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This study aimed to identify the heterogeneity of attitudes toward ageing among older adults in the “early transition period” (the initial 2–4 weeks after nursing homes transition from home to nursing homes). and the mediation effect of self-efficacy between attitudes toward ageing and quality of life (QoL). A total of 300 older adults were enrolled from October 2023 to May 2024. Participants completed the General Information Questionnaire, the Attitudes to Ageing Questionnaire (AAQ), the World Health Organization Quality of Life-Brief (WHOQOL-BREF), and the General Self-Efficacy Scale (GSES). Latent profile analysis (LPA), R3STEP methods, BCH methods, and mediation analysis were conducted to analyze the data. LPA categorized the attitudes toward ageing into three profiles: most negative (18.333%), moderately negative (64.000%), and positive (17.667%). Attitudes toward ageing profiles were associated with the following factors: age, pension, number of children, number of chronic diseases, ADL, willingness to reside in nursing homes, and social isolation. Self-efficacy partially mediates between attitudes toward ageing and the three dimensions of QoL (physical health, psychological health, and environmental health). Older adults during the “early transition period” had negative attitudes toward ageing. It may be related to the Chinese traditional interpersonal communication mode, family culture, and various maladaptive problems. Older adults who have two or more children, chronic diseases, no pension, moderate to severe dependency, involuntary admission to nursing homes, and social isolation are associated with more negative attitudes toward ageing. Mediation analysis reminds that self-efficacy can be used as intervention targets to improve the QoL. The online version contains supplementary material available at 10.1186/s12877-026-07007-7. Show less

The risk of developing psychiatric disorders, particularly stress-related disorders such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), is increased threefold in patients with epilepsy. While this increased risk may arise as a consequence of living with epilepsy, shared neurobiological mechanisms, particularly dysregulation of GABAergic signaling, may also contribute. To investigate this link, we investigated the function of GABAergic neurons co-expressing the neuropeptide cortistatin (CST), which has anticonvulsant effects and is implicated in both MDD and PTSD. Targeting CST+ neurons in the prelimbic cortex (PrL), a rodent brain region that is functionally and anatomically similar to the human dorsal anterior cingulate cortex (dACC), we found that ablating CST+ neurons disrupts context-dependent fear renewal, causes spontaneous convulsive seizures, dramatically increases susceptibility to chemically-induced seizures, and increases anxiety-like phenotypes following stressors. We further show that repeated chemogenetic inhibition of CST+ neurons increases the rate of seizure kindling in female mice, and that disruption of brain derived neurotrophic factor signaling in CST+ neurons phenocopies the effects of acute inhibition. These data support the hypothesis that epilepsy and stress-related psychiatric disorders potentially share common neurobiological mechanisms, and that loss of CST+ neuron function may be a critical feature underlying fear dysregulation and cortical hyperexcitability. Show less

Anxiety is an aggravating comorbidity of many psychiatric disorders that is often underdiagnosed and undertreated, and little is known on the mechanisms underlying its regulation. Here, we find that serum LPA16:0 abundance increases with trait anxiety in both humans and mice; while high LPA16:0 levels are sufficient to reduce the in vitro proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor LPA Show less

Unimolecular triagonists drive substantial weight loss in patients with obesity by engaging the glucagon-like peptide 1 receptor (GLP-1R) and glucose dependent insulinotropic polypeptide receptor (GIPR) to reduce food intake (FI) and the hepatic glucagon receptor (GcgR) to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects, including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R mono-agonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes. We used an adeno-associated virus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure. Agonism of the ectopic GLP-1R with either semaglutide, a cAMP biased GLP-1R analogue (NNC5840), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to peptide agonist treatment alone. This represents a novel mechanism for achieving poly-pharmacology to treat obesity. Show less

Our understanding of the genetic regulation of lipoprotein(a) [Lp(a)] is hindered by the complex structure of the LPA gene, limited non-European datasets and its elusive cellular receptor(s). This review summarizes recent efforts and advances providing new insights on its genetic architecture, variability across ancestries and regulators beyond the LPA gene. Impressive advances in DNA sequencing and bioinformatics now resolve LPA variants and kringle IV-type 2 copy number at scale. This provides new reference datasets and enables tools that unlock hidden variation also from already available sequencing datasets. In parallel, genetic studies broaden our understanding of the regulation of Lp(a) across ancestries and improve genetic risk scores. Finally, while recent studies implicate new mechanisms for Lp(a) uptake, upcoming genome-wide gene knockout screens allow comprehensive, agnostic scans for regulators and receptors. Puzzlingly, this still converges on the LDL receptor, whose exact role in Lp(a) uptake remains enigmatic. Technological advances establish a foundation for more accurate genetic risk assessment across ancestries. These advances are enhancing our understanding of Lp(a) regulation and build a framework for future integrative genetic studies, which may shed new light on the evolution of the Lp(a) trait, adding important context for its physiological and clinical relevance. Show less

This study develops and tests an AI-empowerment Configural Model to explain how artificial intelligence (AI) empowers language learning engagement. Grounded in ecological systems theory (EST) and ecological affordance theory (EAT), the model theorizes AI as an interactive agent within the learning ecosystem. A mixed-methods study of 475 Chinese university language learners demonstrates that AI'S effect on engagement is significantly mediated by the perceived quality of its ecological coupling with teachers, peers, and the environment. Latent profile analysis (LPA) further identifies three distinct learner configurations: low coupling-low engagement, moderate coupling-moderate engagement and high coupling-high engagement, which systematically differ in their coupling of AI. The model ultimately shifts the paradigm from tool implementation to strategic ecological governance, providing a practical basis for designing learning environments that leverage synergistic human-AI coupling to foster deeper, sustained engagement. 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

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 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

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

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

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

Auditory event-related brain potentials such as the mismatch negativity (MMN) and the frequency-following response (FFR) allow exploring speech sound encoding along the auditory pathway. Here, we collected event-related brain potential (ERP) and FFR neural responses to syllables in healthy full-term newborns (N = 17, mean age = 3 days) and adults (N = 21, mean age = 22.7). Participants were passively exposed to alternating blocks of syllables presented at either fast or slow stimulation rates while we recorded electroencephalography (EEG). Specifically, blocks containing the synthetic /oa/ syllable alternated with "oddball" blocks containing three natural syllables differing in place of articulation (one standard /da/ and two deviants /ba/ and /ga/). At the FFR level, we found that 3-day-old newborns (i) exhibit an already functional encoding of vowel pitch, (ii) show an immature encoding of vowel formant structure, replicating previous observations. At the ERP level, the two deviants elicited clear MMN in the two groups, although with different topographies, suggesting an immature sensitivity to place of articulation in newborns. These results confirm the role of experience-dependent developmental factors that may differentially shape FFR and ERPs of speech sound features. Furthermore, this study highlights the feasibility of assessing the hierarchy of neural speech sound encoding in a short experimental session. Show less

Astrocytes are central regulators of neural homeostasis, synaptic function, and neuroinflammatory responses in the central nervous system (CNS). Upon pathological stimuli, astrocytes undergo reactive transformations, producing pro-inflammatory cytokines, reactive oxygen species (ROS), and chemokines, which exacerbate neuronal injury. Flavonoids, a diverse class of polyphenolic compounds found in fruits, vegetables, and medicinal plants, have emerged as potent modulators of astrocyte activity, promoting neuroprotection and cognitive enhancement. These compounds, including quercetin, hesperetin, rutin, casticin, and anthocyanins, attenuate astrocyte-mediated neuroinflammation by suppressing NF-κB, MAPK, TLR, and NLRP3 inflammasome signaling while activating antioxidant pathways such as Nrf2 and PI3K/Akt. Flavonoid-mediated modulation also enhances the synthesis and release of neurotrophic factors, including BDNF, GDNF, NGF, and TGF-β1, which support synaptic plasticity, dendritic spine formation, and network connectivity. By preserving astrocytic homeostasis, reducing gliosis, and regulating astrocyte-microglia crosstalk, flavonoids mitigate cytokine-mediated neuronal damage, restore synaptic integrity, and improve learning and memory in models of neurodegeneration, ischemia, and neuroinflammation. Preclinical evidence suggests that flavonoids can cross the blood-brain barrier, exhibit low toxicity, and synergize with other neuroprotective interventions. Understanding the molecular mechanisms of flavonoid-astrocyte interactions provides insight into precision therapeutic strategies aimed at alleviating neuroinflammation and enhancing CNS resilience, offering promising avenues for the prevention and treatment of cognitive and neurodegenerative disorders. Show less

Recreational sedentary screen time (rSST) is the most prevalent form of discretionary sedentary behavior and is strongly linked to poor health outcomes. However, the relationship between time spent in rSST and other 24-h behaviors is not well understood. The purpose of this study was to examine between- and within-day associations between rSST and other 24-h behaviors that include other non-rSST sedentary time (other-SED), standing (STAND), light physical activity (LPA), moderate-to-vigorous physical activity (MVPA), and total sleep (SLEEP). Baseline data from participants randomized to the StandUPTV study, an intervention aimed to reduce rSST in adults, were included. All 24-h behaviors were assessed continuously for 7-days. The activPAL device was used to assess rSST, other-SED, STAND, LPA, and MPVA; SLEEP was assessed using a GENEactiv accelerometer. rSST was collected using Wi-Fi plugs to capture TV time and tablet app usage. A multilevel modelling approach was used to assess bidirectional associations between rSST (total, daytime, evening) and 24-h behaviors at the between-person (across persons) and within-person (across days) levels, adjusting for age, sex, chronotype, education level, and week versus weekend day. The results were scaled hourly for interpretation. On average, 8.0 ± 1.6 days of continuous daily 24-h behavior data were included from 94 participants (age [M ± SD: 42.3 ± 11.5] years; 82% female; 78% White; BMI [M ± SD: 29.8 ± 7.8] kg/m This is the first known analysis of the bidirectional relationship between rSST and 24-h behaviors. The negative association between rSST and other-SED suggests that rSST may displace rather than contribute to more cumulative sedentary time. These findings advocate that contexts of sedentary behavior should be considered as distinct behavioral targets in intervention development. Future interventions targeting rSST reduction should also include strategies to reduce total sedentary time. NCT04464993. Show less

Tuberculous pyomyositis is a rare and often under-recognized extrapulmonary manifestation of tuberculosis, presenting with non-specific symptoms such as fever and abscess, that may delay diagnosis. We report a unique case of disseminated tuberculous pyomyositis in a 56-year-old male with underlying chronic inflammatory arthritis. The diagnosis was confirmed using CBNAAT, line probe assay (LPA), and histopathology. Currently MRI is the standard imaging modality in use for imaging pyomyositis. Show less

On the basis of life-style changes and statins, current guidelines recommend early combination therapy to reduce LDL cholesterol (LDL-C). Available and future novel non-statin lipid-lowering therapies may have specific advantages in patients with (1) statin intolerance, (2) elevated triglyceride-rich lipoproteins, (3) elevated lipoprotein(a), and (4) rare genetic dyslipidemias. Currently available treatment options to lower LDL-C with proven cardiovascular benefit include statins, ezetimibe, bempedoic acid, and PCSK9 antibodies. The 2025 update of the ESC/EAS dyslipidemia guidelines incorporates recommendations on early combination treatment and management of rare dyslipidemias, which are detailed in this review. Novel LDL-C-lowering strategies, targeting PCSK9 and CETP, may further improve dyslipidemia management. Drugs in development with profound effects on lipoprotein(a) or triglyceride concentration may allow for specific modification of residual cardiovascular risk. Innovative DNA-targeting therapies are moving towards clinical testing in larger studies. Various treatment options for patients with dyslipidemia and distinct characteristics have become available. Future developments may allow for even more tailored treatment, depending on dyslipidemia phenotype. 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

Obesity-related health issues, including cognitive decline linked to hippocampal neurogenesis and neuroplasticity, are gaining more attention as obesity rates rise worldwide. Physical activity is recognized as a potent stimulator of neurotrophic factors. This study examined the impact of six weeks of treadmill training on hippocampal molecular pathways in adult female Zucker diabetic fatty (obese) and Zucker lean rats. Animals were assigned to either treadmill exercise (n = 10) or sedentary control (n = 10) groups. Endurance training (ET) markedly upregulated mRNA expression of brain-derived neurotrophic factor and its receptor. The PI3K/Akt pathway was upregulated only in the trained lean rats and downregulated in the trained obese group compared with sedentary controls. ET elicited divergent effects on neurotrophin-associated PLCγ/PKC/CAMKII signalling between lean and obese groups. Sedentary obese rats primarily utilized the PLCγ/PKC axis, while both trained groups (lean and obese) showed increased CAMKII expression, associated with enhanced synaptic plasticity and memory. Enhanced synaptophysin mRNA indicated improved synaptogenesis and plasticity following ET. Trained obese rats also exhibited reduced expression of the microglial pro-inflammatory marker Iba1, alongside increased markers of oligodendrocyte regeneration and neurofilament expression. Behavioral assessment via the passive avoidance test demonstrated improved learning and memory in trained obese animals. Collectively, these findings suggest that ET may mitigate obesity-induced hippocampal damage, exert neuroprotection, and enhance hippocampal function. Show less

This study was conducted to assess the clinical significance of programmed cell death-ligand 1 (PD-L1)-positive circulating tumor cells (CTCs) as predictive biomarkers for the efficacy of PD-(L)1 inhibitor-based treatment in advanced hepatocellular carcinoma (HCC). We enrolled 59 patients with unresectable HCC who received immunotherapy-based treatment and analyzed CTCs, PD-L1 CTCs were detected in 86.4% (51/59) of patients, with a PD-L1-positive rate of 83.7% (41/49). Compared with the "PD-L1 PD-L1 Show less

Although increased maternal androgens, such as those in polycystic ovary syndrome (PCOS), are associated with a higher incidence of autism spectrum disorder (ASD) in offspring, a causal link has yet to be established. We assessed whether perinatal hyperandrogenization in a murine model recapitulates core ASD traits and compared this model to the maternal immune activation (MIA) model of ASD. Both models produced ASD-like phenotypes, yet they exhibited distinct behavioral subtypes and neurodevelopmental trajectories. Hyperandrogenized offspring showed greater reductions in social communication (neonatal USVs, d = 0.633-0.773; juvenile USVs, d = 1.103-1.216; social preference, d = 0.715), whereas only MIA offspring showed increased repetitive behaviors (d = 0.599). Ex vivo magnetic resonance imaging revealed volume increases in specific cortical regions in both models, with MIA additionally showing absolute cingulate cortex enlargement, and hyperandrogenized mice displaying focal increases in sexually dimorphic regions, despite a 36% reduction in overall brain volume (FDR 10%). Placentas from both groups showed reduced LIX (CXCL5), but distinct immune shifts also emerged: MIA placentas exhibited elevated IL-4 and IL-1β, whereas hyperandrogenized placentas showed increased TNFα. In neonatal brains, both conditions were associated with reduced IL-2, with MIA additionally decreasing IL-17A and IL-12p70, suggesting suppression of Th1/Th17-type cytokine signaling that normally supports proinflammatory and immune-neural interactions. DRD2 and BDNF protein were upregulated in hyperandrogenized fetal brains but downregulated with MIA. These results suggest that hyperandrogenization and MIA act through distinct mechanisms, producing subtle neurodevelopmental and behavioral differences consistent with human ASD subtypes. Show less

Novel therapeutic approaches, such as exosome therapy, have garnered considerable attention for the treatment of central nervous system (CNS)-related disorders. This study aimed to investigate the effect of Neural stem cell-derived exosomes(Exo-NSC) on improving behavioral, molecular, and electrophysiological symptoms. Rats were divided into: control, lesioned groups (Alz, Alz + saline), treatments (Alz + NSC, Alz + Exo-NSC). the nucleus basalis of meynert (NBM) was lesioned using electrical lesion. One week after lesion, saline, NSC, and Exo-NSC were injected into the NBM. Twenty-eight days post-injection, behavioral tests (passive avoidance memory and locomotor activity) and EEG recordings were conducted. Subsequently, hippocampal levels of brain-derived neurotrophic factor (BDNF) and acetylcholine (ACh) were measured. NBM lesioning significantly reduced the step-through latency (STL), decreased alpha and gamma wave frequencies, increased theta and delta wave frequencies, and reduced Ach and BDNF levels compared to the control group. The NSC injection resulted in decreased delta wave frequency, increased gamma wave frequency, and elevated BDNF levels. Meanwhile, Exo-NSC injection significantly increased STL, beta and gamma wave frequencies, and levels of ACh and BDNF compared to lesioned groups. Overall, the findings indicate that Exo-NSC injection may be more effective than NSCs in improving passive avoidance memory. This benefit may stem from elevated hippocampal ACh and BDNF levels in the hippocampus. Show less

Current evidence is unclear due to methodological limitations. We bridge critical knowledge gaps by quantifying the longitudinal changes in movement behaviours and their correlates from early childhood through adolescence. Longitudinal observational cohort study. General healthy child and adolescent sample in Singapore. Growing Up in Singapore Towards healthy Outcomes study participants. We used wrist-worn accelerometry and proxy-reported data to examine movement behaviours (sleep, inactivity, light physical activity (PA; LPA) and moderate-to-vigorous PA (MVPA) and screen-viewing) at ages 5.5, 8, 10 and 12 years and the sociodemographic and maternal lifestyle-related correlates using linear regression models with generalised estimating equations. Among 837 children, sleep, LPA and MVPA declined by 3% (from 9.1 to 8.8 hours/day), 24% (from 5.8 to 4.4 hours/day) and 44% (from 71.3 to 40.1 min/day), respectively, while inactivity and screen viewing increased by 26% (from 8.0 to 10.1 hours/day) and 155% (from 1.8 to 4.6 hours/day), respectively, from ages 5.5 to 12 years. The greatest annual increase in inactivity (0.6 hour/annum) and screen-viewing (0.8 hour/annum) and decrease in LPA (0.3 hour/annum) and MVPA (10.4 min/annum) occurred from ages 8 to 10 years. Girls of Malay ethnicity and lower socioeconomic status, and whose mothers had less favourable movement behaviours, had significantly less sleep, higher inactivity and screen-viewing and/or lower PA. Maternal PA levels and/or sitting time were associated with children's sleep, inactivity and MVPA up to age 8 years, while maternal sitting and screen-viewing behaviours were associated with children's screen-viewing at all ages. Using contemporaneous datasets relevant to the present day, we confirmed that children become less physically active and have longer screen-viewing as they transition into adolescence and highlighted characteristics to be prioritised in future interventions. Show less

Massive open online courses (MOOCs) have transformed global education, yet their long-term effectiveness and evolving learner engagement remain underexplored. This study aims to comprehensively evaluate a nursing MOOC over six years, examining learner engagement, identifying distinct learner profiles, and assessing changes across different developmental stages to inform future MOOC design. A retrospective study was conducted on 4171 completers of the Medical Nursing MOOC on a Chinese MOOC platform, covering eleven semesters from 2018 to 2023. Latent profile analysis (LPA) categorized learners based on unit test scores, and profile distributions were compared across the MOOC's developmental stages. The Medical Nursing MOOC attracted 69,642 registrants with a 5.99% completion rate. Among the 4171 individuals who completed the course, latent profile analysis identified six distinct learner types, demonstrating significant differences in overall learning effect (H = 2823.604, P < 0.001). The chi-squared analysis revealed significant differences between the proportions of the six profiles regarding MOOC developmental stages (χ Findings highlight the evolving role of MOOCs in nursing education. Despite challenges in long-term engagement, the increasing proportion of highly engaged learners and declining dropout rates indicate growing effectiveness and sustainability. These insights provide evidence-based guidance for optimizing MOOC design and implementation. Show less

Data are limited regarding national clinician awareness, testing, and treatment of lipoprotein(a) [Lp(a)]. We conducted a national survey of US clinicians to investigate these issues. An internet-based survey of awareness, testing and treatment of Lp(a) was administered by a medical survey company to clinicians who have been in practice ≥5 years in the US or its territories. 2002 clinicians completed the survey: 47 % were primary care, 35 % cardiology, 9 % endocrinology, and 9 % neurology. 28 % were female, 24 % Asian, 4 % Hispanic, and 3 % Black. Most clinicians agree knowing the Lp(a) level can improve risk assessment and patient engagement. Patients with premature or recurrent CVD events are most likely to be targeted for Lp(a) testing and for prescribing possible future Lp(a)-targeted therapies. Show less

The hepatocytes orchestrate anabolic and catabolic pathways by dynamically modulating mitochondria–endoplasmic reticulum contacts (MERCs) in response to dietary fluctuations. While MERCs exhibit pronounced dietary sensitivity, the underlying regulatory mechanisms remain poorly elucidated. Here, a bimolecular fluorescence complementation-based proximity labeling strategy was utilized to identify the MERCs proteomes in hepatocytes under various nutritional conditions. As a result, many previously uncharacterized MERCs proteins were identified to be sensitive to nutritional state, suggesting that these proteins might play important roles in regulating hepatic metabolism. We further demonstrated that FADS3 accumulates at MERCs under starvation. FADS3 was proved to play important role for the maintenance of MERCs in both cell lines and mice liver. Deficiency of FADS3 in mice liver induces altered sphingolipid metabolism under starvation. Our study provided comprehensive insights into the composition and dynamics of mitochondria-ER contacts in hepatocytes under various metabolic conditions, and also revealed key regulatory proteins linking mitochondria-ER contacts and metabolic adaptation. [Image: see text] The online version contains supplementary material available at 10.1186/s12964-026-02679-5. Show less

Diabetic peripheral neuropathy (DPN), a complication of diabetes, is characterized by complex pathophysiology, high global morbidity, and limited early diagnostic tools. MicroRNAs (miRNAs) have emerged as potential regulators in DPN. This study aimed to investigate miR-210-3p as a diagnostic biomarker for DPN and elucidate its molecular mechanisms in disease progression. A total of 72 type 2 diabetes patients, 75 DPN patients, and 70 healthy controls were enrolled. Serum miR-210-3p expression was measured by RT-qPCR, and its diagnostic value was evaluated using ROC curve analysis. Multivariate logistic regression identified risk factors for DPN in type 2 diabetes patients. In vitro, a high-glucose (HG) induced RSC96 Schwann cell model was established to explore miR-210-3p function. Dual-luciferase reporter experiments demonstrated that miR-210-3p directly targets BDNF. Additionally, CCK-8 assays measured proliferation, flow cytometry analyzed apoptosis, and transwell chambers quantified cell migration. Serum levels of miR-210-3p were markedly elevated in DPN patients compared with both type 2 diabetes subjects and healthy controls (P < 0.001). The diagnostic performance was robust, achieving an AUC of 0.830 (sensitivity 72.0%; specificity 80.6%). Multivariate analysis confirmed miR-210-3p, fasting blood glucose, and glycated hemoglobin A1c as independent DPN risk factors. MiR-210-3p negatively regulated BDNF, and the miR-210-3p inhibitor reversed HG-induced Schwann cell dysfunction, while BDNF knockdown abrogated this protective effect. MiR-210-3p serves as a potential diagnostic biomarker for DPN and regulates Schwann cell function via targeting BDNF, providing novel insights into DPN pathogenesis and therapeutic targets. Show less

The glucagon-like peptide-1 receptor (GLP-1R) has emerged as a promising therapeutic option for alcohol use disorder (AUD), yet the underlying mechanisms and neurocircuitry involved remain unclear. This study aimed to analyze GLP-1R gene expression changes in brain regions associated with alcohol's effects, including the prefrontal cortex (PFC), nucleus accumbens (NAc), and hippocampus (HIP), in mice following 42 days of voluntary ethanol consumption (VEC; 10% v/v) and postmortem samples from 18 patients with AUD. Additionally, we examined the expression of OPRM1 (mu-opioid receptor) and BDNF (brain-derived neurotrophic factor), key targets related to alcohol intake and reward, in the NAc and HIP, respectively. GLP-1R gene expression was significantly reduced in all brain regions of ethanol-exposed mice and AUD patients. These reductions paralleled decreased OPRM1 and BDNF expression in the NAc and HIP, respectively. Pearson and Spearman correlation analyses revealed no significant associations between gene expression and age, RIN, pH, postmortem interval (PMI), body mass index (BMI), smoking status, age of onset of alcohol use, or years of drinking. In summary, chronic alcohol consumption in humans or mice was associated with decreased GLP-1R gene expression in brain regions involved in the reinforcing effects of ethanol. These findings open new avenues for further research into how this emerging receptor could serve as a potential biomarker and therapeutic target in AUD. Show less

Computerized cognitive training allows real-time tracking of performance metrics that may serve as digital biomarkers. This study investigated the value of a novel in-game digital biomarker, RTACC (Reaction Time-Accuracy Correlation), the correlation between reaction time and accuracy, using data from 130 participants with mild cognitive impairment enrolled in the intervention arm of the SUPERBRAIN-MEET randomized controlled trial. Participants underwent a 24-week multi-domain intervention, consisting of computerized cognitive training, physical exercise, nutritional education, vascular/metabolic risk management, and motivation enhancement. RTACC was derived from task-level RT and accuracy and examined in relation to cognitive and biomarker outcomes. Linear regression analysis revealed a significant association between RTACC and changes in Repeatable Battery for the Assessment of Neuropsychological Status scores from baseline to 24 weeks (beta coefficient = -11.90 ± 3.78, T = - 3.14, P = 0.002). RTACC also showed a marginal effect on changes in brain-derived neurotrophic factor levels (beta coefficient = - 3.13 ± 1.64, P = 0.057). Logistic regression analysis demonstrated that RTACC combined with clinical information identified good responders with an area under the receiver operating characteristic curve of 0.73 (95% CI: 0.62-0.84). These findings suggest that this in-game digital biomarker (RTACC) may help identify individuals likely to benefit from multi-domain intervention. Show less

In the phase 3 CLEAR study, lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with clear cell renal cell carcinoma (ccRCC). Previous preclinical studies demonstrated that lenvatinib attenuated tumor-associated macrophage (TAM) infiltration into tumor tissues by inhibiting fibroblast growth factor receptor (FGFR). However, the role of the FGFR pathway in ccRCC remains underexplored. This study aims to evaluate FGFR1-4 expression in ccRCC and investigate its relationship with the tumor microenvironment, particularly TAM. We primarily analyzed FGFR1-4 expression and CD163 positive cell count as estimation of TAM infiltration in 57 ccRCC specimens from patients undergoing nephrectomy using immunohistochemistry. Transcriptomic analysis was performed to assess immune-related gene signature and gene expressions. FGFR1 expression was elevated in over 80% of ccRCC samples and was significantly associated with increased CD163-positive TAM infiltration. FGFR1 expression was also negatively correlated with the IMmotion150 Teff gene signature and the expression of interferon-γ signaling targeted genes such as IFNG, GZMB, and CD274, suggesting an immunosuppressive phenotype. In contrast, FGFR2 and FGFR4 expression were less prevalent, and FGFR3 expression was not detected. This study provides the first comprehensive evaluation of FGFR1-4 expression in ccRCC and suggests that FGFR1 expression may contribute to the immunosuppressive tumor microenvironment by recruiting TAM. These findings indicate that FGFR1 could serve as a potential biomarker for therapeutic strategies and highlight the need for further research to explore FGFR-targeted therapies in ccRCC. Show less