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Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpression
Chronic neuroinflammation with sustained microglial activation occurs in Parkinson’s disease (PD), yet the mechanisms and exact contribution of these cells to the neurodegeneration remains poorly understood. In this study, we induced progressive dopaminergic neuron loss in mice via rAAV-hSYN injection to cause the neuronal expression of α-synuclein, which produced neuroinflammation and behavioral alterations. We administered PLX5622, a colony-stimulating factor 1 receptor inhibitor, for 3 weeks prior to rAAV-hSYN injection, maintaining it for 8 weeks to eliminate microglia. This chronic treatment paradigm prevented the development of motor deficits and concomitantly preserved dopaminergic neuron cell and weakened α-synuclein phosphorylation. Gene expression profiles related to extracellular matrix (ECM) remodeling were increased after microglia depletion in PD mice, which were further validated on protein level. We demonstrated that microglia exert adverse effects during α-synuclein-overexpression-induced neuronal lesion formation, and their depletion remodels ECM and aids recovery following insult.
Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head
Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH.
The closing longevity gap between battery electric vehicles and internal combustion vehicles in Great Britain
Electric vehicles are increasingly being adopted in Great Britain and other parts of the world, driven by the perception that they offer a cost-effective alternative to internal combustion engine vehicles while reducing emissions. However, a key element that underpins this perception is the longevity of electric vehicles, which remains relatively under researched. Here we show that although early battery electric vehicles (BEVs) exhibited lower reliability than internal combustion engine vehicles, rapid technological advancements have allowed newer BEVs to achieve comparable lifespans, even under more intensive use. Longevity is also found to be impacted by engine size, location and make of vehicle. We provide parameter estimates for life mileage that can be used to update life cycle assessment and total cost of ownership studies of different vehicle powertrains. Our results also shed light on BEV diffusion patterns, fleet replacement strategies and end-of-life treatment planning, including the increasingly important debate around BEV battery recycling and second-life options.
Estimating emissions reductions with carpooling and vehicle dispatching in ridesourcing mobility
Ride-hailing services provide on-demand transportation solutions by connecting passengers with nearby drivers through mobile applications. However, carpooling often fails to attract passengers as expected due to inefficient order-matching strategies. This study estimates emissions reductions with order matching and vehicle dispatching in ridesourcing mobility. An explainable machine learning with a hierarchical framework is constructed for arrival time prediction. Considering pick-up and drop-off locations within the expected departure time, on-demand order matching and vehicle dispatching optimization models are built to determine the minimum fleet size and efficient route planning. Real-world experiments are conducted with large-scale ridesharing orders in Beijing, China. In comparison to the current operations, a reduction of 25.25% in fleet size and a simultaneous decrease of 21.65% in pollutant emissions are achieved. Results demonstrate that carpooling and vehicle dispatching processes lead to a slight increase in passenger waiting time while enhancing the operational efficiency of ride-hailing services and reducing pollutant emissions.
Large-scale empirical study of electric vehicle usage patterns and charging infrastructure needs
As global electric vehicle (EV) adoption accelerates, granular analysis of empirical usage and charging patterns remains scarce. This study presents a unique large-scale empirical examination of 1.6 million EVs, including a broad array of vehicle types—private, taxi, rental, official, bus, and special purpose vehicle—across seven major Chinese cities with over 854 million observations of driving and charging events. Our findings illuminate significant heterogeneity in EV usage, battery energy, and charging behavior across vehicle types with notable city differences. Day-time high-power charging presents high loads on the electricity grid across all vehicle types, particularly from service-oriented vehicles, including taxis, rental cars, and buses. The maximum loads also are the highest in the center of the cities. Our study of large-scale EV usage offers critical insights for developing charging infrastructure, managing energy grids, and providing flexibility services, which are pivotal to the evolution of future transport ecosystems.
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