To delineate the dynamic transcriptomic landscape of ossification of the ligamentum flavum (OLF) across normal, immature, and mature stages, identify core genes, and screen stage-specific drug candidates. Normal, immature, and mature OLF tissues (nine samples) from three patients with multilevel OLF were collected for RNA-seq. Differential expression, functional enrichment, and dynamic trend analyses were performed. Key genes were validated using an external GEO dataset. Single-cell and spatial transcriptomics were integrated to determine cellular origin and spatial localization. AI-based drug prediction and molecular docking were conducted. Between normal versus immature, 1026 DEGs were identified; between immature versus mature, 713 DEGs; and between normal versus mature, 1285 DEGs. Upregulated genes were enriched in RNA processing and ribosome biogenesis, whereas downregulated genes were enriched in ECM-receptor interaction. LTBP4 showed progressive downregulation during ossification (AUC = 0.88). Single-cell transcriptomics and spatial transcriptomic analysis of a public multi-omics dataset (GSE255942) revealed that LTBP4 is expressed in fibroblasts, with lower expression in ossified than normal tissues. Virtual knockout of Ltbp4 in fibroblasts recapitulated the OLF transcriptomic signature. AI-based drug prediction identified stage-specific candidates; BRD-K59831625 exhibited the lowest binding energy with LTBP4 (-8.9 kcal/mol). Sustained LTBP4 downregulation drives OLF progression, with fibroblasts as core effector cells. Stage-specific drug candidates were identified. These findings provide new targets for molecular diagnosis and precision treatment of OLF.

To investigate the intra- and interday repeatability of ocular blood flow velocity index (BFVi) measurements using a laser speckle contrast imaging device. BFVi measurements were obtained using XyCAM CRE (Vasoptic Medical Inc., Columbia, MD). Two imaging sessions were performed on the same day (26 eyes) and on different days (20 eyes). For optic nerve head-centered datasets, the analyzed regions included the overall field of view, the optic disc, and a standard temporal peripapillary region. For macula-centered datasets, the regions analyzed were the overall field of view, the foveal avascular zone, and the perifoveal region. For each region, heart rate-adjusted measurements of the peak, dip, and mean BFVi were assessed. For intraday measurements of all the optic nerve head-centered parameters, the coefficients of variation (CVs) ranged from 4.8% to 8.5%, and the intraclass correlation coefficient ranged from 0.74 to 0.98. For all macula-centered parameters, the CVs ranged from 4.7% to 6.2%, and the ICCs ranged from 0.93 to 0.98. For the interday measurements of all the optic nerve head-centered parameters, the CVs ranged from 7.9% to 12.6%, and the ICCs ranged from 0.56 to 0.93. For all the macula-centered parameters, the CVs ranged from 8.6% to 15.0%, and the intraclass correlation coefficient ranged from 0.79 to 0.94. Laser speckle contrast imaging demonstrated strong intraday repeatability and reliability for BFVi measurement in healthy subjects, with good interday reliability for key parameters despite some variability. Laser speckle contrast imaging shows promise for clinical use in ophthalmology due to its robust intraday and good interday reliability for ocular blood flow velocity measurements.

Viral infections during critical periods of pregnancy trigger inflammatory responses that alter offspring brain development and behavior, resulting in psychiatric disorder-associated phenotypes. This condition is commonly referred to as prenatal stress induced by maternal immune activation (MIA). Here, we investigate the effects of MIA on the neurophysiological properties of the dentate gyrus-CA3 circuit, a hippocampal circuit critical for cortical input processing and memory formation, and increasingly implicated in psychiatric disorders. Pregnant Sprague-Dawley dams were systemically administered polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA that elicits a viral-like immune response by activating the Toll-like receptor 3 (TLR3)-NF-kB signaling pathway. Extracellular recordings were performed on acute slices of male offspring at postnatal days 61-80. MIA increased the antidromic population spike amplification at the mossy fiber (MF)-granule cell layer response without modifying the antidromic responses at the CA3-CA3 commissural-associational fibers. Paired pulses with short interstimulus intervals revealed decreased levels of phasic and tonic GABAergic inhibition. In addition, MIA reduced coupling between presynaptic fiber volleys and MF field excitatory postsynaptic potentials (MF fEPSP). At the level of synaptic plasticity, MIA impaired frequency-dependent facilitation and decreased MF fEPSP paired-pulse facilitation, two hallmark forms of short-term plasticity at the MF-CA3 synapse. Lastly, MF-mediated long-term potentiation (MF LTP) and long-term depression (MF LTD) showed altered magnitudes in MIA slices. Collectively, our results indicate that MIA alters neuronal processing and output in the DG-CA3 hippocampal network, supporting the contribution of maternal inflammation to long-term circuit dysfunction associated with viral infections during pregnancy.

Phosphodiesterase-5 inhibitors have beneficial pleiotropic effects and hold promise as adjuvant treatments for cancer, dementia, and other disorders. Sixteen men and women aged 50-60 were administered daily sildenafil/tadalafil for 1 month. We characterized molecular signatures of sildenafil/tadalafil treatment via analyses and multi-omics integration of the serum metabolome and skeletal muscle proteome and transcriptome. In serum, eicosanoids decreased and arginine biosynthesis pathway components increased following sildenafil/tadalafil. In skeletal muscle following sildenafil, blood vessel development and immune response genes increased, indicating augmented angiogenesis and possible inflammation at proximate biopsy sites. Proteins related to telomere maintenance and protein folding increased, suggesting reduced cellular senescence and cellular stress or functional adaptations. In skeletal muscle following tadalafil, there were no differentially expressed genes, and despite reduction of many proteins there were no enriched biological processes. Notably, sildenafil resulted in a more cohesive and substantial molecular signal in skeletal muscle. Multi-omics integration for both treatments revealed significant coexpression patterns. Phosphodiesterase-5 inhibitors showed systemic anti-inflammatory effects, as indicated by reduced serum levels of pro-inflammatory eicosanoids. However, this did not translate to immunohistochemical changes. Additional research is warranted to investigate PDE-5 inhibitor effects on various tissues, which can inform prospective applications for drug repurposing.

22q11.2 deletion syndrome (22q11DS) is strongly associated with aberrant neurodevelopment, including decreased cognitive functioning and schizophrenia spectrum disorders (SSDs). While the different core domains of IQ have distinct clinical ramifications, their collective profile has not been well-characterized in 22q11DS. Here, in the largest 22q11DS sample to date, we elucidate the overall IQ profile, including Verbal and Performance IQ (VIQ and PIQ), Processing Speed (PS), and Working Memory (WM), including associations with developmental stage and SSDs. We included 1,328 individuals with 22q11DS from the International Brain and Behavior Consortium. We derived an overall IQ profile using VIQ, PIQ, PS, and WM scores at initial assessment, from age-appropriate Wechsler scales. Using both cross-sectional and longitudinal IQ data from a subset ( n = 496; 37.35%) of individuals, we examined IQ profiles across three age groups and compared profiles between individuals with and without SSDs. IQ profiles in 22q11DS exhibited differences between IQ domains ( p < 0.001), ranked from relatively strongest to weakest: PS > WM > VIQ > PIQ. This profile was similar across age groups, with scores highest in children, lower in adolescents, and lowest in adults. Individuals without SSDs had higher IQ scores than those with SSDs ( p < 0.001), with no significant domain-specific effects. The results indicate a tendency toward a characteristic IQ profile in 22q11DS, regardless of SSD status. A clinical implication of these divergent IQ domains, in particular the relative weakness in PIQ, is that functional expectations are likely to be overestimated. The domain-specific differences across age-groups highlight the need for repeated and comprehensive cognitive assessments in this high-risk population, and may suggest differing underlying mechanisms that require further investigation.

This study is aimed at evaluating the effects of Zhenwu Decoction (ZWD) on cardiac dysfunction, water-retention-related phenotypes, and brain and kidney injury in rats with doxorubicin-induced chronic heart failure (CHF), and at examining whether these effects were accompanied by changes in AVP, V2R, PKA-Cα, and AQP2-related markers. Rats that met the prespecified CHF criteria after doxorubicin administration were rerandomized to the model, ZWD-L, ZWD-M, ZWD-H, or tolvaptan groups and treated once daily for 14 consecutive days. Cardiac function, biochemical and water balance-related outcomes, histopathology, brain AVP, and renal V2R, PKA-Cα, and AQP2 expression were assessed. The animal was the experimental unit, and the number analyzed is reported for each outcome. Compared with the control group, model rats showed impaired cardiac function; increased ascites and tissue water retention; reduced 24-h urine output; histological injury in the heart, brain, and kidney; and altered AVP, V2R, PKA-Cα, and AQP2-related markers. ZWD treatment was associated with improvement in these measured outcomes, with the magnitude and statistical support varying across doses. Tolvaptan produced the expected aquaretic reference response. Adjusted p values and the number of animals analyzed are reported for each outcome. In this doxorubicin-induced CHF model, ZWD improved cardiac function and water-retention-related phenotypes and was accompanied by changes in AVP, V2R, PKA-Cα, and AQP2-related markers. These data support an association but do not establish pathway mediation, direct target engagement, or heart-brain-kidney crosstalk.

Cerebral small vessel disease (SVD) is a leading cause of stroke, vascular cognitive impairment, and functional decline in older adults. Emerging experimental and translational data implicate glymphatic dysfunction in SVD pathogenesis and in vascular amyloid accumulation. The analysis along the perivascular space (ALPS) index, derived from diffusion tensor imaging (DTI), noninvasively estimates water diffusivity along perivascular pathways and has been proposed as an indirect imaging marker related to glymphatic function. In this study, we aim to determine whether the baseline DTI-ALPS index is associated with baseline SVD burden and subsequent longitudinal changes in SVD markers and amyloid-β deposition in cognitively normal aging. We analyzed 204 cognitively normal participants from the Harvard Aging Brain Study with baseline and follow-up visits separated by 3 years. Primary MRI SVD outcomes were intracranial-volume-normalized white matter hyperintensities (WMH/ICV), and visual SVD ratings (Fazekas, ARWMC, perivascular space, and BOMBS [microbleed scale]). Secondary outcomes included cortical amyloid PET burden (PIB_FS_DVR_FLR). We tested the effects of time, baseline ALPS (z-scored), and the time-ALPS interaction using Bayesian mixed-effects models with subject-specific random intercepts adjusted for baseline age, sex, and education; amyloid models were additionally adjusted for APOE4 status. Continuous outcomes were modeled with Gaussian mixed-effects models, binary outcomes with Bernoulli mixed-effects models, and ordinal outcomes with Bayesian cumulative mixed-effects models. In a sensitivity analysis, ALPS was recalculated after excluding voxels with λ 2 /λ 3 > 1.8, and the models were repeated using the crossing-fiber-adjusted index. Posterior means and 95% HDIs were the primary summaries. Multiplicity was controlled using the Benjamini-Hochberg false discovery rate procedure, and the resulting FDR-adjusted two-sided posterior tail-area p-analogues are reported as p corrected . Over the 3-year follow-up, SVD and amyloid-β burden increased: WMH/ICV (β = 0.096, 95% HDI [0.069, 0.121], p corrected < 0.001), cortical amyloid-β (β = 0.130, 95% HDI [0.106, 0.152], p corrected < 0.001), Fazekas (β = 0.320, 95% HDI [0.088, 0.541], p corrected = 0.010), ARWMC (β = 0.404, 95% HDI [0.165, 0.649], p corrected = 0.004), basal ganglia (β = 0.318, 95% HDI [0.079, 0.546], p corrected = 0.010), and centrum semiovale (β = 0.244, 95% HDI [0.026, 0.450], p corrected = 0.025). PVS scores also increased over time. Higher baseline ALPS was associated with lower Fazekas severity (β = -0.742, 95% HDI [-1.281, -0.201], p corrected = 0.026) and with attenuated amyloid accumulation over time (β = -0.025, 95% HDI [-0.049, -0.001], p corrected = 0.039). In a sensitivity analysis excluding voxels with a high likelihood of substantial fiber crossing, the ALPS-by-time interaction for amyloid burden remained significant (β = -0.028, 95% HDI [-0.052, -0.003], p corrected = 0.022), whereas the baseline association with Fazekas severity was attenuated (β = -0.413, 95% HDI [-0.966, 0.181], p corrected = 0.751). Higher baseline WMH/ICV was associated with poorer baseline global cognition (PACC5) (β = -0.092, 95% HDI [-0.177, -0.011], p corrected = 0.036), processing speed (β = -0.116, 95% HDI [-0.223, -0.010], p corrected = 0.036), and executive function (β = -0.144, 95% HDI [-0.251, -0.029], p corrected = 0.035). Higher baseline amyloid burden was associated with steeper PACC5 decline (β = -0.065, 95% HDI [-0.096, -0.033], p corrected < 0.001). In cognitively normal older adults, higher conventional baseline ALPS was associated with lower Fazekas severity, although attenuation after crossing-fiber adjustment indicates that this cross-sectional relationship was sensitive to the microstructural composition of the ALPS regions. In contrast, higher baseline ALPS was associated with slower short-term amyloid-β accumulation, and this longitudinal association remained significant after crossing-fiber adjustment. Greater baseline amyloid burden was associated with more rapid decline in global cognition, whereas higher baseline WMH volume was associated with poorer baseline global cognition, processing speed, and executive function. These findings support ALPS as a candidate noninvasive diffusion marker associated with longitudinal amyloid-related change, while emphasizing the need for further validation of its relationship with SVD burden and its biological specificity.

Patients with glutaric acidemia type I (GA I) frequently manifest with acute encephalopathy usually triggered by infections and by progressive neurological deterioration. Since the pathogenesis of the brain damage in GA I during inflammatory processes is poorly established, we investigated biomarkers of inflammatory response and neural damage in the cerebral cortex of wild type (WT) and glutaryl-CoA dehydrogenase (GCDH) deficient mice (Gcdh -/- ) receiving acute lysine and lipopolysaccharide (LPS) administration to induce inflammation. Neuromotor development reflexes and the neuroprotective effects of L-carnitine (Carn), whose potent anti-inflammatory properties have been recently described, were also evaluated. LPS increased the gene expression of most parameters of the inflammatory response, which were normalized or attenuated by Carn both in WT and Gcdh -/- mice. Importantly, gene expression of TNF-α, IL-6, NFkB, IκBα, COX-2 and VEGF, and heme oxygenase-1 content were significantly increased in LPS-treated Gcdh -/- relatively to the WT mice. Furthermore, the neuronal biomarker protein NeuN was reduced, whereas the number of vacuoles and neurodegenerative cells were increased in the LPS-treated Gcdh -/- mice, indicating neuronal damage and loss in these animals. Furthermore, the righting and the gait reflexes were altered in the Gcdh -/- mice, reflecting impairment of neuromotor development. Finally, Carn prevented LPS-induced inflammation, neuronal damage, vacuolation, increased neurodegenerative cells and the righting reflex. Our findings suggest that inflammation plays an important role in the pathogenesis of the neurological alterations following infectious/inflammatory processes in GA I patients and that higher doses of Carn should be considered during these episodes.

The degenerating motor neurons of amyotrophic lateral sclerosis (ALS) patients are characterized by the accumulation of cytoplasmic aggregates, specifically enriched in ubiquitinated TDP-43. Expressed mainly in the nucleus and partially in the cytoplasm to execute its role in RNA metabolism, the exact mechanisms that bring TDP-43 to aggregate in disease have yet to be described. Unfolding these processes could bring us closer to effective drug development that is drastically lacking in the ALS research field. Induced pluripotent stem cells (iPSCs) offer a promising platform for studying ALS pathogenesis directly in the relevant human genetic backgrounds of ALS patients. Since 2012, more than 30 published studies have investigated altered cellular and subcellular features in iPSC-derived motor neurons from ALS patients harbouring mutations in the TARDBP gene (encoding for TDP-43 protein). However, there are discrepancies in the obtained results, which call into question the relevance of this model for ALS disease modelling and its use for drug development efforts. Thus, there is a need in the field for a clear and detailed layout and summary of all the published data on ALS modelling using TARDBP mutant iPSC-derived motor neurons. In this systematic review, we analyse all phenotypic assessments that have been done on iPSC-derived motor neurons derived from TARDBP ALS patients on the morphology, functionality and the viability of these cells. We also analyse if this model recapitulates ALS pathology in vitro by comparing studies that looked at TDP-43 and neurofilament aggregation, as well as stress granule dynamics. Importantly, we compare the technical details of all the discussed studies, such as differentiation protocol, age and purity of the used motor neurons and quantification method, in order to discuss how all of these parameters affect the observed phenotypes. Lastly, we also expand our review to all other different cell types that have been differentiated from TARDBP iPSCs, highlighting non-cell autonomous mechanisms of TDP-43-ALS pathophysiology. By integrating findings across studies, this review identifies commonalities and discrepancies, discusses methodological advancements and limitations, and highlights potential therapeutic targets revealed through TARDBP iPSC-derived models.

Despite the female predominance in age- and immune-associated diseases, the pathways underlying sex differences in healthy immune aging remain incompletely understood. Here, we analyze a multi-ethnic single-cell transcriptome of healthy human immune aging (35% Asian), comprising 3.8 million peripheral blood mononuclear cells (PBMCs) from 1,828 individuals aged 19-97 years. Prominent peaks of differential gene expression around 40 (mainly CD4 T cells) and after 60 (mainly CD8 T cells) years of age were accompanied by an age-dependent decline in RNA/protein homeostasis and inflammatory PBMC polarization with sex-dependent kinetics. While females displayed sustained CD8 T cell activation and late-life aging signatures in CD4 T, NK, and B cells, males exhibited early-life fluctuations in CD4 T cell immunometabolism associated with hypomethylation of SSH3 at chromosome 11q13. Deep learning-based biological age clocks stratified for sex outperformed sex-combined models, learning from transcriptional immune trajectories. We thus unravel a nonlinear PBMC aging whereby targeting sex-specific pathways might allow precision geromedicine.

Alzheimer's disease (AD) is not merely a central nervous system disorder; rather, it is a systemic condition profoundly influenced by the peripheral internal environment. Recent research has revealed that imbalances in the gut microbiota (GM) and metabolite disturbances contribute to AD onset and progression. Clinical and animal studies have indicated that AD patients commonly exhibit reduced GM diversity, decreased populations of short-chain fatty acid (SCFA)-producing and indole-producing bacteria, disrupted bile acid (BA) profiles, and elevated levels of trimethylamine N-oxide (TMAO) and kynurenine pathway (KP) activity. These alterations not only reflect gut dysbiosis, but also impair blood-brain barrier (BBB) integrity and amplify neuroinflammation by modulating tight junction proteins and inflammatory signaling through their effects on receptors and transporters such as G protein-coupled receptors(GPR41/43), aryl hydrocarbon receptor(AhR), Farnesoid X receptor(FXR)/ Takeda G protein-coupled receptor 5(TGR5), L-type amino acid transporter 1(LAT1), and Major Facilitator Superfamily Domain containing 2A(MFSD2A). From an integrative perspective, these changes -including short-Chain Fatty Acids (SCFAs) deficiency, elevated TMAO and toxic BA levels, overactivation of the KP, and Lipopolysaccharides (LPS) leakage-often act synergistically, collectively forming key pathological nodes in the "metabolic network-BBB-AD" axis. GM-targeted strategies such as dietary interventions, probiotics and fecal microbiota transplantation (FMT) have demonstrated potential in improving metabolite profiles and BBB homeostasis. Future research should utilize induced pluripotent stem cell-derived organoids and multi-omics integration approaches to elucidate the spatiotemporal dynamics of metabolites within the gut-brain axis (GBA), thereby laying the foundation for precise microbiome-based interventions in AD.

Emotional intelligence (EI) is linked to enhanced cognitive and social functioning, but its neurostructural correlates and relationship with domain-specific creative achievement remain poorly understood. This study examined 266 young adults using the Emotional Intelligence Scale (EIS), the Creative Achievement Questionnaire (CAQ), and structural magnetic resonance imaging (MRI) to test how the brain shapes the EI-creativity relationship. We found that (a) EI was positively related to creative achievement, particularly in artistic domains (dance, creative writing, humour); (b) higher EI was associated with smaller grey matter volume in the superior insular circular sulcus; and (c) right insula volume moderated the EI-creativity relationship in a subdivision- and domain-specific manner: in the superior subdivision, the EI-creativity link strengthened as insula volume decreased, whereas in the anterior subdivision, the EI-scientific creativity link strengthened as insula volume increased. These findings indicated that insular grey matter volume, a hub for emotion-cognition integration, shapes how emotional competence translates into creative achievement, with opposite structural signatures across different insular subregions and creative domains.

The intestinal epithelium is maintained by stem cells at the crypt base, however, acute or chronic inflammation can severely disrupt stem cell function and tissue homeostasis. To characterize mucosal inflammation and tissue damage, we evaluated time-course gene expression changes using a dextran sulfate sodium (DSS)-induced mouse model of colitis. By applying normalization, Z-score transformation, and spline curve modeling, we trace the temporal expression dynamics of key intestinal genes. This computational approach offer insights into the molecular responses during inflammation and may help identifying new biomarkers for chronic inflammatory diseases.

Stroke is the second most common neurological complication in cancer patients after metastases. Cancer-associated coagulopathy (CAC) is an important mechanism of ischemic stroke in this population. We systematically reviewed the epidemiological, clinical, radiological, and pathophysiological features of CAC-related stroke, as well as associated biomarkers and treatment strategies. A systematic search of PubMed/MEDLINE, Scopus, Cochrane Library, and Embase (2000-2025) was performed according to PRISMA 2020 guidelines. Search terms included "stroke", "cancer", "hypercoagulability", "coagulopathy", "disseminated intravascular coagulation", and "non-bacterial or marantic thrombotic endocarditis". Studies published in English or Spanish were included, whereas case reports and review articles were excluded. Data were synthesized qualitatively. Eighty-two studies met inclusion criteria. CAC-related stroke occurs predominantly within six months of cancer diagnosis and is strongly associated with advanced or metastatic disease and a high risk of early recurrence. Adenocarcinoma, particularly lung and pancreatic cancer, is the most frequently associated histological subtype. Proposed mechanisms include mucin-mediated platelet aggregation, tissue factor-driven coagulation, extracellular vesicles, and neutrophil extracellular trap formation, leading to thromboinflammation and platelet-rich thrombi. D-dimer is the biomarker most consistently associated with recurrence and mortality, while C-reactive protein, fibrinogen, CA-125, and transcranial Doppler microembolic signals show limited specificity. Characteristic imaging findings include multiple infarcts involving more than two vascular territories, particularly the 'three territories sign'. Low-molecular-weight heparin and direct oral anticoagulants are the most commonly used secondary prevention strategies. Thirty-day mortality rates range from 25 to 50%. CAC-related stroke is a distinct and underrecognized entity characterized by specific biological and radiological features and poor outcomes. Earlier recognition and optimized antithrombotic strategies may improve prognosis.

Clozapine is highly effective for resistant schizophrenia but limited by neutropenia concerns. In this 30-year series, 27 patients discontinued clozapine and 13 were rechallenged; 61.5% were successfully maintained. No fatalities occurred, and index-episode severity did not predict outcomes. Rechallenge appears safe when guided by individualised risk-benefit assessment.

Sleep disturbance is a prevalent issue among those who have experienced a stroke. The impact of gender on the prevalence of sleep disturbance within Asian stroke populations remains ambiguous. This research seeks to examine the prevalence of sleep disturbance among stroke survivors in Indonesia. This quantitative prevalence analysis was based on the 2018 Indonesian Basic Health Research. A total of 7,147 stroke survivors who answered the sleep disturbance questions were included. The estimated prevalence and regression models were examined utilizing SPSS software. The total prevalence of sleep disturbance among stroke survivors in Indonesia was 28.4% (95% CI: 27.4%-29.4%). Females exhibited a greater frequency of sleep disturbance than males (34.4% versus 26.1%, respectively). When categorized by age group, both females and males exhibited a trend of rising sleep disturbance prevalence with time. Moreover, daily smoking, low educational attainment, rural residency, and insufficient physical activity were correlated with sleep disturbance symptoms in the male cohort. In females, the presence of comorbidities such as cardiovascular disease and asthma was associated with sleep disturbance. This study's findings revealed a significant prevalence of sleep disturbance among stroke survivors in Indonesia. Our findings indicate a gender influence on sleep disturbance prevalence, with females exhibiting a higher prevalence than males. These findings underscore the significance of sleep assessment and treatment in clinical or community environments.

The function of the cerebral cortex is shaped by its anatomical connectivity, yet experimental findings on connection probabilities in local cortical networks remain inconsistent. This study explores structural characteristics of local cortical networks based on distance dependent, Gaussian connectivity profiles. Monolayers of 101 × 101 pyramidal neurons were examined. Their connectivity was based on experimental anatomical or electrophysiological data. In the anatomical setting the connection probability between neighboring neurons was 0.8. In the electrophysiological scenario connection probabilities for adjacent neurons ranged between 0.08 and 0.23. All distance dependent networks were compared to the configuration model which generates degree-preserving but otherwise randomly rewired networks. The networks thus constructed were analyzed applying tools of network science, i.e. average degrees, degree distributions, local clustering coefficients and graph distances. Moreover, the numbers, sizes and spatial dimensions of cliques were investigated as well as the cost of connectivity. Distance-dependent networks differed fundamentally from configuration-model networks across all structural measures. They showed substantially higher local clustering, formed more numerous and more spatially compact groups of strongly connected neurons, and required lower wiring cost. Importantly, the structure of distance-dependent networks was highly sensitive to near-neighbor connectivity: when neurons had a high probability of connecting locally, the network reliably developed tightly wired, spatially localized neuronal clusters. Distance-dependent connectivity gives rise to structural network features that may facilitate the emergence of functional neuronal assemblies. Based on the findings of this study, a general probabilistic rule for local cortical connectivity is proposed that can be used to design artificial neural networks with biologically inspired wiring principles.

The abnormal accumulation of amyloid-beta peptides is a key contributor to Alzheimer's disease. Of these peptides, soluble amyloid-beta oligomers (AβOs) have emerged as potent neurotoxins and early pathological biomarkers. Although AβOs are highly specific biomarkers, their low physiological abundance, structural heterogeneity and matrix interference associated present considerable challenges for conventional diagnostic approaches. Herein, we report a novel fluorescent aptasensor platform for the ultrasensitive detection of AβOs. The platform integrates magnetic preconcentration with a signal amplification strategy based on catalytic hairpin assembly (CHA). To achieve simultaneous selective recognition of AβOs and efficient CHA initiation, magnetic beads were functionalized with rationally designed double-stranded DNA complexes, which were formed through the hybridization of an AβO-specific aptamer and a CHA-initiator fragment. Upon the specific binding of AβOs, the AβO-specific aptamer competitively dissociates from the magnetic beads, thereby unmasking the surface-tethered initiator to trigger the CHA circuit. The circularly generated CHA products serve as a self-amplifying signal indicator, whereas the magnetic beads enhance target-capturing capacity and facilitate the removal of complex matrix interferences prior to amplification. Experimental results revealed that the proposed system exhibited a broad linear detection range from 10 pg mL -1 to 10 ng mL -1 with a detection limit of 4.1 pg mL -1 (r = 0.9821). Furthermore, to demonstrate its applicability, plasma samples from healthy individuals were analyzed. The results indicated that the AβO level ranged from 87 to 290 pg mL -1 . These findings demonstrate the potential of integrating aptamer-mediated magnetic capture with CHA-driven signal amplification for ultrasensitive AβO detection. The spatial separation of AβO-aptamer binding and CHA amplification through magnetic beads effectively minimizes matrix interference while permitting large sample volumes. This strategy has the potential to serve as sensitive tool for early Alzheimer's disease diagnosis.

Major depressive disorder (MDD) is a serious psychological disorder marked by persistent feelings of sadness and a notable decline in daily functioning. Functional Brain Networks (FBNs) have become crucial biomarkers for the diagnosis of MDD, and Graph Convolutional Networks (GCNs) have demonstrated great potential in extracting FBN features. However, existing GCN methods typically depend on large-scale labeled datasets and lack clinical interpretability in MDD identification, which limits their application. We introduce Universum Inspired Graph Contrast Learning (Uni-GCL), a novel graph-based self-supervised learning framework to relieve the demand for training sample size. Additionally, to enhance the clinical interpretability of GCNs, we optimized the Gradient-weighted Class Activation Mapping (Grad-CAM) method to enable it to effectively pinpoint the crucial nodes within the GCN. The Uni-GCL method outperformed previous state-of-the-art approaches. It improved accuracy by 3% at Site 21 and 5% at Site 1. Additionally, Uni-GCL identified that brain regions FGoperc. R, CAU. L, FFG. R, AMYG. L, PUT. L, AMYG. R, PUT. R, THA. L, IFGtriang. R, FFG. L, INS. L, INS. R, HIP. L and HIP. R make significant contributions to the diagnosis of MDD. Uni-GCL can effectively reduce the sample size for model training and improve the diagnostic performance of MDD. Meanwhile, the adapted Grad-CAM provides an effective tool to enhance the interpretability of GCN.

This study aimed to explore the anti-neuroinflammatory mechanism of Ganoderma lucidum against Alzheimer's disease (AD) using network pharmacology and molecular docking, and verify its neuroprotective and anti-neuroinflammatory effects in Aβ1-42-induced AD mice. Common targets were screened and analyzed by KEGG/GO enrichment. Core targets were evaluated by molecular docking and dynamics simulation. Aβ1-42-induced AD mice and LPS-stimulated macrophages were used. Cognitive function, Aβ deposition, tau phosphorylation, and inflammatory gene expression were measured. Network analysis highlighted inflammation-related pathways. Molecular dynamics simulations confirmed stable binding between active components and targets like STAT1, STAT3, JAK2, and TNF. In vivo, G. lucidum extract suppressed abnormal activation of microglia and astrocytes, and reduced pro-inflammatory factors. Following G. lucidum administration, mRNA levels of Jak2 and Stat1 in hippocampal tissue were significantly reduced, suggesting potential regulation of neuroinflammation via the JAK2/STAT1 pathway. Concurrently, G. lucidum down-regulated transcription of key subunits (Ncstn, Aph-1, Pen-2) in the γ-secretase complex, thereby reducing Aβ1-42 production. In vitro experiments similarly confirmed G. lucidum's ability to inhibit LPS-induced IL-6 and TNF-α release from macrophages. Ganoderma lucidum extract alleviates neuroinflammation in AD models, providing experimental evidence for its potential application in AD prevention or therapy.

A child with rhombencephalosynapsis, part of the Gómez-López-Hernández spectrum, developed bilateral corneal hypoesthesia and neurotrophic keratopathy. Recurrent epithelial defects and progressive corneal haze occurred despite conservative therapy with lubrication, serum drops, and topical treatment. A persistent epithelial defect healed rapidly after application of a bandage contact lens. This case highlights the importance of early ophthalmologic surveillance and corneal sensitivity assessment in children with rhombencephalosynapsis. Bandage contact lenses are a safe and effective treatment option in pediatric neurotrophic keratopathy, promoting epithelial healing and helping prevent corneal scarring and vision loss.

In this hypothesis-generating study, we integrated histopathology and transcriptomics in six patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) receiving anti-CD19 CAR-T therapy, stratified into CAR-T-responsive and CAR-T-resistant cohorts by clinical response. Resistant tumors exhibited diffuse growth patterns with cohesive blast sheets, centroblastic morphology, tumor necrosis, and an immune-desert tumor microenvironment. Transcriptomics revealed three transcriptional programs that may correlate with CAR-T resistance: pro-fibrotic/extracellular matrix remodeling, proliferative and pro-survival traits, and immune dysfunction. Exploratory integrative analysis indicated associations between morphological features and pre-existing pathway dysregulation in CAR-T-resistant patients, such as hyperactivated PI3K-Akt-mTOR and impaired antigen presentation. Collectively, these observations imply CAR-T resistance in R/R DLBCL may stem from synergistic interplay among morphological aberrations, dysregulated proliferative/stromal pathways, and local immunosuppression. Pending prospective validation in larger independent cohorts, the candidate biomarkers observed herein may aid outcome prediction and combinatorial regimen design for R/R DLBCL.

Adolescents are vulnerable to poor sleep, and both individual and environmental factors predict youth sleep problems. The present study examined the independent and interactive associations of adolescent sympathetic nervous system reactivity and experiences of parenting with multiple aspects of their sleep. Participants were 579 late adolescents (M age = 17.14 years, 47.3% males, 52.7% females; 62.7% White, 37.3% Black). Sympathetic reactivity was measured via skin conductance level reactivity in response to a lab-based stressor, and participants reported on experiences of parental psychological control. Adolescent sleep was assessed both objectively through actigraphy and subjectively from self-report. Structural equation models demonstrated a consistent pattern of interaction effects, such that higher adolescent skin conductance level reactivity predicted better actigraphy-derived sleep 1 year later at low levels of paternal psychological control, but worse actigraphy-derived sleep at high levels of paternal psychological control. There were no independent or interactive effects for mothers' parenting. Findings are consistent with biological sensitivity to context theory and indicate that high skin conductance level reactivity may reflect appropriate engagement with the environment in low-stress contexts but lead to wear and tear of bioregulatory systems in contexts of high stress, eroding sleep.

Poststroke dysphagia is common and adversely affects patient outcomes, yet no standardised tool exists to assess nursing management capacity in this area. To develop and validate the nursing management capacity in poststroke dysphagia (NMC-PSD) Scale, a self-report instrument measuring nurses' perception of unit-level management capacity. The 35-item scale was adapted from an existing checklist and refined through two rounds of Delphi consultation (I-CVI = 0.80-1.00; S-CVI/Ave = 0.93) and pilot testing. A cross-sectional survey provided psychometric validation. The scale uses a mixed model: a formative structure dimension (resource inputs jointly constituting capacity) alongside reflective process and outcome dimensions. Reliability was evaluated using Cronbach's α for the reflective dimensions and test-retest ICC for the total scale and the human resources composite. In 410 nurses from 12 Chinese provinces, the 26-item reflective core showed adequate internal consistency (process α = 0.97; outcome α = 0.95) and test-retest reliability (ICC = 0.98). Bifactor model fit was good: χ 2 (348) = 699.11, CFI = 0.958, TLI = 0.951, RMSEA = 0.050, SRMR = 0.027. The 26-item reflective core showed dominant unidimensionality (ECV = 0.869, ωH = 0.963) and is recommended as the primary validated metric (range 26-130). Nine formative structural indicators, supported by content validity (S-CVI/Ave = 0.93), are reported separately as descriptive resource inputs. Six specific factors had low independent reliability (ωHS = 0.05-0.19) and serve as conceptual or descriptive groupings only. Mean reflective total score was 54.71 (SD = 18.40); the exploratory weighted index was 207.87 (SD = 66.41). The NMC-PSD Scale demonstrated acceptable psychometric properties as an individual-level measure of nurse-perceived unit capacity. A bifactor re-specification, developed post hoc within the same sample, revealed a dominant general factor underlying the 26 reflective items. Independent cross-validation is warranted. The 26-item reflective total score is recommended as the primary validated metric; nine formative structural indicators are reported separately as descriptive resource inputs. Subscale profiles serve as conceptual or descriptive item groupings only. The 26-item reflective total score supports individual-level inference regarding nurses' perceptions of unit management capacity. Organisational-level benchmarking requires further validation of within-unit agreement and aggregation reliability. The nine structural indicators offer descriptive resource profiling, and the exploratory weighted index remains supplementary pending criterion-related validation against objective administrative indicators.

Analyses of neuroimaging data increasingly leverage the distribution of neurotransmitter receptors derived from positron emission tomography (PET) to bridge the gap between micro- and macro-scale brain function. However, these receptor maps are highly spatially overlapping, which can give rise to interpretive and analytical challenges. Here, we systematically investigate the impact of spatial collinearity among PET maps in the context of Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), a method that uses receptor maps as spatial regressors to derive subject-level molecular-enriched functional connectivity networks. Exhaustive combinatorial analysis across 19 receptor and transporter maps showed that collinearity scales rapidly with the number of receptors modelled simultaneously, and that the underlying correlation structure was relatively stable across parcellation scales, reflecting the intrinsic organisation of neurotransmitter systems. Using test-retest fMRI data from the Human Connectome Project, we demonstrate that modelling greater numbers of receptors degrades the reliability of molecular-enriched networks derived from conventional multivariate REACT models, and that collinearity among receptor maps drives this degradation. An alternative univariate approach, in which each receptor is modelled independently, yielded more reliable networks and, when applied to a within-subjects study of LSD compared to placebo, better recovered the role of the 5-HT 2A receptor in LSD's neural effects. These findings identify spatial collinearity as a fundamental constraint on multivariate molecular-enriched network estimation. We therefore recommend univariate models as the default, with multivariate models used only where specifically motivated and reported alongside the univariate result.

Intimate partner violence-related brain injury (IPV-BI) predominantly affects women and often reflects both structural trauma from mild traumatic brain injury (mTBI), as well as ischemia/hypoxia from non-fatal strangulation (NFS). This polytrauma can impair cognitive function, particularly learning and memory processes, which may contribute to the continuation of the cycle of violence. This study investigates the effects of mTBI and hypoxic/ischemic injury on hippocampal long-term potentiation (LTP), a biological model of learning and memory, to determine if the combination of mTBI+NFS would exacerbate deficits in LTP. Female rats were randomly assigned to either Sham, mTBI, NFS, or mTBI+NFS groups to assess acute injury metrics and LTP capacity 7 days after injury. At the time of injury, NFS and mTBI+NFS groups exhibited significant reductions in blood oxygen saturation, heart rate, and poor neurological assessment metrics. Isolated mTBI and NFS impaired LTP in the CA1 hippocampal region while mTBI+NFS increased synaptic excitability in the CA1 yet impaired CA1 LTP. Contrary to our hypothesis, the combined mTBI+NFS did not exacerbate deficits, but these findings highlight that even a single episode of mTBI or NFS is sufficient to impair hippocampal LTP in the female CA1 region.

Neuronal classification from extracellular electrophysiological recordings is challenging due to intrinsic waveform variability, noise, and technical differences across experiments, technologies, and species. We introduce HIPPIE (High-dimensional Interpretation of Physiological Patterns In Intercellular Electrophysiology), a deep learning framework that combines self-supervised pretraining on unlabeled datasets with supervised fine-tuning to classify neurons from extracellular recordings. Using conditional convolutional joint autoencoders, HIPPIE learns technology-adjusted representations of waveforms and spiking dynamics. Here we show, across mouse, rat, and macaque recordings, that HIPPIE classifies cell types competitively with existing methods while additionally supporting generative analyses that discriminative models cannot perform, including counterfactual decoding of electrophysiological signals under changed experimental conditioning, cross-species latent interpolation, and a cross-modal analysis revealing that spike-timing modalities and waveform morphology encode largely independent dimensions of neuronal identity. HIPPIE is available as both a Python package and a coding-free web application, providing a unified framework for multimodal neuronal classification across technologies, experimental conditions, and species.

Recent evidence demonstrates that the interplay of amyloidogenesis and tauopathy plays a significant role in exacerbating neurodegeneration in Alzheimer's disease. This interplay of molecular pathways aids in the formation and accumulation of amyloid beta and neurofibrillary tangles extracellularly and intracellularly, respectively. These interconnected pathways highlight the need for the simultaneous inhibition of BACE1 and GSK-3β for the mitigation of disease progression. There are several drugs developed against BACE1 and GSK-3β separately, but they have limited therapeutic efficacy and failed in clinical trials. The failure is due to systemic toxicity and off-target side effects, limited blood-brain barrier permeation, and lower therapeutic benefits. Advances in brain-targeted drug delivery approaches aim to provide site-specific drug delivery, co-delivery of dual drugs, and enhanced stability. Nanoformulations such as lipid-based nanoparticles, polymeric nanoparticles, and hybrid nanoformulations with surface functionalization demonstrate better results in pre-clinical studies. Various research studies have established that targeting amyloidogenesis and tau hyperphosphorylation pathways is a promising therapeutic approach for attenuating neurodegeneration, with the integration of nanotechnology. This review article provides insights into the interplay of BACE1 and GSK-3β molecular signaling pathways, examines the limitations of conventional therapies, and highlights the potential of dual-targeting nanoformulations, while emphasizing the challenges of clinical translation and effective therapeutic strategies to overcome these and treat AD.

Aggression is an innate behavior conserved across species, serving as a critical means to compete for food, mating opportunities, and other essential resources. A central question in aggression research is the extent to which inter-individual variability in aggression is shaped by genetic factors. Here, we examine aggressive behaviors in naïve male mice across seven genetically defined strains and find large cross-strain differences. We find a tight correlation between aggressiveness and anxiety levels across strains, but not within the same strain, suggesting strong genetic control of both traits. Pharmacologically elevating anxiety in high-aggression strains reduces aggression, revealing a causal relationship between these behaviors. We further demonstrate that differences in the synaptic and cellular properties of neurons in the ventrolateral ventromedial hypothalamus (VMHvl) largely account for cross-strain variability in male aggression, and that chemogenetically increasing VMHvl excitability enhances attack behavior in a low-aggression strain. Together, these findings reveal the neuronal implementation of the genetic control of innate aggression level.

Post-stroke cognitive impairment (PSCI) affects nearly 30% of stroke survivors and substantially limits functional recovery. Brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase-β (Trkβ) signalling plays an important role in synaptic plasticity and cognitive function; however, the contribution of individual NTRK2/Trkβ isoforms to PSCI remains poorly understood. This study investigated (a) isoform-specific NTRK2 mRNA expression, (b) genetic association of the isoform-specific variant rs6559833 with post-stroke cognitive outcomes and (c) DNA methylation patterns potentially regulating NTRK2 expression using blood as primary biosource. Isoform-specific expression was analysed in 50 subjects, rs6559833 was genotyped in 280 ischemic stroke patients, and DNA methylation was assessed in 10 samples using whole-genome bisulfite sequencing. The TRKβ-FL expression was significantly reduced in stroke patients compared with healthy controls, whereas TRKβ-SHC expression was higher in PSCN individuals than in PSCI patients. The latter showed positive correlation with MEK2 expression and memory performance. The 'TT' genotype of the rs6559833 variant showed marginal associations with post-stroke memory status and overall BMSE scores (p = 0.0442 and 0.0488, respectively). Furthermore, hypermethylation was observed within the NTRK2 gene body and in genes encoding its splicing regulators, whereas no evident difference in promoter methylation was observed. Collectively, these findings suggest that Trkβ-SHC expression may be associated with preserved cognitive function after stroke and indicate a potential relationship between isoform-specific NTRK2 expression, genetic regulation and cognitive outcomes in PSCI.

Colonic inflammation induces profound alterations in the intestinal mucosa that are evident at both macroscopic and microscopic levels, including disruption of epithelial barrier integrity, crypt fission, and immune cell infiltration. Recent advances in single-cell and spatial RNA sequencing have greatly expanded our understanding of the cellular diversity of the colonic mucosa, enabling pathological features to be directly linked to underlying cellular and molecular mechanisms. This chapter demonstrates the application of single-cell RNA sequencing (scRNA-seq) analysis techniques to interrogate stem cell dynamics in the context of inflammatory bowel disease. Using publicly available datasets, the chapter provides a step-by-step workflow implemented in Python, covering data access, loading, integration of multiple datasets, and initial preprocessing. Cells are mapped to large single-cell atlas references to infer cell identities, followed by a pseudobulk analysis strategy to assess inflammation-associated changes in cell phenotypes. Finally, trajectory inference approaches are applied to explore potential mechanisms governing the specification and modulation of key cell types during inflammation. Accompanied by an online resource containing fully annotated scripts, this chapter offers guided instruction in contemporary scRNA-seq analysis workflows. It is intended as an accessible introduction for researchers seeking to develop practical skills in single-cell data analysis that can be readily applied to their own biological questions.

α-Synucleinopathies are marked by persistent neuroinflammation and disabling non-motor symptoms involving nucleus accumbens (NAc) dysfunction, yet the neuroimmune mechanisms linking microglial activation to accumbal synaptic pathology remain poorly understood. Here, we identify α1-antitrypsin (AAT) as a previously unrecognized modulator of cannabinoid receptor 2 (CB2R)-associated signaling in α-syn pathology. An acute transcriptomic screen revealed prominent induction of the Serpina1 gene family, while primary-microglial and chronic AAV-α-syn experiments showed that Cnr2 deficiency amplified Serpina1/AAT responses, consistent with an insufficient compensatory reaction to persistent inflammation. Molecular docking, reciprocal co-immunoprecipitation, and surface plasmon resonance provided complementary evidence supporting an AAT-CB2R association under the respective assay conditions. Functionally, AAT reduced the α-syn-associated elevation of intracellular cAMP in an AM630-sensitive manner and attenuated ATP-evoked Ca 2 ⁺ responses, calpain-1 activity, GSK-3β N-terminal cleavage, and NLRP3/caspase-1-related cytokine production; these effects were substantially diminished in Cnr2-deficient microglia. Calpeptin reproduced key molecular effects, implicating calpain-related proteolysis in this neuroimmune response. In vivo, intracerebroventricular AAT preserved NAc synaptic ultrastructure, ameliorated excitatory synaptic abnormalities in dopamine D2 receptor-expressing medium spiny neurons, and improved fear-memory retrieval, spontaneous alternation, and anxiety-like behavior, without affecting novel object recognition or motor performance. Several effects were attenuated under Cnr2-deficient conditions, although selected electrophysiological responses persisted. Our findings identify AAT-CB2R-linked signaling as a modulator of microglial inflammatory homeostasis and support the therapeutic potential of AAT for NLRP3-associated neuroinflammation and non-motor dysfunction in α-synucleinopathies.

Agitation and aggression in Alzheimer's disease (AD) are highly distressing behavioral symptoms traditionally managed with off-label atypical antipsychotics, despite boxed warnings for increased mortality in elderly patients. The emergence of Auvelity (dextromethorphan-bupropion) provides a critical, non-antipsychotic therapeutic alternative. This combination utilizes bupropion as a CYP2D6 inhibitor to achieve therapeutic central nervous system concentrations of dextromethorphan. Dextromethorphan acts as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, bypassing dopaminergic blockade to promote synaptic plasticity via glutamatergic and monoaminergic modulation. Key clinical trials (ADVANCE-1 and ACCORD) demonstrate that dextromethorphan-bupropion produces rapid, statistically significant reductions in Cohen-Mansfield Agitation Inventory (CMAI) scores. Furthermore, it offers robust long-term maintenance, demonstrating a 3.6-fold lower risk of agitation relapse compared to placebo. The combination therapy was generally well-tolerated in trials, successfully avoiding the sedation, cognitive blunting, and heightened fall risks characteristic of antipsychotics. Clinicians must, however, monitor for blood pressure changes and potential CYP2D6 drug-drug interactions. Dextromethorphan-bupropion represents a highly efficacious, safer paradigm shift in the pharmacological management of AD-associated agitation, offering targeted symptom relief while minimizing the severe risks associated with standard antipsychotic use.

Oligodendrocytes facilitate saltatory conduction and they support both neuronal and axonal survival; thus, when they are diseased or damaged, neurological problems ensue. Oligodendrocyte progenitors (OPCs) have been successfully isolated from rodents using magnetic beads, immunopanning and differential adhesion. Whereas rat OPCs are easy to propagate in vitro , expanding mouse OPCs in vitro has not been straightforward, which is problematic given that mice have been used to generate the majority of genetically engineered disease models. In this study, we developed and characterized a reproducible, straightforward method to prepare large numbers of nearly homogeneous cultures of mouse OPCs. Using the McCarthy and de Vellis mechanical separation method, we isolated OPCs from a mixture of glial cells and plated them onto fibronectin-coated tissue culture plates in a biochemically defined medium supplemented with fibroblast growth factor-2 (FGF-2) and medium conditioned by B104 neuroblastoma cells. However, when maintained in a standard tissue culture incubator, they proliferated very slowly and ∼ 20% died. By contrast, when they were maintained in an incubator with 2% oxygen they proliferated more rapidly and could be expanded for multiple passages with high viability. After three passages, greater than 99% of these OPCs expressed markers of early OPCs. In medium containing only FGF-2 they progressed to late-stage OPCs. When a medium supplemented with T3 was provided, a large subset of OPCs differentiated into O4+/MBP+ oligodendrocytes with sheet-like membranes. However, between 3 and 6 passages, less than 20% of the OPCs differentiated into MBP+ oligodendrocytes and this was associated with a loss of Sox-10. These studies reveal significant differences between mouse and rat OPCs and a role for oxygen tension in mouse OPC proliferation and differentiation.

Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline, with core pathological mechanisms including β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, and impaired synaptic plasticity. Although exercise has neuroprotective effects, the molecular mechanisms by which it mediates peripheral-central communication remain unclear. The concept of the 'muscle-brain dialogue' offers a new perspective on this process. irisin, secreted by skeletal muscle in response to exercise, forms a molecular link between peripheral exercise and central neuroprotection by specifically regulating brain-derived neurotrophic factor (BDNF). This review summarizes the molecular cascade mechanisms of the irisin-BDNF axis in mediating the muscle-brain dialogue: Irisin is synthesized via the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)/fibronectin domain-containing protein 5 (FNDC5) pathway. Current evidence suggests that peripheral irisin may communicate with the central nervous system through mechanisms related to the blood-brain barrier, including potential αVβ5 integrin-mediated interactions, thereby participating in the regulation of BDNF. As a core effector molecule, BDNF improves cognitive decline in AD by enhancing neuroplasticity, reducing Aβ deposition, inhibiting tau hyperphosphorylation, and alleviating neuroinflammation. However, oxidative stress and mitochondrial dysfunction associated with AD pathology negatively regulate this axis, creating a vicious cycle. Therefore, this paper explores potential intervention strategies and the prospects for future translational research, including upstream exercise interventions, midstream barrier-crossing enhancing peptides, and downstream small-molecule TrkB agonists. Targeting this axis provides a new theoretical foundation and translational direction for the early prevention and treatment of AD, as well as for drug development.

Three-dimensional (3D) cancer cell models, such as spheroids, organoids, and organ-on-chip systems, provide more physiologically relevant conditions by preserving native cell-cell and cell-matrix interactions. However, analytical techniques that maintain and assess the intrinsic heterogeneity of these systems have lagged behind their biological complexity. Current approaches either rely on live imaging, which lacks biochemical depth, or destructive, high-content assays like RNA sequencing and mass spectrometry imaging, which require either fixative agents or freezing the 3D model before analysis. The key problem addressed here is the lack of methods that integrate live imaging with high-resolution biochemical analysis at the single-cell level. We developed an integrated platform that bridges this gap by combining live imaging of a 3D cancer model with microsampling and mass spectrometry-based whole single-cell analysis. Using a vascularized organ-on-chip system cultured with HepG2 hepatocellular carcinoma cells under a drug gradient, we demonstrated the platform's ability to capture heterogeneous uptake of the drug Tamoxifen. By modifying the physical barriers of a commercial organ-on-a-chip platform for precise capillary-based microsampling, introducing a single-cell preparation technique to mitigate matrix interference from Matrigel, and incorporating High-field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS), we reduced matrix contamination and enhanced signal-to-noise ratios. This workflow enables non-destructive linkage between dynamic imaging data and single-cell biochemical profiles, preserving the spatial and temporal integrity of 3D tumor models. This platform enables capillary-based single-cell isolation and metabolomic analysis of individual cells from live 3D tumor microenvironments, overcoming limitations of current imaging and molecular methods. By integrating live microscopy with sensitive single-cell mass spectrometry, it offers a new route to investigate cellular heterogeneity, specifically with respect to drug distribution and therapeutic responses in realistic cancer models, advancing translational and preclinical cancer research.

Epitranscriptomics has recently gained significant momentum due to technological advances and translational applications; however, studies on bacterial RNA modifications remain limited. Bacterial RNA is notoriously prone to degradation, and methodologies to investigate the epitranscriptome are challenging. Prior research has shown RNA modifications modulate antimicrobial resistance, virulence and pathogenicity. This research employed CRISPR interference to knock down five known Escherichia coli rRNA modification genes (rlmF, rlmJ, rluD, rsmF and rsmG) in three E. coli strains. These isolates were investigated for growth delays, changes in the proteome and the influence on mRNA modifications via native RNA sequencing. CRISPRi adequately silenced the majority of RNA modification genes in E. coli (> 80% reduction). Significant growth delays were associated with rlmF, rluD and rsmF repression. Unique protein pathways corresponding with RNA modification loss were found for rlmJ (TreB, XylF), rluD (CysH, HycB, PutP, TrpB), rsmF (EvgA) and rsmG (OppC). Known rRNA modification sites for rluD (Ψ) and rsmG (m7G) were detected from analysis of nanopore electrical signal; however, only a weak signal was apparent for m6A (rlmF, rlmJ) and m5C (rsmF) modifications. The inhibition of rRNA modifications resulted in mRNA modification changes, including for genes ompC, cspC, dbhA, dbhB and secY. Our work provides an approach for unravelling the epitranscriptome of E. coli to gain insight into its functional role.

Malignant peripheral nerve sheath tumor (MPNST) carries the highest excess mortality of the cancers associated with neurofibromatosis Type 1, and usually arises from a neurofibroma. We asked whether the transcriptomic differences that distinguish MPNST from neurofibroma reproduce across independent cohorts, and whether a compact score derived from them transports between platforms. We meta-analyzed five public discovery cohorts of primary nerve-sheath tissue (113 MPNST, 79 neurofibromas; 3 platforms) and held out a sixth, independently generated cohort. Neurofibroma and MPNST tissue differed at 1489 genes in two opposing themes: up-regulated mitotic machinery (TOP2A, EZH2, AURKA) and loss of Schwann-cell identity (the transcription factors SOX10 and EGR2, and the myelin genes PMP2 and MPZ). These differences were reproducible. Among the significant genes assayed in all five cohorts, almost all changed in the same direction in everyone, and 93.3% of those detectable in the held-out cohort agreed in direction. Leave-one-cohort-out re-derivation of the pipeline gave a mean AUC of 0.90 across five folds (per-fold 0.84 to 0.97). CD276 (B7-H3) was selectively up-regulated, whereas CD274 and PDCD1LG2 were not. The myelin marker PMP2, a readout chosen retrospectively after the held-out results were known, separated MPNST from neurofibroma in that cohort but left atypical and conventional neurofibromas unseparated (AUC 0.67, p = 0.10). A program score derived without the discovery cohort carrying survival data was associated with shorter survival there, an exploratory single-cohort association. The composition of a compact score varied with platform and preprocessing, so no fixed single-sample classifier is warranted.

Sensory systems are known for their adaptability, responding dynamically to changes in environmental conditions. A key example of this adaptability is the enhancement of tactile perception in the absence of visual input. Despite behavioral studies showing visual deprivation can improve tactile discrimination, the underlying neural mechanisms, particularly how tactile neural representations are reorganized during visual deprivation, remain unclear. In this study, we explore how the absence of visual input alters tactile neural encoding in the rat primary somatosensory cortex (S1). Rats were trained on a custom-designed treadmill with distinct tactile textures (rough and smooth), and local field potentials (LFPs) were recorded from S1 under light and dark conditions. Machine learning techniques, specifically a convolutional neural network, were used to decode the high-dimensional LFP signals. We found that the neural representations of tactile stimuli became more distinct in the dark, indicating a reorganization of sensory processing in S1 when visual input was removed. Notably, conventional amplitude-based analyses failed to capture these changes, highlighting the power of deep learning in uncovering subtle neural patterns. These findings offer new insights into how the brain rapidly adapts tactile processing in response to the loss of visual input, with implications for multisensory integration.

Age of onset is considered a key factor for the heterogeneity in major depressive disorder (MDD). Differential cortical thickness (CT) alteration patterns between youth-onset and adult-onset MDD have been evident, yet the neurobiological factors associated with such divergence remain unknown. CT alteration patterns in youth-onset and adult-onset MDD were derived from the Enhancing NeuroImaging Genetics through Meta-Analysis. We interrogated whether the structural connectome constrains MDD-related CT alterations, followed by identifying likely epicentre regions and examining the hub vulnerability hypothesis. Using the neurotransmitter, transcriptome, and mitochondria atlases, we further explored the neurochemical basis, genetic architecture, and molecular energetic landscape related to the CT alterations. The structural connectome constrained CT alterations in both youth-onset and adult-onset MDD, but the constraint effect was greater in adult-onset MDD. The epicentres were divergent for youth-onset (lateral prefrontal cortex) and adult-onset (orbitofrontal cortex, anterior and middle cingulate gyrus) MDD. The association between CT alterations and connectome degree centrality confirmed the hub vulnerability hypothesis in youth-onset MDD. Moreover, we found common and distinct neurotransmitter systems linked to CT alterations in youth-onset and adult-onset MDD. Transcriptomic contextualization demonstrated that CT alterations in adult-onset MDD were related to gene categories primarily involving synapse, neuron, synaptic transmission, and ion channel activity, yet those in youth-onset MDD were not related to gene expression. Additionally, associations between mitochondrial features and CT alterations were found in adult-onset MDD but not in its youth-onset counterpart. Our findings may illuminate the neurobiological factors related to the spatial patterning of cortical abnormalities in youth-onset and adult-onset MDD.

Older adults undergoing gastrointestinal endoscopy are particularly susceptible to oversedation, hypotension, hypoventilation, hypoxemia, and delayed recovery because physiological and cognitive reserve decline with age. Precision sedation provides a practical approach to these problems by tailoring drug selection, dose titration, monitoring, and supportive measures to the individual patient and the requirements of the procedure. Propofol remains widely used because of its rapid onset and predictable recovery, although cardiorespiratory depression remains dose dependent. Remimazolam and ciprofol may offer greater hemodynamic or respiratory stability in selected patients, while dexmedetomidine and combination regimens can reduce exposure to other sedatives but introduce their own limitations. Monitoring with processed electroencephalography, cerebral oximetry, capnography, and routine hemodynamic assessment may help identify excessive sedation or physiological deterioration when findings are interpreted in clinical context. However, improvements in short-term cardiopulmonary outcomes or recovery should not be assumed to prevent postoperative delirium or longer-term cognitive impairment. In older adults, sedation should therefore aim for the minimum effective depth while avoiding excessive drug exposure and promptly correcting respiratory and circulatory disturbances. Further endoscopy-specific studies are needed to determine whether these strategies improve cognitive and functional recovery.

Empathy is a multidimensional construct encompassing cognitive, affective, and somatic components, yet its white matter correlates have been examined primarily in adults and typically using measures limited to cognitive and affective dimensions. This study explored associations between white matter tract microstructure and multidimensional trait empathy in typically developing children. Twenty-six typically developing children (14 boys, 12 girls; mean age 10.1 ± 2.2 years, observed range 7-15) underwent diffusion MRI. White matter pathways were reconstructed with TRACULA-based probabilistic tractography, and trait empathy was assessed with the Korean version of the Cognitive, Affective, and Somatic Empathy Scales (CASES-K). Along-tract general linear models with within-tract permutation-based cluster correction (5000 sign-flip permutations) tested associations between fractional anisotropy (FA) and empathy scores, controlling for age and sex. At within-tract correction, three clusters showed negative FA-empathy associations: lower FA in the left superior longitudinal fasciculus I (SLF1; p = 0.032) and the genu of the corpus callosum (p = 0.048) with higher total empathy, and lower FA in the left SLF3 with higher affective empathy (p = 0.020). However, no clusters survived correction across the full set of 168 tract-subscale analyses (all false-discovery-rate q ≈ 1.0), so the findings are best interpreted as exploratory and hypothesis-generating. Within these clusters, the negative FA associations coincided with higher radial diffusivity and essentially unchanged axial diffusivity, and remained after controlling for in-scanner motion. These preliminary results are consistent with the possibility that different empathy dimensions relate to partially distinct white matter pathways during childhood. They require replication in larger samples, however, before any mechanistic, maturational, or causal interpretation is warranted.

Immune dysfunction has been implicated in Alzheimer's disease (AD), but the roles of specific immunoglobulin classes remain unclear. We integrated human genetics and plasma biomarker analyses to evaluate immunoglobulin G (IgG), IgA, and IgM in relation to AD. Two-sample Mendelian randomization analyses were conducted with multiple sensitivity analyses. Polygenic risk scores for immunoglobulin classes were developed in the All of Us Research Program and tested in the UK Biobank for associations with AD and dementia, and in two Wisconsin-based cohorts for associations with plasma amyloid beta (Aβ)42/40, phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Higher genetically proxied IgM was consistently associated with lower AD risk, higher Aβ42/40, and lower p-tau217, but not with NfL or GFAP. No consistent associations were observed for IgG or IgA. IgM-related humoral immunity may play a protective role in AD and warrants exploration for early intervention and prevention.

The ventral regions of the hippocampus play a crucial role in emotional responses through projections to the hypothalamus. In this context, the ventral hippocampus sends extensive projections to components of the medial hypothalamic defensive circuit, where projections to the anterior hypothalamic nucleus (AHN) influence both anxiogenic and innate fear responses, as well as contextual fear reactions. This study aims to examine the branching projection pattern of hippocampal cells that directly project to the AHN and identify the complete range of brain regions affected by key hippocampal outputs that drive fear and anxiety. To accomplish this, we first explored the full range of hippocampal cells that project directly to the anterior hypothalamic area using an AAV retroviral vector carrying the enhanced yellow fluorescent protein (EYFP) reporter gene. We found that the hippocampal cells projecting to the anterior hypothalamus were located primarily along the entire rostro-caudal axis of the ventral subiculum. Next, by combining an AAV retro vector injection into the AHN to insert Cre recombinase specifically in the subicular neurons projecting to the anterior hypothalamic region and subicular injections of an AAV vector expressing membrane-bound GFP and the presynaptic protein synaptophysin fused to the red fluorescent protein mRuby in a Cre-dependent manner, we investigated the collateral branching pattern of subicular neurons that project to the AHN. Our results demonstrated that ventral subicular neurons projecting to the anterior hypothalamus exhibit an extensive branching projection pattern that connects to several brain regions involved in various functions, including memory, motivation, arousal, circadian rhythmicity, neuroendocrine regulation, and goal-oriented behavior. This reveals that ventral subicular anterior hypothalamic-projecting cells display a widespread branching projection pattern, uniquely positioning them to influence complex, integrated responses while driving anxiety and fear behaviors.

CD4 + CD25 + FOXP3 + regulatory T cells (Treg) are highly activated in tumors and promote disease progression. Specific, universal targeting of these effector Treg cells is limited by the lack of a conserved signature across human cancers and information on their origin. Here we combine analysis of single-cell RNA-sequencing datasets with spectral flow cytometry and identify a core signature of 88 genes consistently upregulated in intratumoral Treg cells among 9 epithelial cancers. We describe 4 Treg cell subsets - CCR7 + quiescent, CCR8 + effector, CD161 + and intermediate, with distinct tissue distribution, function, differentiation trajectories and molecular drivers. By single-cell T cell receptor sequencing, we observe that protumoral, effector CCR8 + Treg cells exhibit little clonal relationship with other Treg cell subsets inside tumors, but are clonally related to Treg cells in tumor-draining lymph nodes, as well as conventional T cells in tumors. This resource provides insights for development and fine-tuning of CCR8 + Treg cell-targeting therapies in cancer.

Mitochondria are essential organelles that maintain neuronal bioenergetics, redox homeostasis, calcium signaling, and immune regulation. Traditionally, mitochondrial dysfunction has been primarily considered as an intracellular event associated with neuronal injury and neurodegeneration. However, accumulating evidence indicates that mitochondria and mitochondrial components can be transferred between cells, forming an intercellular communication network that dynamically regulates tissue homeostasis and disease progression. Intercellular mitochondrial transfer occurs through contact-dependent pathways, mainly mediated by tunneling nanotubes (TNTs), and contact-independent pathways involving mitochondrial extracellular vesicles (MitoEVs), mitochondria-derived extracellular vesicles (MDEVs), and extracellular mitochondria. In the nervous system, these pathways establish functional interactions among neurons, astrocytes, microglia, satellite glial cells, endothelial cells, and stem cells. Transferred functional mitochondria can restore bioenergetic deficits, whereas damaged mitochondria or mitochondrial components may act as danger-associated molecular patterns (DAMPs) to amplify neuroinflammation. Here, we summarize the molecular mechanisms and biological functions of intercellular mitochondrial transfer in the nervous system, emphasizing its dual roles in bioenergetic rescue, mitochondrial quality control, and neuroimmune regulation. Understanding these processes may provide new insights into neurological disease mechanisms and therapeutic strategies targeting mitochondrial communication.

Spectral power decay (1/f β ) of cortical activity has long been considered of low relevance to the understanding of brain function (e.g., associated with background noise of neuronal activity). However, growing literature suggests that it can reflect optimized spatiotemporal organization of neuronal activity across the cortex serving both cognition and behavior. Thus, clarifying the mechanisms underlying the regulation of this network property could have numerous impacts for the neuroscience field as well as for patients suffering from various neurological disorders with cognitive deficits linked to alterations in brain power decay properties. Using a constitutive knockout mouse and a multifractal wavelet-leaders formalism, we here investigated the involvement of the synaptic adhesion molecule Neuroligin-2, which shapes synaptic inhibition and associates with neurodevelopmental diseases, in modulating spectral power decay properties of the electrocorticographic signal (i.e., the most prominent Hurst exponent "Hm" and its local "Dispersion"). Knockout mice showed increased Hm values across all wake and sleep states together with amplified daily dynamics during wake and paradoxical sleep, and increased Dispersion specifically for slow-wave sleep in comparison with wild-type littermates. Following a 6-h sleep deprivation, Hm daily variations were more altered in knockout mice than controls for wake and paradoxical sleep, but less affected for slow-wave sleep. Importantly, mutant mice display hypersynchronized epileptic-like electrocorticographic events, which were characterized by further increases in Hm and Dispersion. These findings provide support for the involvement of Neuroligin-2 in shaping 1/f β cortical activity properties and bring perspectives, notably, for neurodevelopmental conditions.

The p75 neurotrophin receptor ectodomain (p75NTR-ECD) has been implicated in amyloid-β-related neurotoxicity, but cerebrospinal fluid (CSF) levels in late-life depression (LLD) remain uncertain. We compared clinically diagnosed Alzheimer's disease (AD), LLD, and healthy controls (HC) and reassessed exploratory symptom and cognitive associations. CSF p75NTR-ECD was measured in 50 participants (HC, n = 19; LLD, n = 19; AD, n = 12). The primary linear model adjusted for age, sex, and body mass index. Exploratory symptom and cognitive models additionally adjusted for diagnostic group; six p values underwent Benjamini-Hochberg false discovery rate (FDR) correction. Plate and below-calibrator sensitivity analyses were performed. CSF p75NTR-ECD was higher in HC than in AD (B = 131.2 pg/mL, 95% CI 42.8-219.6, p = 0.005) and higher in LLD than in AD (B = 154.6 pg/mL, 95% CI 68.9-240.3, p < 0.001); HC and LLD did not differ. No symptom or cognitive association remained significant after diagnostic-group adjustment and FDR correction (all q ≥ 0.117). Plate adjustment did not materially change the primary contrasts. Excluding three concentrations below the lowest calibrator preserved the LLD-AD contrast but attenuated the HC-AD contrast. CSF p75NTR-ECD showed preliminary differences across clinically defined groups. Because the sample was small, the recruitment site was perfectly confounded with AD versus non-AD status, and diagnoses were not uniformly biomarker-confirmed, the findings do not establish causality, clinical diagnostic utility, or added value beyond established AD biomarkers and require independent multisite replication.

Single-cell RNA sequencing (scRNA-seq) has revolutionized the ability to resolve cellular heterogeneity within complex tissues, enabling the identification of discrete cell states. Here, we present an in silico analytical pipeline designed to characterize intestinal stem cells (ISC), transit-amplifying (TA) progenitors, and BEST4⁺ enterocyte precursors from human scRNA-seq datasets, with a focus on inflammatory contexts such as inflammatory bowel disease (IBD). The pipeline integrates dataset acquisition, quality control, normalization, dimensionality reduction, unsupervised clustering, and cell type annotation using a reference cell atlas. We implemented iterative subsetting and re-clustering of ISC and TA compartments to identify inflammation-associated subpopulations and epithelial biomarkers. While demonstrated in the context of IBD, this computational framework is broadly applicable to other tissues and pathological conditions where stem/progenitor dynamics underpin disease progression and tissue repair.

Functional neurological recovery after ischemic stroke remains a formidable challenge in neuroscience. Exosomes serve as pivotal mediators of intercellular communication, and the microRNAs (miRNAs) they carry, in particular, offer a promising "cell-free therapy" strategy for promoting neurological repair. This review systematically summarizes the multi-target mechanisms by which exosomal miRNAs regulate the neurovascular unit (NVU) and outlines technical strategies to enhance exosomal therapeutic efficacy through targeted modification and engineered cargo loading, with the aim of constructing a smart drug delivery system capable of precise navigation. Following the trajectory of "natural exosomes-engineered exosomes-clinical translation", this review addresses the core scientific question of how to transform exosomal miRNAs from natural messenger molecules with basic reparative activity into an intelligent therapeutic system for precise targeted delivery. It further explores precision exosome treatment models based on the pathological staging of stroke progression, and integrates single-cell, spatial transcriptomic, and multi-omics technologies to decode the "miRNA-cell source-target cell-signaling pathway" regulatory axis, thereby identifying candidate miRNA combinations with translational potential. Finally, this review provides an in-depth analysis of the core challenges in translating such nanotherapeutic strategies from the bench to the bedside, including manufacturing standardization, quality control, and potency assessment, with the aim of providing a theoretical basis for advancing exosomal miRNA therapies from mechanistic studies to precision stroke treatment.

There has been an increase in the incidence of Autism Spectrum Disorder (ASD) over recent years, which has given rise to an immediate increase in demand for quality intervention and trained professionals. Parental involvement is necessary for a more effective parental training, which will ensure a realistic understanding of their child's difficulties. Previous studies continuously prove that parental involvement in the lives of their children with ASD is beneficial to improvement in their children with ASD. There are no studies that illustrate the challenges that professionals face when trying to involve parents into the intervention. Based on the literature review, it can be projected that an understanding of these factors will help professionals to improvise on strategies to implement parental involvement methods with efficiency and maximize the gains of the individuals with ASD. This study aims to understand the benefits and challenges of rehabilitation professionals in involving parents for treatment of children with ASD, in the manner in which these issues were overcome. Ten professionals (2 from each domain of rehabilitation) were selected to be part of the study. The participants were interviewed using a semi-structured interview questions and the data collected was thematically analysed under the light of Review of Literature. The results of the study clearly show the inevitability of parental involvement in intervention for autism. The study identified five themes: Dual model of Work, Parenting, Socio-cultural Factors, Professional Expertise of Therapist and Limitations with involvement. The present study implies that is important to take the parents' personal psychological challenges into consideration before involving them in intervention. A program that can specifically target the needs of the parent and provide them with the kind of support and knowledge that is necessary for their child can do wonders.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder marked by persistent impairments in social communication and interaction, together with restricted and repetitive behavior or interests. Recent epidemiological data indicate that the prevalence of ASD has continued to increase worldwide. Current behavioral and pharmacological interventions remain limited in efficacy, particularly for associated comorbidities. In this context, metabolic interventions, especially the ketogenic diet (KD), have attracted growing interest as a potential therapeutic strategy. A total of 62 young children with ASD admitted to Hefei Maternal and Child Health Hospital between January 2024 and January 2025 were prospectively enrolled and randomly assigned to a treatment group or a control group (31 per group). Both groups underwent hospital-based rehabilitation training on weekdays and home-based rehabilitation on weekends over a 2-month period. The treatment group additionally received a modified KD, comprising ketogenic nutritional powder and a structured dietary plan, with lunch provided at the hospital on training days while breakfast, dinner, weekend dietary implementation, and home monitoring were managed by caregivers. The control group followed a regular diet along with the same rehabilitation program. Changes in ASD-related symptoms were assessed using the Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS). After two months of intervention, both groups showed significant reductions in ABC and CARS scores compared with baseline (P < 0.05). Between-group comparison of individual change scores showed larger reductions in the treatment group for both ABC (U = 324.000, P = 0.027) and CARS (U = 273.500, P = 0.003). In this cohort of young children with ASD, the modified ketogenic diet combined with rehabilitation training was associated with greater short-term reductions in ABC and CARS scores than rehabilitation alone. The intervention demonstrated acceptable short-term feasibility. The Project was registered on China Clinical Trial Registry (ChiCTR) with the identifier ChiCTR2300075057 ,Registered 24 August 2023, https://www.chictr.org.cn/ .

Stroke can trigger complex systemic pathophysiological responses. By systematically reviewing the pathophysiological mechanisms following stroke and comprehensive intervention strategies, this review proposes a conceptual framework of a self-amplifying vicious cycle comprising neuroinflammation, mitochondrial failure, blood-brain barrier disruption, and microcirculatory no-reflow, while emphasizing the central role of neurovascular unit injury. Furthermore, multimodal approaches, including acute reperfusion therapy, endogenous neuroprotection, neuromodulation, and intelligent rehabilitation, are precisely mapped onto the corresponding cellular and molecular targets within this vicious cycle. Combined with standardized secondary prevention, these approaches are integrated into a standardized continuum-of-care pathway. This review advocates a shift in the diagnostic and therapeutic paradigm from single-target intervention toward multimodal, systemic, and comprehensive intervention, providing guidance for future precision medicine and clinical translation. 脑卒中可引起复杂的全身性病理反应。本文系统梳理脑卒中后的病理生理机制与综合干预策略，提出由神经炎症、线粒体衰竭、血脑屏障破坏及微循环无复流构成的“自我放大恶性循环”概念框架，并强调神经血管单元损伤的核心地位。在此基础上，进一步将急性再灌注、内源性神经保护、神经调控及智慧康复等多模式手段与上述恶性循环中的细胞和分子靶点相对应，并结合规范化二级预防，构建标准化全程管理路径。据此，诊疗模式或应由“单靶点”向“多模式全身综合干预”转变，从而为未来的精准医学与临床转化提供思路。.