Browse Articles

Structurally defined IL-6-like cytokine candidates in bilaterian invertebrates and cnidarians 2306759

Abstract Introduction Type I (4-α-helical bundle) cytokines, including IL-6, are central to vertebrate immunity, but rapid sequence divergence obscures their evolutionary origins and has hindered the identification of homologs in non-vertebrate animals. As core JAK-STAT signaling components are conserved across invertebrates, we hypothesized that, despite extensive loss of primary sequence similarity, a protein with IL-6-like structure and inducible regulation could be conserved across invertebrates. Methods To test this hypothesis, we first screened genomic and transcriptomic resources from bilaterian invertebrates and cnidarians using deep-learning-based structural prediction, defining candidates as ∼200-aa secreted proteins with a predicted 4-helix bundle. We then assessed putative immune function by re-analyzing public RNA-seq datasets from bivalve mollusks (as representative bilaterian invertebrates) and cnidarians challenged with bacteria or subjected to nucleic acid-sensing pathway activation. Results This analysis identified a previously unrecognized family of secreted proteins whose predicted 4-helical bundles align closely with vertebrate IL-6 despite < 20% sequence identity. Transcriptomic meta-analysis revealed robust induction of these IL-6-like genes following immune stimulation in both cnidarians and mollusks. Conclusion Together, our results indicate that type I cytokine-like architectures are more widely distributed across animals than previously appreciated and support an origin predating the Cnidaria-Bilateria split. Funding Source This study was supported by National Institutes of Health Grants R01AI072435 and R35GM122591 Topic Categories Cytokines and Chemokines and their Receptors (CCR)

HSP interaction with individual CD91 ligand binding domains 2255685

Abstract Introduction Heat Shock Proteins (HSPs) are a structurally diverse class of proteins that respond to cellular stress and naturally function to chaperone proteins and peptides throughout the cell. Upon release into the extracellular space, HSPs can act to potentiate immune responses against their chaperoned antigens. HSPs bind the receptor CD91on the surface of antigen presenting cells (APCs) which results in internalization of the HSP+antigen and downstream signaling resulting in APC activation. Interestingly, HSPs that bind CD91 do not share structural homology and result in different patterns of cytokine secretion by APCs following activation. CD91 is comprised of an alpha chain which is responsible for ligand binding and a beta chain which is responsible for signal transduction. Within the alpha chain, 4 separate ligand binding domains have been identified. In these studies, we aim to determine which ligand binding domain(s) are responsible for binding individual HSPs and if differences in binding domain usage promote different patterns of APC activation. Methods To investigate ligand binding, we have expressed individual mini-genes comprised of a single ligand binding domain tethered to the full-length beta chain in multiple cell lines. These mini-gene expressing cell lines will be used in conduction with fluorescently labeled HSPs to assess binding and downstream signaling pathways. Results We have generated minigene constructs spanning the 4 ligand binding domains of the extracellular portion of CD91. These minigenes have been stably expressed in 293T cells and iBMDMs using a lentiviral expression system. We have also subsequently knocked out endogenous CD91 in iBMDM. These cells will be used in binding and competition assays to establish the interaction of various immunogenic HSPs with the respective binding domains of CD91. Conclusion These results will be used to inform and improve HSP based immunotherapeutics. Funding Source NIH Topic Categories Vaccines and Immunotherapy (VAC)

The Surprising Role of SIRPα in T Cell Responses During Acute and Chronic Retroviral Infection 2334984

Abstract Introduction Friend virus infection of mice induces Tregs, facilitating the establishment of chronic infection and CD8+ T cell dysfunction. We reported that splenic FV-specific PD-1+CD8+ T cells expressing SIRPα maintain function, unexpected because SIRPα is an inhibitory myeloid receptor not previously described on T cells. This study further explores the functional capability of SIRPα+ and SIRPα- T cells. Methods Tissues from mice, infected with FV (with naïve controls), were harvested during acute or chronic phase and analyzed by flow cytometry for complex multiparametric immune cell analysis. Liver SIRPα- CD8+ T cells were examined for CTL activity. SIRPα+ and SIRPα- Tregs were compared for suppression. Furthermore, we performed transcriptional profile analysis on these subsets. Results We now demonstrate a more complicated view of SIRPα expression on T cells, discovering that expression on CD8+ T cells is tissue-specific, with expression induced in the spleen but not liver. The SIRPα- T cells from the livers of chronically infected mice are equivalently cytolytic and activated compared to splenic SIRPα+ T cells. In addition, we now demonstrate that SIRPα is expressed on CD4+ Foxp3- T helper and Foxp3+ Tregs during acute infection and identifies cells with distinct functional capabilities. Interestingly, SIRPα expressing T helpers have a unique transcriptional profile and appear to have an increased helper capacity. Additionally, SIRPα+Foxp3+ Tregs exhibit enhanced ability to suppress CD8+ T cell proliferation and are upregulated for multiple activation and chemokine pathways. Conclusion We now show that SIRPα expression, the ligand for CD47 and commonly associated with myeloid cells, occurs on CD8+ and CD4+ T cells in a tissue-specific manner and correlates with distinctive functional capacity. Recently CD47 blockade failed in phase III clinical trials due to increased infection-related deaths, highlighting the need to fully understand this complex immune checkpoint in the context of viral infection. Funding Source Division of Intramural Research, NIAID AI000753 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Boosting Neonatal Immunity: Zymosan-Adjuvanted Intranasal Bivalent Vaccine Shields Against Lethal EV-A71 and EV-D68 Infections 2246328

Abstract Introduction Non-polio enteroviruses, particularly EV-D68 and EV-A71, have emerged as major pediatric threats due to their association with acute flaccid myelitis and high mortality. While intranasal vaccines offer a promising route to block viral entry, their effectiveness is limited by poor induction of protective immunity. Zymosan, a yeast cell wall component, has shown its adjuvant potential in multiple vaccine models. This study aims to develop an effective intranasal vaccine incorporating zymosan to protect against EV-D68 and EV-A71 infections. Methods We first prepared an inactivated EV-D68 vaccine to compare immunogenicity across administration routes. Next, we tested monovalent and bivalent intranasal vaccines with zymosan to assess multi-dose and adjuvant effects. Finally, we evaluated vaccine efficacy in a neonatal mouse model. Results Two doses of inactivated EV-D68 with intranasal priming effectively induced mucosal and systemic immunity. A three-dose regimen further strengthened vaccine-specific immunity, with zymosan amplifying responses in both formulations and enhancing serum neutralization. Serum transfer from the zymosan-adjuvanted triple-vaccinated donors afforded significant protection against both viral challenges. Conclusion These findings demonstrated that combining bivalent antigens with zymosan broadened and enhanced the intranasal vaccine efficacy, providing a promising approach for early-life protection against EV-A71 and EV-D68 infections and advancing nasal spray vaccine strategies. Funding Source National Taiwan University Hospital Topic Categories Vaccines and Immunotherapy (VAC)

A Porous Interfacial Photothermal Layer of Fused Core–Shell Carbon‐Polymer Nanospheres for Directional Salt Crystallization and Zero‐Liquid‐Discharge (Adv. Mater. 43/2026)

Correction to “Mitochondria‐Targeted Nanomotor: H ₂ S‐Driven Cascade Therapy for Hepatocellular Carcinoma”

Prophylactic use of episil oral liquid to prevent oral mucositis during head and neck concurrent chemoradiotherapy: a prospective single-arm study

Abstract Episil oral liquid (episil) has been reported to relieve pain caused by oral mucositis (OM) in cancer patients undergoing chemotherapy and/or radiotherapy. However, its prophylactic use during head and neck concurrent chemoradiotherapy (HN-CCRT) has not yet been evaluated. Based on the known mechanisms of OM progression, we hypothesized that prophylactic use of episil would be more effective than therapeutic use. This study aimed to evaluate the effect of prophylactic episil use on OM during HN-CCRT. This was a prospective, single arm observation study including 22 patients with head and neck cancer who underwent HN-CCRT between 2019 and 2020. Patients received episil prophylactically from the start of treatment. OM pain intensity was assessed using an 11-point numerical rating scale (NRS), and OM severity was graded using the WHO scale. Based on prior studies, the pain score threshold and expected value were set at 5.68 and 3.90, respectively. The highest mean NRS pain score during treatment was 2.73. Grade 3 OM occurred in 13.6% of patients. No patients required treatment interruption or modification due to OM, and all completed prophylactic episil use throughout HN-CCRT. Prophylactic use of episil may be associated with a favorable profile in reducing oral pain and preventing severe OM during HN-CCRT. These findings suggest the potential benefit of the strong, long-lasting bioadhesive barrier formed by episil in potentially preventing the exacerbation of OM due to mucosal infection and trauma.

Immune responses to ORF2-based vaccination and experimental porcine circovirus type 3 challenge in cesarean-derived, colostrum-deprived pigs 2309059

Abstract Introduction PCV3 is a pathogenic member of the family Circoviridae infecting pigs. PCV3-associated disease has been linked to reproductive failure, wasting syndromes, and multisystemic inflammation, although subclinical infections are often reported. Despite global detection, limited experimental studies have hindered comprehensive characterization of PCV3 pathogenesis and host immune responses. Methods Eight-week-old CDCD pigs were intramuscularly vaccinated and boosted with 150 µg of recombinant PCV3 ORF2 protein formulated with 18% (v/v) Emulsigen D and subsequently challenged with 133.33 µg PCV3 via intramuscular (IM) or intranasal (IN) routes. Treatment groups (n = 6/group) included vaccinated or sham-vaccinated pigs subjected to homologous sham or PCV3 challenge by either route. Serum, oral fluids, fecal (FS) and nasal swabs (NS), and PBMCs were collected longitudinally and analyzed by RT-qPCR, ELISA, and flow cytometry. Results No clinical signs were observed throughout the study. Inoculation route and vaccination status significantly influenced the temporal dynamics of PCV3 viremia and viral shedding. IM challenge resulted in earlier, higher viral loads compared with IN challenge, which showed a gradual increase over time. Vaccination prevented viral shedding in FS and NS but only delayed and reduced viremia. Vaccinated pigs developed PCV3-specific IgG prior to challenge, with higher post-challenge levels observed following IN exposure. In contrast, sham-vaccinated challenged pigs exhibited impaired humoral responses. Immune cell profiling revealed a robust early IFN-γ response that was attenuated in vaccinated groups and followed by an increase in regulatory T cells. Conclusion Subclinical PCV3 infection was associated with prolonged viremia. Characterization of a prototype ORF2-based vaccine demonstrated enhanced IgG response, modulation of inflammatory cytokine responses, and prevention of viral shedding, providing insight into PCV3 immunobiology and informing future vaccine development strategies. Funding Source n/a Topic Categories Veterinary and Comparative Immunology (VET)

AXL drives regulatory cDC1 maturation to control CD8 T cell contraction during severe influenza recovery 2267518

Abstract Introduction Axl-dependent activation of XCR1+ cDC (cDC1) leads to regulatory maturation of cDC1 (mregDC1). After IAV infection, mature cDC1 dampen CD8 T cell function, however it is unknown whether this process is Axl-dependent. Methods We generated a mouse strain with a conditional deletion of Axl on Zbtb46-expressing cells (zDC-Axl). The transcriptome of cDC1 was analyzed by scRNA-seq. cDC1 phenotype, apoptotic cell acquisition, and cytokine production was analyzed by flow cytometry. Results Compared to naïve or infected lungs, the transcriptome of cDC1 from lungs in the resolution of IAV infection uniquely upregulates Actn1, Arg2 and Elmo1, genes associated with engulfment and processing of apoptotic cells (AC). The absence of Axl in cDCs resulted in diminished AC engulfment and the loss of PD-L1 and PD-L2 expression on cDC1. In vivo, transfer of Axl-deficient cDC1 failed to reduce the number of effector CD8 T cells. To test the function of Axl-deficient cDC1 in vitro, we sorted cDC1 from the lungs of infected mice in the resolution phase of infection and set up co-cultures with OT-I cells. Compared to WT cDC1, the Axl-/- cDC1 failed to inhibit the production of effector cytokines IFN and Granzyme B, both in effector and naïve OT-I cells. Conclusion Overall, our data show that Axl is required for the acquisition of AC and differentiation and function of mature regulatory cDC1 during the recovery phase of IAV infection. Funding Source N/A Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis 2308923

Abstract Introduction Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron loss and eventual paralysis. While autoimmune mechanisms have long been suspected to contribute to ALS pathology, disease-associated antigen targets have remained elusive. Methods We analyzed if ALS was associated with increased autoreactive T cell responses towards TDP-43, SOD1, and C9orf72, compared to healthy controls. Peptide megapools consisting of 15 amino acid peptides overlapping by 10 residues spanning the entire sequence was synthesized for each protein. Fluorospot assays were used to measure T cell responses to the peptide pools by measuring release of interferon-γ (IFNγ), interleukins 5 (IL-5) and 10 (IL-10). Results We demonstrate that the ALS-associated protein C9orf72 is a major antigenic target in ALS. Epitope mapping revealed multiple immunogenic regions across the C9orf72 protein. While the reactivity was found broadly in ALS subjects, the responses were particularly high ALS donors who carried the C9orf72 hexanucleotide repeat expansion mutation in the non-coding regions of the gene. Importantly, IL-10-mediated responses were significantly higher in individuals with longer predicted survival, suggesting a regulatory and potentially protective influence on disease progression. Conclusion Together, these findings identify the first defined target of autoreactive T cell responses in ALS, and support the hypothesis that disease trajectory is in part shaped by the balance of inflammatory and counter-inflammatory T cell activity. Funding Source Supported by LJI & Kyowa Kirin, Inc. (KKNA- Kyowa Kirin North America), the Swedish Research Council (salary for E.J., grant references 2024-00175), the Freedom Together Foundation (to D.S.), and in part by the Intramural Research Program, NINDS, NIH (A. Topic Categories Neuroimmunology (NEUR)

Unraveling the Immunopathology of Infection-Associated Chronic Illnesses: Sex Differences and Predictive Diagnostics 2267580

Abstract Introduction Infection-associated chronic illnesses (IACI) following Borrelia burgdorferi (Bb) or SARS-CoV2 infection lack objective diagnostics and can induce a multitude of co-morbid conditions including connective tissue disorders which were previously considered to be genetic. We hypothesize that host immune polarization dictates pathology. We employ a translational approach, combining a novel long-term murine model of Bb infection with the deeply phenotyped MAESTRO human IACI cohort to dissect these immunopathologies. Methods We established a 2-year Bb infection model in C3H and BL/6 mice, quantifying joint hypermobility. Novel label-free 3D metabolic imaging visualized the host-pathogen interface in situ. In the parallel MAESTRO clinical study, human IACI patients underwent multi-modal phenotyping including neurocognitive assessments, hypermobility assessments, incorporated with survey data and deep biological sample profiling. Results Long-term Bb infection induced systemic hypermobility only in C3H mice, driven by a maladaptive, mast cell-dominant response causing targeted degradation of Type II collagen. This links an allergic process to tissue damage. In tolerant B6 mice, a macrophage-dominant response drove Bb into an extremely elongated morphology as a novel immune evasion strategy. The MAESTRO cohort mirrors these findings, revealing patient endotypes with mast cell activation, hypermobility, neuroinflammation, and reproductive immunology dysfunction. Conclusion Host immune polarization dictates chronic illness trajectories associated with infection. A maladaptive, mast cell-driven allergic response can directly induce a systemic connective tissue disorder even in the absence of genetic risk factors typically associated with such diseases, offering a new paradigm for infection-induced hypermobility. This work mechanistically links diverse IACI symptoms and supports a therapeutic shift of targeted immunomodulation. Funding Source Emily and Malcolm Fairbairn, MLSC, NIH NIAID RO1 AI 178713-01 Topic Categories Immune Mechanisms of Human Disease (HUM)

Bronchiectasis in Myasthenia Gravis: A Clinically Relevant Comorbidity Defining a High-Risk Triad with Thymoma 2307376

Abstract Introduction Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction, leads to fluctuating muscle weakness, may involve respiratory muscles, and may progress to myasthenic crisis. Bronchiectasis (BE), a chronic airway disease with a prevalence of 234/100,000 in Israel, is described in association with thymic tumors. Its prevalence and clinical relevance in MG remain undefined. Methods We retrospectively studied 238 patients with MG. Demographic, clinical, and immunological data were collected, and BE was confirmed by high-resolution chest CT. A comparison group of 111 patients with thymoma but without MG was evaluated for BE prevalence. Group comparisons were performed using Fisher’s exact test. Logistic regression was used to assess the independent and combined effects of MG and thymoma on BE risk, including interaction analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to quantify associations. Results BE was more frequent in patients with both MG and thymoma (19.6%) compared to MG without thymoma (5.9%, OR 3.9, 95% CI 1.6—9.8, p = 0.0047), thymoma without MG (3.6%, OR 6.5, 95% CI 1.9—22, p = 0.0016), and the general population (0.23%). ORs for BE were significantly elevated in all subgroups compared to the general population: 104.0 (95% CI 51.5—210.0, p = 7.2 × 10⁻17), 26.6 (95% CI 14.3—49.7, p = 1.9 × 10⁻¹²), and 15.9 (95% CI 5.8—43.6, p = 1.5 × 10-4), respectively. MG and thymoma were independently associated with BE, but a negative interaction term (β = —1.41, p = 0.043) suggested overlapping mechanisms. BE was associated with increased risk of myasthenic crisis (30.4% vs. 6.7%, OR = 6.1, p = 0.0017), especially in the presence of thymoma (60% vs. 8.3%, OR = 16.5, p = 0.020). Conclusion Bronchiectasis is an underrecognized but clinically relevant comorbidity in MG, particularly with thymoma, forming a triad associated with a high-risk disease phenotype. Its presence may reflect an autoimmune-mediated form of BE linked to the MG-thymoma spectrum. Funding Source There is no funding for this project Topic Categories Immune Mechanisms of Human Disease (HUM)

Systems immunology approach to mapping malaria disease trajectory identifies conserved gene modules associated with severity 2255965

Abstract Introduction Malaria manifests in a spectrum of clinical outcomes shaped by the complex heterogeneity of both the human host and the Plasmodium parasite, its causative agent. This dynamic and multifactorial host—parasite interaction poses major challenges for effective diagnostics, leading to fragmented observations that hinder the generalizability of findings, and consequently, clinical translation. We hypothesized that a conserved immune response underlies malaria disease trajectories and diverges across patient outcomes. Methods We conducted the largest multicohort analysis of the host transcriptional response to malaria, integrating >3,600 blood transcriptomes from 42 cohorts across 20 countries on six continents spanning children and adults with diverse clinical presentations. Using TIDEPOOL (Trajectory Inference for Disease Endotyping from Pooled data), we applied trajectory modeling to resolve gene modules associated with protective versus detrimental responses, delineating the transcriptional continuum from asymptomatic to severe malaria. Results We identified a robust 208-gene blood signature that distinguishes malaria-infected individuals from uninfected controls (AUROC = 0.875, validation cohort), providing a generalizable framework for molecular diagnosis. TIDEPOOL found that severe malaria was defined by a blood transcriptional program marked by expansion of granulocytes, neutrophils, and monocytes, coupled with depletion of eosinophils, NK cells, B cells, and T cells–reflecting broad immune dysregulation. Within severe cases, we resolved a novel conserved gene signature diagnostic of cerebral malaria. These signatures were consistent across age groups, geographic regions, and parasite strains, underscoring universal host responses to Plasmodium infection. Conclusion Together, our findings reveal a unified framework linking immune dynamics to clinical severity and offer actionable biomarkers to guide next-generation diagnostic and host-targeted therapeutic strategies for malaria elimination. Funding Source Gate Foundation, NIAID Topic Categories Computational and Systems Immunology (COMP)

Host HLA Allelic Variation Shapes Risk of Severe SARS-CoV-2 Infection and Long COVID 2310004

Abstract Introduction We investigated the relationship between imputed human leukocyte antigen (HLA) alleles to COVID-19 clinical severity within the NIH funded All of Us dataset, which integrates electronic health records and genomic sequences of enrolled participants. Methods The base population was defined as any participant who had been administered a SARS-CoV-2 test and provided genomic sequencing data (n = 113,015). Cohorts were refined by COVID-19 conditions: (1) a positive COVID-19 test (n = 20,872), (2) a negative COVID-19 test (n = 88,680), (3) both a positive test and an ICD-10 diagnosis code for pneumonia due to COVID-19 or lower respiratory infection caused by SARS-CoV-2 (n = 1,079), (4) a positive test and a diagnosis code for Long COVID (n = 509), and (5) ONLY and at least 3 positive COVID-19 tests (n = 1,298), and (6) ONLY and at least 3 negative COVID-19 tests (n = 4,884). HLA Class I and Class II allele imputation utilized a global diversity reference panel utilizing the HIBAG “R” package with a median posterior probability rate greater than 92.7% for the 6 HLA alleles. Results Through this approach, we found several alleles significantly associated with protection from and increased risk of severe COVID-19 infection. Conclusion Our findings expand the limited clinical research on the role of HLA haplotypes in the response to SARS-CoV-2, underscoring the usefulness of large, multi-ancestral clinical and molecular datasets in generating testable hypotheses that have potentially significant clinical applications Funding Source NCATS T32, grant number 1T32TR004767-0 and LA CaTS, grant number U54 GM104940, LSUHSC Medical Student Research Enhancement Program Topic Categories Translational and Interventional Immunology (TI)

Nanobody-based Tools for in-depth Research of Immuno-Oncology Targets 2334607

Abstract Introduction Immuno-oncology is a rapidly growing field with an urgent need for well-characterized and highly specific research reagents, particularly in immune checkpoint targeting and acute myeloid leukemia (AML). We have developed recombinant monoclonal nanobodies (VHHs) targeting these critical areas to facilitate research with minimal artifacts and to support the development of new drug candidates. This work addresses current challenges in the field by providing tools that enhance the specificity and reliability of research outcomes. Methods Based on our extensive experience in the field of nanobodies, we have developed VHHs that bind to key immune checkpoint proteins, including TIGIT, TIM3, LAG3, PD1, PD-L1 and CTLA4. Additionally, we have generated VHHs specific to AML typic targets, such as MSLN and FLT3. Each candidate was characterized regarding its affinity, specificity and bound epitope across different applications, including flow cytometry, immunofluorescence or live-cell imaging. Results n/a Conclusion VHHs offer several advantages over conventional antibodies: Their unique structure allows VHHs to bind epitopes different from conventional antibodies. Their monoclonal monovalent nature prevents cross-linking of target proteins, minimizing unwanted side effects such as rapid receptor internalization or activation of intracellular signaling cascades. The absence of an Fc region provides flexibility in combining VHHs with other primary and secondary antibody reagents, while also preventing unwanted Fc signaling, even during extended experiments. Directed and precise labeling with dyes allows quantification of the bound target molecules. Funding Source n/a Topic Categories Technological Innovations in Immunology (TECH)

Physics‐Driven 3D Structural Prediction and Transport Kinetics of Porous Carbons via Random Field and Phase‐Field Evolution

ABSTRACT The complex pore topology of hierarchical porous carbons constrains energy transport, yet conventional research relies on homogenized scalar descriptions, treating pore evolution as a black box. To overcome 3D characterization limits, this study establishes an integrated R&D framework coupling bidirectional performance prediction with physics‐driven 3D structural prediction. A high‐precision bidirectional mapping model ( R 2 = 0.8595) was constructed using CatBoost and differential evolution (DE) to enable target‐oriented inverse optimization. In the structural dimension, we developed a synergistic algorithm combining Gaussian random fields (GRF) and Cahn–Hilliard (C─H) phase‐field dynamics to dynamically predict authentic 3D topologies by simulating interfacial energy‐driven pore evolution. Findings reveal that global connectivity is achieved at a total porosity of 0.46, with specific critical thresholds of 0.15, 0.25, and 0.35 for micro‐, meso‐, and macropores, respectively. By integrating particle tracking, the study identifies transport hotspots contributing 80% of the total flux and calibrates a non‐Darcy kinetic scaling law (exponent n = 1.6357), highlighting mesopores' role in alleviating kinetic bottlenecks. Experimental validation confirms that the inverse‐optimized conditions accurately meet performance targets (error 3.2%–7.4%), while the 3D structural prediction model achieves high‐fidelity restoration of experimental morphologies. This work provides a robust physics‐driven paradigm for transitioning from empirical trial‐and‐error to intelligent, target‐oriented 3D structural prediction and design.

Lanthanide‐Bridged Dual‐Atom Catalysts for Efficient Chlorine Electrosynthesis

ABSTRACT The electrocatalytic chlorine evolution reaction (CER) is central to chlor‐alkali industries and water treatment, yet its practical deployment is still constrained by high energy demands and insufficient selectivity. Here, we report a “mortise‐and‐tenon” strategy using a tulip‐shaped covalent organic framework (Tu‐COF) precursor to construct heteronuclear Ru‐Ln dual‐atom catalysts (Ln = La, Ce, Pr). The pre‐organized micropores of Tu‐COF serve as atomic‐scale nanoreactors, enabling precise confinement and pairing of Ru and lanthanide atoms. Among them, Ru‐Ce delivers outstanding CER performance, achieving 150 mA cm −2 at 1.45 V versus RHE with nearly 100% Faradaic efficiency for Cl 2 evolution and over 500 h stability in a flow cell. Mechanistic studies identify the in situ formed RuCeCl‐N 6 motif as the active site. Density functional theory calculations reveal that adjacent Ce modulates the Ru center's d‐band structure and charge distribution, enhancing initial Cl adsorption on RuCe‐N 6 while optimizing subsequent Cl adsorption on RuCeCl‐N 6 . This lowers the free‐energy barrier for Cl–Cl coupling and suppresses competing OOH * formation, thereby accelerating CER kinetics and intrinsically improving activity and selectivity. This work offers a generalizable strategy for heteronuclear DAC construction and highlights lanthanide‐mediated electronic engineering as a powerful approach to electrocatalyst design.

Fault-controlled reservoir compartmentalization as a control on CO2 storage potential in Jurassic Safa reservoirs, Obaiyed Field, Western Desert, Egypt

Abstract Geological carbon storage in mature hydrocarbon fields requires careful evaluation of reservoir architecture, fault-controlled compartmentalization, and sealing integrity to ensure long-term containment of injected CO 2 . This study presents an integrated geological assessment of the CO 2 storage potential of the Jurassic Safa reservoirs in the Obaiyed Field, located within the Shushan Basin of Egypt’s Western Desert. The primary objective is to evaluate how structural segmentation and reservoir heterogeneity influence storage capacity and containment behavior in a deeply buried tight sandstone system. The study integrates seismic interpretation, well-log–based petrophysical analysis, core-derived permeability measurements, fault seal evaluation, and three-dimensional static geological modeling to characterize reservoir geometry, petrophysical variability, and structural compartmentalization. Results indicate that the Lower Safa Member represents a heterogeneous tight sandstone reservoir with effective porosity ranging approximately from 8 to 18% and permeability values spanning more than one order of magnitude. Porosity–permeability relationships derived from core measurements confirm significant reservoir heterogeneity and limited flow capacity typical of deeply buried clastic systems. Structural interpretation reveals pronounced fault-bounded compartmentalization that restricts lateral connectivity and promotes pressure partitioning within individual reservoir segments. Although storage capacity within individual compartments is modest, the cumulative storage potential of multiple structurally isolated compartments may provide a substantially larger field-scale storage resource. These findings highlight the potential of structurally segmented Jurassic reservoirs in the Western Desert to serve as viable candidates for geological CO 2 storage and demonstrate the suitability of integrated geological screening for evaluating structurally compartmentalized reservoirs as potential CO 2 storage sites.

The generation of abundant inducible pluripotent stem cell derived immunoregulatory dendritic cells to promote antigen-specific immune regulation 2255471

Abstract Introduction Dendritic cells are a rare lineage, consisting of cDC1, cDC2, and the scarce (< 0.3% of blood) DC3. Uniquely, DC3s share monocyte and cDC2 features, marked by co-expression of CD1c and CD14. They promote Th1 and Th17 cells, associate with autoimmunity, and induce CD8+CD103+ tissue-resident memory T-cells that may exacerbate disease. Contrarily, DC3s can be immunosuppressive in a tumor microenvironment. This duality could provide an immunotherapy platform if sufficient-numbers can be obtained. Methods HSPCs were generated from iPSCs via embryoid bodies; HSPCs were cultured for 2 weeks on murine MS5 stromal cells with SCF, FLT3L, and ascorbic acid. To induce regulatory iDC3s (iDC3regs), CD1c+ isolated cells were treated for 24hrs with CHIR99021 (Wnt agonist), L-kyneurine, retinoic acid and IFNγ, IL-10, and/or TGFβ (γ10β), the latter tested alone and in combination. Suppressive function was measured via AlloMLRs. Results iDC3s emerged with a fold-increase of 1096±123 iDC3s per iPSC in 4 maturation states: CD45RA+CD14- (immature), CD45RA-CD14-, CD45RA-CD14+ CD163-, and CD14+CD163 + (mature). Isolated CD1c+ iDC3s cultured with GM-CSF, known to support DC3s, not FLT3L, gradually promoted maturation to a CD14+CD163+ over 3 days. γ10β-iDC3regs were most suppressive, mediated through PDL1 and IDO1. Interestingly, γ10β rapidly induced two states: CD14+CD163- and CD14+CD163+ that resisted inflammatory exposure (TNF+/IL1β/PGE2, LPS, CpG, R848, or GMCSF/IL4). Bulk RNA-seq of these populations is underway to define the regulatory profile and to compare public DC3 datasets. Studies in humanized mouse graft-versus-host disease models will test iDC3regs in vivo regulatory capacity; Studies examining tumor antigen-loaded and activated iDC3s will test their anti-tumor potential. Conclusion We demonstrate efficient generation of iDC3s, define their developmental trajectory, and regulatory potential. These findings reveal how DC3s operate across disease contexts. Funding Source Kidz1stFund, P01CA065493-28 Topic Categories Transplantation Immunology (TRAN)

ILC3s Possess Microbiota-Inducible Acute Wound Healing Potential 2299679

Abstract Introduction Commensal bacteria are key mediators of intestinal inflammation, yet distinguishing beneficial species from potential pathobionts remains challenging. Identification and characterization of human gut commensals could provide insights to design therapeutics to attenuate and heal mucosal inflammation. Methods To identify protective human gut commensals, we collected stool from healthy human donors and colonized germ-free (GF) mice. We used antibiotic depletion to enrich for subsets of bacteria and assessed inflammatory and protective potential in DSS-induced colitis and IL-10KO models. Candidate wound-healing stimulators were isolated and examined in vitro and in vivo. Results GF mice colonized with a human microbiome showed strong protection from lethal DSS challenge, whereas all GF controls succumbed by day 12. These gavaged mice exhibited increased IL-22 production from ILC3s. However, the same human microbiota triggered robust IFNy+, IL-17A+, and IFNy/IL-17A+ CD4+ T cells in IL-10KO mice. Antibiotic treatment reduced bacterial diversity but maintained high IL-22 production and full protection from DSS. Cecal contents from these antibiotic-treated mice did not induce pro-inflammatory T cells in IL-10KO recipients, suggesting enrichment of protective species. From this limited community we isolated Klebsiella oxytoca, which when monocolonized in GF mice conferred strong protection from DSS, reduced histologic damage, and enhanced crypt proliferation. Using mice lacking IL-1R1 and/or IL-23R specifically on ILC3s, we found that K. oxytoca primarily signals through IL-1R1 to induce IL-22 from ILC3s. Conclusion These findings identify K. oxytoca as a human commensal that potently stimulates ILC3-depedent IL-22 to limit intestinal injury and promote epithelial regeneration. Ongoing work is testing its therapeutic potential in radiation-induced enteritis and screening additional human derived bacterial candidates for wound healing activity using an in-vitro screening system. Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)