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The Age of Reason
#OpenToWork: how laid-off US scientists are coping with shattered careers
Are groundbreaking science discoveries becoming harder to find?
Bird feeders have caused a dramatic evolution of California hummingbirds
Beaks have grown longer and larger, and ranges have expanded to follow the feeders
Lotions and perfume can weaken a ‘human oxidation field’ made by your skin
Personal care products may chemically alter the air around us. Whether that’s good or bad remains unclear
Crippling tropical diseases threaten to surge after U.S. funding cuts
Closing of programs that fought neglected diseases imperils drug donation and distribution efforts in 26 countries
Amyloid-beta induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease
Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a...
Chromogranin A deficiency attenuates tauopathy by altering epinephrine-alpha-adrenergic receptor signaling in PS19 mice
Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A (CgA) knockout (CgA-KO) mice. CgA is known to be associated with protein aggregates in the brains of neurodegenerative diseases including Alzheimer's disease (AD). Here, we investigated the role of CgA in Tau pathogenesis in AD and corticobasal degeneration (CBD). CgA ablation in Tauopathy mice (PS19) (CgA-KO/PS19)...
An integrative systems-biology approach defines mechanisms of Alzheimer's disease neurodegeneration
Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila. We also measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease and identified Alzheimer's genetic variants that modify gene expression in disease-vulnerable neurons in...
Human mitochondrial ferritin exhibits highly unusual iron-O<sub>2</sub> chemistry distinct from that of cytosolic ferritins
Ferritins are ubiquitous proteins that function in iron storage/detoxification by catalyzing the oxidation of Fe^(2+) ions and solubilizing the resulting Fe^(3+)-oxo mineral. Mammalian tissues that are metabolically highly active contain, in addition to the widespread cytosolic ferritin, a ferritin that is localized to mitochondria. Mitochondrial ferritin (FtMt) protects against oxidative stress and is found at higher levels in diseases associated with abnormal iron accumulation, including...
Large-scale plasma proteomic profiling unveils diagnostic biomarkers and pathways for Alzheimer's disease
Proteomic studies have been instrumental in identifying brain, cerebrospinal fluid and plasma proteins associated with Alzheimer's disease (AD). Here, we comprehensively examined 6,905 aptamers corresponding to 6,106 unique proteins in plasma in more than 3,300 well-characterized individuals to identify new proteins, pathways and predictive models for AD. We identified 416 proteins (294 new) associated with clinical AD status and validated the findings in two external datasets representing more...
Activation of AMPK by GLP-1R agonists mitigates Alzheimer-related phenotypes in transgenic mice
Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential neuroprotective properties, but their effects on AD and the underlying mechanisms are not well understood. Here we demonstrate that GLP-1RAs can alleviate AD-related phenotypes by activating 5' AMP-activated protein kinase (AMPK) signaling. We found that plasma GLP-1 levels were decreased in AD...
GLP-1R agonists protect against Alzheimer's disease by rewiring energy regulation
No abstract
Chromogranin A deficiency attenuates tauopathy by altering epinephrine-alpha-adrenergic receptor signaling in PS19 mice
Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A (CgA) knockout (CgA-KO) mice. CgA is known to be associated with protein aggregates in the brains of neurodegenerative diseases including Alzheimer's disease (AD). Here, we investigated the role of CgA in Tau pathogenesis in AD and corticobasal degeneration (CBD). CgA ablation in Tauopathy mice (PS19) (CgA-KO/PS19)...
Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure
Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data...
mRNA metabolism regulator human antigen R (HuR) regulates age-related hearing loss in aged mice
Age-related hearing loss (ARHL) is among the most prevalent and complex disorders in older adults. However, the pathogenesis of ARHL remains poorly understood. Using a single-cell transcriptomic landscape of mouse cochlea at five time points (1, 2, 5, 12 and 15 months), we found that the levels of human antigen R (HuR)-a classical RNA-binding protein-increase with age. Here we show that HuR is specifically transported from the nucleus to the cytoplasm in hair cells in both aging mice and...
Endometrial aging is accompanied by H3K27ac and PGR loss
Whether and how endometrial aging affects fertility remains unclear. In our in-house clinical cohort at the Center for Reproductive Medicine of Peking University Third Hospital (n = 1,149), we observed adverse pregnancy outcomes in the middle-aged group after excluding aneuploid embryos, implying the negative impact of endometrial aging on fertility. To understand endometrial aging, we performed comprehensive transcriptomic profiling of the mid-secretory endometrium of young (<35 years) and...
A dynamic and multimodal framework to define microglial states
The widespread use of single-cell RNA sequencing has generated numerous purportedly distinct and novel subsets of microglia. Here, we challenge this fragmented paradigm by proposing that microglia exist along a continuum rather than as discrete entities. We identify a methodological over-reliance on computational clustering algorithms as the fundamental issue, with arbitrary cluster numbers being interpreted as biological reality. Evidence suggests that the observed transcriptional diversity...
Stepping through fear: analysing postural control in elderly women during transitional locomotor tasks
CONCLUSION: The study concludes that while FoF does not impair static balance, it significantly impacts movement initiation and execution in transitional tasks. Prolonged preparation time (S1) in the HIGH FoF group highlights the role of fear in delaying movement. These findings are important for designing interventions to reduce FoF and prevent falls in older adults.
Developing a comprehensive malnutrition prediction model for the elderly in nursing homes
CONCLUSION: This nomogram provides a robust tool for malnutrition risk stratification in nursing homes. Future studies should validate its generalizability across diverse populations and regions.