Browse Articles

Using hand drawings as a visual learning tool to encourage medical students’ understanding of complex contents of innate and adaptive immune responses 2304682

Abstract Introduction Understanding how the innate and adaptive immune systems work to protect the body from infectious diseases, cancer, or autoimmune diseases is indeed challenging for medical students, especially in their first semester of Immunology. Most classes involve the professor delivering content through slides, such as PowerPoint. For some topics, clinical scenario-based questions are introduced at the start of class, asking students to consider what is happening at the cellular level. Despite this approach, many key concepts remain misunderstood. Therefore, new learning strategies are continuously being introduced to improve conceptual understanding in Immunology classes. Methods The learning practice developed aimed to evaluate whether drawing representations of immune cells in the context of innate and adaptative immune responses improves understanding of topics and engagement in the class. Students who have already taken the class are responsible for preparing the hand drawings. Examples of hand drawings include cytotoxic T lymphocytes that can be represented by an angel that recognizes antigens presented by an antigen-presenting cell. These scientific drawings are made available to new students before the class takes place., Results: We do not have a measure of the effectiveness of this practice, but we have had positive feedback from the students. Collectively, students have commented that they find it easier to understand and retain a wide variety of complex topics. In addition, they use these drawings as an initial scenario that can be altered as new information is acquired, allowing them to gain a deeper understanding of the subject. Conclusion We have observed that students get the most out of this visual learning strategy in classes where it is applied. Ultimately, we believe that a similar approach can be useful for students in a situation of communication with patients to explain medical conditions, such as the mechanisms of the disease that the patient faces, and therapeutic strategies.. Funding Source n/a Topic Categories Immunology Education and Communication (EDU)

Loss of STAT1 and Nitric Oxide Signaling Compromises the Development of the Stress Erythropoiesis Niche 2260816

Abstract Introduction Steady-state erythropoiesis generates erythrocytes in the bone marrow to replace senescent cells cleared by the spleen. Inflammation from infection or tissue damage disrupts this balance by skewing hematopoiesis toward myelopoiesis. To compensate, stress erythropoiesis maintains red cell output until inflammation resolves. Unlike steady-state erythropoiesis, stress erythropoiesis depends on TNFα and IFNγ, which recruit short-term hematopoietic stem cells (ST-HSCs) and monocytes to the spleen, where they generate stress erythroid progenitors (SEPs) and form erythroblastic islands (EBIs). IFNγ—STAT1 signaling induces CCL2 expression and CCR2+ monocyte recruitment to initiate this niche, while nitric oxide (NO) signaling later resolves inflammation and supports erythroid maturation. Methods Inflammatory anemia was induced using heat-killed Brucella abortus. Spleens from wild-type, Stat1⁻/⁻, and Nos2⁻/⁻ mice were analyzed for splenomegaly, Ly6C+ monocyte recruitment, SEP proliferation, and BFU-E formation. Flow cytometry and erythrophagocytosis assays characterized monocyte differentiation and SEP maturation. Sickle-cell mouse spleens were also examined for Ly6C+ recruitment and BFU-Es. Results Stat1⁻/⁻ mice showed reduced CCL2 expression, impaired monocyte recruitment, and decreased SEP expansion, indicating STAT1 initiates the inflammatory niche for stress erythropoiesis. Nos2⁻/⁻ mice exhibited greater splenomegaly, delayed anemia recovery, fewer BFU-Es, and disrupted erythroid maturation from excess Ly6C+ monocytes. Sickle cell mice showed similar defects, including increased splenomegaly and reduced BFU-Es. Conclusion STAT1 and NOS2 act sequentially to regulate stress erythropoiesis. STAT1-driven IFNγ signaling initiates monocyte recruitment, while NOS2-derived NO promotes macrophage differentiation, SEP proliferation, and anemia recovery. Low NO in Nos2⁻/⁻ and sickle-cell mice disrupts erythroid regeneration, identifying STAT1—NOS2 signaling as a therapeutic target in inflammatory anemia. Funding Source NIH grant T32GM108563 Topic Categories Hematopoiesis and Immune System Development (HEM)

Mucosal cellular immunology in SARS CoV2 infection and hybrid immunity 2309658

Abstract Introduction Mucosal immunity is critical in protection against COVID-19 respiratory disease. It is still unclear how the dynamics at the site of infection change between vaccination or natural infection alone and hybrid immunity. Growing evidence supports the importance of T-cell response in circumventing escape variants but we lack an understanding of the magnitude and durability of those responses within different tissues and if they correlate to the protective benefits seen during wanning antibody response Methods We utilized the mouse-adapted SARS CoV2 model, collecting upper and lower respiratory tissues to identify the rise and contraction of T-cell responses following the induction of different immune experiences. One group was exposed intranasally to the virus twice where hybrid groups received intramuscular vaccination that either preceded or followed by intranasal virus. Samples were analyzed with multiparameter flow panels to determine intracellular cytokine response and well as the type of memory subpopulations that arose. Results Distinct patterns were identified of T-cell polyfunctionality and memory population development between groups and across tissue types. Regardless of the order of exposure hybrid immunity mice had greater central, effector and tissue resident memory than repeat infection as well as increased cytokine response. Conclusion Hybrid immunity provided a substantial improvement in the development of SARS CoV2 specific T-cells over repetitive natural infection in systemic and mucosal tissues. Mucosal stimulation and cellular immunity are gaps that should be addressed in future vaccine design. Funding Source UC7 AI180310 Topic Categories Mucosal and Regional Immunology (MUC)

The in vivo inhibitory fucntion of the MHC-I a3 domain/CD8a interaction 2329318

Abstract Introduction Since the discovery of the MHC-I α3 domain/CD8α interaction approximately 40 years ago, numerous in vitro studies have demonstrated that this binding stabilizes the MHC-I/TCR complex and facilitates signaling for low-affinity or CD8-dependent TCRs. However, the in vivo significance of this interaction has remained largely unexplored. In this abstract, we present our recent findings regarding the in vivo blockade of the MHC-I α3 domain/CD8α interaction in both the absence and presence of antigen exposure. Methods We employed monoclonal antibodies directed against the α3 domain of MHC class I to selectively disrupt the interaction between the MHC-I α3 domain and CD8α. Specifically, two monoclonal antibodies targeting the α3 domains of H-2Kb and H-2Db were used in C57BL/6 mice. In addition, three monoclonal antibodies specific for the α3 domains of H-2Ld, H-2Dd, and H-2Kd were utilized in the BALB/c mice. These α3 domain—specific antibodies enable precise interrogation of MHC-I α3 domain—CD8α interactions under both antigen-dependent and antigen-independent conditions. Results Our results demonstrate that selective blockade of individual MHC-I α3 domain—CD8α interactions is sufficient to activate CD8+ T cells in the absence of antigen exposure. In the presence of antigen, blockade of either the H-2Db or H-2Kb α3 domain—CD8α interaction enhances ovalbumin peptide—induced, H-2Kb—restricted OT-I CD8+ T cell responses and prevents the development of CD8+ T cell tolerance. Importantly, blockade of either the H-2Db or H-2Kb α3 domain—CD8α interaction also reverses established H-2Kb—restricted OT-I CD8+ T cell tolerance. Conclusion These data suggest that the MHC-I α3 domain—CD8α interaction delivers an inhibitory signal to CD8+ T cells in vivo during antigen-independent homeostasis. In the presence of antigen, this interaction also plays an inhibitory role in vivo at multiple stages of CD8+ T cell activation. Funding Source Elsa Pardee Foundation, OSU startup. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Oxphos, not Glycolysis, Promotes the Survival Of Effector Tc17 Cells 2307301

Abstract Introduction IL-17A+ T cells are implicated in immunity and immunopathology. Fungal infections primarily occur in immunocompromised hosts. We have previously shown that experimental fungal vaccine-induced Tc17 cells are stable, durable, and necessary for sterilizing immunity in CD4+ T cell deficiency. Metabolism is pliable but integral for T cell homeostasis. T cell expansion involves metabolic shift from OXPHOS to glycolysis to meet rapid energy needs, but Tc17 cell metabolic adaptations that portend longevity are poorly defined. Methods We used a mouse model of fungal vaccination to evaluate metabolic adaptations of Tc17 cells in draining lymph nodes by flow cytometry. 2-DG, oligomycin, sodium oxamate, and sodium bicarbonate were used to inhibit glucose uptake, OXPHOS, lactate production, and lactate-induced extracellular acidification neutralization, respectively. Results Effector Tc17 cells were metabolically highly active with higher proliferation and translation than IFN+ CD8+ T (Tc1) cells. Glucose was necessary for Tc17 cell expansion, but with reduced dependency in late expansion despite the higher metabolism. Tc17 cells preferentially channeled glucose to OXPHOS rather than glycolysis, correlated with their higher mitochondrial mass and function. Consistent with this, RNASeq data showed that Tc17 cells, unlike Tc1 cells, showed higher expression of TCA cycle and OXPHOS-related transcripts and low PDHK1 expression, despite a higher glycolysis signature. As glycolysis exuded lactate acidifies the extracellular environment, neutralizing acidification enhanced Tc1 cells, but not Tc17 cells. Similarly, inhibiting lactate production preferentially rescued Tc1 cells. Conclusion The effector Tc17 cells prudently channel the glucose to OXPHOS metabolism over glycolysis meet high energy demand. In contrast, glycolysis-dependent Tc1 cells showed poor survival but countered by inhibition of lactate production. Collectively, effector Tc17 cells are programmed for longevity by adopting OXPHOS than glycolysis. Funding Source NIH-NIAID R01153522 (to SGN) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)

Ultra‐Narrow Pure‐Green MR‐TADF Emitter with an FWHM of 12 nm Enables Superior‐Performance Top‐Emitting OLEDs with EQE Approaching 60%, Power Efficiency Over 300 lm W ⁻¹ , and CIE Coordinates of (0.14, 0.79)

ABSTRACT Achieving pure‐green organic light‐emitting diodes (OLEDs) with both precise spectral positioning and an ultra‐narrow full‐width at half‐maximum (FWHM) remains highly challenging, as red‐shifting emission into the pure‐green regime is often accompanied by enhanced excited‐state relaxation and spectral broadening. Herein, we report a molecular design strategy that reconciles green‐region red‐shift with intrinsic spectral narrowing through the synergistic integration of dibenzofuran fusion and cyano decoration within a meta ‐diboron framework. The proof‐of‐concept molecule DBFCN exhibits intrinsically ultra‐pure green emission in dilute toluene, centered at 519 nm with a very small FWHM of 12 nm, placing it among the narrowest green multi‐resonance thermally activated delayed fluorescence (MR‐TADF) emitters reported so far. The bottom‐emitting OLEDs deliver a maximum external quantum efficiency (EQE max ) of 38.5% and pure‐green emission at 521 nm with an ultra‐narrow FWHM of 13 nm. Owing to the intrinsically ultra‐narrow emission and minimal spectral tail of DBFCN, photon loss in the top‐emitting (TE) configuration is effectively mitigated, leading to markedly enhanced device performance. Consequently, the TE‐device delivers a maximum power efficiency (PE max ) exceeding 300 lm W −1 and a current efficiency (CE max ) of 232.5 cd A −1 , while meeting the green BT.2020 color gamut.

Assessing indirect rebound effects of China’s household energy consumption with input-output and redistribution models

IL-39/IL-39R Signaling Drives Acute Graft-versus-Host Disease by Promoting Pathogenic T-Cell Responses 2259690

Abstract Introduction Acute graft-versus-host disease (aGVHD) remains a life-threatening complication of allogeneic hematopoietic cell transplantation. Among IL-12 family cytokines, the newly identified IL-39, composed of IL-23p19 and EBI3, ligands IL-39 receptor, a complex of IL-23Rα and gp130. IL-39 has been implicated in inflammatory disorders, but its contribution to aGVHD and graft-versus-leukemia (GVL) remains undefined. Methods Murine and human T cells were stimulated with allogeneic APCs in the presence of recombinant human IL-39 (rhIL-39) to test the effect of IL-39 in T-cell response in vitro. Proximity ligation assay (PLA) was used to detect IL-23Rα/GP130 heterodimerization. T-cell pathogenicity in GVHD was measured in murine allogeneic bone marrow transplantion (BMT). The GVL activity was assessed using MLL-AF9 leukemia challenge. A xenogeneic GVHD (xeno-GVHD) model with human PBMCs was used to evaluate IL-39’s effect on human T-celll responses. Results rhIL-39 enhanced proliferation and production of IFN-γ, TNF-α, and GM-CSF, promoted Th1/Th17 polarization, and suppressed Foxp3+Treg differentiation in murine and human T cells. It induced robust STAT1/3 phosphorylation in IL-23Rαhigh Th17 cells and PLA assay confirmed IL-23Rα/gp130 heterodimerization. In murine BMT models, recipients receiving IL-23Rα-/- or DKO donor cells exhibited less GVHD compared to those of WT or IL-12Rβ1-/- cells while preserving GVL activity. rhIL-39 markedly increased GVHD scores, decreased survival, and expanded IFN-γ+, TNF-α+, and IL-17+CD4+ T cells while reducing Foxp3+ Tregs in the recipients of WT but not IL-23Rα-/- T cells. In the xeno-GVHD model, rhIL-39 aggravated GVHD with reduced survival and elevated human T-cell infiltration and inflammatory cytokines. Taken together, IL-39 enhances T-cell pathogenicity in GVHD through IL-23Rα. Conclusion IL-39/IL-39R signaling drives aGVHD pathogenesis and represents a promising therapeutic target for aGVHD while preserving GVL responses. Funding Source NIH, Advancing A Healthier Wisconsin Endowment Topic Categories Transplantation Immunology (TRAN)

Milk Allergen-Induced Eosinophil Activation in Eosinophilic Esophagitis: The IgG4 Pathway 2302520

Abstract Introduction Eosinophilic esophagitis (EoE) is a chronic allergic condition, defined by symptoms of esophageal dysfunction (such as difficulty swallowing, food impactions, nausea, vomiting, etc.) and esophageal eosinophilia [≥³15 eosinophils (Eos) per high-powered field]. Milk is the most common trigger of EoE and is known to induce disease in up to 80% of EoE patients. IgG4 is present in esophageal tissue of active EoE patients and co-localizes with food triggers and Eos-associated proteins. The mechanisms by which IgG4 contributes to allergic inflammation in EoE, however, remain unclear. Methods A peripheral blood sample from an active EoE patient was used to generate food allergen-specific IgG4 monoclonal antibodies (mAbs). Solid-phase immune complexes (ICs) were formed by incubating these IgG4 mAbs (Bos d 8-specific) with Bos d 8-coated ELISA plates and soluble ICs were formed by mixing IgG4 mAbs with Bos d 8 in solution before incubating with eosinophils (Eos). Eos were isolated from the peripheral blood of mildly allergic volunteers using Miltenyi magnetic separation and incubated with ICs for 1 hour. Eos activation was determined by quantifying Eos-derived neurotoxin (EDN) release in culture supernatants. Results Bos d8-specific IgG4 mAbs were successfully generated from antibody-secreting B cells of active EoE patients using the hybridoma technique. Naïve Eos incubated with solid-phase IgG4-Bos d 8 ICs released significantly more EDN compared to Eos incubated with IgG4 alone (477.3 ± 28.1 vs 243.5 ± 8.8, p < 0.01) in a dose-dependent manner. Moreover, Eos pre-treated with Fc-blocker did not show activation upon subsequent incubation with the IgG4-Bos d 8 ICs (278.3 ± 21.3 vs 307.57 ± 7.3). Interestingly, Eos incubated with soluble ICs did not show any activation. Conclusion These findings suggest that the solid phase IgG4-Bos d 8 ICs activate Eos via an Fc-gamma receptor. Further research is needed to confirm whether this process occurs in EoE patients. Funding Source This work was supported by NIH-NIAID R01 AI175232-01 grant to McGowan E. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Dual Immunomodulatory Roles of MARCKS in Proinflammatory and Type I Interferon Signaling in Macrophages 2306298

Abstract Introduction Lipopolysaccharide (LPS) signaling plays a critical role in innate immune responses and inflammation. Myristoylated alanine-rich C-kinase substrate (MARCKS) has been implicated in various signaling pathways; however, its immunomodulatory mechanisms remain unclear. In this study, we used proteogenomic analysis to investigate the function of MARCKS in the LPS response. Unexpectedly, our results revealed that MARCKS acts as both a positive and negative regulator of LPS signaling, suggesting a reciprocal role of MARCKS. This dual role challenges the current understanding of MARCKS function. In macrophages, loss of MARCKS resulted in reduced inflammation, marked by decreased TNF-induced amplification and attenuated activation of NF-κB and MAPK pathways. In contrast, MARCKS deficiency enhanced interferon signaling, with elevated IFN-β production and upregulation of interferon-stimulated genes (ISGs) via the JAK-STAT pathway. These findings reveal a previously unrecognized dual function of MARCKS in modulating both inflammatory and interferon responses, with implications for targeting immune dysregulation in disease Methods   Results   Conclusion   Funding Source This research was supported by the Intramural Research Program of NIAID, NIH. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

Caught in the NET: Stress-Driven Neutrophil Dynamics Alter Behavior 2258480

Abstract Introduction Despite recognized neuroendocrine-immune crosstalk, the effects of psychological stress on neutrophil extracellular trap formation (NETosis) and associated behavioral outcomes are poorly understood. Methods In this study, we investigated the effect of stress and stress hormones on NETosis using a chronic stress paradigm in C57BL/6J mice in vivo and by activating primary human neutrophils in vitro with stress hormones. Results C57BL/6J mice exposed to chronic stress (21days), showed extensive neutrophil expansion and increased NET formation in plasma and isolated neutrophils, quantified using SYTOX-based fluorescence and microscopic assays. Furthermore, activation of human neutrophils with stress hormones epinephrine and cortisol resulted in robust NET formation characterized by neutrophil elastase and visualized by confocal microscopy. Interestingly, induction of NETS in human neutrophils using phorbol myristate acetate (PMA) also increased β2-adrenergic and glucocorticoid receptor expression determined by flow cytometry. Following this, injection of NET components to mice caused behavioral changes such as reduced locomotor activity in open field test. Conclusion Together, our results indicate that stress hormones directly promote NETosis and that neutrophil-neuroendocrine signaling contribute to further stress associated behavioral changes. These findings identify a direct mechanism linking chronic stress, innate immunity and behavioral changes and highlight new targets in psychiatric disease pathophysiology. Funding Source Northeastern university Topic Categories Neuroimmunology (NEUR)

Lymphotoxin Beta Receptor Activity in Fibroblasts Regulates Collagen Synthesis and is Crucial for Lung Fibrosis 2309700

Abstract Introduction Pulmonary fibrosis is a hallmark of severe asthma and other chronic lung diseases and is driven by fibroblast-mediated production of collagen and extracellular matrix components. However, the key signals that regulate fibroblast activation and fibrotic remodeling remain poorly defined. Previous studies have shown that animals lacking TNFSF14 exhibit reduced lung fibrosis, indicating that signaling through its receptor, LTβR, may play a direct role in controlling collagen deposition. Methods This study investigated the role of fibroblast-specific LTβR signaling in allergen-induced lung fibrosis. Mice with tamoxifen-inducible, fibroblast-specific deletion of LTβR were used to assess fibrotic responses during experimental asthma. In parallel, recombinant LIGHT was used to stimulate cytokine-primed human pulmonary fibroblasts (TGFβ, IL-17, or IL-13) to determine whether LTβR signaling directly regulates fibrotic activity. Results Conditional deletion of LTβR in fibroblasts resulted in an almost complete loss of collagen deposition in the lungs following repeated allergen exposure, despite minimal changes in fibroblast accumulation. Consistent with this finding, LIGHT/TNFSF14 strongly induced expression of genes associated with fibrosis and cytoskeletal remodeling in cytokine-primed human pulmonary fibroblasts, including multiple collagen isoforms (COL1A1, COL1A2, COL3A1, COL5A1) and other matrisome-related genes (FN1, TAGLN, ACTA2, SPARC, FLNA). Importantly, this fibrotic transcriptional signature was also detected in fibroblasts isolated from patients with interstitial lung disease. Additionally, LTβR deletion in fibroblasts significantly reduced lung infiltration by neutrophils, macrophages, and T cells, likely due to impaired LIGHT—LTβR—dependent regulation of chemokines and adhesion molecules involved in immune cell recruitment. Conclusion LTβR signaling in fibroblasts is a critical driver of both fibrotic remodeling and inflammatory cell recruitment in severe and chronic lung disease. Funding Source NIH U19 AI070535 Topic Categories Cytokines and Chemokines and their Receptors (CCR)

Development of a Protective Cellular Therapy to Prevent Graft Versus Host Disease Post Allogenic Hematopoietic Stem Cell Transplant 2331939

Abstract Introduction Graft-versus-host disease (GVHD) remains a primary cause of morbidity and mortality post-allogeneic hematopoietic stem cell transplantation (allo-HSCT), driven by donor T cells’ dysregulated inflammation against host tissues. This limits survival and underscores the need for therapies that curb GVHD while preserving graft-versus-tumor (GVT) effects. Innate-like T cell subsets, including MAIT, NKT, and Vγ2 γδ T cells correlate with milder GVHD. These share the BTB-ZF transcription factor PLZF (Zbtb16), a master regulator of innate-like programming. Building on our finding that ectopic PLZF imparts innate-like traits to conventional αβ T cells, we tested if PLZF-overexpressing donor T cells suppress GVHD in vivo. Methods In a B6→BALB/c acute GVHD model, lethally irradiated BALB/c recipients received bone marrow plus purified CD4+/CD8+ T cells from C57BL/6 donors, transduced with retroviral PLZF or empty vector (EV) control (n = 15/group). Mice were monitored daily for survival, clinical scores, and weight loss. Results In mouse models of acute GVHD (B6→BALB/c), adoptive transfer of retrovirally transduced, PLZF-overexpressing conventional T cells markedly delayed disease onset and enhanced survival relative to empty vector-transduced controls. Mechanistically, PLZF-overexpressing conventional T cell promoted expansion of regulatory T cell (Treg) populations, thereby driving a phenotypic shift toward innate-like suppression of alloimmunity. Conclusion These results affirm PLZF overexpression as a viable, programmable approach for GVHD prophylaxis, poised for clinical advancement. Through innate-like T cell reprogramming, this strategy holds promise for revolutionizing allo-HSCT by decoupling immune tolerance from antitumor immunity. Current investigations are evaluating PLZF-overexpressing conventional T cell preservation of graft versus tumor (GVT) activity against leukemia and extending these findings to humanized models. Funding Source NJ PHORCE Topic Categories Transplantation Immunology (TRAN)

Assessing Potential Additivity of Proinflammatory Cytokines and Kifunensine on ADCC Potency 2309647

Abstract Introduction Antibody-dependent cell mediated cytotoxicity, or ADCC, is a process where antibodies coat a target cell, recruiting effector cells to induce target cell death. This process is generally mediated by IgG antibodies and Fcγ receptors, namely FcγRIIIa/CD16a, which is expressed on cytotoxic natural killer cells (CD56dim CD16+). ADCC is targeted for cancer immunotherapy, whereby increasing ADCC potency is expected to improve patient outcome. We explored the impact of cytokine treatment in vitro on ADCC potency using primary natural killer cells, IL-2, IL-15, TNFα, and IL-10. We also evaluated a novel method, altering N-glycan processing, and assessed the interaction of cytokine treatment and N-glycan manipulation on ADCC of primary human NK cells. Methods Primary NK cells were incubated in YTS media supplemented with no cytokines, IL-2, IL-15, TNFα, IL-10, and/or kifunensine. We then evaluated NK cell activity with Raji cells and rituximab to assess cytotoxicity and ADCC potency. Raji cell lysis was determined via flow cytometry. Primary NK cells were also incubated with PHA-L-AF594 to assess how treatments affect NK cell N-glycosylation. Results NK cells treated with kifunensine alone have lower ADCC potency compared to control. NK cells treated with IL-15 and kifunensine increase ADCC potency through kifunensine suppressing the IL-15-dependent increase in natural cytotoxicity. NK cells treated with IL-2 and IL-15 both demonstrated a change in N-glycosylation, which was then subdued when cells were treated with IL-2 + kifunensine and IL-15 + kifunensine. Conclusion IL-15 combined with kifunensine in vitro increased ADCC potency of primary NK cells with minimal impact on NK cell viability. Funding Source U01-AI-148114 from the National Institute of Allergy and Infectious Diseases Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)

Organic–Inorganic Hybrid Hole‐Selective Layer Interface Engineering for Enhanced Photoelectrochemical Water Oxidation on Bismuth Vanadate Photoanodes

ABSTRACT Due to poor carrier migration and sluggish water oxidation kinetics, bismuth vanadate (BiVO 4 ) photoanodes show limited photoelectrochemical (PEC) performance and stability. Coupling a hole‐selective layer (HSL) can mitigate these issues. Here, we construct an organic‐inorganic hybrid HSL by combining a self‐assembled monolayer (Me‐4PACz) with NiO x on BiVO 4 . Through systematic control experiments that decouple the contributions of the individual layers, we quantitatively reveal a genuine synergy between NiO x and Me‐4PACz. NiO x rapidly extracts holes and provides catalytic sites. The Me‐4PACz adopts a vertical, non‐dense orientation, generating a molecular dipole that forms a continuous SAM‐NiO x ‐BiVO 4 energy cascade and lowers the hole transfer barrier. More importantly, we uncover a “local anchoring and remote activation” mechanism: a single Me‐4PACz binds via P–O–Ni to a surface Ni site (passivating a harmful defect), while its electron‐withdrawing effect propagates through the Ni–O–Ni lattice to convert adjacent Ni 2+ into active, defect‑free Ni 3+ sites. The phosphonate group further stabilizes these Ni 3+ centers. The resulting SAM‐NiO x ‐BiVO 4 photoanode achieves a photocurrent density of 6.90 mA cm −2 at 1.23 V versus reversible hydrogen electrode (RHE) and retains stable performance for over 60 h. This work expands SAM applicability in PEC water oxidation and offers a rational design principle for organic–inorganic hybrid photoanodes.

Prediction of chronic obstructive pulmonary disease using machine learning models

Structural Characterization of the Human West Nile Virus Antibody Response 2259814

Abstract Introduction West Nile Virus (WNV) is a mosquito-borne Flavivirus capable of causing febrile and neuroinvasive disease. Rising infection rates and expanding mosquito habitats driven by climate change have increased WNV’s global burden. Current treatment strategies rely largely on vector management, as no licensed vaccines or therapeutics exist. Here, we profile the human antibody response elicited to a subdomain of the WNV Envelope glycoprotein using samples from naturally infected patients. Methods Through structural and biochemical analyses, we defined antibody epitopes, binding poses, and virion engagement patterns associated with neutralizing and cross-reactive antibody responses. Results Two antibodies, W010 and W037, potently neutralize WNV by engaging the lateral ridge epitope on ectodomain III (EDIII), a site that often elicits neutralizing antibodies. Consistent with the limited sequence conservation of this epitope within the Japanese Encephalitis Serocomplex, these mAbs did not exhibit broad neutralization. In contrast, we identified a cross-neutralizing antibody W014, that engages a combination of the lateral ridge and CC’ loop regions of EDIII, leveraging more sequentially conserved motifs. Conclusion Together, these findings delineate structural correlates governing potency and breadth in human WNV antibody responses for the first time, providing a framework for therapeutic antibody development and rational vaccine design. Funding Source HHMI Emerging Pathogen Initiative Award Topic Categories Vaccines and Immunotherapy (VAC)

Comprehensive and Automated Mouse Immune Profiling with CyTOF Technology Reveals Aging-Associated Alterations in Lymphoid and Pulmonary Tissues 2259224

Abstract Introduction Immunosenescence disrupts surveillance and contributes to age-related diseases, yet its mechanisms remain incompletely understood. Deep immune profiling in mouse models is essential to elucidate age-related modulators of disease. High-parameter cytometry with CyTOF™ technology enables identification of 50-plus markers at the single-cell level, providing exceptional resolution without spectral unmixing or compensation. This study leverages CyTOF technology to characterize aging-associated immune alterations in spleen and lung tissues of aged and young adult mice. Methods Aged (75—76 weeks) and young adult (6—8 weeks) C57BL/6J mice were evaluated. Spleen and lung tissues were processed and stained using the 33-antibody Maxpar™ OnDemand Mouse Immune Profiling Panel Kit for spleen and an expanded customized 50-parameter panel for lung. Live-cell CD45 barcoding enabled pooled sample analysis. Data was acquired on a Helios™ CyTOF instrument and analyzed using Maxpar Pathsetter software for automated identification of 38 splenic and 55 pulmonary immune subsets. Results In spleen, aged mice showed reduced frequencies of CD4 and CD8 T cells, NK cells and γδ T cells, with increased PD-1+ T cells and B cells. NK cell maturation was impaired, with altered expression of PD-L1, CD11c and CD49b. In lungs, aged mice exhibited higher frequencies of exhausted CD8 T cells (PD-1+TIM-3+), cytotoxic T cells (granzyme B+) and monocyte-derived dendritic cells, alongside a pro-inflammatory alveolar macrophage phenotype. Overall, 26 splenic and 28 pulmonary subsets showed significant age-related differences. Conclusion This study demonstrates the power of CyTOF immune profiling with automated analysis to uncover aging-associated immune alterations. The Mouse Immune Profiling Panel and Maxpar Pathsetter software provide a scalable and reproducible solution for deep phenotyping in mouse models, facilitating mechanistic insights into immunosenescence and supporting translational research in aging and immune modulation. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

The Impact of Neutrophils on the Resolution of Post-Surgical Pain 2306258

Abstract Introduction It is well established that the immune system contributes to the development of chronic pain, however the intricacies of how the immune system, specifically neutrophils, could also aid in the resolution of pain remains elusive. The aim of this study is to investigate the role of neutrophils on post-surgical pain resolution and gain a better understanding of how they interact with and influence other immune cells to mediate post-surgical pain. Methods By employing a well-established surgical injury model via plantar incision, we investigated the impact of depleting neutrophils on pain sensitivity following surgery, as well as the effect on the immune response. To deplete neutrophils systemically, α-Ly6G was injected intraperitoneally every three days following injury. Mechanical pain was assessed using the von Frey method over the course of two weeks. After surgical injury, the incised skin was collected and processed for the following biological assays: cytokine array, toluidine blue staining, and flow cytometry. Results We validated the efficacy of α-Ly6G injections to deplete neutrophils in the blood and in the skin using flow cytometry. Neutrophil depleted mice showed prolonged pain following surgical incision compared to the control group. In addition, the neutrophil depleted mice have altered cytokine expression with a notable increase in IL-4, a cytokine primarily released by mast cells, and increased mast cell presence and degranulation in the incised skin. Conclusion We have found that neutrophils play a crucial role in the transition from acute to chronic pain. This transition may be mediated by mast cell activity in the paw skin. The presence of neutrophils could be essential to preventing excessive mast cell activity and preventing prolonged pain following surgical injury. Funding Source NIH and DOD Topic Categories Neuroimmunology (NEUR)

Neutrophil—endothelial crosstalk after skin UV exposure orchestrates renal repair in health but drives profibrotic remodeling in lupus 2258618

Abstract Introduction Neutrophils can remigrate from UV-exposed skin to the kidney, but how they instruct renal structural cells is unclear. We tested whether tissue context, healthy vs lupus-like, programs neutrophil—endothelial interactions and phenotypes that tip the skin—kidney axis toward repair or inflammation. Methods Female B6 mice received one UVB dose (500 mJ/cm²). Kidneys and enriched neutrophils underwent 10x scRNA-seq at baseline and day 2. Renal neutrophils in B6 and MRL-lpr mice were profiled by flow cytometry; neutrophils were depleted with anti-Ly6G. Human studies used Visium on LN biopsies and DNA-methylation of urine cells. Results In B6 mice, UV expanded a glomerular endothelial cluster which upregulated angiogenesis/vascular-development transcriptional programs. UV-recruited neutrophils upregulated pro-angiogenic programs and neutrophil depletion blunted renal angiogenic and wound-healing signatures. Ligand—receptor analysis identified Cd177—Pecam1 as a key neutrophil—endothelial interaction. In lupus-like kidneys, UV induced TGFβ/Wnt pathways, which were suppressed with neutrophil depletion. Flow cytometry showed expansion of SiglecF+ neutrophils and loss of inhibitory receptor CD371 (Clec12a) in lupus conditions. Conversely, B6 renal neutrophils upregulated CXCR4 and CD371, consistent with a regulatory/repair phenotype. In lupus nephritis (LN) biopsies, active skin disease was associated with increased renal neutrophil signatures and increased angiogenesis and fibrosis pathway scores in neutrophil-rich regions. Moreover, urinaryl neutrophils were higher in lupus patients with active skin disease. Conclusion Acute UV mobilizes neutrophils that engage renal endothelium, eliciting pro-angiogenic remodeling in health. In lupus-like kidneys, this crosstalk is reprogrammed toward profibrotic/inflammatory signaling. These findings define a UV-driven skin-kidney axis and identify neutrophil checkpoints and endothelial contacts which may be implicated in renal injury in lupus. Funding Source CDMRP Lupus Research Program, NIGMS P20GM130454 Topic Categories Immune Mechanisms of Human Disease (HUM)