Browse Articles

A Critical Role for NKG2D Signaling in beta cell-specific CTL Generation and NOD Diabetes 2257932

Abstract Introduction Type 1 diabetes (T1D) is an autoimmune disorder caused by T cell-mediated destruction of pancreatic β cells. There is a critical need to develop novel therapies for this disease, which requires further understanding of T1D pathogenesis. One pathway that is implicated is signaling through the immune receptor NKG2D. However, NKG2D’s role has remained unclear due to conflicting reports in the literature. Methods We generated multiple novel mouse strains on the non-obese diabetic (NOD) background to better define the role of NKG2D in autoimmune diabetes. We compared diabetes incidence, insulitis, including digital spatial profiling, and islet-specific CD8+ CTL generation between mice genetically deficient in NKG2D (NKG2D KO) and wild-type (WT) mice housed in both specific-pathogen-free (SPF) and germ-free (GF) conditions. Results NKG2D KO mice had delayed diabetes, insulitis, and CD8+ T cell pancreatic infiltration, with the most significant effect in GF and male mice. Further, we found that NKG2D signaling did not occur in the pancreas, that NKG2D ligands were expressed in the pancreatic lymph node, that deletion of NKG2D in CD8+ T cells was required to delay diabetes, that there was reduced differentiation of CTL from islet-specific naive NKG2D KO CD8+ T cells, and that the transcriptome of NKG2D KO CTL was altered. Additionally, we found that blocking NKG2D signaling similarly reduced human CTL differentiation. Conclusion The results of our studies definitively demonstrate that NKG2D in CD8+ T cells plays a critical role in autoimmune diabetes. We show this role is to enhance CTL generation rather than the CTL effector response in islets as previously proposed. Further, our data explain the conflicting reports surrounding NKG2D’s role, as we reveal the existence of redundant, compensatory signaling that is influenced by the microbiome and sex. This inherent redundancy strongly suggests that signaling through NKG2D or its compensatory pathway is critical for islet-specific CTL generation. Funding Source Breakthrough T1D (3-SRA-2023-1412-S-B and 1-INO-2022-1118-A-N), NIH P20GM104936 Topic Categories Basic Autoimmunity (BA)

MEF2C negatively regulates plasmacytoid dendritic cell functions by modulating cholesterol homeostasis 2255238

Abstract Introduction Plasmacytoid dendritic cells (pDCs) are key innate immune cells specialized in producing type I interferons. Our prior research identified MEF2C as a novel transcription factor essential for pDC development, where Mef2c knockdown or knockout drastically reduced pDC frequency. Paradoxically, MEF2C deficiency also impaired pDC function, as evidenced by heightened expression of activation markers (e.g., CD86, MHC-II) and elevated cytokine secretion (e.g., IFN-α, IL-6, TNF-α, and IL-12) upon Toll-like receptor (TLR) stimulation. These opposing roles in pDC development and activation prompted us to elucidate the regulatory mechanisms underlying the immune modulatory activity of MEF2C on pDC effector functions. Methods Given the established link between immune cell activation and metabolic reprogramming, we investigated reactive oxygen species (ROS) production and transcriptomic changes in control and Mef2c-deficient pDCs stimulated with a TLR7 agonist R848. Activation markedly elevated ROS levels in both genotypes, indicating heightened oxidative stress. However, both cellular and mitochondrial ROS were heightened in the absence of Mef2c compared to the controls. We then perform a bulk RNA sequencing examination of both control and Mef2c-deficient pDCs. Results Bulk RNA sequencing revealed that genes encoding metabolic enzymes were differentially expressed in Mef2c-deficient pDCs, with significant enrichment in cholesterol homeostasis pathways. Inhibiting cholesterol synthesis with Simvastatin, a cholesterol synthesis inhibitor, curtailed activation marker expression in both genotypes, implicating excess cholesterol in hyperactivation via disrupted lipid rafts critical for TLR signaling. Conclusion Collectively, these findings uncover a novel role for MEF2C in restraining pDC activation by suppressing de novo cholesterol biosynthesis. Targeting this pathway holds therapeutic potential for modulating pDC responses in autoimmune and inflammatory diseases. Funding Source n/a Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Chlamydia trachomatis serovar D induces Th17-mediated pathology 2257997

Abstract Introduction Infection with Chlamydia trachomatis can result in chronic infection with severe reproductive consequences. The immune response elicited by natural infection fails to protect against reinfection and can also contribute to tissue inflammation and damage. CD4+ T cells are key mediators of protection against C. trachomatis. However, these same cells, together with neutrophils, also contribute to tissue pathology. The identity and effector functions of the CD4+ T cells that contribute to protection, pathology, or both remain poorly defined. Notably, pathology in C. trachomatis is serovar-specific. Infection with serovar D induces severe tissue inflammation in the female upper genital tract, whereas infection with serovar L2 does not. The contrasting yet overlapping immune responses elicited by serovars D and L2 provide a unique model for dissecting the mechanisms that distinguish protective from pathology-inducing immunity. Methods Using a murine model of genital infection, we compared immune responses between infection with serovar D and serovar L2. Flow cytometry and quantitative PCR were used to assess cytokine production and CD4+ T cell polarization, respectively. Single-cell RNA sequencing on uterine CD4+ T cells to characterize transcriptional profiles. Results Infection with serovar D selectively drove the polarization of naïve CD4+ T cells into inflammatory T helper 17 (Th17) cells through the induction of Th17-polarizing cytokines, relative to serovar L2 infection. Single-cell RNA sequencing revealed a Th17-skewed response with transcriptional features of an inflammatory phenotype, including upregulation of Bhlhe40 and Il1r1. Conclusion These findings demonstrate that serovar D promotes pro-inflammatory CD4+ T cell responses that likely contribute to immunopathology in C. trachomatis infection, in contrast to the response elicited by serovar L2. They also underscore the importance of developing a vaccine that elicits protective immunity while minimizing harmful inflammatory responses. Funding Source This work is supported by grants (AI039558 and AI178272) from the National Institutes of Health Topic Categories Mucosal and Regional Immunology (MUC)

Broad reactivity of HLA-E restricted TCRs highlights challenges in universal T cell therapy development 2335164

Abstract Introduction T cell receptor—engineered therapies (TCR-Ts) redirect T cells to tumor antigens presented by human leukocyte antigen (HLA) molecules but are limited by the extreme polymorphism of classical HLAs, restricting broad applicability. HLA-E is a non-classical, functionally monomorphic HLA molecule that presents host- and virus-derived peptides and elicits CD8 T cell responses. Virus-associated malignancies disproportionately affect diverse populations, highlighting the need for broadly applicable immunotherapies. We investigated HLA-E—restricted TCRs as a platform for universal cellular therapy using a cytomegalovirus-derived epitope. Methods Peripheral blood mononuclear cells from CMV-seropositive donors were stimulated with antigen-presenting cells expressing HLA-E—VL9 (VMAPRTLLL). VL9-specific T cells were isolated by tetramer sorting and single-cell TCR sequencing. An HLA-E—null NFAT-luciferase reporter line expressing the VL9-TCR was used to assess activation against HLA-E—peptide complexes and cancer cell lines. Primary CD8 T cells underwent endogenous TCR and HLA-E knockout before VL9-TCR transduction. Results The VL9-TCR exhibited unexpected cross-reactivity to multiple HLA-E—bound peptides, corroborated by structural modeling. Reporter cells showed strong activation against HTLV-1+ and EBV+ leukemia and lymphoma lines, with moderate activation toward HPV+ cancers and healthy primary cells, indicating off-tumor activity. VL9-TCR—Ts demonstrated preferential HLA-E—dependent cytotoxicity against HTLV-1+ targets compared with healthy PBMCs. Conclusion HLA-E—VL9 TCR-Ts exhibit strong anti-tumor activity but also substantial peptide cross-reactivity, highlighting key safety challenges. Although the VL9-TCR itself is unlikely to be clinically viable, these results support HLA-E’s potential as a universal immunotherapy platform. Ongoing work focuses on identifying tumor-specific HLA-E—binding peptides and integrating synNotch logic-gated circuits to determine whether specificity can be enhanced. Funding Source American Society of Hematology, UNC Eshelman Innovation Topic Categories Transplantation Immunology (TRAN)

Thermodynamic Stability Boundary of Hygroscopic Salt‐Embedded Composite Materials for Atmospheric Water Harvesting

ABSTRACT Hygroscopic salt‐embedded composite materials (HSCMs) are promising for sorption‐based atmospheric water harvesting (SAWH), because they combine the high sorption capacities of hygroscopic salts with the kinetics‐enhancing properties of porous matrices. However, extensive efforts have been devoted to enhancing the efficiency of these emerging materials, while their stability has received comparatively less attention. This perspective highlights salt leakage from HSCMs as a critical challenge limiting their long‐term application in SAWH. We first introduce the advantages of HSCMs in arid regions and highlight the issues of salt leakage. We further assess the potential multiscale impacts of salt leakage on materials, systems, environment, and human health. On this basis, we establish a thermodynamic stability boundary framework to estimate the leakage risk of HSCMs by comparing the equilibrium volume of the generated salt solution with the carrying capacity of the matrix. Finally, we propose design strategies to guide the development of next‐generation leakage‐free HSCMs for sustainable SAWH.

Gate‐Tunable Floquet Weyl Photon Emission from Topological Dirac Semimetal <i>Cd</i> ₃ <i>As</i> ₂

ABSTRACT Controlling the electronic structure of Dirac materials with light and electric fields has reconfigured two‐dimensional systems such as graphene, but achieving comparable control in 3D Dirac semimetals has remained a major challenge. Here, we demonstrate all‐optical and electrical control of the band topology of the 3D Dirac semimetal Cd 3 As 2 . Circularly polarized femtosecond light dynamically breaks time‐reversal symmetry, splitting the Dirac nodes into Floquet chiral Weyl nodes. The resulting non zero Berry curvature generates helicity‐dependent transverse anomalous photocurrents, directly detected through terahertz (THz) emission at normal incidence. An applied positive electric field further shifts the Fermi level away from the Dirac point, enlarging the Dirac cone projection. As a result, we achieve precise electrical control over Floquet band engineering, resulting in a 60% modulation of THz emission. Moreover, at oblique incidence, the circular photon‐drag effect induces helicity‐dependent longitudinal photocurrents. By independently controlling the transverse and longitudinal photocurrents, we achieve electrical tuning of the helicity of emitted THz radiation. Our results establish a route to electrically programmable Floquet band engineering and tunable chiral THz sources, opening new opportunities for ultrafast quantum photonics, optoelectronics and topological quantum technologies.

Fluorobenzene‐Mediated Dragging Effect Boosting Bulk/Interfacial Ion Transport Enables −50°C Operation of Long‐Life Potassium‐Ion Batteries

ABSTRACT The small Stokes radius of K + in propylene carbonate (PC) (3.6 Å) potentially promotes fast migration both in the bulk electrolyte and interface. However, the practical applications of potassium‐ion batteries (PIBs) are still hindered by sluggish desolvation kinetics and interfacial instability under low‐temperature conditions. Herein, PC‐based electrolytes with fast ion mobility were designed by coupling the features of high‐concentration electrolytes with the “dragging effect” (non‐solvating interaction) between fluorobenzene (FB) and PC. The optimized electrolyte enriching with contact ion pairs (CIPs) and aggregates (AGGs) exhibits a threefold reduction of viscosity, 40% increased ionic conductivity (∼3.9 mS cm −1 at −10°C), 8% reduced desolvation activation energy (32.5 kJ mol −1 ), and a KF‐rich solid electrolyte interphase (SEI) with a thirteenfold increase of mechanical modulus (16.7 GPa). Consequently, the graphite // K‐FeHCFe full cells maintain over 51% of room‐temperature capacity even at −50°C and exhibit long‐term cycling stability at 25°C (77.4% after 1000 cycles) and −20°C (91.2% after 300 cycles). Furthermore, 70 mAh pouch cells deliver 90% capacity retention after 100 cycles at −10°C. This work elucidates the effects of solvation structure on desolvation kinetics and interfacial stability, providing a design strategy for high‐performance, low‐temperature PIBs.

Identification and functional characterization of an mRNA Cap3 methyltransferase from Acanthamoeba castellani medusavirusi

Modeling water flooding effect on well performance in North Troyes oilfield with complex fracture networks

Post COVID-19 Rise in Postural Orthostatic Tachycardia Syndrome and Antibody Deficiency: Exploring Immunoglobulin Therapy for Symptom Management 2309853

Abstract Introduction Since 2020, we’ve observed an increase in PI patients presenting with antibody deficiencies, despite previously reporting minimal illness or clinical stability before COVID. Concurrently, we’ve documented a rapid rise in Postural Orthostatic Tachycardia Syndrome (POTS). While a handful of POTS patients were seen before 2020, current clinic population is over 40, with an estimated 80% also demonstrating antibody deficiency, most commonly SAD. Methods We performed a retrospective review of patients, as part of an internal process improvement program, with SAD, POTS, and prior COVID infection who received IVIg either at home or our clinic. Results Cohort was female and a median age of 25 and dosing of 0.62g/kg/Q4 weeks/10months. ADRs were mainly headaches and fatigue, with 1 discontinuation due to an ADR. Functional impact included missed school/work and reliance on online education. IgG levels improved in most patients. Outcomes varied, with 2 reported improvements in syncope, dizziness, and activity tolerance, 1 noted improved energy without change in core POTS symptoms; 1 reported diminishing benefit; and 1 discontinued due to severe ADRs. Compared with other POTS treatments, IVIg was rated superior by 2 patients, neutral by 2, and intolerable by 1. Conclusion This review highlights a post COVID increase in patients presenting with both PI and POTS, with an overlap of SAD. IVIg was associated with improved IgG levels and in some, reduced syncope and fatigue, though responses were heterogeneous. The findings suggest possible immunologic contribution to POTS in the context of SAD, but the small sample size limits definitive conclusions. Future research should investigate links between new onset PI/SAD and POTS, the role of COVID in triggering dysautonomia, and whether IVIg can be systematically evaluated as a therapeutic option. Larger, studies are needed to determine whether recurrent infections and immune dysfunction worsen POTS symptoms and whether IVIg can meaningfully improve quality of life. Funding Source NA Topic Categories Translational and Interventional Immunology (TI)

DUSP4 regulates anti-tumor CD8+ T cell response in colorectal cancer 2261306

Abstract Introduction CD8+ T cells play a central role in anti-tumor immunity and are primary targets of tumor immune evasion strategies. Their activation, proliferation and cytotoxic effector functions are tightly regulated by intracellular signaling molecules. Dual-specificity phosphatases (DUSPs) are key signaling regulators that dephosphorylate both serine/threonine and tyrosine residues in their substrates, thereby modulating various cellular processes involved in both cancer development and anti-tumor immunity. DUSP4 is one of the DUSPs whose role in tumor development and anti-tumor immunity remains poorly understood. Methods Wildtype (WT) and DUSP4 knockout (KO) mice were treated with AOM/DSS to induce colorectal tumours to investigate the role of DUSP4 in colorectal cancer (CRC). Naive CD4+ and CD8+ T cells were isolated from WT and DUSP4 KO mice to investigate the function of DUSP4 in regulation of T cell activation, differentiation, and effector function. Expression of DUSP4 in CRC patient samples was determined to analyze its association with patient survival. Results DUSP4 KO exhibit increased colonic tumorigenesis following AOM/DSS treatment. In addition, CRC patients with low DUSP4 expression exhibited significantly lower survival compared to those with high DUSP4. Interestingly, DUSP4 expression in tumor cells did not influence their growth. Instead, the increased tumor development in the KO mice was attributed to a compromised anti-tumor immune response. Further analysis revealed that DUSP4-deficient CD8+ T cells exhibited reduced activation, proliferation and effector function compared to WT cells, associated with increased ERK activation. Moreover, these cells showed elevated exhaustion phenotypes, which can be reversed by inhibition of ERK. Conclusion These findings demonstrate that DUSP4 supports CD8+ T cell-mediated anti-tumor immunity, likely through modulation of ERK activation, and suggest that DUSP4 may serve as a promising therapeutic target for enhancing anti-tumor immune responses. Funding Source Singapore National Medical Research Council Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Investigating the Role of Peripheral Regulatory T Cells in Oral Tolerance to Gluten in Celiac Disease 2259765

Abstract Introduction Celiac disease (CeD) is an immune-mediated enteropathy triggered by CD4+ T-cell recognition of gluten-derived peptides presented by HLA-DQ8, leading to chronic intestinal inflammation. Although regulatory T cells (Tregs) are central to mucosal tolerance, the relative contributions of thymus-derived Tregs (tTregs) versus peripherally induced Tregs (pTregs) remain unresolved. Here, we define the role of pTregs in gluten-driven inflammation using a transgenic mouse model that separates tTreg and pTreg function in the context of HLA-DQ8—restricted antigen presentation. Methods Mice: HLA-DQ8/I-Ab knockout (Ab⁻/⁻) mice were bred with CNS1-deficient (CNS⁻/⁻) mice, which lack pTreg generation, and Foxp3-GFP reporter mice. Four groups were defined by genotype (CNS⁻/⁻ vs. CNS+/+) and diet (gluten-free diet [GFD] vs. regular chow). Experimental designs: (1) Adoptive transfer of CD4+ T cells into TCRα⁻/⁻ recipients, followed by a diet switch. (2) Direct switch from GFD to regular chow. (3) Mucosal adjuvant model using cholera toxin (±gluten) with diet change. Readouts: Body weight and fecal lipocalin-2 were tracked as clinical and inflammatory markers. Immune profiling via flow cytometry was done on mesenteric lymph nodes, lamina propria, and intraepithelial lymphocytes (IELs). Results Across all study arms, CNS⁻/⁻ mice maintained on regular chow developed significant weight loss and elevated fecal lipocalin-2, indicating intestinal inflammation. Flow cytometry revealed increased frequencies of activated lymphocytes in CNS⁻/⁻ mice on regular chow compared with all other groups in different organs. Conclusion This novel mouse model provides a robust platform for studying the role of pTregs in gluten-induced tolerance and celiac disease—associated inflammation. The findings underscore the importance of pTregs in maintaining intestinal immune homeostasis and offer a valuable tool for future mechanistic and therapeutic investigations Funding Source Georgia State university intramural funding Topic Categories Mucosal and Regional Immunology (MUC)

Mapping REV-ERBα’s Protein-Protein Interactions to Understand TH17 Cell Regulation and Inflammation 2258028

Abstract Introduction TH17 cells are a subset of CD4+ T cells that mediate autoimmune and chronic inflammatory pathology. Our lab has previously demonstrated that REV-ERBα, a member of the nuclear receptor superfamily of ligand-regulated transcription factors, represses TH17 development in vitro and protects against relevant models of disease in vivo. While REV-ERBα’s target genes and binding sites have been identified across multiple tissues, little is known about the transcriptional machinery that drives its function. Methods We coupled MiniTurboID proximity labeling with label-free proteomics to 1) identify key proteins that facilitate REV-ERBα-mediated gene repression in primary, murine TH17 cells and 2) further understand how ligands modulate this process. Furthermore, we have conducted a pooled in vivo RNAi screen to examine our proteomics hits in a physiologically relevant context. Specifically, we utilized Il17a reporter REV-ERB deficient and sufficient T-cells along with shRNAs targeting our identified REV-ERBα interactors in a mouse model of colitis. Results Comparison of the REV-ERBα interactome induced by the presence and absence of endogenous ligand binding reveals potential canonical and non-canonical mechanisms of repression. Additionally, comparison of the shRNAs enriched in colon cells expressing high versus low levels of IL-17A have elucidated which REV-ERBα interactors regulate TH17 pathogenicity in a REV-ERB-dependent manner. Conclusion Ultimately, these efforts aim to bolster our understanding of the REV-ERBs, nuclear receptor biology, and TH17 pathogenesis–all of which may inform the development of focused therapeutics for treatment of autoimmune and chronic inflammatory diseases. Funding Source NA Topic Categories Basic Autoimmunity (BA)

Distinct epigenetic and transcriptional landscape of pathogenic CD44s-hiCD49dlo virtual memory CD8+ T cells in alopecia areata 2256633

Abstract Introduction Virtual memory (TVM) CD8+ T cells exhibit memory-like features without prior antigen exposure and provide protection. We previously identified a CD44s-hiCD49dlo subset that acquires pathogenic properties upon IL-12, IL-15, and IL-18 stimulation and mediates alopecia areata (AA) via NKG2D-dependent cytotoxicity. These findings reveal functional heterogeneity within the TVM compartment, suggesting that subsets can transition to a disease-promoting phenotype under inflammation. Based on these findings, we aimed to define the molecular and epigenetic heterogeneity of TVM cells and identify transcriptional regulators driving pathogenic CD44s-hiCD49dlo CD8+ T cell differentiation. Methods We performed joint single-cell RNA sequencing and ATAC sequencing on conventional TVM and CD44s-hiCD49dlo CD8+ T cells isolated from the lymph nodes and skin of AA mice. UMAP projection and clustering defined transcriptional heterogeneity, and pseudotime trajectory analysis inferred differentiation pathways. Integration of transcriptomic and chromatin accessibility data enabled the identification of transcription factors associated with pathogenic transition. Results Single-cell analyses revealed that conventional TVM and CD44s-hiCD49dlo CD8+ T cells form transcriptionally distinct populations. Clustering identified multiple subpopulations within the TVM pool, including a transitional subset located along a pseudotime trajectory leading toward the pathogenic state. Integrated gene expression and epigenomic profiling highlighted RUNX2, RUNX3, and RORα as candidate regulators orchestrating this differentiation program. Conclusion Taken together, these findings delineate a previously unrecognized trajectory from conventional TVM cells to CD44s-hiCD49dlo CD8+ T cells that drive inflammation in AA. The identified regulatory factors define the transcriptional and epigenetic framework underlying this pathogenic transition and represent potential molecular targets for therapeutic modulation of cytotoxic T-cell responses. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

The effect of a high fat diet on cardiac specific immune responses to K. pneumoniae 2258613

Abstract Introduction Sepsis is a serious medical condition that is triggered when the body responds to infection and can result in damaged tissues, organ failure, and death. It is estimated that nearly 49 million people per year are affected by sepsis with nearly 11 million people across the globe succumbing to sepsis each year. Obesity is a noncommunicable disease and its prevalence has increased throughout the years. Worldwide, nearly 890 million people are considered obese. Methods One of our main goals is to learn how obesity could potentially impact the outcome of infection. We are currently utilizing Klebsiella pneumoniae to model sepsis, as it can rapidly disseminate from the lungs to distal sites within days of infection. Others have shown that obesity can play a role in the host response to K. pneumoniae. Our current goal is to define how obesity may alter tissue specific cardiac immune responses using in vivo and in vitro approaches. Results We have measured cytokines in whole tissue homogenates from infected non-obese mice fed a control diet and infected obese mice fed a high fat diet. We are also using various histological techniques to uncover how immunopathology may be affected by infection in the context of high fat diet induced obesity. Conclusion In summary, our studies will help uncover how high fat diet induced obesity could potentially affect cardiac specific immune responses. Funding Source Texas A&amp;M University San Antonio Foundation Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)

DOCK 8 with large vessels Vasculitis 2337558

Abstract Introduction Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent infections, eczema, and elevated serum IgE. Dedicator of Cytokinesis 8 (DOCK8) deficiency, an autosomal recessive form of HIES, is further associated with severe allergies, viral susceptibility, and malignancy risk. We present a case of DOCK8 deficiency in an 11-year-old male who developed large vessel vasculitis involving the aorta and proximal neck vessels, with associated wall irregularities and aneurysmal dilatation–a previously unreported complication in this syndrome. This report highlights the expanding clinical spectrum of DOCK8 deficiency and underscores the importance of monitoring for vascular pathology. Methods An 11-year-old Saudi male with DOCK8 deficiency (diagnosed in infancy with extreme IgE &amp;gt;19,130, eczema, and anaphylaxis) presented with fever. He was tachycardic. CRP was 245 mg/L. Imaging revealed diffuse aortic disease. Results Chest CT showed a dilated, calcified thoracic aorta. Cardiac MRI confirmed large vessel vasculitis: marked wall thickening/enhancement of the entire aorta and proximal neck vessels, with aneurysmal dilatations. No abdominal aneurysm. Brain MRI showed Chiari I malformation, no vasculitis. Management &amp; Outcome Treated with IVIG (2g/kg) and IV methylprednisolone pulse, then oral prednisolone taper. Stable discharge with multidisciplinary follow-up. No surgery required. Conclusion This is the first report of extensive large vessel vasculitis in DOCK8 deficiency, expanding its phenotype. DOCK8 immune dysregulation may predispose to vascular inflammation. Vigilance and advanced imaging are crucial for similar patients. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)

Supramolecular Nanoclusters Enable High‐Performance and Recyclable Epoxy Resins

ABSTRACT Epoxy resins are essential matrix materials for high‐performance composites, yet achieving both superior mechanical properties and recyclability remains a significant challenge. In this study, we report a supramolecular nanocluster (SNs) strategy to simultaneously address these dual demands. The SNs, synthesized via cationic polymerization of an epoxy monomer initiated by a Zn 2 + ‐based liquid coordination complex, incorporate metal‐coordination and hydrogen‐bonding interactions along with flexible polyether chains. When integrated into a highly cross‐linked epoxy network, these nanoclusters form localized reinforcement domains, where rigid supramolecular regions enhance stiffness while flexible segments mitigate stress concentration. The optimized epoxy resin achieves a tensile strength of 134 MPa, a modulus of 4.9 GPa, and a 49% improvement in fracture toughness. Using this resin as a matrix for carbon fiber‐reinforced composites, a notable enhancement is observed in tensile and flexural performance. Furthermore, the embedded Zn 2 + sites act as built‐in catalysts, enabling complete resin hydrolysis via ester bond cleavage within 6 h at 170°C in water. The resulting oligomeric products are directly repurposed as a water‐soluble sizing agent for carbon fibers, establishing a recyclable pathway. This work offers a viable strategy to reconcile the trade‐off between high performance and sustainability in epoxy thermosets.

Orchestrating glucose metabolism: PFKFB2 as a signal-integrating conductor in homeostasis and disease

Battery performance prediction using supervised learning: a comparative study

Abstract Accurate prediction of lithium-ion battery state of charge (SOC) is critical for ensuring safety, durability, and efficient energy management in electric vehicles (EVs). This study presents a systematic comparative analysis of supervised machine learning (ML) models for SOC prediction using the publicly available SiCWell battery dataset. Five regression-based algorithms—Generalized Linear Model (GLM), Gradient Boosting Machine (GBM), Extreme Gradient Boosting (XGBoost), Distributed Random Forest (DRF), and Extremely Randomized Trees (XRT)—are implemented within the H2O framework. The analysis considers six physically measurable battery features derived from voltage, resistance, charge throughput, and current direction. Model performance is evaluated using multiple regression metrics, including MAE, MSE, RMSE, RMSLE, residual deviance, and R², under a consistent train–test evaluation protocol. Results indicate that GLM achieves low prediction errors across both training and testing datasets, suggesting that the selected feature set exhibits a strong linear relationship with SOC within the evaluated operating range. However, ensemble models demonstrate higher variance and sensitivity to hyperparameter configurations, leading to reduced generalization performance. Rather than asserting a universally superior model, this study highlights how dataset characteristics, feature linearity, and model complexity influence SOC prediction accuracy. The findings provide insights into selecting appropriate ML models for battery management systems while emphasizing the importance of dataset transparency, interpretability, and generalization analysis.

Real-Time Single-Cell Kinetics of Innate Immune Activation 2264282

Abstract Introduction The innate immune system depends on a network of signaling pathways to detect and respond to viral infections, yet the degree of interdependence between pathways remains poorly understood. In this study, we investigate whether key innate immune pathways activate in a coordinated or independent manner during viral sensing. Methods Using real-time live-cell imaging of fluorescently tagged signaling proteins, in combination with western blotting, immunofluorescence, and single-molecule RNA FISH, we track the activation dynamics of individual pathways at single-cell resolution in response to diverse viral stimuli. Results Our results reveal that innate immune pathways are activated independently and maintain functionality in the absence of parallel pathways. IRF3, PKR, and RNase L innate immune pathways all retain full capacity to activate independently of each other. Conclusion This finding stands in contrast to prevailing models that propose extensive crosstalk and dependence. These results suggest that innate immune pathways are evolutionarily optimized to operate autonomously, providing a robust antiviral response during conditions of pathway inhibition or disruption. This work challenges assumptions in the field and redefines our understanding of innate immune signaling architecture. Funding Source NIH Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)