OBJECTIVES:To investigate the genetic etiology of a three-generation pedigree affected with piebaldism. METHODS:Next-generation sequencing and Sanger sequencing were employed to detect and verify gene variants. Bioinformatics tools were used to predict the effects of candidate variants on splicing and protein function. RT-PCR and Sanger sequencing were further performed to validate the impact of the variant on RNA splicing, and homology modeling was applied to predict its effect on the three-dimensional structure of the KIT protein. The pathogenicity of the variant was then classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the UK Association for Clinical Genomic Science (ACGS). RESULTS:A heterozygous insertion variant near the splice site, c.1990+8_1990+9insTGCACCATTGGAGGTAAA, was identified in the KIT gene in the proband and was found to co-segregate with the phenotype within the family. RT-PCR and cDNA sequencing revealed that this variant led to aberrant splicing during transcription, resulting in a 21 bp in-frame insertion in the mRNA, which encodes an extra 7 amino acids within the tyrosine kinase domain and may thus affect protein function. In silico predictions, together with the experimental findings, supported classification of this variant as likely pathogenic according to relevant variant interpretation guidelines. CONCLUSIONS:The heterozygous splice-site insertion variant KIT:c.1990+8_1990+9insTGCACCATTGGAGGTAAA is the genetic cause of piebaldism in this pedigree.
Substance use disorder (SUD) is characterized by the persistent prioritization of drug-related cues, which readily trigger intense craving and relapse even after prolonged abstinence. Although previous studies have primarily focused on the mesolimbic dopamine system and fronto-striatal circuits, the mechanisms underlying the aberrant integration of reward value, affective states, attentional allocation, and memory representations remain largely elusive. The claustrum-owing to its extensive bidirectional connectivity with both cortical and subcortical networks and its hypothesized role in salience processing-has increasingly been recognized as a key hub in SUD. Accumulating evidence suggests that the claustrum may contribute to drug-cue salience attribution and reward memory encoding, modulate prefrontal information processing and executive control via its reciprocal projections, and interact with limbic systems to sustain withdrawal-related negative affect, thereby influencing relapse vulnerability. Furthermore, emerging findings from psychedelic research indicate that claustrum-related networks are highly plastic and participate in salience reconfiguration. Collectively, the claustrum may act as a cross-network hub that links reward processing, cognitive control, and affective memory, thereby extending classical circuit models of addiction. This review systematically summarizes the structural connectivity, neuroimaging correlates, and functional mechanisms of the claustrum, and discusses its translational implications for relapse prediction and the development of novel intervention strategies.
OBJECTIVES:To evaluate the effects of digital-driven cardiac rehabilitation on clinical outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS:We retrospectively analyzed data from 1,012 patients who underwent TAVR at the Second Affiliated Hospital, Zhejiang University School of Medicine, between March 2013 and January 2023. Patients receiving conventional rehabilitation were assigned to the control group, whereas those receiving a digital-driven cardiac rehabilitation program, comprising preoperative screening and functional preparation, intraoperative eligibility assessment, postoperative stepwise rehabilitation management, and intelligent home-based rehabilitation, were assigned to the intervention group. Propensity score matching was performed to adjust for baseline confounding. Postoperative intensive care unit (ICU) stay and hospital stay, the incidence of cardiovascular and cerebrovascular adverse events at 30 days, 1 year, and 2 years after TAVR, and functional outcomes, including the 5-meter walk test, 6-minute walk test, and Katz Index, were compared between the two groups. RESULTS:After propensity score matching, 251 patients were included in each group. Compared with the control group, the intervention group had significantly shorter postoperative ICU stays [0 (0, 0) h vs. 0 (0, 1) h, P<0.01] and postoperative hospital stays [3 (1, 7) days vs. 8 (7, 11) days, P<0.01]. The time required to complete the 5-meter walk test was significantly shorter in the intervention group than in the control group at 30 days, 1 year, and 2 years after TAVR (all P<0.01). No apparent increase in the incidence of adverse events was observed in the intervention group at 30 days, 1 year, or 2 years after TAVR. CONCLUSIONS:The present findings suggest that digital-driven cardiac rehabilitation may shorten hospital stay and improve selected functional outcomes in patients undergoing TAVR without an observed increase in postoperative cardiovascular and cerebrovascular adverse events.
Narcotic drug addiction is characterized not only by compulsive drug use and persistent craving after withdrawal but also by systemic consequences of long-term exposure. These include alterations in neural circuits subserving reward, stress, and executive control, as well as skeletal impairments such as reduced bone mineral density and strength, disrupted bone turnover, muscle weakness, and elevated fracture risk. The bone-brain axis, which mediates bidirectional communication between the central nervous system and the skeleton via neural, endocrine, immune, metabolic, and bone-derived signaling, offers an integrative framework for understanding the concurrent neuro-skeletal impairments seen in addiction. Such impairments may not arise independently; rather, they may reflect cross-system pathology driven by interactions among neuroendocrine dysregulation, inflammatory and immune activation, oxidative stress, neurotransmitter disturbances, and feedback from bone-derived factors. Specifically, prolonged drug exposure can alter bone remodeling through the sympathetic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and the hypothalamic-pituitary-gonadal (HPG) axis, while simultaneously disrupting the tissue microenvironment of both brain and bone via inflammatory/immune activation and redox imbalance. Abnormalities in monoamines-dopamine, serotonin, and norepinephrine-may further link addiction-related neurobehavioral changes to bone cell dysfunction. Meanwhile, bone-derived factors such as osteocalcin, sclerostin, lipocalin-2, and bone-derived extracellular vesicles may contribute to feedback regulation of brain function by skeletal tissue. This review summarizes the concurrent impairments of the nervous and skeletal systems associated with narcotic drug addiction, analyzes the potential pathways by which bone-brain axis dysregulation may mediate their interrelationship, and aims to provide a reference for elucidating the mechanisms of somatic comorbidity in addiction and for informing comprehensive intervention strategies.
The clinical efficacy of tumor immunotherapy is constrained by the immuno-suppressive nature of the tumor microenvironment, within which mechanical signals serve as critical modulators of immune responses. Alterations in tumor tissue mechanics-including matrix stiffening, elevated interstitial pressure, and aberrant fluid shear stress-create physical barriers that impede immune cell infiltration and cytotoxic function. Conversely, immune cells detect and interpret these mechanical cues through mechanosensi-tive pathways involving Piezo1, TRPV4, and YAP/TAZ, which regulate their activation, migration, and effector functions. Small-molecule agents targeting these pathways can precisely modulate key mechanosensitive molecules and emerging mechanical immune checkpoints, thereby bridging mechanical sensing with immune effector reprogramming. Interventions that modify microenvironmental mechanical properties-for instance, through extracellular matrix remodeling or softening-can enhance immune cell infiltration and amplify anti-tumor immunity at the tissue level. Engineered mechano-immunotherapeutic strategies, leveraging biomaterials and biomechanical principles, directly modulate membrane mechanics and mechanotransduction in immune or tumor cells to potentiate immune activity and microenvironmental responsiveness. This review synthesizes current knowledge on the mechanical properties of tumors and their microenvironments, the mechanoregulatory mechanisms operating in immune cells, and recent progress in the development of mechanically targeted therapeutics, with the goal of informing future innovation in immuno-oncology.
Methamphetamine (METH) is highly addictive and can cause neurotoxicity when misused over a prolonged period. METH-induced neurotoxicity and addiction involve multi-level biological alterations, including nucleotide polymorphisms, aberrant epigenetic modifications, transcriptional imbalance, protein dysfunction, metabolic dysregulation, and microbial dysbiosis with changes in microbiota-derived metabolites. To systematically dissect these multifaceted changes, genomics has been deployed to identify key gene polymorphisms linked to METH addiction susceptibility and epigenetic changes such as DNA methylation in brain regions following METH exposure. Tran-scriptomics dynamically profiles differential gene expression in addiction-relevant brain areas, particularly in pathways governing synaptic plasticity and neuroinflammation. Proteomics pinpoints the dysregulation of functional proteins associated with synaptic plasticity in response to METH. Metabolomics quantifies neurotransmitter depletion and redox imbalance induced by the drug, while microbiomics reveals gut microbiota dysbiosis and subsequent neural damage via the gut-brain axis. The integrated application of these multi-omics technologies-spanning genetic variation, transcriptional regulation, protein function, metabolic dynamics, and host-microbe interactions-systematically illuminates the complex molecular events underlying METH neurotoxicity and addiction, thereby providing a robust theoretical framework and technical roadmap for identifying early warning biomarkers and devising multi-target combination strategies against METH neurotoxicity and relapse. This review summarizes the current state of single-omics and multi-omics applications in METH neurotoxicity and addiction research, aiming to provide a reference for elucidating pathogenic mechanisms, identifying biomarkers, and discovering potential therapeutic targets.
OBJECTIVES:To develop a health information-seeking behavior (HISB) questionnaire for patients with chronic diseases and evaluate its reliability and validity. METHODS:Based on Wilson's information behavior model, a preliminary questionnaire was developed through literature review, team discussions, two rounds of expert consulta-tions, and a pilot survey. A convenience sample of 368 patients with chronic diseases was recruited from medical institutions in Hangzhou, Jinhua, Lishui, Ningbo, Taizhou, and Wenzhou of Zhejiang Province, between March-May 2023 and August-September 2025. The dimension of health information-seeking channels was analyzed using descriptive statistics. Item analysis for the other three dimensions was performed using item-total correlation and critical ratio methods. Reliability was evaluated using Cronbach's α coefficient and split-half reliability. Content validity was assessed by expert ratings, and structural validity was evaluated using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). RESULTS:The final questionnaire comprised 30 items across four dimensions: health information needs, health information-seeking channels, health information search and acquisition, and health information evaluation. The overall Cronbach's α coefficient was 0.970, and the split-half reliability was 0.781. The scale-level content validity index (S-CVI) was 0.830, and the item-level content validity index (I-CVI) ranged from 0.890 to 1.000. EFA extracted three common factors with a cumulative variance contribution rate of 75.181%. CFA indicated a good model fit. CONCLUSIONS:The HISB questionnaire developed in this study demonstrates good reliability and validity. It can serve as a reliable and valid tool to assess HISB among patients with chronic diseases, providing a basis for healthcare professionals to develop targeted health education interventions.
OBJECTIVES:To examine the association between different multimorbidity patterns and depressive symptoms among middle-aged and older adults. METHODS:Data were obtained from 491 middle-aged and older adults with multimorbidity in the 2020 China Health and Retirement Longitudinal Study (CHARLS). Latent class analysis (LCA) was used to identify distinct multimorbidity patterns. Logistic regression models were subsequently applied to assess the associations between latent classes and depressive symptoms, adjusting for age, sex, marital status, residence, number of chronic conditions, and income. RESULTS:The prevalence of depressive symptoms among individuals with multimorbidity was 37.1%. Three multimorbidity patterns were identified: a cardiometabolic pattern, a digestive-musculoskeletal pattern, and a respiratory pattern. After adjusting for covariates, significant differences in depressive symptoms were observed across patterns. Compared with the cardiometabolic pattern, individuals in the digestive-musculoskeletal pattern had a higher likelihood of depressive symptoms (OR = 1.795, 95% CI: 1.14-2.82), while no significant difference was found for the respiratory pattern. In addition, having four or more chronic conditions (OR = 1.996, 95% CI: 1.15-3.47) and being aged ≥70 years (OR = 2.817, 95% CI: 1.24-6.68) were significantly associated with higher odds of depressive symptoms. CONCLUSIONS:Multimorbidity patterns are associated with depressive symptoms among middle-aged and older adults. The digestive-musculoskeletal pattern is particularly linked to a higher risk of depression. These findings suggest that the impact of multimorbidity on mental health depends not only on the number of chronic conditions but also on specific disease combinations.
OBJECTIVES:To investigate the protective effects of Chinese medicine Bushen Yijing Formula against amyloid β-protein (Aβ) deposition and oxidative damage using models of Caenorhabditis elegans. METHODS:The C. elegans models, including wide-type strains N2, transgenic strains CL4176, TJ356, and LG333, were employed. The herbal components of the formula were water‑extracted, freeze‑dried into lyophilized powder, and added to the culture medium at different concentrations. Oxidative stress was induced by paraquat exposure. Evaluated parameters included lifespan; time to paralysis and pharyngeal Aβ deposition in CL4176; levels of total antioxidant capacity, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) measured by commercial kits; apoptosis detected by acridine orange staining; nuclear translocation of DAF‑16::GFP in TJ356 nematodes and SKN-1::GFP in LG333 nematodes observed under fluorescence microscopy. Molecular docking and dynamics simulations were further performed to assess the binding stability of the active components catalpol and tetrahydroalstonine (THA) with the core targets FOXO and Nrf2. RESULTS:Compared with the normal control group, Bushen Yijing Formula significantly extended the lifespan of N2 nematodes under both oxidative stress and normal conditions (all P<0.01). Compared with the control group of the AD model, Bushen Yijing Formula prolonged the time to paralysis and reduced pharyngeal Aβ deposition in CL4176 (all P<0.01). Compared with the control group in the paraquat-induced oxidative stress model in N2, Bushen Yijing Formula elevated total antioxidant capacity, SOD, CAT, and GSH levels (all P<0.01), decreased MDA and ROS levels (all P<0.05), and attenuated apoptosis. Moreover, the formula promoted nuclear translocation of DAF‑16 and SKN‑1 (all P<0.01). Molecular docking revealed that binding energies of catalpol and THA with FOXO and Nrf2 were all below －7.00 kcal/mol, and dynamics simulations confirmed high stability and favorable affinity for the FOXO-catalpol, Nrf2-catalpol, and Nrf2-THA complexes. CONCLUSIONS:Bushen Yijing Formula alleviates Aβ deposition and its neurotoxicity, enhances antioxidant capacity, and attenuates oxidative stress injury in model nematodes, likely through stable binding and regulation of the FOXO/Nrf2 signaling pathway.
OBJECTIVES:To explore the mechanism of Bushen Yijing Formula (BSYJF) in the treatment of Alzheimer's disease (AD) through an integrated approach combining transcriptomics, network pharmacology, and molecular docking. METHODS:Twelve specific pathogen-free male C57BL/6 mice, aged 6 months, were used in this study. Among them, four wild-type mice served as the normal control group, and eight amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice were randomly divided into a model control group and a BSYJF group, with four mice in each group. Mice in the BSYJF group were orally administered 8.56 mL/kg BSYJF by gavage once daily, while those in the model control and normal control groups received an equal volume of normal saline by gavage. All treatments were continued for 12 consecutive weeks. Cognitive function and hippocampal amyloid β-protein (Aβ) deposition were assessed using behavioral tests and immunohisto-chemistry. Mouse brain tissue samples were subjected to transcriptomic sequencing to identify differentially expressed genes (DEGs). Functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). In parallel, active compounds of BSYJF were screened via the TCMSP and PubChem databases, and AD-related targets were retrieved from GeneCards and other disease databases. Core targets were identified by intersecting these targets with transcriptomic DEGs. Molecular docking and molecular dynamics simulations were employed to evaluate binding affinity between active compounds and core targets, and quantitative polymerase chain reaction (qPCR) was used to validate expression changes of core target genes. RESULTS:BSYJF treatment improved cognitive function and reduced hippocampal Aβ deposition in APP/PS1 mice. Transcriptomic analysis revealed 73 DEGs between the model and BSYJF groups. GO analysis identified enrichment in 281 biological processes, 104 cellular components, and 120 molecular functions. KEGG analysis highlighted 110 pathways, and GSEA supplemented 322 enriched gene sets, many related to the immune system, neurodegenerative diseases, and signaling pathways such as Th17 cell differentiation and NF-κB. Integrated analysis with network pharmacology prioritized 10 core targets. Molecular docking and molecular dynamics simulations indicated strong structural stability and binding affinity of BSYJF bioactive constituents to these core targets. qPCR results confirmed that BSYJF down-regulated the expression of Aurkb, Nr1i3, and Ttk, while upregulating Apob and Ces1d, consistent with the transcriptomic findings. CONCLUSIONS:BSYJF may regulate immune-inflammatory responses and alleviate neuronal damage through a multi-component, multi-target, and multi-pathway approach, thereby improving cognitive function in AD model mice.
OBJECTIVES:To analyze the distribution characteristics of disability-adjusted life years (DALYs) for depressive disorders among adolescents globally and in China, and to explore the dynamic evolution trajectory of depressive levels among Chinese adolescents and their associated influencing factors. METHODS:Based on data from the Global Burden of Disease Study (GBD) 2000-2021, Joinpoint regression models were used to analyze temporal trends in the disease burden of adolescent depressive disorders. Based on data from the China Family Panel Studies (CFPS) 2012-2022, the dynamic evolution of depressive levels among Chinese adolescents was examined. Using CFPS 2022 cross-sectional data (n=3,259), a multivariate hierarchical regression analysis was conducted to identify influencing factors across four dimensions: individual, family, school, and societal, with heterogeneity tests further stratified by gender and age group. RESULTS:GBD data showed that the DALY rates for depressive disorders among Chinese adolescents aged 10-<15 and 15-19 years remained consistently below the global average throughout the study period, yet both exhibited a continuous upward trend, with average annual percentage changes (AAPC) of 1.85% and 1.99%, respectively (both P<0.01), and females showing a faster increase than males. The corresponding global AAPCs for the same age groups were 2.30% and 1.89%, respectively (both P<0.01). CFPS data analysis revealed that depressive levels among Chinese adolescents exhibited a fluctuating trajectory, with an initial decline followed by a subsequent increase during the observation period. The 15-19 age group consistently had higher depressive symptom scores than the 10-<15 age group; females scored higher than males; rural residents scored higher than urban residents; and residents in the western region scored higher than those in the central and eastern regions. Hierarchical regression analysis showed that self-rated health, happiness, interpersonal relationships, school satisfaction, academic performance, and urban residence were protective factors (β=-0.144 to -1.104, all P<0.05), while academic pressure, frequency of quarrels with parents, participation in tutoring classes, and western residence were risk factors (β=0.236 to 1.101, all P<0.05). Heterogeneity analysis indicated that self-rated health, frequency of quarrels with parents, happiness, school satisfaction, and academic pressure had significant effects on both genders (all P<0.01), with larger effect sizes for females; interpersonal relationships, participation in tutoring classes, and academic performance were significantly associated with depressive levels only in females (all P<0.05), while urban-rural status was significantly associated with depressive levels only in males (P<0.05). Happiness (β=-0.502 vs. -0.946) and academic pressure (β=0.951 vs. 1.309) had larger effect sizes for adolescents aged 15-19 years, while school satisfaction (β=-0.732 vs. -0.414) had a larger effect size for those aged 10-<15 years. Interpersonal relationships were significantly negatively associated with depressive levels only in the 15-19 age group (β=-0.252, P<0.05), while participation in tutoring classes (β=1.048, P<0.01) and parental marital status (β=-4.153, P<0.01) were significantly associated with depressive symptoms only in the 10-<15 age group. CONCLUSIONS:Although the overall disease burden of depressive disorders among Chinese adolescents remained below the global average, it showed a sustained upward trend during 2000-2021. Depressive symptoms demonstrated significant heterogeneity across age, gender, urban-rural residence, and geographic region, with influencing factors encompassing multiple dimensions including individual, family, school, and societal levels.
