Browse Articles

Using Inflammation as a Framework to Assess Hepatitis B Vaccine Immunity 2259206

Abstract Introduction Infection with hepatitis B virus (HBV) remains a major global health concern despite being vaccine-preventable for nearly four decades. Although vaccination has significantly reduced disease burden, a subset of individuals fails to develop adequate protection and are classified as non-responders. Methods A longitudinal study evaluated hepatitis B vaccine responses in individuals with or without prior vaccination. Participants received either a 3-dose alum-adjuvanted or 2-dose CpG-adjuvanted vaccine, with a subset receiving a booster. ELISA analyzed blood samples collected on days 1, 8, and 30 to quantify anti-HBs titers, classified as high (≥50 mIU/mL), moderate (10—50 mIU/mL), or low (≤10 mIU/mL). Antibody avidity was measured using a modified ELISA with a chaotropic agent to assess binding strength. Results Age significantly affected vaccine responses. In the booster group, participants under 50 had higher baseline titers, while in the de novo group, younger individuals showed stronger early responses though final titers were similar across ages. Among hypertensive participants, older adults showed slower but steady antibody increases, surpassing younger participants by week 4. Avidity remained stable across both vaccine groups, indicating that prior vaccination increased antibody quantity but not binding strength, which plateaued early. Conclusion Immune recall among previously vaccinated individuals was variable. Although boosters produced a faster antibody rise, a higher proportion of non-responders suggests that prior vaccination does not always ensure lasting protection. Hypertension also shaped vaccine response: while hypertensive individuals achieved early seroconversion, their antibody levels plateaued at lower magnitudes, suggesting impaired immune sustainment possibly linked to vascular inflammation or endothelial dysfunction.Overall, these findings highlight the need for personalized vaccination strategies for individuals with hypertension or advanced age. Funding Source Research reported in this abstract was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number AI158617. Additionally, supported by Hevolution/AFAR New Investigator Award Topic Categories Vaccines and Immunotherapy (VAC)

A sinus-proximal fibroblast niche supports B lymphopoiesis in the developing dura mater 2310272

Abstract Introduction The dura mater serves as a critical immunological niche for the central nervous system, yet the mechanisms governing the emergence of this niche in early life remain understudied. Methods Using a combination of single cell and spatial analyses, lineage tracing approaches, and genetic tools, we chart the development of the murine dural and leptomeningeal immune compartments and functionally interrogate the stromal niches that support meningeal immune cell development. Results In doing so, we uncover a distinctive role for the murine dura mater as a transient niche for B lymphopoiesis in the early-postnatal window. Dural B lymphopoiesis occurs as a wave spanning the first postnatal month, initiated by a shared pool of embryonic progenitors that drives a coordinated, multi-organ wave of early-life extramedullary B lymphopoiesis. B cells born during this window rapidly generate mature B cells, including a developmentally-timed contribution to the marginal zone B cell compartment. In the dura, B cells develop in defined hematopoietic foci proximal to the dural sinuses, positioned in an anatomically-restricted niche bounded by distinct fibroblast subsets composing the outer dura, inner dura, and peri-sinus dura compartments. Sinus-proximal fibroblasts intercalate into B cell foci and express the CNS stromal cell-enriched transcription factor Foxd1 and elevated levels of the pro-hematopoietic chemokine Cxcl12 in the early-life window. Ablation of Cxcl12 from Foxd1-lineage stromal cells severely impairs local B lymphopoiesis in the dura, underscoring the relevance of this unique niche for early life B cell development. Conclusion Together, these data reveal a critical function for dural fibroblasts in shaping the early-life B cell compartment and provide a model for how extramedullary niches may support early-life hematopoiesis. Ongoing work aims to elucidate how dural and other extramedullary niches may compensate for infection-induced loss of medullary B lymphopoiesis in the early-life window. Funding Source Howard Hughes Medical Institute (HHMI) Investigator Program and Emerging Pathogens Initiative (Beth Stevens) National Institutes of Health, Silvio O. Conte Centers for Basic Neuroscience or Translational Mental Health Research (Sponsor Grant# 5P50MH11249 Topic Categories Hematopoiesis and Immune System Development (HEM)

CD97-hi naive CD4 T cells are poised for Th1 responses and reflect inflammatory disease states 2249830

Abstract Introduction Naïve T cells have long been viewed as quiescent precursors with limited roles in disease pathogenesis. However, emerging evidence suggests functional diversity even within this population. Building on our recent findings, we aimed to define the phenotypic and functional relevance of CD97-hi naïve T cells in inflammatory diseases. Methods Single-cell transcriptomic and epigenomic analyses were performed to identify distinct naïve CD4 T cell subsets in humans and mice (approved by institutional IACUC and IRB). Functional characterization was conducted using in vitro primary mouse T cell cultures and in vivo cell transfer models. For humans, we analyzed publicly available single-cell datasets from various disease cohorts, and peripheral blood samples from healthy donors and patients were examined by flow cytometry to validate CD97-hi naïve CD4 T cells. Results Distinct CD97-hi naïve CD4 T cells expressing IL-18R under steady-state conditions were identified in both mice and humans. These cells exhibited strong Th1 differentiation potential, producing robust IFN-γ and showing increased chromatin accessibility at Th1-associated loci. In humans, these cells were significantly enriched in responders to anti—PD-1 therapy as well as in patients with multiple sclerosis, COVID-19, systemic lupus erythematosus, and common variable immunodeficiency, with their frequency correlating with disease states. Conclusion CD97-hi naïve CD4 T cells represent functionally distinct cells capable of sensing and reflecting inflammatory cues and are primed for Th1-type effector responses. Their frequency strongly correlates with multiple inflammatory and immune-mediated diseases, highlighting an unconventional view of naïve T cells–not as passive precursors but as active contributors and potential biomarkers. Funding Source Basic Science Research Program of the National Research Foundation funded by the Korean Government (RS-2024-00334289), Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2024-004 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Peripheral cellular transcriptional changes are associated with Alzheimer’s disease related phenotypes 2330291

Abstract Introduction Alzheimer’s disease (AD) is characterized by pathologies including amyloid, tau, neurodegeneration reflected in established blood biomarkers and track with clinical changes. However, the association between peripheral cell-specific signatures and AD-related phenotypes remain poorly characterized. Methods We analyzed bulk blood transcriptome data from the Mayo Clinic Study of Aging (MCSA) and Emory University Vascular study. We used BayesPrism, CIBERSORTx, and an in-house pipeline CNNreg to deconvolute these data and obtain peripheral cell proportions. Cell type specific transcripts were estimated with BayesPrism. We compared cell proportions between cases (AD/MCI) and controls. Association analysis was performed between cell type specific transcripts and AD-related phenotypes including diagnosis and cognition. Meta-analysis of transcripts associations and gene ontology analysis were conducted to assess the enriched pathways for significant genes. Results In MCSA, B and CD4+ T cells proportions are significantly lower while that of myeloid cells higher in cases. The Emory cohort had similar trends. We identified transcripts associated with AD-related phenotypes in CD4+ T and CD8+ T cells. In CD4+ T cells, transcripts downregulated in case are enriched in response to stimulus pathway, whereas those upregulated in negative regulation of immune response. Downregulation of CD4+ T genes enriched in extracellular matrix disassembly and epigenetic regulation and upregulation of those in protein localization associate with better cognition. In CD8+T cells, genes pertinent to vascular development were downregulated while those to metabolic processes were upregulated in cases. Downregulation of CD8+T genes involved in lipid transportation and upregulation of those in mitochondria associate with better cognition. Conclusion We identified peripheral cellular transcriptional changes associated with AD/MCI phenotypes and involved in important biological pathways, revealing potential disease mechanisms in AD. Funding Source RF1 AG051504 Topic Categories Neuroimmunology (NEUR)

Regulation of Th17 Cell Survival by the CREB/CRTC2—GPR65 Axis: Mechanistic and Translational Insights 2249331

Abstract Introduction Th17 cells are critical mediators of autoimmune inflammation, but the molecular pathways that sustain their survival and metabolic function remain incompletely defined. Our prior studies identified the CREB/CRTC2 transcriptional pathway as a key regulator of Th17 differentiation. Transcriptomic analyses revealed that GPR65, an acid-sensing G protein—coupled receptor, is a direct target of CREB/CRTC2. We hypothesize that GPR65 integrates cAMP—CREB/CRTC2 signaling to maintain Th17 activation and metabolic adaptation under inflammatory conditions. Methods We used human Jurkat T cells to model T-cell activation and assess CREB/CRTC2-dependent regulation of GPR65. T-cell proliferation and survival were analyzed using CFSE and Annexin V flow cytometry. To explore functional roles, CRISPR-Cas9—based knockout of GPR65 is being developed, and in parallel, we have initiated anti-GPR65 monoclonal antibody generation for future mechanistic and therapeutic studies. Results Preliminary data show that activation of the CREB/CRTC2 pathway increases GPR65 expression and enhances metabolic and survival-associated gene signatures in stimulated T cells. Ongoing work will define how GPR65 loss alters these responses. These findings support a model in which CREB/CRTC2-driven GPR65 expression links extracellular acid sensing to Th17-like cell activation. Conclusion This study identifies a novel CREB/CRTC2—GPR65 signaling axis that may regulate T-cell survival and function under inflammatory stress. Understanding this pathway could reveal new therapeutic strategies to modulate pathogenic Th17 responses in autoimmune disease. Funding Source Joseph H. Stahlberg Foundation Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Characterizing the Alveolar Macrophage and Neutrophil Responses to Inhaled Coccidioides Spores using Ce3D-cleared Precision-Cut Lung Slices 2260143

Abstract Introduction Coccidioidomycosis (Valley Fever) is a respiratory disease caused by inhalation of spores from Coccidioides spp, dimorphic fungi endemic to arid regions of the Americas. Although thousands of cases are reported annually, the true incidence is likely far higher. Most infections are cleared asymptomatically, but a subset progresses to severe pulmonary or disseminated disease, suggesting that early host-pathogen interactions at the respiratory barrier critically shape disease outcome. Methods To understand the roles of the various cells coordinating this rapid response, we infected mice with fluorescently-labelled Coccidioides posadasii Δcts2/ard1/cts3 and prepared 1-mm thick clearing-enhanced 3D (Ce3D) precision cut lung slices (PCLS) to investigate 3D spatial aspects of the lung. We utilized Imaris-based 3D spatial analyses to quantify the early cellular spatial dynamics of alveolar macrophages and neutrophils and their interactions with inhaled spores. Results We observed that inhaled spores deposited near the broncho-alveolar duct junction (BADJ). Alveolar macrophages (AM) rapidly migrated locally to phagocytose spores in alveolar spaces and interestingly, in terminal bronchiolar spaces, as well. At low spore doses, AMs were highly effective at capturing most spores, and neutrophils were not recruited to the lung. Conversely, at higher spore doses, AMs no longer effectively phagocytosed spores, suggesting they could be overwhelmed by the increased fungal load. Instead, significant amounts of neutrophils were recruited and contributed to phagocytosis of most of the spores. Finally, we also demonstrated that neutrophils migrated to the site of BADJ infection via both alveolar capillaries and through the pulmonary arteriole, which is an uncharacterized route of neutrophil entry. Conclusion Our work provides a novel spatial perspective of the early dynamics of pulmonary fungal infections by leveraging robust 3D imaging and analyses. Funding Source n/a Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)

Proton Donors Boost Interfacial Water Activation on RuO ₂ ‐Embedded RuWO _x for Durable Acidic Oxygen Evolution

ABSTRACT The activity‐stability dilemma in acidic oxygen evolution reaction (OER) stems from a fundamental trade‐off in the interface hydrogen‐bond network: while promoting interfacial water enrichment, it often impedes efficient proton transfer. Achieving simultaneous enhancement of interfacial water accumulation and deprotonation kinetics remains a critical challenge. Herein, we design a tungsten‐stabilized ruthenium oxide heterostructure (RuWO x ‐300) that overcomes this limitation in acidic OER. The high‐valence W 6+ species induce a localized electrostatic field, which enhances interfacial water enrichment. Concurrently, the W‐O bri ‐Ru moieties serve as active Brønsted acid sites with high proton‐donor capability, accelerating surface deprotonation. As a result, RuWO x ‐300 exhibits exceptional OER performance, requiring overpotentials of only 179 and 231 mV to achieve 10 and 100 mA cm −2 , respectively, and demonstrating remarkable stability for over 4820 h at 50 mA cm −2 , surpassing commercial RuO 2 and most reported Ru‐based catalysts. Through ab initio molecular dynamics (AIMD) simulations and in situ Raman spectroscopy, we elucidate a dual‐functional mechanism: increased interfacial water coverage reduces the activation barrier for O─O bond formation, while proton‐donor‐enhanced transfer kinetics suppresses Ru dissolution. This work establishes a new design principle for highly active and stable acidic OER electrocatalysts via proton‐donor‐mediated interfacial water activation.

Overcoming cetuximab resistance in HNSCC by Hsp90 inhibition to enhance EGFR degradation

Deep learning-based analysis of paraspinal muscle changes in lumbar disc herniation

Clonally expanded cryptic-epitope-specific CD8+ T cells mediate HLA-restricted neurotoxicity in TDP-43-associated frontotemporal dementia 2267088

Abstract Introduction Loss of nuclear repression by TAR DNA-binding protein 43 (TDP-43) in frontotemporal dementia (FTD) induces cryptic exon (CE) inclusion and generation of de novo peptides with potential MHC-I immunogenicity. Although our preliminary work has shown cryptic-epitope-specific CD8+ T cells in amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), their presence, specificity, and functional consequences in FTD remain unknown. Methods We performed DNA-barcoded tetramer screening and single-cell TetTCR-SeqHD profiling on PBMCs from C9orf72- and GRN-associated FTD patients. Identified CE-specific TCRs were reconstructed in human CD8+ T cells to assess HLA-restricted recognition and cytotoxicity toward TDP-43-deficient astrocyte and neuroblastoma models. β₂-microglobulin (β2m) knockdown and cytokine blockade defined antigen and cytokine dependencies. CE-specific TCRs were also redirected into regulatory T cells (Tregs) to evaluate antigen-restricted immune suppression. Results Clonally expanded CE-specific CD8+ T cells were detected in FTD, recognizing epitopes from HDGFL2, IGLON5, and additional FTD-enriched CEs across multiple HLA alleles. These cells displayed effector-memory phenotypes consistent with chronic antigen stimulation. CE-specific TCR-engineered CD8+ T cells selectively recognized and killed HLA-matched, TDP-43-deficient neural cells. This cytotoxicity was abrogated by β2m knockdown, demonstrating an antigen-dependent effector axis. CE-specific TCR-Tregs maintained lineage stability and attenuated CD8+-mediated neural injury in co-culture models. Conclusion These results identify for the first time CE-specific TCRs in FTD, demonstrate their HLA-restricted recognition of neural targets, and establish a mechanistic and regulatory framework linking TDP-43 loss, cryptic epitope presentation, and adaptive immune-mediated neurotoxicity. These findings reveal antigen-specific immunomodulation as a precision therapeutic strategy across the TDP-43 proteinopathy spectrum. Funding Source n/a Topic Categories Neuroimmunology (NEUR)

A multilevel logic for antigen interpretation governs tissue-specific T cell responses 2259289

Abstract Introduction The immune system must balance between protecting the host and limiting collateral damage. However, this tradeoff is almost certainly not uniform as different tissues operate under distinct physiological constraints, pressures, and regenerative capabilities. How tissue-specific tradeoffs are communicated to the immune system remains unclear. This question is particularly relevant for T cells, which possess unique antigen-binding receptors generated through random gene recombination. Thus, a T cell has no intrinsic knowledge of the context in which it will encounter its cognate antigen. Therefore, its fate–whether to become inflammatory or tolerogenic–is determined by how it interprets antigen within its local microenvironment. Since most T cell responses are initiated in lymph nodes (LNs), which collect and integrate information from upstream peripheral tissues, we hypothesized that LNs encode a logic of antigen interpretation that reflects the constraints and tradeoffs of these draining tissues. Methods I conducted high-resolution multiplexed imaging of homeostatic LNs that drain different tissues, measured their baseline cytokine profiles, and leveraged multiple transgenic and KO mouse models, along with adoptive T cell and dendritic cell (DC) transfer experiments. Results Tissue-specific immune regulatory logic follows a hierarchical structure within lymph nodes: DCs → regulatory T cells → conventional T cells. In particular, the state of migratory DCs–derived from peripheral tissues–and the cytokine environment varied substantially across homeostatic LNs, establishing tissue-specific biases in T cell fate. These biases were revealed upon acute regulatory T cell depletion or by activating monoclonal T cells in different sites. Conclusion Our findings reveal a multilevel logic of immune regulation in which migratory DCs and local cytokine milieus shape regulatory T cell and conventional T cell interactions, enabling LNs to translate peripheral tissue constraints into distinct immune programs. Funding Source Department of Energy Computational Science Graduate Fellowship, Mark and Lisa Schwartz Foundation - Ragon Institute Initiative in Artificial Intelligence Machine Learning, and Immunology Topic Categories Computational and Systems Immunology (COMP)

Engineered regulatory T cells (eTregs) for the treatment of type 1 diabetes 2310215

Abstract Introduction Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of β-cells in the pancreatic islets, resulting in insulin deficiency. Currently the best treatment option for T1D is exogenous insulin, which regulates blood glucose levels, but does not change the underlying disease. The increasing number of T1D diagnoses highlight the need for novel therapies. An area of growing interest is the use of regulatory T cells (Tregs) to suppress autoreactive T cells. Clinical trials involving the transfer of autologous ex vivo expanded polyclonal CD4+ Tregs have shown this approach to be safe; however, it has limitations. These include challenges with ex vivo Treg expansion, antigen specificity, loss of immunosuppressive activity, and inherent Treg functional defects due to genetic deficiencies in autoimmune patients. Methods Our group has developed a patented protocol for generating engineered Tregs (eTregs) by expressing two transcription factors critical for Treg function, FOXP3 and Helios in conventional T cells. We hypothesize that our FOXP3+Helios+ eTregs can suppress the islet-specific reactivity of cytotoxic CD8+ T cells (CTLs). To test this hypothesis, we have generated CTLs specific for an islet-specific antigen and FOXP3+Helios+ eTregs, as well as isolated natural Tregs (nTregs), all from the same donor. We then compared the ability of the eTregs with that of nTregs to suppress CTL reactivity against the human β cell line βlox5. Results Preliminary experiments revealed that both the nTregs and eTregs can suppress the cytotoxic function and cytokine secretion of the islet-specific CTLs. Separating the Tregs and CTLs using transwell inserts abrogated the suppressive effect, indicating that suppression is mediated by a cell contact-dependent mechanism. Conclusion These data indicate that FOXP3+Helios+ engineered Tregs can effectively suppress islet specific CTL responses in vitro and support the continued investigation of eTregs as a potential cell-based immunotherapy for T1D. Funding Source Breakthrough T1D (1-INO-2025-1709-A-N), NIH/NIGMS (P20GM130423), Children’s Mercy Hospital Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Psoriasis-like disease prevents squamous skin tumour development by neutrophil-driven inflammation 2251300

Abstract Introduction Psoriasis is a chronic inflammatory skin disease affecting millions of people worldwide. Although growing evidence links chronic inflammation with increased cancer risk, the association between psoriasis and cutaneous squamous cell carcinoma (cSCC) is still elusive. Methods Using cell transplantation and chemical-induced models of cSCC combined with genetic models of psoriasis, we investigated how chronic skin and systemic inflammation affects squamous skin tumour initiation and progression. Results Here we show that in the context of severe psoriasis-like disease, neutrophil-dependent inflammation prevents squamous skin tumour development. Cellular and molecular analyses of psoriasis-like skin at the tumour initiation stage revealed a marked infiltration of CD54—expressing neutrophils, associated with the release of cytotoxic granules and neutrophil extracellular traps (NETs), as well as enhanced senescence and the expression of senescence-associated secretory phenotype (SASP) in keratinocytes. Single-cell RNA sequencing combined with CellChat analysis demonstrated that in psoriasis-like skin, inflammatory N1-like neutrophils mediate re-programming of the cell-cell communication networks, while keratinocytes displayed diminished responsiveness to mitogenic and stem cell-niche signals, including EGF, LIF and WNT. Importantly, neutrophil depletion ameliorated psoriasis-like skin inflammation, abolished the senescence-like phenotype in keratinocytes and restored tumour growth. Conclusion We conclude that the release of neutrophil granules and NETs in psoriasis-like skin eliminate tumour cells and/or mediate oxidative and inflammatory stress-induced senescence in keratinocytes, thereby preventing tumour growth. Taken together, we have defined an innate control of skin tumorigenesis in psoriasis-like disease, which will be relevant for developing cancer prevention strategies. Funding Source H2020-MSCA and ERC Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

CD39 restrains ATP—P2X7-driven inflammatory cell death and neuroinflammation during neonatal Zika virus infection 2333356

Abstract Introduction Zika virus (ZIKV) can cause congenital Zika syndrome (CZS), marked by neuroinflammation and neurodevelopmental damage. Viral infection promotes extracellular ATP (eATP) release, acting as an alarmin that amplifies inflammation via purinergic receptors such as P2X7. CD39 enzyme (ENTPD1) hydrolyzes eATP and may restrain P2X7-dependent inflammatory cell death, but its role in neonatal ZIKV infection remains unclear. Methods THP-1-derived macrophages were stimulated with ZIKV or ZIKV envelope protein (ZIKV-E). Inflammatory readouts and eATP release were assessed, including evaluations with soluble apyrase or Axl-antagonist bemcentinib (R428). In vivo, WT and CD39⁻/⁻ pups were inoculated with ZIKV at postnatal day 3; brains were collected 12 days post-infection for molecular and histological analyses. Key pathways were also tested in P2X7⁻/⁻ mice. Results ZIKV-E increased eATP release and inflammatory responses, increased LDH release with elevated IL-1β/IL-6 and caspase-1/GSDMD-associated pyroptotic signaling; partially attenuated by soluble apyrase. R428 reduced ZIKV-E-induced eATP release, supporting upstream TAM/AXL involvement in purinergic activation. In neonatal brains, ZIKV upregulated CD39 transcripts and CD39 deficiency worsened motor performance and enhanced glial reactivity. CD39⁻/⁻ infection increased ZBP1 and apoptotic/pyroptotic markers (caspase-8, caspase-3, caspase-1, GSDMD), with enhanced association of ZBP1/caspase-3 with glial markers. CD39 deficiency enhanced IFN-β/STAT1 signaling. Conversely, P2X7 deficiency attenuated ZIKV-induced activation of apoptosis/pyroptosis markers, counterbalancing the CD39⁻/⁻ phenotype. Conclusion Our data identify CD39 as an upstream brake on eATP signaling that limits P2X7-linked inflammatory cell death and neuroinflammation during neonatal ZIKV infection, while shaping antiviral IFN responses. Targeting the CD39—P2X7 axis may provide therapeutic opportunities to mitigate neuroinflammatory damage in neurotropic viral infections. Funding Source FAPERJ; CAPES; CNPq; Instituto Nacional Saúde Cerebral (INSC) Topic Categories Viral Immunology (VIR)

The Subset of M1-Paired MHC Class II Conformers is Critical for CD4+ T Cell Activation 2251381

Abstract Introduction MHC class II molecules present exogenous antigen-derived peptide to CD4+ T cells leading to T-cell activation and signaling into the antigen presenting cell. Class II molecules are alpha beta heterodimers which form two distinct conformers via differential pairing of transmembrane domain GxxxG motifs (i.e. M1 and M2-paired class II). Methods Previous studies in mouse I-Ak and human HLA-DR class II used conformer specific mAbs to define unique immunobiological properties of each conformer. This report utilizes site directed mutagenesis, immunoprecipitation, and genetic sequence alignments for mAb characterization. As well as flow cytometry, and in vitro and in vivo T cell stimulation assays. Results Here we report that AMS-32.1, a widely-used anti-I-Ad mAb, is specific for the 20% of M1-paired I-Ad class II expressed by the cell, and 34-5-3S anti-I-Ad mAb is non-conformer specific. While AMS-32.1 engagement of M1-paired I-Ad elicits B-cell calcium signaling, 34-5-3S co-engagement of all class II blocks this response, indicating M2-paired class II inhibits M1-paired class II signaling. In vitro, AMS-32.1 blocks majority of T-cell activation by ova-peptide—I-Ad complexes, even under conditions where peptide is loaded onto both conformers. In studies using a murine model of hepatitis B virus replication, where MHC class II-restricted T-cell-dependent humoral responses are key to antigen clearance, AMS-32.1 administration blocks HBsAg seroconversion, indicating that M1-paired class II is central to the in vivo development of CD4+ T-cell-dependent antibody responses. Conclusion Overall, this study reveals AMS-32.1 is specific for M1-paired I-Ad class II and M1-paired class II molecules are key to CD4+ T-cell activation. Funding Source Research reported was supported by Albany Medical College Institutional Funds and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R03AI165365 (JRD) and R01AI148354 (MDR). The content is so Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)

PEP-R619W Differentially Modulates IFN-I Signaling to Enhance Antiviral Immunity 2260034

Abstract Introduction Persistent Type I interferon (IFN-I) signaling sustains chronic viral infection by inducing expression of negative regulators that suppress immune activation and drive T cell exhaustion. The autoimmune-associated variant PEP-R619W changes immune signaling, yet its impact on the IFN-I-driven pathway remains unclear. We hypothesized that PEP-R619W differentially regulates IFN-I signaling, thereby modulating antiviral immunity. Methods Using CRISPR/Cas9-engineered PEP-R619W C57BL/6 mice, we analyzed protein and cytokine expression by flow cytometry, IFN-signaling via phospho-flow (pSTAT1/pSTAT4), and interferon-stimulated genes (ISGs) by real-time PCR following IFN-β stimulation. Results PEP-R619W Dendritic cells (DCs) exhibited increased pSTAT1 and ISG expression with reduced SOCS3, indicating sustained IFN-I signaling and decreased negative regulation. Conversely, PEP-R619W effector CD8 T cells showed reduced pSTAT1/pSTAT4 expression, but maintained ISRE and GAS driven ISG induction, despite increased Usp18. This suggests preferential attenuation of chronic IFN-I signaling with preserved transcriptional responsiveness. Functionally, these cells produced higher levels of IFN-γ and Granzyme B, particularly in response to the minor gp276-284 epitope of LCMV-cl13, reflecting enhanced effector function and reduced exhaustion. Conclusion PEP-R619W modulates IFN-I signaling in a cell-type-specific manner. It enhances DC activation while preserving the function of CD8 T cells as effector cells. This prevents immune dysfunction and enhances viral clearance. Our data highlight a novel mechanism by which the autoimmune-associated allele, PEP-R619W, rewires sustained IFN-I signaling in a cell-type-specific manner, uncovering potential therapeutic avenues for chronic virus infection. Funding Source CBID CoBRE Research Grant (KU)-P20GM113117 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Rapid and Recyclable Synthesis of Prussian Blue Analogs by Enrichment Crystallization Strategy for Wide‐Temperature Sodium‐Ion Cylindrical Cells

ABSTRACT Manganese hexacyanoferrate (MnHCF) exhibits a high operating voltage, making it a promising candidate as a cathode material for sodium‐ion batteries (SIBs) with high energy density. However, the conventional slow co‐precipitation method suffers from the drawback of being time‐consuming, hindering its scalability for practical applications. Although rapid co‐precipitation strategies can address the above issue and enhance production efficiency, they often lead to uncontrolled crystal growth, resulting in increased vacancy content and lattice water that degrade sodium‐ion storage reversibility and electronic conductivity. Herein, a recyclable high‐stoichiometric enrichment crystallization strategy is introduced to precisely regulate nucleation kinetics under rapid synthesis conditions. This approach effectively suppresses the formation of vacancies and the introduction of lattice water, while also enabling the efficient recycling of precursor solution to save cost. As a result, the synthesized low‐defect MnHCF (MHCF‐R) exhibits higher electronic conductivity and enhanced reversible capacity across a broad temperature window (−40°C to 55°C). Notably, 800 mAh‐level 18650‐type cylindrical cells assembled with MHCF‐R electrodes deliver excellent cycling stability, retaining 81.23% of their initial capacity after 500 cycles. This work offers valuable insights into the fast construction of high‐conductivity, high‐capacity, and wide‐temperature‐tolerant Prussian blue analogs for SIBs.

Substrate recognition and cleavage by mucin degrading O-glycopeptidases from the gut microbe Bacteroides caccae

LAMDEX: an explainable lightweight Android malware detection system for enhancing IoT APP security

Abstract The widespread adoption of the Internet of Things (IoT) has led to a substantial increase in the use of Android applications (apps) designed for IoT operations. Android surpasses all other operating systems (OS) in terms of device usage due to its massive user base of approximately 2 billion active devices. Its popularity extends beyond smartphones, as it is the OS for vehicles, tablets, smart appliances, and various IoT devices. However, this pervasiveness of the Android OS has created security challenges. The rising popularity of Android has fueled the creation and distribution of numerous harmful apps, often crafted to deceive unsuspecting users. These malicious apps pose a serious threat to the security and privacy of Android users, potentially resulting in unauthorized access, data breaches, and other harmful activities. This paper introduces LAMDEX, a lightweight Android malware detection system based on explainable machine learning to improve security and transparency. The proposed system uses features extracted from apps to identify benign and malicious apps. Extensive testing has demonstrated that the proposed system delivers exceptional performance, achieving an accuracy rate of over $$98.8\%$$ , an F1 score of $$99.3\%$$ , and a testing time of just 0.33 s all while operating efficiently with minimal resource usage on the device. Furthermore, the classifier model is explained using Shapley additive Explanation scores, providing insight into the reasoning behind the classification decisions.

Allogeneic CAR-T activity enabled by knockout of LCK 2267386

Abstract Introduction CAR-T technology has achieved great success in treatment of liquid cancers, but poor quality and quantity of the patients’ T cells, and the time taken to produce sufficient CAR-T cells for therapy are major bottlenecks. Allogeneic CAR-T could solve these problems, but can cause Graft versus Host Disease (GVHD). We recently showed that CD28-CAR signaling still works after deletion of kinase LCK, essential for TCR signaling. LCK-KO CAR-T cells signal strongly through CAR and have better in vivo efficacy in both liquid and solid tumor models. They show enhanced persistence, induction of memory, and reduced exhaustion phenotype. The ability to block TCR signals while leaving CAR signaling intact suggested a method to enable allo-CAR-T therapy. The current method for stopping GVHD in allo-CAR-T is to block the TCR itself, usually by KO of the TRAC locus. Methods We knocked CAR constructs into TRAC or LCK loci in human or mouse T cells, then tested these for their ability to cause GVHD in mice. We tested their ability to protect immunodeficient NSG mice from leukemia. Results We find that LCK-knockout CAR-T blocked activation through endogenous TCR equally well as the TRAC knockout, and that both methods block development of GVHD. LCK-KO CAR-T also show superior in vivo persistence compared to TCR KO T cells. CAR constructs using the interdomain B and kinase domains of ZAP70 (“zCAR”) were independent of LCK, and were superior to the standard CAR constructs, particularly in vivo. Conclusion The enhanced persistence of LCK-deficient CAR-T cells is explained by FYN-dependent tonic signaling. Exchanging the CD3ζ element of the CAR construct for the IDB+kinase domains of ZAP70, combined with LCK-knockout, provides enhanced CAR-T activity while inhibiting any TCR-dependent signaling. This blocks any development of GVHD. The ability to separate TCR and CAR/zCAR signaling through knockout of LCK has important clinical implications for improvement of allogeneic CAR-T cells. Funding Source A*STAR Singapore Therapeutics Development Review (STDR) (H24H9a0005) Singapore Ministry of Health’s National Medical Research Council (MOH-000523) Augusta University Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)