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Scientists have unveiled a powerful new tool called PerturbFate that could change how researchers tackle diseases driven by huge numbers of genetic mutations, including cancer and Alzheimer’s. Instead of trying to target every faulty gene individually, the system tracks how different mutations reshape cells over time and identifies the hidden “control hubs” where those pathways converge.

Redox signaling by nitric oxide (NO) is estimated to control a large part of the global proteome via S-nitrosylation (SNO-modification). Here, we report that RNA-binding proteins (RBPs) represent the most significantly enriched class of S-nitrosylation targets, with broad coverage of spliceosomal factors. We demonstrate that NO regulates alternative splicing (AS) and that S-nitrosylation of PTBP1, a central regulator of AS, can massively shift and contextually alter gene expression while further...

Glymphatic dysfunction may contribute to abnormal protein accumulation in Alzheimer's disease (AD). This study investigates associations between an indirect proxy of glymphatic function, plasma neurodegenerative and neuroinflammatory biomarkers, and tau-PET burden across the AD continuum. Data from 407 ADNI participants were utilized. Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) is used as a noninvasive proxy of glymphatic activity. Multivariable linear regression...

Medical image analysis for Alzheimer's Disease (AD) diagnosis faces two key challenges: capturing spatial dependencies between anatomically connected brain regions and providing clinically interpretable explanations. While Convolutional Neural Networks (CNNs) excel at local feature extraction and Vision Transformers handle long-range dependencies, neither explicitly models the relational structure between brain regions-critical for understanding disease progression. We propose a hybrid CNN-GCN...

TAR DNA-binding protein 43 (TDP-43) proteinopathy has recently emerged as a pivotal, yet underrecognized, contributor to the multifaceted neuropathology of Alzheimer's disease (AD). While amyloid-β and tau have long been established as cardinal pathological hallmarks, growing evidence delineates TDP-43 as a critical participant of neurodegeneration, intricately interwoven with amyloid and tau pathologies. TDP-43 mislocalization, post-translational modifications, and aggregation potentiate...

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CONCLUSION: NAC shows potential in modulating mechanisms of muscle deterioration, but evidence remains largely preclinical. Well-designed randomized trials in older adults, particularly with sarcopenia or frailty, are needed.

CONCLUSION: This study provides longitudinal evidence from a large prospective cohort indicating that LHS is an independent predictor of self-reported incident OP in the older population. As a simple and practical tool, handgrip strength testing can aid in the early identification of individuals at high risk for OP in community and clinical settings, providing a basis for implementing targeted preventive strategies, while highlighting the need for future research to confirm the observed...

Transfer RNA (tRNA) halves (tRHs) are generated via the cleavage of tRNAs, but their roles in aging and longevity remain poorly understood. Here, we demonstrate a direct role of tRHs in aging in metazoans. Through a genetic screen using Caenorhabditis elegans, we identify DIS-3/DIS3 as a ribonuclease that catalyzes tRH generation, including 5'-tRH-Gln and 5'-tRH-Asp, from tRNAs. Among them, 5'-tRH-Gln is essential for longevity conferred by various interventions, including dietary restriction....

Limited vaccine availability and logistical barriers during the COVID-19 pandemic have hindered homologous boosting in resource-limited regions. Therefore, heterologous prime-boost regimens have gained attention as versatile and practical alternatives. We evaluated the immunogenicity and longevity of four vaccine regimens in adults from Mozambique and Madagascar: single-dose Ad26.COV2.S (Ad26.S), homologous BBIBP-CorV (BBIBP), and two heterologous combinations (BBIBP-Ad26.S and Ad26.S-BBIBP, in...

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are two types of clonal hematopoiesis (CH) associated with hematological parameters and malignancy risk. Here we show, in genomic data from 546,090 biobank participants, that co-occurring CH (≥2 CH mutations detected) is present in 1.6% of cancer-free individuals and shows strong evidence for selection (up to 804x enrichment). Co-occurrence is more frequent in those with a prior cancer (3.6%),...

Sex differences in obesity are well recognized; however, the identification of sex-specific obesity genes and the mechanisms through which they affect obesity development remain elusive. Here, we identify a germ-cell-specific gene C2orf74, whose expression is responsive to high-fat diet (HFD) and promotes HFD-induced obesity in male mice by restraining lipolysis and limiting the browning of white adipocytes through suppression of androgen receptor signaling, but not in females. Additionally,...

Skin aging, the most visible and accessible manifestation of organismal aging, reflects systemic physiological decline, compromising barrier integrity, immune defense, and regenerative capacity-functions essential for overall tissue homeostasis and longevity. Understanding why and how the skin ages offers crucial insights into tissue homeostasis and systemic aging. Here, we dissect the multi-layered mechanisms of skin aging across the epidermis, dermis, and appendages, highlighting how intrinsic...

Programmed degradation of maternal proteins is essential for the oocyte-to-embryo transition (OET). While pharmacological inhibition studies have established the importance of proteasomes in ovarian reserve maintenance, oocyte maturation and fertilization, the physiological impact of intrinsic proteasome insufficiency and underlying molecular mechanisms remain poorly understood. In mice, endolysosomal vesicular assemblies (ELVAs), specialized membraneless compartments composed of proteasomes,...

Identifying physiological sweet spots (optimal ranges for homeostasis) is essential for precision medicine. However, traditional statistical methods often rely on globally linear or locally jagged models that struggle to capture the smooth, non-linear nature of biological regulation in high-dimensional data. We present the Quantile Feature Selection Network (Q‑FSNet), a neural network-based framework that integrates quantile regression, feature selection, and uncertainty estimation to identify...

INTRODUCTION: Physical activity may enhance cognition in older adults, yet evidence from randomized controlled trials (RCTs) on mechanistic pathways remains inconclusive.

Innate immunity mediated by myeloid cells defends against infection and injury, but when chronically activated, it drives tissue damage and neurodegeneration. Molecular imaging with positron emission tomography (PET) enables noninvasive, real-time monitoring of such processes in vivo. However, most current neuroinflammation PET tracers lack specificity for activated myeloid cells. G protein-coupled receptor 84 (GPR84) is a promising biomarker that is selectively upregulated on activated...

Parkinson disease (PD)-associated mutations in the LRRK2 gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. Here, we show that knockout of the LRRK2-counteracting RAB phosphatase PPM1H causes a gene-dose-dependent...

During wakefulness, neuromodulators operate largely independently to support behavior and cognition. By contrast, sleep reorganizes their activity into a coordinated brain rhythm. During sleep, the major neuromodulators-norepinephrine, acetylcholine, serotonin, and dopamine-exhibit synchronized fluctuations with a periodicity of ~50 seconds. These oscillations appear as recurrent bursts of fast (10 to 30 hertz) electroencephalography activity and are phase-coupled to cerebrospinal fluid flow....

In this cross-sectional cohort we analyzed data from 4260 "health enthusiasts" who purchased at least one saliva-based DNA epigenetic test between 2020 and 2025 and completed detailed lifestyle and supplement questionnaires. A proprietary 9-CpG clock with a mean absolute error of 5.4 years served as the primary biomarker of biological age. High prevalence (71%) of supplement use in this cohort increased our power to study the effects of supplements compared to earlier studies that focused on the...