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Hospitalization-associated disability (HAD) is linked to poor post-discharge outcomes in older individuals with heart failure (HF). We investigated whether HAD could be predicted by physical activity measured using a wearable device. We retrospectively analyzed data from 104 older individuals with HF whose physical activity was recorded for 3 consecutive days after initiating cardiac rehabilitation. Physical activity was categorized as sedentary behavior (≤1.5 metabolic equivalents [METs]), light-intensity physical activity (LPA; 1.6-2.9 METs), and moderate-to-vigorous physical activity (≥3.0 METs). HAD was observed in 31 (29.8%) individuals. LPA duration was significantly shorter in the HAD than non-HAD group (mean [±SD] 45.7±24.9 vs. 121.2±67.4 min/day; P<0.0001). In receiver operating characteristic curve analysis, the optimal LPA cut-off was 68 min/day, with 87.1% sensitivity and 80.8% specificity (area under the curve=0.888; P<0.0001). Physical activity measured using a wearable device may be useful in predicting HAD in older individuals with HF. Show less

Chronic alcohol exposure disrupts blood-brain barrier (BBB) integrity and promotes neuroinflammation, with P2X7 receptor (P2X7R) signaling playing a critical role. Our prior work in male mice linked P2X7R inhibition to reduced extracellular adenosine triphosphate (eATP) release, modulated extracellular vesicle (EV) cargo, and attenuated neuroinflammation in chronic intermittent ethanol (CIE)-exposed mice. However, sex-specific roles of P2X7R signaling and EV-mediated mechanisms in alcohol-induced neuroinflammation remain unclear. Male and female mice were exposed to ethanol vapor for three weeks and treated with Brilliant Blue G (BBG), a P2X7R inhibitor. Compared to their respective CIE-unexposed controls, brain gene expression of tumor necrosis factor-α ( Show less

Dysregulated actions of the bone-derived phosphaturic hormone, fibroblast growth factor-23 (FGF23), underlie the pathophysiology of several diseases. FGF23 is synthesized primarily in osteocytes in response to various endogenous molecules; however, the mechanisms governing FGF23 production are incompletely understood. Glycerol-3-phosphate (G3P), a glycolytic by-product originating from the kidney, critically controls skeletal FGF23 synthesis via its conversion in bone to lysophosphatidic acid (LPA), which stimulates osteocyte FGF23 production. The bioactive vitamin D, 1,25-dihydroxyvitamin D (1,25D), also promotes FGF23 production in osteocytes. We herein demonstrated that LPA requires 1,25D action to raise FGF23 levels in mouse bone explants and mice. RNA sequencing of osteocyte-like Ocy454 cells identified differentially expressed genes (DEGs) uniquely induced by LPA/1,25D co-treatment. These unique DEGs were enriched for the ribosome biogenesis pathway. DEGs concurrently induced by individual LPA and 1,25D treatments were enriched for MAPK signaling, and inhibiting this pathway obliterated LPA/1,25D-induced FGF23 production. DEGs following LPA/1,25D co-treatment were enriched for the cytokine-cytokine receptor interaction pathway. Moreover, LPA/1,25D co-treatment, but not individual LPA and 1,25D treatments, rapidly induced the expression of Il12a, the gene encoding the pro-inflammatory cytokine interleukin-12 alpha-subunit, which responded solely to 1,25D at later times and required MAPK-ERK1/2 signaling. Inhibiting cytokine signaling or knocking down Il12a inhibited, while overexpressing Il12a enhanced LPA/1,25D-induced FGF23 production. However, challenging Ocy454 cells with recombinant bioactive interleukin-12 failed to enhance FGF23 production, suggesting that Il12a plays a noncanonical role. Our results reveal a mechanism of skeletal FGF23 synthesis involving synergistic actions of LPA and 1,25D, advancing our understanding of FGF23 regulation. Show less

The t(10;11)(p13;q14-21) PICALM::MLLT10 chromosomal translocation results in the production of the CALM-AF10 fusion oncoprotein and is a driver mutation in both acute myeloid and T-lymphoblastic leukemia. PICALM::MLLT10 translocated leukemia is primarily an epigenetically driven disease. Global hypomethylation results in genomic instability, while focal H3K79 hypermethylation at target genes induces cell proliferation and blocks differentiation. Nucleocytoplasmic shuttling of CALM-AF10 and its protein partners and impaired endocytosis at the plasma membrane further influence the leukemic phenotype. Leukemias characterized by PICALM::MLLT10 have historically been recognized to portend a poor prognosis; however, insights from larger patient cohorts provide refinement to the prognostic relevance of this chromosomal translocation, highlighting chemotherapy resistance in this leukemic subtype. In addition, a deeper biological understanding of the disease hints at potential therapeutic targets. This approach is demonstrated in the recent promising results achieved utilizing venetoclax, a BCL2 inhibitor, in patients with PICALM::MLLT10 acute leukemia. Herein, we provide updates on the pathophysiology, clinical presentation, prognosis, and treatment of PICALM::MLLT10 acute leukemia. Show less

Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain. This systematic review investigates sex differences in AD and summarizes key findings from neuroimaging studies over the past two decades to examine how genetics, hormones, and lifestyle factors influence neuroimaging biomarkers and their correlation with cognitive decline and AD progression. A comprehensive literature search was conducted across several databases for human studies from 2004 to 2024 related to AD, biological sex differences, and neuroimaging. After a 3-step review process, the final extraction included 120 peer-reviewed studies using various neuroimaging modalities, such as MRI, amyloid-beta PET, tau-PET, and fluorodeoxyglucose (FDG) PET, to investigate sex as a biological predictor variable in adults with or at risk for AD. Over 90% of the reviewed studies identified clear sex-specific patterns of imaging biomarkers related to cognitive reserve, hormonal changes, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle factors. Machine learning studies increasingly incorporate sex as a key variable, revealing sex-specific biomarkers and improving model performance in predicting disease status and progression. Considering biological sex in AD research is essential for improving diagnostic accuracy, tailoring interventions, and health outcomes. This systematic review identifies sex-specific patterns in neuroimaging biomarkers of AD, influenced by cognitive reserve, hormones, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle. Recognizing these differences is crucial for understanding, diagnosis, and treatment efficacy. Show less

SARS-CoV-2 is the causative agent of COVID-19, and although vaccines have reduced disease severity, emerging variants remain a significant public health issue. Broadly effective therapeutics, particularly those targeting host pathways essential for coronavirus infection, are still needed. Here, we used a CRISPR knockout screen to identify druggable host factors required for SARS-CoV-2 infection. The screen revealed NAE1 and FGFR1 as key contributors to infection. Inhibitors, either FDA-approved or those in clinical trials, of these pathways reduced replication of both ancestral and contemporary viral variants. Mechanistic studies showed that FGFR1 promotes viral replication through downstream MEK/ERK signaling, while neddylation appears to support viral entry or infectivity rather than replication itself. In a murine model of severe COVID-19, inhibitors of NAE1 and FGFR1 significantly decreased viral load and lung pathology. These findings support the development of host-targeted antiviral strategies. Show less

CLN3 disease, or Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), is a rare, genetic neurodegenerative condition, typically manifesting in the first decade of life and progressing in severity, with death typically occurring in early adulthood. Despite two decades of natural history research, a clear timeline of CLN3 disease symptom onset and progression remains poorly defined, limiting optimal patient management and therapeutic development. We conducted a literature review and analysed the natural history data to better understand the age of core symptom onset and chronological disease progression. A literature review was undertaken using a pre-defined search strategy focused on CLN3 disease natural history studies, where age at onset for one or more core symptoms was reported in cohorts of ≥ 15 subjects. For each symptom, weighted mean age at onset and weighted standard deviation were calculated, with 95% confidence intervals derived from the weighted standard error. Symptom onset ages were compared using ANOVA. We identified nine natural history studies that met our pre-defined criteria. In total, 423 discrete patients aged between 4 and 39 years were reported. Thirteen core symptoms and a weighted average age at onset and weighted standard deviation were (in years): vision loss (6.1 ± 1.6, This comprehensive summary of available natural history data illustrates mean age at onset of 13 core symptoms of CLN3 disease, and characterises a chronological timeline of disease progression. These results provide much-needed practical, anticipatory guidance to those involved in caring for individuals with CLN3 disease, and serve to highlight the critical importance of collecting globally standardised, quantifiable, longitudinal data for optimising patient management and advancing therapeutic approaches for CLN3 disease. The online version contains supplementary material available at 10.1186/s13023-025-04174-5. Show less

The pervasive nature of social media has given rise to the phenomenon of fear of missing out (FoMO), which poses significant challenges to the mental health of children. By drawing on an individual-centered approach, this study aims to provide a nuanced understanding of FoMO. We delved into the evolving nature of FoMO patterns among 541 Chinese primary school students within a one-year interval. Employing Latent Profile Analysis (LPA) and Random Intercept Latent Transition Analysis (RI-LTA), we uncovered three distinctive profiles of FoMO: Social Sentinels, Worry Warriors and Untroubled Buddies. To predict transitions between these profiles, we examined anxiety and mindfulness. We also investigated the relationship between two related outcomes and latent transitions. The results revealed that the Untroubled Buddies profile was relatively stable, while the Social Sentinels and Worry Warriors profiles showed more frequent transitions over time. Regarding the antecedents, our findings demonstrated that primary school students with high anxiety were more likely to be categorized under the Social Sentinels and Worry Warriors profiles, increasing their risk of transitioning from the Untroubled Buddies profile to the other two profiles over time. Regarding the associations with outcomes, significant differences emerged among the three profiles in terms of emotional and behavioral problems as well as depression at three measurement points. Identifying different FoMO profiles among primary school students and understanding the nature of transitions between these profiles have implications for developing targeted interventions to mitigate FoMO risks among primary school students, as well as preventing individuals from transitioning into profiles associated with higher risks of emotional and behavioral problems and depression. Show less

Lecanemab has been approved for the treatment of mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia based on the efficacy in slowing cognitive decline and preliminary safety data from the phase Ⅲ Clarity AD trial. However, this trial excluded patients with high risk of cerebral hemorrhage, such as individuals with intracranial aneurysms or > 4 microhemorrhages. A 70-year-old male with mild AD, intracranial aneurysm, microhemorrhages, and APOE ε3/ε4 genotype received lecanemab after multidisciplinary evaluation and informed consent. Over six months of intensive monitoring, cognitive function stabilized with no deterioration, daily activities were preserved, microhemorrhages remained stable (with one new small lesion noted at 3 months), and no aneurysm rupture or severe adverse events (including amyloid-related imaging abnormalities) occurred. This case suggests that, despite hemorrhage risks, lecanemab may have a manageable risk-benefit profile in selected real-world AD patients under intensive monitoring and multidisciplinary care, with its application beyond clinical trial criteria requiring more nuanced and individualized consideration. Show less

For young people in Europe, European identity can serve as an important source of solidarity and belonging, especially in times of growing societal polarization. This study investigates European identity development during adolescence with two aims: (1) to identify European identity profiles, their associations with civic and solidarity-related attitudes, and profile changes over time; and (2) to examine the role of school-based experiences in predicting profile membership and transitions. Drawing on longitudinal data from German 9th graders collected at the beginning and end of one school year (N = 1,206; MAge = 14.39 years; 51.7% female), Latent Profile Analysis (LPA) and Latent Transition Analysis (LTA) were used to examine stability and change of European identity profiles. Based on recent process-oriented models, European identity captured the processes of commitment, in-depth exploration, and reconsideration. Civic and solidarity-related correlates of status profile encompassed EU-related attitudes, tolerance, and intentions for civic engagement; school-based predictors included students' supportive relationships and pluralistic learning climate. Analyses revealed four distinct profiles reflecting different levels of identity consolidation, meaningfully associated with civic- and solidarity-related attitudes (i.e., tolerance, intentions for civic engagement). A more pluralistic climate was associated with more elaborate identity profiles at the beginning of the school year, while supportive student-teacher relationships were linked to forms of early closure. Yet, school experiences hardly predicted profile change across time. The findings underscore adolescence as a formative period for developing European identity and highlight both the potential and limitations of schools in supporting youth identity formation. Show less

Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation, characterized by upregulated glycolysis, initiates atherosclerosis, yet the contribution of histone lactylation remains undefined. Although narciclasine exhibits anti-inflammatory and antioxidant properties, its impact on endothelial inflammation in atherosclerosis is unknown. Connectivity Map (CMap) analysis predicted narciclasine as an inhibitor of oscillatory shear stress and TNF-α-induced endothelial inflammation. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with 20 nM narciclasine significantly suppressed ox-LDL-induced expression of VCAM1, ICAM1, SELE, and CCL2, reduced reactive oxygen species (ROS) production, and inhibited monocyte adhesion and migration. In vivo, administration of narciclasine (0.02 mg/kg) attenuated carotid artery endothelial inflammation and macrophage infiltration, consequently reducing early atherogenesis in partial carotid ligation model in ApoE Show less

Neonatal hyperoxia is a key contributor to bronchopulmonary dysplasia (BPD) which is characterized by airway hyperreactivity due to increased contraction and impaired relaxation of airway smooth muscle (ASM). This study investigated whether inhibition of the Rho/Rho-kinase signaling pathway restored tracheal smooth muscle (TSM) relaxation and reactivated the nitric oxide-guanosine 3',5'-cyclic monophosphate (NO-cGMP) pathway in neonatal rats exposed to hyperoxia. Newborn rats (P4) were exposed to either ambient air (AA; n = 61) or hyperoxia (FiO Show less

Oxypeucedanin (OPD) showed anti-allodynia against neuropathic pain (NeuP) in our previous study. In the present study, we aimed to further investigate whether lysophosphatidic acid receptor (LPAR) signaling mediated OPD-induced antinociception against NeuP models. Single OPD treatment dose-dependently reduced pain hypersensitivity, and repeated OPD treatment maintained sustained antinociception without the development of tolerance. Importantly, OPD exhibited a significant curative effect on different stages of NeuP. ROCK and RhoA agonists prevented the therapeutic effect of OPD, while the inhibitors of LPAR, ROCK, and RhoA mimicked OPD-induced antinociception. Notably, OPD treatment attenuated the increases of LPA content and protein expression of LPAR1, RhoA, and Show less

Despite therapeutic advances, atherosclerosis remains a major global health challenge. Most current treatments target systemic risk factors rather than the diseased vascular wall. Our previous work identified genistein, a soy isoflavone, as a cannabinoid receptor 1 (CB1) antagonist capable of suppressing CB1-mediated vascular inflammation and atherosclerosis. However, its poor water solubility and low oral bioavailability limit clinical application. We aimed to develop water-soluble, orally bioavailable CB1 antagonists for atherosclerosis and to investigate the role of endothelial CB1 in hemodynamic regulation. RNA-sequencing datasets from the NCBI GEO repository were analyzed to assess CB1 expression in atherosclerotic patients. Apolipoprotein E-deficient (Apoe We found CB1 was upregulated in atherosclerotic lesions from patients and mice, and in endothelial cells exposed to disturbed flow. Mechanistically, this was driven by ZNF610 and Spi1 binding and KLF4 dissociation at the CB1 promoter. Daidzein, a soy isoflavone structurally similar to genistein, was identified as a novel CB1 antagonist. To enhance solubility and bioavailability, we developed genistein 7-O-phosphate (G7P) and daidzein 7-O-phosphate (D7P). Pharmacological treatment with these isoflavone monophosphates or genetic CB1 ablation reversed disturbed flow-induced endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT). Oral administration of G7P and D7P significantly reduced atherosclerotic plaque formation in mice. This is the first study to identify transcriptional regulators that drive endothelial CB1 upregulation in response to disturbed flow. We further demonstrated that isoflavone monophosphates ameliorate disturbed flow-induced endothelial dysfunction and EndMT via CB1 inhibition, offering promising oral therapeutics for atherosclerosis. Show less

The poor efficacy of chemotherapy for glioma is mainly due to the difficulty of drug penetration through the blood-brain barrier (BBB), as well as the difficulty of drug concentration in the tumor tissue to reach the effective therapeutic level. The emerging tumor-targeted delivery technology can facilitate the precise enrichment of drugs in the tumor site. Apolipoprotein E (ApoE(159-167) Show less

Acute myeloid leukaemia (AML) is a genetically heterogeneous malignancy associated with poor prognosis and limited treatment options. To identify molecular programs conserved across AML subtypes and perturbations, we analysed three RNA sequencing datasets that captured venetoclax treatment under metabolic stress and the knockdown of chromatin regulators (PSPC1, JMJD1C, and RUNX1). Differential expression analysis was performed using DESeq2, followed by functional enrichment and network analyses. An independent AML cell line dataset was used to validate results. We identified a conserved 73-gene transcriptional signature that is consistently dysregulated across perturbations, characterised by the overexpression of CDKN1A, PHGDH, and ALDH1L2, and the downregulation of MYC and E2F targets. Functional analyses implicated cell cycle arrest, metabolic reprogramming, oxidative stress responses, and suppression of proliferative and biosynthetic pathways. PSPC1 emerged as a central hub linking chromatin remodelling to metabolic adaptation. Translational validation in the TCGA-LAML cohort revealed that higher 73-gene enrichment scores were associated with inferior overall survival, and stratification by hub gene expression recapitulated adverse prognostic trends. Collectively, these findings define a stress-adaptive transcriptional program conserved across diverse AML perturbations, providing mechanistic insights into the coupling of metabolism and the cell cycle, and potential therapeutic vulnerabilities. Incorporation of this 73-gene program into patient stratification frameworks may guide biomarker-driven therapies and combination strategies targeting metabolic and apoptotic stress responses. Show less

To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1 This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred. Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials. US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche. Show less

Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment compromises therapeutic efficacy. We developed an innovation CE-SKP/CPH/P2G3 scaffold which effectively repairs focal cartilage defects and emulates native cartilage ontogeny: the superficial CE-SKP hydrogel layer recruits SMSCs and promotes chondrogenesis; the middle CPH hydrogel layer induces chondrocyte hypertrophic calcification, forming cartilage calcified layer; and the basal P2G3 nanofiber membrane isolates subchondral cells, enforcing a top-down developmental sequence and preserving a localized hypoxic niche. Show less

Preschool children's activity patterns differ between weekdays and weekends. Weekdays are constrained by structured educational activities and parental commitments, which limit flexibility, while weekends provide opportunities for extra sleep (SLP), physical activity (PA), and reduced sedentary behavior (SB). This study aims to estimate optimal activity durations for both weekdays and weekends, based on the development of executive function (EF), fundamental movement skills (FMS), and physical fitness (PF) in preschool children. A total of 289 preschool children aged 3-6 years from four kindergartens in Zhejiang Province participated. PA and SLP were objectively measured using accelerometers and the Children's Sleep Quality Questionnaire. EF, which includes working memory, inhibitory control, and cognitive flexibility, was measured using the Early Years Toolbox (EYT). FMS were assessed using the test of gross motor development-3rd edition (TGMD-3), and PF was evaluated according to the National Physical Fitness Measurement Manual (Preschool Children Section). Compositional data regression models were applied to examine the relationship between 24-h movement behaviors and health outcomes on weekdays and weekends. Optimal time-use compositions for each outcome were estimated, and 3D quaternary plots were generated to define the Goldilocks Day at the center of the overlapping regions. 24-h movement behaviors were significantly correlated with EF (weekdays: F = 5.4, This study provides recommendations for time allocation on weekdays and weekends to support the healthy development of preschool children. Show less

Lipoprotein(a) [Lp(a)] and PCSK9 are emerging lipid biomarkers implicated in atherogenesis and residual cardiovascular risk, but their relationship with coronary disease complexity in acute coronary syndrome (ACS) is unclear. This study evaluates their serum levels in first-episode ACS patients versus controls and explores their relationship with SYNTAX score-defined coronary severity. This single-centre observational study enrolled 160 patients presenting with their first episode of ACS (aged 18-75) and 40 age-matched healthy controls. All participants were free from lipid-lowering therapy and major comorbidities. Fasting serum samples were collected to measure the standard lipid profile, Lp(a), and PCSK9 levels. The severity of coronary artery disease was quantified using the SYNTAX score after coronary angiography. The ACS cohort (mean age 55.7 years; 73.1 % male) most frequently presented with STEMI (53.7 %). Traditional risk factors included smoking/tobacco use (48.8 %), diabetes (40.0 %), and hypertension (38.1 %). Median SYNTAX score was 19.4. Compared with controls, ACS patients had significantly lower HDL-C and higher LDL/HDL and cholesterol/HDL ratios. Lp(a) (38.9 vs. 15.9 mg/dL, p < 0.001) and PCSK9 (272.3 vs. 169.6 ng/mL, p < 0.001) were markedly elevated in ACS patients. Neither Lp(a) nor PCSK9 correlated with SYNTAX score. LDL-C showed a modest positive correlation with Lp(a) (r = 0.163, p = 0.040). Higher SYNTAX scores were associated with more extensive multivessel disease. Patients with ACS exhibited significantly higher Lp(a) and PCSK9 levels compared with healthy controls, but these biomarkers did not reflect angiographic disease complexity. Their role may lie more in underlying cardiovascular risk assessment than in predicting anatomical severity. Show less

The ability to permeate the blood‒brain barrier (BBB) remains a major challenge in treating neurological disorders. Molecularly imprinted polymeric nanocarriers (nanoMIPs) are emerging as versatile platforms that integrate antibody-mimetic recognition with exceptional stability, tunable physicochemical properties, and controlled drug release. This review summarizes recent advances in nanoMIP design, including template selection, polymerization strategies, and surface modifications, and explores their potential for targeted brain delivery. Particular emphasis is placed on surface engineering approaches, such as functionalization with apolipoprotein E (ApoE), transferrin, and angiopep-2 ligands, which exploit receptor-mediated transcytosis (RMT) to increase BBB permeation and drug accumulation in pathological brain regions. The therapeutic and diagnostic applications of nanoMIPs in neurodegeneration, brain tumors, and CNS infections are also highlighted. Finally, current limitations and future perspectives are discussed, including biocompatibility, large-scale production, and regulatory considerations, positioning nanoMIPs as a next-generation platform for overcoming BBB-associated barriers, and advancing precision brain therapeutics. Show less

Traditional variable-centred approaches often analyse physical behaviours (sedentary behaviour [SB], light physical activity [LPA], and moderate-to-vigorous physical activity [MVPA]) in isolation, potentially masking their combined effects on outcomes. This study applied latent profile analysis, a person-centred approach, to identify naturally occurring physical behaviour profiles in older adults and examined their associations with physical fitness and physical function. This cross-sectional study included 1,095 older Portuguese adults (≥ 65 years; 765 females). SB, LPA, and MVPA were assessed using accelerometry (Actigraph; Pensacola, Florida) on the right hip and expressed as percentages of waking time. Latent profile analysis was used to identify distinct profiles based on these percentages. Physical fitness was evaluated by Senior Fitness Test battery and handgrip strength. Physical function was assessed using the 12-item Composite Physical Function questionnaire. Generalised linear models, adjusted for age, were used to examine associations between profiles and outcomes. Three distinct profiles emerged for both sexes: "balanced movers" (~ 50% SB, ~ 46% LPA, ~ 4% MVPA), "intermediate movers" (~ 66% SB, ~ 32% LPA, ~ 2% MVPA), and "highly sedentary" (~ 80% SB, ~ 20% LPA, < 1% MVPA). Compared to the "highly sedentary" groups, both "balanced movers" and "intermediate movers" demonstrated better performance on most physical fitness tests and reported higher physical function. Notably, "intermediate movers", performed similarly to "balanced movers" in most measures. Distinct physical behaviour profiles exist among older Portuguese adults. Profiles characterised by lower SB and higher LPA, even when not fully meeting MVPA recommendations ("intermediate movers"), were associated with better physical fitness and physical function compared to the "highly sedentary" profile. This underscores the importance of reducing SB and promoting LPA along with MVPA. By uncovering these behavioural profiles among older adults, latent profile analysis provides valuable insights to guide the development of more personalized interventions for healthy ageing. Show less

Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer's disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies capable of addressing these interconnected pathological mechanisms. Here, an Odorranalectin (OL)-conjugated lipid nanoparticle (siB/QU@L-OL) was engineered for efficient intranasal delivery of β-site APP cleaving enzyme 1 (BACE1) siRNA (siB) and quercetin (QU). siB/QU@L-OL prepared via microfluidics exhibited uniform size distribution, high encapsulation efficiency, and robust stability. Following intranasal administration, OL surface modification enabled binding to L-fucose residues expressed on the olfactory epithelium, reducing mucociliary clearance and facilitating brain transport. Show less

Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology. Show less

Parents play a critical role in influencing their young children's physical activity (PA) and sedentary time (ST). Despite this, many young children (aged 3-4y) and their parents are insufficiently active and engage in high amounts of ST. M-health interventions targeting PA and ST have seldom been tested in this population. The objective of this study was to examine the effectiveness and acceptability of the Active Family m-health intervention on the PA and ST of young children and their parents. Twenty-five stay-at-home parent-child dyads from Canada took part in the 2-week just-in-time micro-randomized controlled trial. Parents received seven text message prompts per day, where they were randomized to receive either a micro-intervention (activity suggestion) or control (no suggestion). Parents and children wore ActiGraph accelerometers to measure ST, light [LPA], and moderate-to-vigorous physical activity [MVPA]. Parents also completed a short online acceptability survey. A centred and weighted least square regression was used to analyze the effect of activity suggestions on the 60-min ST, LPA, and MVPA of parents and children following suggestion randomization. Descriptive statistics and content analysis were used to analyze acceptability survey responses. Micro-interventions were not effective at changing children's or parent's proximal ST (d = 0.01, p = .878; d = -0.09, p = .485, respectively), LPA (d = 0.03, p = .714; d = 0.03, p = .729, respectively), or MVPA (d = -0.05, p = .511; d = 0.10, p = .480, respectively). Interventions became more effective at increasing MVPA over time for parents (b = 0.47, 95%CI = 0.12, 0.83, p = .013). Among children, intervention effectiveness varied by contextual factors (e.g., weather). The intervention was largely acceptable, appropriate, and feasible for parents, though they did offer suggestions for improvement. Overall, micro-interventions did not significantly change parents or young children's proximal movement. Though, this approach showed promise for increasing parent's MVPA over time and for supporting children's activity under specific conditions. Show less

One important element impacting meat quality is fat metabolism, which mainly affects meat features through intramuscular fat deposition. Chinese native yellow-feathered broilers and white-feathered broilers differ significantly in intramuscular fat concentration. This study used transcriptomic and metabolomic sequencing technologies to identify a total of 173 differentially expressed genes and 259 differential metabolites in the pectoral muscles of Chahua Chicken No. 2 and Cobb broiler in order to explore the genetic mechanisms by which lipid metabolism influences meat quality in Chinese indigenous yellow-feathered and white-feathered broilers. These included differentially expressed genes like FABP1, LPL, ELOVL7, SLC27A1, MOGAT1, and ULK2, which were enriched in pathways relevant to lipid metabolism and showed strong associations with γ-linolenic acid and palmitaldehyde, two distinct metabolites. In order to develop local chicken germplasm resources and breed superior indigenous chicken varieties, these candidate genes could serve as the genetic foundation for the variations in meat quality and lipid metabolism between Chinese native yellow-feathered and white-feathered broilers. Show less

Autoimmune uveitis (AU) is a category of sight-threatening diseases with different pathological causes. Transcriptomic analysis of patients with AU revealed a highly oxidative stress profile as well as an up-regulated Show less

Atherosclerosis (AS) progression is driven by multiple interconnected pathological mechanisms. Among them, vascular senescence is both a key accelerator and consequence, interacting with other processes to promote AS development. Traditional monotherapies were limited to achieve synergistic therapeutic effects due to low oral bioavailability and insufficient multi-target efficacy. To overcome these limitations, we developed a baicalein-copper network (Cu-MON) for oral delivery of atorvastatin (ATV), forming a synergistic therapeutic system (CMA). Cu-MON significantly prolonged the gastrointestinal residence and increased the oral bioavailability of ATV without requiring additional excipients. Crucially, Cu-MON regulated senescence-associated genes, enhanced DNA repair pathways, and mitigated DNA damage, effectively counteracting vascular aging. The integrated CMA system combined enzymatic and non-enzymatic dual antioxidant systems to scavenge multiple ROS species. Furthermore, CMA reprogrammed macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, modulated the PPAR-γ/LXR-α/ABCA-1 pathway to enhance cholesterol efflux, inhibited foam cell formation, and regulated hepatic and systemic cholesterol homeostasis. In ApoE Show less

The COVID-19 pandemic has significantly disrupted educational style, potentially affecting the learning adaptation of nursing freshmen who are integral to the future nursing workforce. This study aimed to identify distinct subgroups of nursing freshmen based on their bioecological attributes related to learning adaptation during the pandemic. A multicenter, cross-sectional study was conducted of 1170 first-year nursing students from six higher education institutions in China. Learning adaptation, resilience, parental attachment, interaction anxiety, and mobile phone addiction, were investigated. Latent Profile Analysis (LPA) was utilized to identify distinct profiles. Descriptive statistics indicated a positive level of learning adaptation among participants, with an overall mean score of 3.51 ± 0.57. LPA revealed four distinct profiles: 'Struggling Learners' (5.47%), 'Moderate Engagers' (70.60%), 'Adaptable Strivers' (18.29%), and 'Optimal Adapters' (5.64%), which demonstrated significant differences in adaptation, resilience, parental attachment, interaction anxiety, and mobile phone addiction tendencies (P < 0.05). The study's findings emphasize the heterogeneity in learning adaptation among nursing freshmen and the importance of considering bioecological attributes when developing educational interventions during crisis. Recognizing these profiles can guide the development of targeted strategies to enhance student adaptation and academic achievement. Show less

Dietary fibre is an important regulator of the gut microbiome and is associated with many health benefits. However, high levels of fibre intake have also been reported to exacerbate some diseases. Here, we show that mice fed semi-synthetic diets supplemented with purified inulin fibre develop chronic infections with the parasitic whipworm Trichuris muris, concomitant with dysregulated innate antimicrobial defences, exacerbated mucosal inflammation, and altered tryptophan metabolism. Inhibition of tryptophan catabolism or neutralizing either IL-27 or IL-18 restored infection resistance. Inulin-fed mice developed gut microbiota dysbiosis during parasite infection, with Proteobacteria becoming dominant. However, despite drastic differences in gut microbiota compositions in control- and inulin-fed mice, microbiota transfer and depletion experiments demonstrated that dietary inulin triggered chronic T. muris infection in a microbiota-independent manner. Importantly, removing inulin from the diet within a critical immune development window rapidly restored anti-parasite immunity, indicating direct, time-dependent modulation of mucosal immune responses. These data reveal T. muris-induced dysbiosis as a consequence rather than a causative factor of diet-driven changes in host susceptibility, and establish a direct link between dietary fibre and host defence at mucosal surfaces. Video Abstract. Show less