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IgA binding characteristics of golden hamster and ferret Fcα receptors
Abstract Golden hamster (Mesocricetus auratus) and ferret (Mustela putorius furo) are important animal models in studies of human infectious disease. They are used widely to investigate pathogen-spreading mechanisms and host immunology to evaluate the safety and efficacy of small molecules, biologic drugs and vaccines. To this end, immunoglobulin A (IgA) and its Fcα receptor (FcαR) play critical roles in humans but are not well characterized in these 2 species. Golden hamster and ferret IgA and FcαR were recombinantly expressed, purified, and characterized for N-linked glycosylation site occupancy and binding affinity. Based on sequence and structural alignments, hamster IgA showed greater similarity to human IgA than did ferret, and hinge domains in both small animal models suggested greater structural homology to human IgA2 than IgA1. Despite considerable sequence divergence in both immunoglobulins and receptors, and the lack of binding between ferret FcαR and ferret IgA, human IgA bound to both hamster and ferret FcαR with high affinity. Further, differences in dissociation rates were dependent on test format, suggesting that the 2:1 stoichiometry of human FcαR: IgA is recapitulated in these animals. Overall, this work suggests the suitability of these animals to model protection or pathology driven by interactions between human IgA and host FcαR and will aid in critical and confident interpretation of infection and immunization studies in each species.
Full‐Active‐Unit Molecular Design Strategy Enabling High‐Capacity and Stable Quinone Organic Cathodes for Lithium‐Ion Batteries
ABSTRACT Redox‐active quinones have emerged as promising organic cathode materials (OCMs) for next‐generation lithium‐ion batteries (LIBs). However, their practical application is hindered by rapid dissolution in organic electrolytes and the common molecular design trade‐off where the introduction of non‐active structural motifs diminishes the specific capacity. To address these challenges, we propose a full‐active‐unit molecular design strategy. This approach connects two quinone (9,10‐anthraquinone or 9,10‐phenanthrenequinone) units via C─C single bond to a high‐capacity pyrene‐4,5,9,10‐tetraone core, aiming for both low solubility and high specific capacity. Accordingly, we synthesized 2,7‐bis(9,10‐anthraquinonyl)pyrene‐4,5,9,10‐tetraone (BAPO) and 2,7‐bis(9,10‐phenanthraquinonyl)pyrene‐4,5,9,10‐tetraone (BPPO), both exhibiting low solubility. Electrochemical tests revealed excellent cell performance, particularly for the BAPO cathode, which delivered a high capacity of 317.5 mAh g − 1 at 0.2 C and demonstrated exceptional long‐term cycling stability with 70.2% capacity retention after 9000 cycles at 5 C. This work provides a new molecular design concept for developing quinone cathode materials that simultaneously achieve high capacity and long cycle life.
Chemoimmunotherapy in Deficient DNA Mismatch Repair Metastatic Colorectal Cancer: What COMMIT Can and Cannot Tell Us
APATCP: programmable multi-controller framework for real-time detection and mitigation of complex TCP flooding attacks in SD-IoT networks
Metabolic crosstalk between c-Myc and glutamine utilization sustains IgM+ B-cell immunity in teleosts
Abstract B-cell responses rely on a tightly coordinated interplay between transcriptional programs and metabolic reprogramming. Upon activation, B cells remodel their metabolic profiles, with enhanced glutamine metabolism supporting biomass synthesis and proliferation. However, whether and how glutaminolysis underpins B-cell responses in early vertebrates remains largely unexplored. Here, using the Nile tilapia (Oreochromis niloticus) as a model, we demonstrate that IgM+ B cells markedly increase glutamine utilization upon activation. Glutamine deprivation impaired B-cell activation and proliferation, whereas glutamine supplementation promoted these processes. During Edwardsiella piscicida infection, pharmacological inhibition of glutamine metabolism significantly reduced the expansion of IgM+ B cells and compromised antibody secretion. Mechanistically, glutamine metabolism in tilapia IgM+ B cells was governed by the transcription factor c-Myc. Inhibition of c-Myc disrupted glutaminolysis, leading to diminished B-cell proliferation and antibody production. Upon activation, IgM+ B cells coordinated c-Myc expression and downstream glutamine metabolism through the mTORC1 and ERK signaling pathways, thereby coordinating metabolic and immune functions. Notably, this regulatory mechanism operated in a B cell–intrinsic manner and was independent of T-cell help. Collectively, our findings reveal that teleost B cells possess evolutionarily conserved and sophisticated immunometabolic regulatory programs. This study provides new insights into how metabolic pathways are integrated with immune signaling to control B-cell function, highlighting coordinated immunometabolic regulation as a fundamental mechanism underlying vertebrate B-cell immunity.
Multifunctional Electrode/Neural Integration Interface Enabling Chronic High‐Fidelity Neural Recording and an Order‐of‐Magnitude Neuromodulation Quality
ABSTRACT Neural electrodes face persistent challenges, including inflammation, biofouling, and impedance, which compromise long‐term recording and stimulation quality. Here, we introduced a multifunctional polyamino acid interface that enhances neural interfacing by combining biocompatibility, antimicrobial activity, and antifouling properties. Applied to flexible electrodes, this coating reduces foreign body reaction and preserves neuronal proximity, ensuring stable integration with brain tissue. In chronic rodent models, functionalized electrodes achieve high‐fidelity single‐unit recordings for over 300 days with significantly higher spike amplitudes and yield than bare controls. Notably, the interface enables an order‐of‐magnitude improvement in neuromodulation efficiency, evoking robust motor responses at only 2 µA compared to 100 µA for uncoated probes. Multi‐omics analysis reveals a molecularly profound alteration in the host tissue response, transitioning from a pro‐inflammatory injury signature to an attenuated inflammatory state with improved tissue homeostasis. Furthermore, the interface's resistance to biological “cementing” facilitates damage‐free electrode removal and recovery, preserving the neural architecture and enabling the possibility of chronic replacement. This universal platform offers a promising and practical strategy for the next generation of stable, clinically viable neural–computer interfaces.
Ganoderic acid L attenuates LPS-induced inflammatory lung injury through integrated network pharmacology, transcriptomics and target-engagement analyses
Adipose stem cell vesicles reduce bleomycin-induced dermal fibrosis and oxidative stress in scleroderma mice via circ-Zfyve9
Abstract Systemic sclerosis (SSc) is an autoimmune condition affecting several organs. It is identified by thickening of the dermis, connective tissue affected by collagen accumulation, and vascular injuries that induce hypoxia. The present study aimed to determine whether extracellular vesicles (EVs) from adipose-derived stem cells (ADSCs) attenuated bleomycin-induced skin fibrosis and oxidative stress in scleroderma. ADSCs and their EVs were separated and a bleomycin-induced SSc mouse model was constructed. High-throughput sequencing was employed to study abnormal expression of circular RNAs in SSc skin tissues with or without ADSC-EV treatment. The regulatory mechanism and targets were studied using bioinformatics analysis, luciferase reporting analysis, angiogenic differentiation experiments, and RT-qPCR detection analysis. EVs from ADSCs were successfully isolated. The exosome treatment prevented dermal thickening and fibrosis in bleomycin-induced scleroderma. In addition, circ-Zfyve9 was demonstrated to have an important function in ADSC-EV-mediated skin tissue protection. GPX4 and miR-135 were shown to be downstream targets of circ-Zfyve9. Overexpressing miR-135 or downregulating GPX4 reversed the promotion effects of circ-Zfyve9 on angiopoiesis by increasing lipidosome ROS in EPCs under hypoxic conditions. Overexpressing miR-135 or downregulating GPX4 reversed the inhibition effect of circ-Zfyve9 on fibrosis in myofibroblasts under hypoxic conditions. Overexpressing circ-Zfyve9 increased the therapeutic effect of ADSC-EVs. EVs from ADSCs attenuated bleomycin-induced skin fibrosis and oxidative stress in scleroderma via circ-Zfyve9 delivery.
Interconnected Closed Pores Enable Dense and Facile Sodium Storage in Hard Carbon
ABSTRACT Achieving a high plateau capacity in hard carbon (HC) anodes is one of the most critical prerequisites for high‐energy‐density sodium–ion batteries (SIBs), yet it is fundamentally limited by inaccessible closed pores formed during conventional high‐temperature annealing. Here, we propose a potentially scalable oxidation‐reconfiguration strategy to unlock its latent capacity. By coupling controlled oxidative etching with subsequent thermal reconstruction, an interconnected closed‐pore network is constructed. Oxidative pretreatment opens blocked channels and interconnects isolated voids, while reconstruction promotes void fusion, generating accessible internal reservoirs for the nucleation and storage of quasi‐metallic sodium clusters. This structural evolution and storage mechanism are elucidated by total neutron scattering, SAXS, in situ techniques, and simulations. As a result, the optimized ICP‐HC anode delivers reversible capacity 437 mAh g −1 with an initial Coulombic efficiency of 91.5%. It achieves an initial discharge plateau capacity of 399 mAh g −1 with fast kinetics (300 mAh g −1 at 2C), overcoming the capacity‐rate trade‐off. Furthermore, an NVP//ICP‐HC full cell shows excellent rate capability (96 mAh g −1 at 5C) and stable cycling (95% retention over 200 cycles at 1C). This work provides a scalable strategy for advanced carbon anodes in high‐energy‐density SIBs.
Evaluating supply chain sustainability in industrial clusters through an integrated Fermatean fuzzy RANCOM FUCA approach
Innate immune reprogramming of chicken macrophages by sodium butyrate enhances reactive oxygen species–mediated antimicrobial responses in vitro
Abstract In the established model of classical trained immunity, metabolic and epigenetic hubs serve as central integrators of innate memory. While typically associated with proinflammatory reprogramming, the regulation of autophagy and cellular proteostasis remains essential for guiding macrophage differentiation and ensuring efficient pathogen clearance without excessive inflammation. In this study, we demonstrate that sodium butyrate (SB), a short-chain fatty acid, induces a functional profile that diverges from the canonical pathways observed in classical innate immune training. The induction of an innate reprogrammed state in chicken macrophages by SB is strictly dependent on the cellular developmental stage, occurring only during the early stages of differentiation from chicken bone marrow–derived macrophages but not in fully differentiated cells. This suggests that SB primarily facilitates an innate immune reprogramming with a specific temporal window of sensitivity. Our results show that SB-reprogrammed chicken macrophages exhibit enhanced reactive oxygen species generation, altered cytokine expression, and an increased capacity to kill a diverse range of bacteria. Treatment with chemical inhibitors further demonstrated that these heightened antibacterial effects are directly attributed to increased reactive oxygen species production and autophagy. In summary, these findings indicate that SB induces functional outcomes distinct from classical trained immunity and can elicit innate immune memory through alternative regulatory axes. Our data suggest that distinct innate reprogramming states give rise to alternative activation programs and that innate immune memory exists along a spectrum of phenotypes rather than as a single, uniform state.
Development and validation of the teachers generative AI professional competence scale
Antigen presentation requirements for effective cDC1-based cancer immunotherapy
Abstract Type 1 conventional dendritic cells (cDC1s) are important for generating and sustaining antitumor immunity. Accordingly, the abundance of cDC1s in human tumors correlates with improved outcomes in cancer. Capitalizing on this role, we previously demonstrated that vaccination with murine cDC1s, generated in culture from bone marrow cells (termed here “in vitro–derived cDC1s”), elicits durable tumor control in multiple preclinical models; however, the immunological mechanisms underlying the efficacy of cDC1 vaccination remain unclear. Here, we examined whether in vitro–derived cDC1s resemble tumor-infiltrating DC populations and whether MHC-I and MHC-II antigen presentation contribute to cDC1-mediated tumor control following vaccination in melanoma. As expected, MHC-I or MHC-II deficiency had minimal impact on the transcriptional state of cDC1s in homeostasis or following stimulation with the adjuvant poly dI:dC. Moreover, in vitro–derived cDC1s cultured under steady-state conditions closely resembled tumor-infiltrating cDC1s, whereas their poly dI:dC–stimulated counterparts resembled CCR7+ tumor-infiltrating DC populations, also referred to as mregDCs or LAMP3+ DCs. Our data further show that both MHC-I and MHC-II contribute to tumor control upon cDC1 vaccination and that coexpression of MHC-I and MHC-II on the same cDC1 is necessary for a robust vaccine response. We also identified an important function for host cDC1s in supporting the efficacy of vaccination with in vitro–derived cDC1s, as judged by impaired tumor control in Irf8 + 32−/− mice, which lack endogenous cDC1s. Overall, these results indicate that effective antitumor responses depend on MHC-I and MHC-II antigen presentation by vaccine-delivered cDC1s, with additional contributions from host cDC1s.
A novel optimization of API release using hybrid models
Abstract Polysaccharide-based drug delivery systems have to be closely watched in terms of drug release in the body over time if they want to be able to achieve maximum therapeutic effectiveness and maintain controlled bioavailability. The work presents a data-driven framework that employs Raman spectroscopy and uncertainty-aware machine learning models to anticipate drug release patterns in different biological media. A dataset of 155 experimental samples was dealt with, which also included more than 1,500 Raman spectral features, polysaccharide composition, release time, and environmental medium (Control, Patient, Rat, and Dog). Principal Component Analysis (PCA) was implemented for dimensionality reduction, and modeling was done with the help of Gradient Boosting Regression (GBR) and Lasso Regression (Lasso) supported by newly developed bio-inspired optimization algorithms Attack-Leave Optimizer (ALO), Self-Adaptive Bonobo Optimizer (SABO), and Black-Winged Kite Algorithm (BWKA). Besides k-fold cross-validation, Friedman statistical testing, prediction interval bootstrapping, and Pareto front analysis were used to further assess model robustness and uncertainty. Of the hybrid models, GBBW (GBR-BWKA) was able to attain the highest predictive accuracy with R 2 = 0.931 and RMSE = 0.076 on the test set, thus outperforming baseline models and demonstrating the value of bio-inspired hyperparameter optimization within an uncertainty-aware computational framework. The primary contribution of this work is methodological: the integration of prediction interval estimation, multi-environment modeling, and Pareto-based model selection into a single reproducible pipeline applied to a publicly available polysaccharide Raman release dataset. No new experimental data were generated; the framework is offered as a computational tool to complement existing experimental approaches in controlled-release formulation research.
Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion
Abstract There is substantial interest in developing novel engineering strategies to promote the sustained metabolic fitness of therapeutic T cells. We previously showed that overexpression of RAS homologue enriched in brain (RHEB), a positive regulator of mammalian target of rapamycin complex 1 (mTORC1), promotes aerobic glycolysis and increases the anti-tumor functions of effector CD8+ T cells. To address whether these effects are conserved in CD4+ T cells, we have now examined how enforced activation of mTORC1 activity affects CD4+ T cell differentiation and function. Rheb overexpression induced a more balanced metabolic shift in CD4+ T cells than in CD8+ T cells, with increases in both oxidative phosphorylation and aerobic glycolysis. Although Rheb overexpression initially increased CD4+ T cell activation and proliferation in vitro, the underlying population architecture was complex, involving a shift to both more proliferative, cytotoxic-like cell states as well as more quiescent cell clusters characterised by counter-regulation of mTORC1 activity. Following adoptive transfer, tumor antigen-specific Rheb-transduced CD4+ T cells showed greater persistence but were less efficient than controls in eliminating tumor. This functional deficiency could be explained by a greater propensity of persisting Rheb-transduced CD4+ T cells to develop features of immune exhaustion, as evidenced by expression of multiple co-inhibitory receptors and impaired proliferation upon tumor rechallenge. Together, these data demonstrate the dynamic population response to tuning of T cell mTORC1 and the need to separately appraise cellular outputs of therapeutic CD4+ versus CD8+ T cells when metabolic pathways are manipulated by the same method.
Health, Aging, and Male Attitudes (HAMA) to sexual function loss in a large web-based survey of 6,000 older Japanese men
Generation and characterization of a novel MHC-II tetramer for tracking and characterization of toxin B–specific CD4+ T cell responses
Abstract The gastrointestinal pathogen Clostridioides difficile is a major burden for health systems due to high rates of recurrence. C. difficile pathogenesis is mediated by two virulence factors, toxin A (TcdA) and toxin B (TcdB). Antibodies specific for TcdA and TcdB are correlated with protection from symptomatic recurrence; however, the role for CD4+ T cells is poorly understood in part due to the lack of tools to study the toxin-specific CD4+ T cell response. Our group recently demonstrated the antibody and CD4+ T cell response to C. difficile toxins is impaired via the glucosyltransferase activity of the toxins; however, tools do not exist to study the protective capacity and the phenotype of toxin-specific CD4+ T cells. Therefore, we developed a major histocompatibility complex class II (MHC-II) tetramer to identify TcdB-specific CD4+ T cells via flow cytometry. Herein, we identified an immunodominant epitope (TcdB1961–1975) in the CROPs region of TcdB and optimized an MHC-II tetramer for use in tracking and phenotyping TcdB-specific CD4+ T cell responses following multiple different immunization strategies in mice. Utilizing the tetramer, TcdB-specific T follicular helper cells were detected following TcdB-CROPs messenger RNA lipid nanoparticle vaccination validating the advantage of the tetramer. Furthermore, using a modular messenger RNA vector expressing the TcdB1961 peptide covalently bound to the beta chain of MHC-II, we were able to generate a robust population of TcdB-specific CD4+ T cells. These data outline the generation of new tools for the C. difficile field and lay the groundwork for future studies of toxin-specific CD4+ T cell responses.
PLIBEL and QEC for ergonomic risk assessment in operating room scrub nurses during coronary artery bypass grafting: a pilot study
Skullcapflavone II alleviates osteoarthritis by inhibiting inflammation and ferroptosis via the SLC7A11/GPX4 signaling pathway
Abstract Osteoarthritis (OA), the most prevalent degenerative joint disease, leads to significant disability in the elderly and is characterized by functional and structural deterioration of the knee joint. This study aimed to investigate the therapeutic potential of skullcapflavone II (SkII), a flavonoid known for its anti-inflammatory properties, in the context of OA. Our results demonstrated that SkII markedly suppressed IL-1β–induced extracellular matrix degradation and apoptosis in chondrocytes. Furthermore, SkII reduced reactive oxygen species and malondialdehyde levels while enhancing superoxide dismutase activity and the glutathione/glutathione disulfide ratio. SkII also upregulated the expression of SLC7A11 and glutathione peroxidase 4 (GPX4). Mechanistic investigations revealed that SkII, similar to the ferroptosis inhibitor ferrostatin-1, effectively counteracted erastin-induced apoptosis and extracellular matrix degradation. Both SkII and ferrostatin-1 promoted SLC7A11 and GPX4 expression at transcriptional and protein levels and diminished ferrous ion (Fe2+) accumulation in chondrocytes. In vivo experiments confirmed that SkII treatment attenuated ferroptosis in OA rats by activating the SLC7A11/GPX4 pathway. In conclusion, our findings indicate that SkII alleviates OA progression by inhibiting ferroptosis through the SLC7A11/GPX4 signaling axis. These results underscore the potential of SkII as a promising therapeutic candidate for the treatment and prevention of OA.