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摘要： Il cromosoma 2 umano si è formato all’incirca 1 milione di anni fa, dalla fusione telomerica dei due bracci corti degli autosomi omologhi presenti nelle grandi scimmie e nel progenitore comune ad esse e a Homo sapiens. Dando origine a una struttura bicentromerica, il cromosoma 2 manifesta instabilità alla segregazione/ricombinazione del DNA, da cui deriva aumento nel rischio mutazionale. Evidenze storiche di disordini osteometabolici e di massa adiposa derivati da queste mutazioni sono rintracciabili dal primo millennio a.C. al XXI secolo, suggerendo che questo cromosoma contribuisce alla stabilità evolutiva e individuale delle masse somatiche (free fat mass e fat mass) umane, insieme ad altri autosomi, come 15, 21 e 22, che producono sindromi genetiche dismetaboliche storicamente note. Complessivamente, nell’ultimo milione di anni circa gli intervalli di locus genico 2q31-37 e 2p13-25 avrebbero assicurato il mantenimento del programma evolutivo di sviluppo corporeo in Homo sapiens, confermando che sul cromosoma 2 risiede un controllo fondamentale per la speciazione dell’Uomo moderno.

关键词： angiogenesis   ANGPT2   anti-PD-L1 therapy   IFN-gamma   Tie2  

摘要： Introduction Tumor angiogenesis is a critical biological hallmark of cancer, which involves multiple molecularly regulated signaling pathways, including the angiopoietin (ANGPT)-Tie2 and the vascular endothelial growth factor (VEGF) signaling pathways. Despite initial optimism, targeting tumor angiogenesis in the treatment of lung adenocarcinoma (LUAD) has been unsatisfactory. Currently, monotherapy with PD-1/PD-L1 inhibitors, or their combination with bevacizumab, is considered the standard therapeutic approach for LUAD. Recent studies have shown that immunotherapy suppresses tumor angiogenesis and facilitates vascular normalization. However, whether and how anti-PD-L1 therapy influences tumor vasculature remains *** To investigate the impact of immunotherapy on the vasculature of LUAD, a mouse model of lung adenocarcinoma was established by subcutaneous implantation of Lewis lung carcinoma cells in vivo. The effects of different treatments on microvessel density and pericyte coverage were explored, and the expression of angiogenesis-related factors was analyzed. Furthermore, to explore the molecular mechanisms through which IFN-gamma regulates tumor blood vessels during immunotherapy, we elucidated the specific mechanisms in vitro by means of techniques such as siRNA, ChIP, RT-qPCR, Western blot, and immunofluorescence. Finally, the effects of IFN-gamma on the proliferation, migration, and angiogenic function of endothelial cells (ECs) were evaluated through CCK-8, Transwell, and HUVEC tube formation *** Employing a mouse model of LUAD, we demonstrated that PD-L1 blockade therapy inhibits tumor angiogenesis and normalizes vasculature in an IFN-gamma-signaling-dependent manner. Notably, anti-PD-L1 therapy reduced Tie2 and ANGPT2 expression, and these effects were reversed by the JAK1/2 inhibitor. Mechanistically, we demonstrated that IFN-gamma inhibited Tie2 and ANGPT2 expression in ECs, and suppressed ANGPT2 gene transcription through the AK

关键词： probiotics   alcohol   skeletal muscle   gut-muscle axis  

摘要： Background/Objectives: Recent studies have highlighted the role of the gut-muscle axis, suggesting that modulation of the gut microbiota may indirectly benefit skeletal muscle. This study aimed to evaluate the effects of Lactobacillus fermentum (L. fermentum) supplementation in a model of muscle atrophy induced by chronic ethanol (EtOH) intake, focusing on inflammatory and antioxidant mechanisms. Methods: Sixty 12-month-old female Balb/c mice were divided randomly into three groups (n = 20/group): (1) Ethanol (EtOH) group, receiving ethanol daily for 8 and 12 weeks to induce systemic oxidative stress and inflammation;(2) Ethanol + Probiotic (EtOH + P) group, receiving both ethanol and L. fermentum supplementation for the same durations;and (3) Control (Ctrl) group, receiving only water. Muscle samples were analyzed for the fiber morphology, inflammatory markers, oxidative stress indicators, and satellite cell (SC) activity. All data were tested for normality using the Shapiro-Wilk test before applying a parametric analysis. A statistical analysis was performed using one-way ANOVA followed by a Bonferroni post-hoc test. The level of significance was set at p < 0.05. Results: EtOH exposure caused significant atrophy in all muscle fiber types (type I, IIa, and IIb), with the most pronounced effects on oxidative fibers. L. fermentum supplementation significantly reversed atrophy in type I and IIa fibers, accompanied by a significant reduction in IL-6, TNF-alpha, and Hsp60 expression levels, indicating the protective effect of L. fermentum against oxidative stress and inflammation. Moreover, the probiotic treatment increased MyoD expression in SCs, suggesting enhanced regenerative activity, without histological evidence of fibrosis. Conclusions: These findings suggest that L. fermentum supplementation could counteract EtOH-induced skeletal muscle damage by reducing inflammation and oxidative stress and promoting muscle repair, indicating its potential as an adjuvant, in

关键词： genetic polymorphisms   cardiovascular risk   PON1   APOA5   IL6   CETP  

摘要： Background: Cardiovascular disease remains the leading cause of death worldwide, and dyslipidemia is a critical, modifiable risk factor. Aim: We sought to evaluate the relationship between polymorphisms in CETP (rs3764261), APOA5 (rs662799), IL6 (rs1800796), and PON1 (Q192R) and lipid parameters, and to assess their contribution to dyslipidemia and overall cardiovascular risk in an urban cohort from Cauca, Colombia. Methods: In this cross-sectional observational study, 304 participants aged 40-69 years were enrolled. Clinical, anthropometric, and biochemical data were collected, and genotyping was performed for the four target polymorphisms. We used descriptive statistics to characterize the sample, non-parametric tests to compare lipid levels by genotype, and multivariable logistic regression to identify independent predictors of dyslipidemia. Results: Individuals with dyslipidemia exhibited significantly higher total cholesterol and VLDL levels, lower HDL levels, and an elevated Castelli II index compared with the non-dyslipidemia group. Although CETP genotype frequencies differed between groups, only the APOA5 rs662799 variant was significantly associated with increased VLDL levels, suggesting its potential role as a genetic biomarker of cardiovascular risk. Conclusions: Our findings underscore the interplay between metabolic factors and genetic variants in the pathogenesis of dyslipidemia. Notably, the APOA5 rs662799 polymorphism emerged as a key determinant of VLDL concentration, highlighting its promise for personalized cardiovascular risk stratification and management in this population.

摘要： ObjectiveRheumatoid arthritis (RA)-associated anticitrullinated protein antibodies (ACPAs) target various antigens by binding short citrulline amino acid motifs, resulting in heterogeneous ACPA profiles among patients. Here we analyzed ACPA patterns by recognized citrulline motifs in relation to the RA risk factors HLA-DRB1 shared epitope (SE) alleles and history of *** factor (RF) and anticyclic citrullinated peptide (CCP2) isotypes, 15 anti-Cit- and four anti-Carb/Acet-peptide-IgG, were centrally measured in 6,907 patients from five Scandinavian RA cohorts using fluoroenzyme immunoassay and a custom-made multiplex solid-phase microarray. HLA-DRB1 SE alleles were imputed from single-nucleotide polymorphism genotyping ***-citrulline peptides derived from four multicitrulline peptides (Cit Fib alpha 36-50, Cit Fib beta 60-74, Cit TNC5, and Cit Vim60-75) showed differential binding patterns, supporting recognition of citrulline motifs rather than long peptides. Four citrulline peptides (Cit Fib beta 36-52, Cit Fib beta 60-74-Cit3, Cit Fil307-324, and Cit Vim60-75-Cit1) captured 97% of IgG anti-CCP2+ patients. Patient subsets based on ACPA, anti-Carb/Acet, and RF displayed differences in ACPA composition and disease activity but not comorbidities. Different ACPAs overlapped, but when dichotomizing patients based on high reactivity to peptide citrulline motifs, only ACPA to nonglycine citrulline motif associated with HLA SE alleles. In IgG anti-CCP2+ patients, 90% of those with only high nonglycine ACPA were HLA SE allele carriers compared with 67% in the group with glycine motif-only ACPA (odds ratio 4.5). Smoking status associated with IgA and glycine motif *** citrulline-glycine motifs are prevalent ACPA targets, our data reveal that HLA SE alleles are primarily associated with ACPA to nonglycine citrulline motifs, providing insight in ACPA T cell dependance. Yet, the etiologic significance of ACPA targeting di

关键词： COVID-19   CD38+HLA-DR+ T cells   T cells   single-cell transcriptomics   mortality risk factor  

摘要： Background The COVID-19 pandemic remains a global health challenge. Severe cases often respond poorly to standard treatments, highlighting the necessity for novel therapeutic targets and early predictive *** We utilized flow cytometry to analyze peripheral immune cells from healthy, bacterial pneumonia patients, and COVID-19 patients. The expansion of activated T cells (CD38+HLA-DR+), monocytes, and myeloid-derived suppressor cells (MDSCs) were detected and correlated with clinical outcomes to evaluate prognostic potential. The single-cell RNA sequencing (scRNA-seq) was applied to characterize the critical cell subset associated with prognosis and elucidate its phenotype in *** We revealed a significant increase in CD38+HLA-DR+ T cells in non-survivor COVID-19 patients, establishing them as an independent risk factor for 28-day mortality. The scRNA-seq analysis identified the CD38+HLA-DR+ T cell as a terminally differentiated, Treg-like subset exhibiting both activation and exhaustion characteristics. This subset presented the highest IL-6 and IL-10 mRNA levels among all T-cell subsets. Further functional analysis demonstrated its enhanced major histocompatibility complex class II (MHC-II) cross-signaling and correspondingly enriched cytoskeletal rearrangement processes. In addition, there was dysregulated NAD+ metabolism in CD38+HLA-DR+ T cells via scRNA-seq, accompanied by elevated adenosine and decreased NAD+ levels in serums from COVID-19 *** We identified the selective expansion of CD38+HLA-DR+ T cells as a novel prognostic indicator for COVID-19 outcomes. These cells' unique activated-exhausted phenotype, along with their impact on NAD+ metabolism, provides new insights into COVID-19 immunopathogenesis.

摘要： The tiger mosquito (Aedes albopictus) is an invasive exotic species that has gradually colonized Europe, first detected in Switzerland in 2003. Beyond being a nuisance and an indirect threat to biodiversity, it is a public health concern. It can transmit arboviral diseases (for example, dengue, chikungunya, and zika). Colonized regions in Switzerland apply surveillance and control measures against the tiger mosquito to prevent secondary human transmission. We illustrate these measures with the case of Geneva. Healthcare professionals play a critical role in managing this emerging public health risk. Early diagnosis of these infections in returning travelers, adherence to recommendations for individual protection in suspected cases of arboviral disease and public health measures help reduce the risk of local transmission.

关键词： 桑叶多糖   免疫调节   细胞因子   肠道菌群   鸡  

摘要： 研究旨在探究不同pH值条件下制备的桑叶多糖（Mulberry leaf polysaccharide,MLP）对免疫新城疫（Newcastle disease,ND）疫苗鸡血清中抗体、细胞因子以及肠道菌群的影响。试验比较水提、酸提、碱提三种提取方法对桑叶多糖中总多糖含量、多糖得率的影响；在免疫NDV前3 d,3个给药组每只分别饲喂4 mg酸提桑叶多糖、碱提桑叶多糖和水提桑叶多糖，连续饮水给药7 d,28日龄时二免同法给药，35日龄时测定胸腺和脾脏器官指数，首免后第7和21天测定鸡血清NDV抗体效价及鸡血清白细胞介素-2(IL-2)、γ-干扰素（IFN-γ）、白细胞介素-4(IL-4)和肠道分泌型免疫球蛋白A(sIgA)含量，35日龄时采用16S rDNA测序分析盲肠微生物菌群结构。结果显示：pH3、pH9和pH11条件下制备的桑叶多糖平均多糖得率显著高于除pH5外的其他各组（P<0.05）,pH5的总多糖得率显著高于其他各组（P<0.05）；与免疫对照组相比，鸡首免后第7天，3种桑叶多糖均能显著提高血清NDV抗体水平（P<0.05），碱提桑叶多糖显著提高鸡血清细胞因子（IL-2、IL-4、IFN-γ）和肠道sIgA含量（P<0.05）；与免疫对照组相比，碱提桑叶多糖、酸提桑叶多糖和水提桑叶多糖均能提高盲肠菌群普拉梭菌和乳杆菌属相对丰度差异不显著（P>0.05）。结果表明，桑叶多糖具有显著的免疫调节作用且碱提效果最优，在一定程度上改善肠道菌群结构，维持肠道健康。

摘要： Signal peptide peptidase-like (SPPL) proteases, members of the intramembrane aspartyl protease family, have attracted increased interest due to their involvement in immune cell differentiation and cellular glycan structure regulation. However, the enzymatic domain involved in substrate recognition remains enigmatic. Here we provide evidence that the N-terminal protease-associated (PA) domains of the SPPL2 subfamily are involved in substrate recognition and discrimination of substrates that differ slightly in their luminal/extracellular domain. Presence of the SPPL2c PA domain impairs SPPL2a/b mediated tumor necrosis factor alpha (TNF alpha) initial cleavage, kinetics, and processivity in cells and in vitro. In contrast, the SPPL2a PA domain enhances processing by SPPL2b. Additionally, we demonstrate non-canonical shedding activity of SPPL3 on full-length TNF alpha and that the ability for consecutive cleavage differs within the SPPL-family and is mainly based on the SPPL2a/b membrane spanning body. This provides the basis to finally understand the mechanistic differences of these homologous proteases.

关键词： sepsis   adrenal dysfunction   necroptosis   gene knockout mice   hydrogen sulfide   TNF alpha  

摘要： Background: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H2S) in sepsis-induced adrenal dysfunction. Methods: A cecal ligation and puncture (CLP)-induced sepsis mouse model was employed. Adrenocortical-specific mixed lineage kinase domain-like pseudokinase (MLKL) knockout (MLKL-KO) and cystathioneine beta-synthase (CBS) knockout (CBS-KO) mice were generated using Cre-loxP technology and adrenocortical-specific Cre tool mice. In vitro experiments utilized TNF alpha-stimulated Y1 adrenocortical cells. The treatments included the H2S donor NaHS, TNF alpha inhibitor R-7050, necroptosis inhibitor NSA and CBS inhibitor AOAA. Pathological assessment involved hematoxylin-eosin (H&E) staining and a Western blot analysis of necroptosis markers (the phosphorylation of MLKL (p-MLKL) and phosphorylation of receptor-interacting protein kinases 1 (p-RIPK1)). Results: Sepsis induced adrenal congestion, elevated TNF alpha levels, and activated necroptosis (increased p-MLKL/p-RIPK1) in wild-type mice. H2S treatment attenuated adrenal damage, reduced TNF alpha, and suppressed necroptosis. MLKL knockout reduced septic adrenal dysfunction, whereas CBS knockout exacerbated septic adrenal dysfunction. In vitro, TNF alpha induced Y1 cell necroptosis, which was reversed by H2S or NSA. AOAA exacerbated TNF alpha-induced necroptosis in Y1 cells. Conclusions: H2S inhibits TNF alpha-mediated necroptosis, thereby preserving adrenal integrity in sepsis. Targeting the TNF alpha-necroptosis axis and enhancing endogenous H2S production may represent novel therapeutic strategies for sepsis-associated adrenal dysfunction.