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Cerebral small vessel disease (SVD) is frequently comorbid with Alzheimer's disease (AD), and brain endothelial cells (BECs) express genes associated with AD genetic risk. However, the epigenome of neurovascular cells and its intersection with genetic risk remain unexplored. Here, we generated gene regulomes for human BECs, mural cells, and other brain cell types and showed that AD heritability is primarily immune related, with a modest BEC enrichment. On the other hand, SVD heritability is...

Cerebral small vessel disease (SVD) is frequently comorbid with Alzheimer's disease (AD), and brain endothelial cells (BECs) express genes associated with AD genetic risk. However, the epigenome of neurovascular cells and its intersection with genetic risk remain unexplored. Here, we generated gene regulomes for human BECs, mural cells, and other brain cell types and showed that AD heritability is primarily immune related, with a modest BEC enrichment. On the other hand, SVD heritability is...

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Mutations in human leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein containing both a kinase and a GTPase, are a leading cause of the familial form of PD. Pathogenic LRRK2 mutations increase LRRK2 kinase activity. While the bulk of LRRK2 is found in the cytosol, the protein associates with membranes where its Rab GTPase substrates are found, and under certain conditions, with microtubules. Integrative...

Protocols for deriving midbrain dopaminergic (mDA) neurons for Parkinson's disease (PD) modeling and therapy remain incompletely benchmarked against in vivo references. To establish transcriptomic standards, we generated an integrated human fetal whole-brain atlas and a midbrain subatlas. Whole-brain analysis revealed strong region-specific signatures, underscoring the need for global mapping before refined midbrain annotation. We implemented this two-tier strategy, BrainSTEM (Brain Single-cell...

The Centers for Medicare & Medicaid Services' (CMS) Guiding an Improved Dementia Experience (GUIDE) Model represents a landmark opportunity to improve outcomes for persons with dementia and their caregivers and scale comprehensive dementia care through a structured service delivery and alternative payment approach. The National Dementia Care Collaborative (NDCC), a coalition of scientific and clinical leaders in evidence-based dementia care, works to promote comprehensive dementia care. Drawing...

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disorder characterized by accelerated aging. The accumulation of an abnormal and toxic protein called progerin within HGPS nuclei disrupts cellular processes, including gene expression and DNA repair. Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defense, is one of the hallmarks of HGPS. To identify novel molecular mechanisms underlying HGPS pathogenesis, we...

One of the key hallmarks of aging is the breakdown of proteostasis-the finely tuned balance of protein synthesis, folding, trafficking, and degradation that maintains proteome integrity and cellular function. In this study, we employed ^(15)N metabolic labeling to assess protein turnover in young and aged mice. Among the proteins examined, cystatin C exhibited the largest age-related reduction in turnover, alongside decreases in other proteins involved in neuroprotection, structural stability,...

Shorter leukocyte telomere length (LTL) is associated with aging-related cardiovascular diseases, but its relationship with heart failure with preserved ejection fraction (HFpEF) in high-risk Chinese patients with hypertension under 65 years remains unclear. In this observational prospective study, we investigated 646 patients with hypertension aged < 65 years with diabetes, coronary heart disease (CHD), or ≥ 3 cardiovascular risk factors. Baseline assessments included clinical evaluation,...

Tardigrades survive extreme environments partly through the damage suppressor (Dsup) protein, which protects DNA from ionizing radiation and oxidative stress. Dsup is largely unstructured but binds nucleosomes to shield DNA from damage. To investigate its protective role in a whole organism, we expressed the Ramazzottius varieornatus Dsup gene in the nematode Caenorhabditis elegans. Transgenic worms tolerated x-ray exposure and oxidative stress without apparent toxicity and exhibited a notable...

CONCLUSIONS: The three known factors associated with verbal memory performance (age, sex, and educational attainment) are also significantly associated in Hispanic individuals, including those who spoke English or Spanish as their FSL. However, the strength of several factors differed substantially across groups, including age and sex. The study highlights the importance of considering factors predicting cognitive aging outcomes in large, well-characterized, but separate demographic groups.

Genetic regulation of alternative splicing constitutes an important link between genetic variation and disease. Nonetheless, RNA splicing is regulated by both cis-acting elements and trans-acting splicing factors. Determining splicing events that are directed primarily by the cis- or trans-acting mechanisms will greatly inform our understanding of the genetic basis of disease. Here, we show that long-read RNA-seq, combined with our new method isoLASER, enables a clear segregation of cis- and...

Single-cell studies have discovered abundant cancer-associated genetic/phenotypic changes in non-cancerous cells, strikingly contrasting with the infrequency of cancer. Epidemiological data have revealed decades-long plateaus of breast cancer incidence in the contralateral breast and twins/relatives following the first/proband's diagnosis, unlike the well-known continuous increase of population-level incidence with age, the latter ostensibly attributable to the successive accumulation of...

Aging reduces testicular function by lowering sperm quality and testosterone, worsened by diseases. Morphine addiction harms male reproduction by disrupting hormonal balance and increasing testicular oxidative stress and inflammation. Regular physical exercise can help counteract these effects by boosting antioxidants and supporting sperm production. This study explores how exercise mitigates inflammaging and testosterone decline by modulating the NF-κB signaling pathway in aged male rats with...

Aging is a complex process that includes chronological aging and cellular aging. Although chronological aging is irreversible, cellular aging, which is reversible, is closely associated with chronological aging. Understanding the complexity of the impact and mechanisms of aging on the male reproductive function is crucial in maintaining male fertility. This study reviews the effects and mechanisms associated with aging in males on male reproductive health. It also provides potential therapeutic...