KEY POINTS:Global deletion of angiopoietin-2 protected against the progression of CKD. Endothelial cell-derived angiopoietin-2 drove early inflammation by promoting endothelial activation. Tubular epithelial cell-derived angiopoietin-2 contributed to functional decline and kidney fibrosis in advanced CKD. BACKGROUND:CKD is driven by inflammation, vascular dysfunction, and fibrosis, with emerging evidence implicating angiopoietin-2 as a key mediator. While angiopoietin-2 is produced by endothelial cells and upregulated in injured tubular epithelial cells (TECs), the distinct contributions of endothelial cell-derived and TEC-derived angiopoietin-2 remain unclear. This study defines the cell type-specific roles of angiopoietin-2 in CKD pathogenesis. METHODS:We examined kidney transcriptomes and outcomes from the Taipei Renal Transcriptomics and Outcomes Investigation cohort, with fibrosis assessed by histology and RNA sequencing. Global, endothelial cell-specific, and TEC-specific angiopoietin-2 knockout mice were subjected to experimental CKD. Kidney injury, inflammation, vascular changes, and fibrosis were evaluated using histologic, molecular, and imaging analyses. RESULTS:In patients with CKD, elevated kidney ANGPT2 mRNA was associated with lower estimated glomerular filtration rate, greater kidney fibrosis, and adverse kidney outcomes. Global deletion of angiopoietin-2 in mice preserved kidney function and reduced inflammation, vascular rarefaction, and fibrosis during CKD progression induced by an adenine diet. Transcriptomic profiling revealed suppression of proinflammatory and profibrotic pathways and enhancement of peroxisomal lipid metabolism. Endothelial cell-specific deletion of angiopoietin-2 attenuated early inflammatory signaling and endothelial activation but failed to prevent late-stage vascular rarefaction and fibrosis. By contrast, TEC-specific deletion preserved kidney function and reduced fibrotic and vascular injury in late-stage CKD, without impacting early inflammation and endothelial activation. Mechanistically, angiopoietin-2 promoted macrophage recruitment and matrix deposition through cell-specific pathways, without directly altering metabolism of TECs. CONCLUSIONS:This study identifies angiopoietin-2's contribution to CKD pathogenesis through distinct roles of endothelial and tubular epithelial sources. Endothelial deletion mainly reduced early inflammation, while tubular epithelial deletion limited progressive injury and advanced fibrosis.

Oxidative phosphorylation (OXPHOS) and mitophagy are functionally interconnected cellular processes, the defects of which are considered key driving forces behind the pathogenesis of Parkinson’s disease (PD). UQCRC1, a core subunit of the mitochondrial respiratory chain complex III, is a recently identified familial PD gene whose pathogenic mutations result in OXPHOS stress. Given its importance, however, the role of UQCRC1 in idiopathic PD as well as mitophagy has not been investigated. In this study, we collected 19 datasets comprising postmortem substantia nigra from 150 cases of non-disease controls and 185 cases of PD or incidental Lewy body disease (iLBD), and the meta-analysis of the UQCRC1 mRNA level showed reduced expression in idiopathic PD, suggesting the potential of UQCRC1 as a biomarker. Leveraging the SH-SY5Y cells and fly models, we showed that mitophagy was impaired upon UQCRC1 mutation or depletion. Notably, insufficiency of PINK1 mRNA was associated with UQCRC1 deficiency, and overexpression of Pink1 rescued the locomotion and mitophagy defects in the fly models with neuronal loss of uqcrc1. Treatment with two PINK1 activators, kinetin and MTK458, resulted in similar protective effects in the fly and cell models. Overall, we identified OXPHOS stress led by deficiency of UQCRC1 as an etiology of mitophagy defects in PD and PINK1 as a therapeutic target for UQCRC1-associated PD.

The decline of glomerular filtration is a hallmark of aging. Methylglyoxal (MG) is a uremic toxin known to induce aging-like changes; however, whether its mechanism of action is similar remains unclear. We compare the underlying mechanisms of MG and aging using Drosophila nephrocytes as a model. In addition to lower body weight, reduced locomotion, and shorter lifespans, MG caused filtration defects and induced cellular senescence in nephrocytes similar to the effects of aging, with a corresponding upregulation of the LXR/RXR signaling pathway. Mechanistically, we found that MG and aging both increased reactive oxygen species (ROS). Antioxidant treatments and inhibition of the LXR/RXR pathway both improved the filtration function. In addition, MG and aging both reduced the level of Jub, which is a protein essential for the integrity of the slit diaphragm structure. Overexpressing jub enhanced slit diaphragm structure and prevented MG-induced functional decline. Together, the findings reveal parallel features between MG and aging, and show that inhibiting LXR/RXR signaling, reducing ROS, or strengthening the slit diaphragm structure can preserve the filtration function of Drosophila nephrocytes.

Brain glymphatic system function as measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) index has been associated with brain disorders, but its association with mortality and other diseases remains underexplored. This prospective study included 34,268 participants from the UK Biobank with MRI data collected since August 2014. The DTI-ALPS indices‌ of the left and right hemispheres and the average index were calculated‌. The incident mortality and morbidity were defined as the death and disease (cancer, cardiovascular, respiratory, digestive, and neurodegenerative disease) reported between the MRI collection date and December 2021. Cox proportional hazard regression analyses were used to assess the association of DTI-ALPS indices with all-cause and cause-specific mortality and morbidity. We found that a higher DTI-ALPS index, indicated better glymphatic function, was associated with reduced risks of all-cause mortality (HR, 95% CI: 0.85, 0.78–0.93; P < 0.001), cardiovascular disease (CVD)-specific mortality (HR, 95% CI: 0.77, 0.63–0.93; P = 0.01), and neurodegenerative disease-specific mortality (HR, 95% CI: 0.56, 0.37–0.84; P = 0.01). Furthermore, an elevated DTI-ALPS index was associated with reduced risks of CVD (HR, 95% CI: 0.92, 0.89–0.96; P < 0.001) and neurodegenerative disease (HR, 95% CI: 0.68, 0.58–0.80; P < 0.001). The findings deepen the understanding of the role of brain glymphatic system in health.

Variants in the CRB1 gene cause retinal degeneration and subsequent vision impairment in patients of retinitis pigmentosa (RP). No treatments are currently available to cure or impede the progression of CRB1-associated retinopathy. Previous studies have revealed alterations in the endolysosomal systems and autophagy in the absence of CRB1, but their roles in the pathogenesis of CRB1 retinopathy are unclear. Here, we examined the disease mechanism of CRB1 retinopathy using loss-of-function mutants of crumbs (crb), the Drosophila homolog of CRB1. We found that the loss of crb results in overactivation of autophagy in the eye. We also discovered that dihydroceramide desaturase encoded by infertile crescent (ifc), was up-regulated in crb mutants. Overexpression of ifc inhibited autolysosomes and alleviated Atg1-induced autophagic cell death. Mechanistically, ifc enhanced the binding of Rac1 to Atg8 and increased the autophagosomal localization of active Rac1, thus inhibiting autophagy. Importantly, autophagy inhibitions achieved through ifc overexpression, chloroquine treatment, or Beclin-1 RNAi all ameliorated the neurodegeneration of crb mutant eyes. Together, these findings highlight the mechanism of dihydroceramide desaturase in modulating autolysosome functions in crb mutants, providing new insights for developing treatments against CRB1 retinopathy.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) serves as a bridging intervention for subsequent definitive haemorrhagic control. This study compared the clinical outcomes of REBOA and resuscitative thoracotomy (RT) in patients with bleeding below the diaphragm. Materials and Methods: This retrospective cohort study included adult trauma patients who presented to the Trauma Quality Improvement Program between 2020 and 2021 and who underwent either REBOA or RT in the emergency department (ED). Patients with severe head and chest injuries, characterised by an Abbreviated Injury Scale (AIS) score greater than 3, were excluded. The clinical data of patients treated with REBOA and those treated with RT were compared, and multivariable logistic regression (MLR) was employed to identify prognostic factors associated with mortality. Results: A total of 346 patients were enrolled: 138 (39.9 %) received REBOA, and 208 (60.1 %) received RT at the ED. Patients in the RT group underwent ED cardiopulmonary resuscitation (CPR) more frequently (58.2 % vs. 23.2 %; p < 0.001) and had a higher mortality rate (87.0 % vs. 45.7 %; p < 0.001). Patients who died had lower Glasgow Coma Scale scores (6 [4.5] vs. 11 [4.9]; p < 0.001), underwent more ED CPR (58.6 % vs. 9.8 %; p < 0.001), and received RT more frequently (74.2 % vs. 26.5 %, p < 0.001). The MLR revealed that the major prognostic factors for mortality were systolic blood pressure (odds ratio [OR] 0.988, 95 % confidence interval [CI] 0.978-0.998; p = 0.014), ED CPR (OR 11.111, 95 % CI 4.667-26.452; p < 0.001), abdominal injuries with an AIS score >= 4 (OR 4.694, 95 % CI 1.921-11.467; p = 0.001) and RT (OR 5.693, 95 % CI 2.690-12.050; p < 0.001). Conclusions: In cases of blunt trauma, prompt identification of the bleeding source is crucial. For patients with bleeding below the diaphragm, REBOA led to higher survival rates than did RT. However, it is important to consider the limitations of the database and the necessary exclusions from our analysis.

Cerebral small vessel disease (CSVD) is a leading cause of age-related cognitive decline and neurological disorders, yet its precise characterization in large populations has been constrained by reliance on subjective neuroimaging ratings. To address this, we developed CSVDtransformer, a foundation model that simultaneously quantifies six key CSVD biomarkers from structural brain MRI. In 3,718 subjects, the model achieved excellent accuracy (mean AUC = 0.904) in measuring periventricular and deep white matter hyperintensities, Fazekas scores, enlarged perivascular spaces, lacunar infarcts, and cerebral microbleeds. Validation across two independent, external datasets (N=568) confirmed its robust generalizability. As a clinical decision-support tool, it augmented neurologist assessment relative accuracy by 20%. Application to 59,772 UK Biobank participants revealed distinct associations of these quantified biomarkers with incident stroke, dementia, and psychiatric disorders. Large-scale multi-omics analysis identified 1,365 significant plasma protein correlates and 14 novel genetic loci for these CSVD biomarkers. These associations implicate pathways of endothelial dysfunction, inflammation, and lipid metabolism. Mendelian randomization analyses provided evidence for causal relationships between specific vascular-metabolic proteins and CSVD biomarkers, such as positive effect of EFEMP1 and negative effect of EPO on CSVD. Furthermore, drug-target enrichment analysis highlighted the potential for targeting TFPI and EPO to address vascular dysfunction associated with CSVD. Our study establishes CSVDtransformer as a scalable foundation model that deciphers the complex systemic biology of cerebral microvascular health. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0546300), the National Key R&D Program of China (No. 2023YFC3605400), the National Natural Science Foundation of China (No. 82472055, 62433008, 82071201, 81971032 and 92249305), the Shanghai Pilot Program for Basic Research - Fudan University 21TQ1400100 (25TQ010), and Shanghai Science and Technology Commission Program (23JS1410100), the Science and Technology Innovation 2030 Major Projects (no. 2022ZD0211600), the Shanghai Municipal Science and Technology Major Project (no. 2018SHZDZX01), the Research Start-Up Fund of Huashan Hospital (no. 2022QD002), the Excellence 2025 Talent Cultivation Program at Fudan University (no. 3030277001), Shanghai Talent Development Funding for the Project (no. 2019074), and the Zhangjiang Lab, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Shanghai Academy of Natural Sciences (SANS), Shanghai Medical College, Fudan University. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used openly available human data that were originally located at the official website of UK Biobank (http://www.ukbiobank.ac.uk/). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All software and methods used in our study are publicly available. The code to reproduce the results can be accessed at https://github.com/weikanggong1/CSVDtransformer.git.

Spinocerebellar ataxia type 36 (SCA36) is a neurodegenerative disease caused by expanded (GGCCTG)n hexanucleotide repeat sequence in the NOP56 gene. While the expanded repeats could transcribe and form toxic RNA foci within neurons, recent evidence indicates that translation of these repeats produces dipeptide repeats (DPR) that contribute to neurotoxicity. The relative impact of hexanucleotide RNA repeats (HRR) and DPR on the neurodegeneration of SCA36 remains unclear. Here, we established a Drosophila SCA36 model to dissect the neurotoxic effects of HRR and DPR. The fly model recapitulates the cellular defects observed in SCA36 patient fibroblasts, validating its relevance for mechanistic study of SCA36. Further engineering the transgenes to express individual DPRs reveal Proline-Glycine-DPR (PG-DPR) as the most potent neurotoxin causing progressive motor and sensory dysfunction. Expressing a series of the SCA36 transgenes with varying HRR lengths demonstrates an age- and length-dependent adult-onset neurodegeneration. Interestingly, sequence modification of the transgenes to exclusively express HRR or DPR alone causes a milder phenotype, indicating both HRR and DPR contribute partially to the pathogenicity of SCA36. Therefore, this model provides a valuable platform for screening drug targeting either HRR- or DPR-mediated toxicity of SCA36. Suppression of the RNA elongation factor SUPT4H1 ortholog reduces RNA foci in cell culture. However, expression level of SUPT4H1 was not changed in SCA36 patient cells. Interestingly, knockdown of the Drosophila SUPT4H1 ortholog or 6-azauridine treatment to suppress RNA transcription aggravates the neurodegenerative phenotypes in both the fly models and patient-derived fibroblasts, highlighting the complex interplay of pathomechanisms in SCA36. These results underscore the need for carefully evaluating the potential side effects when designing therapeutic interventions for SCA36.

BACKGROUND:Cognitive decline and the progression to Alzheimer's disease (AD) are traditionally associated with amyloid-beta (Aβ) and tau pathologies. This study aims to evaluate the relationships between microstructural white matter injury, cognitive decline and AD core biomarkers. METHODS:We conducted a longitudinal study of 566 participants using peak width of skeletonized mean diffusivity (PSMD) to quantify microstructural white matter injury. The associations of PSMD with changes in cognitive functions, AD pathologies (Aβ, tau, and neurodegeneration), and volumes of AD-signature regions of interest (ROI) or hippocampus were estimated. The associations between PSMD and the incidences of clinical progression were also tested. Covariates included age, sex, education, apolipoprotein E4 status, smoking, and hypertension. RESULTS:Higher PSMD was associated with greater cognitive decline (β=-0.012, P < 0.001 for Mini-Mental State Examination score; β<0, P < 0.05 for four cognitive domains) and a higher risk of clinical progression from normal cognition to mild cognitive impairment (MCI) or AD (Hazard ratio=2.11 [1.38-3.23], P < 0.001). These associations persisted independently of amyloid status. PSMD did not predict changes in Aβ or tau levels, but predicted changes in volumes of AD-signature ROI (β=-0.003, P < 0.001) or hippocampus (β=-0.002, P = 0.010). Besides, the whole-brain PSMD could predict cognitive decline better than regional PSMDs. CONCLUSIONS:PSMD may be a valuable biomarker for predicting cognitive decline and clinical progression to MCI and AD, providing insights besides traditional Aβ and tau pathways. Further research could elucidate its role in clinical assessments and therapeutic strategies.

Although glymphatic function is involved in Alzheimer’s disease (AD), its potential for tracking the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD (n = 47), mild cognitive impairment (n = 137), and normal controls (n = 235) from the Alzheimer’s Disease Neuroimaging Initiative. Decreased ALPS-index was observed in AD dementia, prodromal AD, and preclinical AD patients. Lower ALPS-index was significantly associated with faster changes in amyloid PET burden (AV45 PET) and AD-signature ROI volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of ALPS-index with cognitive decline were fully mediated by amyloid PET and brain atrophy. Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD.

Autophagic decline accompanies age and causes a deterioration in proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for macroautophagic/autophagic degradation and exocytosis. Loss of Drosophila Rab27 in αβp brain neurons enhances longevity, underscoring its neuronal role and systemic effect. To understand the underlying mechanisms, we characterized the cell autonomous and non-autonomous functions of Rab27. Rab27 expression increased in midlife, providing a temporal manipulation window. Depleting Rab27 at that timepoint activated autophagy and sustained neuronal maintenance. At the organismic level, Egfr (Epidermal growth factor receptor) ligand was reduced and Akt kinase underphosphorylated in the Rab27 KO fly body, indicating a widespread signaling cascade. Finally, Rab27 KO ameliorates the neurotoxicity in a fly α-synucleinopathy model. Altogether, our results highlight a neuronal autophagy regulator exerting systemic effects that are crucial for neuronal maintenance and improving longevity.Abbreviation: Atg autophagy-related genes;EGF: epidermal growth factor; Egfr: Epidermal growth factor receptor;EGFR: epidermal growth factor receptor; foxo: forkhead box, sub-groupO; mTor: mechanistic target of rapamycin; MTOR: mechanistic target ofrapamycin; spi: spitz.

Brain glymphatic activity, as indicated by diffusion-tensor imaging analysis along the perivascular space (ALPS) index, is involved in developmental neuropsychiatric and neurodegenerative diseases, but its genetic architecture is poorly understood. Here, we identified 17 unique genome-wide significant loci and 161 candidate genes linked to the ALPS-indexes in a discovery sample of 31,021 individuals from the UK Biobank. Seven loci were replicated in two independent datasets. Genetic signals located at the 2p23.3 locus yielded significantly concordant effects in both young and aging cohorts. Genetic correlation and polygenic overlap analyses indicate a common underlying genetic mechanism between the ALPS-index, ventricular volumes, and cerebrospinal fluid tau levels, with GMNC (3q28) and C16orf95 (16q24.2) as the shared genetic basis. Our findings enhance the understanding of the genetics of the ALPS-index and provide insight for further research into the neurobiological mechanisms of glymphatic clearance activity across the lifespan and its relation to neuropsychiatric phenotypes. Here, the authors perform a genome-wide association study of the ALPS-index, identifying 17 unique genome-wide significant loci, unraveling mechanisms of brain glymphatic activity and providing insight for its relation to neuropsychiatric phenotypes.

Purpose:To quantitate the levels of various ceramide species in the vitreous of patients with proliferative diabetic retinopathy (PDR) and to investigate the role of vitreal ceramides in the pathogenesis of PDR. Study Design:A case control study. Methods:We collected vitreous samples from 25 type 2 diabetes patients with PDR and 25 age- and sex-matched nondiabetic controls undergoing vitrectomy. The levels of ceramide species (C16:0, 18:0, 20:0, 22:0, 24:1, and 24:0) were measured by ultra-high-performance liquid chromatography-tandem mass spectrometry with positive electrospray ionization mode. The correlation of baseline characteristics, blood test data, and clinical manifestation of PDR were analyzed with vitreal ceramides levels. Results:The total level of ceramides was substantially higher in the PDR group than the control group (18.626 ± 19.264 versus 3.524 ± 2.456 pmol/mg protein; P < 0.001). Among ceramides of various acyl chain lengths, the increases of very-long-chain (VLC) ceramides (C22-C24) were more drastic than those of long-chain ceramides (C16-C20). In the PDR group, VLC ceramide species accounted for 76.1%, whereas in the control group, C16 ceramide predominated at 40.5%. Based on the multivariate linear regression analysis, diagnosis of diabetes (β = 14.5751; P = 0.0327) and lower body mass index (β = -2.1396; P = 0.0173) were significantly associated with higher level of VLC ceramides. Intravitreal injection of anti-VEGF leads to insignificant reduction of VLC ceramides (P = 0.068). Conclusions:Vitreal ceramide levels were elevated in diabetic subjects, especially the VLC species, which may contribute to the pathogenesis of diabetic retinopathy.

Identifying circulating metabolites associated with dementia, cognition, and brain volume may improve the understanding of dementia pathogenesis and provide novel insights for preventive and therapeutic interventions. This cohort study included a total of 87,885 participants (median follow-up 9.1 years, 54% female) without dementia at baseline from the UK Biobank. 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Cox proportional regression was used to examine the associations of each metabolite with incident dementia (cases = 1134), Alzheimer’s disease (AD; cases = 488), and vascular dementia (VD; cases = 257) during follow-up. Dementia-associated metabolites were further analyzed for association with cognitive deficits (N = 87,885) and brain volume (N = 7756) using logistic regression and linear regression. We identified 26 metabolites associated with incident dementia, of which six were associated with incident AD and five were associated with incident VD. These 26 dementia-related metabolites were subfractions of intermediate-density lipoprotein, large low-density lipoprotein (L-LDL), small high-density lipoprotein (S-HDL), very-low-density lipoprotein, fatty acids, ketone bodies, citrate, glucose, and valine. Among them, the cholesterol percentage in L-LDL (L-LDL-C%) was associated with lower risk of AD (HR[95%CI] = 0.92[0.87-0.97], p = 0.002), higher brain cortical (β = 0.047, p = 3.91 × 10 -6 ) and hippocampal (β = 0.043, p = 1.93 × 10 -4 ) volume. Cholesteryl ester to total lipid ratio in L-LDL (L-LDL-CE%) was associated with lower risk of AD (HR[95%CI] = 0.93[0.90-0.96], p = 1.48 × 10 -4 ), cognitive deficits (odds ratio = 0.98, p = 0.009), and higher hippocampal volume (β = 0.027, p = 0.009). Cholesteryl esters in S-HDL (S-HDL-CE) were associated with lower risk of VD (HR[95%CI] = 0.81[0.71-0.93], p = 0.002), but not AD. Taken together, circulating levels of L-LDL-CE% and L-LDL-C% were robustly linked to risk of AD and AD phenotypes, but not with VD. S-HDL-CE was associate with lower risk of VD, but not with AD or AD phenotypes. These metabolites may play a role in the advancement of future intervention trials. Additional research is necessary to gain a complete comprehension of the molecular mechanisms behind these associations.

Background::Neuroticism has been associated with numerous health outcomes. However, most research has focused on a single specific disorder and has produced controversial results, particularly regarding mortality risk. Here, we aimed to examine the association of neuroticism with morbidity and mortality and to elucidate how neuroticism affects trajectories from a healthy state, to one or more neuroticism-related disorders, and subsequent mortality risk.Methods::We included 483,916 participants from the UK Biobank at baseline (2006-2010). Neuroticism was measured using the Eysenck Personality Questionnaire. Three clusters were constructed, including worry, depressed affect, and sensitivity to environmental stress and adversity (SESA). Cox proportional hazards regression and multistate models were used. Linear regression was used to examine the association between neuroticism and immune parameters and neuroimaging measures.Results::High neuroticism was associated with 37 non-overlapping diseases, including increased risk of infectious, cardiometabolic, neuropsychiatric, digestive, and respiratory diseases, and decreased risk of cancer. After adjustment for sociodemographic variables, physical measures, healthy behaviors, and baseline diagnoses, moderate-to-high neuroticism was associated with a decreased risk of all-cause mortality. In multistate models, high neuroticism was associated with an increased risk of transitions from a healthy state to a first neuroticism-related disease (hazard ratio [HR] [95% confidence interval (CI)] = 1.09 [1.05-1.13], P <0.001) and subsequent transitions to multimorbidity (1.08 [1.02-1.14], P = 0.005), but was associated with a decreased risk of transitions from multimorbidity to death (0.90 [0.84-0.97], P for trend = 0.006). The leading neuroticism cluster showing a detrimental role in the health-illness transition was depressed affect, which correlated with higher amygdala volume and lower insula volume. The protective effect of neuroticism against mortality was mainly contributed by the SESA cluster, which, unlike the other two clusters, did not affect the balance between innate and adaptive immunity. Conclusion::This study provides new insights into the differential role of neuroticism in health outcomes and into new perspectives for establishing mortality prevention programs for patients with multimorbidity.

Short and long sleep durations are associated with multiple physical, psychiatric and neurodegenerative diseases, yet their potentially shared and distinct biological mechanisms remain unclear. Here, using data from UK Biobank participants aged 38-73 years, we have characterized the in-depth genetic architecture of short (<= 7 h) and long (>= 7 h) sleep groups, along with their associations with behaviors, neuroimaging and blood biomarkers. The two sleep groups exhibited independent genetic architectures and distinct immunometabolic and proteomic profiles. Notably, long sleep showed more significant associations with cardiovascular-related biomarkers (for example, cholesterol), brain structures (for example, hippocampus) and plasma proteins (for example, GDF15), whereas short sleep demonstrated greater genetic overlap with psychiatric conditions, particularly depression. Mendelian randomization further supported this dissociation by showing that long sleep duration is probably a consequence of multiple brain disorders and cardiovascular diseases, whereas short sleep duration has a potential causal effect on various brain and physical illnesses. Our findings advance our understanding of the relationship between sleep and health conditions by revealing distinct biological origins and genetic mechanisms underlying short and long sleep duration.

Background::Physical activity, sedentary behavior (SB), and sleep duration are associated with brain health. Effects of those on developing Parkinson’s disease (PD) are poorly investigated. This study aimed to examine the independent and joint associations of physical activity, SB, sleep with PD risk.Methods::We analyzed data on 401,697 participants from the UK Biobank cohort, which was enrolled in 2006–2010. Physical activities were measured based on a questionnaire. Sleep and SB time were defined through self-reported total number of hours. Models fitted with restricted cubic spline were conducted to test for linear and non-linear shapes of each association. Cox proportional hazards regression models were used to estimate the association of three modifiable behaviors.Results::Our analytic sample included 401,697 participants with 3030 identified cases of PD (mean age, 63 years; 62.9% male). PD risk was 18% lower in the high total physical activity group (95% CI, 0.75–0.90), 22% lower in the high leisure-time physical activity (LTPA) group (95% CI, 0.71–0.86) compared with the low level and 14% higher in the high sleep duration group (95% CI, 1.05–1.24) compared to moderate group. Total SB time was irrelevant with PD risk, while high TV viewing showed a 12% increase of PD risk compared to the low group (95% CI, 1.02–1.22). Low computer use (0 h/day) was associated with a 14% higher risk compared to 1 h/day use (95% CI, 1.04–1.26). Those associations were independent. A combination of 7 h/day sleep, moderate-to-high computer use, and moderate-to-vigorous intensity of LTPA showed lowest PD risk (HR, 0.70; 95% CI, 0.57–0.85).Conclusions::Physical activity, SB, and sleep were associated with PD risks separately. Our findings emphasize the possibility for changing these three daily activities concurrently to lower the risk of PD. These findings may promote an active lifestyle for PD prevention.

Recent expansion of proteomic coverage opens unparalleled avenues to unveil new biomarkers of Alzheimer's disease (AD). Among 6,361 cerebrospinal fluid (CSF) proteins analysed from the ADNI database, YWHAG performed best in diagnosing both biologically (AUC = 0.969) and clinically (AUC = 0.857) defined AD. Four- (YWHAG, SMOC1, PIGR and TMOD2) and five- (ACHE, YWHAG, PCSK1, MMP10 and IRF1) protein panels greatly improved the accuracy to 0.987 and 0.975, respectively. Their superior performance was validated in an independent external cohort and in discriminating autopsy-confirmed AD versus non-AD, rivalling even canonical CSF ATN biomarkers. Moreover, they effectively predicted the clinical progression to AD dementia and were strongly associated with AD core biomarkers and cognitive decline. Synaptic, neurogenic and infectious pathways were enriched in distinct AD stages. Mendelian randomization did not support the significant genetic link between CSF proteins and AD. Our findings revealed promising high-performance biomarkers for AD diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms. Using a data-driven proteomics design and a high-throughput platform, this study highlights the value of CSF YWHAG for Alzheimer's diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms.

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.Abbreviations: DEAF1: Deformed epidermal autoregulatory factor-1; FOXO: Forkhead box O; MuSC: Muscle Stem Cell; PAX7: Paired box 7; PIK3C3: Phosphatidylinositol 3-kinase catalytic subunit type 3.

AbstractPAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot–Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSCM70R variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSCM70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC-associated CMT2.