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Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi revealed how regulatory T cells prevent autoimmune disease

Cascadia and San Andreas fault zones appear to generate synchronized earthquakes

We investigated the roles of Rac guanine-nucleotide exchange factor (Rac-GEF) P-Rex1 in glucose homeostasis using Prex1^(-/-) and catalytically inactive Prex1^(GD) mice. P-Rex1 maintains fasting blood glucose levels and insulin sensitivity through its Rac-GEF activity but limits glucose clearance independently of its catalytic activity, throughout aging. Prex1^(-/-) mice on a high-fat diet are protected from diabetes. The increased glucose clearance in Prex1^(-/-) mice may stem in part from...

While progressive cognitive decline is the defining feature of Alzheimer's disease (AD), many patients also develop prominent neuropsychiatric symptoms, including anxiety and depression. The circuit-level mechanisms underlying these distinct symptom domains remain poorly understood, and treatments that address both cognitive and noncognitive aspects of AD are limited. Here, we identify anatomically, molecularly, and functionally distinct subpopulations of supramammillary (SuM) neurons that...

Zinc plays a critical role in memory, learning, and neuronal function, with dysregulation increasingly implicated in neurodegenerative diseases such as Alzheimer's disease (AD). This study aimed to investigate whether changes in the expression of zinc transporter proteins, ZnT3 and ZIP3, in the retina mirror those in the brain, and to explore their potential as non-invasive biomarkers for early AD detection. Immunofluorescence and Western blotting were used to assess ZnT3 and ZIP3 expression in...

Predictors of immune checkpoint inhibitor response in cancer remain elusive. From a previous phase 2 neoadjuvant immunotherapy window-of-opportunity study, we present the single-cell RNA and T cell receptor (TCR) sequencing analysis of 57 pre- and post-treatment tumor biopsies from head and neck cancer patients treated with durvalumab (anti-PD-L1) alone or with tremelimumab (anti-CTLA-4), identifying key cellular and molecular predictors of immune checkpoint inhibitor (ICI) response. Malignant...

BACKGROUND: Despite the success of immune modulation in the treatment of relapsing multiple sclerosis, disability progression is a major problem driven by multiple mechanisms. Comorbidities (eg, vascular risk) and ageing are thought to augment these neurodegenerative pathologies. In the phase 2b MS-STAT trial of simvastatin (80 mg) versus placebo in secondary progressive multiple sclerosis (SPMS), the adjusted difference in brain atrophy rate between groups was -0·254% per year: a 43% reduction....

CONCLUSION: The ABC community program might be a scalable collaborative dementia care model targeting socially vulnerable people living with dementia.

As government websites go dark, some nonprofits are trying to fill the void

Alzheimer's disease (AD) has long resisted effective treatments due to its pathological heterogeneity and cell-type-specific regulatory changes. In this issue of Cell, Li et al. leverage single-cell RNA sequencing and drug repurposing to propose a promising combination therapy, validated through real-world evidence and mouse models, that targets multiple AD-relevant cell types.

Alzheimer's disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug...

Neuroimaging and machine learning are advancing research into the mechanisms of biological aging. In this field, 'brain age gap' has emerged as a promising magnetic resonance imaging-based biomarker that quantifies the deviation between an individual's biological and chronological age of the brain. Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in up to 56,348 individuals unveiled a heritability of...

Cells use information about their environments and internal states to decide whether to proliferate, differentiate, or enter non-proliferative states such as quiescence and senescence. But how do they integrate this information to make unambiguous decisions? Here, we describe how the interaction between two independent condensates, P-bodies and Whi3-dependent condensates, enables individual yeast cells to integrate information about their biological age and the presence of potential mates during...

Spaceflight provides a unique environment that profoundly influences stem cell biology. Experiments aboard the International Space Station (ISS) and in simulated microgravity have revealed altered stem cell proliferation, differentiation, and stress responses, unveiling possibilities for modeling impacts of spaceflight and harnessing microgravity for biomanufacturing. Stem cell-derived organoids and tissue models flown in space are yielding insights into development, disease, and aging...

Aging is the main determinant of chronic diseases and mortality, yet organ-specific aging trajectories vary, and the molecular basis underlying this heterogeneity remains unclear. To elucidate this, we integrated genomic, epigenomic, transcriptomic, proteomic, and metabolomic data, employing post-genome-wide association study methodologies to systematically investigate the molecular mechanisms of nine organ-specific aging clocks and four blood-based epigenetic clocks. We uncovered genetic...

CONCLUSIONS: The findings of this cross-sectional study suggested that differential marital status has a variable impact on the risk of developing age acceleration, with significant gender differences. All indications are that men benefit more from marriage in the aging process, which is food for thought.

Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes....

Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic...