Aggregator

The complex kinetics of disease-related amyloid aggregation of proteins such as α-Synuclein (α-Syn) in Parkinson's disease and Aβ42 in Alzheimer's disease include primary nucleation, amyloid fibril elongation and secondary nucleation. The latter can be a key accelerator of the aggregation process. It has been demonstrated that the chaperone domain BRICHOS can interfere with the secondary nucleation process of Aβ42. Here, we explore the mechanism of secondary nucleation inhibition of the BRICHOS...

Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on...

Production of specialized proresolving mediators (SPMs) during the resolution phase in the acute inflammatory response is key to orchestrating complete resolution. Here, we uncovered a trihydroxy resolvin in fresh human saliva. We identified and determined its complete stereochemistry as 7S,16R,17R-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid (17R-RvD2) using total organic synthesis and matching of physical properties. The 17R-RvD2 was produced by activated human M2-like macrophages,...

NKG2D ligands (NKG2DLs) are broadly expressed in cancer. To target these, we describe an adaptor chimeric antigen receptor (CAR) termed NKG2D/Dap10-12. Herein, T cells are engineered to co-express NKG2D with a fusion protein that comprises Dap10 joined to a Dap12 endodomain. NKG2D/Dap10-12 T cells elicit compelling efficacy, eradicating or controlling NKG2DL-expressing tumors in several established xenograft models. Importantly, durable responses, long-term survival, and rejection of tumor...

Alzheimer's disease (AD), commonly known as senile dementia, is a neurodegenerative disease with insidious onset and gradually worsening course. The brain is particularly sensitive to senescence, and neuronal senescence is an important risk factor for the occurrence of AD. However, the exact pathogenesis between neuronal senescence and AD has not been fully elucidated so far. Neuronal senescence is characterized by the permanent stagnation of the cell cycle, and the changes in its structure,...

Skeletal muscles are essential for locomotion and body metabolism regulation. As muscles age, they lose strength, elasticity, and metabolic capability, leading to ineffective motion and metabolic derangement. Both cellular and extracellular alterations significantly influence muscle aging. Satellite cells (SCs), the primary muscle stem cells responsible for muscle regeneration, become exhausted, resulting in diminished population and functionality during aging. This decline in SC function...

The intricate organization of distinct cellular compartments is paramount for the maintenance of normal biological functions and the orchestration of complex biochemical reactions. These compartments, whether membrane-bound organelles or membraneless structures like Cajal bodies and RNA transport granules, play crucial roles in cellular function. Liquid-liquid phase separation (LLPS) serves as a reversible process that elucidates the genesis of membranelles structures through the self-assembly...

Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Using iPSCs derived from a male MAD patient carrying homozygous LMNA p.R527C, premature aging phenotypes are recapitulated in multiple mesenchymal lineages, including mesenchymal stem cells (MSCs). Comparison...

Genetic factors play a significant role in determining an individual's longevity. The present study was aimed at identifying genetic variants associated with longevity in Indian population. Long living individuals (LLIs), aged 85+, were compared with younger controls, aged 18-49 years, using data from GenomegaDB, a genetic database of Indians living in India. An in-house developed custom chip, having variants associated with various cancers, cardiovascular, neurological, gastro-intestinal,...

Understanding the genetics of kidney function decline, or trait change in general, is hampered by scarce longitudinal data for GWAS (longGWAS) and uncertainty about how to analyze such data. We use longitudinal UK Biobank data for creatinine-based estimated glomerular filtration rate from 348,275 individuals to search for genetic variants associated with eGFR-decline. This search was performed both among 595 variants previously associated with eGFR in cross-sectional GWAS and genome-wide. We use...

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Identifying cell populations associated with risk variants is essential for uncovering cell-specific mechanisms that drive disease development and progression. Integrating genome-wide association studies (GWAS) with single-cell RNA sequencing (scRNA-seq) has become an effective strategy for detecting trait-cell relationships. The accumulation of trait-related single cell data has led to an urgent need for its comprehensively processing. To address this, we developed sc2GWAS...

CONCLUSION: Among healthy, physically active older adults, ALMI and incidence of sarcopenia were not improved by treatment of daily 2000 IU vitamin D, daily 1 g omega-3s, or a simple home exercise program compared with control over 3 years.

Lineages of rod-shaped bacteria such as Escherichia coli exhibit a temporal decline in elongation rate in a manner comparable to cellular or biological aging. The effect results from the production of asymmetrical daughters, one with a lower elongation rate, by the division of a mother cell. The slower daughter compared to the faster daughter, denoted respectively as the old and new daughters, has more aggregates of damaged proteins and fewer expressed gene products. We have examined further the...

Ethylene is widely recognized as a positive regulator of leaf senescence. However, how plants coordinate the biosynthesis of ethylene to meet the requirements of senescence progression has not been determined. The rate-limiting enzyme in the ethylene biosynthesis pathway is ACC synthase. AtACS7 was previously considered one of the major contributors to the synthesis of "senescence ethylene" in Arabidopsis. However, the "brake signal" that fine-tunes the expression of AtACS7 to ensure optimal...

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CONCLUSIONS: In this cohort, several community-wide social/environmental factors were associated with MCI. While clinicians should continue to encourage older adults to modify their individual risk factors, policy changes are needed to mitigate social determinants of health in the community.