The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdh high DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1 high interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.

Traumatic brain injury (TBI) frequently results in persistent emotional and cognitive dysfunction, yet the neural mechanisms underlying these deficits remain incompletely understood. This study examined the impact of non-severe TBI (nTBI) on emotional processing, with a focus on brain activation, functional connectivity, effective connectivity, and their relationship to cognitive performance. Twenty right-handed male nTBI participants (mean age: 30.70 11.78 years) and 20 age-matched healthy male controls (mean age: 27.85 7.73 years) underwent functional magnetic resonance imaging (fMRI) while viewing emotional images from the International Affective Picture System (IAPS). Brain activation was analyzed using Statistical Parametric Mapping (SPM12). Functional connectivity was assessed with seed-based analysis (medial visual network, mVN) using the CONN toolbox. Effective connectivity was evaluated using dynamic causal modeling (DCM) and parametric empirical Bayes (PEB). Neuropsychological assessments covering memory, intelligence, and executive function were included to characterize general cognitive function within the cohort, with exploratory analyses examining relationships with connectivity measures. Compared to controls, the nTBI group exhibited reduced activation in the calcarine cortex and lingual gyrus during emotional processing. Functional connectivity analysis showed decreased mVN connectivity with the frontal pole and dorsal anterior cingulate cortex (dACC), with increased mVN-ACC and mVN-supramarginal gyrus connectivity specifically during negative emotion processing. Effective connectivity analysis revealed altered directional influences within visual-limbic-cognitive control networks, including altered mVN-to-dACC and right amygdala-to-dACC connectivity patterns, as well as valence-specific modulation of self-inhibition. Exploratory analyses suggested potential correlations between connectivity alterations and cognitive performance, though these relationships varied across domains and should be interpreted cautiously. Non-severe TBI disrupts emotional network function by altering both functional and effective connectivity, particularly in visual, limbic, and cognitive control regions. These alterations may contribute to emotional dysregulation following injury. Findings support the relevance of brain connectivity-based markers in understanding post-TBI emotional processing and highlight potential targets for intervention. Interpretations should be made cautiously, given the study limitations, including the use of static visual stimuli and a homogenous male sample.

Cognitive-behavioral therapy (CBT) is the first-line treatment for obsessive-compulsive disorder (OCD), yet a significant number of patients do not achieve remission or substantial symptom relief. This study aims to enhance the prediction of CBT outcomes in OCD by integrating demographic, clinical, and neuroimaging data using machine learning (ML) models. We conduct a comprehensive analysis on a well-characterized clinical sample, employing a rigorous validation scheme to avoid data leakage, and comparing multiple ML algorithms to minimize bias. Out of four different ML models trained on demographic and clinical data, structural MRI, and resting-state MRI functional connectivity data, no model was able to predict CBT success significantly above chance level in the present sample. Although clinical and demographic data enabled 64%-66% accuracy for predicting remission, this did not reach statistical significance after permutation testing. Pre-treatment symptom severity emerged numerically as the most promising predictor of remission, aligning with previous studies, but did not pass the significance threshold in the present study. Despite efforts to identify neuroimaging predictors, neither functional nor structural MRI features significantly contributed to the prediction models. These findings suggest that robust, individualized brain-based predictions for mental health outcomes remain challenging with the available data and sample size.

Somatic mechanical stimulation (e.g., acupuncture) exerts systemic immunomodulatory effects, yet the cellular bridge translating peripheral physical force into visceral repair remains elusive. Here, employing a custom interpretable deep learning framework (CARSS) on single-cell RNA sequencing data, we identify CD34 + PDGFR + telocytes (CPTCs) as the primary mechanosensors in both fascia and colon during bacterial colitis. We show that somatic mechanotherapy triggers an AP-1/Hsp70-dependent transcriptional program in fascial CPTCs, inducing systemic Wnt elevation, which elicits a "transcriptional resonance" in colonic CPTCs, reprogramming their communication network from an inflammatory amplifier to a Wnt-driven regenerative hub. Mechanistically, this axis activates epithelial -catenin/Myc signaling, suppressing apoptosis and restoring barrier integrity independent of immune cells. Our findings define a CPTC-Driven Mechano-Resonance Axis, where CPTCs serve as synchronized relay stations that convert somatic mechanical stimulation into systemic regenerative microenvironments.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition shaped by both genetic predispositions and environmental influences. Early-life stresses (ELS), notably maternal separation (MS), can lead to behavioral impairments similar to core ASD features. Recent research indicates that disruptions in the gut-brain axis may significantly contribute to the neuropsychiatric effects of ELS. This study investigates the role of chlorogenic acid (CGA), a plant-derived polyphenol, in a mouse model of MS-induced ASD-like behaviors. Mice subjected to MS were treated with CGA via intraperitoneal injection over 2 weeks. Behavioral assessments included the open field, passive avoidance, elevated plus maze, marble burying, and three-chamber social interaction tasks. Histologic changes were assessed using H E staining. Alterations in antioxidant capacity and gene expression were assessed in hippocampal and colonic samples using the FRAP method and qRT-PCR, respectively. CGA administration led to marked improvements in behavioral functions, such as enhanced memory, increased social engagement, and reductions in repetitive, depression, and anxiety-like behaviors. At the molecular level, CGA treatment was associated with lower hippocampal oxidative stress, elevated antioxidant capacity, decreased levels of hippocampal inflammatory markers, alongside beneficial histological changes in hippocampus and colon samples. Furthermore, CGA modulated the expression of tight junction proteins like Claudins (CLDN1, CLDN5, and CLDN12) in the colon and hippocampus, suggesting a protective effect on gut and brain barrier integrity. In summary, MS disrupts the neuro-immune balance and behavior by affecting the gut-brain axis. CGA shows promise in restoring these systems, highlighting its potential as a complementary intervention for conditions related to ASD.

The endocannabinoid system (ECS) plays a key role in regulating neurogenesis and inflammatory processes in the brain. The increasing prevalence of Cannabis use among women highlights the importance of understanding sex-specific effects of cannabinoids, particularly in the context of hormonal interactions. This study aimed to investigate the effects of delta-9-tetrahydrocannabinol (THC) and estradiol benzoate (EB) on adult hippocampal neurogenesis (AHN) and inflammation in ovariectomized female Wistar rats. Sixteen rats were allocated to four experimental groups receiving THC, EB, both treatments, and vehicle. Immunohistochemical analyses were conducted to evaluate markers of proliferation (Ki-67), neurogenesis (doublecortin and PSA-NCAM), cannabinoid receptor expression (CB1), and inflammation (COX-2 and TNF- ) in the hippocampal formation. The administration of THC significantly increased Ki-67 immunoreactivity, suggesting enhanced cell proliferation. A trend toward increased doublecortin expression was observed, particularly in EB-treated animals. THC also modulated CB1 receptor expression, with significant increases in the dentate gyrus and hilus following combined THC and EB treatment. Furthermore, THC reduced inflammatory markers, with region-dependent decreases in COX-2 and TNF- expression. These findings indicate that THC influences markers associated with hippocampal cell proliferation, neurogenesis, cannabinoid signaling and inflammation in female rats, and that some of these effects depend on estradiol status. The interaction between cannabinoids and gonadal hormones may represent an important mechanism underlying sex-specific neurobiological responses and suggests potential targets for therapeutic intervention in neuropsychiatric disorders.

Chronic neuroinflammation in response to abnormal protein aggregates has been implicated as a critical mechanism in several neurodegenerative diseases, and the modulation of signaling pathways associated with inflammation is being explored as a potential strategy for new therapeutics. In Alzheimer's disease (AD), the neuroinflammation hypothesis also starts to influence the landscape of drug discovery in place of the previously regarded amyloid hypothesis. As such, the objective of this review is to compile recent advanced in the discovery of anti-neuroinflammatory compounds developed through chemical synthesis and structural modification, providing an overview of current trends in drug discovery strategies and scaffold redesign for the development of the next-generation of anti-neuroinflammatory therapeutics. It was found that the compounds described in the publications could be categorized into four groups: modification of natural compounds, rational drug design, drug screening approaches, and drug repurposing. While the categorization seems to be similar to drug discoveries in other fields, with the modification of natural compounds accounting for most publications, specific observations could still be made. Namely, the growing interest in the multitarget-directed ligand approach reflects the increasing recognition of AD as a multifactorial disease. Despite this, further research is required to identify additional effective activities or the appropriate combinations besides anti-neuroinflammatory activity. Lastly, this review also gives brief overview regarding physicochemical properties of central nervous system-active agents, of which anti-neuroinflammatory compounds are parts of, and suggests the adoption of in silico prediction models as screening tools before the use of in vitro or in vivo models.

RhoA-a member of the Rho family of GTPases-critically regulates synaptic plasticity and immune cell function, which have emerged as key mechanisms in schizophrenia pathogenesis. In this study, we measured RHOA mRNA expression levels in the peripheral blood mononuclear cells (PBMCs) from patients with acute schizophrenia and healthy controls. We also conducted integrative bioinformatics analyses to investigate transcription factors (TFs) and genetic variants in miRNAs predicted to regulate RHOA mRNA expression in schizophrenia. Quantitative real-time PCR (qPCR) revealed a significant upregulation of RHOA mRNA expression in the PBMCs from patients with acute schizophrenia compared with controls. Although sex-stratified analysis showed a significant association in males, the group sex interaction was not significant. Moreover, multivariable robust regression adjusted for sex, educational level, age, BMI, and smoking confirmed a significant group effect, reflecting higher RHOA mRNA expression in patients than in controls. Integrative bioinformatics analyses identified five candidate miRNAs (hsa-miR-183-3p, hsa-miR-574-5p, hsa-miR-4429, hsa-miR-4686, and hsa-miR-5002-5p) that were differentially expressed in schizophrenia and predicted to target RHOA. Subsequent analysis revealed six variants within these candidate miRNAs with the highest predicted G values and potential to affect mature miRNA expression. Moreover, 10 hub TFs (EP300, HDAC1, TP53, CREBBP, HDAC2, ESR1, MYC, JUN, SP1, and BRCA1) were predicted to regulate RHOA mRNA expression. These findings suggest that RHOA upregulation in PBMCs may be associated with the pathophysiology of schizophrenia. Further investigations are needed to validate these results and elucidate the mechanistic role of RHOA dysregulation in the disorder.

Dysfunctional microRNAs and GABAergic interneurons are features of Alzheimer's disease (AD). The role of neuronal microRNA155 (miR155), elevated in both AD and Down syndrome (DS), remains unknown. We utilized in silico analyses of published databases, MIR155-deleted and -overexpressing human induced pluripotent stem cell (hiPSC)-derived cells, cortical organoids, and amyloid beta precursor protein (APP)/PS1-miR155 knockout mouse. MIR155HG (miR155 host gene) colocalizes with APP in a neuron-specific, topologically associated domain (TAD) in chromosome 21. In human neural stem cells (NSCs), neurons, and cortical organoids, MIR155 deletion enhanced NSC proliferation and GABAergic interneuron generation. MIR155 overexpression inhibited NSC marker expression and GABAergic interneuron generation. In APP/PS1 mice, miR155 deletion induced the expansion of hippocampal NSCs and increased hippocampal GABAergic interneurons. Our findings, alongside the extensive studies of the role of microglial miR155 in neuroinflammation, reveal previously unrecognized miR155 roles in hippocampal NSC dynamics and GABAergic interneuron development, highlighting miR155 as a therapeutic target.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated peripheral neuropathy with heterogeneous and often incomplete responses to current immunotherapies, but the underlying immune basis remains poorly defined. Although CIDP shares features of immune-mediated demyelination with multiple sclerosis (MS), the two diseases affect distinct anatomical compartments and exhibit divergent therapeutic responses, suggesting fundamentally different underlying immune programs. Here, we address this gap by defining the peripheral immune architecture of CIDP using an integrated, multi-modal approach. Peripheral blood was obtained from 20 patients with CIDP and 20 age- and sex-matched healthy controls. Single-cell RNA sequencing was performed in a discovery subset and integrated with publicly available MS peripheral blood datasets to provide a cross-disease reference framework. The single-cell analysis was designed as an exploratory discovery step to identify candidate immune signatures. Transcriptomic, pathway, and ligand-receptor analyses were complemented by cytokine profiling and flow-cytometric validation in the full cohort. CIDP exhibited broad inflammatory activation with preferential enrichment of type I interferon and inflammasome-related programs compared with MS. Despite reduced B-cell frequencies, CIDP showed transcriptional enrichment of germinal center-associated programs, indicating a dissociation between cell number and activation state. In parallel, CD8 effector T cells demonstrated enhanced cytotoxicity and cytoskeletal remodeling programs, supported by increased expression of actin-regulatory genes and strengthened intercellular signaling interactions. In contrast, MS showed greater enrichment of integrin-talin-vinculin signaling pathways in B cells and CD4 T-cell subsets, consistent with trafficking-related immune mechanisms. Together, these findings indicate a coordinated immune axis linking B-cell dysregulation and cytotoxic CD8 T-cell activation in CIDP. Integrated peripheral immune profiling identified candidate CIDP-associated immune signatures including dysregulated B-cell activation despite numerical reduction and a prominent cytotoxic CD8 T-cell program within a type I interferon- and inflammasome-skewed inflammatory milieu. These findings provide an exploratory framework for understanding peripheral immune dysregulation in CIDP and warrant further translational studies in larger, treatment-stratified cohorts.

The dialogue between the immune and nervous systems in the central nervous system (CNS) is a fundamental challenge in neuroscience and neuroimmunology. Microglia, the brain's resident immune cells, continuously communicate with neurons to maintain brain homeostasis, support development, and orchestrate responses to injury. We adapted the CEBPA/SPI1 transcription factor overexpression approach to generate induced microglia-like cells (iMG) from human embryonic stem cells (hESCs), establishing a reproducible and standardized baseline framework for neuron-microglia co-culture. iMG characterization included assessment of key microglial markers (GPR34, MMP9, TMEM119, IBA1, P2Y12), phagocytic capability benchmarked against the human microglial cell line HMC3, and high-resolution scanning electron microscopy (SEM). iMGs were then co-cultured with hESC-derived NGN2-induced neurons (iNeu), with systematic optimization of seeding ratios and temporal parameters. iMGs expressed key microglial markers and demonstrated phagocytic capabilities comparable to HMC3 cells. In co-culture, iMGs exhibited remarkable phenotypic plasticity, with upregulation of both homeostatic and activation-associated microglial genes. Reciprocally, neurons showed increased expression of maturation and synaptic markers, indicating a bidirectional crosstalk. SEM revealed spatially variable iMG morphology - transitioning from ramified to amoeboid forms depending on proximity to neuronal structures. This contact-based in vitro system provides a versatile platform for investigating neuroimmune interactions, designed to be further integrated with additional CNS cell types, and applicable to the study of microglial activation, neuron-microglia signalling, and the impact of infections on CNS homeostasis.

This study aimed to construct a multidisciplinary medication management program based on the Timing It Right Theory (TIR) and evaluate its effects on medication adherence, medication beliefs, and medication knowledge in patients with ischemic stroke. A total of 143 patients with ischemic stroke from a tertiary hospital in Zhejiang from January to October 2024 were enrolled in the study. To avoid cross-contamination, patients were assigned to an intervention group ( n = 70) and a control group ( n = 73) based on their hospital floor. The research team systematically searched relevant Chinese and English databases and developed a TIR-based Medication Management Program for patients with ischemic stroke. The control group received routine medication guidance and discharge education. In addition to routine care, the intervention group received TIR-based medication management from admission to 3 months after discharge. Medication knowledge was assessed using Medication Knowledge Questionnaire at baseline and discharge. Medication adherence and medication beliefs were assessed using the 8-item Morisky Medication Adherence Scale and the Beliefs about Medicines Questionnaire-Specific at baseline, discharge, and 1 and 3 months after discharge. The trends and differences between the two groups were analyzed. Non-significant differences were found in baseline scores of medication knowledge, medication adherence, or medication beliefs between the two groups ( p 0.05). At discharge, the medication knowledge score in the intervention group (38.21 6.02) was significantly higher compared to that in the control group (34.62 4.98) ( p 0.05). Repeated measures analysis of variance demonstrated significant differences in medication adherence and medication belief scores between the two groups at discharge, 1 month after discharge, and 3 months after discharge ( p 0.05). Medication adherence scores in the intervention group were higher than those in the control group at all follow-up time points. In the Beliefs about Medicines Questionnaire, the intervention group had higher necessity scores and lower concerns scores than the control group, and the differences were statistically significant ( p 0.05). The multidisciplinary medication management program assigned to TIR can effectively improve medication knowledge, optimize medication beliefs, and enhance medication adherence in patients with ischemic stroke.

Restraint stress is known to induce damage to vital organs. Previous work indicates that acute restraint stress (ARS) causes significant hepatic injury in mice. Interestingly, while the liver gradually recovered following removal of the stressor, stress-induced behavioral abnormalities persisted for up to 7 days after stress cessation. Soluble epoxide hydrolase (sEH) plays a key regulatory role in neuroinflammation and mood disorders. However, whether and how hepatic sEH upregulation contributes to ARS-induced neurological damage remains unknown. In a mouse model of ARS, behavioral tests were used to assess neurological impairment. Hepatic function was evaluated by blood flow measurement, metabolomics, and serum ALT/AST levels. Hepatic sEH expression was examined by IHC and western blot, and EETs and IL 6 were quantified with biochemical kits. Microglial activation and neuronal injury in the hypothalamus were assessed by IHC, and IL 6 expression in hypothalamic neurons was visualized by immunofluorescence double staining. Restraint stress-induced behavioral abnormalities in mice. These abnormalities persisted for at least 7 days and were accompanied by reduced hepatic blood flow, liver injury, and perturbation of arachidonic acid metabolism. Stress markedly upregulated hepatic sEH expression, decreased epoxyeicosatrienoic acids (EETs), and increased interleukin-6 (IL-6). In the hypothalamus, sEH expression was elevated, microglia exhibited M1-type activation (CD86+), and neuronal loss occurred, while IL-6 levels within hypothalamic neurons was increased. Treatment with the sEH inhibitor TPPU significantly ameliorated stress-induced behavioral abnormalities, liver injury, hypothalamic neuroinflammation, and the abnormal intraneuronal increase of IL-6. These findings reveal that ARS elicits behavioral abnormalities via the liver-brain axis mediated by hepatic sEH upregulation, which reduces EETs and promotes IL-6 release, leading to hypothalamic microglial activation and subsequent neuronal injury. These results identify hepatic sEH as a potential therapeutic target and highlight the liver-brain axis as a critical mediator in ARS-induced behavioral abnormalities and neurological damage.

The complex interplay between brain regions that support emotional experience and their link to individual differences is a topic of active research. Additionally, there has been growing interest in using functional gradients to investigate human cortical organization during both rest and film fMRI. Among these, several studies demonstrated improved brain fingerprinting performance, reflecting greater neural identification capability of film fMRI against rest fMRI despite higher subject synchronization during film-watching than in rest. Comparably, in this work we study the relation between individual differences, in particular, state anxiety and openness scores, and brain activity during the processing of emotional scenes in films, through functional gradients. In addition to including subcortical regions, we propose a new exploratory framework for computing functional gradients based on a subset of frames selected using emotional annotation data of films, resulting in emotion-informed functional gradients. Then we evaluate the variance in emotion-informed gradients across subjects and employ these same gradients in the prediction of individual differences. For emotion-informed functional gradients, the highest predictability of state anxiety was found for scenes of negative valence and medium-high arousal, corresponding to the typical location of anxiety within the valence-arousal-power emotional space. Additionally, predictability of state anxiety tended to be negatively correlated to inter-subject variability. In contrast, predictability of openness was found to be highest during scenes with low arousal and positively correlated to inter-subject variability. Although preliminary, these findings suggest that macroscale brain organization is affected by emotional experience, and that frame selection based on the latter could be useful to remove non-subject-specific variability while extracting subject-specific information related to the emotion experience. It also suggests that frame selection increases inter-subject variability allowing the extraction of more subject-specific information. Thus, expanding on the idea of brain fingerprint in film fMRI, our results provide initial evidence that emotional experiences enhance disentanglement of various domains of individual differences. Moreover, depending on the individual difference of interest, fMRI acquired during more or less constrained paradigms would be more suitable to reveal different properties of brain function.

Graph theory provides a promising technique to investigate Alzheimer's disease (AD)-related alterations in brain network properties. However, there are discrepancies in the reported disruptions that occur to network topology across the AD continuum. In this study, we examined whether diagnostic group differences in graph metrics are attributed to differences in denoising approach used in fMRI processing. Resting state data from 60 cognitively normal (CN), 55 Mild Cognitive Impairment (MCI), and 38 AD participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were denoised using 11 pipelines including combinations of confound regression (head motion parameters, white matter [WM], cerebrospinal fluid [CSF], global signal), volume censoring (scrubbing, spike regression), and component-based noise removal (Independent Component Analysis-based Automatic Removal of Motion Artifacts [ICA-AROMA], anatomical and temporal component correction). Graph metrics representing network segregation (clustering coefficient, modularity, local efficiency), network integration (largest connected component, path length, global efficiency), and small-worldness were calculated. The results revealed that diagnostic group differences in modularity and local efficiency were dependent on denoising approach, especially in high-parameter regression models in combination with censoring methods (36 parameters and spike regressor or volume censoring). Independent of denoising approach, CN exhibited more segregated (clustering coefficient) but less integrated (largest component, path length, global efficiency) networks than MCI and AD. Independent of diagnosis, denoising strategy significantly affected the magnitude of all metrics, particularly models including global signal regression. Collectively, these results suggest that the directionality of the diagnostic differences in network topology, particularly in global metrics of network segregation, can vary based upon the denoising approach employed, although the effect size is small. Transparent reporting of preprocessing decisions is critical for the accurate interpretation of graph theoretical findings in the context of AD and a better understanding of the mechanisms underlying pathological aging.

The relationship between alcohol consumption and the incidence of myocardial infarction (MI), stroke and all-cause mortality exhibits significant regional variation. This prospective study aimed to investigate this association analyzing data from a cohort of Swedish men aged 45-50 years at baseline, evaluating subgroups over various time intervals, and compiling data on cardiovascular endpoints. The Coeur study, conducted between 1993 and 1995, included 973 middle-aged male employees out of a randomly selected sample of 1144 individuals from a Swedish automotive company. Participants were followed for 30 years using national health registers. The accumulated incidence of first-time stroke, first-time MI and all-cause mortality was calculated and adjusted for cardiovascular risk factors. Data analysis employed time-to-event methods (Kaplan-Meier's estimates and hazard ratios) and measures of association (odds ratios and correlation analysis). No statistically significant association was observed between alcohol consumption and stroke ( p 0.05). However, alcohol consumption was associated with lower odds of MI (OR = 0.57, 95% CI: 0.41-0.79) and a slight increase in survival time (HR = 0.997, 95% CI: 0.995-1.000). Alcohol consumers had a median survival advantage of 1.3 years compared to non-consumers. All beverage types showed a negative association with all-cause mortality (total alcohol: OR = 0.57; beer: OR = 0.68, 95% CI: 0.50-0.92; wine: OR = 0.55, 95% CI: 0.41-0.75). Conversely, beer consumption was linked to higher odds of MI (OR = 1.70, 95% CI: 1.05-2.75). While alcohol consumption in middle-aged men after 30 years follow-up is associated with increased survival time, beer correlates with a higher likelihood of MI.

Following traumatic brain injury (TBI), inflammation of the nerve and death of nerve cells are intimately associated with the unfavorable prognosis of TBI patients. This study aims to examine the function of programmed cell death protein-1 (PDCD1) signaling in neuroinflammation and nerve cell death following TBI in mice, as well as its impact on the recuperation of cognitive, memory, and motor capabilities, and to initially analyze its underlying mechanism. In vivo investigations employed a controlled cortical impact (CCI) murine model. BV-2 cells were activated with lipopolysaccharide (LPS) to create an in vitro model of microglial inflammation. The outcome indicates that TBI significantly and temporarily increased the expression of PDCD1 in vivo, with PDCD1 mostly expressed in microglia and neurons, but not in astrocytes. Knockdown of PDCD1 led to an increase in the protein expression levels of IL-1 , iNOS, and Bax, whereas the levels of Bcl-2, p-PI3K, and p-Akt dropped. Nonetheless, the overexpression of PDCD1 yielded contrary outcomes; furthermore, LY294002 may partially counteract the effects of PDCD1 overexpression and diminish its expression levels. And the results of further cell experiments in vitro were consistent with those in vivo. PDCD1 expression is elevated in both in vivo TBI models and in vitro microglial inflammation models. Moreover, PDCD1 mitigates neuroinflammation and nerve cell death, at least partially, via the PI3K/Akt pathway.

Tau phosphorylated at threonine 217 (p-tau217) is interesting increasingly as "star biomarker" in the field of Alzheimer's disease (AD) diagnosis due to the highest accuracy in detecting AD pathology and predicting future cognitive decline. Here, we developed an ultra-trace blood-based diagnostic platform for p-tau217, termed magnetic-particle-based Immunol Rolling-circle-amplification/Cas12a Assay (MPIRCA). In this approach, the operational process included two main stages: the preparation of All@MP (encompassing immobilization, capture, and binding) and the subsequent one-pot RCA/Cas12a reaction. Through the Ab-DNA, immunoassay was successfully converted into DNA-based molecular diagnostic technology (one-pot RCA/Cas12a reaction) to achieve ultra-high sensitivity with 1 fg/mL limitation of detection. The optimized assay exhibited excellent linearity across a range from 1 fg/mL to 1 ng/mL. The study presents a high feasible diagnostic strategy that combines one-pot operation, high sensitivity and selectivity, offering considerable potential for blood-based diagnosis and management of Alzheimer's disease (AD).

Gastrointestinal (GI) dysfunction has been reported in autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A). However, GI dysfunction in GFAP-A has not been sufficiently investigated. This study aimed to analyze the clinical features of GFAP-A patients with GI dysfunction and explore potential pathogenic mechanisms. From January 1, 2016, to April 30, 2024, patients diagnosed with GFAP-A based on CSF GFAP-IgG positivity at the Third Affiliated Hospital of Sun Yat-sen University were enrolled. Clinical parameters and GI dysfunction assessed by the I-FEED scoring system were collected. Pathological examination was performed in a subset of patients. And the preliminary role of GFAP-IgG in the enteric plexus was investigated. Among 92 enrolled individuals (male:female = 68:24; median age 39.5 years), gastrointestinal dysfunction occurred in 72 cases (78.3%). Manifestations included constipation in 38 cases (41.3%), paralytic ileus in 30 cases (32.6%), fecal incontinence in 3 cases (3.26%), and diarrhea in 1 case (1.09%). Severe GI dysfunction (I-FEED score 6) was associated with higher disease severity (admission mRS 5.0 vs. 3.0, p 0.001), longer hospitalization (21.5 vs. 15.5 days, p = 0.029), increased ICU admission (50.0% vs. 10.5%, p 0.001), higher rates of respiratory failure, autonomic dysfunction, and infections, worse CSF profiles (elevated protein, leukocytosis, hypoglycorrhachia). Pathological analysis revealed prominent CD8 and CD4 T-cell infiltration in the colonic wall and a specific loss of GFAP enteric glia. Furthermore, we demonstrated that anti-GFAP-IgG derived from the cerebrospinal fluid (CSF) of GFAP-A patients binds specifically to the enteric plexus within mouse colonic tissues. Our findings collectively suggest that severe GI dysfunction could be a marker of disease severity and poor prognosis in GFAP-A, and indicate that its potential mechanism may involve the specific binding of anti-GFAP-IgG to the enteric plexus and subsequent enteric glia loss.

Semantic fluency is commonly assessed in the diagnostic work-up of individuals with suspected cognitive impairment due to neurodegenerative disease. Semantic fluency has a predictive value for survival in clinical AD and in healthy elderly individuals, but it is unknown if this also applies to biomarker-confirmed AD and non-AD memory clinic patients. Potential associations with and added value of imaging biomarkers of amyloid pathology and neurodegeneration have yet to be explored. From our clinical registry, we included patients who were assessed at a memory clinic with the neuropsychological assessment battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-NAB) and whose vital status could be retrieved in 07/2024. We tested the association of semantic fluency performance at first assessment and over time (and, for comparison, further CERAD-NAB subtest scores) with mortality risk using age-adjusted single-predictor Cox proportional hazard models. Amyloid status (positive vs negative on clinical PET reads) and global cognitive impairment (MMSE) were included as covariates. In addition, we explored associations between semantic fluency performance and both regional cortical glucose metabolism (FDG PET) and global amyloid load (centiloids; PiB PET). Finally, the predictive value of global amyloid load and glucose metabolism in comparison to and in combination with semantic fluency performance was assessed. 583 patients were included (age 68.9 8.7, 45% female). 280 patients (48%) had died and 303 (52%) were alive after a median of 8.0 years [95% C.I. 7.7-8.4]. Better semantic fluency (age-, sex- and education adjusted Z score, based on normative data) was significantly associated with lower mortality risk (HR = 0.71 [0.63 - 0.80], Bonferroni-corrected p 0.001). Its predictive value was higher than that of all other CERAD-NAB subscores (e.g., memory, visuospatial abilities). Semantic fluency remained a significant predictor when amyloid status and global cognitive impairment were accounted for (HR = 0.75 [0.61 - 0.91], p = 0.0035). In patients with more than one assessment (N = 163), longitudinal change of semantic fluency (derived from a linear mixed effects model) was also a significant predictor (HR = 0.66 [0.53-0.83], p 0.001). In 218/583 patients who had received amyloid and FDG PET, worse semantic fluency was associated with decreased FDG uptake of left inferior and middle temporal, dorsolateral frontal, and posterior parietal cortical regions (Bonferroni-corrected p 0.05), but not with amyloid load. FDG uptake of the left IFG (pars opercularis) was itself a predictor of survival (HR = 0.68 [0.55 - 0.84], Bonferroni-corrected p 0.05), but to a lesser degree than semantic fluency (and MMSE, naming and figure drawing). Predictive accuracy of semantic fluency was further improved by including FDG uptake of the right anterior cingulate (Bonferroni-corrected p = 0.078). Global amyloid load was not associated with survival. Survival of memory clinic patients can be predicted by semantic fluency, independently from amyloid status and global cognitive impairment. Anterior cortical glucose metabolism is itself a significant predictor of survival and slightly improves prediction by semantic fluency.

Lipid metabolism plays an important role in neurodegenerative diseases, including Parkinson's disease (PD). However, the relationship between lipid profiles and excessive daytime sleepiness (EDS) remains unclear. This study aimed to explore the relationship between lipid parameters and EDS in PD patients, especially focusing on gender differences. A total of 176 PD patients were included in this study, and clinical data was collected. The Epworth Sleepiness Scale (ESS) was used to classify patients into PD EDS (ESS 8) and PD non-EDS (ESS 8) groups. Univariate and multivariate analyses, along with receiver operating characteristic (ROC) analyses, were performed to detect potential biomarkers for EDS in PD. In male PD patients, univariate analysis indicated an association between disease duration, Hoehn-Yahr (H-Y) stage, and lipid parameters (total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)) and EDS. Multivariate analysis identified TC and HDL-C as significant predictors, especially HDL-C. The TC/HDL-C ratio (AUC = 0.745) and non-HDL-C (defined as TC - HDL-C, AUC = 0.691) exhibited high predictive ability for EDS. Female PD patients, in contrast, showed no significant link between lipid parameters and EDS. Instead, motor dysfunction (UPDRS score) and psychological factors (HAMD/HAMA scores) were the main predictors of EDS in females. Research findings indicate a significant gender difference in the factors influencing EDS in PD patients. In male PD patients, lipid metabolism disorders (elevated TC, reduced HDL-C) predict EDS, with TC/ HDL-C and non-HDL-C as potential biomarkers. In female PD patients, motor and psychological factors primarily contribute to the risk of EDS.

The Cairo spiny mouse (Acomys cahirinus), a promising animal model in neuroscience, lacks a detailed neuroanatomical map of its cerebral cortex. This study aims to delineate the location and internal subdivision of the sensorimotor cortex, specifically the region controlling the hindlimb. For this purpose, retrograde tracing from the lumbar spinal cord using Fast Blue was combined with immunohistochemical characterization using neuronal markers (NeuN, SMI-32, and calbindin 28 kDa) in adult animals. Fast Blue-labeled neurons were identified in layer V within the cortical region defined as the sensorimotor cortex responsible for hindlimb control. Within this region, the general cytoarchitecture was defined using NeuN, which allowed visualization of all cortical layers. The border between the lateral and medial sub-areas was clearly identified by SMI-32 immunostaining, which showed denser labeling in the lateral zone (presumably the primary somatosensory cortex) compared to the medial zone (presumably the secondary motor cortex). Within the defined layers and sub-areas, a comprehensive analysis of the calbindin-expressing interneuron population was performed, revealing significant interareal differences in soma size and cellular density of calbindin-positive neurons exclusively within layers III-IV. These findings provide the first detailed map of the hindlimb sensorimotor cortex in spiny mice, establishing a crucial neuroanatomical foundation for future studies using this novel model in sensorimotor research.

Activation of microglia and inflammatory response play a central role in the pathological process following intracerebral hemorrhage (ICH). In this study, single-nucleus transcriptomic and proteomic profiling was performed to investigate microglial changes after ICH. A significant upregulation of complement receptor C5aR1 was identified, particularly enriched in microglial subsets exhibiting a pro-inflammatory phenotype. The cellular localization and temporal expression dynamics of C5aR1 were validated by immunofluorescence staining, Western blotting, and quantitative PCR, demonstrating its sustained elevation in microglia after ICH. Pharmacological inhibition with the selective C5aR1 antagonist PMX205 markedly reduced the release of inflammatory cytokines, alleviated neuronal damage, and improved neurological function. Proteomic profiling and subsequent validation suggested that CCR5 may be associated with C5aR1-related inflammatory responses after ICH. Collectively, these findings suggest that C5aR1 serves as a regulatory factor in microglia-mediated neuroinflammation following ICH, and that targeting this pathway may offer a promising therapeutic strategy for hemorrhagic stroke.

Globally, acute ischemic stroke (AIS) continues to be a major contributor to death and long-term functional impairment. The present work investigates the clinical relevance of miR-369-3p in AIS and how it regulates brain microvascular endothelial cells. Quantitative measurements of serum miR-369-3p were conducted in a cohort comprising 138 individuals with AIS and 120 healthy controls. ROC curve analysis and Cox proportional hazards regression were employed to evaluate diagnostic and prognostic performance of miR-369-3p. Human brain microvascular endothelial cells (hCMEC/D3) were exposed to oxygen-glucose deprivation followed by reoxygenation (OGD/R), allowing assessment of how miR-369-3p influences cell viability, inflammatory responses, and the expression of adhesion molecules. Downstream target genes were identified through bioinformatics analysis and validated using a dual-luciferase assay. A statistically significant reduction in serum miR-369-3p levels was observed among AIS patients relative to controls (P 0.001), and this miRNA demonstrated favorable diagnostic accuracy. Lower expression of miR-369-3p emerged as an independent predictor of poorer functional outcomes, as assessed by the modified Rankin Scale (mRS) score at 90 days post stroke. In cellular studies, upregulation of miR-369-3p mitigated the loss of cell viability induced by OGD/R, reduced the production of pro inflammatory cytokines and lowered the levels of ICAM 1 and VCAM 1. Furthermore, VAV3 was confirmed as a direct target of miR-369-3p; restoring VAV3 expression counteracted the protective effects conferred by miR-369-3p. Serum miR-369-3p may serve as a non-invasive diagnostic and prognostic biomarker for AIS. Mechanistically, miR-369-3p protects against ischemic endothelial injury by targeting VAV3 and mitigating inflammation and adhesion molecule expression.

The immune and inflammatory responses following ischemic stroke involve aberrant DNA exposure, immunothrombosis, and innate immune activation. Post-stroke, damage-associated DNA signals from multiple sources may activate DNA-sensing pathways; however, how DNA from distinct sources links peripheral immune activation with inflammatory amplification within the brain remains incompletely understood. Among these, neutrophil extracellular traps (NETs), as DNA-rich extracellular structures, may represent a potential link connecting vascular inflammation, immunothrombosis, and intracerebral DNA sensing. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a key DNA-sensing axis, mediates distinct inflammatory and stress responses across various stroke-associated cell types. This review summarizes the mechanisms of DNA recognition, NET-mediated immunothrombosis, and neuroinflammatory damage, as well as the functional characteristics of cGAS-STING signaling in different cell types. Based on current evidence, we propose a potential NETs-cGAS-STING inflammatory amplification framework: NET-derived DNA may contribute to DNA-sensing activation within the ischemic brain and promote microglial inflammatory responses, while the resulting inflammatory factors and chemotactic signals may further promote neutrophil recruitment and secondary NET formation, thereby potentially creating a feed-forward loop linking peripheral immune activation with neuroinflammation. We further discuss the spatiotemporal heterogeneity of this axis, therapeutic targets, and challenges for clinical translation. Overall, the NETs-cGAS-STING framework provides an integrated conceptual perspective for understanding the intercellular interactions underlying DNA recognition and the sustained amplification of inflammation following stroke, and offers insights into future precision immune interventions tailored to disease stage, lesion characteristics, and cell-specific responses.

Associations between patterns of brain connectivity and brain structural features have transdiagnostic relevance to psychopathology. There is considerable evidence for disruptions to the hippocampus and temporoparietal brain systems in psychotic disorders. The present study examines structure-function relationships-specifically, the relation of hippocampal volume with patterns of temporoparietal effective connectivity-in youth at clinical high-risk for psychosis (CHR-P) and healthy controls (HCs). Participants at CHR-P and HCs completed clinical symptom measures and magnetic resonance imaging at baseline (n = 388, 42.5% female, age = 19.8 4.2) in the second cohort of the North American Prodrome Longitudinal Study. Group Iterative Multiple Model Estimation established a common functional network of temporoparietal effective connectivity in the full sample. Next, supervised (assuming the CHR-P and HC groups represent classes) and unsupervised (data-driven) clustering procedures interrogated effective connectivity parameters relevant to subsamples. Mean difference tests by unsupervised cluster membership determined whether clusters formed based on temporoparietal effective connectivity differed in hippocampal volume. Clusters were also compared on representation of CHR-P and positive and negative symptom totals to determine whether unsupervised clustering recovered clinical features. Unsupervised clustering generated two clusters that differed significantly in right hippocampal volume and attenuated positive and negative symptoms with small-to-medium effect sizes. The cluster demonstrating reduced right hippocampal volume reported greater symptoms. Unsupervised clustering did not recover diagnostic groups. Findings are consistent with literature indicating the transdiagnostic relevance of hippocampal volume to organizational properties of brain functional networks and patterns of temporoparietal connectivity.

Over the past decade, the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium has transformed preclinical Alzheimer's disease (AD) research by addressing critical limitations in traditional mouse models that failed to translate to human disease. By leveraging human genetic discoveries, MODEL-AD has developed 70 genetically informed mouse models, standardized phenotyping pipelines, and an open-access data infrastructure aligned with late-onset AD biology. These models incorporate human risk variants, environmental factors, and aging to better capture disease complexity, including emerging recognition of mixed pathologies such as vascular contributions, Lewy body disease, and TDP-43 proteinopathy. Despite substantial progress, key challenges remain, including modeling multimorbidity, integrating aging, and improving translational predictability. Here, we outline a strategic roadmap spanning short-, intermediate-, and long-term approaches to refine disease modeling, enhance preclinical testing rigor, and support precision medicine. Continued investment in MODEL-AD will be essential to accelerate therapeutic discovery and establish a scalable framework for studying complex neurodegenerative diseases.

Benign prostatic hyperplasia (BPH) represents a highly prevalent age-related disorder, traditionally managed through androgen-driven pathways. However, the limited efficacy of conventional hormonal therapies in a substantial subset of patients necessitates the investigation of alternative pathogenic mechanisms. The emergence of single-cell RNA sequencing (scRNA-seq) has provided the necessary resolution to map cellular heterogeneity and microenvironmental dynamics within the prostate. This review synthesizes recent advancements in applying scRNA-seq to BPH research, highlighting a transition from a homogeneous, hormone-centric view toward recognizing BPH as a complex, heterogeneous process driven by multifaceted cell-immune interactions. We detail how scRNA-seq has identified distinct cellular subsets within the hyperplastic transition zone, including novel basal epithelial subtypes and activated fibroblast populations that contribute directly to nodule formation and disease progression. Furthermore, we examine the central role of chronic inflammation, mediated by immune cell infiltration and senescence-associated secretory phenotypes (SASP), in perpetuating a proliferative microenvironment. The technology also clarifies mechanisms underlying treatment resistance and identifies potential biomarkers and novel therapeutic targets beyond the androgen axis, such as the CXCL13/CD4 + T cell axis and granzyme K pathways. Looking forward, integrating scRNA-seq with spatial multi-omics aims to construct a comprehensive spatiotemporal atlas of BPH, facilitating molecular subtyping and the development of precision, microenvironment-targeted therapies. In conclusion, scRNA-seq is redefining the pathophysiological landscape of BPH, offering a path toward innovative, non-androgenic therapeutic strategies aimed at achieving true disease modification.

Cervical cancer progression is driven not only by persistent high-risk human papillomavirus infection but also by multilayered post-transcriptional regulatory networks that reshape tumor cell behavior and the tumor microenvironment. Among these regulators, circular RNAs (circRNAs) have emerged as pivotal modulators of oncogenic signaling. Initially characterized as competing endogenous RNAs (ceRNAs), circRNAs were shown to promote cervical cancer growth, invasion, and chemoresistance by derepressing key oncogenic targets. However, recent evidence expands this paradigm, revealing that circRNAs are subject to epitranscriptomic modification and function as dynamic scaffolds integrating RNA-binding proteins, translational machinery, inflammatory signaling, and metabolic pathways. In cervical cancer, m6A-dependent regulation and reader-mediated translational control enhance circRNA stability and amplify oncogenic outputs, linking RNA modification to metabolic reprogramming and hypoxia adaptation. Concurrently, circRNAs modulate inflammatory cascades such as IL6/JAK/STAT3 and NF- B, contributing to immune suppression and tumor microenvironment remodeling. These tumor-intrinsic and immune-extrinsic mechanisms converge on metastatic reprogramming, enabling lipid metabolic flexibility, lymphangiogenesis, autophagy activation, and therapeutic resistance. This review synthesizes current evidence to propose a unified regulatory landscape in which circRNAs function as central nodes connecting ceRNA circuits, epitranscriptomic modulation, immune signaling, and metabolic plasticity. Unlike previous reviews that primarily summarized circRNA-mediated ceRNA networks, canonical oncogenic pathways, or biomarker potential, this review adopts a systems-level perspective and critically integrates epitranscriptomic regulation, RNA-binding protein interactions, immune-inflammatory signaling, metabolic plasticity, and metastatic reprogramming. We further distinguish directly validated cervical cancer mechanisms from emerging or hypothetical regulatory layers, thereby providing a clearer conceptual framework for future mechanistic and translational studies.

Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are increasingly viewed as conditions influenced by systemic immune and metabolic disturbances beyond the central nervous system (CNS). Emerging evidence suggests that infection-driven intestinal dysbiosis may function as an upstream contributor to systemic inflammation through disruption of gut barrier integrity. Increased permeability can facilitate the translocation of microbial components and metabolites into circulation, potentially influencing host immune programming via epigenetic mechanisms. Among CNS immune cells, microglia appear particularly susceptible to such peripheral cues due to their longevity and capacity for stimulus-dependent transcriptional adaptation. Experimental studies indicate that transient systemic immune challenges may induce persistent chromatin-level alterations within microglial regulatory regions, thereby reshaping their responsiveness to subsequent inflammatory stimuli or age-related stressors, including oxidative stress, chronic low-grade inflammation (inflammaging), and age-associated decline in cellular homeostatic and repair mechanisms. This phenomenon, often described as innate immune memory, may contribute to sustained neuroinflammatory activity and impaired synaptic function across the lifespan. Microbiota-derived metabolites, including short-chain fatty acids and tryptophan catabolites, have been implicated in modulating host transcriptional pathways through histone deacetylase inhibition and receptor-mediated signaling.

Aperiodic neural activity (1/f EEG) has been proposed to reflect the balance between excitatory and inhibitory (E/I) inputs, with steeper spectral slopes reflecting increased inhibition and flatter slopes indicating excitation. This activity is also thought to reflect the temporal coordination of neural firing, offering insights into fundamental brain dynamics. Recent studies have shown that the 1/f slope is sensitive to stimulus onset, characterized by initial inhibitory shifts followed by excitatory rebounds, which may reflect cognitive control mechanisms involved in suppressing distractions and preparing goal-directed responses. However, previous research has relied on fixed temporal windows and insufficient control of ERP contamination, limiting our understanding of rapid control dynamics. Here we used newly developed time-resolved analyses to study 1/f spectral slope modulation during a Picture-Word Interference task, focusing on two canonical cognitive control markers: the Congruency Effect (CE) and Congruency Sequence Effect (CSE). Forty-nine participants categorized pictures while ignoring congruent or incongruent words. Behaviorally, we replicated robust CE and CSE patterns. Spectral slope analyses showed that incongruent trials elicited steeper slopes-consistent with increased inhibition-particularly in frontal and central regions, reflecting conflict-related control engagement. Moreover, CSE analyses revealed dynamic slope modulations across frontal, central, and occipital components over time, suggesting control adjustments influenced by previous trial congruency. These results provide the first within-trial time-resolved evidence that aperiodic 1/f EEG activity can track both immediate conflict resolution and cognitive adjustments, offering a temporally sensitive neural marker of cognitive control, albeit with effects that are small in magnitude on average.

In vertebrate peripheral nerves, damaged axons can regrow after injury, but the outcomes of regeneration are variable and often incomplete. Schwann cells in injured nerves are important for repair, but their actions at different positions and stages of nerve repair are not well understood. We have investigated the roles of Schwann cells in a larval zebrafish nerve injury model, in which nerves are visible in living animals during development, the initial injury response, and regrowth of transected axons. After mechanical injury, distal Schwann cells adopted a repair phenotype characterized by changes in gene expression, elongation, and ability to guide axons across the injury site. In contrast, proximal Schwann cells associated with axons that regrew along aberrant paths at the injury site. In erbb2 mutants with greatly decreased Schwann cells, developmental axon growth was normal, but axonal regrowth after transection was greatly slowed and often misdirected. By examining animals with nerves partially populated by Schwann cells, we found that axons could regrow through regions devoid of Schwann cells, provided that at least one distal Schwann cell was at the injury site. Timelapse imaging revealed that distal Schwann cells contacted axons, which then regrew along the correct path. In irf8 mutants with greatly decreased macrophages, debris from transected axons was cleared on schedule, and axonal regrowth was normal. Our studies demonstrate that Schwann cells immediately distal to the injury site have a unique and essential role in axonal regrowth.

Primary Sj gren's syndrome (pSS) is a chronic autoimmune disorder. Dysregulated interferon-gamma (IFN- ) signalling is implicated in pSS pathogenesis, yet the underlying mechanisms remain elusive. This study aimed to identify key IFN- -associated diagnostic genes and delineate their roles in immune dysregulation using peripheral blood transcriptomic and single-cell RNA sequencing (scRNA-seq) data. Publicly available Gene Expression Omnibus (GEO) datasets were used, and the bioinformatics findings were further supported by reverse transcription-quantitative PCR (RT-qPCR) validation. Peripheral blood transcriptomic data from training and validation cohorts were analysed, and key genes were screened using machine learning algorithms, receiver operating characteristic (ROC) curve analysis, and differential expression analysis. A diagnostic model and nomogram were subsequently constructed. Immune infiltration, pathway enrichment, and gene regulatory networks were also investigated, while scRNA-seq analysis was performed to characterize cellular heterogeneity, pseudotime trajectories, and cell-cell communication. Four key genes, HERC6, IL15, CD58 and PTGS2, were identified, and the resulting diagnostic model and nomogram demonstrated high diagnostic accuracy. Immune profiling revealed marked dysregulation of the immune microenvironment in pSS, accompanied by extensive alterations in metabolic and signalling pathways. Pathway enrichment analysis further demonstrated both distinct and shared functional roles of the four key genes. Single-cell analysis suggested that macrophages may act as central regulators in pSS pathogenesis, as evidenced by altered pseudotime trajectories, enrichment in early differentiation states, and intensified cell-cell communication networks. RT-qPCR further confirmed the significant upregulation of HERC6, IL15, and PTGS2 in patients with pSS. Collectively, this study established an IFN- -associated diagnostic model for pSS and implicated macrophages as potential key contributors to immune dysregulation through altered differentiation, enhanced intercellular communication, and IFN- -associated gene expression. These findings provide new insights into the pathogenesis of pSS and identify potential diagnostic biomarkers and therapeutic targets.

Diabetic retinopathy (DR), a common microvascular complication of diabetes mellitus, has been associated with ferroptosis-related pathological mechanisms. Evidence indicates that ferroptosis may contribute to retinal injury and disease progression. The present analysis aimed to characterize ferroptosis-associated cell subsets and their roles in the progression of DR. Single-cell RNA sequencing data derived from diabetic rat models of DR were obtained from the Gene Expression Omnibus database. A total of 464 ferroptosis-related genes were used to calculate ferroptosis scores. Data processing and analysis were performed using the Seurat R package, with differentially expressed genes identified via the FindAllMarkers function. Functional enrichment analyses were conducted using the clusterProfiler package. Protein-protein interaction networks were constructed using the STRING database, and intercellular communication was predicted using CellChat. Key findings were validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Cell clustering identified nine principal retinal cell types. Compared with normal control groups, the DR group demonstrated altered proportions of M ller cells, vascular endothelial cells, microglia, and cone photoreceptor cells. Ferroptosis-score-related differences were most evident in M ller cells and rod cells. In the revised WT-baseline sensitivity analysis, the high-ratio ferroptosis-score cell distribution remained significantly altered in Rod and M ller cells after multiple-testing correction. This study identified key ferroptosis-associated retinal cell populations, with an emphasis on the functional roles of ferroptosis-associated M ller cell subsets in the context of DR. These findings provide further insight into the cellular mechanisms underlying DR and highlight potential molecular targets for therapeutic intervention.

Fast, highly constrained sensorimotor acts require rapid coordination of distributed cortical systems on subsecond timescales. Here, we used source-resolved magnetoencephalography to characterise time-locked cortical connectivity during voluntary swallowing in 74 healthy adults. Cluster-based network statistics revealed focal swallowing-related connectivity changes confined to anatomically selective subnetworks. Undirected phase-lagged connectivity identified theta- and low-gamma weighted phase lag index (wPLI) effects involving somatosensory, motor, supramarginal, and insular regions. Directed connectivity revealed sparse high-gamma phase slope index (PSI) subnetworks centred on the primary somatosensory cortex and anterior insula. Time-window analyses demonstrated temporally evolving low-gamma interactions between posterior parietal and insular regions, while laterality analyses showed rightward theta-band directed asymmetries during later swallowing phases. In contrast, global graph-theoretical metrics and node-level hub measures remained largely stable after correction for multiple comparisons. These findings indicate that voluntary swallowing is supported by focal, frequency-specific, and temporally structured cortical interactions rather than broad global network reconfiguration.

Of the 3 published trials, only 1 showed possible efficacy of endovascular treatment (EVT) compared to best medical treatment (BMT) alone for medium or distal vessel occlusions (MDVO), whereas the others were neutral. Procedural conditions may affect the outcome. This is a post-hoc analysis of the randomised, controlled DISTAL trial, conducted in 55 centers between 12/2021 and 7/2024. Patients with isolated MDVO within 24 hours of last seen well randomised to EVT plus BMT were treated under general anaesthesia (GA), conscious sedation (CS) or local anaesthesia (LA) at investigators' discretion. Endovascular treatment under different anaesthesia modalities was compared head-to-head, and to BMT alone. Among 491 patients included in the analysis, 224 received EVT plus BMT (108 GA, 64 LA, 52 CS) and 267 received BMT alone. Compared to BMT alone, EVT under CS was associated with worse 90-day modified Rankin Scale (median 2.5 vs 2.0; adjusted odds ratio [aOR] 0.51 [95% CI 0.29-0.90]), whereas no difference was observed between EVT under other anaesthesia modalities and BMT alone. Symptomatic intracranial haemorrhage occurred more frequently after EVT under GA compared to BMT alone (8.3% vs 2.6%; aOR 3.37 [95% CI, 1.22-9.66]). LA was associated with higher odds of better functional outcome (aOR 2.11 [95% CI, 1.09-4.12]) and lower mortality (aOR 0.28 [95% CI, 0.08-0.95]) compared to CS, whereas there was no difference to GA. The lack of superiority of EVT plus BMT over BMT alone in DISTAL may not have been driven by anaesthesia modality.

Multimodal integrated analysis reveals the key metabolic regulatory mechanism of butterfly orchid petal color and identifies the core genes of the anthocyanin biosynthesis pathway. Phalaenopsis aphrodite Rchb. f. (Phalaenopsis) is a globally important ornamental plant in the floriculture industry. Flower color is a critical trait determining its commercial value. To reveal the molecular mechanism of flower color formation and the conserved functions of key genes in Phalaenopsis, we performed transcriptome and metabolome multi-omics analyses on three cultivars with distinct petal colors with Pa_1 (white), Pa_2 (rose red) and Pa_3 (dark red). Integrated omics analysis confirmed that flavonoids and their glycosides are the primary pigments governing floral color variation, with the phenylpropanoid and flavonoid biosynthesis pathways serving as the core conserved regulatory routes. Key pathway structural genes, including Chalcone synthase (CHS), Flavanone 3-hydroxylase (F3H), Dihydroflavonol 4-reductase (DFR), and Anthocyanidin synthase (ANS), were significantly upregulated in dark-colored petals and positively regulate flavonoid metabolites (such as naringenin, luteolin, hesperetin, taxifolin, and leucocyanidin) to promote the accumulation of anthocyanins and flavonoids. WGCNA identified the core hub gene Phalaenopsis Chalcone synthase-Red1 (PhaCHS-R1), which belongs to the chalcone synthase family and performs a conserved limiting catalytic function in flavonoid synthesis in the petals of Phalaenopsis flowers. Such a role for PhaCHS-R1 was further demonstrated via the VIGS approach, an RNA silencing-mediated strategy which significantly decreased anthocyanin and flavonoid contents in the petals of flowers of VIGS plant, to result in the treated flowers displaying a distinctly lighter color. This study clarified the conserved regulatory mode of the phenylpropanoid-flavonoid pathway and elucidated the conserved function of PhaCHS-R1, providing important conserved gene resources for molecular breeding of flower color in Phalaenopsis and ornamental plants.

Histopathologic staging models of neuronal -synuclein pathology (n-asyn) in Lewy body disease (LBD) seldom evaluate brain regions with direct synaptic connectivity to model the role of microglial processes. We address this gap by testing the hypothesis that, within the well-defined synaptic connectivity of the intrahippocampal circuit, n-asyn is associated with activated microglial phenotypes. We selected a cohort of autopsy-confirmed LBD patients and minimal age-related copathologies (n = 62) and a control cohort of cognitively healthy patients with isolated hippocampal tau accumulation (i.e., primary age-related tauopathy, PART; n = 12), to control for neurodegenerative pathology without amyloid plaques. We immunostained consecutive hippocampal sections for n-asyn and established markers of activated microglial phenotypes, Iba1, HLA-DR, and CD68. With validated digital histology methods, we measured percent area occupied (%AO) of each marker in 6 hippocampal subfields to compare and correlate microglial morphologic and proteomic activation phenotypes between cohorts and used linear mixed effects models to compare the %AO between subfields while covariying for demographics. We also constructed groups of n-asyn restricted to the cornu ammonis (CA) 2-3 subfields (Focal Subtype) or widespread n-asyn within additional subfields (Widespread Subtype) to model hypothesized n-asyn spread within the intrahippocampal circuit. LBD patients exhibited increased HLA-DR and CD68%AO in most hippocampal subfields compared with PART. In LBD patients, all microglial markers were the highest in the CA2. CA2 n-asyn correlated with HLA-DR and CD68 but not Iba1%AO. Patients classified as Widespread Subtype had worse cognitive impairment and increased CA2 HLA-DR and CD68%AO. CA2 HLA-DR and CD68%AO correlated with distal n-asyn in retrograde, but not anterograde connected subfields. Our data show that activated microglial phenotypes in the CA2 of LBD patients are associated with worse clinical outcomes and retrograde n-asyn transmission. These data suggest that measures of microglial states can refine LBD histopathological progression models.

The long-term treatment outcomes for peri-implantitis (PI) are more unstable and unpredictable than periodontitis (PD). Histological evidence suggests that the epithelial barrier and immune system around the implant are weaker than those around natural teeth. In transcriptomic aspects, compared to periodontitis and PI, the specific molecules and cell types involved in the pathogenesis of PI have not been fully established. In the current study, gingival tissue samples were collected from patients, and single-cell RNA sequencing was used to analyze the heterogeneities of epithelial barriers, immune defenses, and related response molecules in soft tissues around natural teeth and implants. Our work supports that the disruption of the epithelial barrier around the implant was one of the causes of PI. The cell communication between epithelial cells and stromal cells was inhibited by the midkine (MDK)-nucleolin (NCL) pathway. The breakdown of the defense structure of connective tissue aggravated the progress of PI. In vitro evidence demonstrated MDK's functional role in stromal regeneration through overexpression experiments. These findings provide critical molecular insights into the pathogenesis of PI and offer a strong rationale for the development of early, targeted clinical interventions aimed at preserving epithelial integrity and restoring immune defense in peri-implant soft tissues.

Ischemia-reperfusion injury (IRI) is a major reason for adverse prognosis in ischemic stroke, with multiple signaling pathways involved in this process. This study aims to explore the role of the novel autophagy receptor CCDC50 in cerebral IRI and its molecular mechanism. Cellular oxygen-glucose deprivation/reoxygenation model and middle cerebral artery occlusion (MCAO) animal model were adopted in this study. Quantitative real-time polymerase chain reaction, Western blot, immunofluorescence, and immunohistochemistry assays were applied to detect the expression and subcellular localization of key molecules including LL37, CCDC50, STING, IRF3, Rspondin3, and autophagy-related proteins. Co-immunoprecipitation was performed to explore protein-protein interactions. Enzyme-linked immunosorbent assay and flow cytometry were utilized to determine the levels of inflammatory cytokines and the M1/M2 polarization phenotypes of microglia. Additionally, 2,3,5-triphenyltetrazolium chloride staining was carried out to measure cerebral infarct volume. Results revealed that LL37 directly bound to CCDC50 and facilitated its ubiquitination and degradation. This process disrupted the interaction between CCDC50 and STING, thereby triggering the activation of the STING/IRF3 signaling pathway. Conversely, CCDC50 enhanced autophagy and restrained the STING/IRF3 pathway activation. It further drove microglial polarization toward the anti-inflammatory M2 phenotype, blocked pro-inflammatory M1 phenotype transition and inflammatory cytokine secretion, and ultimately alleviated neuronal damage. The above in vitro molecular mechanisms were also validated in the MCAO model. By enhancing autophagy, CCDC50 suppresses the STING/IRF3 pathway and facilitates M2 polarization of microglia, ultimately mitigating cerebral ischemia-reperfusion injury. In contrast, LL37 counteracts this protective effect by mediating CCDC50 degradation. This study identifies novel potential therapeutic targets for ischemic stroke.

Neuropathic pain is a chronic pain disorder refractory to conventional analgesics. Iron-dependent neuronal ferroptosis has been implicated in its pathogenesis. G protein-coupled receptor 4 (GPR4), a proton-sensing receptor, is involved in inflammation and ferroptosis, but its role in neuropathic pain and spinal neuronal ferroptosis remains unclear. Neuropathic pain was induced in rats using the spared nerve injury (SNI) model, and GPR4 expression and its effects on pain behaviors, neuronal ferroptosis, and spinal inflammation were examined. GPR4 was inhibited by a selective antagonist or small interfering RNA (siRNA), while Ras homolog family member A (RhoA) and Yes-associated protein (YAP) were activated via intrathecal injection of specific agonists. Spinal GPR4 expression was significantly upregulated and neuronal ferroptosis was induced by SNI, as evidenced by increased iron accumulation, lipid peroxidation, and dysregulated ferroptosis-related protein expression. SNI-induced mechanical allodynia, cold hyperalgesia, neuronal ferroptosis, and spinal inflammation were attenuated by GPR4 inhibition or knockdown. Mechanistically, the spinal RhoA/YAP signaling pathway was activated by SNI, and this activation was reversed by GPR4 inhibition. Furthermore, the analgesic and anti-ferroptotic effects of GPR4 inhibition were abolished by RhoA or YAP activation. It is demonstrated that GPR4 regulates neuropathic pain, neuronal ferroptosis, and spinal inflammation via the spinal RhoA/YAP signaling pathway, suggesting that GPR4 inhibition may represent a promising novel therapeutic strategy for neuropathic pain.

This review synthesizes the mechanisms, applications, and evidence gaps regarding pulsed radiofrequency (PRF) in the rehabilitation of post-stroke complications to guide its standardized integration. PRF, a minimally invasive neuromodulation technique, modulates neuronal excitability without thermal damage. Emerging evidence highlights multi-target effects, including improved microcirculation, suppressed neuroinflammation, and regulated neurotrophic factors. Clinically, PRF effectively alleviates refractory post-stroke pain and may indirectly ameliorate post-stroke depression while facilitating motor recovery. Image-guided procedures targeting specific nerves demonstrate favorable safety profiles. Despite promising outcomes for stroke rehabilitation, current evidence relies primarily on small case series and preclinical studies. Significant gaps remain in standardized protocols and high-quality randomized controlled trials. Further validation of long-term efficacy and safety is essential to establish PRF's definitive role in comprehensive post-stroke management.

Older-onset Leber hereditary optic neuropathy (LHON) may present without obvious optic disc swelling, which can delay diagnosis. We explored whether acute-phase retinal nerve fiber layer (RNFL) thickening on optical coherence tomography is less prominent with increasing age in genetically confirmed LHON. We retrospectively reviewed patients with m.11778G A LHON who underwent OCT within 90 days of symptom onset. Circumpapillary RNFL thickness was measured using ZEISS CIRRUS HD-OCT. Age-adjusted RNFL was calculated as measured RNFL thickness minus age-expected thickness derived from same-device external East Asian normative datasets. Age was analyzed primarily as a continuous variable using median quantile regression adjusted for onset-to-OCT interval and spherical-equivalent refractive error. A supplementary comparison was performed between patients aged 50 and 50 years. Twenty-seven eyes from 27 patients were included. The median age was 35 years; 18 patients were aged 50 years and 9 were aged 50 years. Increasing age was associated with smaller age-adjusted global RNFL thickening. The strongest sectoral association was observed in the superior quadrant. In the supplementary age-group analysis, the 50-year subgroup showed less prominent age-adjusted RNFL thickening than the 50-year subgroup. Acute-phase RNFL thickening may be less prominent with increasing age in m.11778G A LHON, particularly in patients aged 50 years. LHON should not be excluded solely because RNFL thickening is inconspicuous in older-onset cases.

An extra copy of the amyloid precursor protein (APP) gene causes autosomal dominant Alzheimer's disease (AD) and AD in Down syndrome (DS), but the factors underlying variability in age at onset (AAO) remain unclear. We investigated whether sporadic AD risk variants modify AAO. We analyzed clinical and genetic data from 100 APP duplication (APPdup) carriers and 957 individuals with DS. Cox models assessed associations of apolipoprotein E (APOE) 2 and 4 and the AD genetic risk score (AD-GRS; excluding APOE and chromosome 21 variants) with AAO. Mean AAO was earlier in APPdup than DS (51 7 vs. 53 6 years; P = 0.0005). APOE 2 delayed onset (hazard ratio [HR] = 0.47, P 0.0001), whereas APOE 4 (HR = 1.5, P = 0.0003) and higher AD-GRS (HR = 1.3 per standard deviation, P 0.0001) accelerated onset. Predicted median AAO differed by 10 years between lowest and highest genetic risk. Sporadic AD genetic risk factors are important modifiers of AAO in APPdup and DS, explaining part of the marked variability in onset.

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by recurrent vascular events in large, medium, or small vessels. These events contribute to cardiovascular disease primarily through thrombosis and atherosclerosis (AS). Carotid atherosclerosis (CAS) represents a particularly high-risk manifestation of subclinical AS in patients with APS. However, the shared molecular signatures linking APS and CAS remain unclear. Bulk transcriptome datasets from Gene Expression Omnibus (GEO) were analyzed to identify differentially expressed genes (DEGs) in APS and CAS. Common DEGs were characterized by Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and protein-protein interaction analyses. Candidate hub genes were prioritized by integrating Least Absolute Shrinkage and Selection Operator (LASSO), random forest, weighted gene co-expression network analysis (WGCNA), and MCODE, followed by diagnostic evaluation in independent datasets. Upstream regulatory networks and immune infiltration were assessed using in silico approaches. Single-cell RNA-seq was used to determine cell-type specificity. Genome-Wide Association Study (GWAS) summary statistics were integrated via MAGMA and intersected with expression signatures and OMIM-curated genes to prioritize additional candidates. A total of 4,264 DEGs were identified in APS and 838 DEGs in CAS, including 52 common DEGs (43 upregulated and nine downregulated). These common DEGs were enriched in plasma-membrane and actin-cytoskeleton-related functions, with nominal KEGG signals involving oxytocin, Jak-STAT, and PI3K-Akt pathways. Cross-method prioritization highlighted CLEC4A and P2RY13 , which showed consistent dysregulation and exploratory diagnostic performance across discovery and validation datasets and exhibited stage-associated patterns in carotid plaques. Immune deconvolution suggested that CLEC4A / P2RY13 tracked with myeloid- and mastcell-related signals in CAS and with neutrophil-related signals in APS. Single-cell analysis indicated predominant expression in the mDC/cDC compartment and positive associations with mast-cell proportions in CAS. MAGMA/OMIM integration further implicated TLR8 (APS) and IL18 / HAND2 (CAS) as additional candidates. Collectively, our results nominate CLEC4A and P2RY13 as candidate genes potentially involved in shared APS-CAS immune-related pathways, with expression changes associated with CAS progression among APS patients.

Vaccination relies on innate and adaptive responses initiated at the injection site followed by activation in draining lymph nodes. However, high-plex, spatially resolved maps that couple injection site signals with transcriptomic programs in draining lymph nodes over time are still lacking. Here, we used spatial transcriptomics to map early responses to an adjuvanted recombinant haemagglutinin (rHA) protein vaccine formulated with Sanofi's proprietary oil-in-water adjuvant AF03. Mice received intramuscular rHA-protein or PBS. Injection site muscle and draining lymph nodes were collected at Days 1 and 7 post-prime for GeoMx Digital Spatial Profiling (DSP) and CosMx Spatial Molecular Imaging (SMI) single-cell imaging. In lymph nodes, rHA-protein vaccination induced early innate pathway activation in non-follicular regions at Day 1. By Day 7, adaptive pathways were enriched within follicles, with differentially expressed genes (DEGs) linked to germinal center (GC) formation, transcriptional regulation and signaling. These changes coincided with expansion of a proliferative GC-like B-cell cluster within the follicular area. At the injection site, 20x20 M spatial grids were used rather than segmented cells. Clusters, enriched for fibroblast and muscle cells showed Day 1 induction of chemokines and interferon stimulated genes, concentrated in fibroblast rich stromal layers. These spatially organized tissue programs were accompanied by transient systemic cytokine elevations and increased antigen-specific IgG titers. Together, these data provide a previously unresolved view of what, when and where local inflammation and lymph node organization are spatially and temporally associated during early responses following vaccination with an adjuvanted rHA-protein vaccine.

Non-typhoidal Salmonella (NTS) is a leading cause of bacterial gastroenteritis worldwide, yet the pathogenic differences among co-circulating dominant clones remain poorly understood. A 7.5-year surveillance study (2017-2024) was conducted using NTS isolates from patients with acute diarrheal illness in Huzhou, China. Quantitative IEC-6 cell-based adhesion and invasion assays, comparative genomics, transcriptomic profiling, and protein-protein interaction network analysis were integrated to compare the dominant sequence types (STs). Among 188 NTS isolates, 35 serotypes and 36 STs were identified. Three STs predominated: ST34 (26.1%, mainly monophasic S. Typhimurium ), ST11 (15.4%, exclusively S. Enteritidis ), and ST19 (13.3%, classical S. Typhimurium ). ST34 showed significantly enhanced epithelial adhesion in IEC-6 cells, whereas increased invasion was observed only in comparison with ST11 and not with ST19. Comparative genomics and transcriptomics identified an intact Gifsy-1 prophage as an ST34-specific genetic element encoding the T3SS effectors GogB and SteE/SarA, with gogB and steE/sarA being the only virulence genes consistently upregulated in ST34 versus both ST11 and ST19. Protein-protein interaction network analysis positioned these effectors as peripheral components of a 14-member prophage-associated module. All 49 ST34 isolates carried the intact Gifsy-1 prophage, whereas ST19 isolates harbored only truncated versions and ST11 completely lacked this element. ST34 also carried a broad antimicrobial resistance gene repertoire, including frequent tetracycline and sulfonamide resistance determinants and sporadic detection of clinically important beta-lactamase genes. These findings identify an intact Gifsy-1 prophage encoding GogB and SteE/SarA as a candidate module associated with enhanced epithelial adhesion in ST34, a dominant NTS lineage with an extensive antimicrobial resistance repertoire.

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD + salvage pathway, has emerged as an important regulatory node linking metabolic homeostasis to neuroinflammatory responses. However, although pharmacological inhibition of NAMPT may attenuate inflammatory activation, it may also reduce intracellular NAD + availability, thereby exacerbating mitochondrial dysfunction and disturbances in energy metabolism. Here, we found that 6-month-old APP/PS1 mice exhibited an abnormal, cell type-specific distribution of NAMPT in the brain, characterized by reduced neuronal NAMPT and increased microglial NAMPT. This abnormality was accompanied by disrupted NAD + homeostasis, marked neuroinflammatory activation, mitochondrial structural and functional impairment, increased -amyloid (A ) burden, and impaired learning and memory ability. FK866 (1 mg/kg per injection, once every other day for 12 weeks) alone exerted limited effects and was insufficient to ameliorate the overall pathological phenotype. By comparison, a 12-week aerobic treadmill exercise program markedly ameliorated cognitive impairment, attenuated A pathology, suppressed neuroinflammation, and improved mitochondrial integrity and bioenergetic function in APP/PS1 mice. More importantly, under NAMPT-inhibited conditions, exercise still preserved hippocampal NAD + homeostasis and maintained significant neuroprotective effects. Compared with exercise alone, the combined intervention with exercise and FK866 further improved selected indices related to A pathology, neuroinflammation, oxidative stress, and mitochondrial damage. These additional effects may be associated with increased NAD + biosynthesis through the NMNAT3 pathway, as well as reduced NAD + consumption and neuroinflammatory activation through the suppression of CD38 and PARP1 expression.

Older adults with bipolar disorder (BD) are at high risk for severe mood symptoms, cognitive difficulties, and early mortality; however, underlying brain alterations have received little study. Gray matter decreases in ventral prefrontal cortex (VPFC) seen in younger persons with BD, and additionally in dorsal PFC (DPFC), are implicated. Here, cortical thickness was examined in an international sample. Cortical thickness in 34 regions was measured from structural magnetic resonance imaging data using enhancing neuroImaging genetics through meta-analysis pipelines for individuals with BD (n = 308) and non-psychiatric comparison participants (n = 287), ages 40-70y, from six Global Aging and Geriatric Experiments in BD (GAGE-BD) consortium sites. Group differences were assessed for VPFC, DPFC and remaining cortical regions, covarying for scanner, age and sex. Results were considered significant corrected for false discovery fate (FDR) at p FDR 0.05. Relationships with demographic and clinical factors were explored. Cortical thickness was significantly lower among BD in VPFC and DPFC, and additional distributed regions (p FDR 0.05) and negatively associated with age (p 0.05); group and age did not interact significantly. Relationships with BD subtype and medications were observed; lithium was associated with higher frontal pole and anterior cingulate thickness (p FDR 0.05). In this international middle and older aged adult BD sample, lower VPFC cortical thickness was observed, suggesting these deficits persist from younger age. DPFC and additional regions of reduced cortical thickness could contribute to the older adult BD phenotype. Cortical thinning was more pronounced among older individuals regardless of diagnosis. Lithium may lessen cortical thinning.

Post-stroke recovery remains limited despite advances in acute reperfusion therapies, underscoring the need to better understand underlying mechanisms that shape repair. Microglia, the resident immune cells of the central nervous system, orchestrate responses to ischemic injury and critically influence neurovascular remodeling, axonal reorganization, and functional recovery. Emerging evidence indicates that inflammatory preconditioning can reprogram microglial responses to subsequent insults, yet the exact intracellular signaling pathways mediating this adaptive state remain incompletely defined. Here, we used a chemogenetic approach to selectively activate Gq signaling in microglia employing a microglia-specific DREADD mouse model. This strategy mimics Gq-coupled receptor activation in microglia in the absence of peripheral immune engagement. Pre-ischemic Gq activation significantly reduced infarct sizes at 24 h after experimental stroke in female mice and at 7 days in both sexes. Morphological analyses revealed that Gq-conditioned microglia exhibited increased structural complexity, adopting a highly ramified, spatially compact phenotype and higher CD68 expression, indicating increased phagocytic activity. Transcriptional profiling demonstrated that Gq activation primes autophagy-related defense pathways in microglia, resulting in upregulation of interferon-stimulated genes 7 days after stroke in both sexes. Together, our findings identify Gq signaling as a key modulatory pathway capable of reprogramming microglial phenotype and enhancing stroke recovery. These results highlight the plasticity of microglial signaling networks and support targeted modulation of microglial Gq pathways.

White matter integrity is a sensitive marker of cerebrovascular health and aging. Physical activity may promote white matter health, but previous studies were limited by self-reported activity and small sample sizes. We examined the association between accelerometer-based physical activity and novel indices of white matter integrity while identifying potential mediators. We analyzed cross-sectional baseline data from 4188 participants (58% women, mean age: 55.4 years) of the Rhineland Study, a prospective cohort study in Bonn, Germany. Physical activity measures (independent variables) were derived from activPAL3 micro-accelerometers. Fractional anisotropy, mean diffusivity, free water fraction, orientation dispersion, and neurite density (outcomes) were obtained from 3 T MR images for the whole brain and across 27 white matter tracts. We performed multivariable polynomial regression and mediation analyses for cardiometabolic and inflammatory factors. Higher energy expenditure was related to lower orientation dispersion, with the association leveling off at higher amounts (standardized linear = -0.153 [-0.183; -0.122]; quadratic = 0.034 [0.017; 0.051]; both p 0.001). Physical activity was linked to lower neurite density in motor tracts ( s between -0.133 and -0.056, all p 0.001). However, with advancing age, physical activity became more strongly associated with higher neurite density and lower mean diffusivity of supratentorial fibers. Body weight, cardiometabolic, and inflammatory factors partly mediated effects of physical activity on white matter microstructure. Physical activity is related to white matter integrity in a nonlinear, age- and region-specific way. Physical activity's effects are greatest in sedentary and older individuals, likely mediated through its impact on body composition, cardiometabolic health, and systemic inflammation.

Diabetic kidney disease (DKD) is a frequent complication of type 2 diabetes and is closely linked to systemic inflammation. Peripheral blood mononuclear cells (PBMCs) are markers of systemic inflammatory and metabolic stress. It is unknown if metabolism-related transcriptomic alterations in these cells is associated with DKD. Using the nCounter Human Metabolic Pathways Panel we profiled PBMC metabolic transcripts in individuals with type 2 diabetes or DKD and in controls (n = 12/group), and integrated transcriptomic data with clinical, inflammatory, and mitochondrial parameters. Patients with DKD showed increased inflammatory biomarkers and reduced PBMC mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Metabolism-related transcriptomic profiling identified 13 differentially expressed genes across groups. DKD subjects displayed downregulation of SLC7A11 versus controls and HLA-DQA1 versus type 2 diabetes, and upregulation of CPT1A and GBA1 versus controls. CPT1A upregulation was confirmed by RT-qPCR and supported by external GEO datasets, though ROC analyses indicated a limited discriminatory performance. Pathway analyses revealed enrichment of immune-related, fatty acid oxidation, and fructose-6-phosphate pathways and reduced cell proliferation pathways in DKD patients. Inflammatory markers correlated positively with energy-regulating pathways and negatively with anabolic processes. In conclusion, these findings suggest that PBMCs reflect immunometabolic remodeling in response to DKD, thus highlighting an association between systemic inflammation, mitochondrial dysfunction, and altered energy metabolism in circulating immune cells.

Artificial chemical synapses, which specifically identify, transmit, and process molecular information, find promising applications in precision medical diagnosis, neural-electronic interface, and in-memory computing. However, to implement biomarker-triggered neuronal excitability modulation with artificial iontronic devices remains a significant challenge. Herein, we demonstrate a capture DNA integrated angstrom-fluidic chemical synapse in which the intramembrane ionic conductance can be switched between excitatory and inhibitory states by specific DNA-target interactions on the outer membrane surface. Experimental results and theoretical calculations unveil that capture of specific biomarker results in a bidirectional space charge polarization, and establishes opposite local concentration gradient at the membrane surface. Driven by this reversible concentration gradient, cation influx or efflux modulate the number density of ionic charge carriers inside the membrane, analogy to the hyperpolarization and depolarization modes of biological chemical synapses. Using a convolutional neural network algorithm to process the ionic conductance enhancement and depletion signals, we develop a diagnostic approach for early prostate cancer with 100% accuracy for both retrospective analysis of 105 clinical specimens, and prospective double-blind trials (n = 10). This work sheds light on artificial chemical synapses based medical diagnosis, and provides a blueprint for neural-like iontronic network for chemical information processing.