Immunosenescence-the age-associated remodeling of the immune system-has emerged as a potential modifier of chronic inflammatory disease. This review examines the evidence that immunosenescence may contribute to the chronicity, refractoriness, and therapeutic heterogeneity of uveitis, and considers the clinical and translational implications of this framework. It first outlines the features of immune aging, including thymic involution, contraction of the naïve T cell pool, accumulation of memory and terminally differentiated populations, and a chronic low-grade inflammatory state (inflammaging), and discusses signaling pathways that have been associated with these processes, including AMPK-mTOR, NF-κB, cGAS-STING, and JAK-STAT. It then evaluates three complementary but unequal lines of evidence relevant to uveitis: direct human observations from peripheral blood and intraocular fluids, mechanistic support from experimental models, and contextual inference from age-associated ocular disorders. Collectively, these data suggest that age-related immune remodeling may promote breakdown of ocular immune privilege, blood-retinal barrier dysfunction, persistent cytokine signaling, and incomplete response to conventional therapy in selected uveitis phenotypes. Finally, this review discusses therapeutic implications, including Treg enhancement, cytokine-directed approaches, and advanced drug delivery, while emphasizing that direct evidence of immune rejuvenation in human uveitis remains lacking. Ageing does not simply amplify ocular inflammation; it may attenuate selected acute immune responses while impairing resolution and tissue resilience, with effects that depend on disease context. By bridging geroscience and ocular immunology, this review offers a translational framework for understanding refractory intraocular inflammation and highlights future priorities for biomarker development, patient stratification, and precision medicine in uveitis.

Accurate identification of allergenic proteins is critical for allergic mechanism research, clinical allergy diagnosis and targeted immunotherapy. Current prediction methods suffer from three critical drawbacks: insufficient modeling of residue spatial structures, shallow cross-modal feature fusion without bidirectional interaction, and poor generalization ability on low-homology allergens with rare conformations. To tackle these challenges, this paper constructs a dual-branch multimodal fusion model combining Bidirectional Long Short-Term Memory (Bi-LSTM) and Graph Attention Network (GAT). The Bi-LSTM branch captures sequential contextual correlations of protein physicochemical features, while the GAT branch mines spatial interaction relationships between amino acid residues from protein graph structures. A four-head bidirectional cross-modal attention module is designed to realize deep dynamic information interaction between two modalities and fully exploit their complementary information. Furthermore, a self-supervised node feature reconstruction auxiliary task is integrated into the training process, paired with label-smoothed Focal Loss to form a dual-loss optimization framework, which enhances the discriminability of extracted features and improves model robustness on rare allergen samples. Experiments conducted on a balanced allergen dataset containing 10,000 protein sequences demonstrate that our model achieves state-of-the-art performance, with Accuracy and F1-Score both reaching 0.9980, outperforming 14 mainstream baseline models across all six evaluation metrics. Ablation experiments and t-SNE feature visualization further verify the synergistic effectiveness of each core module in the proposed architecture. The multimodal fusion framework proposed in this work provides an effective computational tool for large-scale high-precision allergen protein screening and offers a reference paradigm for other protein property prediction tasks in bioinformatics.

Schizophrenia (SCZ) is a serious neuropsychiatric disorder with a complex etiology. Neuroinflammation has received much attention as a crucial contributor to the pathogenesis of SCZ. S-propargyl-L-cysteine (SPRC), a synthesized analog of S-allyl-L-cysteine, increases endogenous hydrogen sulfide (H2S) synthesis and exerts potent antioxidative and anti-inflammatory effects. However, its potential role in SCZ-related neuroinflammation remains unclear. The aim of the present study was to investigate whether SPRC protects against ketamine-induced schizophrenia-like symptoms and to explore underlying mechanisms related to cystathionine-γ-lyase (CSE)/H2S signaling and nuclear factor-κB (NF-κB) activation. Behavioral alterations were assessed using the open-field test, Y-maze test, and prepulse inhibition analysis. Neuronal damage in the hippocampus was evaluated using Nissl staining, while changes in the CSE/H2S pathway, mature brain-derived neurotrophic factor (mBDNF), inflammatory pathways, and pyroptosis pathway were also analyzed. SPRC was found to effectively reverse ketamine-induced hyperactivity and anxiety, as well as improve working memory and sensorimotor gating defects. Furthermore, SPRC prevented neuronal loss across the hippocampal CA1, CA3, and dentate gyrus subregions. The mechanism of action involves the reversal of CSE activity and H2S production, maintenance of mBDNF, as well as the suppression of NF-κB translocation. This is also characterized by reduction in tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. Additionally, SPRC inhibited nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation, caspase-1-mediated pyroptosis, and interleukin-1β (IL-1β) secretion. Taken together, these findings demonstrate that SPRC alleviates ketamine-induced behavioral deficits and neuroinflammation in mice, likely via restoration of the CSE/ H2S pathway and suppression of NF-κB/NLRP3-mediated pyroptosis.

Mild cognitive impairment (MCI) is a clinically heterogeneous condition characterized by substantial variation in structural abnormalities and cognitive impairment. However, existing neuroimaging-based approaches are limited by insufficient modeling of coordinated gray-white matter alterations and vulnerability to site effects in multi-center data. Here, we propose a Macro-Micro Structural Integration (MMSI) framework for characterizing structural-deviation heterogeneity and identifying imaging-derived MCI subgroups. The framework integrates gray-matter morphological features derived from structural magnetic resonance imaging and white-matter microstructural features derived from diffusion MRI. A Dual-Condition Variational Autoencoder was developed to separate biological variation from site-related effects and learn a site-robust normative representation using cognitively normal participants. Tract-specific MMSI scores were subsequently derived to quantify each participant's structural deviation from the normative reference. In a multi-center clinical cohort (N = 860), Gaussian mixture modeling of the tract-wise MMSI profiles identified lower- and higher-deviation MCI subgroups that exhibited significant differences in global cognition, delayed memory, and word recognition. Comparisons with conventional imaging biomarkers, machine-learning classifiers, and statistical harmonization methods further supported the value of the proposed framework. Evaluation in the Alzheimer's Disease Neuroimaging Initiative cohort demonstrated a concordance accuracy of 0.769 between the imaging-derived groups and the clinically predefined early- and late-MCI categories, exceeding the gray matter-only and white matter-only models by 7.7 and 12.3 percentage points, respectively. Transcriptomic association analysis identified KRT77 and CACNA1B as significantly associated with tract-specific MMSI scores after false discovery rate correction. Functional enrichment of the PLS-derived MMSI-associated gene set implicated biological processes related to neural signal transduction, learning and memory, calcium signaling, and immune responses. Together, these findings indicate that the MMSI framework provides a site-robust and interpretable approach for characterizing cross-sectional structural-deviation heterogeneity in MCI and offers preliminary biological support for the identified imaging patterns.

High-performance photonic computing fundamentally demands physical memory units that are both low-loss and cost-effective. In this work, four sets of microfiber knot resonators (MKRs) were fabricated using a three-electrode tapering technique, featuring insertion loss below 0.2 dB and quality factors ranging from 104 to 105. The devices are subsequently packaged with polydimethylsiloxane (PDMS), maintaining a total loss less than 1.0 dB. Utilizing these packaged MKRs, a feedback-free photonic reservoir computing (FF-PRC) system is constructed. Experimental results demonstrate that as the Q-factor increases, the normalized mean square errors (NMSEs) for the Mackey-Glass and Santa Fe time-series prediction tasks dropped from 0.390 and 0.420 to 0.022 and 0.034, respectively, while the system achieves a classification accuracy of 97.5% on the MNIST dataset. The proposed FF-PRC system, enabled by ultra-low-loss MKRs, exhibits low-error and high-accuracy performance in processing complex temporal tasks. This eliminates the need for external feedback loops specifically for computing tasks whose memory requirements match the intrinsic photon lifetime of the MKRs, offering a standalone and cost-effective memory unit solution for neuromorphic photonic edge nodes.

Conventionally, vaccine design has focused on identifying antigens that induce durable T and B cell memory and provide long term protection against subsequent encounters with the same pathogen. Unconventionally, a growing number of epidemiological, preclinical, and clinical studies demonstrate that live vaccines, including Bacillus Calmette Guérin (BCG), measles-containing vaccines, and oral polio vaccine, induce protection through trained immunity, a form of metabolically and epigenetically mediated memory in innate immune cells and their progenitors. This concept is particularly relevant during early life, when adaptive immune responses are constrained and innate immunity represents the principal line of host defence. In this review, we discuss the unique characteristics of neonatal and infant immunity, summarize current evidence for trained immunity induced by childhood vaccines, and describe the bidirectional interplay between innate and adaptive immune memory. We further highlight the potential of trained immunity to broaden protection against severe infections, improve vaccine efficacy, and provide therapeutic opportunities for non-infectious paediatric diseases, including cancer and allergic disorders. Harnessing trained immunity represents a conceptual shift in paediatric vaccinology and may guide the development of next generation vaccines that provide broader and more resilient protection during the period of greatest immunological vulnerability.

BackgroundHearing loss is a well-established risk factor for dementia. However, the clinical relevance of everyday listening difficulties after the diagnosis of Alzheimer's disease (AD) remains insufficiently understood, particularly in relation to cognition and behavioral and psychological symptoms of dementia (BPSD). Functional hearing difficulty refers to perceived difficulties in everyday listening situations that are not fully captured by standard audiometric thresholds.ObjectiveTo examine the associations between caregiver-rated functional hearing difficulty, cognitive measures commonly used in clinical practice, and overall BPSD severity in patients with AD.MethodsThis single-center cross-sectional study included 101 patients with clinically diagnosed AD attending a memory clinic. Functional hearing difficulty was assessed using a caregiver-based structured interview. Associations with widely used cognitive measures and BPSD severity, operationalized as the Neuropsychiatric Inventory five-domain total score, were examined using regression models adjusted for relevant covariates.ResultsGreater functional hearing difficulty was selectively associated with poorer verbal fluency, whereas no significant associations were observed with other cognitive measures. Functional hearing difficulty was also associated with greater BPSD severity. Exploratory analyses showed a pattern statistically consistent with an indirect association via verbal fluency.ConclusionsCaregiver-rated functional hearing difficulty was selectively linked to verbal fluency and BPSD severity in patients with AD. These findings suggest that functional hearing difficulty may capture communication-related cognitive processes relevant to everyday functioning beyond global disease severity, although longitudinal studies are needed to clarify temporal relationships.

The dorsal striatum, recognized as a primary input nucleus of the basal ganglia, has traditionally been viewed as a crucial center for motor control. However, emerging evidence over the past five decades has sparked a paradigm shift, underscoring its vital role in a wide array of higher-order cognitive functions such as procedural learning, habit formation, working memory, executive function, and inhibitory control. This expanded understanding is grounded in the dorsal striatum's intricate architecture, which includes GABAergic Medium Spiny Neurons (MSNs) that form both the direct and indirect pathways, a diverse array of interneurons, and a compartmental organization characterized by striosomes and matrix. Furthermore, the dorsal striatum plays a pivotal role within the cortico-basal ganglia-thalamo-cortical loops and is influenced by the midbrain dopaminergic system. Dysfunction of the dorsal striatum, marked by neurotransmitter imbalances-such as dopaminergic depletion in Parkinson's Disease (PD) and cholinergic deficits in Alzheimer's Disease (AD)-along with synaptic plasticity impairments and the aggregation of pathological proteins (e.g., α-synuclein in PD and amyloid-β/tau in AD), is closely associated with cognitive decline in major neurodegenerative disorders. This review aims to provide a systematic overview of the structural and functional foundations of the dorsal striatum in cognitive regulation. It delineates the pathological mechanisms that contribute to cognitive impairments observed in PD and AD and addresses current challenges as well as future research directions. The goal is to establish a comprehensive framework that positions the dorsal striatum as a shared therapeutic target for cognitive dysfunction across various diseases, thereby offering valuable insights for the development of early diagnostic biomarkers and innovative intervention strategies.

The reduction of α7 nicotinic acetylcholine receptor (nAChR) in the hippocampus con-stitutes one of the neuropathological features observed in the brains of individuals with Alzheimer's disease (AD), and α7 nAChR is crucial to cognitive process. However, studies involving α7 nAChR knockout mice have not demonstrated any abnormal brain structure or damage to hippocampal neurons, a discrepancy likely driven by widespread developmental compensatory signaling reprogramming triggered by permanent whole-body α7 nAChR deletion from embryonic stages. This limitation renders traditional knockout lines unable to recapitulate the adult-onset, hippocampus-restricted α7 nAChR insufficiency characteristic of human AD, creating an unaddressed knowledge gap regarding whether isolated α7 nAChR loss in mature hippocampal neurons independently drives AD-related neurodegeneration and cognitive dysfunction.

Replicating systems sustained by error-prone enzymatic amplification can undergo critical transitions between persistence and extinction. In RNA viruses, such transitions are classically governed by mutation rates and fitness landscape topographies, giving rise to error thresholds and lethal mutagenesis. Motivated by experimental evidence that polymerase-targeting antivirals limit replication, we analyze replicating systems with explicit time lags in replication-enzyme availability by means of delay differential equations. Our approach is not equivalent to a simple renormalization of the rate of replication, since explicit delays introduce memory and temporal nonlocality into the dynamics. We identify a lag-induced critical transition driven by the loss of temporal coordination between genome expression and replication. At fixed mutation and replication rates ensuring persistence, populations cross an extinction threshold solely due to replication delays. In our delay-extended quasispecies model, the timing of replicase availability emerges as an independent dynamical control parameter, defining a route to extinction that is fundamentally distinct from transitions driven by mutation rates or replicative fitness. These results further suggest that perturbing the temporal coordination of viral replication may provide an alternative antiviral strategy for driving viral populations toward collapse. More generally, we propose that the extinction mechanism described here constitutes a form of lag-time-induced tipping, which we denote as τ-tipping.

Memories of winning experiences reinforce dominance hierarchies, yet mechanisms encoding these long-lasting "winning memories" remain unclear. Here, we introduce a combined Tube & Conditioned Place Preference (CPP) paradigm and applied fiber photometry, genetic manipulations, and optogenetics to characterize social competition between adult male mice. We found that initial victories trigger dopamine D2 receptor-mediated calcium activities of astrocytes in the medial prefrontal cortex (mPFC) and subsequent glutamate release. This mechanism enhances dopaminergic responses in mPFC neurons projecting to the nucleus accumbens (NAc), thereby consolidating winning memories. Upon ablation of D2 receptors in mPFC astrocytes, this effect is abolished, hindering generation of new dominance memories and a stable social hierarchy. Our findings reveal an astrocyte-driven mechanism by which mesocortical dopamine signaling reinforces victory-related neural plasticity, and provide broad insights into the cellular basis of social dominance and its underpinnings in motivational and affective disorders.