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To explore latent profiles of social isolation in maintenance haemodialysis (MHD) patients and to analyse the factors influencing different latent profiles. Multicentre cross-sectional study. Between November 2024 to March 2025, 305 MHD patients from the haemodialysis centres of three hospitals in Henan Province, China, were recruited using a convenience sampling method. All participants completed the general information questionnaire, Lubben Social Network Scale 6 (LSNS-6), UCLA Loneliness Scale-6 (ULS-6) and Personal Mastery Scale. Latent Profile Analysis (LPA) was used to classify the participants into potential subgroups with different types of social isolation. The influencing factors of profiles were explored by univariate analysis and multiple logistic regression analysis. Social isolation of 305 patients can be divided into three profiles: the family-friend dual isolation group (14.10%), friend isolation-only group (47.54%), and social network well-being group (38.36%). Multivariable logistic regression analysis revealed that monthly personal income, living arrangement, social participation, dialysis time, post-dialysis fatigue, number of comorbidities, loneliness and personal mastery were identified as factors influencing the profiles. There is heterogeneity in social isolation among MHD patients. It is therefore necessary to implement targeted intervention measures based on the distinct characteristics of each subgroup to facilitate their social reintegration. Nurses should identify differences in social isolation among MHD patients. It is necessary to establish tripartite connections between families, hospitals and communities, and develop personalised psychosocial interventions to alleviate social isolation. The study identified distinct subgroups of social isolation among MHD patients, while emphasising the impact of psychological resources such as loneliness and personal mastery on social isolation. This may offer critical insights for nurses to develop targeted interventions for patients' social health. The study followed the STROBE guidelines for cross-sectional studies. No patient or public involvement. Show less

Psychosomatic disorders are conditions in which physical (somatic) symptoms are triggered or aggravated by psychological distress. These disorders result from complex interactions among the endocrine, central nervous, and immune systems. Emerging evidence indicates that gut microbiota (GM) dysbiosis, epigenetic alterations, and immune system dysregulation play pivotal roles in the pathogenesis of psychosomatic disorders and may serve as potential biomarkers for disease states and therapeutic outcomes. This review first outlines how epigenetic dysregulation contributes to psychosomatic disorders through altered expression of genes such as GRM2, TRPA1, SLC6A4, NR3C1, leptin, BDNF, NAT15, HDAC4, PRKCA, RTN1, PRKG1, and HDAC7. We then examine current evidence linking psychosomatic disorders with changes in GM composition and GM-derived epigenetic metabolites, which influence immune function and neurobiological pathways. The core focus of this review is on therapeutic interventions-including probiotics, prebiotics, postbiotics, fecal microbiota transplantation, and targeted dietary approaches-that modulate the gut-brain axis through epigenetic mechanisms for the management of psychosomatic disorders. Finally, we highlight the current challenges and future directions in elucidating the interplay between epigenetics, the GM, and psychosomatic disease mechanisms. In this context, human iPSC-derived multicellular organoids may serve as powerful platforms to unravel mechanistic pathways underlying inter-organ interactions. Show less

Non-invasive brain stimulation (NIBS) techniques-including repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation (TBS), paired associative stimulation (PAS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS)-have emerged as valuable tools for modulating neural activity and promoting plasticity. Traditionally, their effects have been interpreted within a binary framework of long-term potentiation (LTP)-like and long-term depression (LTD)-like plasticity, largely inferred from changes in motor evoked potentials (MEPs). However, existing models do not fully capture the complexity of the biological processes engaged by these techniques and despite extensive clinical application, the cellular and molecular mechanisms underlying NIBS remain only partially understood. This systematic review, conducted in accordance with the PRISMA 2020 guidelines, synthesizes evidence from in vivo, in vitro, and ex vivo studies to delineate how NIBS influences neurotransmission through intracellular signaling, gene expression, and protein synthesis at the cellular level. Emphasis is placed on the roles of classical synaptic models, grounded in Ca Show less

Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in Show less

Pure membranous lupus nephritis (pMLN, ISN/RPS-class V) is a rare form of lupus nephritis (LN). Despite being associated with significant comorbidities, it has traditionally been considered a less aggressive subtype. Emerging data challenges this perception, highlighting its potential for chronic kidney disease progression and kidney failure. pMLN is pathologically defined by subepithelial immune-complex deposits and typically presents with nephrotic syndrome, preserved renal function, and fewer systemic/immunologic manifestations compared to proliferative LN (ISN/RPS-classes III/IV). Repeat biopsies reveal frequent histological class switching from pMLN to proliferative and mixed LN forms, underscoring the dynamic nature of the disease and the limitations of clinical markers in reflecting histological activity. While the ISN/RPS kidney biopsy classification provides important prognostic insight, it does not fully capture underlying molecular heterogeneity. Recent advances in precision medicine, including proteomic and biomarker studies (e.g., EXT1/2, NCAM1), offer promising tools for patient stratification and tailored treatments. International guidelines now recommend immunosuppressive therapy for pMLN, aligning treatment strategies more closely with those for proliferative and mixed LN. Overall, pMLN should be considered a distinct but clinically relevant LN subtype requiring personalized management based on clinical, histological and molecular features. Long-term monitoring is essential, as baseline presentation does not reliably predict treatment response or disease trajectory. Show less

Sarcopenia is a progressive, age-related loss of skeletal muscle mass, strength, and function, strongly associated with frailty, disability, and chronic disease. Its pathogenesis involves chronic low-grade inflammation, hormonal imbalance, and impaired anabolic signaling, making biomarkers essential for diagnosis, prognosis, and intervention monitoring. This review systematically analyzes randomized controlled trials (RCTs) evaluating the impact of physical exercise on biomarkers relevant to sarcopenia. Exercise modulates both pro-inflammatory markers (e.g., IL-6, TNF-α, CRP) and anti-inflammatory cytokines (e.g., IL-10, IL-15), while also affecting growth factors like IGF-1, myostatin, and follistatin. These changes support muscle anabolism, reduce catabolic signaling, and improve physical performance. In addition, we highlight a growing class of emerging exerkines, including irisin, apelin, beta-aminoisobutyric acid (BAIBA), decorin, brain-derived neurotrophic factor (BDNF), and meteorin-like factor (Metrnl). These molecules exhibit promising roles in mitochondrial health, lipid metabolism, muscle regeneration, and immune modulation, key processes in combating inflamm-aging and sarcopenic decline. Despite encouraging findings, biomarker responses remain heterogeneous across studies, limiting translational application. The integration of biomarker profiling with exercise prescription holds the potential to personalize interventions and guide precision medicine approaches in sarcopenia management. Future large-scale, standardized trials are needed to validate these biomarkers and optimize exercise protocols for aging populations. Show less

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) represent a growing global health concern with no definitive cure. Increasing evidence suggests that mind-body practices like yoga may offer neuroprotective benefits by modulating stress, neuroinflammation, and neuroplasticity. This narrative review explores the clinical outcomes, mechanistic insights, and biomarker evidence supporting yoga as a therapeutic intervention for AD and PD. Different studies indicate that regular yoga improves motor and cognitive functions, mood, and quality of life in affected individuals. At the molecular level, yoga enhances neurotrophic factors such as brain-derived neurotrophic factor (BDNF), reduces pro-inflammatory cytokines (e.g., IL-6, TNF-α), mitigates oxidative stress, and may preserve gray matter volume in key brain regions. These findings support the hypothesis that yoga induces favorable neuroplastic adaptations that may slow neurodegeneration. Despite encouraging early results, heterogeneity in study design, intervention duration, and sample size issues have limited the incorporation of neuroimaging and biomarker endpoints, which means further studies are warranted to clarify yoga's therapeutic potential and mechanism in ND management. Show less

Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP×TL interaction term. AD risk was associated with shorter TL (β = -0.18, We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis. Show less

Axon growth is an essential cellular process during neural development, and its dysregulation contributes to numerous neurodevelopmental disorders. During axon growth, extracellular signals direct neurons to extend projections that connect with their synaptic targets. Paxillin is a key member of adhesion sites that control motility by linking the intracellular actin cytoskeleton to the extracellular matrix. Paxillin also binds to the cytoskeletal protein, tubulin. However, little is known about the role of adhesion proteins in neurons. Here, we use conditional paxillin knockout mice to investigate how loss of paxillin in pyramidal cortical neurons affects developing neuron morphology. Surprisingly, loss of paxillin in pyramidal cortical neurons caused no change in axon length or soma area between control ( Show less

APOE is the greatest genetic risk factor for late-onset Alzheimer's disease (AD). In humans, APOE has three isoforms: APOE2 (E2), APOE3 (E3), and APOE4 (E4); E4 increases AD risk, while E3 is neutral and E2 decreases risk. In the brain, APOE is predominantly produced by astrocytes, where it binds lipids to form HDL-like particles, and plays a central role in lipid homeostasis, Aβ clearance, and neuroimmune modulation. Its lipidation state is critical for function, with E4 being poorly lipidated compared to E2 and E3, contributing to the pathogenic effects of E4 while also offering a potential therapeutic target. We have previously demonstrated that the HDL-mimetic peptide 4F increases APOE secretion and lipidation in wild-type mouse astrocytes and counteracts the inhibitory effects of Aβ42. Here, we assessed the ability of 4F to mitigate E4-associated dysfunction using primary astrocytes from humanized E3 and E4 knock-in mice and isogenic human iPSC-derived astrocytes and cerebral organoids. Results showed that 4F enhanced APOE secretion and lipidation in both cellular and organoid models in the absence or presence of aggregated Aβ42. Compared to E3 astrocytes, E4 astrocytes were prone to Aβ42-induced inhibition of APOE secretion and lipidation and increased accumulation of lipid droplets. 4F treatment ameliorated the inhibitory effects of Aβ42 and reduced lipid droplet accumulation. These findings support the therapeutic potential of HDL-mimetic peptides for E4-associated dysfunction in AD. Show less

Exploding head syndrome (EHS) is a parasomnia characterized by the perception of loud noises originating from inside the head during sleep transitions, often accompanied by visual phenomena and fear. Treatment remains challenging due to unknown etiology and limited therapeutic options. We report a 75-year-old man with chronic exploding head syndrome experiencing lightning-like sensations, thunder-like sounds, sleep paralysis, and intense fear during sleep onset. Episodes occurred multiple times weekly for over five years. Initial treatments, including gabapentin, valproic acid, amitriptyline, and buspirone, proved ineffective. The patient was subsequently treated with sublingual ketamine, starting at 25 mg every third night and escalating to nightly dosing. After one month, episode frequency decreased from 3-4 times weekly to once every two weeks. By three months, episodes occurred monthly with reduced intensity. After six months, the patient experienced only occasional sleep paralysis with the complete resolution of exploding head syndrome and reported improved quality of life. Ketamine's mechanism likely involves N-methyl-D-aspartate (NMDA) receptor modulation, brain-derived neurotrophic factor release, and σ1 receptor agonism, promoting neuroplasticity and sleep regulation. This case represents a reported successful treatment of exploding head syndrome with ketamine, suggesting a potential therapeutic approach for this refractory parasomnia. Further studies are warranted to evaluate ketamine's efficacy in exploding head syndrome treatment. Show less

To identify latent profiles of demoralization among older adults with disabilities, analyze their influencing factors, and examine their associations with active aging. From February to July 2025, a convenience sample of 411 older adults with disabilities was recruited from a tertiary hospital in Anhui Province, China. Data were collected using a general information questionnaire, the Chinese version of the Demoralization Scale, and the Active Aging Scale. Latent profile analysis (LPA) was performed based on demoralization subscale scores. Univariate and multinominal analyses were employed to investigate the influencing factors, and the Kruskal-Wallis The prevalence of demoralization syndrome was 49.1%. LPA identified three distinct profiles: the Well-Adapted Group (53.3%), the Disheartened-Helpless Group (23.8%), and the Fully Demoralized Group (22.9%). The Kruskal-Wallis Nearly half of the older adults with disabilities experienced demoralization, with heterogeneous subgroups identified. The active aging status of demoralized subgroups requires urgent attention. These findings suggest the need for targeted interventions tailored to the characteristics of each profile to improve mental health and promote active aging in this population. Show less

Type 2 diabetes (T2D) is associated with cognitive decline, but the role of We analyzed 883 Brazilian adults with T2D (median age 68 years) from primary care, excluding those with dementia. Cognitive function was assessed using Mini-Mental State Examination (MMSE), and Show less

Levonorgestrel (LNG), a synthetic progestin widely used in emergency contraception, is increasingly taken frequently and often without medical supervision. With rising concerns that repeated exposure to such hormones may adversely affect brain function, this study investigated whether chronic LNG administration impairs cognitive-like behavior and alters key neurochemical pathways in female Wistar rats. Experimental rats were assigned to three groups receiving normal saline (control) or LNG (4 or 8 µg/kg) every alternate day for 60 days. Cognitive performance was assessed using the Morris water maze (MWM) and novel object recognition (NOR) tests. Hippocampal tissues were subsequently analyzed for glutamatergic markers and downstream signaling molecules involved in learning and memory. Chronic LNG exposure (4 and 8 µg/kg) impaired both spatial and non-spatial memory, evidenced by prolonged escape latency and reduced path efficiency in the MWM, along with a decreased discrimination index in the NOR test. Neurochemically, LNG significantly reduced hippocampal levels of glutamate, N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor ligands, protein kinase A (PKA), calcium/calmodulin-dependent kinase II (CaMKII), and brain-derived neurotrophic factor (BDNF), with the 8 µg/kg dose exerting more pronounced effects. Repeated LNG administration leads to notable cognitive deficits, likely mediated by impairments in glutamatergic signaling and downstream molecular pathways essential for synaptic plasticity. These findings underscore potential neurocognitive risks associated with prolonged LNG exposure. Show less

Evaluate the association between functional recovery and a panel of specific neuronal biomarkers, in a cohort of stroke patients. Serum levels of neuronal specific enolase (NSE), neurofilament light chain (NfL), brain derived neurotrophic factor (BDNF), amyloid-β Linear regression was performed to predict changes in clinical scales during follow up, according to baseline biomarkers levels. NSE at T0 was a significant predictor of improvement in FAC and RMI, where the higher the NSE concentration, the smaller the improvement. Therefore, baseline NSE explained 39% of the variation in FAC and 31% in RMI over time. No significant differences were observed with respect to other scales or other biomarkers. This exploratory study suggested that serum NSE may be a predictor of functional mobility recovery in post-acute stroke patients and represents a useful tool for patients' stratification. Show less

Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-throughput screening. However, automated methods for evaluating and characterizing blastoid morphology are lacking. We developed a deep-learning model-deepBlastoid-for automated classification of live human blastoids using only brightfield images. The model processes 273.6 images per second with an average accuracy of 87%, which is further improved to 97% by integrating a Confidence Rate metric. deepBlastoid outperformed human experts in throughput while matching accuracy in blastoid classification. We demonstrated the utility of the model in two use cases: (i) systematic assessment of the effect of lysophosphatidic acid (LPA) on blastoid formation and (ii) evaluating the impact of dimethyl sulfoxide (DMSO) on blastoid formation. The evaluation results of deepBlastoid using over 10,000 images were consistent with the known drug effects and showed subtle but significant effects that might have been overlooked in manual assessments. The publicly available deepBlastoid model enables researchers to train customized models based on their imaging and protocols, providing an efficient, automated tool for blastoid classification with broad applications in research, drug screening, and Show less

Bidirectional intergenerational support is linked to late-life mental health, yet the underlying mechanisms remain unclear. Guided by intergenerational solidarity and social support theories, we examined how distinct support profiles relate to mental health among Chinese older adults, testing self-rated health (SRH) as a mediator and social participation as a moderator. We analyzed 7,843 adults aged ≥60 from the 2020 China Longitudinal Aging Social Survey. Latent profile analysis (LPA) identified bidirectional support profiles; group differences in mental health were assessed using the Bolck-Croon-Hagenaars (BCH) approach, followed by mediation and moderated-mediation models with bootstrap inference (5,000 resamples). Four profiles emerged-High Support-High Interaction-High Closeness (HS-HI-HC; 47.02%), Child-High Support-Low Interaction-High Closeness (CS-LI-HC; 33.46%), Moderate Support-Moderate Interaction-Low Closeness (MS-MI-LC; 10.37%), and Low Support-Low Interaction-Moderate Closeness (LS-LI-MC; 9.16%). Mental health differed across different profiles, with HS-HI-HC showing the best mental health levels (the lowest scores). SRH partially mediated these associations (for instance, HS-HI-HC indirect effect = -0.186, 95% CI -0.245 to -0.131). Social participation attenuated benefits of high family support but buffered risks under low support. Bidirectional intergenerational support is heterogeneous in China; profiles characterized by reciprocity and closeness show the most favorable mental health. SRH accounts for a modest but meaningful share of these associations, and social participation can substitute for-or amplify-the benefits of family support depending on profile. Findings inform profile-tailored community and family interventions to promote healthy aging. Show less

It is unclear whether the different Alzheimer's disease (AD) progression trajectories of apolipoprotein E (APOE) ɛ4 carriers is reflected by blood phosphorylated tau (p-tau) analytes. We assessed longitudinal trajectories in plasma p-tau181, 217, and 231, in amyloid beta-positive (A+) and negative (A-) APOE ɛ4 carriers (E+) or non-carriers (E-). We included 2039 participants from the observational Translational Biomarkers in Aging and Dementia (TRIAD) and Alzheimer's Disease Neuroimaging Initiative cohorts, categorized into 840 A-E-, 251 A-E+, 386 A+E4-, and 616 A+E4+. Longitudinal data were available for 1045 participants. In TRIAD, ALZpath p-tau217 (β = 0.45, p = 0.02) and p-tau217+ These findings suggest p-tau217 as a marker of faster progression in APOE ɛ4 carriers, highlighting its potential in disease stratification. Blood phosphorylated tau (p-tau)217 increases faster in apolipoprotein E (APOE) ɛ4 carriers with amyloid pathology. p-tau181 and p-tau231 do not increase faster in APOE ɛ4 carriers. APOE ɛ4 carriership does not change p-tau in individuals without amyloid pathology. Show less

Severe hypertriglyceridemia causing acute pancreatitis may necessitate intensive care unit (ICU) admission. Management of hypertriglyceridemia in this setting requires therapies that result in rapid triglyceride lowering that are different from therapies used in the outpatient setting. The purpose of this narrative review is to explore strategies for managing hypertriglyceridemia-induced acute pancreatitis (HTGP) in the ICU. Patients may develop acute pancreatitis when triglyceride levels exceed 500 mg/dL, either as their primary reason for admission to the ICU or as an adverse effect of medications received during ICU care. Rapid reduction of triglycerides is attained through activation of lipoprotein lipase (LPL), an enzyme essential for the removal of triglycerides from the plasma. Treatment modalities include therapeutic plasma exchange and the combination of insulin and heparin infusions for acute treatment, although there is no consensus on optimal dosing. Fibrates are recommended as first-line agents in prevention of hypertriglyceridemia-induced pancreatitis in high-risk patients. Several therapies are used for acute management of HTGP in the ICU setting. Further research is necessary to refine treatment protocols and establish best practices for managing HTGP in critically ill patients. Show less

Protein lysine methacrylation (Kmea) is a recently identified post-translational modification whose biofunction remains poorly understood. Until now, there has been no chemical labeling method for Kmea modification, which has severely hindered the discovery and functional studies of methacrylated proteins. Here, we developed a photocatalytic thia-Michael reaction system for the chemoselective labeling of protein methacrylation. By exploiting the dual effect of steric hindrance and the stability of the generated C-center radical, the reaction interference of the structural isomer crotonylation can be efficiently avoided. Based on this reaction, a multifunctional water-soluble benzenethiol-azide probe azDSH was designed and synthesized, and a workflow for the specific labeling, enrichment, and identification of Kmea proteins was developed. Proteomic identification of histone and nuclear protein extracts and whole-cell lysate revealed a number of novel Kmea proteins and modification sites besides histones, such as HMGB1, TdIF2, UHRF1, HNRPD, BRWD1, TAF1, TACC1, and SETD3, providing new targets for the study of epigenetic regulation. This study provides an effective method for the analysis of protein methacrylation modifications in biological systems. Show less

Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NF-κB signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NF-κB, and inflammasome (NLRP3/or NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-κB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART-treated macaque revealed macrophage-rich plaques with p21 Show less

Solid-tubulocystic variant of intrahepatic cholangiocarcinoma (ST-iCCA) is newly described entity characterized by two distinct histologic growth patterns: (1) solid sheets of tumor cells with focal necrosis giving pseudopapillary appearance and (2) tubular or pseudoglandular structures containing pink, colloid-like material. Tumor cells are inhibin-positive and harbor NIPBL::NACC1 fusion gene. To date, only 28 cases of ST-iCCA have been documented. While prior molecular studies provided insights into ST-iCCA, genetic profiles of individual histologic components have not been explored. This study presents first transcriptomic analysis comparing the solid/pseudopapillary and pseudoglandular components of ST-iCCA. Two cases of histologically confirmed ST-iCCA were identified for RNA sequencing which was performed on solid/pseudopapillary component, pseudoglandular component, and normal tissue. Analysis revealed distinct gene expression profiles for each pattern. Solid/pseudopapillary component uniquely overexpressed DMRTA1, NEXMIF, PRDM6, SORCS3, and NALF, while pseudoglandular component exhibited unique overexpression of HRG, ITIH3, TAT, APOA2, CP, ALDOB, CPS1, F2, KHG1, SERPINC1, HPX, C9, ADGRF1, MUC21, SAA2, SPRR2A, SAA1, FGL1, CFHR1, and LBP. These findings establish unique gene signatures for these variants of ST-iCCA, providing potential biomarkers for differential diagnosis, prognosis and targeted therapy. The distinct genetic profiles may also uncover novel therapeutic targets to address the aggressive nature of ST-iCCA. Show less

The Gastrointestinal (GI) microbiome and gut-brain axis are associated with the progression and pathology of Alzheimer's disease (AD). Amyloid deposition is thought to be a driver of AD, causing synaptic dysfunction and neuronal death in the brain. Chronic constipation is a common gastrointestinal (GI) dysmotility in AD patients, which impacts patient outcomes and quality of life. It is unknown if enteric amyloidosis disrupts myenteric neuron function and causes GI dysmotility. Untreated male and female APP/PS1 (a transgenic murine model of brain amyloidosis) and sex-matched control mice were followed until 12 months of age. A separate cohort of mice was treated with a vehicle or the beta-secretase (BACE1) inhibitor, lanabecestat, starting at 5 months of age until 7 months. GI motility was assessed in all mice by measuring whole GI transit in vivo. Propulsive colonic motility and GI smooth muscle contractions were measured ex vivo. At 7 or 12 months old, amyloidosis in the brain and myenteric plexus was determined by immunohistochemistry or ELISA; the myenteric neural density, including the cholinergic and nitrergic neurons, was evaluated by immune staining and RT-PCR; expression of pro-inflammatory factors in the GI wall was assessed by RT-PCR. By 7 months of age, male and female APP/PS1 mice developed abundant amyloid plaques in the brain. Aged untreated male APP/PS1 mice also demonstrated Aβ deposition in the colonic myenteric ganglia, which was associated with increased fecal output and faster whole GI transit starting at 4-7 months old, but vehicle- and lanabecestat-treated male APP/PS1 mice had similar GI motility to their non-genetic controls until 7 months old. None of the female APP/PS1 mice showed GI dysmotility or myenteric amyloidosis. Two months of lanabecestat treatment effectively reduced amyloid plaque burden in the brains of female APP/PS1 mice but not in male APP/PS1 mice. Treatment with lanabecestat did not affect myenteric Aβ intensity or GI motility in all APP/PS1 mice. All APP/PS1 mice did not show myenteric neuronal degeneration or inflammation until 12 months old. APP/PS1 mice do not recapitulate myenteric amyloidosis persistently and lack the phenotype of constipation observed in human AD patients; these mice should not be considered an adequate murine model for studying the role of myenteric amyloidosis in GI dysmotility. An adequate animal model with myenteric amyloidosis is required for further study. Show less

While previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposition underlying suicidal behaviors in diverse populations. This study aimed to conduct a large-scale investigation of the suicidality spectrum (SP) to generate new insights into its biology and epidemiology. Leveraging ancestrally diverse participants (SI N This study provides convergent genetic evidence for both shared and phenotype-specific components of suicidal behaviors and delineates their associated factors spanning from proximal clinical and behavioral traits to more distal social determinants. These findings refine our understanding of the etiology of suicidal behaviors and may inform targeted strategies for suicide prevention in both clinical and public health settings. Show less

Over the last 20 years, tributyltin (TBT) has been reported to cause metabolic disruption in both invertebrates and vertebrates, highlighting the need for further detailed analysis of its physiological effects. This study aimed to investigate the metabolic-disrupting effects of TBT from the behavioral to the molecular level. Adult specimens of the great pond snail (Lymnaea stagnalis) were exposed to an environmentally relevant concentration (100 ng L Show less

The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4 Show less

Diabetic retinopathy (DR) is the main cause of blindness worldwide, and its prevalence rate is constantly rising. More in-depth exploration of its risk factors and pathogenic mechanisms is needed. This study systematically identified potential therapeutic targets for DR by evaluating causal effects of 16,989 genes and 2,923 proteins on DR/subtypes via two-sample Mendelian randomization (MR), validated with colocalization/Summary-data-based Mendelian randomization (SMR). National Health and Nutrition Examination Survey (NHANES) 1999-2010 cross-sectional data (weighted logistic/Restricted cubic spline (RCS)) pinpointed key risk factors; MR explored their links to DR subtypes. Bioinformatics (bulk and single-cell transcriptomics) analyzed molecular mechanisms of shared targets (gene expression, immune infiltration, pathway enrichment). Machine learning selected key targets for models. Finally, two-step mediation MR examined how targets regulate DR via risk factors. This study identified 64 core targets with causal links to DR. Subtype analysis revealed 2,128 causal genes and subtype-specific targets (e.g. 52 for background DR, 66 for proliferative DR). SMR validated these findings. NHANES data highlighted body mass index (BMI), stroke, hypertension (HBP), and C-reactive protein (CRP) as key DR risk factors, confirmed by MR. Transcriptomics identified 29 differentially expressed genes associated with both risk factors and DR, linked to immune cell regulation. Machine learning selected core targets (LY9, WWP2, etc.) and built a nomogram for DR risk prediction. Functional enrichment showed these targets enriched in chemokine/cytokine and immune-inflammatory pathways. Two-step mediation MR further revealed LY9, ARHGAP1, and WWP2 influence DR subtypes via regulating BMI, CRP, and HBP. This study systematically elucidates the key risk factors, potential molecular mechanisms, and core regulatory targets of DR through multi-omics integration, causal inference, and bioinformatics approaches. The results indicate that inflammation, immune dysregulation, and metabolic disorders play crucial roles in the pathogenesis of DR. Key genes such as LY9, ARHGAP1, and WWP2 could serve as potential intervention targets, offering theoretical foundations and strategic support for early warning and precision treatment of DR. Show less