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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and synaptic dysfunction and represents the most prevalent etiology of dementia, accounting for an estimated 60-70% of all clinically diagnosed cases worldwide. The growing focus on microglia-neuron interactions in AD research highlights their diverse, region-specific responses, which are driven by the functional and pathological heterogeneity across different brain regions. Therefore, investigating the interactions between microglia and neurons is of crucial importance. To explore the regional heterogeneity of microglia-neuron crosstalk in AD, we integrated human single-nucleus RNA sequencing data from the prefrontal cortex (PFC), hippocampus (HPC), and occipital lobe (OL) provided by the ssREAD database. Our study delineated four microglial subtypes and uncovered a pseudotime trajectory activation trajectory leading to the disease-associated microglia (DAM) phenotype. The transition along this trajectory is driven and stabilized by a key molecular switch: the coordinated downregulation of inhibitory factors (e.g., LINGO1) and upregulation of immune-effector and antigen-presentation programs, which collectively establish the pro-inflammatory DAM state. Furthermore, we observed that each brain region displayed unique microglia-neuron communication patterns in response to AD pathology. The PFC and OL engage a THY1-ITGAX/ITGB2 signaling axis; the HPC predominantly utilizes the PTPRM pathway. Notably, THY1 dysregulation strongly correlates with pathology in the PFC, HPC, and OL, suggesting that microglia-neuron crosstalk in AD possesses both heterogeneity and commonality. The main contribution of this study is the systematic characterization of region-specific microglia-neuron interactions and the identification of THY1 as a potential mediator that may be targeted therapeutically to modulate microglial function in affected brain regions. Show less

How schoolchildren distribute their time between movement behaviours may be impacted by the neighbourhood environment. Few studies have investigated the associations between the physical and social environment and the full movement behaviour composition, including times spent in moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary behaviour, and sleep, and their findings are inconsistent. Therefore, our aim was to investigate this association in a large, national-representative sample of schoolchildren from major cities and regional/remote areas. We used data from the Longitudinal Study of Australian Children and the Child Health CheckPoint study, collected among 1230 child-parent pairs (child age range: 10–12 years). Parents were asked about neighbourhood general safety, access to destinations and services, and social capital and cohesion. Children’s time spent in MVPA, LPA, sedentary behaviour, and sleep was assessed using wrist-worn GENEActiv accelerometers. The associations between the physical and social environment characteristics (independent variables) and movement behaviour composition expressed as isometric log ratio coordinates (dependent variables) were examined using multiple linear regression analyses, adjusted for age, body mass index, pubertal status, sex, and socioeconomic position. Among schoolchildren from regional/remote areas, access to destinations and services (Pillai’s trace = 0.030; These findings highlight the importance of access to destinations and services, as well as social capital and cohesion, in shaping the movement behaviour composition among schoolchildren from regional/remote areas. More research is needed to draw conclusions about the association between neighbourhood environment and movement behaviour composition among schoolchildren from major cities. The online version contains supplementary material available at 10.1186/s12966-026-01879-z. Show less

White matter hyperintensities (WMH) on T2-weighted brain magnetic resonance imaging (MRI) are common in aging and associated with small vessel cerebrovascular disease. Standard segmentation methods treat these lesions as uniform binary entities, fundamentally reducing WMH signal by flattening a complex spectrum of tissue damage into a single label. Most WMH methods threshold voxel intensities to estimate lesion volume, missing richer characterization achievable by combining fluid-attenuated inversion recovery (FLAIR) with diffusion MRI. We introduce Voxel-wise Correlation of Neighbors (VCON), a cross-modal framework that quantifies voxel-level relationships between intensity values on T2-weighted FLAIR scans and fractional anisotropy (FA) on diffusion MRI within individuals. VCON generates hypothesis-driven WMH labels by identifying regions where increased FLAIR signal is negatively correlated with FA, suggesting underlying microstructural damage. Using MRI data from over 2,500 participants in community-based aging cohorts, we validated VCON through multi-scale analysis, age-association modeling, scanner comparisons, and intensity-based clustering of WMH into spatially coherent zones with distinct microstructural profiles. VCON revealed a gradient of WMH signal variation that tracks with age and diffusion metrics across scanners and segmentation methods. These results demonstrate that binary WMH masks may obscure clinically important variation in lesion characteristics. VCON reframes lesion segmentation as characterizing microstructural heterogeneity, offering additional structure-informed characterization beyond conventional binary methods by leveraging multimodal MRI signal variation. Show less

Colorectal cancer (CRC) remains a major global health challenge, underscoring the need for reliable biomarkers to improve prognosis and therapeutic stratification. In this study, we comprehensively investigated the expression pattern, clinical significance, molecular functions, and immunological implications of LINGO1 in CRC. Integrative analyses of TCGA and GEO datasets, together with validation in 72 clinical CRC samples, demonstrated that LINGO1 is markedly overexpressed in tumors and strongly associated with advanced clinicopathological features and poor patient outcomes. Functional experiments revealed that both knockdown of LINGO1 in SW480 and LoVo cells and overexpression of LINGO1 in HCT116 cells significantly modulate malignant phenotypes, including proliferation, migration, invasion, and angiogenic capacity. Transcriptome-wide and pathway enrichment analyses further indicated that high LINGO1 expression is linked to epithelial-mesenchymal transition, angiogenesis, Wnt/β-catenin signaling, and other oncogenic pathways. Immunogenomic profiling, supported by multiplex immunofluorescence staining, showed that elevated LINGO1 is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T-cell infiltration and diminished GZMB expression, alongside upregulation of multiple immune checkpoint molecules. Collectively, our findings identify LINGO1 as a novel oncogenic driver and immune-modulatory biomarker in colorectal cancer, with potential value for prognosis and therapeutic targeting. Show less

The brain-derived neurotrophic factor (BDNF) plays a crucial role in neuroprotection, and we have previously demonstrated BDNF-mediated neuroprotective effects in mesenchymal stromal cells (MSCs). The present study aimed to investigate whether BDNF-overexpressing MSCs enhance the therapeutic efficacy of naïve MSCs in a preclinical model of severe neonatal intraventricular hemorrhage (IVH). We exposed primary rat neuronal cells to 40 U of thrombin overnight Show less

Sufficient physical activity has the potential to mitigate the late effects of cancer, but objective data of activity levels in patients after pediatric bone cancer are scarce. This study aimed to objectively assess physical activity levels in this population and explore differences based on patient- and treatment-related factors. As part of a cross-sectional study of a nationwide cohort of patients treated for pediatric bone sarcoma, we assessed physical activity using an accelerometer, the ActiGraph GT9X Link. Physical intensity levels were categorized as sedentary, light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) and compared between subgroups stratified by sex, age, tumor location, type of surgery for tumors around the knee, and time since local therapy. Among 79 participants, 47% were female, and median age at evaluation was 19.8 years (IQR 17.5-23.9) with a median of 5.9 years (IQR 2.9-11.7) since local therapy. Mean daily sedentary time was 643 min (SD = 104), 127 min per day (SD = 58) was spent in LPA, and 63 min per day (SD = 35) in MVPA. Seventy-eight percent of participants met the World Health Organization's recommended level of MVPA. No significant differences in intensity levels were found between the various subgroups. Pediatric bone sarcoma patients seem to regain participation in higher-intensity activities post-treatment, with physical activity levels comparable to the general population. No surgical approach is superior in terms of physical activity. Implications for Cancer Survivors Shared decision-making is important in guiding the choice of local therapy and should be informed by lifestyle and individual preferences. High sedentary time suggests scope for improvement in survivorship care. Show less

Koolen-de Vries Syndrome (KdVS) is a neurodevelopmental disorder (NDD) caused by KANSL1 haploinsufficiency with no treatment options. To investigate neuronal network activity in KdVS, human induced pluripotent stem cell (hiPSC)-derived neurons from KdVS patients and controls were cultured on microelectrode arrays (MEAs). KdVS networks exhibited reduced burst rates and increased variability in burst rhythmicity. To bridge molecular and functional aspects of the syndrome, we applied MEA-seq, integrating electrophysiological recordings with high-throughput transcriptome profiling. This analysis revealed a negative correlation between the NDD-associated gene CLCN4 and network burst rate. Knockdown of CLCN4 in KdVS neurons restored network bursting toward control levels, highlighting how transcriptome profiling can identify mediators linking genetic defects to relevant physiological phenotypes. We also identified significant correlations between mitochondrial gene expression and network activity and consequently confirmed impaired mitochondrial function in KdVS hiPSC-derived neurons. Using the KdVS transcriptomic signature for computational screening against the LINCS drug perturbation database, we predicted compounds capable of reversing dysregulated gene expression. Ten candidates were prioritized for experimental validation, focusing on mitochondrial function. Among these, the antioxidant phloretin improved multiple aspects of the KdVS-related network activity phenotype, reduced reactive oxygen species, and rescued synaptic density across patient lines, revealing its potential as a therapeutic candidate. Together, these findings demonstrate that integrative MEA-seq profiling can connect molecular and electrophysiological alterations in KdVS, providing a robust framework for identifying novel drugs and druggable pathways for KdVS and potentially other neurodevelopmental disorders. Show less

Generation of specific antibodies against peptides by immunization requires their covalent conjugation to protein carriers to override their inherently weak immunogenicity. The vast majority of bioconjugation approaches to achieve peptide-protein constructs rely on thiol-maleimide chemistry and capitalize on a wide array of commercial maleimide-functionalized protein carriers. Disulfide-rich peptides (DRPs) possess a rigid, constrained structure that makes them ideal for designing synthetic mimics of protein regions/domains. For bioconjugation purposes, the introduction of a single spare thiol moiety into a linear peptide antigen is straightforward, while DRPs' disulfide bonds are prone to intramolecular thiophilic attack by the reactive thiolate. This unintended reactivity competes with the desired Michael addition to the maleimide moiety, ultimately disrupting the native disulfide bridging framework. As a result, DRP's tertiary structure will be altered, affording an immunogen that is a poor mimic of the native target. Although a few studies have explored the late-stage introduction of thiol-containing cross-linkers into DRP antigens for their conjugation onto protein carriers, the stability of DRPs' disulfide pattern in the presence of an extra thiol has never been examined. In this study, we systematically evaluated the influence of different spacers in "DRP-spacer-thiol" constructs under thiol-maleimide reaction conditions. Our results highlight how both linker length and flexibility are key to maintaining DRP disulfides unaltered, providing a general approach to achieve DRP bioconjugation by thiol-maleimide chemistry. We have applied our approach to a small DRP predicted to closely mimic a surface-accessible epitope of the full LINGO-1 protein and obtained a very specific antibody response upon immunization; the resulting polyclonal IgG was able to selectively bind the full-length protein in a cellular context, with stringent selectivity across its four homologs. Show less

REM (rapid eye movement) sleep deprivation causes serious impairments in hippocampus-dependent learning and memory. This study examined whether the angiotensin II receptor blocker telmisartan, given at two different doses, could reduce cognitive deficits and affect molecular pathways related to chronic REM sleep deprivation. Thirty-two male Wistar-Albino rats (200-280 g, 3 months old) were randomly divided into four groups (n = 8): control, sleep deprivation (SD), telmisartan-treated SD groups at 1 mg/kg (SD+Tel1) and 3 mg/kg (SD+Tel3). Chronic REM sleep deprivation was induced for 21 days using the modified multiple platform (MMP) method. Telmisartan or distilled water was administered orally once daily. Cognitive performance was tested in the Morris water maze, assessing escape latency and time spent in the target quadrant. After behavioral tests, hippocampal and prefrontal cortex samples were analyzed for brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), glycogen synthase kinase-3 beta (GSK-3β), monocarboxylate transporter 2 (MCT2), and lactate dehydrogenase (LDH) levels, while plasma samples were analyzed for corticosterone (CORT) levels. Brain levels of malondialdehyde (MDA), reduced glutathione (GSH), nitrate, and glycogen were also measured. Sleep-deprived rats showed impaired learning and memory with longer escape latency and reduced time spent of target quadrant. Telmisartan-treated SD groups demonstrated significantly improved cognitive performance, increased BDNF and CREB expression, decreased GSK-3β levels, and balanced oxidative stress markers. In conclusion, telmisartan protected against cognitive and biochemical damage caused by chronic REM sleep deprivation, likely through modulation of GSK-3β/CREB/BDNF signaling and reduction of oxidative stress. Show less

Hodgkin lymphoma (HL) is one of the most common cancers during adolescence. Advances in treatment have achieved survival rates exceeding 90%. However, long-term treatment-related sequelae, including cardiovascular disease and metabolic syndrome, significantly affect the quality of life of survivors. Physical activity (PA) is considered a key strategy to mitigate these risks. Current studies predominantly rely on subjective assessments of movement behavior, which may lack accuracy. This cross-sectional study aims to use device-based monitoring to characterize levels of sedentary behavior and physical activity in survivors of childhood-diagnosed HL. Specific objectives were to evaluate these behaviors across age and gender groups and to assess compliance with physical activity guidelines for the adult population. The study involved 51 participants (59% female), with a median age of 25 years, a median age at diagnosis of 16 years, and a median time since diagnosis of 11 years. PA and sedentary behavior (SB) were measured over seven days using the Axivity AX3 accelerometer with a 24-hour wear protocol. Movement behavior was categorized into SB, light PA (LPA), moderate PA (MPA), and vigorous PA (VPA). Group differences in movement behaviors were examined using non-parametric tests, and results are presented as medians with interquartile ranges. Participants had a median daily time of 704.8 min in SB (IQR 127.9), 181.2 min in LPA (IQR 81.3), 110.2 min in MPA (IQR 68.8), and 2.8 min in VPA (IQR 2.8). Combined moderate-to-vigorous physical activity (MVPA) accounted for a median of 115 min per day (IQR 69.8). Significant differences in LPA were observed: men spent less time in LPA compared to women (p = 0.032), and younger participants spent less time in LPA compared to older participants (p = 0.006). While 100% of participants met the WHO-recommended threshold of > 150 min of MPA per week, only 14% met the guideline of > 75 min of VPA per week. Our study indicates that survivors diagnosed with childhood HL can achieve the levels of MVPA recommended by current adult PA guidelines, despite undergoing chemotherapy and radiotherapy. Additionally, significant differences in low-intensity PA were identified: men and younger participants spent less time in LPA compared to women and older participants, respectively. These findings highlight the importance of monitoring movement behaviors in long-term follow-up care to identify survivors with insufficient physical activity and excessive sedentary behavior and to implement targeted interventions to reduce long-term cardiovascular and metabolic risk. Given the cross-sectional design, causal relationships and changes in physical activity behavior over time cannot be inferred. Show less

Tetralogy of Fallot with pulmonary atresia (ToF-PA) requires precise delineation of extracardiac pulmonary blood supply to guide optimal palliation, especially in duct-dependent physiology. We report an 8-month-old infant with late-onset central cyanosis and recurrent cry-triggered hyper cyanotic spells. Computed tomography (CT) thoracic angiography showed classic ToF with short-segment pulmonary atresia, a malaligned perimembranous ventricular septal defect, and hypoplastic yet confluent branch pulmonary arteries. A long, tortuous patent ductus arteriosus (PDA) provided dominant pulmonary flow, with severe focal juxtaductal stenosis just before insertion into the left pulmonary artery and reduced distal pulmonary arborization. A small ostium secundum atrial septal defect was identified. Minor systemic collaterals were seen, without large dominant major aortopulmonary collateral arteries, suggesting duct-dominant physiology potentially amenable to pulmonary artery rehabilitation. This case highlights late deterioration from progressive PDA-left pulmonary artery narrowing and underscores CT angiography as a key decision map for catheter or surgical palliation and operative planning. Show less

Maternal immune activation (MIA) during pregnancy has been implicated as a key environmental risk factor in autism spectrum disorder (ASD). Interferon-alpha (IFN-α), a type I interferon, may disrupt fetal neurodevelopment, yet its mechanistic impact remains insufficiently understood. This study explores the effects of maternal IFN-α exposure on neurobehavioral and neurobiological outcomes in a Wistar rat model. Pregnant rats received IFN-α on gestational day 10, and offspring were evaluated through behavioral assays, neurochemical analyses, and histopathological assessments. IFN-α exposure resulted in significant reductions in GABA, 5-HIAA, and GAD-67 levels, particularly in male offspring, indicating neurotransmitter dysregulation. Histologically, neuronal loss was observed in the hippocampal CA1 and CA3 regions and cerebellar Purkinje cells. Astrocyte activation, reflected by increased GFAP immunoreactivity, was prominent, suggesting a neuroinflammatory response. Additionally, reduced brain-derived neurotrophic factor (BDNF) and elevated tumor necrosis factor-alpha (TNF-α) levels support the presence of inflammation-induced synaptic dysfunction and impaired neuroplasticity. Behaviorally, male offspring exhibited reduced sociability and impaired social novelty recognition. Both sexes demonstrated deficits in motor coordination and exploratory activity. These findings align with core ASD phenotypes and underscore a heightened male vulnerability. Overall, the study provides compelling evidence that prenatal IFN-α exposure leads to persistent neuroimmune, neurochemical, and structural alterations resembling ASD. The results highlight the need for further research into immune-mediated neurodevelopmental disruptions and sex-specific vulnerabilities, offering potential pathways for preventive and therapeutic interventions targeting MIA-related risk mechanisms. Show less

Physical inactivity strongly predicts poor prognosis in chronic obstructive pulmonary disease (COPD) but is often underrecognized. We investigated whether combining patient-reported outcomes (PROs) with myokine profiling enhances detection of inactivity in COPD. In this multicentre cross-sectional study, 73 patients with stable COPD underwent PRO assessment (modified Medical Research Council dyspnea scale (mMRC), dyspnea-specific PROs (PROMs-D), COPD Assessment Test (CAT), Shortness of Breath Daily Activities Questionnaire (SOBDA-Q), and Kihon Checklist (KCL)), serum myokine measurement, and accelerometer-based physical activity evaluation, stratified into 1.0-1.5 METs (low-intensity/sedentary), ≥ 3.0 METs (moderate), total activity (METs·h), and step count. Correlation and logistic regression analyses were performed. mMRC and PROMs-D correlated negatively with moderate activity and step count. Among myokines, growth differentiation factor-15 (GDF-15), fatty acid binding protein 3 (FABP3), and brain-derived neurotrophic factor (BDNF) showed moderate associations with physical activity: GDF-15 and BDNF with low-intensity, GDF-15 with moderate, and FABP3 and BDNF with step count. Combined PRO-myokine models outperformed single markers, with areas under the curve of 0.77 for low-intensity activity, 0.82 for moderate activity, and 0.86 for step count. In conclusion, integrating PROs and myokines improves the specificity and accuracy of inactivity detection in COPD. This multidimensional strategy may facilitate early, personalized interventions. Show less

Movement behaviours, including moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), sedentary behaviour (SB), and sleep, influence childhood adiposity. However, their collective impact on adiposity from a sex-specific perspective remains underexplored. Our research examined the sex-specific longitudinal associations of 24-h movement behaviours with body mass index (BMI) and abdominal adiposity among children. In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study, we repeatedly measured 24-h movement behaviours using wrist-worn accelerometers (ActiGraph GT3x) and assessed adiposity (BMI, abdominal circumference, and MRI-based abdominal fat volumes) at three time points (ages 5.5-6, 7.5-8, and 10-10.5 years) within the same children in a longitudinal design. Compositional multivariable linear mixed-effect modelling and isotemporal substitution were used to estimate the associations. 531 children (49.5% girls) were included in the analysis. Significant interactions between movement behaviours and sex were observed across all outcomes. In girls, higher MVPA relative to other behaviours was linked to lower BMI [-0.8 (-1.5, -0.1) kg/m²] and total abdominal adiposity [-225.5 (-451.6, -2.5) mL], while in boys, longer sleep duration was associated with lower BMI [-1.6 (-3.2, -0.1) kg/m²] and total abdominal adiposity [-624.2 (-1225.6, -31.3) mL]. The isotemporal substitution model showed that replacing 30 min of LPA/SB with MVPA reduced BMI and abdominal circumference by 1-2% and MRI-measured abdominal adiposity by 6-9% in both sexes. However, replacing LPA/SB with sleep reduced BMI and abdominal circumference by 1% and MRI-measured adiposity by 3-6% only in boys, with no changes in girls. These associations were pronounced on visceral adiposity. This study highlights sex-specific associations of movement behaviours with adiposity in school-aged children, with stronger associations observed in MRI-derived measures compared to conventional adiposity indices. Replacing LPA/SB with MVPA reduced BMI and abdominal adiposity in both sexes, with particularly pronounced effects on visceral adiposity. However, sleep replacement benefits were observed only in boys, suggesting the need for gender-sensitive approaches in lifestyle interventions. Show less

Major depressive disorder is a severe mental health condition characterized by persistent depressed mood and loss of interest. Current first-line pharmacotherapies often exhibit limited therapeutic performance and adverse side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising, safe, and noninvasive alternative intervention with demonstrated neuromodulatory efficacy. Nevertheless, its mechanisms remain unclear. This study investigated whether the antidepressant properties of taVNS are associated with the microbiota-gut-brain axis, focusing on the potential crosstalk between differentially expressed hippocampal proteins and the gut microbiota. A chronic unpredictable mild stress (CUMS) rat model of depression was established, and taVNS was administered for 14 days. Hippocampal proteomic profiling was performed using data-independent acquisition. Fecal metagenomic sequencing was conducted to characterize alterations in gut microbial communities. Key signaling pathways were validated using Western blot, qRT-PCR, HE staining, and transmission electron microscopy, all of which were employed to systematically assess behavioral, proteomic, microbial, and molecular changes. Proteomics and molecular analyses revealed that taVNS upregulated hippocampal expression of glutamate ionotropic receptor N-methyl-D-aspartate type subunit 1 (GluN1) and brain-derived neurotrophic factor (BDNF), while simultaneously restoring mitogen-activated protein kinase (MAPK) signaling activity. Metagenomic profiling demonstrated that taVNS increased the abundance of TaVNS significantly alleviated depression-like behaviors in CUMS-exposed rats. The underlying mechanism may involve the restoration of synaptic function of glutamatergic neurons by regulating the GluN1/MAPK/BDNF signaling pathway. In addition, taVNS reshaped the gut microbiota, markedly increasing the abundance of Show less

Lecanemab is an anti-Aβ antibody approved in China for mild cognitive impairment (MCI) and mild dementia. Real-world application requires comprehensive assessment beyond MMSE scores, considering factors like ARIA risk. This single-center, real-world study aims to evaluate its efficacy in an expanded population, observe biomarker changes, and assess its safety profile in clinical practice. We recruited adults aged 40-90 with early AD from the PUMCH Dementia Cohort. A total of 42 patients received lecanemab treatment, of whom 29 completed the 6-month treatment evaluation. Participants had confirmed amyloid and tau pathology and met clinical criteria (CDR ≤ 1, CDR-SB ≤ 8and MMSE ≥ 18). Comprehensive assessments included neuropsychological testing, CSF and plasma biomarkers (Lumipulse G1200), multi-sequence 3T MRI (volumetric and ALPS index analysis), and amyloid/tau PET imaging (Centiloid quantification). All were monitored for adverse reactions. Matched control groups (matched for sex, age, APOE genotype, disease severity, and baseline therapy) were established for comparison of longitudinally changes in cognitive function, daily living ability and structure MRI. Treatment was effective even for patients with lower MMSE scores but still classified as having mild dementia by CDR. A significant median Centiloid reduction of 30.9 was observed, with a 24.1% amyloid PET negativity rate after six months. While scores on cognitive and functional scales (CDR-SB, ADL) significantly worsened, indicating disease progression, the rate of progression was significantly slower compared to the control group. Structural MRI showed significant volume reduction in multiple brain regions and increased ventricular volume post-treatment, with no statistically significant change in the ALPS value. The rate of brain volume reduction is faster than that in the control group. Plasma biomarker dynamics (Aβ This study confirms the clinical efficacy, biomarker changes, and safety profile of lecanemab treatment over a 6-month period, demonstrating its positive therapeutic value and a favorable safety profile in the Chinese population with AD. Show less

To investigate the genetic causality between Human blood cell (HBC) traits and sporadic lymphangioleiomyomatosis (sLAM) by mediation joint multi-omics and eQTL Mendelian randomization analysis. Quality control processes were followed to select eligible instrumental variables strongly associated with 35 kinds of HBC traits. Independent cohort of European ancestry with sLAM and lung function genome-wide association study (GWAS) summary statistics were used separately. We utilized a two-step MR approach to explore potential mediators and evaluate the proportion of effect mediated in the associations linking HBC trait candidates to sLAM. Finally MR analysis integrating single cell expression quantitative trait loci (sc-eQTL) from 14 immune cell types with GWAS of sLAM was conducted. Increased level of basophil count was positively associated with higher risk of sLAM (BASO#; OR = 3.878, 95%CI:1.137–13.221, For the first time, this study leverages mediation analysis and multi-omics MR integrated with sc-eQTL data to elucidate the roles of HBC traits, immune cells, inflammatory proteins, VEGF-related proteins and immune cell-specific genes in the pathogenesis of sLAM among the European populations. The online version contains supplementary material available at 10.1186/s13023-026-04224-6. Show less

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent inflammatory disorder characterized by nasal obstruction and polyp formation. Despite its prevalence, the complex pathogenesis of CRSwNP remains not fully understood, hindering the development of effective treatments. This study aims to delineate the immunological landscape of CRSwNP by integrating single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) approaches. We conducted a systematic MR analysis using summary statistics from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data. The identified genes were further scrutinized through scRNA-seq analysis of CRSwNP tissues to assess cell-specific expression patterns. Pathway enrichment and protein-protein interaction (PPI) network analyses were performed to explore the biological mechanisms underlying CRSwNP. The MR analysis identified several genes, including HLA-DRB1, HLA-DQA1, and HLA-DQB1, as significantly associated with CRSwNP. The scRNA-seq analysis validated these findings, revealing cell-specific enrichment in basal cells. Notably, these genes were found to be involved in immune cell recruitment and the reshaping of the immune microenvironment. Furthermore, the study highlighted the role of genes like TCF7L1, KANSL1-AS1, and POLR2J3, which showed contrasting expression patterns and potential regulatory roles in CRSwNP. This integrative study provides novel insights into the molecular and cellular underpinnings of CRSwNP. The identified genes and their role in immunopathogenesis offer potential therapeutic targets and highlight the importance of cell-specific gene expression in disease mechanisms. The combination of MR with scRNA-seq represents a powerful approach to elucidate complex traits and may pave the way for precision medicine in CRSwNP management. Show less

Sepsis remains a leading cause of mortality in intensive care units (ICUs) worldwide, necessitating improved diagnostic and prognostic tools. This study aimed to estimate the novel sepsis biomarkers, including presepsin, interleukin (IL)-27, hepcidin, and plasma chitotriosidase in ICU patients with sepsis, evaluating their potential for enhancing early diagnosis and monitoring. This prospective study was conducted over 18 months at JSS Medical College and Hospital, Mysuru, India. The study included 73 ICU patients above 18 years diagnosed with bacterial sepsis based on Quick Sequential Organ Failure Assessment score and procalcitonin (PCT) levels. Blood samples were collected and analyzed using enzyme-linked immunosorbent assay with respective biomarker kits. Demographic data, clinical parameters, and laboratory values were recorded. Correlations between novel biomarkers and PCT were assessed using Pearson correlation analysis. The study population had a mean age of 55.7 years, with 60.3% male participants. Hypertension (56.16%) and type 2 diabetes mellitus (49.32%) were the most common comorbidities. Abnormal presepsin levels were observed in 53.4% of participants, showing a strong positive correlation with PCT ( r = 0.763, P < 0.001). Hepcidin levels were abnormal in 76.7% of participants, demonstrating a moderate positive correlation with PCT ( r = 0.522, P < 0.001). Only 11.0% of participants had abnormal IL-27 levels, with a weak, nonsignificant correlation with PCT ( r = 0.172, P = 0.540). All participants (100%) had abnormal chitotriosidase levels, showing a weak but significant positive correlation with PCT ( r = 0.234, P = 0.047). This study supports the potential of presepsin and hepcidin as novel biomarkers for sepsis in ICU patients. These markers showed strong correlations with PCT and high rates of abnormal levels in sepsis patients. IL-27 and chitotriosidase showed less promise in our study population. Integrating these novel biomarkers, particularly presepsin and hepcidin, into clinical practice could potentially improve early diagnosis and management of sepsis in critical care settings. Show less

Multiple sclerosis (MS) is a debilitating neurological disorder involving concurrent immune-mediated demyelination and progressive neurodegeneration. Although disease-modifying therapies (DMTs) effectively modulate peripheral immune responses and reduce relapse rates, they are ineffective at halting disease progression and promoting central nervous system (CNS) repair. This review outlines a new therapeutic approach that targets two important microRNAs: miR-219, which stimulates oligodendrogenesis and remyelination, and miR-146a, which regulates innate immune responses and neuroinflammation. We present compelling evidence showing that the dysregulation of these microRNAs establishes a cycle of inflammatory damage and regenerative failure in chronic MS lesions. Preclinical models show that supplementing with miR-219 drives oligodendrocyte precursor cell (OPC) differentiation and myelin restoration by repressing critical inhibitors, such as PDGFRα and LINGO-1. Concurrently, miR-146a modulates neuroinflammatory cascades by regulating the NF-κB pathway, promoting the polarization of microglia toward a protective M2 phenotype, and enhancing OPC maturation. Despite its therapeutic potential, there are significant challenges to its translation, including optimizing CNS-targeted delivery systems, navigating microRNA pleiotropy, and establishing biomarker-driven treatment paradigms. We propose that a dual-targeting approach leveraging advanced nanocarriers for spatiotemporal microRNA delivery represents a transformative frontier in MS therapeutics, potentially bridging the critical gap between immunomodulation and genuine neurorestoration. Show less

This study aimed to evaluate the memory health benefits of Neurocaf™, a standardized green coffee bean extract. Neurocaf was characterized for the presence of 5-hydroxytryptamide esters, eicosanoyl-5-hydroxytryptamide (EHT), and chlorogenic acids using HPLC-PDA detector. The inhibitory kinetics of Neurocaf against acetylcholinesterase (AChE) were assessed in vitro. Cognitive efficacy was further investigated in a scopolamine-induced amnesia mouse model. In a 25-day study, male Swiss albino mice (25-30 g) were pretreated orally with Neurocaf (200 or 400 mg/kg body weight) or donepezil (3 mg/kg body weight) for 14 days followed by behavioural assessments and a 7-day co-treatment with scopolamine (0.75 mg/kg, i.p.). Neurocaf exhibited mixed competitive AChE inhibition in vitro (IC₅₀ = 298.4 µg/mL). At 400 mg/kg, it significantly enhanced spatial memory performance, demonstrated by reduced transfer latency in the elevated plus maze (p < 0.01) and decreased escape latency in the Morris water maze (p < 0.001). The extract dose-dependently suppressed brain AChE activity and elevated acetylcholine levels in scopolamine-treated mice. Furthermore, it attenuated oxidative stress, upregulated BDNF/TrkB signaling, modulated apoptotic protein expression (increased Bcl2, decreased Bax), and inhibited caspase activation, offering neuroprotection against scopolamine-induced neuronal damage. These findings highlight the potential memory functions of Neurocaf, supporting its further evaluation as a candidate functional food or dietary supplement for brain health. Show less

Dysregulated blood lipids are a major predictor of cardiovascular events. A recent genome-wide association study (GWAS) with five clinically relevant lipid traits in 1.65 million individuals implicated over 770 genomic regions in regulating blood lipid metabolism. To translate these associations into clinical applications, a functional understanding of their roles in lipoprotein metabolism, transport and remodeling (LPmtr) is required. Here, we report the deep molecular fine-mapping of 554 of these lipid risk loci using 168 lipoprotein-related traits and all possible ratios between them in over 273,000 participants of the UK Biobank. We identified new ratio-based markers of pathways shared by multiple LPmtr genes, such as the linoleic acid fraction of the polyunsaturated fatty acid pool to reveal potential causal genes at poorly characterized lipid risk loci, the percentage of esterified cholesterol moieties in LDL particles as a proxy for soluble LDL receptor levels, and the HDL fraction of total lipoprotein particle number as a predictor of incident myocardial infarction. We demonstrate how lipoprotein fine-mapping can generate new hypotheses for drug target development while uncovering new mechanisms relevant to hyperlipidemia. Ratio-driven clustering further implicated miR-148 in TG secretion, linking ER-stress responses at postprandial state to VLDL metabolism via mTORC1, shown through series of integrated cellular assays and mouse studies. Moreover, consistent with its regulatory influence on lipid flux we identify miR-148a a previously unrecognized determinat of Show less

In recent studies elevated lipoprotein(a) (Lp(a)) levels have been identified as an independent and causal risk factor for atherosclerosis and coronary heart disease. This study aims to perform a comparative early health technology assessment (HTA) of olpasiran and pelacarsen for secondary prevention of coronary heart disease (CHD) in patients with atherosclerotic cardiovascular disease, familial hypercholesterolemia, and elevated Lp(a). We developed a Markov state transition model to simulate the progression of a cohort of 597 patients with history of coronary heart disease (CHD) as myocardial infarction, coronary artery disease or peripheral artery disease, familial hypercholesterolaemia in the treatment arms of OCEAN(a)-Outcomes trial (NCT05581303) [16] and Lp(a) HORIZON trial (NCT04023552). Baseline risks of CHD, costs and utilities were obtained from published sources. Clinical trial data were used to derive reductions in lipoprotein(a). Mendelian randomization study data were used to estimate clinical benefits. Annual discounting was 3.5%. The treating strategy comprising olpasiran 150 mg every 3 months in addition to standard of care saved 3.29 QALYs, compared with standard of-care alone. With 3.5% annual discounting, there were 0.23 QALYs saved. The treating strategy comprising pelacarsen 80 mg every month in addition to standard of care saved 8.63 QALYs, compared with standard of-care alone (undiscounted). With 3.5% annual discounting, there were 0.58 QALYs saved. We found that olpasiran was highly cost-effective at the annual price of 10,424.78 BGN, compared with standard-of-care alone. Pelacarsen was highly cost-effective at the annual price of 6105.99 BGN. The threshold applied is that of gross domestic product (GDP) per capita as indicated by the National Council on prices and reimbursement of medicinal products in Bulgaria. Show less

Previous studies indicate that ambulance personnel have an increased risk of ill health. Shift work and time spent on physical behaviours during work and leisure are factors that could be related to health, however the research is limited. Thus, the aim of this study was to describe patterns of physical behaviours during and after work among Swedish ambulance personnel and to analyse the associations between physical behaviours and different work shifts. In this observational study, the physical behaviours of 63 ambulance personnel were measured over seven days using two accelerometers. Accelerometer data was processed using the MATLAB program Acti4, to identify physical behaviours i.e. sleep, being sedentary, light physical activity (LPA), and moderate to vigorous physical activity (MVPA), during and after work. To determine the association between shift types (independent) and patterns of physical behaviours (dependent), a Multivariate Analysis of Variance was performed on data processed according to compositional data analysis. At work, the highest proportion of both MVPA and being sedentary occurred during day shifts, compared to night and 24-h shifts (MVPA: 7% vs 4% and 5%; sedentary time: 62% vs 44% and 54% respectively). Night and 24-h shifts included 31% and 18% sleep, respectively. During the after-work periods, the highest proportions of MVPA were observed after 24-h shifts (8%). Overall, there was no statistically significant difference in physical behaviours during work and after work for various shift types. However, in a sub-analysis restricted to night and 24-h shifts, a statistically significant association between shift type and composition of physical behaviours during work was observed (η In general, ambulance personnel were physically active both during and after work. At the same time, work hours entailed a substantial amount of sedentary time. Shift type was not associated with the pattern of physical behaviours among ambulance personnel. However, during 24-h shift a lower proportion of the time was spent sleeping compared to during night shift. Studies with larger sample sizes are needed to confirm these results. The online version contains supplementary material available at 10.1186/s12889-026-27335-y. Show less

The quality of informal care for people with dementia (PwD) has gained increasing importance, as most PwD prefer home-based care over institutional placement. However, evidence-based intervention programs tailored to distinct care quality profiles remain limited. Additionally, the absence of clear thresholds to identify PwD receiving low-quality informal care poses a challenge for research and clinical practice. Thus, this study aimed to identify the profiles of quality of care (QoC) among informal caregivers of PwD, explore influencing factors of different profile, and determine the optimal cut-off score of the Exemplary Care Scale (ECS). A cross-sectional survey was conducted. A total of 213 dyads of PwD and their informal caregivers were recruited from memory clinic, rehabilitation clinic, and neurological clinic of a tertiary hospitals and communities in Wuhan, Hubei, China, between July 15, 2023, and July 14, 2024. Latent profile analysis (LPA) was employed to identify QoC profiles. Multinomial logistic regression was performed to explore influencing factors of profile membership. Receiver Operating Characteristic (ROC) analysis was conducted to determine the ECS cut-off score. Three distinct QoC profiles were identified: high (24.41%), moderate (44.60%), and low (30.99%). Among informal caregivers, lower monthly income, insufficient social support, and higher perceived overload were associated with low QoC profile, whereas, better quality of pre-illness relationship with PwD and greater activities of daily living (ADL) of PwD were associated with high QoC. ROC analysis yielded an optimal ECS cut‑off score of 15, with high sensitivity (0.993) and specificity (0.955). This study identified three distinct QoC profiles among caregivers of PwD, underscoring the heterogeneity of informal care quality. The identified predictors and the validated ECS cut‑off score of 15 provide an empirical basis for developing tailored screening tools and targeted interventions for high‑risk caregiver subgroups. Show less