibility, Digit Span Task to assess working memory, and Mackworth Clock Test to assess sustained attention on the Psychology Experiment Building Language (PEBL) toolkit. Serum was assayed for tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10). Results indicate significant EF decline in PASC, inversely correlated with serum TNF-alpha concentrations, approximately 562 +/- 225 days after the onset of infection. Thus, there exists protracted EF decline in PASC, persistent even beyond 1 year after the onset of infection. Increased levels of TNF-alpha are observed to be associated with poorer executive functioning in PASC.

关键词： Real-world evidence   Observational studies/registry   biological DMARD  

关键词： Sarcopenia   Whole-genome sequencing   Rare coding variant   Human leukocyte antigen  

摘要： Introduction: Age-related alterations in muscle tissue morphology and function, as well as chronic pro-inflammatory conditions, contribute to the development of sarcopenia. To elucidate the multidimensional pathogenesis of sarcopenia, we performed a comprehensive genetic analysis, including common variants, rare variants, and human leukemia antigen (HLA). Methods: A total of 129 older adults were analyzed using whole-genome sequencing (WGS), including 67 sarcopenia patients and 62 normal controls. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 consensus. WGS data and associated clinical data were obtained from the National Center for Geriatrics and Gerontology Biobank in Japan. We performed logistic regression adjusted for age, sex, and body mass index for common variant (minor allele frequency [MAF] >= 0.01), rare variant (MAF <0.01), and HLA analyses. For the functional analysis, we performed RNA interference using human myoblasts and estimated gene expressions (MYOG, MYMK, MYMG) by quantitative PCR. Results: Rare variant analysis identified five rare coding variants of genes - SLC41A3, SYNRG, CLUAP1, CCHCR1, and ALDH2 - expressed in skeletal muscle. Of these, a deleterious frameshift deletion in SLC41A3 was associated with the pathogenesis of sarcopenia (p = 0.0012, odds ratio [OR] = 11.52, 95% confidence interval [CI] = 2.62-50.69). This deletion significantly reduced expression of myogenin (MYOG), a factor involved in myoblast differentiation (p = 0.0094), but did not affect the fusion of myogenic cells. We also discovered a new protective allele, HLA-DPB1*02:01 associated with sarcopenia (OR = 0.17, 95% CI = 0.060-0.51, p = 0.0015), which has a high occurrence rate in the Northeast Asian population. Conclusion: Rare variant analysis identified a deleterious frameshift deletion in SLC41A3 as a risk factor for sarcopenia. Our findings suggest that the suppression of MYOG could play a role in myogenesis or muscle maintenance, al

摘要： Genetic variation in the human leukocyte antigen (HLA) region is thought to influence susceptibility to and severity of a variety of infectious diseases. Several studies have explored a possible relationship between HLA genetics and SARS-CoV-2 infection, although mixed results, small sample sizes, and difficulty controlling for exposure risk have made it difficult to draw firm conclusions. Here, a dataset of 419,234 subjects with HLA genotype data and COVID-19 PCR test results was studied. A baseline analysis was performed to examine the association of non-HLA factors on COVID-19 positivity. Then, multivariate logistic regressions, incorporating single and paired HLA alleles, were performed and then corrected for significant factors from the baseline analysis. Proxies for socioeconomic status and exposure risk were significantly associated with COVID-19 positivity across all ancestry groups studied. Forty-one single HLA alleles displayed significant association with COVID-19 positivity;after controlling for socioeconomic status and exposure risk, only eight significant associations remained. Additionally, two HLA allele pairs were associated with test positivity after correction. Of all variables, socioeconomic status showed the greatest effect size. The results from this study suggest that many, if not all, of the reported associations between HLA alleles and SARS-CoV-2 infection may be spurious, owing to confounding factors.

关键词： biological DMARD   Systematic review  

关键词： Innate immunity   Adaptive immunity  

摘要： Background: Interleukin-1 beta (IL-1β) is an inflammasome-dependent pro-inflammatory cytokine implicated in T cell-driven autoimmune diseases [1]. To exert its function, IL-1β requires activation, typically through the cleavage of pro-IL-1β [2, 3]. Dysregulation of IL-1β has been linked to the pathogenesis of various chronic inflammatory and autoimmune diseases, including rheumatoid arthritis and juvenile idiopathic arthritis [4]. However, the precise mechanisms underlying IL-1β production in T cell-mediated autoimmunity remain unclear. Objectives: Exploring the cellular and molecular mechanisms of IL-1β production directed by T cells for treating T cell-mediated autoimmune diseases. This study aimed to investigate whether and how activated T cells induce IL-1β production in human primary monocytes, macrophages, and dendritic cells (DCs). Methods: Primary human monocytes, memory CD8+ T cells and memory CD4+ T cells isolated from PBMCs were used in this study. Monocytes were differentiated into GM-CSF-induced MDM and M-CSF-induced MDM by the addition of recombinant human GM-CSF or M-CSF, respectively. For DC generation, monocytes were cultured with recombinant human GM-CSF and IL-4. Monocytes/macrophages/DCs were co-cultured with memory T cells at a ratio of 1:3 and stimulated by LPS&nigericin or anti-human CD3 antibody. Small interfering RNAs (siRNA), neutralizing antibodies or inhibitors were used to study the function of genes. The knockdown efficiency was determined by quantitative PCR and western blotting. Flow cytometry, enzyme-linked immunosorbent assay (ELISA), caspase-1 activity assay and western blotting were used to quantify the production of proteins. Results: Co-culturing autologous primary T cells with myeloid cells (monocytes, macrophages, and dendritic cells) revealed that both memory CD4+ and CD8+ T cells induce the expression of both pro-IL-1β and cleaved IL-1β. Antibody blocking experiments showed that the upregulation of pro-IL-1β requires the com

关键词： Tuberculosis   Latent tuberculosis infection   Biomarker   Diagnosis   IL-8   IL-33   IL-18  

摘要： PurposesA leading cause of death from infectious diseases worldwide is tuberculosis (TB), and it often arises from latent infection. New diagnostic tests for latent tuberculosis infection (LTBI) are needed. Therefore, this study aimed to identify novel biomarker signatures in whole human blood to distinguish between active tuberculosis (ATB) and *** LEGENDplex (TM) kits were used to evaluate the secretion levels of 20 cytokines triggered by ESAT-6/CFP10 antigen in whole blood of ATB, LTBI, and healthy controls, and to search for cytokine combinations utilized to distinguish between ATB and ***-8, IL-18, IL-33, MCP-1, MIG (baseline levels);IL-8, IL-33, IL-1 beta, MCP-1, MIG, IL-10, I-TAC (ESAT-6/CFP10-stimulated levels);and IL-18, IL-33, IL-1 beta, IL-10, TNF-alpha (ESAT-6/CFP10-stimulated minus baseline levels) had the potential to distinguish ATB from LTBI. Our data shows that the sensitivity and specificity of targeted IL-8 and IL-33 distinguishing between ATB and LTBI were 83.3% and 93.75%, and the diagnostic accuracy was 89.28%, and the sensitivity and specificity of targeted IL-18 and IL-33 distinguishing between ATB and LTBI were 91.67% and 81.25%, with the diagnostic accuracy was 85.71%.ConclusionsOur data suggest that IL-8/IL-33 and IL-33/IL-18 together can be utilized as immunological markers to differentiate between LTBI and ATB. A novel TB diagnostic protocol was established, offering novel perspectives to create better tests.

关键词： Innate immunity   Cytokines and Chemokines   Targeted synthetic drugs   Adaptive immunity  

关键词： lupus(1)   B cell(2)   IL-4(3)   TLR7(4)   transcriptomics(5)   autoantibodies(6)  

摘要： TLR7 stimulation of T-bet+CD11c+IgD-CD27- double-negative 2 (DN2) B cells is crucial for autoantibody formation in systemic lupus erythematosus (SLE). Here, we show that administration of IL-4 for five weeks significantly reduced autoantibodies and T-bet+CD11c+ IgD- B cells in autoimmune BXD2 mice treated with R848, a TLR7 agonist. Single-cell transcriptomics analysis indicates that following two doses of in vivo administration, IL-4 redirected development toward follicular, CD23+ germinal center (GC), and DN4-like memory B cells compared to treatment with R848 alone. While IL-4 enhanced genes related to antigen processing and presentation, it also suppressed R848-induced Ki67+ GC B cells in vivo. In vitro stimulation of SLE patient B cells with a DN2 polarizing cocktail revealed that IL-4 reduced the expression of interferon response and DN2 signature genes, promoting a population of CD23+T-bet- DN4 B population. These findings suggest that developmental reprogramming by IL-4 counteracts TLR7-promoted DN2 and GC B cells in SLE.