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Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer

23 hours 30 minutes ago
RAS family proteins, including HRAS, NRAS, and KRAS, are frequently mutated in cancer. Although there has been recent success in designing inhibitors that target oncogenic RAS, they elicit resistance and treating RAS-driven cancer remains difficult. Here, employing a proteomic analysis, we find that multiple spliceosome components are upregulated in the nuclei of cells undergoing RAS-induced senescence. This upregulation depends on RAS signalling and occurs in both senescent preneoplastic and...
Verena Wagner

Deep single-cell decoding of human pancreatic islets reveals T2D β-cell gene expression defects

23 hours 30 minutes ago
Pancreatic islets maintain glucose homeostasis through coordinated action of endocrine and affiliate cell types and are central to type 2 diabetes (T2D) genetics and pathophysiology. Our understanding of robust human islet cell type-specific alterations in T2D remains limited. Here, we report comprehensive single-cell transcriptome profiling of 245,878 human islet cells from 48 donors spanning non-diabetic, pre-diabetic, and T2D states, and we identify 14 distinct cell types detected in every...
Khushdeep Bandesh

Sister chromatid separation determines the proliferative properties upon whole-genome duplication via homologous chromosome arrangement

23 hours 30 minutes ago
Whole-genome duplication (WGD) of diploid cells triggers various cell fates, such as cell death, cell cycle arrest, and proliferation with chromosome instability, contributing to broad bioprocesses, including differentiation, tumorigenesis, or aging. However, factors determining the post-WGD cell fates remain largely unknown. In this study, we found that cytokinesis failure (CF) and mitotic slippage (MS), two major routes of WGD induction, differentially affected post-WGD viability and...
Masaya Inoko

Comparative analysis of naked mole-rat thermogenesis and its potential to maintain euthermia in response to cold

23 hours 30 minutes ago
The naked mole-rat (NMR) is a subterranean rodent known for its unique thermal biology, exceptional longevity, and resistance to cancer and hypoxia. However, its thermal biology remains controversial, with various reports describing NMRs as poikilotherms, heterotherms, mesotherms, or partial homeotherms. Here, we investigated whether the thermogenic potential of NMR brown adipose tissue and its UCP1 differ from those in mice and whether the lack of thermal insulation causes extreme changes in...
Aleksei Mikhalchenko

In situ and real-time monitoring of intracellular activities in single live cells using a nanopore probe

23 hours 30 minutes ago
Monitoring molecular activities within single live cells is vital for understanding cellular differentiation, senescence, heterogeneity, and disease progression. However, conventional single-cell analyses often rely on micromanipulation or extraction followed by downstream measurements, which cannot capture in situ real-time dynamics. Fluorescent labeling and electrochemical methods provide temporal resolution but face limitations in labeling, substrate scope, and multiplexing. Here, we present...
Xiaobin Huang

<em>C. elegans</em> somatostatin/allatostatin C signaling regulates sleep, metabolism, survival, and memory via a sleep-active neuron

23 hours 30 minutes ago
Somatostatin/allatostatin C signaling regulates sleep, metabolism, memory, and longevity, but the underlying neuronal mechanisms remain unclear. We investigated the Caenorhabditis elegans somatostatin/allatostatin C ortholog NLP-99 and its receptor NPR-16. We found that the wake-active AIY neurons release NLP-99 to activate NPR-16. NPR-16 is G(i/o) coupled and acts cell nonautonomously to activate the sleep-active RIS neuron while acting autonomously in RIS to inhibit calcium activation and the...
Byoungjun Park

Multitissue, multi-time point transcriptomic atlas of aging in mice and rats

23 hours 30 minutes ago
To determine the genes and pathways that are up- or down-regulated in a consistent manner throughout the rodent lifespan, we generated a high N age-related gene expression atlas in mice and rats, by profiling 28 tissues in male and female C57BL/6J mice and 32 tissues in male Sprague Dawley rats (>5000 samples) over multiple time points. We identified age-related genes and pathways that change either early in life, at mid-age, late in life, or linearly throughout the animals' lifespan. Linear...
Tea Shavlakadze

Non-telomeric TRF2 regulates differentiation-associated genes to maintain neural stem cell identity

23 hours 30 minutes ago
Depletion of TRF2 from chromosome ends causes telomeric fusions and genome instability in mammals, but in mouse neural stem cells (mNSCs), Trf2's role is non-telomeric. Although essential for mNSC proliferation and survival, Trf2 does not protect telomeres, aligning with findings that Trf2 is dispensable for telomere protection in pluripotent stem cells. In Trf2-deficient adult mNSCs (Trf2fl/fl; Nestin-Cre), proliferation decreased and neuronal differentiation was impaired, yet no telomere...
Soujanya Vinayagamurthy

Wobble-board dynamics as a scalable assay of long-latency reflex function in aging

23 hours 30 minutes ago
Understanding how aging reshapes balance is essential for targeted assessment and rehabilitation. Because wobble boards impose continuous instability, their kinematics may provide a noninvasive readout of long-latency (transcortical) reflex function in ecologically valid conditions. We analyzed wobble-board dynamics in healthy younger adults ( 19 -- 35 y, n = 29 ) and community-dwelling older adults ( 56 -- 70 y, n = 29 ) performing with and without a concurrent cognitive load (Trail...
Theodoros Deligiannis

Interpretable deep learning reveals spatiotemporal MRI features of brain aging that align with neurodegeneration

23 hours 30 minutes ago
Cortical thinning and atrophy are hallmarks of brain aging that have been characterized using magnetic resonance imaging (MRI). Brain aging involves many neuroanatomic features whose effects on brain structure remain unexplored. To address this challenge, we trained interpretable deep neural networks (DNNs) to estimate brain age (BA) from T(1)-weighted (T(1)w) MRI. By identifying MRI features unapparent to humans, DNNs can find aging-related structural alterations above and beyond cortical...
Nikhil N Chaudhari

The Role of the Glymphatic System in Alzheimer's Disease: Mechanisms, Evidence, and Therapeutic Implications

23 hours 30 minutes ago
Alzheimer's disease (AD) is an aging-associated neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation and progressive cognitive decline. Increasing evidence implicates the glymphatic system, a brain-wide perivascular pathway involved in cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, in the removal of Aβ, tau, and other solutes relevant to AD pathogenesis. Aging-related alterations in aquaporin-4 polarization, arterial pulsatility, sleep...
Yaran Li