Activation Of Immune Pathways Research Articles

Interferon-signaling pathways are upregulated in people with HIV with abnormal pulmonary diffusing capacity (DL CO ).

People with HIV (PWH) are at greater risk of developing lung diseases even when they are antiretroviral therapy (ART)-adherent and virally suppressed. The most common pulmonary function abnormality in PWH is that of impaired diffusing capacity of the lungs for carbon monoxide (DL CO ), which is an independent risk factor for increased mortality in PWH. Earlier work has identified several plasma biomarkers of inflammation and immune activation to be associated with decreased DL CO . However, the underpinning molecular mechanisms of HIV-associated impaired DL CO are largely unknown. Cross-sectional pilot study with PWH with normal DL CO (values greater than or equal to the lower limit of normal, DL CO ≥ LLN, N = 9) or abnormal DL CO (DL CO < LLN, N = 9). We compared the gene expression levels of over 900 inflammation and immune exhaustion genes in PBMCs from PWH with normal vs. abnormal DL CO using the NanoString technology. We found that 26 genes were differentially expressed in the impaired DL CO group. These genes belong to 4 categories: 1. Nine genes in inflammation and immune activation pathways, 2. seven upregulated genes that are direct targets of the interferon signaling pathway, 3. seven B-cell specific genes that are downregulated, and 4. three miscellaneous genes. These results were corroborated using the bioinformatics tools DAVID (Database for Annotation, Visualization and Integrated Discovery) and GSEA (Gene Sets Enrichment Analysis). The data provides preliminary evidence for the involvement of sustained interferon signaling as a molecular mechanism for impaired DL CO in PWH.

Production of some cytokines as a reflection of various immunoregulatory mechanisms in post-covid myocarditis

Currently, the problem of persistent myocardial damage in patients who have had COVID-19 has become one of the most pressing in the practice of cardiologists. The main mechanisms of the pathogenesis of post-COVID myocarditis are associated with a violation of immunoregulation caused by long-term persistence of the virus in the heart muscle and the launch of autoimmune processes that can lead to myocardial remodeling, the formation of myocardiosclerosis and the development of heart failure or arrhythmia. The purpose of this study was to assess the dynamics of the production of certain cytokines (IFNg, IL-4, IL-17А), which may indirectly reflect the activation of various immune response pathways in patients with post-COVID myocarditis, depending on the duration of the disease and the degree of heart failure. The study included 32 patients with post-COVID myocarditis, 36 patients with myocardial cardiosclerosis, and 10 apparently healthy individuals. It was found that in all patients with post-COVID myocarditis, the content of IFNg, IL-4, IL-17А in the blood serum was higher than in patients with myocardial cardiosclerosis (p 0.001; p 0.05; p 0.01, respectively) and conditionally healthy individuals (p 0.001; p 0.01; p 0.001, respectively). Compared with the group of patients with no or moderate severity of symptoms of heart failure (functional class 0–II), those with more severe heart failure (functional class III) had a higher level of interferon gamma (p 0.05). When comparing the results obtained with similar indicators in patients with myocardial cardiosclerosis who have the same degree of heart failure, no statistically significant differences were obtained. The maximum content of IFNg in post-COVID myocarditis was observed in the 2nd week of the disease (p 0.001 compared with the control group); then its level gradually decreased and by the end of the 2nd month there were no longer any significant differences. The opposite trend was observed in relation to the content of IL-4 and IL-17А: in the first two weeks, no statistically significant differences were detected with the control group, but then their content increased quite quickly (p 0.001 compared with the control group by the end of the first month of the disease) and continued to remain the same high until the end of the 2nd month. Thus, monitoring the content of IFNg, IL-4, IL-17А in blood serum can to some extent provide an idea of the sequence of development of the immune response in post-COVID myocarditis. An increase in IFNg levels in the early stages of the disease is probably associated with an increase in the manifestations of heart failure. Th17-mediated mechanisms may be involved in the process of myocardial remodeling resulting in myocardial cardiosclerosis.

Cyclophilin A promotes porcine deltacoronavirus replication by regulating autophagy via the Ras/AKT/NF-κB pathway

Porcine deltacoronavirus (PDCoV) is an important enteric coronavirus that has caused major worldwide economic losses in the pig industry. Previous studies have shown that cyclophilin A (CypA), a key player in aetiological agent infection, is involved in regulating viral infection. However, the role of CypA during PDCoV replication remains unknown. Therefore, in this study, the role of CypA in PDCoV replication was determined. The results demonstrated that PDCoV infection increased CypA expression in LLC-PK1 cells. CypA overexpression substantially promoted PDCoV replication. Proteomic analysis was subsequently used to assess changes in total protein expression levels after CypA overexpression. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to further determine the mechanisms by which CypA affects viral replication. Proteomic analysis revealed that CypA protein overexpression significantly upregulated 75 differentially expressed proteins and significantly downregulated 172 differentially expressed proteins. The differentially expressed proteins were involved mainly in autophagy and activation of the host innate immune pathway. Subsequent experimental results revealed that the CypA protein promoted viral replication by reducing the levels of natural immune cytokines and mitigated the inhibitory effect of chloroquine (CQ) on viral replication. Further investigation revealed that CypA could activate the Ras/AKT/NF-κB pathway, mediate autophagy signalling and promote PDCoV replication. In summary, the findings of this study may help elucidate the role of CypA in PDCoV replication.

A Carrier-Based Quantitative Proteomics Method Applied to Biomarker Discovery in Pericardial Fluid

Data-dependent liquid chromatography tandem mass spectrometry is challenged by the large concentration range of proteins in plasma and related fluids. We adapted the SCoPE method from single-cell proteomics to pericardial fluid, where a myocardial tissue carrier was used to aid protein quantification. The carrier proteome and patient samples were labeled with distinct isobaric labels, which allowed separate quantification. Undepleted pericardial fluid from patients with type 2 diabetes mellitus and/or heart failure undergoing heart surgery was analyzed with either a traditional liquid chromatography tandem mass spectrometry method or with the carrier proteome. In total, 1398 proteins were quantified with a carrier, compared to 265 without, and a higher proportion of these proteins were of myocardial origin. The number of differentially expressed proteins also increased nearly four-fold. For patients with both heart failure and type 2 diabetes mellitus, pathway analysis of upregulated proteins demonstrated the enrichment of immune activation, blood coagulation, and stress pathways. Overall, our work demonstrates the applicability of a carrier for enhanced protein quantification in challenging biological matrices such as pericardial fluid, with potential applications for biomarker discovery. Mass spectrometry data are available via ProteomeXchange with identifier PXD053450.

New Therapies for Highly Sensitized Patients on the Waiting List.

Exposure to HLA alloantigens through pregnancy, blood products, and previous transplantations induce powerful immunologic responses that create an immunologic barrier to successful transplantation. This is commonly detected through screening for HLA antibodies using Luminex beads coated with HLA antigens at transplant evaluation. Currently accepted approaches to desensitization include plasmapheresis/low-dose or high-dose intravenous Ig plus anti-CD20. However, these approaches are often unsuccessful because of the inability to remove high titer circulating HLA antibodies and limit rebound responses by long-lived anti-HLA antibody secreting plasma cells (PCs) and memory B cells (B MEM ). This is especially significant for patients with a calculated panel reactive antibody of 99%-100%. Newer desensitization approaches, such as imlifidase (IgG endopeptidase), rapidly inactivate IgG molecules and create an antibody-free zone by cleaving IgG into F(ab'2) and Fc fragments, thus eliminating complement and cell-mediated injury to the graft. This represents an important advancement in desensitization. However, the efficacy of imlifidase is limited by pathogenic antibody rebound, increasing the potential for antibody-mediated rejection. Controlling antibody rebound requires new strategies that address the issues of antibody depletion and inhibition of B MEM and PC responses. This will likely require a combination of agents that effectively and rapidly deplete pathogenic antibodies and prevent immune cell activation pathways responsible for antibody rebound. Here, using anti-IL-6 receptor (tocilizumab) or anti-IL-6 (clazakizumab) could offer long-term control of B MEM and PC donor-specific HLA antibody responses. Agents aimed at eliminating long-lived PCs (anti-CD38 and anti-B-cell maturation antigen×CD3) are likely to benefit highly HLA sensitized patients. Complement inhibitors and novel agents aimed at inhibiting Fc neonatal receptor IgG recycling will be important in desensitization. Administering these agents alone or in combination will advance our ability to effectively desensitize patients and maintain durable suppression post-transplant. After many years of limited options, advanced therapeutics will likely improve efficacy of desensitization and improve access to kidney transplantation for highly HLA sensitized patients.

Secretory Phenotype in Peripheral Blood Mononuclear Cells of Elderly Patients with Rheumatoid Arthritis.

This study aims to investigate the expression differences of peripheral blood mononuclear cells (PBMCs) in patients with elderly rheumatoid arthritis (ERA). Differentially expressed genes (DEGs) of PBMCs between young patients with RA (RA_Y) and elderly patients with RA (RA_A) were identified by RNA sequencing using the DESeq2 package, followed by bioinformatics analysis. The overlapped targets of the current DEGs and proteomic differentially expressed proteins (another set of unpublished data) were identified and further validated. The bioinformatics analysis revealed significant transcriptomic heterogeneity between RA_A and RA_Y. A total of 348 upregulated and 363 downregulated DEGs were identified. Gene functional enrichment analysis indicated that the DEGs, which represented senescence phenotype for patients with ERA, were enriched in pathways such as Phosphatidylinositol3 kinase/AKT serine-threonine protein kinase (PI3K/Akt) signaling, Mitogen-activated protein kinases (MAPK) signaling, toll-like receptor family, neutrophil degranulation, and immune-related pathways. Gene set enrichment analysis further confirmed the activation of humoral immune response pathways in RA_A. Quantitative polymerase chain reaction validated the expression of five representative DEGs such as SPTA1, SPTB, VNN1, TNXB, and KRT1 in PBMCs of patients with ERA. Patients with ERA have significant senescence phenotype differences versus the young patients. The DEGs identified may facilitate exploring the biomarkers of senescence in RA.

Long non-coding RNAs in ferroptosis and cuproptosis impact on prognosis and treatment in hepatocellular carcinoma

Ferroptosis and cuproptosis are recently discovered forms of cell death that have gained interest as potential cancer treatments, particularly for hepatocellular carcinoma. Long non-coding RNAs (lncRNAs) influence cancer cell activity by interacting with various nucleic acids and proteins. However, the role of ferroptosis and cuproptosis-related lncRNAs (FCRLs) in cancer remains underexplored. Ferroptosis and cuproptosis scores for each sample were assessed using Gene Set Variation Analysis (GSVA). Weighted correlation network analysis identified the FCRLs most relevant to our study. A risk model based on FCRLs was developed to categorize patients into high-risk and low-risk groups. We then compared overall survival (OS), tumor immune microenvironment, and clinical characteristics between these groups. The IPS score and ImmuCellAI webpage were used to predict the association between FCRL-related signatures and immunotherapy response. Finally, we validated the accuracy of FCRLs in hepatocellular carcinoma cell lines using induction agents (elesclomol and erastin). Patients in different risk subgroups showed significant differences in OS, immune cell infiltration, pathway activity, and clinical characteristics. Cellular assays revealed significant changes in the expression of AC019080.5, AC145207.5, MIR210HG, and LINC01063 in HCC cell lines following the addition of ferroptosis and cuproptosis inducers. We created a signature of four FCRLs that accurately predicted survival in HCC patients, laid the foundation for basic research related to ferroptosis and cuproptosis in hepatocellular carcinoma, and provided therapeutic recommendations for HCC patients.

Combined coagulation and inflammation markers as predictors of venous thrombo-embolism and death in COVID-19.

The COVID-19 pandemic related to SARS-CoV-2 virus was responsible for global pandemic. The severe form of the disease was linked to excessive activation of immune pathways together with a systemic cytokine storm response and thrombotic venous or arterial complications. Factors predicting severe outcomes including venous and/or pulmonary thrombosis (VT) and death were identified, but the prognostic role of their combination was not addressed extensively. We investigated the role of prognostic factors from the coagulation or inflammatory pathways to better understand the outcome of the disease. For this, we prospectively studied 167 SARS-CoV-2-positive patients from admission in intensive care units (ICU) or emergency departments from four academic hospitals over a 14-month period. Besides standard biology, we assessed serum concentrations of inflammatory markers, coagulation factors and peripheral blood cells immunophenotyping. Thirty-nine patients (23.3%) developed VT and 30 patients (18%) died. By univariate analysis, C-reactive protein (CRP) level > 150 mg/L, interleukin-6 (IL-6) ≥ 20 pg/mL, D-dimers > 1,500 μg/L, ADAMTS13 activity ≤ 50%, Von. A combination of coagulation and inflammatory markers can refine the prognostication of severe outcome in COVID-19, and could be useful for the initial evaluation of other types of viral infection.

Bacteria colonization and gene expression related to immune function in colon mucosa is associated with growth in neonatal calves regardless of live yeast supplementation

BackgroundAs Holstein calves are susceptible to gastrointestinal disorders during the first week of life, understanding how intestinal immune function develops in neonatal calves is important to promote better intestinal health. Feeding probiotics in early life may contribute to host intestinal health by facilitating beneficial bacteria colonization and developing intestinal immune function. The objective of this study was to characterize the impact of early life yeast supplementation and growth on colon mucosa-attached bacteria and host immune function.ResultsTwenty Holstein bull calves received no supplementation (CON) or Saccharomyces cerevisiae boulardii (SCB) from birth to 5 d of life. Colon tissue biopsies were taken within 2 h of life (D0) before the first colostrum feeding and 3 h after the morning feeding at d 5 of age (D5) to analyze mucosa-attached bacteria and colon transcriptome. Metagenome sequencing showed that there was no difference in α and β diversity of mucosa-attached bacteria between day and treatment, but bacteria related to diarrhea were more abundant in the colon mucosa on D0 compared to D5. In addition, qPCR indicated that the absolute abundance of Escherichia coli (E. coli) decreased in the colon mucosa on D5 compared to D0; however, that of Bifidobacterium, Lactobacillus, and Faecalibacterium prausnitzii, which could competitively exclude E. coli, increased in the colon mucosa on D5 compared to D0. RNA-sequencing showed that there were no differentially expressed genes between CON and SCB, but suggested that pathways related to viral infection such as “Interferon Signaling” were activated in the colon mucosa of D5 compared to D0.ConclusionsGrowth affected mucosa-attached bacteria and host immune function in the colon mucosa during the first 5 d of life in dairy calves independently of SCB supplementation. During early life, opportunistic pathogens may decrease due to intestinal environmental changes by beneficial bacteria and/or host immune function. Predicted activation of immune function-related pathways may be the result of host immune function development or suggest other antigens in the intestine during early life. Further studies focusing on the other antigens and host immune function in the colon mucosa are required to better understand intestinal immune function development.

Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways.

Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel genes that are involved in microglia activation, glutamate production, and signaling pathways. These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.

Immune subtyping of ER-positive, PR-negative and HER2-negative breast cancers by immunohistochemistry: Molecular basis and clinical relevance.

e12553 Background: The diversity and plasticity behind ER+/PR−/HER2− breast cancer (BC) remain underexplored. In our previous work, an immune subtype classification for ER+/PR-/HER2- BC with RNA-seq data was established to distinguish between immune-hot and -cold tumors to provide guidance for immune checkpoint inhibitor (ICI) therapy. However, considering the economic costs, the clinical application of sequencing methods is limited. This study aimed to identify biomarkers of the immune subtype classification and develop a diagnostic procedure for ER+/PR-/HER2- BC immune subtyping based on the immunohistochemistry (IHC) technique, thereby identifying candidates of ICI therapy and refining treatment strategies for ER+/PR-/HER2- BC. Methods: RNA-seq data for 411 patients diagnosed with ER+/PR-/HER2- BC were obtained from the METABRIC database (METABRIC cohort). The immune subtype classification was established by consensus clustering with 1480 immune-related genes. Biomarkers for each immune subtype were identified from differentially expressed genes and validated using logistic regression and ROC curve analysis. Validation of the immune classification was conducted using RNA-seq data from the GEO and TCGA databases. Transcriptomic gene chip sequencing was performed on surgical specimens from 15 ER+/PR-/HER2- BC patients in our center (Chip cohort) to classify the immune subtypes. Biomarkers identified were validated and a diagnostic procedure was designed using IHC techniques. Results: In the METABRIC cohort, immune subtypes including Clusters 1-5 were established. Five biomarkers including DCN, SPP1, CXCL9, STC2, and SRGAP1 were identified, with the AUC values of ROC curves being 0.90, 0.82, 0.99, 0.70, and 0.89, respectively. Notably, Cluster 3 exhibited higher infiltration of CD8+ T cells, B cells, and M1 macrophages, with a greater association with immune activation pathways, thus being defined as the immune-hot subtype. Cluster 1, also showing a moderate immune cell infiltration, was characterized by a more pronounced stromal infiltration. In the Chip cohort, IHC revealed that Cluster 3 exhibited the highest levels of CD8+ T cell and B cell infiltration as well as PD-L1 expression, suggesting a potential benefit from ICI therapy. In contrast, Cluster 1 demonstrated the most extensive infiltration of endothelial and fibroblast cells. The other subtypes were characterized by a suppressed immune microenvironment, especially in Cluster 2, where an infiltration of SPP1+ macrophages was observed. A diagnostic procedure was designed with the biomarkers using IHC techniques. Conclusions: This study validated the immune subtype classification for ER+/PR-/HER2- BC. An easy-to-use IHC-based diagnostic procedure was developed, facilitating the identification of potential ICI therapy candidates in clinical practice at a lower cost.

Immunoglobulin and T cell receptor repertoire changes induced by a prototype vaccine against Chagas disease in naïve rhesus macaques

BackgroundA vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1 parasite antigens was found to be safe and immunogenic in naïve macaques.MethodsWe used RNA-sequencing and performed a transcriptomic analysis of PBMC responses to vaccination of naïve macaques after each vaccine dose, to shed light on the immunogenicity of this vaccine and guide the optimization of doses and formulation. We identified differentially expressed genes and pathways and characterized immunoglobulin and T cell receptor repertoires.ResultsRNA-sequencing analysis indicated a clear transcriptomic response of PBMCs after three vaccine doses, with the up-regulation of several immune cell activation pathways and a broad non-polarized immune profile. Analysis of the IgG repertoire showed that it had a rapid turnover with novel IgGs produced following each vaccine dose, while the TCR repertoire presented several persisting clones that were expanded after each vaccine dose.ConclusionsThese data suggest that three vaccine doses may be needed for optimum immunogenicity and support the further evaluation of the protective efficacy of this vaccine.

Construction and validation of a necroptosis-related prognostic signature in acute myeloid leukemia.

Acute myeloid leukemia (AML), an uncommonly low 5-year survival and high mortality rate, is a potentially catastrophic diagnosed subtype of leukemia. The development of new prognostic markers is urgently needed to guide its treatment. Necroptosis is a newly defined biological process for regulating cell death, and previous studies have confirmed that the abnormality of the physical function can lead to multiple malignancies. Here, we performed necroptosis-related genes (NRGs) to build a predictive model in the Cancer Genome Atlas (TCGA)-AML patients, thus exploring the correlation between the NRG prognosis signature (NRG score) of this model and immune infiltration, pathway activity, clinical features, and immunotherapy. Besides, we computed the statistical measure Spearman rank correlation between the NRG score and the Log IC50 values of therapeutic agents. Subsequently, we divided the TCGA-AML cohort into 2 groups, one with high scores and the other with low scores depending on the model score. AML patients with high NRG scores exhibited a lower estimated overall survival (OS) rate than those with low NRG scores, which was confirmed in the validation set. The prognostic value of the constructed NRG signature to the AML, independent of other variables, was demonstrated by uni- and multivariate stepwise regression analysis. When comparing the infiltrating states of specialized cells associated with immune system from the 2 groups, B cells naive, Plasma cells, and monocytes represented significant differences among various subgroups of samples. Moreover, the 30 hallmark-related pathways related to necroptosis characteristics were remarkably different between the high/low NRG score groups. And patients showed remarkable NRG score distribution in clinical features of bone marrow lymphocyte, category, and FAB classifications. Besides, we found that the BIRB0796, VX680, Vorinostat, and Axitinib positively related with NRG score, whereas CI. 1040, PD. 0325901, Z.L LNle. CHO, and AZD6244 negatively correlated with the NRG score. These drugs may provide a reference for subsequent treatment.

Prognositic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.

Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents, with a poor prognosis. Anchorage-dependent cell death (anoikis) has been proven to be indispensable in tumor metastasis, regulating the migration and adhesion of tumor cells at the primary site. However, as a type of programmed cell death, anoikis is rarely studied in osteosarcoma, especially in the tumor immune microenvironment. This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma. Anoikis-related genes (ANRGs) were obtained from GeneCards. Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus (GEO) databases. ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis (WGCNA) algorithm. Machine learning algorithms were performed to construct long-term survival predictive strategy, each sample was divided into high-risk and low-risk subgroups, which was further verified in the GEO cohort. Finally, based on single-cell RNA-seq from the GEO database, analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment. A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified, from which 3 genes (MERTK, BNIP3, S100A8) were selected to construct the prognostic model. Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis (all P<0.05). Additionally, characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway. The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.

#2423 Molecular classification of lupus nephritis based on immune pathway profiling—correlations with histological class and clinical manifestations

Abstract Background and Aims The ISN/RPS 2003 classification is the current gold standard histopathological classification for lupus nephritis (LN), and has important roles in guiding treatment and predicting prognosis. The classification system, largely based on light microscopy features, does not inform the underlying immunological aberrations. A classification based on molecular typing of immune-related pathways may better stratify LN patients and help select treatments that target specific immune cascades. Method The normalized expression matrix and clinical data were extracted from Gene Expression Omnibus database, Human Cell Atlas (Hacohen-Human-CELseq2) and Nephroseq. Four chip datasets (GSE127797, 32591, 69438 and 37463) and one single cell dataset were analyzed. Sample gene set enrichment analysis (ssGSEA) method was used to derive immune phenotype with gene expression data. The hierarchical clustering with ssGSEA scores of selected gene sets was used to classify LN tissues. Functional characterization and protein-protein interactions of the differential expression genes (DEGs) of three groups were compared with healthy donors using Metascape (absolute log FC &amp;gt; 1 and adjusted P-value &amp;lt; .05). Kruskal-Walli test and chi-square test were performed to compare the clinical parameters of the different groups. Results We analyzed 96 immune-related gene sets in the glomerular and tubulointerstitial regions of LN kidney biopsy samples. The immune-related genes were categorized into three clusters (Immune-Mild, Immune-Moderate and Immune-Severe) based on the degree of immune pathway activation. Interferon-stimulated genes are a hallmark of LN, with high signals in all three clusters. When compared to other groups, the Immune-Mild cluster from the glomerular region showed no T-cell activation or T cell receptor pathway. Also, the Immune-Mild (tubulointerstitial) group also showed minimal lymphocyte activation or migration. Protein-protein interactions networks with MOCDE components further suggested that STAT1 and ISG15 the hub genes in different clusters. The gene expressions of hub genes were then compared among epithelial cells and 21 immune cells from LN and heath controls. Immune clusters are correlated with clinical phenotypes, in which Immune-Mild Group (Glomerular) showed high prevalence of Class II and V LN, and Immune-Mild (Tubulointerstitial) showed more Class V LN. Immune-Severe group also showed higher degree of proteinuria and blood pressure but lower eGFR compared to Immune-Moderate and Immune-Mild groups. Conclusion A new molecular classification of LN based on the degree of immune pathway activation shows correlation with clinical manifestations and may potentially guide personalized therapy in LN patients.

Identification of clear cell renal cell carcinoma subtypes by integrating radiomics and transcriptomics

ObjectiveThis study aimed to delineate the clear cell renal cell carcinoma (ccRCC) intrinsic subtypes through unsupervised clustering of radiomics and transcriptomics data and to evaluate their associations with clinicopathological features, prognosis, and molecular characteristics. MethodsUsing a retrospective dual-center approach, we gathered transcriptomic and clinical data from ccRCC patients registered in The Cancer Genome Atlas and contrast-enhanced computed tomography images from The Cancer Imaging Archive and local databases. Following the segmentation of images, radiomics feature extraction, and feature preprocessing, we performed unsupervised clustering based on the “CancerSubtypes” package to identify distinct radiotranscriptomic subtypes, which were then correlated with clinical-pathological, prognostic, immune, and molecular characteristics. ResultsClustering identified three subtypes, C1, C2, and C3, each of which displayed unique clinicopathological, prognostic, immune, and molecular distinctions. Notably, subtypes C1 and C3 were associated with poorer survival outcomes than subtype C2. Pathway analysis highlighted immune pathway activation in C1 and metabolic pathway prominence in C2. Gene mutation analysis identified VHL and PBRM1 as the most commonly mutated genes, with more mutated genes observed in the C3 subtype. Despite similar tumor mutation burdens, microsatellite instability, and RNA interference across subtypes, C1 and C3 demonstrated greater tumor immune dysfunction and rejection. In the validation cohort, the various subtypes showed comparable results in terms of clinicopathological features and prognosis to those observed in the training cohort, thus confirming the efficacy of our algorithm. ConclusionUnsupervised clustering based on radiotranscriptomics can identify the intrinsic subtypes of ccRCC, and radiotranscriptomic subtypes can characterize the prognosis and molecular features of tumors, enabling noninvasive tumor risk stratification.

Comparative Pathogenesis of Two Lineages of Powassan Virus Reveals Distinct Clinical Outcome, Neuropathology, and Inflammation.

Tick-borne flaviviruses (TBFV) can cause severe neuroinvasive disease which may result in death or long-term neurological deficit in over 50% of survivors. Multiple mechanisms for invasion of the central nervous system (CNS) by flaviviruses have been proposed including axonal transport, transcytosis, endothelial infection, and Trojan horse routes. Flaviviruses may utilize different or multiple mechanisms of neuroinvasion depending on the specific virus, infection site, and host variability. In this work we have shown that the infection of BALB/cJ mice with either Powassan virus lineage I (Powassan virus) or lineage II (deer tick virus) results in distinct spatial tropism of infection in the CNS which correlates with unique clinical presentations for each lineage. Comparative transcriptomics of infected brains demonstrates the activation of different immune pathways and downstream host responses. Ultimately, the comparative pathology and transcriptomics are congruent with different clinical signs in a murine model. These results suggest that the different disease presentations occur in clinical cases due to the inherent differences in the two lineages of Powassan virus.

Prognostic model incorporating immune checkpoint genes to predict the immunotherapy efficacy for lung adenocarcinoma: a cohort study integrating machine learning algorithms.

This study aimed to develop and validate a nomogram based on immune checkpoint genes (ICGs) for predicting prognosis and immune checkpoint blockade (ICB) efficacy in lung adenocarcinoma (LUAD) patients. A total of 385 LUAD patients from the TCGA database and 269 LUAD patients in the combined dataset (GSE41272 + GSE50081) were divided into training and validation cohorts, respectively. Three different machine learning algorithms including random forest (RF), least absolute shrinkage and selection operator (LASSO) logistic regression analysis, and support vector machine (SVM) were employed to select the predictive markers from 82 ICGs to construct the prognostic nomogram. The X-tile software was used to stratify patients into high- and low-risk subgroups based on the nomogram-derived risk scores. Differences in functional enrichment and immune infiltration between the two subgroups were assessed using gene set variation analysis (GSVA) and various algorithms. Additionally, three lung cancer cohorts receiving ICB therapy were utilized to evaluate the ability of the model to predict ICB efficacy in the real world. Five ICGs were identified as predictive markers across all three machine learning algorithms, leading to the construction of a nomogram with strong potential for prognosis prediction in both the training and validation cohorts (all AUC values close to 0.800). The patients were divided into high- (risk score ≥ 185.0) and low-risk subgroups (risk score < 185.0). Compared to the high-risk subgroup, the low-risk subgroup exhibited enrichment in immune activation pathways and increased infiltration of activated immune cells, such as CD8 + T cells and M1 macrophages (P < 0.05). Furthermore, the low-risk subgroup had a greater likelihood of benefiting from ICB therapy and longer progression-free survival (PFS) than did the high-risk subgroup (P < 0.05) in the two cohorts receiving ICB therapy. A nomogram based on ICGs was constructed and validated to aid in predicting prognosis and ICB treatment efficacy in LUAD patients.

Cerebrospinal fluid α-synuclein adds the risk of cognitive decline and is associated with tau pathology among non-demented older adults

BackgroundThe role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood.MethodsA total of 331 non-demented individuals were included in the study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition.ResultsHigher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1.ConclusionsThese findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.

A murine model of post-acute neurological sequelae following SARS-CoV-2 variant infection.

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. In the brain, no detectable viral RNA and minimal residential immune cell activation was observed in the surviving mice post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and gene expression levels associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent systemic T helper 1 prone cellular immune responses and strong sera neutralizing antibodies against Delta and Omicron variants months post-acute infection. Overall, our findings suggest that infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long-COVID patients and provides new insights into the role of systemic and brain residential immune factors in PASC pathogenesis.