Extracellular matrix in vascular homeostasis and disease
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Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19
COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1–CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.
Post-processing methods for delay embedding and feature scaling of reservoir computers
Reservoir computing is a machine learning method that is well-suited for complex time series prediction tasks. Both delay embedding and the projection of input data into a higher-dimensional space play important roles in enabling accurate predictions. We establish simple post-processing methods that train on past node states at uniformly or randomly-delayed timeshifts. These methods improve reservoir computer prediction performance through increased feature dimension and/or better delay embedding. Here we introduce the multi-random-timeshifting method that randomly recalls previous states of reservoir nodes. The use of multi-random-timeshifting allows for smaller reservoirs while maintaining large feature dimensions, is computationally cheap to optimise, and is our preferred post-processing method. For experimentalists, all our post-processing methods can be translated to readout data sampled from physical reservoirs, which we demonstrate using readout data from an experimentally-realised laser reservoir system.
Efficient computation using spatial-photonic Ising machines with low-rank and circulant matrix constraints
Spatial-photonic Ising machines (SPIMs) have shown promise as an energy-efficient Ising machine, but currently can only solve a limited set of Ising problems. There is currently limited understanding on what experimental constraints may impact the performance of SPIM, and what computationally intensive problems can be efficiently solved by SPIM. Our results indicate that the performance of SPIMs is critically affected by the rank and precision of the coupling matrices. By developing and assessing advanced decomposition techniques, we expand the range of problems SPIMs can solve, overcoming the limitations of traditional Mattis-type matrices. Our approach accommodates a diverse array of coupling matrices, including those with inherently low ranks, applicable to complex NP-complete problems. We explore the practical benefits of the low-rank approximation in optimisation tasks, particularly in financial optimisation, to demonstrate the real-world applications of SPIMs. Finally, we evaluate the computational limitations imposed by SPIM hardware precision and suggest strategies to optimise the performance of these systems within these constraints.
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.
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