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关键词： Miocene  

摘要： Records from the Miocene il-Blata section in Malta offer insights into the depositional environments of the Central Mediterranean following an Early Miocene restriction of the Mesopotamian Seaway (c. 20 Ma). Inorganic and organic stable carbon isotope values suggest relatively steady depositional environments, whereas authigenic iron dolomite abundances exhibiting substantial delta O-18 and delta C-13 variations at a sequence scale indicate dynamic sedimentation conditions leading to differential diagenesis. Petrographically, the dolomitic levels exhibit matrix-selective dolomitization, occasional silicification and phosphatization, and textural indicators pointing to subsurface microbial influences. These features collectively point to complex shallow burial diagenesis. In addition, the presence of framboidal pyrite and gypsum infilling foraminiferal chambers, along with the absence of large planktonic foraminifera, suggests the development of palaeoenvironmental stress imposed by a density-stratified water column affecting the pore waters. Towards the top of the studied succession, a shift from organic to siliceous deposits reflects water column perturbations possibly linked to changes in oceanic circulation associated with a temporary re-opening of the Mesopotamian Seaway. This study not only underscores the hydrochemical controls exerted by North African terrigenous fluxes over the Mediterranean, but also highlights the intricate interplay between shifting depositional environments and shallow burial diagenetic processes in shaping the geochemical and textural fabrics of authigenic mineral assemblages.

关键词： Child   Leukemia   Prognosis   T-cell  

摘要： Objective To investigate the clinical manifestations, long-term survival, and prognosis of childhood T-cell acute lymphoblastic leukemia (T-ALL). Methods Case *** clinical data of 43 T-ALL children who were diagnosed and treated in Children′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2010 to December 2021 were retrospectively *** were stratified for treatment according to the CCCG-ALL regimen, and the correlation of prognosis with the condition at initial diagnosis, early treatment response, and induced remission was *** Kaplan-Meier survival curve was used to analyze the survival rate, and the survival rates were compared between groups by the Log-rank *** multivariate Cox regression model was used to analyze the impact of multiple factors on the long-term survival of children. Results T-ALL patients accounted for 9.5% (43/451) of the total number of acute lymphoblastic leukemia patients admitted to the hospital at the same *** median onset age of the 43 T-ALL patients was 7 years (1-13 years).Of the 43 patients included, 14 patients (32.6%) had concomitant mediastinal widening, 8 patients (18.6%) had concomitant giant mediastinal masses, and 4 patients (9.3%) had early precursor T-cell acute lymphoblastic leukemia (ETP-ALL) at initial *** 43 children were treated according to the CCCG-ALL intermediate- and high-risk group *** them, 33 children (76.7%) achieved sustained remission, 5 children died, and 5 children had a *** of September 30, 2024, the median follow-up time was 62 months (1-170 months), the 10-year event-free survival rate was (80.2±6.4)%, and the 10-year overall survival rate was (86.6±5.8)%.The median relapse time and 10-year cumulative relapse rate of the 5 relapsed children were 28 months (7-58 months) and (13.7±5.8)%, *** relationship of prognosis with clinical characteristics at initial diagnosis and induced remission in 43

关键词： CD56dim NK   HLA-I   NK cells   anti-tumour immunity   deconvolution   lower-grade glioma   prognosis   transcriptional signature  

摘要： BACKGROUND:Human leukocyte antigen class I (HLA-I) plays a pivotal role in shaping anti-tumour immunity by influencing the functionality of T cells and natural killer (NK) cells within the tumour microenvironment. METHODS:Here, we explored the transcriptional landscape of HLA-I molecules across various solid cancer transcriptomes from The Cancer Genome Atlas (TCGA) database and assessed the impact of HLA-I expression on the clinical significance of tumour-infiltrating CD56 and CD56 NK cells. RESULTS:Our analysis revealed that high HLA-I expression correlated with reduced patient survival in the TCGA lower-grade glioma (LGG) cohort, with this association varying by histopathological subtype. We then estimated the relative abundance of 23 immune and stromal cell signatures in LGG transcriptomes using a cellular deconvolution approach, which revealed that LGG patients with low HLA-I expression and high CD56 NK cell abundance had better survival outcomes compared to those with high HLA-I expression and low CD56 NK cell abundance. Furthermore, HLA-I expression was positively correlated with various inhibitory NK cell receptors and negatively correlated with activating NK cell receptors, particularly those within the killer cell lectin-like receptor (KLR) gene family. High co-expression of and predicted poor survival outcomes in LGG patients, whereas low and high abundance predicted more favourable outcomes, suggesting a potential modulatory role of HLA-I on the tumour-infiltrating cytotoxic CD56 NK cell subset. CONCLUSIONS:Overall, our study unveils a potential role for deregulated HLA-I expression in modulating the clinical impact of glioma-infiltrating CD56 NK cells. These findings lay the foundation for future in-depth experimental studies to investigate the underlying mechanisms.

摘要： BACKGROUND:JAK inhibition (JAKi) is effective in seronegative spondyloarthropathy (SpA) spectrum disorders, but TYK2 inhibition failed in SpA spectrum ulcerative colitis, and tofacitinib showed minimal benefit in Crohn's Disease, which highlights the complex role for JAK-STAT signaling in different inflammatory processes. In this study, we investigated whether JAKi might paradoxically activate entheseal innate immunity and aimed to identify the key regulatory cytokines involved in this process. METHODS:Spinal entheseal tissue was activated with TLR agonists, including TLR4 and IL-1 family proteins and entheseal T cell were activated with anti-CD3/anti-CD28 plus IL-23/IL-1β. JAKi via upadacitinib (JAK1/JAK2), deucravacitinib (TYK2) and ritlecitinib (JAK3) inhibition was evaluated using multiplex cytokine assays, intracellular flow and bulk RNAseq and cytokine blocking or stimulation. RESULTS:Following IFNγ stimulation, JAK1 inhibition blocked STAT1 phosphorylation in entheseal cells and strongly blocked activated entheseal T cell TNFα, IL-17A and IL-17F production. The opposite effect was evident in entheseal myeloid cell with exaggerated TLR4 and other adjuvant-mediated cytokine production including IL-23 (~10-fold increase; p < 0.001) or TNFα (~10-fold increase; p < 0.0001). This myeloid effect was induced by upadacitinib and deucravacitinib, but not ritlecitinib, suggesting IL-10R JAK1/TYK2 signaling. Bulk RNAseq showed multifaceted impact of JAKi on myeloid activation with strong M1 type monocyte polarisation under TLR4 stimulation and JAK1 inhibition confirmed by flow cytometry. Direct IL-10 inhibition recapitulated inflammatory cytokine elevations and IL-10R agonist largely, but not completely, rescued this phenotype. CONCLUSIONS:These findings help explain the emergent efficacy of TYK2 blockade in SpA spectrum related arthritis that is not IL-10 dependent but indicates why such strategies may not be a panacea for SpA spectrum disorder related intestinal inflam

关键词： CD1-restricted T cells   Diet-induced dyslipidemia   Mycobacterium tuberculosis   Mycolic acid   Transgenic mice  

摘要： Dyslipidemia, characterized by altered lipid profiles, influences host immune responses against infections, including Mycobacterium tuberculosis (Mtb). While the effects of dyslipidemia on conventional T cell responses are well documented, its impact on group 1-CD1 restricted T cells, a distinct subset of lipid antigen-specific unconventional T cells, during Mtb infection remains unclear. In this study, we developed a double-transgenic mouse model expressing human group 1 CD1 (hCD1Tg) and mycolic acid (MA)-specific CD1b-restricted T cell receptor (DN1Tg) in a Rag-deficient and low-density lipoprotein receptor-deficient background to investigate how diet-induced dyslipidemia affects the functionality of MA-specific T cells and their role in anti-Mtb immunity. We found that diet-induced dyslipidemia led to increased IFN-γ production by MA-specific T cells, which promoted mycobacterial clearance in vitro. Mechanistically, this enhanced IFN- γ production was associated with increased TCR signaling and enhanced glycolysis in DN1 T cells, rather than changes in antigen presentation by dendritic cells. However, dyslipidemia also increased apoptosis in DN1 T cells, which may have impaired their ability to control mycobacterial infection in vivo, resulting in reduced bacterial clearance. These findings highlight a complex interplay between diet-induced dyslipidemia and lipid antigen-specific T-cell responses in Mtb infection, providing insights for potential therapeutic strategies to mitigate dyslipidemia-induced changes in T-cell functions.

关键词： Anti-PoRV effect   Lactobacillus plantarum   STING-IFN-I pathway  

摘要： BackgroundRotavirus infection represents a major etiology of severe diarrheal disease in neonatal and weaned piglets, causing substantial economic burdens to the global swine industry. Lactobacillus plantarum, a ubiquitous probiotic in natural ecosystems, has demonstrated multifaceted biological functions. The stimulator of the interferon gene (STING) is involved in type I interferon (IFN-I) mediated host antiviral innate immunity, which is a pivotal adaptor in response to the microbial DNA/RNA-activated signaling pathways. Emerging evidence suggests that certain probiotic strains can activate the STING-dependent pathway to induce IFN-I responses. In the present study, we successfully isolated a strain of Lactobacillus plantarum (designated LP1)from porcine intestinal contents and investigate its potential to counteract porcine rotavirus (PoRV) infection via modulation of antiviral signaling ***1 exhibited superior tolerance to simulated gastrointestinal conditions (pH 3.0 and 0.3% bile salts) compared with other isolated Lactobacillus strains. In vitro adhesion assays demonstrated that LP1effectively colonized porcine intestinal epithelial cells (IPEC-J2) without inducing cytotoxicity or apoptosis. Animal experiments also confirmed the protective effect of LP1 in mice against rotavirus, by reducing body weight loss, promoting viral clearance in feces, and alleviating intestinal mucosal damage. Mechanistic investigations identified STING-IRF3 pathway activation as the pivotal antiviral mechanism. Both phosphorylation of STING and IRF3 in LP1-treated IPEC-J2 cells accompanied by upregulated transcription and secretion of IFN-beta and interferon-stimulated genes (ISGs). Consistent findings were observed in intestinal tissues of LP1-protected mice with STING pathway activation correlating with reduction in viral titers. Crucially, STING inhibitor (C-170) administration could reverse LP1-mediated antiviral ***1 exerts potent anti-PoRV activ

关键词： antipsychotics   cytokines   electroconvulsive therapy (ECT)   interleukins   treatment-resistant schizophrenia (TRS)  

摘要： : Resistance to antipsychotic treatment in patients suffering from schizophrenia is linked to immune system disequilibrium. One effective therapeutic option for treatment-resistant schizophrenia is electroconvulsive therapy (ECT); however, its impact on cytokines remains poorly understood. The aim of this study is to evaluate the impact of ECT on cytokines (IL-1β, IP-10, IL-17, TNFα, IL-10, and soluble receptor for IL-2 (sIL-2R)) in TRS patients. Additionally, correlations between cytokine concentrations and schizophrenia symptoms severity are explored. : Cytokine and receptor concentrations were measured in eight TRS patients before and after ECT and in 13 healthy participants from control group. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the severity of the symptoms. : Before ECT, TRS patients exhibited significantly higher concentrations of IL-1ß, IL-10, IL-17, and IP-10 compared to the control group, whereas no significant differences were observed in sIL-2R and TNF-α. In the TRS patients, ECT induced a significant reduction in IL-10, IL-17 and IP-10 levels, while IL-1β, TNF-α, and sIL-2R remained unchanged compared to pre-ECT. ECT also led to clinical improvement in schizophrenia symptoms, as measured by PANSS. Furthermore, correlations between cytokine levels and PANSS results were found. : The above results suggest that clinical improvement in TRS patients following ECT is associated with immune modulation, especially with the steadiness between pro- and anti-inflammatory systems. However, further research is required to elucidate these mechanisms in greater detail.

关键词： chronic obstructive pulmonary disease (COPD)   emphysema   long non-coding interleukin-7 receptor α-subunit gene (lnc-IL7R)   machine learning   percentage of low attenuation area (LAA%)  

摘要： Chronic obstructive pulmonary disease (COPD) remains a leading cause of death worldwide, with emphysema progression providing valuable insights into disease development. Clinical assessment approaches, including pulmonary function tests and high-resolution computed tomography, are limited by accessibility constraints and radiation exposure. This study, therefore, proposed an alternative approach by integrating the novel biomarker long non-coding interleukin-7 receptor α-subunit gene (), along with other easily accessible clinical and biochemical metrics, into machine learning (ML) models. This cohort study collected baseline characteristics, COPD Assessment Test (CAT) scores, and biochemical details from the enrolled participants. Associations with emphysema severity, defined by a low attenuation area percentage (LAA%) threshold of 15%, were evaluated using simple and multivariate-adjusted models. The dataset was then split into training and validation (80%) and test (20%) subsets. Five ML models were employed, with the best-performing model being further analyzed for feature importance. The majority of participants were elderly males. Compared to the LAA% <15% group, the LAA% ≥15% group demonstrated a significantly higher body mass index (BMI), poor pulmonary function, and lower expression levels of (all < 0.01). Fold changes in were strongly and negatively associated with LAA% ( < 0.01). The random forest (RF) model achieved the highest accuracy and area under the receiver operating characteristic curve (AUROC) across datasets. A feature importance analysis identified fold changes as the strongest predictor for emphysema classification (LAA% ≥15%), followed by CAT scores and BMI. Machine learning models incorporated accessible clinical and biochemical markers, particularly the novel biomarker , achieving classification accuracy and AUROC exceeding 75% in emphysema assessments. These findings offer promising opportunities for improving emphysema classificati

摘要： Human induced pluripotent stem cells (iPSCs) offer a promising source for chimeric antigen receptor (CAR)–engineered natural killer (NK) products. However, complex iPSC-NK (iNK) manufacturing challenges clinical use. Here, we identified LiPSC-GR1.1 as a superior iPSC line for iNK production. By engineering LiPSC-GR1.1 with a mesothelin (MSLN)–targeting CAR and interleukin-15 (IL-15), we achieved robust differentiation of iPSCs into mature activated iNK cells with enhanced tumor killing efficacy, superior tumor homing, and vigorous proliferation. Single-cell transcriptomic analysis revealed that transforming growth factor–β (TGF-β)–producing tumor cells up-regulated major histocompatibility complex molecules and down-regulated MSLN post–CAR-IL-15 iNK treatment. Tumor-infiltrating CAR-IL-15 iNK cells exhibited high levels of CAR, IL-15, and NK-activating receptors, negligible checkpoint exhaustion markers, and extremely low levels of NK suppressive factors CISH, TGFBR2, and BATF, enabling them to sustain activation, metabolic fitness, and effective tumor killing within TGF-β–rich hypoxic tumor microenvironment. Overall, we developed ***-IL-15–engineered GR1.1-iNK therapy with enhanced antitumor efficacy for solid tumor treatment. Copyright © 2025 The Authors, some rights reserved.