Calcium connects lysosomal damage to stress granule formation
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Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer
Lysosome-mediated autophagy (including mitophagy) is crucial for cell survival and homeostasis. Although the mechanisms of lysosome activation during stress are well recognized, the epigenetic regulation of lysosomal gene expression remains largely unexplored. Menin, encoded by the MEN1 gene, is a chromatin-related protein that is widely involved in gene transcription via histone modifications. Here, we report that menin regulates the transcription of specific lysosomal genes, such as CTSB, CTSE, and TFE3, through MLL-mediated H3K4me3 reprogramming, which is necessary for maintaining lysosomal homeostasis. Menin also directly controls the expression of SQSTM1 and MAP1LC3B to maintain autophagic flux in a manner independent of AMPK/mTORC1 pathways. Furthermore, loss of menin led to mitochondrial dysfunction, elevated levels of reactive oxygen species (ROS), and genome instability. In genetically engineered mouse models, Men1 deficiency resulted in severe lysosomal and mitochondrial dysfunction and an impaired self-clearance ability, which further led to metabolite accumulation. SP2509, a histone demethylase inhibitor, effectively reversed the downregulation of lysosomal and mitochondrial genes caused by loss of Men1. Our study confirms the previously unrecognized biological and mechanistic importance of menin-mediated H3K4me3 in maintaining organelle homeostasis.
Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching
Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how cancer cells sense solid stress, thereby exacerbating malignancy, remains elusive. In this study, our clinical data suggest that elevated stress in metastatic solid tumors is highly associated with the expression of cytoskeleton-associated protein 4 (CKAP4). Intriguingly, CKAP4, as a sensitive intracellular mechanosensor, responds specifically to solid stress in a subset of studied tumor micro-environmental elements through liquid–liquid phase separation. These micron-scaled CKAP4 puncta adhere tightly onto microtubules and dramatically reorchestrate their curvature and branching to enhance cell spreading, which, as a result, boosts cancer cell motility and facilitates distant metastasis in vivo. Mechanistically, the intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation due to the Cav1.2-dependent calcium influx, which collectively remodels microtubules. These findings reveal an unprecedented mechanism of how cancer cells sense solid stress for cancer malignancy and bridge the gap between cancer physics and cancer cell biology.
Cell2fate infers RNA velocity modules to improve cell fate prediction
RNA velocity exploits the temporal information contained in spliced and unspliced RNA counts to infer transcriptional dynamics. Existing velocity models often rely on coarse biophysical simplifications or numerical approximations to solve the underlying ordinary differential equations (ODEs), which can compromise accuracy in challenging settings, such as complex or weak transcription rate changes across cellular trajectories. Here we present cell2fate, a formulation of RNA velocity based on a linearization of the velocity ODE, which allows solving a biophysically more accurate model in a fully Bayesian fashion. As a result, cell2fate decomposes the RNA velocity solutions into modules, providing a biophysical connection between RNA velocity and statistical dimensionality reduction. We comprehensively benchmark cell2fate in real-world settings, demonstrating enhanced interpretability and power to reconstruct complex dynamics and weak dynamical signals in rare and mature cell types. Finally, we apply cell2fate to the developing human brain, where we spatially map RNA velocity modules onto the tissue architecture, connecting the spatial organization of tissues with temporal dynamics of transcription.
Higher income is associated with greater life satisfaction, and more stress
Is there a cost to our well-being from increased affluence? Drawing upon responses from 2.05 million U.S. adults from the Gallup Daily Poll from 2008 to 2017 we find that with household income above ~$63,000 respondents are more likely to experience stress. This contrasts with the trend below this threshold, where at higher income the prevalence of stress decreases. Such a turning point for stress was also found for population sub-groups, divided by gender, race, and political affiliation. Further, we find that respondents who report prior-day stress have lower life satisfaction for all income and sub-group categories compared to the respondents who do not report prior-day stress. We find suggestive evidence that among the more satisfied, healthier, socially connected, and those not suffering basic needs deprivations, this turn-around in stress prevalence starts at lower values of income and stress. We hypothesize that stress at higher income values relates to lifestyle factors associated with affluence, rather than from known well-being deprivations related to good health and social conditions, which may arise even at lower income values if conventional needs are met.
Personalized bioceramic grafts for craniomaxillofacial bone regeneration
The reconstruction of craniomaxillofacial bone defects remains clinically challenging. To date, autogenous grafts are considered the gold standard but present critical drawbacks. These shortcomings have driven recent research on craniomaxillofacial bone reconstruction to focus on synthetic grafts with distinct materials and fabrication techniques. Among the various fabrication methods, additive manufacturing (AM) has shown significant clinical potential. AM technologies build three-dimensional (3D) objects with personalized geometry customizable from a computer-aided design. These layer-by-layer 3D biomaterial structures can support bone formation by guiding cell migration/proliferation, osteogenesis, and angiogenesis. Additionally, these structures can be engineered to degrade concomitantly with the new bone tissue formation, making them ideal as synthetic grafts. This review delves into the key advances of bioceramic grafts/scaffolds obtained by 3D printing for personalized craniomaxillofacial bone reconstruction. In this regard, clinically relevant topics such as ceramic-based biomaterials, graft/scaffold characteristics (macro/micro-features), material extrusion-based 3D printing, and the step-by-step workflow to engineer personalized bioceramic grafts are discussed. Importantly, in vitro models are highlighted in conjunction with a thorough examination of the signaling pathways reported when investigating these bioceramics and their effect on cellular response/behavior. Lastly, we summarize the clinical potential and translation opportunities of personalized bioceramics for craniomaxillofacial bone regeneration.
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