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To synthesize clinical, cognitive, safety, and mechanistic evidence on supervised high-intensity interval training (HIIT) after stroke and translate key findings into practice. We conducted a narrative review of supervised HIIT interventions in adults after stroke. Electronic searches of PubMed and Web of Science identified studies published between January 1, 2014, and September 30, 2025. Eligibility criteria emphasized feasibility, safety, and neurofunctional outcomes (six-min walk distance, gait speed, peak aerobic capacity, activities/participation, and cognition). Quantitative pooling was not performed, and the findings were qualitatively synthesized. To explain biological plausibility, mechanistic and translational sources were reviewed irrespective of the year and summarized separately. HIIT was feasible under guideline-concordant screening and monitoring, with no serious adverse events. Consistent gains were observed in aerobic capacity, walking endurance, and usual gait speed, whereas activity/participation effects were mixed. Cognitive benefits were domain-specific and the clearest for executive functions. Mechanistic signals (e.g., brain-derived neurotrophic factor (BDNF), frontal oxygenation, and endothelial function) support biological plausibility. Supervised HIIT appears safe and clinically useful for augmenting locomotor and aerobic outcomes after stroke and may preferentially enhance executive cognition. Implementation should complement task-specific therapy and follow standard screening and monitoring procedures. Future work should refine dose- and phase-specific protocols to maximize application to daily function. Show less

Following their domestication, chickens were translocated around the world to novel environments. Through a combination of natural and artificial selection, chickens adapted to these local conditions, creating significant genetic diversity across populations worldwide. Studying this diversity in the context of local environmental conditions may offer insights into mechanisms of adaptation to environmental stressors. In this study, we analyzed genomic data from the Chicken Genomic Diversity Consortium, applying multiple statistical approaches, including fixation index (F The online version contains supplementary material available at 10.1038/s41598-026-41813-8. Show less

Hypertension-linked renal fibrosis leads to the gradual loss of renal function and eventually progresses to end-stage renal failure, which exhibits poor clinical efficacy and is difficult to reverse. Therefore, clarifying the development mechanism of hypertension-linked renal fibrosis is crucial for its prevention and treatment. In this review, we conducted an in-depth exploration of the pivotal elements, along with their detailed mechanistic linkages in the pathogenesis of hypertension-linked renal fibrosis. It was found that the renin-angiotensin-aldosterone system (RAAS) is overactivated in hypertension. Angiotensin II (Ang II) and aldosterone (Aldo) jointly cause the abnormal accumulation of reactive oxygen species (ROS) by increasing the activity and expression of Nox2 and Nox4, inducing the inhibition and uncoupling of endothelial nitric oxide synthase (eNOS), enhancing expression of selected microRNAs (miRNAs), and reducing glucose-6-phosphate dehydrogenase (G6PD) expression. In turn, elevated ROS trigger renal inflammation by activating the mitogen-activated protein kinase (MAPK)-nuclear factor-kappa B (NF-κB) pathways as well as ferroptosis. Thereafter, renal inflammation can promote the process of renal fibrosis by activating the transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), and lysophosphatidic acid (LPA). This review not only emphasizes the core role of the mechanistic axis that plays a crucial role in the development of hypertension-driven renal fibrosis-the "RAAS-ROS-inflammation-fibrosis" axis-but also proposes promising therapeutic strategies targeting this axis, including modulating RAAS activity, controlling the increase in ROS, inhibiting inflammation, and blocking fibrotic progression. It aims to provide novel insights and potential therapeutic directions for hypertension-related renal fibrosis in the future. Show less

This study employs latent profile analysis (LPA) to identify potential categories of nurse burnout and to analyze differences in characteristics and influencing factors across burnout categories. From June to August 2025, a mixed sampling approach combining convenience and snowball sampling was used to recruit nurses from hospitals of varying levels in Southwest China. Three tools were used for data collection: A self-designed routine information questionnaire, Maslach Burnout Inventory-General Survey (MBI-GS) and Practice Environment Scale of the Nursing Work Index (PES-NWI), LPA identifies potential categories of nurses' professional burnout and uses multivariate logistic regression analysis to explore the factors associated with these categories. This study comprised a total of 809 participants. LPA identified four distinct latent classes of nursing burnout: Class 1, low-burnout-high-efficacy (11.5%); Class 2, mild-burnout-unfulfilled (33.9%); Class 3, moderate-burnout-exhausted (44.6%); and Class 4, severe-burnout-dysfunctional (10.0%). Multivariate logistic regression analysis showed that age, years of work experience, hospital level, nurses' participation in hospital management, nursing quality standards, staffing and resource adequacy, and medical care cooperation are significant predictors of burnout among nurses ( Nurse burnout in southwest China is mainly moderate to severe and exhibits distinctive characteristics. It is recommended to implement personalized interventions tailored to the specific characteristics of nurses' professional burnout to alleviate the situation. Particular attention should be given to nurses with fewer than five years of experience by providing enhanced job support and psychological assistance to help them navigate critical periods of professional burnout. These measures aim to safeguard nurses' physical and mental health, improving the overall quality of nursing, and promoting the healthy development of global medical care. Show less

The utility of emerging lipid markers-apolipoprotein B (apoB) and lipoprotein(a) (Lp[a])-for improving atherosclerotic cardiovascular disease (ASCVD) risk assessment beyond traditional lipid measures remains uncertain, particularly in young adults. To evaluate associations of traditional and emerging lipid markers with ASCVD and assess the incremental value of emerging markers beyond established risk models. This prospective cohort study included adults aged 18 years or older without cardiovascular disease from 3 US cohort studies (Coronary Artery Risk Development in Young Adults, the Framingham Heart Study Offspring, and the Multi-Ethnic Study of Atherosclerosis [MESA]). Data were analyzed from April to June 2025. Lipid markers, including low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, total-to-HDL cholesterol ratio, apoB, and Lp(a). Hazard ratios (HRs) for incident ASCVD per-SD increase in lipid marker levels, estimated using Cox proportional hazards regression models adjusted for demographic and clinical factors, and model performance metrics (Harrell concordance index [C-index], net reclassification improvement [NRI], and mean calibration) comparing models including the risk estimated by the Predicting Risk of Cardiovascular Disease Events (PREVENT) base equations against models that additionally included each lipid marker. Among 10 519 participants (mean [SD] age, 48.3 [15.7] years; 53.0% female), 1103 ASCVD events occurred during a median follow-up of 21.3 (IQR, 16.5-26.0) years. ApoB was positively associated with ASCVD events, especially in younger adults aged 18 to 39 years (adjusted HR [AHR] per-SD increase, 1.53; 95% CI, 1.30-1.79) vs those aged 40 years or older (AHR, 1.13; 95% CI, 1.06-1.20) (P < .001 for interaction). Lp(a) as a continuous variable was associated with a marginal increase in ASCVD in adults aged 40 years or older (AHR, 1.07; 95% CI, 1.00-1.16) but not in younger adults (AHR, 1.02; 95% CI, 0.87-1.19) (P = .61 for interaction). When dichotomized (>50 vs ≤50 mg/dL), Lp(a) was associated with ASCVD in adults aged 40 years or older (AHR range, 1.36; 95% CI, 1.13-1.64) but not in younger adults (AHR, 0.98; 95% CI, 0.66-1.45) (P = .42 for interaction). Adding apoB to 10-year ASCVD risk estimated by the PREVENT base equations was associated with improved risk reclassification in younger adults (continuous NRI, 0.67; 95% CI, 0.23-1.09) but not in those aged 40 years or older (continuous NRI, 0.16; 95% CI, -0.05 to 0.27). ApoB was also associated with improved 30-year risk reclassification in younger adults (continuous NRI, 0.47; 95% CI, 0.02-0.84). Dichotomized Lp(a), but not continuous Lp(a), was associated with improved 10-year NRI only in MESA (0.13; 95% CI, 0.03-0.24). In this cohort study of 10 519 adults, adding apoB to PREVENT-estimated ASCVD risks was associated with improved risk reclassification, particularly in younger adults. However, the clinical importance of these modest improvements remains uncertain. Show less

Doxorubicin (Dox) is a potent cytotoxic medication, yet its adverse properties are undeniable obstacles to its clinical use. The objective of the existing research was to inspect the potential beneficial actions of lurasidone (Lura) against the neurotoxicity and cardiotoxicity triggered by Dox in rats. Sixty rats were equally allocated to four groups: Control group; Dox group; Lur (1 mg/kg) + Dox group; Lura (3 mg/kg) + Dox group. For 18 days, Lura (1 and 3 mg/kg) was given orally, starting 7 days before giving six doses of Dox (2.5 mg/kg every other day, i.p). Lura attenuated Dox-instigated cardiac injury as assured by the decrease in cardiac troponin-I (cTn-I), kg) and creatine kinase MB (CK-MB) levels. In addition, Lura remarkably declined Dox-triggered neuronal dysfunction, as confirmed by diminished anxiety and depression-alike behaviors in the open field (OFT) and forced swimming (FST) tests, respectively. Furthermore, Lura replenished cardiac and brain antioxidant markers, mitochondrial modulator, PGC-1α, and significantly decreased inflammatory mediators, miR34a-5p, and pro-apoptotic caspase-3 levels. In the brain, Lura also mitigated the induction of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor-1 (Iba-1). In the same context, Lura pretreatment upregulated the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/phosphoinositide 3-kinase (PI Show less

Osteoporosis (OP) is a metabolic bone disease characterized by low bone mineral density (BMD), and its pathogenesis involves endoplasmic reticulum (ER) stress-related cell death. This study aimed to identify diagnostic biomarkers associated with ER stress-related cell death in OP and explore their underlying mechanisms. The training dataset (GSE56815), validation dataset (GSE56814), and single-cell RNA sequencing (scRNA-seq) dataset (GSE147287) were downloaded. Differentially expressed genes (DEGs) between OP patients and controls were identified. Candidate genes were obtained by intersecting DEGs with ER stress-related genes and programmed cell death (PCD)-related genes. Machine learning was used to screen intersection genes, and biomarkers were determined via expression level analysis. Gene set enrichment analysis (GSEA), immune cell infiltration analysis, drug prediction and molecular docking, scRNA-seq analysis, key cell screening, cell communication analysis, and pseudotime analysis were performed. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) were further conducted. A total of 28 candidate genes were obtained by intersection. CAMKK2 and DAPK3 were confirmed as biomarkers, and were consistently down-regulated in both datasets and verified by RT-qPCR. GSEA analysis revealed that biomarkers were enriched in cytokine-cytokine receptor interaction. Correlations between biomarkers and activated dendritic cells were found via immune cell infiltration analysis. Preliminary computational analyses indicated that drugs including calcitriol and danazol may potentially interact with the biomarkers in a stable manner. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were identified as potential key cells via scRNA-seq analysis. Complex interactions involving BM-MSCs, such as ANGPTL4-CDH11 mediating BM-MSC self-communication, were revealed by cell communication analysis. Dynamic expression of biomarkers during BM-MSC differentiation was shown by pseudotime analysis: CAMKK2 fluctuated with differentiation stages, while DAPK3 shifted from high to low then high expression. CAMKK2 and DAPK3 were confirmed as diagnostic biomarkers for OP, providing insights into OP diagnosis and potential therapeutic targets. Show less

To identify latent self-management profiles in people living with HIV (PLWH) with dyslipidemia and factors associated with profile membership, thereby facilitating targeted clinical intervention. A cross-sectional survey was conducted from December 2024 to June 2025 among 333 PLWH with dyslipidemia at Nanjing Second Hospital. Data were collected via sociodemographic/disease-related questionnaire, the HIV Self-Management Scale (HIVSMS), and the Health Literacy Management Scale (HLMS). Latent profile analysis (LPA) was performed in Mplus 8.3, and multinomial logistic regression was used to examine factors associated with profile membership. Fit indices (entropy = 0.993) supported a three-profile solution: low self-management-low social support-seeking (C1, 42.3%), moderate self-management-stable (C2, 37.8%), and high self-management-emotion regulation dominant (C3, 19.8%). Seeking social support was relatively low across profiles. Compared with C1, C2 membership was significantly associated with higher education and income, lipid-lowering medication use (OR 3.735, 95% CI 1.597-8.736), and CD4 350-500 cells/μL, and was less likely among participants with VL >1000 copies/mL or chronic comorbidities (all P < 0.05). Compared with C1, C3 membership was significantly associated with HIV infection duration ≥5 years, higher education and income, CD4 >500 cells/μL, and higher HDL-C, and was less likely among those with VL >1000 copies/mL (OR 0.037, 95% CI 0.004-0.380) or chronic comorbidities (all P < 0.05). Compared with C2, C3 membership was independently associated with higher health literacy (HL) (OR 1.038 per point, 95% CI 1.012-1.064) and was less likely among those with LDL-C ≥3 mmol/L (P < 0.05). We identified three distinct self-management profiles among PLWH with dyslipidemia. Profile membership was significantly associated with HL and socioeconomic, HIV-related, lipid-related, and comorbidity factors, supporting the need for profile-tailored strategies to improve self-management. Show less

Depression is increasingly recognized as a disorder involving immune brain interactions beyond classical monoaminergic dysfunction. Among immune components, T cells have emerged as key regulators linking peripheral immune dysregulation to central neuroinflammation and impaired neuroplasticity. Accumulating clinical and preclinical evidence indicates that alterations in T cell subsets, including regulatory T cells, Th1 cells, and Th17 cells, contribute to depressive pathophysiology through coordinated effects on blood-brain barrier permeability, glial activation, cytokine signaling, and neurotrophic support. This review synthesizes current evidence on the mechanisms by which T cells migrate into the central nervous system and modulate depressive behaviors. Particular emphasis is placed on the T cell regulation of brain derived neurotrophic factor signaling, and a role for T cell derived extracellular vesicles as modulators of immune neural communication and neuroplasticity. Finally, we discuss the therapeutic implications of targeting T cells in depression, including modulation of T cell subset balance, cytokine-based interventions, microbiota immune regulation, and inhibition of pathogenic T cell trafficking into the brain. Together, these findings position T cells as central orchestrators of immune neural crosstalk and promising targets for mechanism informed immunotherapies in depression. Show less

Cardiovascular and renal diseases exhibit a close bidirectional interaction, which often leads to the development of cardio-renal syndrome (CRS)-a clinical condition in which cardiac dysfunction further aggravates renal injury. Type I CRS is characterized by acute kidney injury secondary to acute heart failure, and this sub-type is closely related to elevated morbidity and mortality in patients with coronary artery disease (CAD). Despite the availability of traditional biomarkers, there is an unmet need for more sensitive indicators to identify high-risk patients for Type I CRS in CAD patients. The apolipoprotein B (ApoB)/apolipoprotein A1 (ApoA1) ratio has emerged as a promising predictor of cardiovascular risk, yet its role in CRS remains unclear. This study aimed to evaluate the association between the ApoB/ApoA1 ratio and Type I CRS in patients with CAD, and to assess its value as a biomarker for identifying high-risk patients. A retrospective cohort study was carried out on 269 CAD patients complicated with heart failure who were hospitalized in our hospital from 2022 to 2024. According to the estimated glomerular filtration rate (eGFR) results, the enrolled patients were divided into two subgroups: the simple heart failure (SHF) group and the type I CRS group. Data on demographics, clinical history, biochemical measurements, echocardiographic and coronary angiography assessments, and renal function were collected. A multivariable logistic regression model was used to assess the association between the ApoB/ApoA1 ratio and CRS, adjusting for potential confounders. Correlation analyses were performed to explore the relationships between key variables and the occurrence of type I CRS. A multivariable logistic regression model was used to assess the association between the ApoB/ApoA1 ratio and CRS. Furthermore, a receiver operating characteristic (ROC) curve was constructed to evaluate the predictive accuracy of the ApoB/ApoA1 ratio for type I CRS. A total of 269 patients were enrolled. Significant differences were observed between the simple heart failure (SHF) group and the CRS group in terms of age, history of diabetes mellitus, levels of triglycerides (TG), apolipoprotein A1 (apo-A1), apolipoprotein B (apo-B), ApoB/ApoA1 ratio, and serum creatinine (Scr). Patients in the CRS group were older, had a higher proportion of diabetes mellitus, higher levels of TG, apo-B, and Scr, a higher ApoB/ApoA1 ratio, but lower levels of apo-A1 compared to the SHF group. Multivariable logistic regression analysis identified age and the ApoB/ApoA1 ratio as independent risk factors for CRS. The receiver operating characteristic (ROC) curve analysis showed that the ApoB/ApoA1 ratio had a moderate level of predictive accuracy for Type I CRS, with an area under the curve (AUC) of 0.782. The ApoB/ApoA1 ratio is moderately associated with the risk of developing Type I CRS in patients with CAD. This ratio could serve as a clinically relevant biomarker for early identification of in-hospital Type I CRS risk in CAD patients with acute heart failure, potentially aiding in the implementation of early and targeted interventions to improve patient outcomes. Show less

Depressive disorders represent a major contributor to the global burden of disease, with persistently rising prevalence rates posing significant challenges to individual quality of life and public health systems. Existing first-line medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) typically require 2-4 weeks to take effect, with complete remission rates below 60%. Approximately one-third of patients discontinue treatment within 90 days due to adverse reactions including gastrointestinal discomfort, weight changes, or sexual dysfunction. Consequently, exploring interventions with faster onset and improved tolerability holds significant clinical importance. A systematic search of seven databases-PubMed, Embase, Web of Science, Cochrane CENTRAL, CNKI, AMED, and Scopus-identified randomised controlled trials (RCTs) and mechanism studies published between 2010 and 2025. A qualitative synthesis method analysed clinical efficacy and adverse reactions, integrating evidence from metabolomics, epigenetics, and network pharmacology. Botanical drug identification was performed in accordance with ConPhYMP guidelines, with all species names validated taxonomically against the Medicinal Plant Names Services (MPNS) and Plants of the World Online (POWO) databases. Twenty-one RCTs (n = 2,766) and three mechanistic studies were included. Findings indicated that Xiaoyao Formula Existing evidence preliminarily supports potential advantages of Xiaoyao Formula in treating depressive disorders, including possibly earlier onset of action, good tolerability, and potential additional benefits in female subgroups. However, given limitations such as small sample sizes, short intervention durations (6-12 weeks), and predominantly combination therapy rather than monotherapy comparisons, these conclusions should be regarded as suggestive or indicative findings rather than definitive efficacy. Long-term efficacy and generalisability across populations require further validation. Future studies should conduct multicentre, large-sample clinical trials with ≥24-week follow-up, incorporating wearable digital phenotyping technologies to confirm its application value in precision psychiatry. Show less

This study aims to investigate the effects of mulberry anthocyanin (MA) in high-fat and high-cholesterol (HFHC) diet-fed ApoE-/- mice. ApoE-/- mice were randomly divided into control (ACON), mulberry fruit anthocyanin extract (MFAE), cyanidin-3-glucoside (C3G) group 1 (C3GT), and C3G group 2 (C3GP). After 7 weeks of HFHC diet feeding and following 2-3 weeks of treatment, samples were collected and analyzed. The C3GT group significantly decreased low-density lipoprotein (7.3 ± 1.5 mmol/L) and interleukin-1β (355.4 ± 41.7 pg./mL) levels. Moreover, the MFAE (636.3 ± 90.7 pg./mL), C3GT (611.5 ± 65.4 pg./mL), and C3GP (757.5 ± 47.6 pg./mL) significantly increased glutathione peroxidase (GSH-PX) levels compared with those in the ACON group. The MA treatments significantly increased the number of MA treatment may attenuate AS-associated risk factors by decreasing inflammatory factor-related gut microbial genera. The mechanism may be related to regulating liver glutamine, ATP, and related metabolic pathways. Show less

Social connectedness promotes healthy aging and is associated with lower risk for psychological disorders and cognitive decline. However, little is known about the mechanisms underlying these relationships, and whether different network features are associated with unique health benefits. We used comprehensive data from 386 community-dwelling older adults with and without cognitive impairment to test the relationship between psychological and cognitive function and their personal social networks. Data were collected using a multisite sampling strategy, and included detailed social network interviews and comprehensive measures of episodic memory, executive function, and language. Longitudinal effects were evaluated using a subsample at high-risk for decline, having either at least one copy of APOE ε4 or a current diagnosis of impairment ( The online version contains supplementary material available at 10.1038/s41598-026-44571-9. Show less

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive memory impairment and cognitive decline, significantly impacting the quality of life for millions worldwide. Understanding the intricate molecular pathways linking AD pathology to memory dysfunction is crucial for developing effective therapies. This narrative review aims to elucidate the key molecular mechanisms underlying memory impairment in AD. We conducted a comprehensive literature search across major scientific databases (e.g., PubMed, Scopus, Web of Science) focusing on peer-reviewed studies (original research, reviews) exploring the molecular links between AD pathology and memory deficits. The review identifies and details several interconnected molecular pathways driving memory impairment in AD: (1) Synaptic dysfunction and neuronal loss triggered by amyloid-β (Aβ) peptide accumulation and aggregation; (2) Intracellular transport disruption and neurodegeneration caused by tau protein hyperphosphorylation and aggregation; (3) Exacerbation of cognitive deficits by neuroinflammation, mediated through activated microglia and pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6); (4) Impairment of synaptic plasticity and cognitive function due to dysregulation of neurotrophic factors, particularly brain-derived neurotrophic factor; (5) Contributory roles of oxidative stress, mitochondrial dysfunction, disrupted neurotransmission (e.g., acetylcholine, GABA), and apoptotic pathways. This review comprehensively unravels the critical molecular links between AD pathology and memory impairment, emphasizing the interplay of Aβ, tau, neuroinflammation, neurotrophic factor dysregulation, and other mechanisms. Targeting these interconnected pathways represents a promising strategic approach for developing therapies to mitigate cognitive decline and improve outcomes in AD patients. Show less

Ketamine's ability to lift mood and spur new synapse growth has put glutamate biology at the center of modern neurotherapeutics. Yet the drug's intravenous route, monitoring requirements, and dissociative effects make it a poor candidate for long-term prevention of Alzheimer's disease (AD). This hypothesis article proposes a low-cost oral glutamatergic regimen that targets early synaptic and glutamatergic dysfunction in AD pathogenesis. Here we advance a testable hypothesis: an all-oral "synaptogenic stack" could mimic ketamine's downstream benefits-namely, the rise in brain-derived neurotrophic factor and the activation of mechanistic target of rapamycin (mTOR)-while avoiding its toxicities. The stack combines three inexpensive agents that have decades of human use. First, dextromethorphan, kept in circulation with a small dose of a CYP2D6 inhibitor, provides gentle NMDA antagonism. Second, piracetam acts as a positive modulator of AMPA receptors, boosting fast excitatory transmission. Third, oral L-glutamine replenishes presynaptic glutamate stores and buffers against excitotoxic spill-over. Working in concert, these drugs should reduce extrasynaptic NMDA stress, enhance AMPA throughput, and preserve dendritic spine density in the aging brain. If this mechanism proves sound, the regimen offers a low-cost, scalable way to delay the clinical onset of AD, particularly in people who already show prodromal biomarkers or genetic risk. Prospective trials are needed to evaluate safety, target engagement, and long-term cognitive outcomes. Show less

The persistence of latent HIV-1 reservoirs remains a major barrier to achieving a cure for HIV. While latency-reversing agents (LRAs) have been extensively studied, latency-promoting agents (LPAs) offer a complementary strategy to silence viral transcription and prevent immune activation. Here, we propose that modulation of IRF7-driven transcription may represent a novel approach to control HIV-1 latency, by characterizing the role of the Janus kinase 2 inhibitor (JAK2i) pacritinib as a novel latency-promoting agent (LPA). The impact of JAK2i on HIV-1 reactivation, immune activation, and IRF7 expression were evaluated in lymphoid and myeloid HIV-1 latency models, as well as Pacritinib effectively suppressed HIV-1 latency reversal induced by LRAs without triggering immune activation. Mechanistically, pacritinib downregulated IRF7 expression at both transcript and protein levels, correlating with reduced HIV-1 transcription. Overexpression of IRF7 restored LTR transactivation, confirming its central role in HIV-1 transcription and latency. Co-immunoprecipitation assays revealed a direct interaction between IRF7 and the viral transactivator Tat. Furthermore, pacritinib selectively inhibited multiply spliced HIV-1 transcripts, suggesting a blockade at late transcriptional stages. Pacritinib acts as a potent LPA by silencing HIV-1 transcription through IRF7 downregulation, supporting a promising "block and lock" strategy for functional cure approaches. Targeting IRF7 may enable durable suppression of the viral reservoir without immune activation, supporting the development of "block and lock" therapies. Show less

Fatty acid-binding proteins (FABPs) influence cellular energy metabolism by regulating fatty acid kinetics. They also play a vital role in neuronal apoptosis following cerebral infarction. Resveratrol (RSV) has demonstrated neuroprotective effects in ischemic stroke; however, its regulatory impact on FABPs and associated pathways requires further investigation. This study aimed to explore the potential mechanisms by which RSV protects ischemic stroke neurons by regulating fatty acid metabolism. A weighted gene co-expression network analysis revealed significant enrichment of FABP5 in fatty acid metabolism-related pathways in rats with middle cerebral artery occlusion (MCAO). Modulating FABP5 expression level may influence post-infarction neuronal recovery. Molecular docking experiments demonstrated that RSV exhibited strong binding affinity with FABP5. In the MCAO-group of rats, administering different doses of RSV led to a significant decrease in cerebral infarct area and improved neurological function with increased RSV doses. Concurrently, the expression of FABP5 and neuron-specific enolase in brain tissue decreased, whereas the expression of the brain-derived neurotrophic factor increased and neuronal morphology improved. Further experiments using FABP5 overexpression and inhibition models revealed that FABP5 overexpression exacerbated neuronal apoptosis and suppressed the expression of adenosine monophosphate (AMP)-activated protein kinase (AMPK) protein, whereas FABP5 inhibition reduced neuronal apoptosis and enhanced AMPK protein expression. RSV downregulates FABP5 expression in cerebral infarction tissues and potentially mediates the AMPK-related pathways to ameliorate neuronal apoptosis. Show less

Microglia-neuron contacts have been shown to regulate neural network activity through the formation and elimination of synapses. The pathogenesis of major depressive disorder is accompanied by a decline in brain-derived neurotrophic factor (BDNF) signaling, associated with increased microglia activity that disrupts cognitive function. The actions of both typical and rapid-acting antidepressant drugs, which have been shown to increase BDNF signaling through the tropomyosin receptor kinase B (TrkB) receptor, decrease microglia activation and the levels of pro-inflammatory cytokines. Examining the link between BDNF signaling and the microglial pro-inflammatory response, we demonstrate that TrkB signaling elicits the neuronal secretion of CD22 (Siglec-2), a sialic acid-binding immunoglobulin-type lectin, to inhibit microglial activation and alleviate depression-like symptoms. In a male chronic mild stress (CMS) mouse model of depression decreased expression of the postsynaptic scaffolding protein PSD-95 and Gαi1/3 were found to compromise TrkB signaling leading to reduced CD22 levels in hippocampal tissue. Restoration of TrkB-Gαi1/3-Akt signaling with dSyn3, a peptidomimetic compound targeting the PDZ3 domain of PSD-95, enhanced CD22 expression to inhibit microglial activation, promote dendritic spine formation and rapidly mitigate depression-like symptoms. Furthermore, hippocampal overexpression of CD22 in neurons was sufficient to reduce microglial activation and depressive-like behaviors in male CMS mice. S-ketamine, a rapid-acting antidepressant, increased CD22 expression to mitigate depression-like symptoms. While neuronal knockdown of CD22 in the hippocampus did not significantly impair the rapid (within 4 h) antidepressant effects typically observed with S-ketamine or dSyn3 administration, strikingly, knockdown of CD22 attenuated the long-acting (within 3 days) antidepressant effects of S-ketamine or dSyn3, as evidenced by sustained immobility in the TST (tail suspension test) and FST (forced swim test), and a lack of improvement in sucrose preference. In contrast, a single dose of fluoxetine failed to increase CD22 expression or inhibit microglia activity. These results suggest that rapidly-acting anti-depressant drugs enhance TrkB-induced neuronal expression and secretion of CD22 to promote the homeostatic state of microglia required for antidepressant actions. In male depression mice, dSyn3 facilitates BDNF-induced TrkB-PSD-95-Gαi1/3 complex formation to increase Akt-mTOR activation as well as synaptic and spine density in the hippocampus. TrkB signaling increases CD22 expression and secretion from neurons blocking microglial activation in the hippocampal region of male CMS mice. Show less

Obesity and Alzheimer’s disease (AD) are epidemiologically associated. The locus coeruleus (LC)—the brain’s primary and most significant source of norepinephrine—is one of the earliest sites of neurodegeneration in AD. The LC participates in feeding behavior through connections with the hypothalamus. The cellular composition of the LC has been characterized at single-cell resolution. However, the constituent cellular signatures of genes related to energy homeostasis—such as the melanocortin pathway genes—in the LC are unclear. We performed single-nucleus RNA sequencing and spatial transcriptomics (Visium) in the human LC, and HiPlex RNAscope in the LC of mice. The melanocortin pathway gene The online version contains supplementary material available at 10.1186/s40478-026-02287-x. Show less

Several lines of evidence suggest that genetic factors underlie variability in response to lithium, although pharmacogenetic studies, particularly in African populations, are limited. This study aimed to examine the genetic factors associated with lithium response among Ethiopian patients diagnosed with bipolar disorder (BD). This study was conducted at Amanuel Mental Specialized Hospital (AMSH) in Addis Ababa, Ethiopia, involving 101 patients diagnosed with BD and on lithium therapy for at least six months. Participants were selected from a larger cohort recruited for the Neuropsychiatric Genetics of African Populations - Psychosis, Ethiopia (NeuroGAP-P-E) project. The study investigated the association between lithium response and genetic polymorphisms of 22 genes with 53 SNPs implicated in lithium's mechanisms of action. Clinical response to lithium was assessed using the Alda scale, where those with total Alda > 7 were categorized as good responders (GR) and those with Alda < 7 as insufficient responders (IR). Genotyping was performed using PCR-free whole-genome sequencing. Among the participants, 32.5% were classified as GR, while 67.5% were IR. Significant associations were identified between lithium's response and specific SNPs. Notably, the BDNF rs6265 variant (Val166Met) showed stronger correlation, with the CC genotype being more frequent (p = 0.0001) in IR, while the rs2030324 A allele and AA genotype were more frequent in GR (p < 0.05). Variants in GSK-3β (rs334558) and dopamine receptor genes, such as DRD1 (rs4532) and DRD2 (rs1800497) also demonstrated significant associations with treatment outcomes (p < 0.05). However, after adjustment for multiple testing using false discovery rate (FDR), only polymorphisms within BDNF and DRD1 remain statistically significant. Multivariable analysis revealed that whilst AKT1_rs10138227 TT (p < 0.05) genotypes were positive predictors, BDNF_rs962339 GG, DRD2_rs1800497 AG/GG and GSK-3β_rs334558 AG were negative predictors of good response. The data collectively show that variants in BDNF, dopamine receptor genes, and the AKT1/GSK3B pathway were linked to lithium's response in BD. AKT1 rs10138227 TT genotypes predicted better response, while BDNF rs962339 GG, DRD2 rs1800497 AG/GG, and GSK-3β rs334558 AG were associated with poor outcomes. These findings highlight the role of genetic variations in predicting lithium's response. Show less

Familial lipoprotein lipase (LPL) deficiency typically occurs during childhood and is characterized by severe hypertriglyceridemia, accompanied by episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. The clearance of chylomicrons from plasma is impaired, causing triglyceride accumulation and giving the plasma a milky/lactescent/lipemic appearance. Symptoms typically resolve when total dietary fat is restricted to 20 g/d. Acute management focuses on maintaining triglyceride levels using insulin, plasmapheresis, blood exchange transfusion, and heparin, although few of these interventions have proven effective in infants. Here, we report a rare case of severe hypertriglyceridemia in a 40-d-old infant who presented with respiratory distress, xanthoma, hepatosplenomegaly, and lipemic samples. Plasmapheresis resulted in a reduction in triglyceride levels and clinical improvement, and further evaluation confirmed a diagnosis of LPL deficiency. Familial LPL deficiency can occur during early infancy, with life-threatening complications. A consensus on the acute management of hypertriglyceridemia in the pediatric population needs to be meticulously established after exploring possible treatment strategies, including plasmapheresis. Show less

Anorexia nervosa (AN) is a complex psychiatric disorder with both psychiatric and metabolic underpinnings. This study aims to explore the genetic architecture of AN and the interplay between its psychiatric and metabolic components. Through a meta-analysis of AN GWAS data from European and Finnish populations, we identified a novel genome-wide significant locus near the SOX5 gene. Genetic correlation and Mendelian randomization analyses revealed shared and potentially causal relationships between AN and multiple psychiatric and metabolic traits. Local genetic correlation analysis identified 185 significant genomic regions contributing to shared heritability between AN and correlated phenotypes, with 100 loci demonstrating pleiotropic effects across multiple traits. The MTAG analyses identified 86 significant loci (34 overlapping with local genetic correlation results), including 25 novel loci such as brain-relevant VAMP2 (17p13.1) and metabolic-neurological hubs LPL (8p21.3) and BDNF (11p14.1). Gene Co-expression Network Analysis (WGCNA) further identified key gene modules associated with both metabolic and neurological pathways, particularly highlighting synaptic signaling and lipid metabolism. Single-cell transcriptomic analysis further resolved this genetic risk to the cellular level, confirming its concentration in limbic and striatal GABAergic neurons and extending the implicated circuitry to include cortical regions involved in motor function. These findings collectively demonstrate the intricate genetic interplay between psychiatric and metabolic pathways in AN, underscoring the necessity of an integrated approach to understanding its pathogenesis. Show less

Neurodegenerative and mental disorders impose significant global disease burdens and pose serious social and economic challenges. Physical exercise (PE) exerts beneficial effects on brain health, contributing to a reduction in the risk of Alzheimer's disease (AD), Parkinson's disease (PD), depression, anxiety, and post-traumatic stress disorder (PTSD). To understand these effects of PE, a variety of molecules released from various tissues in response to PE have been discovered, which are collectively called 'exerkines'. In particular, the skeletal muscle acts as an endocrine organ, secreting exerkines and is included in the category of myokines that facilitate direct or indirect crosstalk between the muscle and the brain. Although muscles actively interact with organs such as the liver, pancreas, and adipose tissue, the precise mechanisms of muscle-brain communication have yet to be fully elucidated. In the skeletal muscle, the types of exerkines secreted and their effects vary depending on the PE modality. Furthermore, these exerkines can cross the blood-brain barrier (BBB) to exert direct effects or act indirectly Show less

Frailty is associated with increased risks of falls, disability, hospitalization, and mortality. The 24-h movement behaviors (24HMB) framework conceptualizes sleep, sedentary behavior (SB), light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) as mutually constrained components of daily time use and may inform frailty prevention and management. This scoping review maps evidence on associations between 24HMB and frailty and identifies methodological gaps to inform future research and nursing practice. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and follows Joanna Briggs Institute (JBI) guidance. We searched PubMed, Embase, CINAHL, and Web of Science. We included observational studies of adults aged ≥18 years. Exposures were objectively measured or validated self-reported sleep, SB, LPA, and MVPA, including step counts, breaks in SB, isotemporal substitution models (ISM), and compositional data analysis (CoDA). Outcomes were frailty or prefrailty assessed using validated instruments. Quality was appraised with JBI tools. Thirty-three studies showed good methodological quality. Longer SB, particularly prolonged, uninterrupted bouts, was associated with higher frailty. Greater MVPA was consistently associated with lower frailty. Light-intensity physical activity was generally beneficial but often attenuated when MVPA or total activity volume was modeled. Sleep fragmentation and poor sleep quality were associated with frailty. Isotemporal substitution models and compositional data analysis indicated that reallocating sedentary time to MVPA would yield the largest theoretical benefit, followed by reallocating to LPA. Higher daily step counts and more frequent or higher-intensity breaks in SB were associated with lower frailty. Evidence supports a 24-h integrated movement-behavior approach centered on MVPA, combined with reducing prolonged SB and improving sleep quality, for the prevention and nursing management of frailty. The study design and analytical protocol were prospectively registered on the Open Science Framework (OSF). The unique identifier is S39Y4, and the publicly accessible URL is https://doi.org/10.17605/OSF.IO/S39Y4. Show less

This study investigates the independent and interactive effects of apolipoprotein E (APOE) genotypes and white matter hyperintensities (WMH) on distinct neuropsychiatric symptom (NPS) phenotypes in patients with Alzheimer's disease (AD). We enrolled 325 AD patients consecutively diagnosed at a specialized memory clinic between May 2024 and May 2025. All participants underwent comprehensive clinical assessments-including the Chinese Mini-Mental State Examination (CMMSE), Activities of Daily Living (ADL) scale, and the Neuropsychiatric Inventory (NPI)-as well as 3T brain MRI for WMH quantification and APOE genotyping. First, we compared NPS profiles and cognitive/functional scores across APOE genotype groups (ϵ2/ϵ2-ϵ2/ϵ3, ϵ3/ϵ3, ϵ3/ϵ4, ϵ4/ϵ4) using analysis of variance (ANOVA) or Kruskal-Wallis tests, as appropriate. Second, we applied mediation analysis (PROCESS macro Model 4, 5,000 bootstrap samples) to examine whether WMH burden mediates the association between APOE genotype (X) and outcomes including CMMSE total score and domain-specific NPS subscores (delusions, agitation, irritability, euphoria). Significant differences emerged across APOE genotypes in both cognition (CMMSE, p < 0.05) and functional status (ADL, p < 0.05). At the symptom level, carriers of at least one ϵ4 allele exhibited higher agitation scores than non-carriers (p < 0.05); notably, the ϵ4/ϵ4 homozygotes showed significantly greater severity in delusions, agitation, irritability, and euphoria compared with all other genotype groups (all p < 0.05). Mediation analyses revealed no statistically significant indirect effect of APOE genotype on any outcome via WMH, indicating that WMH does not mediate these associations. Instead, APOE genotype exerted robust direct effects on both cognitive performance and specific NPS domains. APOE genotype-particularly the ϵ4/ϵ4 homozygous status-is associated with more pronounced cognitive decline and a distinct, severe NPS profile in AD, especially involving delusions, agitation, Euphoria, and irritability. These associations are independent of WMH burden, suggesting that APOE exerts direct neurobiological effects on neuropsychiatric manifestations. Thus, APOE genotyping holds dual clinical value: not only as a well-established biomarker for AD risk and diagnosis but also as a potential prognostic indicator for behavioral and psychological symptoms-offering actionable insights beyond conventional neuroimaging markers. Show less

High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallmark of HNSCC is the rapid growth of its vasculature. Here, we identify an epigenetic mechanism whereby HMGA1 promotes tumor progression and angiogenesis via upregulation of fibroblast growth factor-binding protein 1 (FGFBP1). Show less

Orthodontic tooth movement (OTM) is a biomechanically driven process governed by dynamic cellular and molecular signaling interactions between neural and skeletal systems. This review synthesizes current evidence on neuron-bone cell crosstalk and the coordinated involvement of immune and vascular components in regulating alveolar bone remodeling during OTM. Key neural contributors include sensory neurons (nociceptors), autonomic neurons, central nervous system (CNS) circuits, and Schwann cells, which communicate with osteoblasts, osteoclasts, and periodontal ligament cells to modulate their proliferation, differentiation, and functional activity. These interactions are mediated by defined signaling pathways, including neuropeptide signaling (CGRP-CLR, SP-NK1, NGF-TrkA, BDNF-TrkB), axon guidance signaling (Sema3A-PlexinA/Nrp1), adrenergic signaling (β2-AR-dependent pathways), and intracellular cascades such as Rac1-β-catenin, RhoA/ROCK2, and Notch3. Sensory nerves function as primary initiators by releasing neuropeptides that promote osteoclastogenesis in pressure zones and osteogenesis in tension zones, while simultaneously shaping local immune responses and vascular remodeling. The autonomic nervous system exerts context-dependent regulation, with sympathetic signaling favoring bone resorption and parasympathetic pathways emerging as modulators of osteogenesis and neurovascular homeostasis. CNS circuits integrate sensory and autonomic inputs to coordinate OTM kinetics and pain perception. Together, these neuro-osteogenic signaling networks define mechanistic targets for improving orthodontic outcomes and pain management via neuromodulation. Show less

Post-stroke depression (PSD) is a common neuropsychiatric complication affecting 30-50% of stroke survivors, impairing rehabilitation, quality of life, and prognosis. This narrative review synthesizes recent evidence on PSD pathogenesis (neurotransmitter dysregulation, neuroinflammation, impaired neuroplasticity; psychosocial factors such as stress and social support deficits; gene-environment interactions including 5-HTT and BDNF polymorphisms), clinical interventions (pharmacotherapy with SSRIs/SNRIs, psychotherapy including CBT, neuromodulation via rTMS/tDCS/ECT, novel agents such as ketamine, and multidisciplinary models), and prevention (risk stratification, early screening with PHQ-9/HAMD, personalized biological/psychosocial strategies, and digital monitoring). Despite gaps in long-term data and validated biomarkers, multidisciplinary integrated care and precision medicine approaches offer promising avenues to optimize screening, early intervention, prevention, and long-term outcomes for stroke survivors. Show less

Neuropathic pain (NP) frequently co-occurs with depression (DP), exhibiting complex pathogenesis and limited clinical treatment options. This study aims to investigate the efficacy of Eupalinolide B (EB) in alleviating NP co-occurring with DP and its potential molecular mechanisms. Combining network pharmacology, molecular docking, and molecular dynamics simulations to screen potential targets for EB, validated through transcriptomic data. Using a sciatic nerve branch-preserving injury (SNI) mouse model, we assessed pain and depression-like behaviors through von Frey testing, hot plate testing, tail suspension testing, forced swimming testing, and open field testing. Concurrently, Western blotting, immunofluorescence, and Nissl staining were employed to analyze relevant molecules and neuropathological alterations. Network pharmacology and bioinformatics analysis identified EGFR, PTGS2, and JUN as the key targets for EB in treating NP combined with DP. Behavioral studies showed that 20 mg/kg of EB significantly alleviated pain in SNI mice and improved depressive-like behaviors. Mechanism research indicated that EB downregulated the expression of EGFR and PTGS2, inhibited the activation of microglia and astrocytes, and reduced neuronal damage. Additionally, EB could upregulate the expression of synaptic proteins (PSD95, SYN1, and BDNF) in the hippocampus. EB alleviates neuroinflammation by reducing EGFR and PTGS2 protein expression, modulates synaptic plasticity, and improves pain-depression comorbidity. EB may represent a promising therapeutic approach for pain-related depression. Show less