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关键词： Positive ions  

摘要： Hybrid solid-state electrolytes, which combine ionic liquids with metal-organic frameworks, offer a promising approach to enhancing the safety and energy density of next-generation batteries. A thorough understanding of the interplay between the solid and liquid phases in hybrid solid-state electrolytes is crucial for optimizing their performance as battery electrolytes. This study investigates how interactions between different ionic liquid-based electrolytes and the metal-organic framework ZIF-8 influence the coordination and dynamics of Li+ in confinement. To this end, we examine five different ionic liquids, varying the chemical nature of the cation. Raman spectroscopy, supported by 2D solid-state NMR and simulations, are used to elucidate Li+ coordination and ion-wall interactions. The impact of these interactions on local Li+ dynamics and charge transport in the ionic liquid-ZIF-8 hybrid system is investigated using 7Li spin relaxation, impedance spectroscopy, and simulations. The results reveal a competitive interaction between Li+ and the ionic liquid cation with the ZIF-8 framework, which can be fine-tuned by modifying the molecular structure of the ionic liquid cation. As a consequence, local Li+ dynamics is enhanced, depending on the ionic liquid cation. The beneficial interactions in the confined system can even make Li+ the fastest diffusing species, in contrast to bulk electrolyte, where Li+ transport is limited by strong Li-anion clusters. Thus, blocking Li+-framework interactions through other competitive interactions might be an effective strategy to enhance Li+ dynamics and increase Li conductivity in a hybrid solid-state electrolyte. Although confinement within the ZIF-8 model system leads to an overall decrease in conductivity, this study provides valuable insights into the design of hybrid electrolytes for next-generation battery applications.

关键词： antibody-mediated rejection   DSA   HLA molecular mismatch   eplet   risk score  

摘要： Donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) play a crucial role in antibody-mediated rejection, a major barrier to successful organ transplantation. Donor-recipient HLA molecular in-compatibility critically influences DSA susceptibility, commonly assessed by analyzing mismatches in the HLA eplet repertoire. This study, including six distinct liver, lung, and kidney transplant cohorts from two cen-ters (978 donor-recipient pairs), explores associations between individual eplet mismatches and DSA devel-opment. Certain mismatched eplets are strongly linked to DSA development, while others show weaker as-sociations, a trend consistent across different organ types. Machine learning leverages these hierarchical associations to develop an eplet risk score (ERS), outperforming traditional eplet mismatch assessments. Furthermore, T cell proliferation in mixed lymphocyte reaction in vitro correlates with the ERS, attenuated by antibody-mediated inhibition of a mismatched DSA-associated eplet. These results establish the differen-tial immunological impacts of mismatched HLA eplets as integral in clinical practice and therapeutic innovation.

关键词： Hantaan virus (HTNV)   Nucleocapsid protein (NP)   pan-MHC-II epitope   Immunoreactivity  

摘要： During viral infection, CD4+ helper T-cell is indispensable for the establishment of the humoral immune protection, CTL activation, and even long-term memory response. It requires MHC-II molecules in viral structural antigens process and presentation. HTNV NP epitopes exhibited high affinity to both of HLA-II superfamilies and H-2-I genes in the present study. Immunogenicity and conservation analyses identified 34 selective epitopes, later validated by molecular docking (MD) with MHC-II structures. NP 15-mer peptides and MHC-II haplotypes were found to interact bidirectionally through hierarchical clustering. In brief, epitopes that exhibit immunoreactivities for a wide range of MHC-II molecules reflect the biomedical practice of vaccination, while haplotype clusters reflect individual differences in T-cell antigen presentation. Then, 11 HTNV variants showed three amino acid substitutions in three epitopes, with little impact on their pan-HLA-II immunoreactivity. Safety analyses indicated that the 34 selective epitopes exhibit favorable safety profiles for potential applications. Finally, we validated the immunogenicity of the selective epitopes using ELISA, ELISpot, and flow cytometry. In conclusion, our work provides a comprehensive assessment of the pan-MHC-II immunoreactivity of HTNV NP and lays the theoretical and technical foundations for the development of protective epitope vaccines in the context of population immunity.

关键词： Clinical Trial   Rheumatology   THERAPEUTICS  

摘要： Introduction Biological disease modifying antirheumatic drugs (bDMARDs) have a central role in the treatment of rheumatoid arthritis (RA). Tumour necrosis factor inhibitors (TNFis) are commonly used as first-line agents, while non-TNFis (tocilizumab, abatacept and rituximab) have shown to be non-inferior to TNFis in head-to-head trials. In case of TNFi inadequate response, using other mechanisms of action provides a better response than using an alternate TNFi. Which non-TNFi bDMARD administered subcutaneously to allow for ambulatory management to choose in case of first line TNFi inadequate response has not been tested in a randomised clinical trial, while observational data support a potential superiority of tocilizumab over abatacept. Methods and analysis The SUNSTAR (SUbcutaNeouS Tocilizumab vs Abatacept in TNF Alpha inadequate responders for the treatment of Rheumatoid arthritis) study is a 52-week prospective, randomised, multicentre, open-label, superiority phase IV trial comparing subcutaneous tocilizumab with abatacept in a 1:1 ratio. Patients with active RA (Disease Activity Score-erythrocyte sedimentation rate >3.2 and Clinical Disease Activity Index (CDAI) >10) and with inadequate 3-month response to a first or second TNFi are included in 25 centres in France. The primary outcome is the CDAI improvement at week 24. Intention-to-treat analysis will be applied primarily. The secondary outcome is a composite outcome of the percentage of responders defined as a CDAI<10, no use of rescue treatment after week 12 and no experimental treatment change, at weeks 12, 24 and 52. Ethics and dissemination Ethics approval was obtained from the committee for the protection of persons (Comité de protection des personnes Sud Méditerranée I 17.00608.001744). The findings from this study, whether positive or negative, will be published in peer-reviewed journals and will be presented at national and international conferences. The results will inform future recommendations on

关键词： Neutrophilic dermatoses   Sweet’s syndrome   Inflammation   Fibroblast   Interferon   Neutrophil   Sweet’s syndrome   SS   pyoderma gangrenosum   PG   formalin-fixed paraffin-embedded   FFPE   interferon   IFN   single-nucleus RNA sequencing   snRNA-Seq   bulk RNA sequencing   bulk RNA-Seq   healthy controls   HC   plasmacytoid dendritic cells   pDCs   dendritic cells   DCs   IFN response factor 1   IRF1   fibroblast   FB   myeloid   MY   keratinocyte   KC   lymphoid   LYM  

摘要： Background Sweet’s syndrome is an inflammatory skin disease characterized by robust neutrophil infiltration into the dermis. Its pathogenesis and distinguishing features compared to other neutrophilic dermatoses, such as pyoderma gangrenosum, remain poorly understood. Objective To define the cellular and molecular landscape of Sweet’s syndrome skin. Methods Single-nucleus and bulk transcriptomics were performed on archival clinical skin samples from patients with Sweet’s syndrome, pyoderma gangrenosum, and healthy controls. Functional experiments were performed with primary human cells for mechanistic validation. Spatial transcriptomics with single-molecule resolution mapped cell types to tissue location. Results A prominent interferon signature was identified in Sweet’s syndrome skin greater than in tissues from pyoderma gangrenosum and healthy controls. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, spatial transcriptomics revealed two positionally distinct interferon-activated fibroblast subsets: CXCL1+ fibroblasts near neutrophil infiltrates and CXCL12+ fibroblasts distal to these infiltrates. Conclusion This study defines the cellular and molecular landscape of neutrophilic dermatoses and implicates dermal immune-acting fibroblasts in Sweet’s syndrome pathogenesis through type I interferon recognition and neutrophil recruitment.

关键词： CSF1R   Epidermis   IL-34   Langerhans cells   Squamous cell carcinoma   AD   atopic dermatitis   AML   acute myeloid leukemia   CAGE   Cap Analysis of Gene Expression   cSCC   cutaneous squamous cell carcinoma   ERK   extracellular signal–regulated kinase   FAK   focal adhesion kinase   FIRE   Fms-intronic regulatory element   GVHD   graft-versus-host disease   HNSCC   head and neck squamous cell carcinoma   HPV   human papillomavirus   LC   Langerhans cell   OSM   oncostatin M   SCC   squamous cell carcinoma   STAT   signal transducer and activator of transcription   TSS   transcription start site  

摘要： The mononuclear phagocyte system depends upon CSF1R and its 2 ligands, CSF1 and IL-34. IL-34 is expressed constitutively in the skin in mice and humans from a conserved keratinocyte-specific promoter, suggesting a specific function in epidermal homeostasis. IL-34 deficiency leads to loss of Langerhans cells, the major antigen-presenting cell of the epidermis. Decreased IL-34 expression has been reported in inflammatory and malignant epithelial skin diseases, including atopic dermatitis, psoriasis, eczema, UV-damaged skin, response to common skin sensitizers and various types of squamous cell carcinomas. We discuss the possible contribution of the loss of IL-34 to immune dysregulation in the skin.

关键词： 胶质瘤   IL-18   生物信息学   生物标志物  

摘要： 目的 利用生物信息学技术分析白细胞介素-18(interleukin-18,IL-18)与脑胶质瘤患者临床病理特征的关系。方法 利用UALCAN分析IL-18在低、高级别脑胶质瘤中的表达与患者临床病理特征相关性;通过c Bio Portal分析IL-18基因突变情况;选取手术切除且经病理证实的109例标本(24例脑膜瘤,85例各级别恶性脑胶质瘤)为研究对象,应用免疫组织化学染色法检测IL-18表达。结果 生物信息学研究结果发现,IL-18低表达组的低级别脑胶质瘤(LGG)患者生存期更长(P<0.01),IL-18水平对胶质母细胞瘤(GBM)患者生存期无明显影响(P>0.05)。在LGG中,星形细胞瘤组织中IL-18表达水平明显高于少突星形细胞瘤和少突胶质细胞瘤(P<0.01);与TP53突变组比较,TP53非突变组IL-18表达水平显著降低(P<0.01)。与正常脑组织样本比较,GBM组织样本IL-18表达水平显著升高(P<0.01),GBM组织中无论TP53是否突变,IL-18表达水平均明显升高(P<0.01);根据IL-18启动子甲基化状态,TP53非突变组与TP53突变组比较,IL-18表达水平显著增加(P<0.01)。免疫组织化学染色结果发现,IL-18表达与患者年龄、肿瘤大小及肿瘤分级之间关联密切,≥50岁脑胶质瘤患者IL-18表达水平明显增强;肿瘤体积越大,IL-18表达越强,低级别脑胶质瘤组织(Ⅰ+Ⅱ期)IL-18表达明显低于高级别脑胶质瘤组织(Ⅲ+Ⅳ期)(P<0.01)。结论 低级别脑胶质瘤患者中,IL-18可能具有抑制肿瘤发生、发展作用,而在高级别脑胶质瘤患者中,IL-18可能是促进胶质瘤进展的因素之一。

关键词： Cell migration/adhesion   Immunotherapy   Neuroscience   Oncology   T cells  

摘要： The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused nonantigen specific autologous lymphocytes could accumulate in intracranial tumors. We observed that nonspecific autologous CD8+ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared with IL-2. Pretreatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and nontumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8+ T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression (CD9). We also observed that IL-7 increases S1PR1 transcription in human CD8+ T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors and that pretreatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pretreatment can be combined with T cell-activating therapies.

关键词： 3D spheroids   Colorectal cancer   IL-12   Immunomodulation   Nanomedicine   pH-responsiveness  

摘要： Metastatic colorectal cancer (CRC) has the dismal 5-year survival rate of only 14%, and immunotherapies fail to improve the patient outcome. One reason for the poor response rate is the slightly acidic (similar to 6.5) immunosuppressive microenvironment. Interleukin 12 (IL-12) is a highly potent pro-inflammatory cytokine that can stimulate tumor immune cells and reverse immunosuppression by inducing interferon gamma (IFN-gamma) expression. However, its clinical applications are hindered by systemic side effects. In this study, we developed pH-responsive polymeric nanoparticles (NPs) encapsulating IL-12 to enhance its therapeutic efficacy into the tumor microenvironment (TME). IL-12-loaded pH-responsive NPs induced antitumoral pro-inflammatory response in macrophages at pH similar to 6.5, determined by increased IFN-gamma levels and nitric oxide (NO) release, without affecting metabolic activity. In contrast, IL-12-loaded pH non-responsive PLGA NPs showed much lower macrophage activation. To validate the specificity and efficacy in a complex immune-rich microenvironment, we developed a novel CRC 3D immuno-spheroid by incorporating human monocyte-derived macrophages with tumor cells in collagen, mimicking CRC spatial organization and extracellular matrix. The interaction of IL-12 pH-responsive NPs induced macrophage polarization, by providing a reduction of M2-like markers (CD14 + CD163+) while increasing pro-inflammatory M1-like counterparts (CD14 + CD86+). Moreover, IL-12 pH-responsive NPs increased IFN-gamma levels and reduced anti-inflammatory IL-10 secretion. Overall, this study provides two major findings (1) a pH-responsive NP system to effectively deliver IL-12 to the TME and reprogram local macrophages into pro-inflammatory phenotype;(2) a macrophage-enriched human 3D immuno-spheroid in vitro system as a tool to test the effectivity of immunomodulatory NPs.