IntroductionPeripheral nerve injury (PNI) is characterized by limited regenerative capacity and incomplete functional recovery. Schwann cells (SCs) are essential for nerve repair, but their clinical application is constrained by limited availability. Ectomesenchymal stem cells (EMSCs), derived from neural crest lineage, represent a promising alternative; however, their inefficient differentiation into SC-like cells remains a key limitation. This study investigated whether activation of Hedgehog signaling via Sonic hedgehog (Shh) could enhance SC-like differentiation and improve nerve regeneration.MethodsEMSCs were isolated from rat nasal mucosa and transduced with adenoviral vectors to overexpress Shh. SC-like differentiation was assessed using RT-qPCR, Western blot, immunofluorescence, and ELISA. Transcriptomic analysis compared EMSCs with primary SCs. A short-gap rat sciatic nerve defect model was established as an initial proof-of-concept in vivo model, and animals received vehicle, EMSCs, Shh-EMSCs, or autograft treatment. Functional recovery, electrophysiology, histology, and ultrastructural analyses were performed.ResultsTranscriptomic analysis revealed that EMSCs possess a partial SC-related transcriptional profile but lack sufficient Hedgehog activation. Shh overexpression activated canonical Hedgehog signaling, evidenced by increased Gli1/2 expression and nuclear translocation. Shh-EMSCs showed enhanced expression of SCs markers (P75, GFAP, MBP, S100β), increased secretion of neurotrophic factors (BDNF, NT-3), and reduced inflammatory cytokines. In vivo, Shh-EMSCs significantly improved functional recovery, nerve conduction velocity, and gait performance compared with EMSCs alone. Histological and ultrastructural analyses demonstrated increased axonal regeneration, improved organization, and enhanced myelination compared with unmodified EMSCs, although autograft repair remained superior or more complete in several outcome measures.ConclusionHedgehog signaling contributes to SC-like differentiation of EMSCs. Shh-mediated activation promotes a pro-regenerative phenotype and enhances nerve repair-related outcomes in a short-gap sciatic nerve defect model, suggesting that Shh-EMSCs may serve as a potential cell-based strategy for peripheral nerve repair.
Microglia derived from human induced pluripotent stem cells are regulated by osteopontin, an endogenous extracellular matrix protein maintaining immune homeostasis
IntroductionMicroglia are brain-resident immune cells responsible for maintaining homeostasis, coordinating responses to injury and disease, and mediating regeneration. Upon activation, they undergo dynamic changes in morphology, gene expression, and function, reflecting the nature and context of the stimuli encountered. Although pharmacological modulation of microglia holds great promise for treating various neurological disorders, its development is hampered by a major translational roadblock: Human microglial cell lines commonly used in preclinical studies, as well as primary rodent microglia, substantially limit the translatability of results. Here, we aimed to generate microglia from human induced pluripotent stem cells (hiPSCs) and to demonstrate their physiological responsiveness to the brain-endogenous, context-relevant ligand osteopontin (OPN).Materials and methodsMicroglia generated from two healthy hiPSC lines were stimulated with OPN, lipopolysaccharide (LPS), or their combination for 24 h and subsequently analyzed. Microglial identity and the expression of the phagocytic cell marker cluster of differentiation 68 (CD68) were determined by immunocytochemistry. Cell viability was assessed by propidium iodide (PI)/Hoechst staining, morphological activation was evaluated using Sholl analysis, and inflammatory gene expression changes were assessed by RT-qPCR.ResultshiPSC-derived microglia acquired a native central nervous system (CNS)-specific immunophenotype, expressing the microglia-specific markers ionized calcium-binding adapter molecule 1 (IBA1), transmembrane protein 119 (TMEM119), PU.1, and Spalt-like transcription factor 1 (SALL1), while remaining negative for Myb and membrane-spanning 4-domains, subfamily A, member 7 (MS4A7) at the protein level. Exposure to LPS led hiPSC-derived microglia to adopt a rounded, process-retracted shape and to increase CD68 protein intensity, a surrogate marker of lysosomal and phagocytic activity, while downregulating the anti-inflammatory marker cluster of differentiation 206 (CD206) at the transcriptional level. OPN induced a distinct microglial functional state characterized by intermediate morphology, increased CD68 intensity, and reduced homeostatic gene expression, without eliciting robust inflammatory gene expression. Intriguingly, OPN prevented LPS-induced microglial cell death, and when hiPSC-derived microglia exposed to LPS were additionally treated with OPN, the morphological effects of LPS were reversed.ConclusionOPN induced a distinct early response profile in hiPSC-derived microglia, characterized by intermediate morphological remodeling, increased CD68 intensity, and reduced homeostatic gene expression, without overt pro-inflammatory gene expression. These findings support the role of OPN as a physiological priming signal in microglia and highlight hiPSC-derived microglia as a model for studying regulators of microglial modulation.
Enhancing hematoma expansion prediction in hypertensive intracerebral hemorrhage based on habitat and perihematomal edema radiomics from non-contrast CT: a dual-center study
ObjectivesCharacterizing the microenvironmental habitats within the hematoma may yield crucial imaging biomarkers and improve the early prediction of hematoma expansion (HE) in patients with hypertensive intracerebral hemorrhage (HICH). Our objective was to construct and validate a combined model that integrates clinical data with whole-hematoma radiomics, habitat radiomics of the hematoma, and perihematomal edema (PHE) radiomics features extracted from non-contrast computed tomography (NCCT) images for preoperative HE prediction.MethodsThis retrospective dual-center cohort of 353 HICH patients. Based on baseline NCCT images, radiomics features were extracted from the whole hematoma, three distinct habitats within the hematoma, and the PHE region. Five models were constructed: a clinical model, a whole-hematoma radiomics model, a habitat-based radiomics model, a PHE radiomics model, and a combined model. Model performance was evaluated using receiver operating characteristic (ROC) curve analysis.ResultsThe combined model integrated with smoking history, island sign, maximum distance of the PHE, and the whole-hematoma, habitat, and PHE radiomics models, achieved the best predictive performance. In the training, testing, and validation sets, the combined model predicted the area under the curve for HE as 0.951 (95% CI: 0.915–0.986), 0.937 (95% CI: 0.883–0.991), and 0.939 (95% CI: 0.888–0.989), respectively.ConclusionThe NCCT-based combined model integrating clinical data, whole-hematoma radiomics, habitat radiomics, and PHE radiomics improves HE prediction in patients with HICH, providing a noninvasive tool with potential for guiding treatment strategies.
Transcutaneous auricular vagus nerve stimulation: mechanisms, applications, and research progress
This review systematically examines the mechanisms of action, optimization of stimulation parameters and targets, and the research progress in the application of taVNS for neurological disorders and systemic conditions. Rather than merely cataloging existing findings, this review critically synthesizes recent advances with a focused emphasis on two core aspects: (1) the mechanistic convergence and divergence among neuroimaging, autonomic, and molecular pathways underlying taVNS effects; and (2) the methodological challenges and biomarker-driven strategies for optimizing stimulation parameters and personalizing treatment. By prioritizing these key directions over exhaustive enumeration of clinical applications, this review aims to provide a conceptually structured framework that distinguishes genuine progress from descriptive accumulation. Moreover, compared with previously published reviews on similar topics, the present work offers a distinctive contribution by integrating multi-modal mechanistic evidence into a testable model of taVNS action and critically evaluating the translational gap between parametric optimization in research settings and standardized clinical implementation. Furthermore, it provides an outlook on future research directions and technological developments, aiming to offer a comprehensive theoretical framework to inform both clinical translation and foundational research in this rapidly evolving field.
The metabolic layer of cognition: integrating metabolomics, breathomics, and systems neuroscience
Cognitive neuroscience has made substantial progress in mapping neural activity underlying perception, memory, and decision-making. However, widely used methods such as functional magnetic resonance imaging and electrophysiology primarily measure indirect physiological correlates of neuronal activity and provide limited access to the biochemical processes that support neural signaling. In this review, we propose that metabolism might constitutes a critical intermediate layer linking neural activity and behavior. Drawing on advances in metabolomics and breathomics, we examine how mass spectrometry-based analytical techniques enable sensitive detection of metabolites, neurotransmitters, lipids, and volatile organic compounds that could reflect metabolic processes associated with neuronal signaling and cognitive states. We synthesize emerging research at the intersection of neuroenergetics, systems neuroscience, and metabolic profiling, highlighting how these approaches can complement established neuroimaging and electrophysiological methods. In particular, we discuss the potential of volatile organic compounds in exhaled breath as non-invasive indicators of systemic metabolic responses accompanying cognitive processes. At the same time, we address key conceptual and methodological challenges in interpreting peripheral metabolic signals in relation to brain activity, including the influence of systemic physiology, microbiome metabolism, and environmental factors. Finally, we outline future directions for integrating metabolomic and breathomic measurements with neural and behavioral data in multimodal experimental frameworks. Incorporating metabolic dynamics into systems-level models may provide a new perspective on how cognition emerges from interactions between brain activity and whole-body physiology.
Global research landscape, knowledge structure, and emerging trends in adverse childhood experiences and personality disorders: a bibliometric analysis
BackgroundThe relationship between adverse childhood experiences (ACEs) and personality disorders (PDs) has attracted sustained attention in psychiatry, psychology, and public health. Existing studies have mainly examined epidemiological associations, specific PDs diagnoses, or mechanisms, whereas bibliometric evidence mapping the field’s knowledge structure and thematic evolution remains limited. This study aimed to characterize trends, contributors, collaboration networks, core themes, and frontiers in ACEs–PDs research.MethodsEnglish-language publications on ACEs and PDs were retrieved from Web of Science Core Collection, Scopus, and PubMed from inception to December 31, 2025. After year screening, document-type filtering, and deduplication, 5,084 records were included. Bibliometric analyses were performed using R, VOSviewer, and CiteSpace. The merged dataset was used to examine annual trends, countries/regions, institutions, authors, journals, and keyword co-occurrence, while WoSCC records were used for co-citation analysis, keyword clustering, and burst detection.ResultsACEs–PDs research showed sustained growth, with a marked increase after 2000. The United States occupied a central position in publication output, citation impact, and international collaboration, while the United Kingdom, Germany, Canada, the Netherlands, and Australia also showed strong influence. Harvard University, the University of London, and Ruprecht Karls University Heidelberg were leading institutions; Zanarini M, Fonagy P, Schmahl C, Paris J, and Kleindienst N were key contributors. Influential journals mainly covered psychiatry, personality disorders, child maltreatment, trauma, and developmental psychopathology. Keyword analyses identified childhood adversity, personality disorder, borderline personality disorder, depression, childhood sexual abuse, and post-traumatic stress disorder as core themes. VOSviewer and CiteSpace analyses indicated that hotspots have expanded from childhood abuse, PDs diagnosis, and psychiatric comorbidity to emotion dysregulation, non-suicidal self-injury, social support, functional connectivity, early intervention, and mechanism validation. Highly cited publications revealed a knowledge base centered on childhood abuse/trauma, borderline personality disorder, psychiatric comorbidity, emotion regulation, and neurobiological mechanisms.ConclusionThis study maps development and knowledge structure of ACEs–PDs research. Findings suggest a shift from exposure–outcome association studies toward comorbidity, intermediate phenotypes, neurobiological mechanisms, and clinical translation. Future research should strengthen longitudinal and cross-cultural designs, consider ACE type, timing, duration, and severity, and integrate neuroimaging, inflammatory, epigenetic, and clinical-course phenotypes.
Adjunctive berberine for schizophrenia with metabolic syndrome: a systematic review and meta-analysis
BackgroundAntipsychotic-induced metabolic syndrome complicates the clinical management of schizophrenia. This investigation seeks to examine berberine’s efficacy and safety as adjunctive therapy in schizophrenia patients with metabolic syndrome.MethodsA thorough literature search was executed across international (PubMed, Cochrane Library, EMBASE) and Chinese (China National Knowledge Infrastructure, WanFang Data) databases to retrieve randomized controlled trials (RCTs) examining adjunctive berberine for schizophrenia with metabolic syndrome. Data extraction and synthesis were conducted by three independent reviewers employing RevMan 5.3 software.ResultsThree eligible RCTs (n = 233) were incorporated. Adjunctive berberine demonstrated superior efficacy over controls in reducing body weight (standardized mean difference (SMD) = −0.56, I² = 0%; P = 0.0003), body mass index (SMD = −0.51, I² = 0%; P = 0.0001), waist circumference (SMD = −0.31, I² = 20%; P = 0.04), total cholesterol (mean difference (MD) = −0.43, I² = 63%; P = 0.004), triglycerides (MD = −0.31, I² = 0%; P < 0.0001), and fasting plasma glucose (MD = −0.30, I² = 0%; P = 0.005). No significant differences existed in low density lipoprotein cholesterol (MD = -0.27, I² = 75%; P = 0.1), high density lipoprotein cholesterol (MD = -0.02, I² = 31%; P = 0.56), glycated hemoglobin (MD = -0.22, I² = 67%; P = 0.21), systolic blood pressure (MD = -1.62, I² = 0%; P = 0.17), or diastolic blood pressure (MD = -1.68, I² = 39%; P = 0.15).ConclusionThis systematic review provides preliminary evidence supporting adjunctive berberine as a promising intervention for improving certain metabolic parameters in schizophrenia patients with metabolic syndrome. Larger, high-quality RCTs are needed to confirm these observations.
Shared reading is associated with fewer emotional/behavioral problems and better prosocial behavior in preschool children: a cross-sectional study in western China
BackgroundThe home literacy environment, particularly shared reading, plays a critical role in preschool children’s cognitive and socioemotional development. However, its associations with emotional and behavioral problems remain underexplored in large-scale studies. This study examined the relationship between shared reading and emotional/behavioral problems as well as prosocial behavior in preschool children.MethodsA cross-sectional study was conducted using stratified cluster sampling across 189 kindergartens in a major city in western China. A total of 21,366 parent-child pairs were included. Shared reading was assessed with the reading subscale of the StimQ-P (score range 0–22), which evaluates quantity, diversity of concepts and content, and interactivity quality. Emotional and behavioral problems were measured using the parent-reported Strengths and Difficulties Questionnaire (SDQ). Multivariate logistic regression and generalized additive models were employed to examine associations, adjusting for child age, gender, parental socioeconomic factors, lifestyle variables, and parental mental health (CES-D).ResultsHigher shared reading scores were significantly associated with lower odds of emotional/behavioral problems (adjusted OR = 0.96 per point increase, 95% CI: 0.95–0.97, P < 0.0001) and higher odds of adequate prosocial behavior (adjusted OR = 1.09, 95% CI: 1.08–1.10, P < 0.0001) in fully adjusted models. All four dimensions of shared reading showed independent associations. Nonlinear analyses revealed threshold effects, with associations becoming stronger above approximately 18 points for total difficulties and 15 points for prosocial behavior. These associations were largely consistent across subgroups after correction for multiple testing.ConclusionIn this large cross-sectional study conducted in western China, higher levels of shared reading were associated with lower odds of emotional/behavioral problems and higher odds of prosocial behaviors among preschool children. The results suggest possible threshold patterns in these associations. However, given the cross-sectional nature of the study, causality cannot be established.
Global trends and neurobiological frontiers of manual therapy in sleep disorders: integrating bibliometrics with clinical evidence
BackgroundSleep disorders not only impair nocturnal rest but also significantly compromise daytime functioning, emotional regulation, and overall mental well-being. Beyond conventional pharmacological treatments, manual therapy has emerged as a promising non-pharmacological intervention. Specifically, emerging evidence suggests its benefits may extend to alleviating psychological distress and enhancing mood. This study employs a bibliometric approach to systematically investigate the current status, research hotspots, and future trends of manual therapy for sleep disorders, with an emphasis on its psycho-physiological outcomes.MethodsPublications related to manual therapy for sleep disorders were retrieved from the Web of Science Core Collection (WoSCC). Bibliometric visualizations and analyses were conducted using VOSviewer and CiteSpace. Furthermore, clinical trial records from PubMed were extracted to assess the translational and clinical advancements in this field.ResultsThe analysis included 594 publications originating from 321 institutions across 63 countries. The overall trend demonstrates a consistent annual increase in both publication volume and citation impact, reflecting escalating academic interest. Keyword and literature co-occurrence analyses indicate that exploring neurobiological mechanisms and circadian rhythm regulation are the predominant research frontiers.ConclusionBibliometric evidence indicates that research on manual therapy for sleep disorders is evolving toward multidimensional and interdisciplinary integration. Manual therapy increasingly emerges as a key complementary treatment, exerting therapeutic effects via the regulation of 5-hydroxytryptamine (5-HT) and the Hypothalamic-Pituitary-Adrenal axis (HPA axis). Its safety and efficacy represent distinct advantages; however, future clinical translation necessitates multi-center validation and standardized sham-controlled protocols.
Prevalence of depression in patients with advanced cancer receiving palliative care: a meta-analysis of self‐report instruments
BackgroundAlthough the prevalence of depression in patients with advanced cancer receiving palliative care has been widely reported, the estimates vary substantially. This meta-analysis aimed to determine the pooled prevalence of depression in patients with advanced cancer receiving palliative care and identify its potential moderating factors.MethodsA comprehensive literature search was conducted in PubMed, Web of Science, Scopus, Embase, Cochrane Library, CINAHL, and PsycINFO from inception to April 1, 2026. We calculated pooled prevalence estimates using a random-effects model and assessed heterogeneity using the I² statistic. Subgroup analyses and meta-regression were performed to explore potential sources of heterogeneity.ResultsA total of 29 studies comprising 6054 patients with advanced cancer receiving palliative care were included, yielding a pooled prevalence of depression of 50.9% (95% CI: 41.2-60.5%). Subgroup analyses and meta-regression showed that the pooled prevalence varied significantly by study design and assessment tool.ConclusionsOur findings indicated that depression was very prevalent in patients with advanced cancer receiving palliative care. However, the pooled estimate should be interpreted with caution because the extremely high statistical heterogeneity remained largely unexplained, even after conducting subgroup analyses and meta-regression. Furthermore, the adoption of suitable assessment tools and the implementation of valid screening and care strategies are essential to alleviate emotional distress in this vulnerable group.Systematic review registrationPROSPERO, identifier CRD420261368352