Browse Articles

Linking multi-barrier permeability with cognitive dysfunction in Borrelia infection-associated chronic illness 2257467

Abstract Introduction Infection-Associated Chronic Illnesses (IACI), such as Post-Treatment Lyme Disease (PTLD), are a significant public health crisis. Despite antibiotic treatment, at least 10% of patients develop debilitating, long-term symptoms like severe cognitive dysfunction, or “brain fog”. Progress in understanding and treating IACI is hindered by a critical lack of objective, mechanism-based biomarkers for diagnosis and predicting disease course. The current diagnostic model, relying on symptom-based criteria, is often inadequate. Our central hypothesis is that a breakdown in the body’s barriers is a foundational mechanism in IACI that drives systemic inflammation and neurocognitive dysfunction. Methods We analyzed preliminary data from the MAESTRO study, assessing human PTLD patients across cognitive tasks involving processing speed and oculomotor control. We measured plasma biomarkers for neural injury, astrogliosis, and multi-barrier disruption. This was complemented by an animal model of Lyme disease in C3H mice. In the animal model, we used an Evan’s blue dye assay to visualize gut barrier permeability and observed mouse behavior. Results Individuals with PTLD demonstrated measurable cognitive deficits that co-occurred with elevated plasma levels of biomarkers for neural injury (NfL), astrogliosis (GFAP), and multi-barrier disruption (occludin, sCD14). This link was supported by our animal model, in which infected C3H mice showed severe gut barrier compromise. Additionally, infected mice displayed a profound “frozen,” immobile behavior, providing a compelling animal correlate for the functional decline and malaise experienced by human patients. Conclusion Our findings suggest that therapies aimed at restoring barrier function could have broad utility for patients. These approaches should be investigated for their potential impact on some of the most debilitating IACI symptoms, including impaired neurocognitive function. Funding Source Emily and Malcolm Fairbairn donor advised fund, Massachusetts life sciences, NIH NIAID RO1 AI 178713-01 Topic Categories Immune Mechanisms of Human Disease (HUM)

High-Throughput Proteomic Profiling of Hepatocyte Response to Oncologic Compounds for Toxicity and Immune Risk Prediction in Drug Development 2259796

Abstract Introduction The clinical success of immune modulatory compounds is inevitably accompanied by new risks of toxicity. Even well established therapies such as corticosteroids can result in paradoxical liver inflammation when delivered systemically, whereas immune checkpoint inhibitor therapy can result in a range of immune-related adverse events (irAEs), including rare but fatal myocarditis. The development of new immune modulating therapies requires scalable strategies for early toxicity screening. We previously leveraged the Nomic platform, capable of absolute quantification of 1000 proteins in high-throughput and low cost, to identify ∼500 compounds limiting adipocyte inflammation. Here, we leveraged Nomic’s Omni 1000 to capture potential toxicities. Methods Cell cultures of human hepatocytes or cardiomyocytes were treated with 510 bioactive compounds at 3 doses; after 48h, supernatants were collected and 1000 proteins were quantified. Results Consistent with clinical observations, corticosteroids such as methylprednisolone displayed anti-inflammatory properties, while paradoxically increasing the expression of pro-inflammatory SAA and IL-6 in hepatocytes. Cytotoxic compounds were characterized by the release of normally intracellular proteins (ex: GAPDH, MAPK3, IRF3, etc.) into the supernatant, including PHA-793887, a CDK inhibitor that led to fatal liver failures due to toxic effects that went undetected pre-clinically, but were captured here. Mechanistic information was also captured: for example, cycloheximide, an inhibitor of protein synthesis, resulted in reduced levels of hundreds of proteins, and so-called “superinduction” of IL-6, at low doses; at high doses, widespread cell death occurred. Conclusion This ability of high-plex proteomics to distinguish bioactivity from toxicity enabled us to discern anti-inflammatory compounds with acceptable toxicity profiles from compounds with severe toxicity risks, highlighting its value for the development of new immunomodulatory therapies. Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)

Single-cell buoyant mass reveals CD8+ T-cell fitness and predicts melanoma checkpoint response 2251212

Abstract Introduction Reliable, label-free evaluations of systemic T-cell fitness are lacking. Most biomarkers are tumor-intrinsic (e.g., TMB, PD-L1) or rely on molecular readouts (gene expression, cytokines) that provide only partial insight into a T cell’s integrated functional potential. We hypothesized that an intrinsic physical property of resting CD8+ T cells could integrate composition and state to reveal functional heterogeneity. We therefore asked whether single-cell buoyant mass can resolve hidden CD8+ states and predict response to immune checkpoint blockade (ICB) in a clinical study. Methods We engineered a live-cell, label-free SMR microfluidic sorter and paired it with transcriptomic/proteomic profiling. Ex vivo functional assays quantified proliferation, memory re-expression, and exhaustion propensity. In a neoadjuvant melanoma cohort, we profiled pre-treatment circulating CD8+ T cells and computed two features: mean heavy-cell mass and fraction of heavy cells. Results Resting CD8+ T cells showed a bimodal buoyant-mass distribution of light and heavy populations. Heavy cells were biosynthetically primed, expanded faster, re-expressed CD62L more readily, and resisted exhaustion; light cells accumulated mitochondrial mass, proliferated more slowly, and exhausted earlier after delayed activation. In a neoadjuvant melanoma cohort, pre-treatment heavy-cell metrics predicted pathologic response to checkpoint blockade and outperformed tumor mutational burden. Predictive information resided in subtle heavy-population shifts captured by SMR. Conclusion Buoyant mass resolves hidden T-cell heterogeneity and provides an integrated, stimulation-independent biomarker of systemic immune fitness. This fast, label-free readout supports patient stratification and broader immunotherapy applications. As the first/lead author, I will present these findings and the translational path to a clinical diagnostic. Funding Source D.K. Ludwig Fund for Cancer Research, MIT Center for Precision Cancer Medicine, and Stand Up to Cancer Convergence Program 3.1416. Topic Categories Translational and Interventional Immunology (TI)

MHC-II polymorphisms regulate non-cognate negative selection of CD4 T cell orchestrators of type-1 diabetes 2267361

Abstract Introduction T cell-mediated autoimmune diseases, such as type-1 diabetes (T1D), occur when breaks in tolerance mechanisms allow lymphocytes to target healthy tissue. The strongest genetic linkage for T1D susceptibility results from the homozygous expression of MHC-II alleles carrying particular β-chain polymorphisms. Why heterozygous expression of these MHC-II alleles does not confer a similar predisposition remains unresolved. Methods NOD mice were generated carrying I-Ag7 β-chain 56/57 with a Pro-Asp, I-Ag7-PD, sequence, as well as I-Ag7-deficient, I-Ag7-null, mice. We tracked T1D development and characterized islet infiltrates from MHCII homozygous, hemizygous and heterozygous NOD mice. Additionally, we probed the thymic development and peripheral expansion of the β-islet specific T cell repertoire utilizing tetramers for known MHCII and MHCI epitopes. Results MHCII homozygous, I-Ag7-WT/WT, and hemizygous, I-Ag7-WT/null, developed T1D, while dominant protection occurred in heterozygous I-Ag7-PD/WT NOD mice. Islet infiltrates of protected mice showed reduced CXCR6+ CD4 T cells and a loss in CD8 T cells. Thymic analysis showed a loss in high-affinity β-islet specific cells and correlated with decreased CD4SP development beginning at the DP stage. Surprisingly, protective I-Ag7-PD molecule are less efficient at presenting cognate islet autoantigens, do not prime β-islet specific CD4 T cells in vivo nor elicit increased allogeneic responses. However, I-Ag7-PD activates increasing numbers of DP thymocytes compared to I-Ag7-WT. Expansions of islet-specific CD4 T cells occur in all I-Ag7-WT bearing mice, yet only CXCR6+ cells emerge in T1D susceptible mice. Adoptive transfer of CXCR6+ CD4 T cells reveals an ability to induce cross priming islet-specific CD8 T cells and drive T1D development. Conclusion These data argue that pathogenic islet-specific CD4 T cell clones can be subject to negative selection following recognition of self-peptide/I-Ag7-PD ligands that are distinct from the cognate autoantigen. Funding Source n/a Topic Categories Basic Autoimmunity (BA)

SCGB1D2 is a Sex-Specific Mucosal Defense that impacts Lyme Disease Susceptibility 2251807

Abstract Introduction Lyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Infection-Associated Chronic Illness (IACI) post-exposure to Borrelia burgdorferi (B. burgdorferi) skews female and Lyme disease increases risk for multiple gynecological conditions. The mechanisms of which are not well defined. We identify Secretoglobin family 1D member 2 (SCGB1D2), a small secreted protein, as a sex-biased host mucosal defense factor for Lyme disease. Methods We used genetic and epidemiological data from FinnGen and the Estonian Biobank to identify variants associated with Lyme disease risk. Protein expression data from Human Protein Atlas were assessed. Functional studies tested recombinant SCGB1D2 reference and missense (P53L) proteins for their ability to inhibit Bb growth in vitro. In vivo effects were validated using a murine infection model. Results A common SCGB1D2 variant is linked to higher Lyme disease susceptibility. The recombinant reference protein markedly inhibited Bb growth, while the P53L variant showed reduced efficacy. In mice, recombinant SCGB1D2 injected with the bacteria lowered total bacterial burden longitudinally. Expression analyses confirmed SCGB1D2 is expressed in the cervix and sweat gland cells. Importantly, there are sex-differences in sweat patterns. SCGB1D2 expression is progesterone receptor—dependent and has been implicated in reproductive conditions such as endometriosis. Conclusion SCGB1D2 is a sex-dependent host defense factor that restricts B. burgdorferi growth and influences Lyme disease susceptibility. These data suggest broader implications in sex differences and mucosal defense to B. burgdorferi. SCGB1D2’s localization to skin and secretory tissues, hormonal immune modulation, and B. burgdorferi antimicrobial properties reveal not only a larger understanding of Lyme disease sex differences in mucosal defense but also a novel therapeutic potential for Lyme disease. Funding Source Emily and Malcolm Fairbairn, Instrumentarium Science Foundation and Academy of Finland, Finnish Medical Foundation, Younger Family, and Bay Area Lyme Foundation Topic Categories Mucosal and Regional Immunology (MUC)

Metasurface‐Enabled Light‐Driven Liquid Crystal Elastomer Actuators (Adv. Mater. 45/2026)

Impact‐Resistant Hydrogels Via Quaternary Ammonium‐Regulated Networks

ABSTRACT Hydrogels are increasingly explored as structural candidates for impact‐mitigation and protection systems because of their biocompatibility, softness, and design versatility. However, conventional hydrogels typically suffer from inadequate mechanical properties and environmental instability, which severely hamper their practical applications. Here we report the use of quaternary ammonium‐regulated networks to overcome these limitations, without the need for cumbersome postprocessing or high energy consumption. The approach enables controlled structural organization in polymers containing regularly spaced polar groups (e.g., polyvinyl alcohol, poly(acrylic acid), and polyacrylamide), transforming large, densely packed rigid domains into dynamic, adaptable supramolecular architectures. This arises from strong quaternary‐ammonium–polymer associations that restrict local chain mobility and promote ordered segmental packing. Consequently, by tuning polymer composition, the hydrogels have widely tunable mechanics from brittle to ductile behavior, with ultimate stresses of 32.9–101.9 MPa, strains of 29%–1670%, and toughness values of 22.7–434.1 MJ m − 3 . They also show exceptional impact‐resistant performance (426.7 MPa), combined with high energy dissipation (96.02%) and puncture resistance (1.3 J), which compares favorably to those of other tough hydrogels and even natural materials. The presented strategy is generalizable to other polymers, and could expand the applicability of structural hydrogels to more mechanically demanding conditions.

Spatial heterogeneity and source apportionment of potentially toxic metal(loid)s in farmland soil in Jiange, Southwest China

T cell differentiation drives programs of resistance to PD-1-mediated inhibition 2260353

Abstract Introduction Research into basic PD-1 biology, together with the clinical picture of cancer patients treated with PD-1 blockade, converge to emphasize that PD-1 engages complex signaling networks to support T cell homeostasis, differentiation and immune responses. However, there is a lack of comprehensive understanding in the molecular cascades engaged by PD-1 in functionally distinct T cell subpopulations. Methods We use a combination of functional immuno-assays, transcriptional and proteomic profiling of human T cells to demonstrate that effector T cells acquire programs of resistance to PD-1 signaling as they progress through the trajectory from naïve-to-memory differentiation. Results Overall, PD-1 mediated stronger inhibition via PD-L2 compared to PD-L1. However, we observed differences in the functional responses to PD-1 signaling driven by T cell subset heterogeneity independent of the level of PD-1 expression. In naïve and central memory T cells, PD-1 inhibited cytokine production, cell cycle progression and cellular metabolism. Functional inhibition by PD-1 in these subsets was observed in the presence and absence of CD28 co-stimulation. In contrast, PD-1 ligation led to small inhibition of cytokine production in effector T cells. Critically, the functional, proliferative and metabolic signatures of terminally differentiated effector CD8 T cells were not affected upon stimulation in the presence of PD-1. Integrated transcriptomic and proteomic profiling of highly purified naïve and memory T cells demonstrated that effector T cell differentiation is associated with the development of resistance programs to PD-1-mediated inhibition. Central and effector memory T cells sharing the same T cell receptor and stimulated in the presence of PD-1 confirmed gradual loss of sensitivity to PD-1 signaling in effector T cells. Conclusion Together, our findings elucidate the cellular and molecular etiologies associated with sensitivity and resistance to PD-1 signaling. Funding Source The Mathers Foundation, NIH NIGMS Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Monoclonal antibody therapy for rabies disease: long term impact on central nervous system recovery 2257695

Abstract Introduction Lyssaviruses are the causative agent for rabies, a disease that is uniformly fatal in humans without post-exposure prophylaxis (PEP). Once infection reaches the central nervous system (CNS), PEP is no longer effective. Using a mouse model of lethal rabies disease, we previously demonstrated that peripheral administration of a single dose of neutralizing human monoclonal antibody (mAb), A6, which targets the viral glycoprotein, is highly effective at protecting against lethality. Notably, A6 is effective even when administered following robust replication of virus in the CNS. Moreover, A6 is effective at reducing or even fully reversing multiple signs of disease, including weight loss and limb paralysis. Methods Motor function analyses demonstrated improved motor function of infected A6-treated animals compared to infected untreated controls during the acute phase of disease, but significant impairment compared to uninfected control animals over the post-recovery phase, even months post-treatment. In this study, we perform immunohistochemistry on tissue samples collected at multiple time points post-infection to investigate the underlying mechanisms that may account for failure to completely recover motor function. Results Via stains for inflammatory markers of blood brain barrier (BBB) integrity, initial findings suggest diminished BBB function in both infected untreated animals and infected A6-treated animals. Conclusion These findings corroborate previous data that have suggested structural damage to the CNS, and further suggest that elements of this damage may be beyond repair, despite rescue from mortality and partial functional recovery. Funding Source NIH, DoD USUHS Topic Categories Vaccines and Immunotherapy (VAC)

The role of Glutamine metabolism in conventional Dendritic Cells and the downstream polarization of CD4+ T-cells 2258081

Abstract Introduction Allergy induced asthma is defined as a chronic disease that plagues the airways of approximately 60% all asthmatic patients. Allergic asthma is characterized through the symptomatology of inflamed or thickened airways, over production of mucus, and airway hyperresponsiveness (AHR). This disease is typically initiated by irritants such as pet dander, pollen, fungi, and pollutants eliciting a type 2 immune response. Within the type 2 classified immune response there are several immune cells involved. Allergen specific IgE promotes mast cell activation and degranulation in both humans and animals. Initiation of this response depends on activation of a specialized subset of T follicular helper (Tfh) cells called Tfh13 which induces high-affinity IgE production by B cells. Tfh13 cell differentiation from naïve CD4+ T cells is induced by antigen presenting cells, such as conventional dendritic cells (cDCs), following allergen exposure. Recent studies have identified cellular metabolism as a key regulators of DC phenotype and function. Methods C57BL/6 mice were intranasally stimulated with Alternaria Alternata prior to treatment with CB839, a glutaminase I inhibitor. We then intraperitoneally (i.p.) administered cell permeable succinate or alpha-ketoglutarate. On day 8 we euthanized mice and collected mediastinal draining lymph nodes. Results Previous lab members found that stimulation with the allergen Alternaria alternata as compared to LPS, a metabolic shift in cDCs caused a significant accumulation of the TCA cycle metabolites alpha ketoglutarate and succinate, but a decrease in fumarate and malate. Following this we found that upon alternaria stimulation, both succinate and alpha ketoglutarate administration were able to rescue the inhibition of Tfh13s observed with glutaminase I inhibition. Other T cell subsets were unaffected. Conclusion This finding illustrates the role of glutamine-derived metabolites in the polarization of T-cells. Funding Source NHLB1-NIH (RO1HL162991) to RKM Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Deciphering the role of extrafollicular-derived IgM on germinal center memory and long-lived plasma cell responses to Influenza virus infection 2257479

Abstract Introduction Most if not all the IgM secreted early after Influenza virus infection by B-1 and B-2 cells is derived from antibody-secreting cells (ASCs) developing in rapidly forming extrafollicular (EF) B cell responses. We previously demonstrated that the lack of the early-derived IgM significantly reduces the later-induced IgG response to influenza A virus (IAV) infection. The mechanisms underlying this effect on IgG remain to be fully explored. Here we hypothesize that EF-derived IgM affects antigen retention and stimulation of germinal center (GC) B cells, promoting stronger selection for memory and plasma cell differentiation in GCs. Methods Flow cytometry, ELISPOT, ELISA. Results To investigate the impact of reduced EF response output on GC functionality, we infected secreted IgM knockout (s-IgM KO) mice with IAV and analyzed the draining mediastinal lymph nodes (medLN) for alterations in GC B cell frequencies at day 14 post-infection. Our initial studies demonstrate significant reductions in both frequency and total numbers of GC B cells in s-IgM KO mice compared to wild-type (WT) controls. Moreover, we found that s-IgM KO mice harbored significantly fewer CD80+,CD73+, Influenza hemagglutinin (HA)-specific memory B cells at 30 days post infection (p.i) and decreased HA+ plasma cells in the bone marrow compared to WT mice at 45 days p.i. Antigen-specific serum and bone marrow antibody levels were assessed by ELISA and ELISPOT, and female s-IgMKO mice showed a reduction in IgG levels compared to WT after 45 days p.i. Conclusion Collectively, this data suggests that early EF-derived IgM responses are critical to support maximal GC outputs. Understanding these mechanisms may provide valuable insights for optimizing vaccine strategies against IAV infections. Funding Source N/A Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Allogeneic Tissue Tregs Improve Disease Outcome in Models of Acute Lung and Kidney Injury 2259889

Abstract Introduction Foxp3+ T regulatory cells (Tregs) are important mediators of tissue homeostasis and immune tolerance, known for suppressive capabilities as well as noncanonical tissue repair functions. Acute inflammatory diseases such as acute lung injury (ALI) and acute kidney injury (AKI) are life-threatening conditions characterized by unchecked inflammation and maladaptive tissue repair. Methods We engineer Tregs for stable expression of Foxp3, a rapamycin-activated chemically inducible signaling complex that provides targeted IL-2 signaling, and expression of the tissue damage alarmin receptor ST2. Results Engineered cells (Tissue EngTregs) recapitulate the gene signature observed in naturally occurring Tissue Tregs based on bulk RNAseq analysis. We assessed the ability of a murine surrogate cell (mEngTreg) to achieve efficacy in mouse models of ALI and AKI. mEngTregs showed efficacy in all models based on key disease-specific biomarkers. In ALI, mEngTreg treatment was associated with restored blood oxygen saturation, reduced immune infiltrates by flow cytometry, lower levels of BAL inflammatory cytokines, and reduced tissue damage by H&E. In AKI, mEngTregs treatment led to lower levels of serum creatinine, Blood Urea Nitrogen, NGAL, and Kim-1 as well as reduced tubular degeneration, cast formation, and loss of brush border by H&E. Conclusion Overall, these data support the development of a potent off-the-shelf allogeneic engineered Treg therapy for human acute lung or kidney diseases. Funding Source NIH-SBIR, venture Topic Categories Vaccines and Immunotherapy (VAC)

High risk blood myeloid dysregulation is elevated in obesity and is reduced by lifestyle interventions 2251787

Abstract Introduction We recently described the Human Immune Dysregulation Evaluation Framework (Hi-DEF) to quantify myeloid and lymphoid dysregulation across infectious and non-infectious illness using peripheral blood gene expression (Moore et al, Nature Medicine). Using the Hi-DEF framework, we evaluated the baseline immune dysregulation in patients with obesity and quantified the changes in immune dysregulation due to lifestyle changes and medical interventions. Methods We assessed the association of obesity with myeloid dysregulation in the Framingham Cohort using linear regression. In two additional datasets (GSE66175, GSE19790), we assessed the effect of dietary interventions and bariatric surgery on myeloid dysregulation using paired Wilcoxon rank sum test pre- and post- intervention and Pearson correlation. Results In the Framingham cohort (n = 5321), myeloid dysregulation score was associated with BMI (p = 2.2e-6) after correcting for age and sex. Patients assigned to diet/exercise experienced significant reductions in myeloid score after 3 months (n = 63, p = 1.2e-7), which was not seen in controls (n = 63, p = 0.29). Change in myeloid score was significantly correlated with change in weight loss (r = 0.32, p = 0.006). This reduction in myeloid dysregulation was also seen post-bariatric surgery (n = 11, p = 0.0001). Conclusion Patients with obesity have significantly higher myeloid dysregulation compared to healthy subjects, which is modifiable with lifestyle and medical interventions. Funding Source 5K12TR004930-02 Topic Categories Computational and Systems Immunology (COMP)

The Role of Tyro3—Axl—Mertk Receptors in Uterine Immune Regulation During Pregnancy: A Multilevel Analysis in Mouse Models 2266974

Abstract Introduction Successful pregnancy requires immune tolerance and controlled inflammation at the maternal—fetal interface. The Tyro3—Axl—Mertk (TAM) receptor tyrosine kinases and their ligands Gas6 and Protein S modulate immune homeostasis. Their temporal roles in uterine regulation during implantation and decidualization remain unclear. We hypothesized that TAM signaling is essential for establishing uterine tolerance and tissue remodeling. Methods Uterine tissues were collected from mice in estrus and on gestational days 1, 4, 5, 8, 15, and 21. Warfarin was used to pharmacologically inhibit TAM activation. Immunohistochemistry, Western blotting, RT-qPCR, and ELISA were performed to assess expression and cytokine profiles. Immunoprecipitation was conducted once due to limited phospho-specific antibody availability, but the phosphorylation results obtained were clear and interpretable. Results AXL expression peaked at days 4—5 and localized to the primary decidual zone, whereas MERTK and PROS1 increased later (days 8—15). GAS6 was abundant at D0—D4 but decreased after D5. TYRO3 shifted from luminal epithelium to decidual and embryonic regions. Warfarin inhibited phosphorylation of all TAM receptors, restricted their expression to epithelial layers, and suppressed GAS6 and PROS1 signals. Cytokine imbalance followed (↔IL-10, TNF-α, IFN-γ). Notably, TAM inhibition on day 5 completely prevented decidualization, confirming its necessity for uterine remodeling. Conclusion TAM receptor signaling dynamically regulates uterine immune tolerance and tissue remodeling. Inhibition at the implantation window disrupts cytokine equilibrium and blocks decidualization, suggesting that the Tyro3—Axl—Mertk axis is indispensable for establishing the tolerogenic environment required for successful pregnancy. Funding Source This project was supported by the Scientific and Technological Research Council of Türkiye (TÜBİTAK) with project number 116S459. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Novel HIV-1 p24 Epitope Identified for the Amerindian HLA-B*39:02 Allele 2252620

Abstract Introduction HLA drives HIV evolution by selecting polymorphisms within the HIV proteome. HLA-B*39:02 is frequent in populations with Amerindian ancestry such as Mexico. It has been associated with better HIV outcomes and selection of p24-Gag polymorphisms. However, its HIV-specific responses remain unknown. Here, we characterized an HLA-B*39:02—restricted p24 epitope eliciting strong immune responses and show that polymorphisms alter peptide-HLA binding. Methods We recruited 14 men living with HIV and expressing HLA-B*39:02 with less than 60 days on TAR. The magnitude of cytotoxic T lymphocyte (CTL) responses were assessed by IFN-γ ELISpot using overlapping p24 9-mer peptides containing previously identified HLA-B*39:02—associated positions (315 and 319). Peptide binding affinity was assessed by peptide competition assays with substitutions at positions 315 (R, T, G) and 319 (D) using fluorescein-labeled peptides by flow cytometry. Positive CTL responses and IC50 values were compared by Mann-Whitney test. Results The p24 VKNWMTETL peptide, containing HLA-B*39:02 — associated positions 315 and 319) induced strong IFN-γ CTL responses (median of 574 SFU/million PBMCs). Position 315 variants showed distinct binding affinities: N315T maintained affinity, while N315R had lower affinity compared with N315T (IC50 406.2 vs. 204.0 nM; p = 0.0019). The E319D substitution appeared to have no effect on binding affinity compared with the wild-type peptide (IC50 237.9 nM vs. 204.0 nM; ns). In silico modeling of the HLA-B39:02 binding pocket confirmed these findings, indicating that N315G was the least favorable variant, markedly reducing peptide—HLA interaction. Conclusion We identified the first HIV p24 epitope presented by HLA-B*39:02 VKNWMTETL, which elicited strong CTL responses. Variations within this peptide altered its binding affinity to HLA-B*39:02. These findings support this new epitope is as a potential candidate for vaccine or immunotherapeutic strategies in populations with Amerindian ancestry. Funding Source Consejo Nacional de Humanidades, Ciencia y Tecnologia (CONACYT), CF-2019-2558583, Mexico city, Mexico Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)

Prolonging the Triplet Excited‐State Lifetime via Tandem Through‐Space Conjugation in Tetracationic Cyclophanes for Efficient Metal‐Free Photoredox Catalysis

ABSTRACT Prolonging the triplet excited‐state lifetime is essential for developing efficient photocatalytic systems. Herein, a series of viologen‐based cyclophane derivatives ( 2 , 6 , and 8 ) featuring TSC were designed and synthesized, with TSC‐boxes 6 and 8 incorporating a unique combination of cyclophane structures and TSC units. Compared with 2 and 6 , which possess only a single TSC unit, TSC‐box 8 with a tandem TSC structure exhibits enhanced spin‐orbit coupling and a narrower singlet‐triplet energy gap. These attributes endow TSC‐box 8 with favorable photoelectric properties, including photoluminescence and an apparent one‐step four‐electron redox behavior. Nanosecond transient absorption spectroscopy revealed efficient formation of the triplet excited state, prolonging the triplet excited‐state lifetime, thereby enabling effective generation of O 2 •− and •OH. As a photocatalyst, TSC‐box 8 efficiently mediates metal‐free photoredox catalysis, affording benzimidazole derivatives in up to 99% yield and enabling the selective oxidation of toluene to benzaldehyde within 1 h (yield: 90%, conversion: 96%) and to benzoic acid within 5 h (yield: 97%, conversion: 98%). This work provides a strategic approach to designing long‐lived triplet excited‐state systems for metal‐free photocatalysis.

Redox‐Targeting Synergy With Dual Mediators for Prussian Blue Analogue Flow Batteries

ABSTRACT Aqueous redox‐targeting flow batteries (RTFBs) are highly promising electrochemical energy storage systems due to their high energy density, long cycle life, and high safety. Dual‐molecule redox‐targeting (DMRT) system simplifies the matching between redox mediators (RMs) and solid materials. However, the interaction between RMs and solid material is not well clarified in reported works. Here, a 4‐OH‐TEMPO/[Fe(CN) 6 ] 3−/4− ‐NiHCF||Zn DMRT flow battery is developed in this work, delivering an outstanding energy density of 75.04 Wh L −1 (9.09 times higher than that of blank flow battery), excellent coulombic efficiency (99.9%), solid material utilization (82.9%), and capacity retention (99.7% per cycle) at 10 mA cm −2 . Importantly, a redox‐targeting synergy mechanism of two RMs is elucidated through various experimental and theoretical validations, wherein [Fe(CN) 6 ] 3−/4− facilitates Fe‐Fe electronic delocalization and Na + extraction, while 4‐OH‐TEMPO accelerates Fe‐N interfacial charge exchange. The dual‐mediator design exhibits distinct SOC‐dependent contributions, quantitatively revealed by time‐resolved operando ultraviolet‐visible (UV‐Vis) spectroscopy. Meanwhile, frequency‐resolved operando distribution of relaxation times‐electrochemical impedance spectroscopy (DRT‐EIS) clarifies that direct NiHCF‐mediator interfacial coupling governs the redox‐targeting resistance. This work deepens the mechanistic understanding of redox‐targeting chemistry in DMRT systems, advancing high‐energy‐density aqueous flow batteries.

A Planarity‐Hindrance Co‐Balance Strategy to Develop Antiparallel H‐Aggregates With Minimal Absorbance Blueshift for Type I Photodynamic Therapy

ABSTRACT H‐aggregates offer intrinsic features for type I photodynamic therapy (PDT) by concurrently promoting triplet state formation and strengthening charge transfer ability. However, their exploitation remains limited by the inherently large absorption blueshift (usually >100 nm) arising from strong H‐type excitonic coupling in conventional parallel‐packed H‐aggregates, forcing short‐wavelength laser excitation with poor tissue penetration. Herein, this study reports a planarity‐hindrance co‐balance strategy to develop donor‐π‐acceptor‐based antiparallel‐packed H‐aggregates with minimal absorption blueshift for type I PDT. The results demonstrate that π‐bridge planarization drives H‐packing, while donor‐site steric tuning dictates the blueshift by modulating slipping angles and π‐π overlapping degree, and a steric threshold (Me/OMe) is identified beyond which blueshift becomes invariant. The optimized MTBSIC molecules form H‐aggregates with an exceptionally small blueshift of 15 nm over its monomers. MTBSIC H‐aggregates further display markedly enhanced type I ROS generation and improved photothermal conversion ability over their amorphous counterparts possessing similar monomeric photophysical properties. Mechanistic analyses reveal that H‐packing promotes both intersystem crossing and intermolecular charge transfer/separation, synergistically boosting type I ROS production. MTBSIC H‐aggregates further achieve potent tumor inhibition with high biocompatibility both in vitro and in vivo. This work establishes a generalizable molecular design paradigm for near‐monomer‐like H‐aggregates for high‐performance phototheranostics.

Humulus lupulus L. seed: an underrated source of valuable active phytochemicals