Search Results (338)

Herpes simplex virus type 2 (HSV-2) is the primary pathogen responsible for genital herpes. Predominantly transmitted via sexual contact, HSV-2 not only poses significant physical and psychological burdens on infected individuals but also substantially elevates the risk of HIV acquisition and represents a potentially fatal threat to newborns. Following primary infection, HSV-2 establishes lifelong latent infection within the sacral ganglia. Currently, there are no vaccines or therapeutics capable of eradicating this latent virus reservoir or effectively preventing initial infection. The core impediment to developing such interventions lies in the incomplete elucidation of the protective immune mechanisms against HSV-2 and its precise molecular pathogenesis. The host immune response against HSV-2 hinges critically on the coordinated interplay between innate and adaptive immunity. The innate immune system, serving as the first line of defense, acts to curtail early viral replication and initiate adaptive responses. This is achieved through mechanisms, including the genital mucosal barrier, activation of Toll-like receptors (TLRs), the cGAS-STING signaling pathway, interferon (IFN)-mediated antiviral effector functions, and activation of innate immune cells such as natural killer (NK) cells and dendritic cells (DCs). Crucially, however, HSV-2 counteracts these host defenses by expressing immune modulatory proteins (e.g., ICP0, ICP27, ICP35) that target key host antiviral signaling pathways, thereby affecting immune evasion. Within the adaptive immune response, neutralizing antibodies generated by the humoral immunity can provide localized protection at mucosal sites, but their protective efficacy is limited due to sophisticated viral immune evasion mechanisms. Cellular immunity, particularly mediated by CD4+ T cells, constitutes the core mechanism for viral clearance and suppression of recurrent outbreaks. Notably, tissue-resident memory T cells (TRMs) play a pivotal role in controlling the reactivation of latent HSV-2 within the ganglia. This review integrates current research advances to delineate the innate and adaptive immune mechanisms engaged during HSV-2 infection from the perspective of the dynamic host–virus interplay, with an ultimate aim to provide a theoretical foundation informing the rational development of preventive vaccines and therapeutic agents against HSV-2. Full article

The coronavirus disease 2019 (COVID-19) pandemic has been associated with a wide range of neurological complications, among which persistent cognitive impairment and memory deficits are increasingly recognized as key symptoms of the post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID). Although clinical and epidemiological studies have documented these symptoms across diverse patient populations, the underlying neurobiological mechanisms remain incompletely understood. Growing evidence from human studies, neuropathological analyses, and experimental models indicates that neuroimmune and inflammatory processes plays a central role in COVID-19-associated cognitive dysfunction. As the brain’s resident immune cells, microglia are vital for synaptic health, neuroplasticity, and memory, yet these processes may be compromised after SARS-CoV-2 infection. Systemic inflammation, blood–brain barrier (BBB) disruption, endothelial injury, and cytokine signaling can induce sustained microglial activation and priming, leading to inflammasome activation, complement-mediated synaptic remodeling, oxidative stress, and impaired hippocampal neurogenesis. These processes collectively disrupt neural circuits involved in learning and memory and may underlie the persistent “brain fog” reported by COVID-19 survivors. This review synthesizes clinical, biomarker, neuroimaging, and mechanistic evidence linking SARS-CoV-2 infection to microglia-mediated neuroinflammation and memory impairment. In contrast to prior reviews that broadly describe neuroinflammation in COVID-19, we integrate multidimensional evidence into a microglia-centric immunovascular framework that highlights converging pathogenic pathways underlying cognitive symptoms. We further discuss emerging biomarkers of glial activation and evaluate current and prospective therapeutic strategies targeting microglial and neuroimmune pathways. Understanding the role of microglial dysregulation in post-COVID cognitive impairment may facilitate the development of targeted interventions to mitigate long-term neurological consequences of COVID-19. Full article

Micro-scale waterfront spaces play a critical role in contemporary urban regeneration by supporting everyday activities and place-based experiences. However, existing studies often rely on linear evaluation approaches and insufficiently address the asymmetric effects of functional, environmental, and cultural attributes on residents’ landscape satisfaction. This study investigates the satisfaction structure of micro-scale waterfront spaces along the Grand Canal in Wuxi, China, with a particular focus on nonlinear demand mechanisms. A mixed-method framework integrating grounded theory, the Delphi method, and the Kano model was employed to identify key landscape attributes and classify their satisfaction effects. The results reveal a hierarchical satisfaction mechanism characterized by “basic–performance–attractive” attributes. Fundamental functional and environmental factors, such as accessibility, safety, water quality, and cultural authenticity, function as must-be attributes that primarily prevent dissatisfaction. Environmental comfort and social facilities act as one-dimensional attributes that linearly enhance satisfaction, while cultural narratives, memory-related elements, and ecological esthetics emerge as attractive attributes that significantly elevate emotional engagement when present. Sensitivity analysis further identifies priority intervention factors with the greatest impact on satisfaction improvement. These findings demonstrate the asymmetric nature of residents’ landscape satisfaction and provide a phased optimization framework for the sustainable regeneration of heritage-based micro-scale waterfront spaces, emphasizing basic reliability, experiential enhancement, and cultural resonance. Full article

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease in which persistence of immunological memory underlies disease recurrence and progression toward atopic comorbidities. Evidence indicates that pathogenic tissue-resident memory T cells (TRM), including Th2- and Th22-skewed subsets, among others, persist in both lesional and clinically resolved skin and rapidly re-initiate inflammation through production of IL-4, IL-13, IL-22 and IL-31, promoting barrier dysfunction and pruritus. In parallel, circulating CLA⁺ memory T cells retain skin-homing capacity and contribute to flare reactivation, while IgG1⁺CD23 IL-4Rα⁺ type-2 memory B cells (MBC2) constitute a reservoir for high-affinity IgE production, linking cutaneous inflammation with allergic comorbidities. These adaptive memory compartments are sustained by epithelial alarmins, dendritic cell–derived chemokines such as CCL17, CCL22 and CCL18, and the OX40/OX40L costimulatory pathway, which promotes differentiation, survival and tissue retention of memory T cells. Clinical and transcriptomic studies show how, although IL-4/IL-13 blockade reduces circulating type-2 responses, Th2A cells, Tc2 cells and activated dendritic cells can persist in clinically resolved skin, providing a mechanistic basis for relapse after treatment withdrawal. Together, these findings support the relevance of targeting memory-imprinting pathways as a promising mechanism to achieve durable disease modification in AD. Full article

For decades, immunology has followed a clear paradigm: immunological memory resides only within the adaptive immunity, as a unique property of lymphocytes giving the host the ability to recognize specific antigens and offer long-term protection. However, this raises an important question: how valid is this belief in light of new evidence? The discovery of trained immunity shows that innate immune cells can also develop lasting functional changes. This finding prompts a profound reconsideration of the traditional framework. Trained immunity is a functional reprogramming of the innate immune cells driven by long-term epigenetic and metabolic reprogramming, resulting in enhanced responses upon subsequent exposure to the same pathogen or even to unrelated stimuli. The presence of pattern recognition receptors (PRRs) on innate immune cells already suggested a certain level of specificity in this compartment thanks to the engagement of a PRR by a pathogen-associated molecular pattern (PAMP) inducing memory-like properties in the responding cell. While such partial specificity can enhance protection, it may also amplify aberrant inflammatory circuits, thereby contributing to the initiation or worsening of autoimmune and chronic inflammatory diseases. This dual nature of trained immunity raises important questions for the field: is trained immunity ultimately harmful or beneficial in autoimmunity, and can its mechanisms be harnessed therapeutically rather than pathologically? The present Perspective will address these issues by examining recent findings that reveal the specificity, pathogenic potential, and translational opportunities in given examples of autoimmune diseases (ADs). Full article

Background/Objectives: Older adults with neurocognitive and psychological disorders are often institutionalized in nursing homes, which negatively affects well-being and mood, and may accelerate cognitive decline. Immersive virtual reality (VR) is a promising non-pharmacological countermeasure, but VR-headset discomfort limits its usability in this population. Therefore, this study examined the tolerability and feasibility of an immersive VR room, which provides customizable interactive environments projected across four walls at 360° and enables shared experiences, to enhance positive affect and engagement in nursing home residents. Methods: Twenty nursing home residents were initially enrolled, and nineteen completed five 10 min sessions in the immersive VR room accompanied by a caregiver. State positive and negative effects were assessed using the visual analogue scale (VAS) and the Observed Emotion Rating Scale (OERS), and participants’ verbal feedback was collected during and after the sessions. Results: VAS scores indicated that VR room immersion was feasible and well-tolerated, with most participants feeling secure and experiencing increased positive affect during and just after the sessions. OERS scores and observations revealed frequent expressions of pleasure, interest, and active engagement with both the VR environments and the caregiver. Participants’ reports valued the enjoyable and relaxing experience provided by immersion in the VR room, noting the realism and aesthetics of the environments and nature-related elements, which allowed them to travel virtually and evoke personal memories. Conclusions: Immersive VR room sessions were well tolerated, enhanced positive affect, and may support cognitive functioning by fostering active engagement and social interaction. Given that this is a feasibility study with a small cohort and short follow-up, the present findings should be considered preliminary and confirmed in larger, controlled, longer-term studies. Full article

The involvement of the immune system in pulmonary fibrosis is established, the precise contributions of tissue-resident memory T (T_RM) cells are still poorly defined. This study sought to define the contribution of CD4⁺ T_RM cells to pulmonary fibrosis, their origin, and regulatory mechanisms. We combined bioinformatic analysis of human fibrotic lung single-cell RNA-sequencing data with experiments in a bleomycin-induced C57BL/6 mouse model. Flow cytometry, targeted in vivo depletion, lymphocyte trafficking blockade, cell co-culture, and pharmacological inhibition were employed. CD4⁺ T_RM cells were observed at higher frequencies within fibrotic lung tissue. Their presence correlated with disease severity, and they were found to exhibit a pro-inflammatory and pro-fibrotic phenotype. Their specific depletion alleviated fibrosis. These cells primarily originated from recruited circulating lymphocytes, as blocking this recruitment reduced T_RM accumulation and attenuated disease. Furthermore, the Notch signaling pathway was activated in fibrotic lung CD4⁺ T_RM cells, and its inhibition suppressed their differentiation and impaired their pro-fibrotic function. We conclude that CD4⁺ T_RM cells are pathogenic drivers in pulmonary fibrosis, originating from circulating precursors and being regulated by Notch signaling, underscoring their relevance for therapeutic intervention. Full article

Objectives: Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) merges multidrug resistance with hypervirulence, posing unprecedented therapeutic challenges. This study aimed to evaluate the efficacy of a recombinant fusion protein vaccine, KPC-Pal, designed to target both the carbapenemase KPC-2 and the virulence-associated peptidoglycan-associated lipoprotein Pal. Methods: The KPC-Pal fusion protein was constructed, expressed, and purified. Its protective efficacy was systematically assessed in a murine pneumonia model by measuring antigen-specific antibodies, cytokine profiles, and memory cell populations. The synergistic effect with the antibiotic meropenem was evaluated both in vitro and in vivo. Furthermore, the interaction with innate immune signaling via TLR2 was investigated. Results: Immunization with KPC-Pal conferred superior protection, resulting in significantly higher survival rates and reduced bacterial burdens in the lungs compared to immunization with either KPC-2 or Pal alone. It induced a robust Th2-biased humoral response and a mixed Th1/Th2/Th17 cellular immune profile, along with enhanced formation of tissue-resident memory T cells. Antibodies generated against KPC-Pal enhanced the efficacy of meropenem in vitro and in animal models, demonstrating a synergistic effect. While Pal alone strongly activated TLR2-driven inflammatory pathways, the KPC-Pal fusion selectively modulated MAPK signaling, mitigating excessive cytokine production. Additionally, KPC-Pal vaccination elicited cross-reactive antibodies against KPC-3 and KPC-33 variants. Conclusions: KPC-Pal functions as both an antigen and a self-adjuvant, offering a promising dual-target strategy for combating K. pneumoniae infections. Full article

Background/Objectives: Cholangiocarcinoma (CCA) is characterized by a heterogeneous immune microenvironment, where the prognostic significance of CD8⁺ tissue-resident memory T (T_RM) cell activation and spatial positioning remains to be fully elucidated. This study investigated how the activation phenotypes and their spatial distribution relative to tumor cells influence anti-tumor immunosurveillance and predict clinical outcomes in CCA. Methods: Multiplex immunohistochemistry (mIHC) and single-cell RNA sequencing (scRNA-seq) were employed to characterize naïve (PD-1⁻CD103⁺CD8⁺) and exhausted (PD-1⁺CD103⁺CD8⁺) subsets. G-cross function analysis was utilized to quantify the spatial proximity between these specific T_RM subsets and tumor cells, correlating the spatial interaction with patient overall survival. Results: scRNA-seq profiling revealed that PD-1⁻CD103⁺CD8⁺ T_RM cells were enriched in genes associated with lymphocyte activation and cytotoxicity, while PD-1⁺CD103⁺CD8⁺ T_RM cells exhibited an exhaustion signature. Spatially, PD-1⁻CD103⁺CD8⁺ T_RM cells exhibited increased interactions with tumor cells, whereas PD-1⁺CD103⁺CD8⁺ T_RM cells showed reduced engagement. Therefore, the close proximity of PD-1⁻CD103⁺CD8⁺ T_RM cells to tumor cells was identified as a significant predictor of favorable clinical outcomes. Conclusions: The activation state of CD8⁺ T_RM cells combined with their spatial localization constitutes a critical prognostic factor in CCA. Effective anti-tumor immunosurveillance relies on the direct engagement of naïve T_RM cells with tumor cells. These findings highlight the potential of PD-1-targeted immunotherapies to remodel the spatial proximity of the tumor microenvironment, potentially promoting the redistribution of effector cells into tumor-proximal regions. Full article

Clarifying the complex interaction between climate risks and the new energy industry chain is of key significance to advancing the energy transition and strengthening industrial chain robustness. This research pairwise-matches the climate physical risk and the climate transition risk with the entire range of the new energy industry chain segments, comprehensively examining the pairwise interactive relationships. By applying the MF-ADCCA series of methods, it was revealed that there are prevalent asymmetric cross-correlated multifractal characteristics between climate risks and the new energy industry. The long-term memory under the upward trend of the market is distinctly stronger than that under the downward trend. Given that this correlation can indirectly reflect market efficiency differences, this paper constructs the Hurst Volatility Sensitivity Index (HVI) and the Hurst Asymmetry Index (HAI) and further proposes the Unified Market Efficiency Index (UMEI). Its innovative advantage resides in the balanced integration of volatility efficiency and structural symmetry, in turn enabling a comprehensive assessment of the new energy market efficiency under climate risk perturbations. Static analysis reveals that the overall market efficiency of the new energy industry under the climate transition risk is generally higher than that under the climate physical risk, and the market efficiency of mature upstream and midstream new energy segments is significantly superior to that of the downstream. Dynamic evolution characteristics indicate that market efficiency has typical time-varying traits, the evolution of which is often driven by significant policies or extreme events. The climate transition risk tends to trigger aperiodic structural adjustments, while the climate physical risk mostly induces periodic efficiency fluctuations. This study furnishes solid evidence for the new energy market in coping with climate risks. Full article

Rapid N-1 security assessment in modern power systems faces a critical conflict between computational timeliness and the heavy reliance on labeled data for high-fidelity models. To mitigate this issue, a unified framework co-optimizing a physics-informed neural network (PINN) and memory-resident computing is proposed. At the algorithm level, power flow equation residuals are incorporated into the PINN formulation as physical regularization terms. This integration facilitates better alignment with electrical constraints and improves generalization capabilities under small-sample conditions. At the system level, a heterogeneity-aware asynchronous parallel computing architecture is developed. In this architecture, pull-based scheduling and lock-free memory mapping are utilized to mitigate straggler effects, thereby reducing synchronization latency and I/O overhead. Numerical case studies on the IEEE 39-bus system demonstrate that the physics mismatch is reduced by nearly two orders of magnitude compared to a baseline deep neural network (DNN), and the total execution time for scanning 20,000 contingencies is decreased by 34.0%. Full article

Background: Immune checkpoint blockade (ICB) has revolutionized lung adenocarcinoma (LUAD) therapy, yet predictive bio-markers remain suboptimal. We hypothesized that BCL2A1 expression in CD8⁺ T cells may reflect immune endurance and complement PD-L1 in predicting ICB response. Methods: Integrating bulk and single-cell RNA-seq across multiple LUAD cohorts, this study performed differential expression, survival, and pathway analyses in a discovery cohort (n = 60) and validated findings across five independent cohorts (n = 126). Results: Single-cell profiling identified BCL2A1 enrichment in tissue-resident memory and proliferating subsets that appeared preferentially expanded in responders; cell–cell communication analysis revealed that BCL2A1^high CD8⁺ T cells exhibited significantly enhanced outgoing signaling capacity (p = 0.0278), with proliferating subsets serving as intra-CD8⁺ coordination hubs and MIF pathway interactions achieving the highest intensity among all axes examined. BCL2A1 was significantly upregulated in responders (FDR < 0.05) and associated with improved ICB survival (HR = 0.43, p < 0.05), but not in non-ICB settings, suggesting treatment-specific prognostic relevance. A tri-marker model integrating BCL2A1, PD-L1 (CD274), and a 27-gene HOT score demonstrated favorable predictive performance (AUC = 0.826 discovery; macro-AUC = 0.774 validation), outperforming PD-L1 alone (AUC = 0.706) and established signatures including TIDE, IPS, TIS, and IFNG. Cross-platform simulations suggested high reproducibility (ρ = 0.982–0.993). Conclusions: These findings suggest BCL2A1 may serve as a bio-marker of CD8⁺ T-cell survival and enhanced intercellular coordination, and its integration with PD-L1 and immune activation markers may yield a reproducible ICB response predictor, pending clinical validation. Full article

Age-related chronic, low-grade inflammation, known as inflammaging, contributes to tissue damage and disease. In the lungs, inflammaging leads to abnormal tissue remodeling, reduced function, and decreased immunity. A key factor in inflammaging is declining acetylcholine signaling, which normally suppresses inflammation and promotes tissue repair. We tested whether increasing acetylcholine responsiveness could reverse age-related lung damage. Aged mice were treated with donepezil to increase acetylcholine availability. After six months, blood oxygen saturation and voluntary activity were significantly improved. Histologically, treated mice showed a reversal of alveolar enlargement (a hallmark of emphysema) and complete restoration of elastic fibers. Donepezil treatment also dramatically increased bronchus-associated lymphoid tissue (iBALT) formation. iBALT is the repository of tissue-resident memory lymphocytes, including memory cholinergic lymphocytes that produce acetylcholine to suppress inflammation during secondary infections. The age-related loss of iBALT contributes to the increased risks associated with respiratory infection in the elderly. This indicates that age-related lung function and respiratory immune deficits can be modulated by improving acetylcholine signaling. Repurposing an approved medication provides a direct pathway to clinical application for improving respiratory health and infection resistance during aging. Full article

This study investigates how a Long Short-Term Memory (LSTM) model internally represents baseflow contributions in snowmelt-driven, semi-arid mountain basins with heterogeneous geologic characteristics. Five basins in the Sangre de Cristo Mountains of northern New Mexico, spanning fractured Precambrian bedrock and sedimentary-volcanic terrain, were used to evaluate both model performance and interpretability. Baseflow dynamics were inferred post hoc using the Baseflow Index (BFI) and a two-reservoir HEC-HMS (Hydrologic Engineering Center’s Hydrologic Modeling System) model. Although baseflow components were not explicitly included in model training, internal cell state activations exhibited strong correlations with both shallow and deep baseflow components derived from the HEC-HMS model. To better understand how these relationships may change under climatic stress, BFI-based baseflow patterns were further analyzed under pre-drought and drought conditions. Results indicate that the internal LSTM states differentiated patterns consistent with short- and long-residence flow paths, reflecting physically interpretable hydrologic behavior. This work demonstrates the potential of LSTM models to provide valuable insights into baseflow generation and groundwater–surface water interactions, which is especially critical in water-scarce regions facing increasing drought frequency. Full article

This study examines how the sense of home for people with dementia is shaped not only by physical settings but by dynamic atmospheric compositions emerging through memory, sensation, and everyday practices. Building on a preliminary literature mapping that identified three dimensions of home in later-life care environments—safe space, small world, and connection—we developed a multisensory co-design toolkit combining key-element cards and curated olfactory prompts. The study was conducted in a dementia-friendly residential care facility in Italy. Nine residents with mild–moderate dementia (aged 75–84) participated in two group sessions and six individual sessions, facilitated by two design researchers with care staff present. Data consist of audio-recorded and transcribed interviews, guided olfactory sessions, and researcher fieldnotes. Across sessions, participants articulated “small worlds” as micro-environments composed of meaningful objects, bodily comfort, routines, and sensory cues that supported emotional regulation and identity continuity. Olfactory prompts, administered through a low-intensity and participant-controlled protocol, supported scene-based autobiographical recall for some participants, often eliciting memories of domestic rituals, places, and relationships. Rather than treating home-like design as a fixed architectural style, we interpret home as continuously re-made through situated sensory–temporal patterns and relational practices. We translate these findings into atmospheric design directions for dementia care: designing places of self and refuge, staging accessible material memory devices, embedding gentle olfactory micro-worlds within daily routines, and approaching atmosphere as an ongoing process of co-attunement among residents, staff, and environmental conditions. The study contributes a methodological and conceptual framework for multisensory, narrative-driven approaches to designing home-like environments in long-term care. Full article