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The present study was conducted to construct structure connectivity (SC) and functional connectivity (FC) between different hippocampal subregions and the whole brain based on structural and function Magnetic Resonance Imaging, and to explore the changes in hippocampal subregions structural and functional connectivity in the different stages of Alzheimer's Disease (AD). 117 participants (75 female, 42 male) aged 60-88 years were recruited from the Sino-Longitudinal Study on Cognitive Decline in...

We recently showed that the next-generation epigenetic aging clock CheekAge was significantly associated with 33 different health and disease signals across 25 publicly available MethylationEPIC datasets. We additionally uncovered DNA methylation sites that played a disproportionately important role in driving the ability of CheekAge to associate with each of these variables. We dubbed these "pro" CpGs because of their ability to promote a given association. Here, we identify 2,639 common DNA...

New method places inactivated viruses directly into mice’s gums

Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological...

The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a...

CONCLUSIONS AND IMPLICATIONS: Health promotion interventions can improve clinical outcome indicators for prefrail older adults and possess potential advantages in terms of cost-effectiveness. However, the benefits largely depend on the type and duration of the intervention. When assessing these factors together, home-based health promotion interventions seem to be a particularly beneficial strategy, offering both cost efficiency and meaningful improvements in prefrailty status.

The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslinks (DPCs). To understand how SPRTN's promiscuous protease activity is confined to cleavage of crosslinked proteins, we reconstitute the repair of DPCs including their modification with SUMO and ubiquitin chains in vitro. We discover that DPC ubiquitylation strongly activates SPRTN independently of SPRTN's known ubiquitin-binding domains. Using protein structure prediction, MD simulations and NMR...

As a cardinal marker of brain ageing, lifetime brain atrophy obtained from a cross-sectional magnetic resonance image promises to boost statistical power to uncover novel genetic mechanisms of neurodegeneration. By analysing five young and old adult cohorts, we perform the most definitive study on lifetime brain atrophy's measurement and correlates. It is simply calculated from the relationship between total brain volume and intracranial volume, using the difference, ratio, or...

Physical activity (PA) is one of the most fundamental traits in the animal kingdom, has pervasive health benefits, and is genetically influenced. Using data from the Million Veteran Program, we conducted genetic analyses of leisure, work and home-time PA. For leisure, we included 189,812 individuals of European ancestry (SNP-based heritability (h²) = 0.083 ± 0.005), 27,044 of African ancestry (h² = 0.034 ± 0.017) and 10,263 of Latin American ancestry (h² = 0.083 ± 0.036) in a cross-ancestry...

With concerns about aging dams and nonstationary changes in hydrologic extremes (e.g., flooding), questions arise about whether existing dams may be at risk of failure and pose threats to society. Here, we analyzed 33 dams across the United States to investigate temporal trends in dam overtopping probabilities of annual maximum dam water levels. These dams were selected because of the availability of public domain long-term time series of uncontrolled water levels (50 years or longer). We...

The choroid plexus (ChP) is a complex ventricular structure that forms a semi-permeable barrier between the blood and cerebrospinal fluid (CSF). It is responsible for CSF secretion and clearance, contains macrophages, and is one of the few sites within the central nervous system (CNS) where T cells are present. Additionally, the ChP plays a role in detecting peripheral inflammation, which leads to the modulation of its epithelial cell function. Despite its critical importance in maintaining...

CONCLUSIONS: This study reveals that LST and MVPA may play a causal role in the process of aging. Accordingly, public health efforts to promote increased physical activity and reduce sedentary time can effectively combat accelerated aging.

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking, and LRRK2-activating mutations are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including protein phosphatase, Mg2^(+)/Mn2^(+) dependent 1H (PPM1H), which acts on phosphorylated Rab 8A (phosphoRab8A) and phosphoRab10. Here, we report a phosphatome-wide small interfering RNA (siRNA) screen that identified PPM1M as a...

Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimer's disease, and its accumulation exhibits a rich spatiotemporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatiotemporal process is orchestrated, namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production, or both. To address this, we develop a...

The accumulation of senescent endothelial cells within the endothelium leads to vascular dysfunction. Independent studies have linked miR-217, a senescence-associated microRNA and FOXO3, a longevity factor, to cellular senescence in different study models. However, their roles and direct interaction in endothelial replicative senescence (RS) remain to be investigated. This study sought to investigate the role of miR-217/FOXO3 axis in endothelial cell senescence. Young and RS HUVEC models were...

Longitudinal studies provide conflicting evidence regarding the impact of vitamin D deficiency on cognitive performance in older individuals. The present study aimed to investigate whether vitamin D deficiency is a risk factor for poorer trajectories in global cognition and specific cognitive domains over a six-year follow-up period. This cohort study analysed data from 2625 participants aged 50 years or older from the English Longitudinal Study of Ageing. Vitamin D [25-hydroxyvitamin D,...

DNA-protein crosslinks (DPCs) are endogenous and chemotherapy-induced genotoxic DNA lesions and, if not repaired, lead to embryonic lethality, neurodegeneration, premature ageing, and cancer. DPCs are heavily polyubiquitinated, and the SPRTN protease and 26S proteasome emerged as two central enzymes for DPC proteolysis. The proteasome recognizes its substrates by their ubiquitination status. How SPRTN protease, an essential enzyme for DPC proteolysis, achieves specificity for DPCs is still not...