👤 Oisin Boyle

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

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

This study investigated the antifungal performance of copper-based antimicrobial coatings developed by Gencoa Ltd., previously validated against bacterial ESKAPE pathogens, alongside newly formulated titanium oxide coatings, against key agricultural fungal pathogens: Alternaria alternata, Botrytis cinerea, Cladosporium cucumerinum, and Fusarium oxysporum. Testing was conducted both in vitro and in field trials within an actively used polytunnel. In vitro assays included a modified ISO 846 agar plate protocol and a six-well plate fungal colonization assay simulating high humidity conditions. Field trials assessed coating performance under real-world exposure. Copper-containing coatings: pure copper, copper oxynitride, and copper-doped titanium oxide, consistently demonstrated significant antifungal activity, effectively reducing spore germination and colonization. Titanium oxide coatings without copper showed minimal effect, performing similarly to uncoated polyethylene. While copper-based coatings were highly effective, some susceptibility to surface degradation under prolonged moisture was observed. However, antifungal activity often persisted in degraded areas of samples with high copper content. Copper-based antimicrobial coatings offer strong potential for preventing fungal colonization on agricultural surfaces, outperforming titanium oxide formulations under both laboratory and field conditions. Optimization to enhance durability will further improve their suitability for long-term use in protected cultivation systems. Show less

The glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide (GLP-1R) receptor agonists are insulin secretagogues that have long been shown to improve glycemic control and dual agonists have demonstrated successful weight loss in the clinic. GIPR and GLP-1R populations are located in the dorsal vagal complex where receptor activity-modifying proteins (RAMPs) are also present. According to recent literature, RAMPs not only regulate the signaling of the calcitonin receptor, but also that of other class B G-protein coupled receptors, including members of the glucagon receptor family such as GLP-1R and GIPR. The aim of this study was to investigate whether the absence of RAMP1 and RAMP3 interferes with the action of GIPR and GLP-1R agonists on body weight maintenance and glucose control. To this end, WT and RAMP 1/3 KO mice were fed a 45% high fat diet for 22 weeks and were injected daily with GLP-1R agonist (2 nmol/kg/d; NN0113-2220), GIPR agonist (30 nmol/kg/d; NN0441-0329) or both for 3 weeks. While the mono-agonists exerted little to no body weight lowering and anorectic effects in WT or RAMP1/3 KO mice, but at the given doses, when both compounds were administered together, they synergistically reduced body weight, with a greater effect observed in KO mice. Finally, GLP-1R and GIP/GLP-1R agonist treatment led to improved glucose tolerance, but the absence of RAMPs resulted in an improvement of the HOMA-IR score. These data suggest that RAMPs may play a crucial role in modulating the pharmacological actions of GLP-1 and GIP receptors. Show less

The incidence of obesity and metabolic syndrome (MetS) has rapidly increased worldwide. Roux-en-Y gastric bypass (RYGB) achieves long-term weight loss and improves MetS-associated comorbidities. Using a mouse model with a humanized lipoprotein metabolism, we elucidated whether improvements in lipid and glucose metabolism after RYGB surgery are body weight loss-dependent or not. Male ApoE*3Leiden.CETP (ApoE3L.CETP) mice fed Western type diet for 6 weeks underwent RYGB or Sham surgery. Sham groups were either fed ad libitum or were body weight-matched (BWm) to the RYGB mice to discriminate surgical effects from body weight loss-associated effects. Before and after surgery, plasma was collected to assess the metabolic profile, and glucose tolerance and insulin sensitivity were tested. Twenty days after surgery, mice were sacrificed, and liver was collected to assess metabolic, histological and global gene expression changes after surgery. RYGB induced a marked reduction in body weight, which was also achieved by severe food restriction in BWm mice, and total fat mass compared to Sham ad libitum mice (Sham AL). Total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C) and ceramide were strongly reduced 20 days after surgery in RYGB compared to BWm mice. Glucose tolerance and insulin sensitivity improved 13 days after surgery similarly in RYGB and BWm mice. Liver histology confirmed lipid reduction in RYGB and BWm mice while the transcriptomics data indicated altered genes expression in lipid metabolism. RYGB surgery improves glucose metabolism and greatly ameliorates lipid metabolism in part in a body weight-dependent manner. Given that ApoE3L.CETP mice were extensively studied to describe the MetS, and given that RYGB improved ceramide after surgery, our data confirmed the usefulness of ApoE3L.CETP mice after RYGB in deciphering the metabolic improvements to treat the MetS. Show less

Intraplaque hemorrhage (IPH) drives atherosclerosis through the dual metabolic stresses of cholesterol-enriched erythrocyte membranes and pro-oxidant heme/iron. When clearing tissue hemorrhage, macrophages are typically seen storing either iron or lipid. We have recently defined hemorrhage-associated macrophages (HA-mac) as a plaque macrophage population that responds adaptively to IPH. This study aimed to define the key transcription factor(s) involved in HO-1 induction by heme. To address this question, we used microarray analysis and transfection with siRNA and plasmids. To maintain physiological relevance, we focused on human blood-derived monocytes. We found that heme stimulates monocytes through induction of activating transcription factor 1 (ATF-1). ATF-1 coinduces heme oxygenase-1 (HO-1) and Liver X receptor beta (LXR-β). Heme-induced HO-1 and LXR-β were suppressed by knockdown of ATF-1, and HO-1 and LXR-β were induced by ATF-1 transfection. ATF-1 required phosphorylation for full functional activity. Expression of LXR-β in turn led to induction of other genes central to cholesterol efflux, such as LXR-α and ABCA1. This heme-directed state was distinct from known macrophage states (M1, M2, Mox) and, following the same format, we have designated them Mhem. These results show that ATF-1 mediates HO-1 induction by heme and drives macrophage adaptation to intraplaque hemorrhage. Our definition of an ATF-1-mediated pathway for linked protection from foam cell formation and oxidant stress may have therapeutic potential. Show less