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Paneth cell metaplasia (PCM), a metaplastic change associated with chronic inflammation in ulcerative colitis (UC), may be linked to UC-associated neoplasia (UCAN). However, no endoscopic method currently exists for detecting PCM. This study aimed to develop and validate a novel endoscopic staining technique-CV-SCAN-for identifying PCM and UCAN, and to explore the molecular characteristics of the stained areas. This retrospective observational study included 131 patients with UC undergoing surveillance colonoscopy. CV-SCAN involved spraying an ultra-diluted solution (0.006%) of crystal violet from the descending colon to the rectum. Biopsies were obtained from stained and non-stained areas and evaluated histologically and molecularly. RNA expression profiles were analyzed via microarray and real-time RT-PCR. The diagnostic performance of CV-SCAN for detecting PCM was assessed, along with its correlation with UCAN history. CV-SCAN visualized sharply demarcated, purple-stained areas corresponding to PCM or UCAN. PCM was significantly associated with a history of UCAN. Uniform, dark staining was characteristic of PCM, while UCAN showed heterogeneous staining with small round pits. CV-SCAN achieved a sensitivity of 81.3% and a specificity of 84.9% for PCM detection. Molecular analysis revealed upregulation of Paneth cell-specific (DEFA5, DEFA6), small intestinal (CCL25, APOC3), and UCAN-associated (IL17RC) genes, along with downregulation of SATB2 in stained areas. CV-SCAN is a novel and effective endoscopic staining method for detecting PCM and UCAN in patients with UC. It enables risk stratification through direct visualization of precancerous changes and may facilitate early detection and targeted surveillance. Show less

In anticipation of updates to cholesterol guidelines globally, evidence since the most recent iteration of recommendations across US and Europe for risk assessment and lipid management are reviewed. ASCVD risk estimation is at the core of determining lipid lowering goals and consideration for therapies. In primary prevention, incorporation of the PREVENT equations will be featured in updated guidelines, which will likely demarcate new, lower risk thresholds compared to the prior Pooled Cohort Equations. Additionally, the use of coronary artery calcium (CAC) improves risk estimation to inform medication allocation and LDL-C goals beyond traditional risk factor risk estimation. To achieve lower LDL-C, many adults will need multiple lipid-lowering medications. For high-risk individuals, combination therapy with low/moderate intensity statin and ezetimibe or bempedoic acid should be considered. Additionally, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapies can be used to attain lower LDL-C in high-risk individuals, including those with clinical ASCVD or a high CAC burden. In very-high risk patients, treatment to LDL-C values as low as <30 mg/dL further reduces ASCVD risk without significant adverse events. Among individuals treated with PSCK9i therapy, those with elevated Lp(a) may have greater ASCVD risk reduction and may be a patient population that is prioritized for PCSK9i until therapies directly targeting Lp(a) are available. An ASCVD risk-based approach should be the foundation for determining LDL-C goals with consideration that multiple lipid-lowering therapies are often necessary for high and very-high risk patients who were treated to very low LDL-C in more recent randomized controlled trials. Show less

Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanisms. Using quantitative proteomic analysis on the plasma of bacteraemic participants, we demonstrate that wild-type toxigenic Salmonella induced secretion of lysozyme (LYZ) and apolipoprotein C3 (APOC3). Recombinant typhoid toxin or Salmonella infection recapitulated LYZ and APOC3 secretion in cultured cells, which involved ATM/ATR-dependent DDRs and confirmed observations in typhoid fever. LYZ caused spheroplast formation, inhibited the Salmonella type 3 secretion system, and intracellular infections. LYZ expression was regulated by p53 in a cell type-specific manner and driven by mitochondrial oxidative stress that caused nuclear DDRs and p53-mediated senescence responses. Addition of LYZ inhibited oxidative DNA damage and resulting senescence responses caused by typhoid toxin. Our findings may indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever. Show less

Gallbladder adenosquamous carcinoma (GBASC) is an uncommon, highly aggressive neoplasm characterized by the coexistence of both glandular and squamous cells. Representing fewer than 5% of gallbladder malignancies, GBASC demonstrates a more aggressive behavior and has poorer prognosis, posing considerable challenges for early diagnosis and effective management. We present a case of GBASC in a 52-year-old woman who achieved long-term tumor-free survival by surgery, as well as targeted and immunotherapy after the operation. Targeted gene sequencing and bioinformatics analysis tools, including STRING, GeneMANIA, Metascape, TRRUST, Sangerbox, and cBioPortal, were used to analyze the biological functions and features of the mutated genes in GBASC. A total of 16 mutations ( Comparative analyses with other gallbladder carcinoma subtypes revealed GBASC to have distinct clinical phenotypes, molecular alterations, functional characteristics, and enriched signaling pathways. Moreover, there is an urgent need for standardized treatment protocols. Show less

Hereditary Multiple Osteochondromas (HMO) is a rare autosomal dominant skeletal disorder caused by heterozygous loss-of-function mutations in EXT1 or EXT2, which encode glycosyltransferases essential for heparan sulfate (HS) biosynthesis. Whether haploinsufficiency alone suffices or biallelic inactivation is required for osteochondroma formation remains a central unresolved question. In this study, we employed CRISPR/Cas9 combined with PiggyBac transposon technology to introduce a second pathogenic mutation (c.1883+1G>T) into patient-derived induced pluripotent stem cells (iPSCs) carrying a heterozygous EXT1 c.1126C>T mutation. This approach enabled the generation of isogenic iPSC lines: wild-type (WT), single-mutant (SM), and double-mutant (DM). These iPSCs were differentiated through induced mesenchymal stem cells (iMSCs) into chondrocytes. Biallelic EXT1 mutation in DM cells led to significant upregulation of SOX9, COL2A1, and ACAN, elevated glycosaminoglycan (GAG) levels, and markedly reduced HS, whereas SM cells remained indistinguishable from WT. Three-dimensional (3D) chondrogenic organoid cultures revealed that DM organoids were enlarged and structurally disorganized, partially recapitulating key histopathological features of osteochondromas. Transcriptomic analysis identified the Wnt signaling pathway as the most significantly enriched pathway among differentially expressed genes following EXT1 loss. Collectively, these findings provide direct human cellular evidence that complete EXT1 inactivation-not haploinsufficiency-drives aberrant chondrogenesis, likely through impaired sequestration of morphogen ligands, thereby supporting the Two-hit pathogenic model. Show less

Lipoprotein (a) [Lp(a)] is a lipoprotein similar to low-density lipoprotein (LDL), which binds to a characteristic component: apolipoprotein (a). The plasma Lp(a) level is mainly determined by genetic factors, with variations across ethnic groups. In adults, various epidemiological and genetic studies have shown that elevated Lp(a) levels are an independent risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis, associated with inflammatory, atherogenic, and thrombotic mechanisms. Given that the distribution, variability, and prognostic value of this marker in the pediatric population have been less investigated, the objective of this review is to analyze the available evidence on the behavior of Lp(a) as a risk marker in children and adolescents, current recommendations for its measurement in pediatrics, and treatment prospects. Show less

Osteoarthritis (OA) often coexists with metabolic traits (MTs), causing significant disability. Our study aims to uncover the shared genetic mechanisms between OA and MTs, revealing novel OA-MT related genes, proteins and pathways. We first explored the clinical associations between OA and MTs based on UK Biobank data. Using GWAS statistics for 9 OA subtypes and 51 MTs, we identified both global and regional genetic correlations. Multi-trait GWAS helped revealed credible genes and relevant pathways through various methods. Protein-level analyses were also conducted to identify key proteins. We developed polygenic scores (PGS), machine learning models and drug repurposing strategies were explored to translate these findings into clinical applications. We identified 152 trait pairs with significant associations and 709 local regions linked to OA-MT. Key SNVs like rs13135092 (SLC39A8) and rs34811474 (ANAPC4) were associated with multiple OA-MT pairs. Lipid and glucose metabolism emerged as central pathways, with tissue-specific enrichment analyses revealing key gene clusters in hepatocytes, arteries, and brain regions. Protein-level analyses identified 205 protein subgroups. PGS integrating MTs outperformed model based solely on OA, improving AUC by 17.5%. Causal gene-based models showed strong diagnostic accuracy (average AUC = 0.875 in external cohorts). Drug prediction highlighted fenofibrate as a promising treatment among 71 candidates. This study provides new insights into the genetic links between OA and MTs. We identified genes, proteins, and pathways related to comorbidities, revealing shared mechanisms, highlighting the potential of integrating metabolic factors to improve OA prediction, diagnosis, and treatment. Show less

Atherosclerosis (AS), a chronic inflammatory process driven largely by macrophage-mediated plaque formation, remains poorly understood in mitochondrial-macrophage crosstalk. While CYBA polymorphisms correlate with cardiovascular risk, the functional role of CYBA in connecting mitochondrial dysfunction to macrophage phenotypic alteration and functional modulation remains largely unknown. In this study, we integrated multi-omics profiling of AS immune microenvironments with mitochondrial-associated gene sets. Machine learning and single-cell RNA sequencing identified CYBA as a key oxidative stress regulator. CYBA expression was significantly upregulated both in oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages and in atherosclerotic lesions, with immunofluorescence confirming macrophage enrichment. Show less

WNT-β-catenin activation is observed in around 50% of all patients with hepatocellular carcinoma (HCC), through either gain-of-function mutations in CTNNB1 (which encodes β-catenin) or loss-of-function mutations in AXIN1 or APC. Currently, first-line therapies for HCC are immune checkpoint inhibitor (ICI) combinations, and β-catenin-active HCCs have garnered increased attention due to their unique tumour immune microenvironment (TIME). This pathway is known to drive an immune-excluded TIME, but clinical investigations have provided a more nuanced perspective, with the emergence of a new 'immune-like' subclass of HCC that is paradoxically enriched for CTNNB1 mutations and has high levels of T cell infiltration. As such, patients and animal models with β-catenin activation treated with ICIs exhibit heterogeneous responses. Additionally, these tumours exhibit higher fatty acid oxidation to fuel tumour growth owing to a unique metabolic milieu shaped by zone 3 metabolism, which is a physiological function of WNT-β-catenin signalling in the liver lobule. Biomarkers to detect molecular subclasses of patients for targeted therapies are being developed. In this Review, we discuss advances in our understanding of the TIME and metabolism of β-catenin-active HCC, driven by in vitro and in vivo models and single-cell and spatial sequencing, and their implications for the treatment of a subset of HCCs using precision therapies against WNT-β-catenin signalling. Show less

Postpartum depression (PPD) is linked to neuroimmune dysregulation. Brexanolone, an intravenous formulation of the neurosteroid allopregnanolone and the first FDA-approved treatment for PPD, produces rapid and sustained antidepressant effects. However, its long-term mechanisms of action remain unclear. This study evaluated brexanolone's prolonged impact on two groups of biomarkers in whole blood: inflammatory mediators and growth/differentiation/neurotrophic factors. Whole blood was also maintained in culture (4 h) and subjected to lipopolysaccharide (LPS) stimulation of the TLR4 inflammatory pathway. Ten individuals with moderate-to-severe PPD received brexanolone and were assessed before, and at 6 h, ~7, and ~30 days post-infusion. BDNF significantly increased and remained elevated through 30 days, representing a sustained neurotrophic response. In contrast, inflammatory mediators CCL11, IL-6, TNF-α, and IL-18 showed rapid reductions by 6 h. TNF-α suppression lasted up to 7 days, while CCL11 and IL-6 remained suppressed through 30 days. These changes were associated with reductions in Hamilton Depression Rating Scale (HAM-D) scores over time. LPS-stimulated whole blood cultures revealed suppression of TLR4-induced CCL11, IL-1β, IL-6, IL-8, IL-18, TNF-α, HMGB1, and MIP-1β at 6 h. IL-8, IL-18, and TNF-α remained suppressed through 7 days, while IL-1β and CCL11 remained suppressed through 30 days, aligning with sustained HAM-D score improvements. Biomarker × time interactions suggested dynamic regulation of inflammatory and neurotrophic pathways. Given the small sample size, these findings should be interpreted as a pilot study, but they indicate that brexanolone promotes both rapid and sustained anti-inflammatory and neurotrophic effects supporting lasting symptom remission in PPD. Show less

To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. Genome-wide association study data were obtained from the UK Biobank Pharma Proteomics Project, FinnGen, and the Million Veteran Program. We used a four-stage analytical framework: Stage 1 applied Mendelian randomization and Bayesian colocalization to evaluate associations between 2923 plasma proteins and glaucoma; Stage 2 used summary-based Mendelian randomization to explore transcriptomic and epigenomic associations of the identified proteins with glaucoma risk; Stage 3 involved a prospective association analysis of protein levels and incident glaucoma in the UK Biobank cohort, including 40,170 glaucoma-free participants; and Stage 4 systematically evaluated the druggability of the prioritized protein targets. We identified 26 plasma proteins with putative causal associations with glaucoma, six of which were novel: COL24A1, KAZALD1, EBAG9, CSNK1D, AZI2, and AXIN1. COL24A1 (odds ratio [OR] = 0.85; 95% confidence interval [CI], 0.80-0.90; PFDR < 0.001; PP.H4 = 0.95) and EFEMP1 (OR = 0.88; 95% CI, 0.83-0.92; PFDR < 0.001; PP.H4 = 0.98) emerged as the most compelling candidates. To further elucidate the regulatory mechanisms, multiomics analyses indicated that epigenetic modifications and alternative splicing events affecting these genes were associated with elevated glaucoma risk. Notably, EFEMP1 was significantly associated with glaucoma incidence in the prospective cohort analysis (fully adjusted Cox model: hazard ratio = 1.61; 95% CI, 1.29-2.00; PFDR = 0.002), demonstrating strong predictive performance (C-index = 0.811, area under the curve = 0.806) and representing a promising therapeutic target. Our findings provide new insights into the proteomic basis of glaucoma and highlight promising opportunities for developing targeted therapies. Show less

This study aimed to identify distinct patterns of chronic disease resource utilization among patients with chronic obstructive pulmonary disease (COPD) and to examine their association with illness uncertainty. A cross-sectional study. This study enrolled COPD patients hospitalized in the Department of Respiratory Medicine at a tertiary hospital in Zhejiang Province, China, between April and December 2023. All participants completed a general information form, the Chronic Illness Resource Survey (CIRS), and the Mishel Uncertainty in Illness Scale (MUIS). Latent profile analysis (LPA) was conducted to identify subgroups of resource utilization patterns. Subsequently, hierarchical linear regression was employed to assess the associations between these patterns and illness uncertainty. Ethical approval was obtained from the Institutional Review Board of the Fourth Affiliated Hospital of Zhejiang University (Approval No. K2022057). A total of 308 participants were included. Two latent classes of resource utilization were identified: the Suboptimal Utilization Group ( Distinct patterns of chronic disease resource utilization exist among COPD patients and are significantly associated with illness uncertainty. Healthcare providers should recognize these subgroups and implement targeted interventions to enhance access to disease-related support resources, thereby mitigating illness uncertainty. Understanding COPD patients' varying patterns of resource utilization enables healthcare professionals and related industries to deliver personalized, resource-based interventions tailored to individual needs, ultimately reducing illness-related uncertainty and improving disease management outcomes. Show less

To ensure high phototransduction efficiency in the retina, the precise subcellular localization of signaling molecules must be tightly orchestrated by scaffold proteins. Aberrant localization of these scaffold proteins not only disrupts the transition of photoelectrical signals but also triggers endoplasmic reticulum (ER) stress, which leads to photoreceptor apoptosis. However, it is unknown how these proteins are localized to specific subcellular compartments of photoreceptors or how protein mislocalization is coupled with apoptotic signaling. Herein, we observed a specific spatiotemporal expression pattern of the scaffold protein, Axin1, in the mouse retina. We found that Axin1 is essential for the retinal localization of S-opsin chromoprotein in the outer segment of photoreceptors. Moreover, retinal Axin1 deficiency disrupts light perception, accompanied by cone photoreceptor loss and ER stress. In addition, knockdown of Axin1 exacerbates ER stress-induced apoptosis of cone-derived 661W cells. Consistently, pharmacological elevation of Axin1 protein level alleviates tunicamycin-induced ER stress and apoptosis via inhibition of GSK3β activity. Thus, our findings demonstrate that Axin1 plays a pivotal role in organizing the phototransduction complex and ensuring photoreceptor survival in the retina. Show less

Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly linked to mortality. Organ aging reflected both genetic and environmental determinants: brain aging was associated with lifestyle, the GABBR1 and ECM1 genes, and brain structure. Distinct organ-specific pathogenic pathways were identified, with the brain and artery clocks linking synaptic loss, vascular dysfunction and glial activation to cognitive decline and dementia. The brain aging clock further stratified Alzheimer's disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4. Together, proteomic organ aging clocks provide a biologically interpretable framework for tracking aging and disease risk across diverse populations. Show less

Dietary unsaturated fat, protein, and carbohydrate have well-established effects on HDL (high-density lipoprotein) cholesterol levels, but whether these effects are connected causally to coronary heart disease (CHD) has been called into question. Protein-based minor HDL subspecies are emerging as novel and likely causal biomarkers, direct or inverse, for risk of CHD, diabetes, and other conditions. HDL-raising drugs such as CETP (cholesteryl ester transfer protein) inhibitors raise certain HDL subspecies that have adverse effects on CHD risk. We hypothesize that dietary unsaturated fat, protein, and carbohydrate differentially affect 15 minor protein-based HDL subspecies with diverse functionality in lipid metabolism, antioxidation, immunity, hemostasis, and protease inhibition. We analyzed the apo (apolipoprotein) A1 concentrations of 15 minor HDL subspecies after 4 weeks on each diet in 141 participants in the OmniHeart trial (Optimal Macronutrient Intake Trial to Prevent Heart Disease), a randomized 3-period crossover, controlled feeding study. The diet rich in carbohydrate contained 58% carbohydrate, 27% fat, and 15% protein, and the diets rich in unsaturated fat and protein replaced 10% of carbohydrate with unsaturated fat or protein, respectively. Unsaturated fat replacing dietary carbohydrate increased concentrations of apoA1 in lipid metabolism subspecies including HDL that contains apoA2, apoE, or apoC1 that has been associated with reduced risk of CHD. Protein replacing carbohydrate increased apoE HDL, consistent with lower CHD risk, and decreased concentrations of several other HDL subspecies that were associated with higher risk of CHD including HDL that contains PLMG (plasminogen), A2M (alpha-2-macroglobulin), or apoL1. Network analysis showed connections between functional groups of HDL subspecies that are quantitatively affected by dietary macronutrients. Replacing dietary carbohydrate with unsaturated fat or protein raised levels of protein-based HDL subspecies associated with lower risk of CHD or lowered the levels of those associated with higher risk of CHD. Minor HDL subspecies with diverse functions may mediate the association of dietary patterns with risk of CHD. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00051350. Show less

Working memory training (WMT) has been shown to improve WM in healthy older adults, patients with mild cognitive impairment, and individuals with HIV, including improvements in WM network efficiency. This randomized study explored near-transfer and far-transfer effects of WMT and examined whether Participants were recruited from local communities. After screening and baseline evaluation, participants were randomized to either 25 sessions of adaptive or nonadaptive WMT (as an active control) over 5-8 weeks. Nontrained near-transfer WM tests, far-transfer tests, and self-reported executive functioning were performed at baseline, 1-month, and 6-month follow-ups. Genotyping included A total of 107 participants (60 with HIV, 47 SN) completed adaptive WMT, and 70 active controls (36 with HIV, 34 SN) completed nonadaptive WMT. Overall, 96 adaptive WMT participants and 68 active controls completed the 1-month follow-up while 77 adaptive WMT participants and 37 active controls completed the 6-month follow-up. Adaptive WMT led to higher improvement indices in SN participants than in the HIV group (training*HIV serostatus: Adaptive WMT improved near-transfer WM, far-transfer performance, and self-reported executive functioning in all participants, but more sustained effects among participants with HIV. These findings suggest that adaptive WMT can be an effective adjunctive therapy for cognitive deficits in PWH, especially in those with This study provides Class IV evidence that adaptive WMT improves near-transfer WM, far-transfer performance, and self-reported executive functioning in patients with or without HIV, regardless of Show less

Calcific aortic valve disease (CAVD) involves pathological mineralization, but the roles of chemokine signaling and ferroptosis remain unclear. This study investigated the regulatory function of C-C motif chemokine ligand 5 (CCL5) in CAVD progression via the chemokine pathway and ferroptosis. Bioinformatics analysis and single-cell RNA sequencing analysis were performed to identify hub genes and potential cell types. Human aortic valve interstitial cells (VICs) were treated with osteogenic medium (OM) to induce calcification. Apoe CCL5 was identified as a key hub gene in CAVD. Knockdown of CCL5 significantly attenuated OM-induced VICs calcification, osteogenic differentiation, oxidative stress, and ferroptosis. Similar protective effects were observed in vivo, with reduced valve thickening and calcification in Apoe CCL5 promoted CAVD progression by activating the chemokine signaling pathway to induce ferroptosis. Targeting CCL5 may offer a novel therapeutic strategy for CAVD. Show less

Circulating metabolites can identify biochemical risk factors related to Alzheimer's disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic acid and N-glycan pathways were associated with Aβ42:Aβ40. Through several dimensionality reduction approaches, we identified an APOE-ε4 dependent relationship between lysophosphatidylcholines (lysoPCs) carrying polyunsaturated fatty acids and biomarker-supported AD and P-tau biomarkers. In an independent dataset of 110 postmortem brain tissues from non-Hispanic white participants, lysoPCs in the brain were also associated with AD neuropathological features. Our results show that biomarker-based diagnostic criteria identified an APOE-ε4 dependent association with lysoPCs, which play a critical role in the transport of neuroprotective polyunsaturated fatty acids into the brain, and AD. Show less

Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment. Show less

African American (AA) adults have a high burden of late-life cognitive impairment (CI) and dementia but remain underrepresented in genetic epidemiology studies. Genetic risk and cardiometabolic diseases (CMDs) contribute to dementia risk. This study investigated whether genetic susceptibility and CMDs were associated with a composite CI outcome and whether CMDs modified these associations. In AA participants within the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we assessed the association of a dementia polygenic risk score (PRS), APOE ε4 carrier status, and three prevalent CMDs: stroke, coronary artery disease (CAD), and type 2 diabetes (T2D) with a composite outcome of CI and dementia as a contributing cause of death (DCCD). We used logistic regression adjusted for age, sex, education, income, body mass index, smoking status, alcohol intake, physical activity, hypertension, low-density lipoprotein, and C-reactive protein. Interaction terms were included to assess whether CMDs modified the associations between genetic risk and the composite outcome. Of 8,838 participants, 516 (5.84 %) developed CI or had DCCD. In fully adjusted models, high polygenic risk (highest vs lowest PRS tertile) was associated with increased odds of the composite outcome [odds ratio (OR): 1.42; 95 % confidence interval (CI): 1.12-1.78], as was APOE ε4 carrier status (OR: 1.46; 95% CI: 1.21-1.78). Among CMDs, stroke (OR: 1.45; 95% CI: 1.04-2.02) and T2D (OR: 1.31; 95% CI: 1.06-1.61) were significantly associated with increased odds of the composite outcome. However, the association between genetic risk and the composite outcome did not significantly differ by CMD status. Genetic risk and CMDs independently contributed to dementia-related outcomes, indicating their relevance in understanding dementia risk among AA adults. Show less

Plasma biomarkers of Alzheimer's disease (AD) pathology are frequently tested in specialized research settings, which limits the generalizability of findings. Using electronic health records and banked plasma, we evaluated plasma biomarkers-phosphorylated tau 217 (p-tau Participants (n = 617; 44% Black/African American; 41% female) were selected from the University of Pennsylvania Medicine BioBank with plasma assayed using Fujirebio Lumipulse. International Classification of Diseases (ICD) Ninth and Tenth Revision codes determined AD dementia (ADD) (n = 43), mild-cognitive impairment (MCI) (n = 140), unspecified/non-AD cognitive impairment (CI) (n = 106), and cognitively normal cases (n = 328), and other medical histories. APOE ε4, body mass index (BMI), metrics of kidney function (eg, estimated glomerular filtration rate [eGFR]), and liver disease were derived from electronic health records. Multivariable models identified factors related to plasma levels. Previously established cutpoints classified AD status ("AD+," "AD-," or "Intermediate"). Plasma p-tau In this real-world dataset, we identified effects of multimorbidities on plasma biomarkers, especially kidney function. The p-tau Show less

Plasma biomarkers may aid Alzheimer disease (AD) diagnosis and prognosis. Cardiovascular risk contributes to cognitive decline in AD, but whether it modifies the relationship between plasma biomarkers and cognitive status has not been assessed in a large multisite cohort. We aimed to explore if cardiovascular risk moderates plasma AD biomarkers' relationship with cognitive status. We included cognitively normal (n=301) participants and participants with mild cognitive impairment or probable AD (n=444) from the Bio-Hermes-001 study. Cardiovascular risk was quantified using the Atherosclerotic Cardiovascular Disease risk calculator. Logistic regression analyzed associations of cardiovascular risk and plasma biomarkers (amyloid beta 42/amyloid beta 40, phosphorylated tau [p-tau]181, p-tau217, apoE4 [apolipoprotein E]) with cognitive status. Moderation by cardiovascular risk was tested in each model. We included 745 participants (mean age=72.3 years; 423 [56.8%] female). Plasma biomarkers and cardiovascular risk were independently associated with cognitive status across models; the strongest association was with p-tau217 (odds ratio [OR], 2.33 [95% CI, 1.89-2.9]; Plasma AD biomarkers and cardiovascular risk were independently associated with cognitive status, with cardiovascular risk moderating the p-tau181 and p-tau217 cognitive status relationships. If certain plasma biomarkers and cardiovascular risk independently contribute to dementia risk, cardiovascular risk assessment should complement other biomarker evaluations in cognitive screening. Results should be interpreted with caution as associations might be primarily driven by age and sex. Future research including education and genetic risk is needed to clarify the studied relationships. Show less

Health and financial literacy decline in aging, but it is unclear why. In this study, we hypothesized that older people who are carriers of the APOE ε4 allele exhibit a steeper decline in literacy over time. Participants were 851 community-dwelling older adults without dementia at analytic baseline (188 ε4 carriers and 663 noncarriers). Literacy was assessed at baseline and each year thereafter for up to 14 years. In a linear mixed-effects model adjusted for age, gender, and education, ε4 was associated with a lower starting level of literacy (b = -3.60, SE b = 1.00, p < 0.001) and, critically, a roughly 40% steeper decline in literacy over time (b = -0.41, SE b = 0.14, p = 0.004). The association between ε4 and literacy decline persisted after adjusting for global cognition at baseline (b = -0.35, SE b = 0.14, p = 0.012) and among a subgroup of participants with no cognitive impairment at baseline (b = -0.34, SE b = 0.14, p = 0.016). ε4 contributes to literacy decline among older adults, presumably due in part to the accumulation of neuropathologies associated with ε4. We discuss the potential clinical implications of ε4-related literacy decline. Show less

We aimed to examine how coronary artery calcium (CAC) and its progression relate to cognitive function in midlife, an important time for cognitive aging. We studied participants enrolled in the prospective CARDIA (Coronary Artery Risk Development in Young Adults) study, a longitudinal cohort of Black and White adults aged 18 to 30 years at baseline, who completed CAC measurements using computed tomography at year 15 (2000-2001; our baseline), had at least 1 follow-up CAC measurement at years 20 (2005-2006) or 25 (2010-2011), and completed cognitive assessments with a battery of 5 tests at years 30 (2015-2016) or 35 (2020-2022). CAC progression was defined as: (1) CAC >0 at follow-up among participants with baseline CAC=0; (2) an annualized change of ≥10 units at follow-up among those with 00) and CAC progression. Among the 2341 participants (mean baseline age 40.3±3.6 years; 56% female), baseline CAC >0 (9%) was associated with lower processing speed, verbal memory, and global cognition, whereas CAC progression (26%) was associated with lower processing speed and global cognition after adjusting for demographics, education, physical activity, depressive symptoms, APOE ε4 allele, and baseline CAC score. The standardized cognitive differences (95% CI) for CAC progression versus no progression were -0.14 (95% CI, -0.23 to -0.06) for the Digit Symbol Substitution Test and -0.09 (95% CI, -0.17 to -0.01) for the Montreal Cognitive Assessment. CAC progression was associated with worse midlife processing speed and global cognition, independent of baseline CAC score and established risk factors. Repeated CAC assessments may offer clinical value for identifying individuals at increased risk for midlife cognitive decline. Show less

Atherosclerosis can trigger various cardiovascular and cerebrovascular diseases with complex pathogenesis. Macrophage proliferation, inflammatory responses, and lipid phagocytosis, which induce foam cell formation and accumulation, are critical in the development of early atherosclerotic lesions. The role of 3-Hydroxystearic acid (C18-3OH), a recently identified gut microbiota-derived metabolite, in atherosclerosis has not yet been clarified. This study aimed to investigate the role of the ALKBH5/PAX-8/ABCA1 pathway in C18-3OH-mediated regulation of macrophage cholesterol efflux and atherosclerosis and explore novel mechanisms of ABCA1 regulation from the perspective of m6A modification. RT-qPCR and Western blotting were used to detect gene and protein expression, respectively. ChIP-Seq was used to screen PAX-8 target genes, and ChIP-qPCR was used to validate PAX-8 binding to ABCA1. The SRAMP platform was used to predict m6A modification sites in PAX-8 mRNA sequences. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) was used to measure m6A modification levels of PAX-8 mRNA in foam cells. UHPLC-OEMS untargeted metabolomics were used to analyze differential fatty acid metabolites in an atherosclerotic mouse model. Specific kits were used to detect serum liver function markers (aspartate transaminase, AST; alanine aminotransferase, ALT), renal function markers (serum creatinine, Scr; blood urea nitrogen, BUN), and lipid profiles (HDL-C, TG, LDL-C, TC). Aortic sinus sections were prepared, and H&E, Oil Red O, and Masson staining were used to evaluate atherosclerotic plaques. The results demonstrated that C18-3OH promoted cholesterol efflux in foam cells and alleviated lipid accumulation by upregulating ABCA1 expression. C18-3OH inhibited ALKBH5, increased PAX-8 mRNA m6A modification and PAX-8 expression, and upregulated ABCA1 to enhance cholesterol efflux. Serum metabolomics revealed reduced C18-3OH levels in high-fat diet-fed apoE-/- atherosclerotic mice. C18-3OH suppressed aortic ALKBH5 expression, elevated m6A modification of PAX-8 mRNA, and increased PAX-8 and ABCA1 expression. Furthermore, C18-3OH improved lipid metabolism and reduced the atherosclerotic plaque area in apoE-/- mice. This study clarifies the impact and mechanisms of gut microbiota-derived C18-3OH on atherosclerosis progression, providing novel strategies for the precise prevention and treatment of atherosclerosis. Show less

Depressive symptoms are common in older adults and have been associated with the risk of Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD), but the mechanisms and biomarkers underlying this association remain unclear. We included baseline data from 11,947 non-demented adults aged ≥ 70 years at enrollment in the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial. Linear regressions were used to examine cross-sectional associations between AD/ADRD blood-based biomarkers (BBMs) and baseline depressive symptoms. Interactions between sex or apolipoprotein E (APOE) ε4 carrier status and BBMs were examined. Higher glial fibrillary acidic protein (GFAP) was associated with higher depressive symptoms. We did not observe an association between amyloid beta 42/40 ratio, phosphorylated tau181, or neurofilament light chain with depressive symptoms; interactions between sex or APOE ε4 with depressive symptoms were not significant. In this large, community-based cohort of older adults, plasma GFAP was associated with greater depressive symptoms. Plasma glial fibrillary acidic protein was associated with depressive symptoms. Neuroinflammation may underlie depressive symptoms in this group. Future research is needed to examine sex differences in this association. Show less

To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic characteristics, health literacy, confidence in self-care contributions, family intimacy, and profile membership. We recruited 275 dyads of patients with COPD and their family caregivers from five tertiary hospitals between May and November 2022 using convenience sampling. Latent profile analysis (LPA) was used to identify distinct profiles of caregiver self-care contributions. Univariate analysis and multinomial logistic regression were subsequently conducted to examine associations between participant characteristics and profile membership. LPA identified four distinct profiles of caregiver self-care contributions: low-contributing, under-monitored, maintenance-prioritized, and high-contributing. Significant differences were observed across these profiles in terms of patients' symptom severity, exacerbation frequency, number of hospitalizations, caregivers' education levels, caregiving duration, health literacy, confidence in self-management contributions, and family intimacy using univariate analysis. Multinomial logistic regression analysis revealed that caregivers' education levels, caregiving duration, confidence in self-management contributions, and health literacy were significant predictors of profile membership. Caregiver self-care contributions for patients with COPD can be characterized by four distinct profiles, with caregivers' educational level, health literacy, and confidence in self-management identified as key factors associated with profile membership. Show less

Organic and organic-inorganic hybrid materials exhibiting room-temperature phosphorescence (RTP) and long persistent luminescence (LPL) materials have attracted growing attention for various time-resolved optoelectronic applications. To date, realizing intrinsically distinct RTP and LPL emissions within a single material system remains elusive, yet it is crucial for unlocking multifunctional applications such as multilevel optical encryption. Here, a Mn Show less