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BackgroundCognitive decline represents a major challenge in aging populations. Probiotics have been proposed to influence cognitive function through gut-brain interactions, but clinical findings remain inconsistent.ObjectiveThis study evaluated the effects of probiotic supplementation on cognitive function as the primary outcome, and on BDNF levels, inflammatory markers, and oxidative stress biomarkers as secondary outcomes in adults aged 50 years and older.MethodsA systematic search of PubMed, EBSCO, ProQuest, and Google Scholar was conducted through 1 May 2024 using predefined search terms related to probiotics, cognitive function, BDNF, inflammation, and antioxidant activity. Study quality was assessed using the RoB 2 tool. Meta-analyses were performed using random-effects models, and publication bias was explored using Egger's test where study counts permitted.ResultsSixteen studies demonstrated significant improvement in cognitive function among participants receiving probiotics compared to placebo. Cognitive function, measured using the Mini-Mental State Examination (MMSE), yielded a standardized mean difference (SMD) of 0.747 (95% CI 0.307-1.186) which corresponds to moderate-to-large effects. In comparison, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) showed significant results with an SMD of 0.340 (95% CI 0.032-1.366) which corresponds to small-to-moderate effects. Probiotics also led to significant changes in several biochemical parameters, including BDNF, TNF-α, 8-OHdG, IL-6, IL-10, MDA, TAC, and GSH. Multi-strain probiotics showed better results compared to single-strain.ConclusionsProbiotic supplementation may offer modest cognitive benefits in aging populations, particularly in studies enrolling cognitively impaired individuals, but substantial heterogeneity and limited biomarker evidence restrict the certainty of these findings. Larger, longer-duration, and standardized trials are needed to clarify the clinical relevance and potential biological pathways underlying probiotic effects on cognition. Show less

Intracerebral hemorrhage (ICH) is a destructive cerebrovascular disease, whose secondary injury can trigger severe neuroinflammatory responses. Resolvin D1 (RvD1), as an endogenous specific pro-resolving mediator, has been demonstrated to possess significant anti-inflammatory effects. However, how brain networks relate to RvD1 biosynthesis and the therapeutic potential of RvD1 in post-hemorrhagic repair processes within the brain remain unclear. Serum RvD1 levels were measured at admission and discharge in 40 ICH patients, and their correlation with neurological functional outcomes was analyzed. Combining neuroimaging and Mendelian randomization, we investigated the association between brain network integrity and genetically predicted plasma RvD1 levels. Network pharmacology identified key targets, and an oxyhemoglobin-induced BV2 microglial model validated RvD1's BDNF-dependent anti-inflammatory and anti-apoptotic effects. Serum RvD1 levels decreased from admission to discharge during recovery, with significant correlation between its changes and neurological improvement. Neuroimaging and MR analysis revealed that brain network integrity is significantly associated with genetically predicted plasma RvD1 levels, partially explaining interindividual prognostic variation. Mechanistically, RvD1 modulates microglial metabolism, alleviates oxidative stress, and promotes anti-inflammatory polarization involving the BDNF/AKT signaling network. Genetically predicted plasma RvD1 levels correlate with macro-level brain network integrity while simultaneously promoting micro-level neural repair. This approach overcomes limitations of previous single-pathway or static indicator studies, offering novel biomarkers and intervention strategies with predictive and therapeutic potential for ICH. Show less

Glaucoma is a progressive neurodegenerative disease that affects retinal ganglion cells (RGCs), ultimately leading to vision loss. In this study, we investigated gene therapy-mediated transduction of RGCs and examined axonal transport changes in the optic nerve using a viral vector designed to upregulate tropomyosin receptor kinase B (TrkB) expression. TrkB expression was evaluated in retinae and optic nerves of rats following genetic intravitreal delivery of AAV2-TrkB. Axonal transport and preliminary mitochondrial changes were assessed in optic nerves by immunohistochemical staining for kinesin and voltage-dependent anion channel (VDAC), a mitochondrial component. The results revealed an approximately 30% increase in TrkB expression in the retina, which was confirmed to be vector-driven by a P2A tag attached to the TrkB protein. This increased protein expression could be seen independent of injury and in eyes with elevated intraocular pressure. Observations along the optic nerve of rats treated with AAV2-TrkB revealed elevated transport of TrkB along axons (50% in TrkB, 120% in P2A tag) and significant increases in kinesin (12%) and VDAC (16%) immunoreactivity. This study provides early indications that improving TrkB expression in the eye may increase anterograde transport of motor proteins, which in turn could improve mitochondrial transport within the optic nerve. Show less

Lipoprotein(a), Lp(a), is a genetically determined, lifelong risk factor for atherosclerotic cardiovascular disease (ASCVD). Despite broad guideline support for universal one-time testing, Lp(a) measurement remains rare in clinical practice. This review summarizes recent advances in machine learning-based strategies that can enhance the efficiency, yield, and equity of Lp(a) screening. To date, three studies have developed and validated machine learning models to identify individuals with elevated Lp(a) using routinely available clinical variables. The ARISE framework, derived from the UK Biobank and validated across multiple US cohorts, reduced the number needed to test by more than 50% while maintaining consistent discrimination across demographic subgroups. Additional studies have confirmed the feasibility of decision-tree and neural network models to improve case finding for elevated Lp(a) in both clinical and population-based settings. Machine learning-based strategies provide a scalable means of operationalizing universal Lp(a) testing recommendations within health systems. When developed using unbiased data, externally validated, and assessed for fairness and interpretability, these models can support systematic identification of individuals with elevated Lp(a) and integration of Lp(a) measurement into routine cardiovascular risk assessment. Show less

Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition in Saudi Arabia, with genetic susceptibility remaining incompletely characterized. Reduced brain-derived neurotrophic factor (BDNF) activity has been implicated in MDD. The Val66Met polymorphism (rs6265), involving the substitution of valine (Val, G allele) with methionine (Met, A allele), impairs activity-dependent BDNF secretion. This study examined the frequency of Val66Met and its association with MDD in a Saudi cohort. A case-control study was conducted, including 87 patients with MDD (44 males, 43 females; mean age 44.2 ± 11.5 years) and 87 healthy controls (39 males, 48 females; mean age 28.7 ± 8.4 years). Genotyping was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction. Unadjusted and age- and sex-adjusted logistic regression analyses were applied under genotype-specific, dominant, recessive, and allelic models. The Val/Val (GG) genotype was more frequent in controls than patients (54.0% vs. 34.5%), whereas the Met/Met (AA) genotype was detected exclusively in patients (21.8% vs. 0%; χ The BDNF Val66Met polymorphism is associated with MDD susceptibility in Saudis. The Met (A) allele, particularly in homozygosity, confers increased risk, while the Val/Val genotype appears protective, supporting population-specific genetic contributions to depression. Show less

Species from octopi to humans engage in play. This review examines how epigenetic mechanisms, such as DNA methylation, may regulate play behaviour across taxa. We frame play through historical definitions, categorizing it into object, locomotor, and social forms, and examine how each may be linked to epigenetic shifts, for example in brain-derived neurotrophic factor (BDNF) expression. We then explore the role of domestication in enhancing play via methylation of stress and sociality genes, comparing domesticated chickens, dogs, and foxes to their wild kin. We link the neurobiology of play, spanning the hypothalamic-pituitary-adrenal (HPA) axis and reward circuits, to epigenetic modulation. Assessing the evolutionary fitness advantages of play, we compare adaptive benefits against the surplus resource theory. Despite its presence in many taxa, there remains limited direct evidence for a role of epigenetic mechanisms in play, and we urge research into the developmental and adaptive roles of play across a wider range of species. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by extreme hypertriglyceridemia (>1000 mg/dL), recurrent pancreatitis, and lipoprotein lipase (LPL) deficiency. FCS is caused by biallelic loss-of-function variants in LPL or in 4 other genes encoding its cofactors and regulators, including LMF1 (lipase maturation factor 1). Variants in LMF1 are rare and present only in 1% to 2% of the FCS cases. To assess in 3 patients with severe hypertriglyceridemia and recurrent pancreatitis and in whom a homozygous LMF1 duplication, initially classified as a variant of uncertain significance (VUS) was identified, post-heparin LPL activity. We collected demographics, fasting lipid profiles, and body mass index, and performed next-generation sequencing using a targeted panel that included canonical FCS genes. A homozygous in-frame duplication in LMF1 (c.914₉₂₈dup; p.Ser309_Phe310dup) was identified. Variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines and cross-referenced with public archive of reports of the relationships among human variations and phenotypes (ClinVar), The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff (HGMD), Leiden Open Variation Database (LOVD), The Single Nucleotide Polymorphism database (dbSNP), The Genome Aggregation Database (gnomAD), and in-house databases. LPL activity was assessed in post-heparin plasma using a radiometric assay. All 3 patients were homozygous for c.914₉₂₈dup (this variant was classified as a VUS) and exhibited markedly reduced LPL activity (<20% of normal). Clinical manifestations were consistent with FCS, including extreme triglyceride elevations and recurrent pancreatitis. One patient died from fulminant pancreatitis. The combined clinical, biochemical, and genetic evidence supports the reclassification of LMF1 c.914₉₂₈dup (p.Ser309_Phe310dup) as likely pathogenic according to ACMG/AMP guidelines and indicates its association with severe pancreatitis. Show less

Lipoprotein apheresis (LA) is the only approved treatment for patients with elevated lipoprotein(a) [Lp(a)]. The Lp(a)FRONTIERS APHERESIS trial investigated whether pelacarsen reduces the need for LA in patients from Germany with elevated Lp(a) and established cardiovascular disease (CVD). Adult patients with Lp(a) levels >60 mg/dl who had undergone ≥35 LA sessions in the prior year were randomized to receive pelacarsen 80 mg or placebo every 4 weeks for 52 weeks. Weekly LA sessions were performed if the Lp(a) measurement from the prior visit was >60 mg/dL. The primary endpoint was the rate of performed LA sessions normalized to the weekly LA schedule (the number of actual LA sessions divided by the number of planned LA sessions during the 52-week period). Secondary endpoints were time to LA avoidance (for ≥24 consecutive weeks) and total LA avoidance from week 12 to week 52. Fifty-one patients were randomized (mean age 61.7 years, mean Lp(a) at baseline 85.4 mg/dL, and mean 44.0 LA sessions in the past 12 months), with 25 of 26 (96.2%) in the pelacarsen arm and 23 of 25 (92.0%) in the placebo arm completing the study. Baseline characteristics were generally balanced between treatment arms. Pelacarsen reduced the mean rates of LA (0.16 vs 0.93 in placebo, odds ratio 0.006, 95% confidence interval [CI] 0.003, 0.013; P < .0001) and substantially increased the hazard of achieving LA avoidance (hazard ratio: 88.3; P = .0014; median time to achieve LA avoidance: 6.1 weeks) and total LA avoidance (odds ratio: 163.2; P = .0005). The placebo-adjusted Lp(a) change from baseline at week 52 was -72% (95% CI: -79%, -61%; P < .0001). Treatment emergent adverse events were similar between arms, except for mostly mild injection site erythema (pelacarsen 38.5%; placebo 0%). Pelacarsen is a highly effective and well-tolerated Lp(a)-targeted therapy that substantially reduces the need for LA in patients with elevated Lp(a) and established CVD. NCT05305664. Show less

White adipose tissue (WAT) expansion occurs through generation of new adipocytes from adipose progenitor cells (APC). The objective of this study was to characterize and validate a new transcriptional profile of APC. Single-cell (sc)/nuclei (sn) RNA-Seq was performed on nuclei from whole WAT (n = 20), cells from WAT stromal vascular fraction (n = 5), and cultured APC in vitro (n = 8) using ICELL8 smart-Seq technology. Additional snRNA-Seq was performed on WAT using 10x genomic platform. Pseudotime analyses and differentiation of hiPSCs was used to track the temporal patterns of novel gene signatures. Immunohistochemistry was performed to validate a new marker. A pre-adipocyte population was found across the four independent datasets that expressed known pre-adipocyte markers (ZNF423 and DLK1) in addition to genes typically associated with neurogenes (DPP10, PTRPT, CTNNA2, NRXN3, CTNNA2, PTPRD, CNTNAP2 and RBFOX1). The expression of these genes were temporally regulated with adipocyte differentiation. Immunohistochemistry analyses confirmed these pre-adipocytes are located in the neurovascular niche of WAT but are not neurons or endothelial cells. This work has defined a new transcriptional signature of pre-adipocytes in human subcutaneuous WAT that are distinct from mesencyhmal stem cell populations and represent novel targets for WAT expansion. Show less

To evaluate the safety, tolerability, and potential functional signals associated with cord blood serum (CBS) eye drops as adjunctive treatment in patients with open-angle glaucoma (OAG) already under intraocular pressure (IOP)-lowering therapy. In this monocentric prospective pilot study, 20 OAG patients (37 eyes) received topical CBS eye drops 8 times daily for 60 days, in addition to their standard hypotensive therapy. Ophthalmic evaluations were performed at baseline (V1), end of treatment (V4), and 60 days after discontinuation (V5), and included best-corrected visual acuity (BCVA), IOP, visual field (VF), pattern electroretinography (PERG), and retinal nerve fiber layer (RNFL) thickness. Statistical analyses assessed changes in functional and structural parameters. The treatment was well tolerated, with no adverse events and no significant changes in IOP or BCVA. Visual field mean deviation (MD), PERG parameters, and RNFL thickness showed non-significant variations across visits. A statistically significant RNFL thinning was observed in the infero-temporal sector between V1 and V4, although likely due to outlier effects. Linear mixed model analysis showed a significant increase in N95 amplitude at V5 compared to V4 when baseline MD was considered as a covariate. CBS eye drops were safe and well tolerated in this glaucoma population. Although no statistically significant functional or structural improvement was observed, some exploratory signals suggest potential neuroretinal involvement that warrants further investigation in larger, controlled studies. Show less

The ability of neurons to communicate via synapses is called synaptic transmission, and it is an essential process of brain functioning and plasticity. Its interference has been discovered as a common molecular trait in a broad range of neurological and psychiatric ailments. Nevertheless, in spite of increasing evidence within the disease context, the existing knowledge is still rather disunified, and the molecular processes are poorly incorporated into coherent, cross-disorder models. This narrative review addresses this gap by concisely synthesising recent advances in molecular genetics, synaptic proteomics, neuroimaging, and systems neuroscience to provide an integrated overview of synaptic dysfunction across neurological and psychiatric disorders. It reviews the role of the changes in vesicle trafficking, calcium dynamics, neurotransmitter receptor signalling, brain-derived neurotrophic factor (BDNF) action, and glia-mediated synaptic plasticity in the pathophysiology of conditions like schizophrenia, autism spectrum disorder (ASD), Alzheimer's disease (AD), epilepsy, major depressive disorder (MDD), and Parkinson's disease (PD). The emerging tools that have translational relevance, as pointed out by the review, include single-cell RNA sequencing, spatial proteomics, and synaptic positron emission tomography (PET) imaging, with the capabilities of providing disease-specific and patient-level insights into the pathology of synapses. This review establishes the convergence of the dysfunction, as well as therapeutic potential, through the presentation of a systems-level, cross-diagnostic framework at the level of the synapse. It ends with a prospective report of where precision medicine, development of new biomarkers, and lifespan research efforts are required to incorporate synaptic biology in translational neuroscience. Show less

Hypertrophic cardiomyopathy (HCM) is a complex myocardial disorder with heterogeneous clinical presentations and structural manifestations. This study aimed to assess the distribution, clinical characteristics, and diagnostic approaches in a regional cohort of patients with HCM. Patients diagnosed with HCM at a tertiary cardiomyopathy clinic between October 2021 and November 2024 were retrospectively analyzed. Patients were classified into obstructive, latent obstructive, non-obstructive, or apical phenotypes based on clinical and imaging findings. Comprehensive demographic, clinical, and imaging data were collected for detailed analysis, providing valuable insights into the phenotypic diversity of HCM. The cohort included 701 patients with a median age of 53 years of whom 68% were male. The phenotypic distribution comprised 9.3% apical, 38.1% non-obstructive, 32.5% resting obstructive, and 20.1% latent obstructive HCM. Implantable cardioverter-defibrillator implantation was more common in obstructive phenotypes, particularly in the latent obstructive group. Although late gadolinium enhancement (LGE) was more frequently observed in apical HCM, post-hoc analysis showed no significant difference in prevalence across subgroups. In contrast, LGE extent was significantly greater in the apical group. Genetic testing, performed in 32% of patients, revealed a 44% positivity rate, with MYBPC3 and MYH7 being the most commonly detected mutations. The overall mortality rate was 2.8%, with heart failure identified as the leading cause of death. In this large regional cohort of HCM patients, obstructive and non-obstructive phenotypes were predominant, with a notable burden of genetic mutations and a low overall mortality rate primarily driven by heart failure. These findings emphasize the clinical heterogeneity of HCM and highlight the importance of comprehensive diagnostic evaluation. Show less

The present study aimed to investigate the combined impact of lipoprotein (a) [Lp(a)] and low-density lipoprotein (LDL) subfractions on cardiovascular outcomes in patients with acute coronary syndrome (ACS). The study enrolled 2061 ACS patients from Tianjin Chest Hospital. Participants were categorized into 4 groups based on their Lp(a) and the concentration of the sixth component particles of LDL(LDL-P6). The primary endpoint was the occurrence of major adverse cardiovascular events (MACE). The relationship between LDL-P6, Lp(a), and MACE was evaluated. Over a mean follow-up period of 5.4 years, 456 (22.1%) patients experienced MACE. Multivariate analysis identified both LDL-P6 and Lp(a) as significant independent predictors of MACE in ACS patients. Those in the highest-risk group had a substantially higher incidence of MACE compared with the lowest-risk group (HR 5.718; 95% CI 3.703-8.829; Show less

This study aimed to evaluate serum brain-derived neurotrophic factor levels, stress, and quality of life in leprosy patients, and to explore their interrelations. A cross-sectional study was conducted from September 2024 to May 2025 at 3 hospitals in Medan, Indonesia, involving 45 leprosy patients aged ≥ 18 years who met inclusion criteria. Serum brain-derived neurotrophic factor levels were measured using ELISA, stress was assessed using the Perceived Stress Scale-10, and quality of life was evaluated through the WHOQOL-BREF questionnaire. Descriptive statistics, Shapiro-Wilk normality test, and Spearman's rank correlation were used for analysis. The mean serum brain-derived neurotrophic factor level was 7.38±3.37 ng/mL. Patients with multibacillary leprosy without reaction had higher brain-derived neurotrophic factor levels than those with type 1 or type 2 reactions. Stress levels were mild in 42.22% and severe in 28.89% of patients. Quality of life scores varied widely. A strong negative correlation was found between brain-derived neurotrophic factor and stress (r=-0.953, p< 0.0001), and a strong positive correlation between brain-derived neurotrophic factor and quality of life (r=0.962, p< 0.0001). These findings suggest that serum brain-derived neurotrophic factor levels are associated with psychological well-being in leprosy patients and may serve as a potential biomarker for mental health monitoring in this population. Show less

The incidence of multiple sclerosis (MS) has increased in recent years. Its pathogenesis involves the interaction between various elements, with interleukin 27 (IL-27) playing a key role in autoimmunity. The presence of the IL-27 receptor on astrocytes emphasizes its involvement in the disease's progression. The study aims to investigate possible associations between IL27 rs181206, serum level of IL27, and the development of MS. The study comprised 70 MS patients and 70 seemingly healthy controls. They were genotyped for IL27 rs181206 using the Taqman allelic discrimination approach, and their serum IL27 levels were estimated using ELISA. The frequency of TT genotype, T allele, and IL27 serum level were significantly higher among MS patients compared to controls. There was no significant difference between IL27 serum levels among different genotypes in both MS patients and controls; however, individuals with TT genotype showed higher levels of IL27 than those with CC genotype. TT genotype and T allele can increase the risk of developing MS. On the other hand, carrying the C allele may be associated with a lower risk of MS development. Understanding IL27 genetics and epistatic interactions can help clarify IL27's role in MS pathogenesis and utilize it as a therapeutic target. Show less

Interleukin 1 receptor-associated kinase 1, 4 (IRAK 1/4) inhibitor exerts anti-inflammatory and immuno-modulatory effects; however, its role in high-fat diet-induced vascular dysfunction and cognitive impairment is not known, and therefore investigated in the present study. Animals were fed either a high-fat diet (60% Kcal fat) or a chow diet (10% Kcal fat) for 12 weeks to induce hyperlipidemia and weight gain. High-fat diet-fed animals were then treated with vehicle, IRAK1/4 inhibitor (2.2 mg/kg, i.p.) and a reference drug, Orlistat (20 mg/kg, oral gavage), for 4 additional weeks. Protein levels were assessed by ELISA or Western blotting, and mRNA by RT-PCR. IRAK1/4 inhibitor and reference drug, Orlistat treatment, prevented HFD-induced increase in body weight gain, fasting blood glucose and plasma lipids, improved discrimination between the familiar and the novel arm in the Y-Maze test, alleviated percent avoidance in two-way active avoidance, and freezing percent in contextual fear conditioning test. The treatments attenuated the levels of systemic inflammatory cytokines IL-1β, CRP, as well as TNF-α, IL-6 and protein expression of Iba-1, GFAP, HIF-1α, and restored the BDNF levels in the pre-frontal cortex of HFD-fed treated mice. IRAK 1/4 inhibitor exerted these effects by blocking proteasomal degradation of IκB-α protein in the pre-frontal cortex of HFD-treated mice. In addition, the treatments prevented HFD-induced increase in vascular ICAM-1, VCAM-1, MCP-1, COX-1 and COX-2 mRNA expression, and restored vascular eNOS mRNA levels as well as the Acetylcholine (300 ρM-300 μM) induced relaxations of PE (1 µM) pre-contracted aortic rings. IRAK1/4 inhibitor attenuates HFD-induced inflammation, vascular dysfunction and cognitive impairment in obese mice. Show less

Alzheimer's disease (AD) pathology disrupts functional brain connectivity long before symptoms emerge. African Americans face elevated AD risk, yet underlying mechanisms remain unclear. Genetic risk differs by ancestry: APOE-ε4 strongly predicts late-onset AD in European ancestry, whereas ABCA7 rs115550680 confers substantial risk in African ancestry. Yet, how these variants influence neural function in African Americans is unclear. The medial temporal lobe (MTL) is an early target of AD pathology and resting-state functional Magnetic Resonance Imaging (rs-fMRI) measures of dynamic network connectivity (hereafter "flexibility"), the brain's capacity to dynamically reconfigure connectivity, provide a sensitive metric of network adaptability, potentially preceding structural decline. However, comparative influence of APOE-ε4 and ABCA7 rs115550680 on MTL flexibility and subregional volumes in this population is unknown. 146 older African Americans (Mean Show less

The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. We comprehensively characterized efferocytosis in CRS and determined its association with inflammatory endotypes and clinical outcomes in CRSwNP. Efferocytosis-related marker expression between nasal polyps and healthy nasal mucosa was detected by quantitative real-time PCR and immunohistochemistry. Public single-cell RNA sequencing profiles of CRS were reanalyzed to dissect efferocytosis at single-cell resolution. Associations between efferocytosis and tissue inflammation were evaluated by Spearman correlation. Regression models and receiver operating characteristic analyses assessed the predictive capability of efferocytosis for CRSwNP recurrence. Compared with controls, CRSwNP exhibited widespread efferocytosis deficiency, including "find me" signals (CX3CR1, S1PRs, P2RY2, GPR132), "eat me" signals (ITGAV, MerTK, Tim1, ADGRB1), "don't eat me" signal CD300a, postengulfment signals (ABCA1, NR1H3/2, PPARδ/γ), and bridging molecule MFGE8. Macrophages, the principal efferocytic cells, shifted from homeostatic C3 Insufficient phagocytosis and increased antiphagocytosis activity are hallmarks of efferocytosis deficiency in CRS and are associated with the severity of inflammation and the clinical outcome of CRSwNP. Show less

Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by the FMR1 premutation allele, is associated with brain degeneration, yet the mechanisms behind this neurodegeneration still need to be elucidated. Apoε polymorphism has been widely implicated in brain aging in cognitively healthy individuals and brain deterioration in Alzheimer's disease. This study aimed to examine the interaction of Apoε genotypes, FXTAS clinical symptoms, FMR1 molecular measures, and age, towards brain pathophysiology and cognitive functions. This longitudinal study includes MRI data collected from 205 male premutation carriers with and without FXTAS clinical symptoms and compared to 86 healthy male controls aged 40-85 years. The investigation includes FXTAS-related brain volumes, IQ, self-control behaviors, FMR1 molecular measures, and Apoε genotypes. In carriers with FXTAS, the presence of the Apoε2 allele showed a possible association with more favorable neuroimaging markers, such as reduced white matter hyperintensities, and lower incidence of the middle cerebellar peduncle sign, patterns that were not observed in carriers without FXTAS. Specifically, the presence of Apoε2 allele exhibited a potential protective effect on brain degeneration, and cognitive functions among FXTAS patients; on the contrary, the Apoε4 allele was associated with a worsening of brain volume and brain degeneration in carriers with no FXTAS symptoms. The identification of Apoε genotypes in FMR1 premutation carriers before any clinical symptoms of FXTAS are observed may improve symptomatic management leading to better outcomes for these individuals. Show less

Exercise-induced inflammation has been shown to influence iron metabolism. Conversely, ischemic preconditioning (IPC) has been proposed as a strategy to modulate post-exercise response, especially inflammation and neurotrophic factor secretion. In this study we analyzed the effects of a 14-days IPC intervention on the post-exercises changes of the selected Iron metabolism, inflammation and neurotrophic markers in the population of non-training healthy young man. Forty healthy, untrained young men voluntarily participated in this study and were randomly assigned to two groups: an IPC group (n = 20), which underwent a 14-day IPC intervention, and a placebo (SHAM) group (n = 20). Five participants from the IPC group and seven from the SHAM group did not complete the protocol and were excluded from the analyzes. Venous blood samples were collected at rest, immediately after and 2 h after the Wingate test. Selected inflammatory and neurotrophic markers were analyzed, including IL-6, IL-10, IL-15, LIF, BDNF, IGF-1, NGF, sAPPα, FSTL-1, and GDF-15. Additionally, serum levels of iron (Fe), hepcidin (Hpc), ferritin (Fer), erythroferrone (ERFE), and erythropoietin (EPO) were assessed. IPC increased resting ferritin (~ + 9%, p < 0.05), hepcidin (~ + 12%, p < 0.05), and erythroferrone (~ + 10%, p < 0.05) concentrations. The intervention also enhanced post-exercise IGF-1 (+ 8%, p = 0.03) and sAPPα (+ 10%, p = 0.04) release and reshaped cytokine profiles, with greater early elevations of GDF-15 and IL-15 (p < 0.05) and faster normalization of FSTL-1 within 2 h (p < 0.05). IPC further affected neurotrophic signaling, showing lower 2-h post-exercise BDNF levels (p < 0.05) and distinct IGF-1 kinetics (p < 0.01). Anaerobic performance remained unchanged (p > 0.05). Ischemic preconditioning induces coordinated alterations in iron metabolism and modulates inflammatory and neurotrophic responses to anaerobic exercise, without affecting physical performance in untrained individuals. Show less

Although immune-mediated diseases (IMDs) and major depressive disorder (MDD) commonly co-occur, the bidirectional relationship between them remains to be fully elucidated. Using data from the prospective UK Biobank cohort, we evaluated the bidirectional associations by time-varying Cox proportional hazards regression models and assessed shared genetic architecture using genome-wide association study summary statistics. Additionally, we employed collagen-induced arthritis (CIA) and chronic social defeat stress (CSDS) mouse models to investigate the relationship between rheumatoid arthritis (RA) and depression. Over 5,226,841 person-years of follow-up, 23,534 incident MDD cases were identified. The presence of any IMD was associated with higher MDD risk (hazard ratio [HR]: 1.95; 95% CI: 1.89-2.01). Conversely, 59,742 incident cases of IMD were documented. MDD was associated with increased IMD risk (HR: 1.47; 95% CI: 1.40-1.54). We observed significant global genetic correlations between IMDs and MDD (r Show less

Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD. Show less

Neuroendocrine regulation of reproductive function represents a complex system based on the integration of signals between the central nervous system and peripheral organs. In recent years, particular attention has been given to the role of neuropeptides - such as kisspeptin, brain-derived neurotrophic factor (BDNF), and orexins - in the pathogenesis of disorders associated with menstrual irregularities. This review provides a detailed analysis of the molecular mechanisms underlying neuropeptide regulation in functional hypothalamic amenorrhea (FHA), primary ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS).Recent experimental studies are summarized, including stress-induced models of persistent estrous cycle arrest in laboratory animals and simulation of PCOS and POI using dietary and pharmacological interventions, respectively. Additionally, the review highlights publications demonstrating the significant role of impaired neuropeptide signaling in the development of reproductive disorders in women.The integration of fundamental research with clinical practice not only enhances our understanding of the pathophysiology of amenorrhea but also opens promising avenues for the development of novel therapeutic strategies, such as the use of kisspeptin agonists or other agents aimed at restoring reproductive function in women with various forms of menstrual dysfunction. Show less

To investigate longitudinal changes in neuroimmune biomarkers during acute exacerbations of chronic obstructive pulmonary disease (AECOPD), their modulation by standard therapy, and prognostic implications for 90-day outcomes. In a prospective cohort, 266 hospitalized AECOPD patients were stratified into worsened ( Compared with controls, AECOPD patients exhibited higher IL-6, TNF-α, PD-1, and MMP-9, alongside reduced BDNF and IL-10. Stable patients demonstrated partial biomarker normalization, whereas worsened patients retained a pro-inflammatory profile. Corticosteroids and antibiotics attenuated cytokine elevations, and oxygen therapy facilitated BDNF recovery. Low BDNF and high MMP-9 predicted spirometric decline, while elevated PD-1 and MMP-9 were associated with increased 90-day readmission risk. A dual-axis model incorporating neurotrophic and immune exhaustion markers outperformed GOLD classification for risk prediction. Neuroimmune biomarkers capture recovery heterogeneity in AECOPD. The proposed dual-axis model improves prognostic accuracy and may inform personalized management strategies. Show less

Acute necrotizing encephalopathy (ANE) in children is a critical condition characterized by rapid progression, high mortality rates and potentially cytokine storm imvolvement. Early-stage ANE lacks distinctive clinical features, and its initial symptoms resemble those of febrile seizures (FS) despite differing outcomes. In this study, we utilized FS as a control to identify plasma biomarkers associated with the cytokine storm in ANE through plasma proteomic analysis. We identified 398 differentially expressed proteins in ANE patients, including 345 upregulated and 53 downregulated proteins, which were enriched in biological pathways such as antigen processing and presentation, cell chemotaxis, immune responses, metabolism, and cell matrix adhesion. Using weighted gene co-expression network analysis (WGCNA), we further identified protein modules and hub proteins related to the cytokine storm and ultimately selected eight key proteins (APOE, GAPDH, TPI1, SPP1, ENO1, COL1A1, LUM, and A2M) as immunopathogenic biomarkers. These findings were validated in an independent cohort using targeted quantitative proteomics, with ROC analysis demonstrating their diagnostic potential. This study provides a foundation for early ANE diagnosis and highlights promising targets for therapeutic intervention. Show less

The cytoplasmic fate of messenger RNAs (mRNAs) is dictated by the balance of translation and mRNA degradation, governed in part by the 3' poly-adenosine tail and cytoplasmic poly(A)-binding proteins (PABPCs). Deadenylases remove poly(A) to initiate mRNA decay, while sequence-specific RNA-binding factors, including Pumilio proteins (PUM1 and PUM2), modulate these processes. We investigated how human PUM1&2 repress target mRNAs by accelerating their degradation. We found that the poly(A) tail plays a central role in PUM repression, dependent on the interplay of deadenylases and PABPCs. PUM-mediated repression requires the CCR4-NOT deadenylase but not the poly(A) nuclease. PUMs associate with and require PABPC1 and PABPC4 to repress. In the absence of PABPCs, both PUM targets and non-targets become unstable, bypassing PUM control. Increasing PABPC inhibits PUM activity in a concentration-dependent manner by stabilizing poly(A) mRNAs. The results support a Goldilocks principle, wherein PABPC abundance tunes the response of mRNAs to PUM-mediated repression through protection of poly(A) from deadenylation. We propose that this principle may apply to other poly(A) dependent regulatory factors. Variation of PABPC levels across tissues and development suggests physiological relevance for this mechanism. Show less

Type II diabetes mellites (TIIDM) characterized by hyperglycemia, insulin resistance, insensitivity, and pancreatic β-cell atrophy has gained concern due to high rise in such cases globally. This study highlighted the therapeutic potency of a novel polyherbal formulation (PHF) of Phyllanthus urinaria and Adhatoda vasica Nees mice by in vitro, in vivo, and in silico analysis in high-fat diet (HFD)-streptozotocin (STZ)-induced Swiss albino. The findings showed significant inhibition of α-amylase and α-glucosidase activity of the PHF along with decreased blood glucose level, increased glycogen and serum insulin level, elevated mRNA expression of GIPR and GLP1R, GLUT2, GLUT4, INSR, INS1, INS2, TCF7L2, and Pdx1 in both low and high dose of PHF-treated mice as compared to HFD-STZ-induced diabetic mice. Western blot results also demonstrated augmented insulin protein level in both PHF-treated groups. Okanin and vomicine, identified from LCMS analysis as potent antidiabetic bioactive compounds bind to dipeptidyl peptidase 4 (DPP4) with a binding energy of -8.04 and -7.81 kcal/mol, respectively, as compared to standard drug metformin (-5.33 kcal/mol). Inhibition of DDP-4 by bioactives of PHF aids in enhanced secretion of incretion hormones leading to insulin secretion thereby established itself as a complementary and alternative therapeutics in the management of diet-induced TIIDM. Show less

This study aimed to explore the professional quality of life among nursing assistants and identify latent profiling, and examine their relationships with perceived organizational support and self-efficacy. A cross - sectional survey study was conducted. Nursing assistants from two hospitals in Shenzhen, China, were recruited through convenience sampling. Demographic characteristics, perceived organizational support, self-efficacy, and professional quality of life were measured using validated scales. Latent profile analysis (LPA) identified subgroups of professional quality of life, and logistic regression examined the associations of demographic factors, organizational support, and self-efficacy with profile membership. A total of 354 nursing assistants were included in this study. The professional quality of life was classified into three profiles: "adaptive group", "stress group", and "high burden group" comprising 216, 102, and 36 nursing assistants, respectively. Statistical differences were observed among the three groups in terms of demographic characteristics such as gender, ethnicity, certification, and professional title (P < 0.05). Additionally, instrumental support, emotional support, and self - efficacy differed significantly among the groups (P < 0.05). Gender (female), licensure, professional title (primary and mid - level), emotional support, and self - efficacy were predictors of nursing assistants' professional quality of life. These findings may facilitate the identification of different profiles of nursing assistants for targeted training programs aimed at improving their professional quality of life. Furthermore, intervention strategies emphasizing emotional support, and self - efficacy may offer valuable approaches for enhancing professional quality of life. Show less

This pilot randomized controlled trial (RCT) evaluated the efficacy of a behavioral intervention grounded in the Capability-Opportunity-Motivation-Behavior (COM-B) model delivered via online coaching and newsletters for promoting physical activity (PA) in people newly diagnosed with multiple sclerosis (PNDwMS). This unblinded, parallel-group, RCT included 50 PNDwMS (disease duration ≤ 2 years) who were randomized into either PA intervention (n = 25) or waitlist control (WLC) (n = 25) conditions. The intervention was delivered over 16 weeks by a researcher uninvolved in randomization. Data were collected pre- and post-intervention. Primary outcomes included device-measured (steps/day, light PA [LPA], moderate-to-vigorous PA [MVPA]) and self-reported PA (Godin Leisure-Time Exercise Questionnaire [GLTEQ] and International Physical Activity Questionnaire [IPAQ]). Secondary outcomes included fatigue, depression, anxiety, and health-related quality of life (HRQOL). Data were analyzed (intent-to-treat) using condition-by-time mixed-effects ANOVA. There were significant condition-by-time interactions on device-measured (MVPA) and self-reported (IPAQ) PA as well as depression and mental HRQOL (all p ≤ .05). There were moderate and significant improvements in MVPA (Δ11.2 min/day, 95% CI: 8.8, 13.7, d = 0.5) and IPAQ (Δ11.4 units, 95% CI: 10.4, 12.3, d = 0.7), HADS-D (Δ1.4 units, 95% CI: 1.3, 1.5, d = 0.5), and SF-12 MCS (Δ5.6 units, 95% CI: 5.1, 6.1, d = 0.6) scores in the PA intervention condition, but not in the WLC condition. These findings provide preliminary evidence for the efficacy of the COM-B-based behavioral intervention for increasing PA and improving mental health outcomes in PNDwMS. Show less

Aortic valve calcification increases leaflet stiffness and contributes to the development of calcific aortic valve disease. The molecular and cellular mechanisms underlying calcification remain unclear. Here, we aimed to investigate the role of PRMT3 (protein arginine methyltransferase 3) in valvular calcification and calcific aortic valve disease progression. Both aortic valve leaflets and valvular interstitial cells from patients were used to evaluate the expression pattern and investigate the underlying mechanism of PRMT3 in calcific aortic valve disease pathogenesis. High-cholesterol diet-fed Apoe (apolipoprotein E)-deficient ( We found that PRMT3 expression was significantly upregulated during aortic valve calcification. RUNX2 (runt-related transcription factor 2) recruited P300 to promote PRMT3 expression through histone H3 lysine 27 acetylation. Moreover, We identify a previously unrecognized posttranslational mechanism regulating PCSK9 stability in valve interstitial cells during calcific aortic valve disease and establish a link between PRMT3-mediated arginine methylation and valve-specific lipid-osteogenic coupling. Show less