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The benefits of physical activity are well-documented, and healthy habits established in childhood often continue into adulthood. Recent research has shown that schoolyards provide a valuable platform for children to be physically active, with greener spaces in particular enhancing both physical and mental well-being. The City of Stockholm has formally decided to reconstruct 20 schoolyards, incorporating more play areas and greenery. This study will evaluate the impact of these reconstructions, aiming to increase physical activity levels among schoolchildren across all socioeconomic groups, while also contributing to climate change mitigation in urban environments. This study will utilize a stepped-wedge design, where each school undergoing schoolyard reconstruction will serve as both a control and intervention site. Over four years, from 2024 to 2027, five schools will have their schoolyards reconstructed each summer. Control data will be collected in the spring prior to the reconstruction, with follow-up data collected in the spring after the reconstruction. We aim to recruit 3 600 children aged 6 to 12 years. The primary outcome will be changes in physical activity, measured via accelerometers. Secondary outcomes will include changes in musculoskeletal fitness, perceptions of the schoolyard, and environmental impact. Given the 24-hour constraint of daily time, movement behaviors (e.g., MVPA, LPA, SB, and sleep) will be treated as compositional data. Log-ratio transformation will be applied and introduced as outcomes in general linear mixed models, with schools treated as random effects. This large-scale study has the potential to set new guidelines for physical health policies in schools across the City of Stockholm, potentially influencing the well-being of an even greater number of children. Additionally, the study could provide valuable insights into strategies for mitigating climate change through urban design, offering a model for sustainable school environments that promote both health and environmental resilience. The trial has been registered on ClinicalTrials.gov the 19th of May 2023, with the reference number NCT05865782. The online version contains supplementary material available at 10.1186/s12889-026-26609-9. Show less

Memantine (Mem), an uncompetitive antagonist of the N-methyl-D-aspartate receptor (NMDAr), has demonstrated neuroprotective effects in preclinical stroke models by reducing excitotoxic damage. However, the efficacy of low acute doses administered during the immediate post-ischemic phase remains insufficiently characterized. Male rats underwent permanent middle cerebral artery occlusion (pMCAO) and received a single intraperitoneal dose of Mem (5 mg/kg) two hours post-occlusion. Neurological deficits were assessed using the modified Neurological Severity Score (mNSS). Infarct area and neuronal preservation were quantified using MAP2 immunohistochemistry. BDNF and PSD95 protein levels were measured by ELISA, and their gene expression was evaluated via RT-PCR. Mem treatment significantly reduced infarct area (p = 0.000029) and attenuated neurological deficits (p < 0.0001). MAP2 immunoreactivity was higher in the Mem-treated group (p = 0.000003), indicating preservation of neuronal structure. BDNF protein levels did not differ between the pMCAO and pMCAO+Mem groups; PSD95 protein and its corresponding DLG4 mRNA were increased in the pMCAO group compared with Sham. In the other groups, levels remained unchanged. Early administration of low-dose memantine confers acute neuroprotection after stroke by reducing tissue damage and preserving neuronal integrity, without affecting ischemia-induced BDNF and PSD95 protein and gene expression. These findings suggest a selective early neuroprotective mechanism and highlight the need for long-term and sex-inclusive studies to further evaluate memantine's therapeutic potential. Show less

Interleukin 4 (IL-4)-mediated apoptosis is involved in the pathogenesis of atherosclerosis both through efferocytosis overload and direct cellular signalling pathways. This study explored the mechanism of dehydrocorydaline (DHC), a potential therapeutic agent for atherosclerosis derived from Corydalis yanhusuo. An experimental model of atherosclerosis was established in high-fat diet-induced ApoE Show less

Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by repetitive behaviors, social deficits, and comorbid phenotypes, with rising prevalence. Its unclear pathogenesis and symptom heterogeneity hinder therapy development. Chrysin, a flavone from bee products and plants, shows diverse biological effects but limited ASD studies. Therefore, this study examines chrysin's impact on ASD behaviors and comorbidities. Pregnant Wistar rats received 600 mg/kg valproic acid (VPA) on Embryonic day (ED) 12.5 intraperitoneally to induce ASD phenotypes. Neurodevelopmental milestones were evaluated on postnatal day (PND) 3-20. Twenty-seven male offspring were used for the study. The control (n = 9 ), the VPA-exposed offspring were randomly divided into two groups: a VPA + vehicle group (n = 9) and a VPA + chrysin treatment group (n = 9). The animals received distilled water or chrysin (100 mg/kg p.o) from PND21-42. Typical and atypical baseline behaviours were done on PND21 and repeated on PND42. Serum corticosterone, prefrontal cortex (pFC), and hippocampal (HPC) neurotransmitters, Histone deacetylase (HDAC), BDNF, and caspase-3 were evaluated with ELISA, while Shank3, p-AKT, and pS6 were evaluated with immunohistochemistry and Western blot. Data were analysed using One-way or Two-way ANOVA at α < 0.05. The VPA-exposed pups exhibit signs of developmental delay compared to the controls. Chrysin also ameliorated hyperalgesia (2.659 ± 0.2628vs4.257 ± 0.3272), depressive-like behaviour (68.86 ± 3.912vs138.5 ± 9.526), and anxiety (189.6 ± 20.58vs95.10 ± 7.716). Autistic-like, sociability (0.46 ± 0.039vs0.28 ± 0.06), and social novelty (0.77 ± 0.08vs-0.28 ± 0.19) were improved by Chrysin. Chrysin increased the level of serum corticosterone (22.45 ± 1.77vs13.90 ± 0.49) when compared to VPA-only. In the prefrontal cortex and hippocampus, the levels of serotonin, GABA, and dopamine increased, while glutamate levels decreased. The levels of HDAC (1.28 ± 0.12vs2.56 ± 0.10; 1.22 ± 0.11vs1.35 ± 0.18), and Caspase3 (10.33 ± 0.72vs16.79 ± 0.85; 4.50 ± 0.53vs6.45 ± 0.78) were reduced compared to VPA-only, while increasing the levels of BDNF (21.25 ± 0.63vs14.73 ± 0.57; 17.86 ± 1.23vs7.39 ± 0.56). Chrysin increased the expression of SHANK3(1.43 ± 0.1311vs0.6588 ± 0.02533; 0.8895 ± 0.1092 vs. 0.1961 ± 0.1401), p-AKT (0.8923 ± 0.04518vs0.2493 ± 0.03399; 1.011 ± 0.09692vs0.4969 ± 0.08145), and pS6 in the pFC and HPC. Chrysin may have ameliorated valproic acid-induced Autistic-like behaviours by upregulating epigenetic and translational control of scaffolding protein synthesis, and preserving neurotrophic signalling, in male Wistar rats exposed to VPA in utero. Show less

Microglia are the brain's resident immune cells that respond to injury and disease by transitioning between homeostatic and reactive states. These cell state transitions determine whether microglia promote or resolve inflammation in the central nervous system (CNS). In this study, we explored the role of Ca Show less

Our understanding of the intrinsic mechanisms that drive the regeneration of damaged axons after a spinal cord injury is still limited. Microtubules are core components of the eukaryotic cytoskeleton and are essential for axonal growth, in part because their stability is governed by post-translational modifications in mature neurons. Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are expressed in multiple extra-pancreatic tissues, suggesting biological functions beyond classical endocrine signaling; however, their roles in neuronal cytoskeletal regulation are not well defined. Here, we investigated the effects of GIP in cultured cortical neurons. GIP enhanced microtubule stability and increased the number of axons crossing an inhibitory chondroitin sulfate proteoglycan (CSPG) border. Mechanistically, GIP promoted microtubule acetylation via α-tubulin N-acetyltransferase 1 (αTAT1), the major acetyltransferase for α-tubulin, by suppressing αTAT1 ubiquitination and thereby reducing its proteasomal degradation in inhibitory environments. Although the upstream mechanism remains to be determined, this study provides the first evidence that GIP/GIPR signaling modulates microtubule dynamics, highlighting a potential strategy to re-activate neuronal growth machinery after injury. Show less

Gastrointestinal (GI) motility is controlled by the coordinated activity of enteric neurons, glial cells, and resident muscularis macrophages (mMφs). Apolipoprotein E (ApoE) is highly expressed in mMφs, but its functional role in the gut remains unclear. We hypothesized that mMφ-derived ApoE regulates intestinal motility under physiological and stress conditions. Global ApoE knockout mice, bone marrow chimeras, and macrophage-specific ApoE-deficient mice were used to assess the impact of ApoE loss on gut transit, immune response, and neuromuscular integrity in both homeostatic and postoperative ileus (POI) settings. (1) Single-cell RNA sequencing revealed that muscularis macrophages highly express ApoE, with further upregulation after intestinal manipulation. (2) Bone marrow chimera experiments showed that hematopoietic-derived ApoE only partially contribute to the maintenance of gut motility. (3) Global ApoE deficiency led to mild impairment of intestinal transit and increased glial activation, accompanied by an expansion of the macrophage population and elevated gene expression of inflammatory cytokines. (4) Macrophage-specific deletion of ApoE did not affect gastrointestinal transit or tissue morphology under normal conditions. Although highly expressed and dynamically regulated in muscularis macrophages, ApoE is largely dispensable for intestinal neuromuscular function at baseline and during postoperative ileus. Show less

Cardiovascular disease is a major cause of human morbidity and mortality. Drug strategies for the prevention of the disease are largely centered on the interaction of low-density lipoprotein receptor (LDLR) with the apolipoprotein B-100 (apoB-100) protein on low-density lipoprotein (LDL). Recently, the structure of apoB-100 on LDL was determined in the absence and presence of LDLR, using cryo-electron microscopy. A remarkable structural feature of apoB-100 is the lack of any significant tertiary structure within the C-terminal two-thirds of the protein (>3000 residues). Instead, apoB-100 forms amphipathic helices and β-sheets on the phospholipid surface of LDL, which envelops its neutral lipid core. The apoB-100 ligand binding domain for LDLR includes multiple points on a circumferential β-belt and on the N terminus. In the course of this study, we also observed several instances of structural heterogeneity in apoB-100. The various conformations may allow apoB-100 to accommodate different size lipoprotein particles and to permit recognition by other apolipoproteins or receptors. Show less

Methotrexate (MTX) is used in treating several malignancies. However, MTX neurotoxicity remains a significant clinical side effect, leading to cell division malformation, and neurogenesis impairment. Chrysin, a flavonoid compound found in natural products, demonstrates various biological characteristics, including neuroprotective and antioxidant properties. The purpose of this study was to investigate the ameliorative effect of chrysin on oxidative damage and neurogenesis impairment caused by MTX. Male Sprague-Dawley rats were randomly divided into four groups, including the vehicle, MTX (75 mg/kg), chrysin (10 mg/kg), and chrysin+MTX groups. Chrysin was orally administered for 15 days. MTX was administered intravenously on days 8 and 15. The hippocampal neural stem cells were evaluated using sex determining region Y-box 2 (sox2) and nestin immunofluorescence staining. Antioxidant enzyme expression and the levels of oxidative stress marker were assessed. Additionally, the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), brain-derived neurotrophic factor (BDNF), cAMP-response element binding (CREB), and phosphorylated CREB (pCREB) were evaluated using Western blotting. Results showed that MTX significantly decreased the activity of antioxidant enzymes and produced oxidative stress. MTX also impaired neurogenesis, evidenced by decreased sox2 and nestin-positive cells and decreased expression of Nrf2, BDNF, CREB, and pCREB in the hippocampus and prefrontal cortex. However, chrysin significantly reversed the effects of MTX on these parameters. In conclusion, chrysin exhibits neuroprotective effects against MTX-induced neurogenesis impairment by upregulating antioxidant enzyme activity, reducing oxidative stress, and improving protein expression related to neurogenesis. Show less

Capacities for giving compassion to others, being open to others' compassion, and self-compassion are not always balanced for everyone. Identifying unique compassion profiles provides a holistic understanding of how the balance or imbalance among different facets of compassion relates to psychopathology and well-being. Using latent profile analysis (LPA) with U.S. college students ( Show less

Despite significant advances in lipid-lowering therapeutics, residual lipid risk persists in patients with or at risk of atherosclerotic cardiovascular disease (ASCVD), even after optimizing low-density lipoprotein (LDL) cholesterol. Emerging evidence highlights the role of non-LDL cholesterol fractions, such as remnant cholesterol, lipoprotein(a) [Lp(a)], apolipoprotein B (apoB), and non-high-density lipoprotein (HDL) cholesterol, as key contributors to residual ASCVD risk. Remnant cholesterol, Lp(a), and LDL cholesterol represent three independent lipoprotein species causing ASCVD, while apolipoprotein B (apoB) and non-HDL cholesterol integrate the other three variables. Thus, clinically interpreting elevated apoB and non-HDL cholesterol is potentially complicated since remnants, Lp(a), and LDL cause ASCVD by different mechanisms and by varying proportions in different patients. Indeed, recent research into the pathophysiology of lipid-driven atherogenesis and development of ASCVD has revealed novel mechanisms that in turn suggest new therapeutic strategies targeting non-LDL lipid components. Elevated remnant cholesterol jointly with elevated LDL cholesterol contributes to arterial wall cholesterol deposition, plaque development, and ASCVD endpoints. Furthermore, the additional triglyceride content in remnant particles may theoretically promote intimal inflammation and possibly plaque rupture and erosion, independently contributing to atherogenesis and ASCVD. The lipid component and pro-inflammatory properties of Lp(a) could similarly contribute directly to atherosclerotic plaque development and ASCVD. In addition, the homology with plasminogen of the defining apolipoprotein(a) moiety of Lp(a) has long been speculated to confer anti-fibrinolytic and pro-thrombotic properties that could produce more severe ASCVD outcomes independent of atherogenesis. This review explores the evolving understanding of residual lipid risk in ASCVD, practical guidance for clinicians today, recent advances in therapeutic interventions, and their implications for clinical practice, aiming to optimize lipid management beyond LDL cholesterol reduction today and in the future. Show less

Coronary heart disease (CHD) remains a leading cause of cardiovascular morbidity and mortality worldwide, posing a global health threat. In recent years, angiotensin-like proteins (ANGPTLs) have emerged as a research focus in CHD due to their critical role in regulating lipid metabolism and inflammation. ANGPTLs are a class of secreted glycoproteins that primarily regulate lipid metabolism by influencing lipoprotein lipase activity. Dysfunction of these proteins leads to dyslipidemia, thereby promoting the formation of atherosclerotic plaques. Additionally, ANGPTLs act as pro-inflammatory factors, accelerating the development of endotheliitis. Current ANGPTL-targeted therapeutic strategies (monoclonal antibodies, small interfering RNA) have advanced to clinical trial stages, demonstrating favorable safety, tolerability, and lipid-lowering effects in humans. These approaches hold promise as novel preventive and therapeutic measures for CHD. This paper aims to elucidate the multifaceted role of ANGPTLs in CHD, summarize existing drug research, and outline future research directions, emphasizing the broad prospects of ANGPTL-targeted therapies in CHD prevention and treatment. Show less

Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantation evaluations of small-diameter vascular grafts is predominantly based on healthy animal models. However, the majority of patients who undergo vascular transplantation are afflicted with vascular diseases, such as hyperlipidaemia or atherosclerosis. In this study, we constructed an ApoE gene knockout atherosclerotic mouse model and investigated the patency and regenerative performance of small-diameter vascular grafts in a diseased environment. We prepared heparinized Poly (ε-caprolactone) (PCL) vascular grafts (PCL-Hep) using electrospinning technology. By taking advantage of the physical adsorption of heparin, rapamycin (RM) was loaded onto the surface of grafts to obtain PCL-Hep-RM vascular grafts, which exhibited exceptional mechanical properties and drug sustained-release characteristics. Subsequently, the PCL-Hep-RM vascular grafts were implanted into the carotid arteries of atherosclerotic mice. The results demonstrated that PCL-Hep-RM significantly enhanced the patency rate and suppressed intimal hyperplasia in comparison with the PCL control group. This study offers novel concepts and methodologies for addressing challenges such as the low long-term patency rate and luminal stenosis of vascular grafts in a diseased environment, thereby promoting the translational medicine research of small-diameter vascular grafts. Show less

Most genomic studies compare the genomes of long-living adults to those of the general population to identify potential genetic markers of longevity. We propose a refined approach: focusing on the genetic makeup of healthy, long-living adults to detect mechanisms promoting both longer lifespan and improved quality of life. To this end, we analyzed medical and genomic data from 3,703 long-living adults aged ≥90 years and 22,354 individuals aged 18-75 years (total N = 26,057). Using whole-genome sequencing (WGS) and a genome-wide association study (GWAS), we found that variants with significant and negative associations with longevity in the GWAS were located in genes such as APOE, APOC1, and CFAP46, which are implicated in an increased risk of age-related diseases. However, the presence or absence of these variants should not be considered a definitive determinant of longevity or sustained health after the age of 90. We found that healthy longevity was positively associated with variants within the MYO18B, TBC1D28, and LOC105376454 genes. To demonstrate the multifactorial nature of the examined phenotypes, we constructed polygenic score models that accounted for nonlinear interactions among the predictors. Trial registration: Clinical Trials NCT06268132 (for long-living adults). Registered 22 February 2024 (retrospectively registered). Show less

Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the "trial and error" approach in choosing the most effective antidepressant treatment for each patient allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, cross the blood-brain-barrier, and be highly sensitive to changes in both synaptic activity and neuronal receptor signaling. Here we present evidence that expression of the brain-enriched circRNA, CDR1as, is associated with symptomatic response to SSRI treatment, and regulated by serotonin and Brain-Derived Neurotrophic Factor (BDNF) receptor activity. We present data using circRNA-specific PCR in baseline whole blood samples from two independent cohorts, drawn from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) and the Biomarkers of ANTidepressant RESponse (ANTARES) clinical studies, showing that before treatment CDR1as is differentially expressed between future symptomatic responders and non-responders to treatment with the SSRI sertraline. Additional data from naturalistic antidepressant response studies further highlight the association between CDR1as and antidepressant effects of SSRIs as a class. In addition, we show that CDR1as levels are altered following sertraline treatment in responders with the trajectory of change post-treatment associated with long-term remission. Furthermore, we report that levels of CDR1as in the blood can specifically predict remission with SSRI treatment, but not response/remission with Placebo or Bupropion treatments. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting mouse Cdr1as is strongly regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment. Show less

The neurovascular unit (NVU) represents a multicellular functional ensemble pivotal to the preservation of cerebral homeostasis, encompassing endothelial cells, pericytes, glial cells (astrocytes, microglia, oligodendrocytes), and neurons. This complex orchestrates the regulation of blood-brain barrier (BBB) integrity, cerebral blood flow (CBF), and the metabolic microenvironment requisite for neuronal viability and functional competence. Accumulating lines of evidence have underscored that NVU dysfunction constitutes a critical early pathological event in neurodegenerative disorders, including Alzheimer's disease (AD) and vascular dementia (VaD). The present review summarizes the structural composition and core physiological functionalities of the NVU, with particular emphasis on the emerging role of lipid metabolism dysregulation in mediating NVU impairment-an aberrant process encompassing lipid droplets, apolipoprotein E (APOE), ATPase phospholipid transporting 11B (ATP11B), triggering receptor expressed on myeloid cells 2 (TREM2), and ATP-binding cassette (ABC) transporters. We further delineate the mechanisms by which disrupted lipid homeostasis elicits neuroinflammation, amplifies oxidative stress, impairs amyloid-β (Aβ) clearance, and precipitates BBB breakdown, ultimately culminating in cognitive decline. Simultaneously, this review examines controversies within the field, such as the specific role of apolipoprotein E ε4 allele (APOE4) in disease and highlights the significant pathophysiological differences between preclinical animal models and human diseases. Therapeutic strategies targeting lipid metabolism or the blood-brain barrier still face considerable challenges in clinical translation. Meanwhile, emerging tools such as lipidomics contribute to systematically analyzing the associated dysregulated lipid networks, thereby aiding in the identification of novel therapeutic targets. Show less

This study aimed to investigate the effects of L-borneol on the molecular, biochemical, and histological damage caused by acrylamide (ACR) in the hippocampus of adult male Wistar rats. It also examined the impact of L-borneol on spatial memory and anxiety-like behaviors in these animals. Animals were divided into four groups: control, L-borneol, ACR, and ACR + L-borneol. ACR (25 mg/kg) and L-borneol (50 mg/kg) were administered orally for 21 consecutive days. L-borneol reduced levels of malondialdehyde and nitric oxide, increased glutathione content, and enhanced superoxide dismutase activity in the hippocampus of rats treated with ACR. In addition, L-borneol lowered the expression of pro-inflammatory markers, nuclear factor-κB, and inducible nitric oxide synthase in the hippocampus. It effectively prevented changes in the expression of apoptosis-related genes, which are associated with decreased neuronal death in the cornus ammonis 1 and dentate gyrus regions. Moreover, L-borneol increased the expression of sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), brain-derived neurotrophic factor, and alpha 7-nicotinic acetylcholine receptors, while reducing the expression and activity of acetylcholinesterase. Finally, L-borneol improved spatial memory and reduced anxiety-like behaviors. In conclusion, L-borneol enhances behavioral performance in ACR-exposed animals by decreasing oxidative and nitrosative stress, as well as inhibiting inflammation and apoptosis. It appears that the upregulation of the SIRT1/Nrf2/HO-1 signaling pathway and the stimulation of acetylcholine signaling are crucial for mitigating ACR-induced neurotoxicity. Show less

Cholesteryl ester transfer protein (CETP) plays a central role in plasma lipid transport, facilitating the exchange of neutral lipids, such as cholesteryl esters and triglycerides, between lipoproteins. Despite the existence of several lipid-carrying/binding proteins in the family, such as lipopolysaccharide-binding protein (LBP), bacterial permeability increasing protein (BPI), and phospholipid transfer protein (PLTP), the structural and mechanistic uniqueness of CETP in neutral lipid transfer remains underexplored. Moreover, the involvement of PLTP in neutral lipid transfer is still debated, with researchers presenting conflicting mechanisms. Therefore, this study investigates the distinct structural ability of CETP in mediating neutral lipid exchange compared to other lipid-binding proteins. The study also emphasizes that simple protein modeling based on templates may not guarantee structural integrity unless validated through simulations. To achieve our objectives, we employed molecular docking, comparative molecular dynamics simulations, structural analysis, and lipid-protein interaction profiling with representative neutral lipids. In addition, protein-lipid affinities, tunnel architecture, and conformational flexibility were examined to characterize CETP's unique features and evaluate the quality of the constructed model for PLTP. The results demonstrated that a tunnel-like hydrophobic channel in CETP facilitates bidirectional neutral lipid transfer, unlike the compartmentalized binding pockets observed in other proteins. In addition, the neutral lipids' unfavorable conformational orientation was not affected in PLTP, whereas the same unfavorable conformation is changed to a favorable conformation in CETP, making only the lipid-carrying protein have the ability to transfer the neutral lipids. In conclusion, our findings highlight that the CETP is a specialized neutral lipid carrier with a unique structural mechanism distinct from typical lipid-binding proteins. This comparative insight enhances understanding of the structural plasticity of each lipid-carrying protein and the reliability of the modeled structure. Show less

Cerebrospinal fluid (CSF) proteomics offers insights into molecular changes in aging and Alzheimer's disease (AD). Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with Show less

Oxidative stress-induced enteric neuropathy is a key driver of slow-transit constipation (STC), primarily through disrupted mitochondrial dynamics and neuronal degeneration. To address this, we developed a bioengineered oral delivery system that supports neuronal recovery and actively enhances mitochondrial membrane fusion. A self-assembling amphiphilic peptide (GFF) was synthesized to encapsulate rhein (RH), a natural anthraquinone with antioxidant, anti-inflammatory, and microbiota-regulating properties. A BDNF-derived tetrapeptide was integrated to further potentiate neurotrophic effects. These components were co-assembled into a therapeutic nanofiber (RFI), which was embedded in a chitosan/sodium alginate hydrogel for sustained oral delivery. In vitro and in vivo studies demonstrated that RFI significantly improved neuronal viability and gastrointestinal motility. Mechanistic investigations revealed that RFI is associated with activation of the AKT signaling pathway and enhancement of mitochondrial membrane fusion, collectively contributing to the restoration of mitochondrial network integrity and neuronal protection. This multifunctional nanoplatform offers a promising therapeutic approach to STC by combining targeted delivery with direct modulation of mitochondrial function. Show less

Women show higher levels of Alzheimer's disease (AD) pathology than men, but the implications for cognitive decline remain unclear. Determining the extent to which tau burden differentially accelerates cognitive decline in men and women will provide critical insights into sex-specific pathways of disease progression. We leveraged tau positron emission tomography (PET), amyloid beta (Aβ) PET, apolipoprotein E (APOE) ε4 genotyping, and longitudinal cognitive data over approximately 8.6 (standard deviation [SD] = 3.8) years from 1007 cognitively unimpaired adults across three cohorts. Cognitive trajectories were modeled with linear mixed-effects regression including sex × tau × time interactions, and results were synthesized using random-effects meta-analysis. Higher tau burden in medial and lateral temporal regions was associated with faster cognitive decline in women than in men. High tau burden carries a disproportionately greater cognitive cost for women, underscoring the need for sex-specific approaches to early detection and therapeutic intervention in AD. A meta-analysis across three independent cohorts shows that female cognitive advantage at low tau shifts to vulnerability at higher tau. Sex differences in tau-related cognitive decline were consistent after accounting for amyloid burden. Sex-specific rates of cognitive decline should be considered in clinical trial design. Show less

Familial hypercholesterolemia is a monogenic Mendelian disorder characterized by elevated LDL cholesterol and premature atherosclerotic cardiovascular disease. It is caused by pathogenic variants in LDLR , APOB , and PCSK9 , with rarer involvement of LDLRAP1 and APOE . Despite advances in molecular diagnostics, no causative variant is identified in approximately 25-75% of clinically diagnosed cases. Familial hypercholesterolemia is currently defined as an autosomal semi-dominant disorder with a gene-dosage effect, whereby biallelic pathogenic variants result in markedly more severe phenotypes than heterozygous variants. Terminology for homozygous familial hypercholesterolemia has been refined. Former terms such as 'true homozygote', 'compound heterozygote', and 'double heterozygotes' have been replaced by monogenic biallelic forms, with identical or different variants, and digenic biallelic forms involving two familial hypercholesterolemia-associated genes. Polygenic risk score (PRS) and lipoprotein(a) measurement help explain familial hypercholesterolemia-like phenotypes in patients without a monogenic cause and enable determination of polygenic severe hypercholesterolemia and/or hyperlipoproteinemia(a). Although advances in molecular genetics have improved variant detection, interpretation remains challenging. Integration of case-level data and functional studies, including high-throughput LDLR assays and APOB structural analyses, has enhanced variant pathogenicity classification. Combining monogenic variant detection, PRS determination and lipoprotein(a) assessment enables comprehensive diagnosis, tailored risk stratification, and personalized familial hypercholesterolemia management. Show less

Non-suicidal self-injury (NSSI) is highly prevalent among adolescents with depression, yet the heterogeneity of underlying temperamental risk factors remains poorly understood. Traditional variable-centered approaches fail to capture how distinct affective temperaments co-occur within individuals. This study aimed to identify latent profiles of affective temperaments and examine their association with NSSI, exploring the statistical mediating role of cognitive emotion regulation (CER). A cross-sectional study was conducted from February 2025 to September 2025 at the First Hospital of Hebei Medical University. A total of 290 adolescents (aged 10–19) diagnosed with Major Depressive Disorder were recruited, with 282 valid responses included in the final analysis. Participants completed the TEMPS-A, CERQ, and ASHS. Latent Profile Analysis (LPA) was utilized to identify temperament subgroups. Mediation analysis with bootstrapping was performed to test the indirect effects of CER strategies. LPA identified three distinct profiles: Resilient/Low-risk (Class 1, 32.6%), Anxious-Depressive (Class 2, 46.1%), and Mixed-Dysregulated (Class 3, 21.3%). The Mixed-Dysregulated group, characterized by simultaneous elevations in depressive, anxious, irritable, and cyclothymic temperaments, exhibited the highest frequency (45.2 ± 21.3 times/year) and prevalence (98.8%) of NSSI compared to other groups ( The findings delineate a specific “Mixed-Dysregulated” risk phenotype within adolescent depression that is associated with severe NSSI. Interventions should move beyond standard depression care to target cognitive flexibility and emotional regulation skills. Statistical mediation analysis suggests that this risk is mediated by maladaptive cognitive emotion regulation strategies. Not applicable. Show less

This study investigated the latent profiles of reproductive concerns among women of childbearing age with systemic lupus erythematosus (SLE) and analyzed the differences in the characteristics across these profiles. A questionnaire was administered to 332 female patients of childbearing age with SLE at four tertiary-grade general hospitals in Mianyang City, China. We used a general information questionnaire, the Reproductive Concerns After Cancer Scale (RCAC), the Medical Coping Modes Questionnaire (MCMQ), and the Social Support Rating Scale (SSRS). A latent profile analysis (LPA) and multiple logistic regression models were employed to investigate the characteristics of the latent profiles and the factors that influence reproductive concerns. The total score for the reproductive concerns among women with SLE of childbearing age was moderate (58.45 ± 13.51). Four latent profiles were identified: low reproductive concern–high infertility acceptance (12.66%), moderate reproductive concern–concern about personal health (18.95%), moderate reproductive concern–concern about the child’s health (45.64%), and high reproductive concern–balance (22.75%). The model fit indices that support the four latent profiles included high entropy (0.92) and a significant result of the Lo–Mendell–Rubin (LMR) adjusted likelihood ratio test ( The reproductive concerns observed among women of childbearing age with SLE exhibited significant heterogeneity. In the field of clinical nursing, personalized intervention measures should be developed based on distinct categorical characteristics and influencing factors to reduce reproductive concerns among members of this patient population. Show less

Acute respiratory distress syndrome (ARDS) has a high clinical mortality rate and continues to draw research attention regarding its mechanisms and potential treatments. Disruption of the endothelial barrier is a primary pathological feature, and glycocalyx degradation is a key factor contributing to this disruption. Human umbilical cord mesenchymal stem cells (hucMSCs) exhibit strong anti-inflammatory and immunomodulatory effects, making their application in ARDS treatment an area of increasing interest. Proteomic screening identified Cxcl12 as a protein secreted by hucMSCs. In male C57 mice and cell models, lipopolysaccharide (LPS) was used to induce injury, followed by interventions with hucMSCs or hucMSCs with silenced Cxcl12 to assess glycocalyx-related proteins SDC-1, HS, and the repair marker EXT-1. To evaluate downstream signaling, the CXCR4 receptor was inhibited and related indicators were examined. Silencing Cxcl12 reduced the therapeutic effect of hucMSCs on LPS-induced glycocalyx damage. Inhibition of CXCR4 also weakened the effect of Cxcl12. These findings indicate that hucMSCs alleviate LPS-induced glycocalyx damage in pulmonary vascular endothelial cells by secreting Cxcl12, which activates the downstream receptor CXCR4, providing a therapeutic effect for ARDS. Show less

The liver X receptor (LXR) is expressed as α and β subtypes (NR1H3/NR1H2), which play both separate and overlapping roles in cholesterol metabolism. As ligand-regulated transcription factors, LXRα and LXRβ are activated by oxysterol. The two isoforms have high percent identity, sharing nearly identical structures and binding pockets. With these similarities, it is not clear how ligands distinguish between LXRα and LXRβ binding pockets. Yet, the ability to design isoform-specific modulator is highly dependent on this knowledge. Here, we test the hypothesis that, despite high structural similarity, the dynamic behavior of the receptors is distinct and can reveal fundamental differences between the isoforms. Using molecular dynamics simulations on a library of 27 oxysterols, we compare dynamic contacts, fluctuations and allosteric signaling in the ligand binding domains of both receptors. We quickly identify stability differences linked to subtle changes in secondary structure and inter-residue contacts. Using our reconstructed sequence of ancestral vertebrate LXR, we reveal that both receptors inherited distinct structural and/or dynamical features of the ancestor which underlie their dynamic differences. Show less

Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here, we perform a meta-analysis of 4 published GWAS plus 2 new GWAS, totaling 4710 AML cases and 12 938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P = 1.35 × 10-8; EFR3B, POMC, DNMT3A, and DNAJC27), which also significantly associates with patient survival (P = 6.09 × 10-3). Our analysis also identifies 3 new genome-wide significant risk loci for disease subgroups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P = 7.0 × 10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P = 3.28 × 10-8; PARD3B) and 2p21 (rs79918355; P = 1.60 × 10-9; EPCAM). We also investigated loci previously associated with the risk of clonal hematopoiesis (CH) or CH of indeterminate potential and identified several variants associated with the risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease subgroup specific risk loci. Show less

ObjectivesTo characterize the rs1042034 allele distribution in Vietnamese adults with untreated hypercholesterolemia and evaluate its impact on baseline lipid profiles and the early lipid-lowering response to rosuvastatin 20 mg.Materials and MethodsIn this cross-sectional exploratory study, 79 adults with low-density lipoprotein cholesterol [LDL-C] ≥ 3.4 mmol/L were enrolled and treated with rosuvastatin 20 mg plus lifestyle advice for 3 months. Genotypes were determined by TaqMan real-time PCR with Sanger sequencing validation. Baseline and 3-month lipid panels (LDL-C, high-density lipoprotein cholesterol [HDL-C], total cholesterol, non-HDL-C, triglycerides) were measured. Between-group comparisons used Kruskal-Wallis/ANOVA as appropriate; analysis of covariance (ANCOVA) models adjusted for baseline values assessed genotype (TT vs. CT + CC) effects on posttreatment lipids. Multivariable linear regression examined age, sex, and body-mass index as predictors; false discovery rate correction was applied.ResultsBaseline lipid concentrations did not differ significantly by genotype (overall LDL-C 4.37 ± 0.62 mmol/L; total cholesterol 6.62 ± 0.77 mmol/L). After three months, LDL-C reductions differed markedly by genotype ( Show less

Inter-individual responses to omega-3 and omega-6 polyunsaturated fatty acid (PUFA) interventions vary substantially, complicating standardized dietary recommendations and suggesting a role for genetic differences that influence fatty acid biosynthesis, metabolism, and downstream health effects. A PRISMA 2020-guided systematic search of PubMed, Embase, and Web of Science identified adult studies assessing nutrigenetic interactions in the context of PUFA interventions and outcomes, yielding 132 eligible studies (79 Tier 1; 53 Tier 2) that collectively indicate pathway-specific genetic control of PUFA handling. Across 38 studies (combined 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