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Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity
Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.
Neuronal guidance factor Sema3A inhibits neurite ingrowth and prevents chondrocyte hypertrophy in the degeneration of knee cartilage in mice, monkeys and humans
Osteoarthritis (OA) is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms. Normal articular cartilage maintains at aneural state. Neuron guidance factor Semaphorin 3A (Sema3A) is a membrane-associated secreted protein with chemorepulsive properties for axons. However, the role of Sema3A in articular cartilage is still not clear. In the present studies, we investigated the functions of Sema3A in OA development in mice, non-human primates, and patients with OA. Sema3A has a protective effect on cartilage degradation, validated by the organoid culture in vitro and confirmed in chondrocyte-specific Sema3A conditional knockout mice. We demonstrated that Sema3A is a key molecule in maintaining cartilage homeostasis from chondrocyte hypertrophy via activating the PI3K pathway. The potential usage of Sema3A for OA treatment was validated in mouse and Rhesus macaque OA models through intra-articular injection of Sema3A, and also in patients by administering Sema3A containing platelet-rich plasma into the knee joints. Our studies demonstrated that Sema3A exerts a critical role in inhibiting neurite ingrowth and preventing chondrocyte hypertrophy in cartilage, and could be potentially used for OA treatment.
An umbrella review of health outcomes following traumatic brain injury
While numerous reviews have assessed the association between traumatic brain injury (TBI) and various mental and physical health outcomes, a comprehensive evaluation of the scope, validity, and quality of evidence is lacking. Here we present an umbrella review of a wide range of health outcomes following TBI and outline outcome risks across subpopulations. On 17 May 2023, we searched Embase, Medline, Global Health, PsycINFO, and Cochrane Database of Systematic Reviews for systematic reviews and meta-analyses. We compared risk ratios across different outcomes for risks compared with people without TBI and examined study quality, including heterogeneity, publication bias, and prediction intervals. The study was registered with PROSPERO (CRD42023432255). We identified 24 systematic reviews and meta-analyses covering 24 health outcomes in 31,397,958 participants. The current evidence base indicates an increased risk of multiple mental and physical health outcomes, including psychotic disorders, attention-deficit/hyperactivity disorder, suicide, and depression. Three outcomes—dementia, violence perpetration, and amyotrophic lateral sclerosis—had meta-analytical evidence of at least moderate quality, which suggest targets for more personalized assessment. Health-care services should review how to prevent adverse long-term outcomes in TBI.
Resolving the fundamentals of the J-integral concept by multi-method in situ nanoscale stress-strain mapping
The integrity of structural materials is oftentimes defined by their resistance against catastrophic failure through dissipative plastic processes at the crack tip, commonly quantified by the J-integral concept. However, to date the experimental stress and strain fields necessary to quantify the J-integral associated with local crack propagation in its original integral form were inaccessible. Here, we present a multi-method nanoscale strain- and stress-mapping surrounding a growing crack tip in two identical miniaturized fracture specimens made from a nanocrystalline FeCrMnNiCo high-entropy alloy. The respective samples were tested in situ in a scanning electron microscope and a synchrotron X-ray nanodiffraction setup, with detailed analyzes of loading states during elastic loading, crack tip blunting and general yielding, corroborated by a detailed elastic-plastic finite element model. This complementary in situ methodology uniquely enabled a detailed quantification of the J-integral along different integration paths from experimental nanoscale stress and strain fields. We find that conventional linear-elastic and elastic-plastic models, typically used to interpret fracture phenomena, have limited applicability at micron to nanoscale distances from propagating cracks. This for the first time unravels a limit to the path-independence of the J-integral, which has significant implications in the development and assessment of modern damage-tolerant materials and microstructures.
Measuring age-dependent viscoelasticity of organelles, cells and organisms with time-shared optical tweezer microrheology
Quantifying the mechanical response of the biological milieu (such as the cell’s interior) and complex fluids (such as biomolecular condensates) would enable a better understanding of cellular differentiation and aging and accelerate drug discovery. Here we present time-shared optical tweezer microrheology to determine the frequency- and age-dependent viscoelastic properties of biological materials. Our approach involves splitting a single laser beam into two near-instantaneous time-shared optical traps to carry out simultaneous force and displacement measurements and quantify the mechanical properties ranging from millipascals to kilopascals across five decades of frequency. To create a practical and robust nanorheometer, we leverage both numerical and analytical models to analyse typical deviations from the ideal behaviour and offer solutions to account for these discrepancies. We demonstrate the versatility of the technique by measuring the liquid–solid phase transitions of MEC-2 stomatin and CPEB4 biomolecular condensates, and quantify the complex viscoelastic properties of intracellular compartments of zebrafish progenitor cells. In Caenorhabditis elegans, we uncover how mutations in the nuclear envelope proteins LMN-1 lamin A, EMR-1 emerin and LEM-2 LEMD2, which cause premature aging disorders in humans, soften the cytosol of intestinal cells during organismal age. We demonstrate that time-shared optical tweezer microrheology offers the rapid phenotyping of material properties inside cells and protein blends, which can be used for biomedical and drug-screening applications.
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