An Inflammation-Centric View of Neurological Disease: Beyond the Neuron

Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system ("neuroinflammation"), especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia) and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell-cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenousmechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation

P2X7 Receptors as a Transducer in the Co-Occurrence of Neurological/Psychiatric and Cardiovascular Disorders: A Hypothesis

Background. Over-stimulation of the purinergic P2X7 receptor may bring about cellular dysfunction and injury in settings of neurodegeneration, chronic inflammation, as well as in psychiatric and cardiovascular diseases. Here we speculate how P2X7 receptor over-activation may lead to the co-occurrence of neurological and psychiatric disorders with cardiovascular disorders. Presentation. We hypothesize that proinflammatory cytokines, in particular interleukin-1β, are key players in the pathophysiology of neurological, psychiatric, and cardiovascular diseases. Critically, this premise is based on a role for the P2X7 receptor in triggering a rise in these cytokines. Given the broad distribution of P2X7 receptors in nervous, immune, and vascular tissue cells, this receptor is proposed as central in linking the nervous, immune, and cardiovascular systems. Testing. Investigate, retrospectively, whether a bidirectional link can be established between illnesses with a proinflammatory component (e.g., inflammatory and chronic neuropathic pain) and cardiovascular disease, for example, hypertension, and whether patients treated with anti-inflammatory drugs have a lower incidence of disease complications. Positive outcome would indicate a prospective study to evaluate therapeutic efficacy of P2X7 receptor antagonists. Implications. It should be stressed that sufficient direct evidence does not exist at present supporting our hypothesis. However, a positive outcome would encourage the further development of P2X7 receptor antagonists and their application to limit the co-occurrence of neurological, psychiatric, and cardiovascular disorders

P2X7 Receptors in Neurological and Cardiovascular Disorders

P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. Several P2X receptor subtypes, including P2X7, have the unusual property of changing their ion selectivity during prolonged exposure to ATP, which results in a channel pore permeable to molecules as large as 900 daltons. The P2X7 receptor was originally described in cells of hematopoietic origin, and mediates the influx of Ca2+ and Na+ and Ca2+ and Na+ ions as well as the release of proinflammatory cytokines. P2X7 receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1β, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X7, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X7 receptors provides an inflammatory stimulus, and P2X7 receptor-deficient mice have substantially attenuated inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X7 receptor activity, by regulating the release of proinflammatory cytokines, may be involved in the pathophysiology of depression. Apoptotic cell death occurs in a number of vascular diseases, including atherosclerosis, restenosis, and hypertension, and may be linked to the release of ATP from endothelial cells, P2X7 receptor activation, proinflammatory cytokine production, and endothelial cell apoptosis. In this context, the P2X7 receptor may be viewed as a gateway of communication between the nervous, immune, and cardiovascular systems

Curcumin Prevents Acute Neuroinflammation and Long-Term Memory Impairment Induced by Systemic Lipopolysaccharide in Mice

Systemic lipopolysaccharide (LPS) induces an acute inflammatory response in the central nervous system (CNS) (\u201cneuroinflammation\u201d) characterized by altered functions of microglial cells, the major resident immune cells of the CNS, and an increased inflammatory profile that can result in long-term neuronal cell damage and severe behavioral and cognitive consequences. Curcumin, a natural compound, exerts CNS anti-inflammatory and neuroprotective functions mainly after chronic treatment. However, its effect after acute treatment has not been well investigated. In the present study, we provide evidence that 50 mg/kg of curcumin, orally administered for 2 consecutive days before a single intraperitoneal injection of a high dose of LPS (5 mg/kg) in young adult mice prevents the CNS immune response. Curcumin, able to enter brain tissue in biologically relevant concentrations, reduced acute and transient microglia activation, pro-inflammatory mediator production, and the behavioral symptoms of sickness. In addition, short-term treatment with curcumin, administered at the time of LPS challenge, anticipated the recovery from memory impairments observed 1 month after the inflammatory stimulus, when mice had completely recovered from the acute neuroinflammation. Together, these results suggest that the preventive effect of curcumin in inhibiting the acute effects of neuroinflammation could be of value in reducing the long-term consequences of brain inflammation, including cognitive deficits such as memory dysfunction

Real-practice thromboprophylaxis in atrial fibrillation

This retrospective observational study was based on databases of the Local Health Authority of Treviso, Italy. It evaluated the prevalence and the effectiveness of oral anticoagulation treatment (OAT) for the management of nonvalvular atrial fibrillation (NVAF) in everyday clinical practice. Out of 6,138 NVAF patients, only 3,024 received Vitamin K antagonist (VKA). Potential barriers decreasing the probability of being treated with VKA were female sex, older age, antiplatelet treatment and history of bleeding. In addition, VKA-treatment was not in line with current ESC and AIAC guidelines, since the patients at high or low risk of stroke were under-or over-treated, resp. Among VKAtreated patients, 73 % of subjects were not at target with anticoagulation. OAT resulted to be effective in reducing stroke risk. However, stroke events were significantly influenced also by previous stroke or transient ischemic attack (hazard ratio, HR = 2.99, p < 0.001) and by previous bleeding events (HR = 1.60, p < 0.001)

Baryonic Screening Masses in High Temperature QCD

We compute the screening masses of fields with nucleon quantum numbers for a wide range of temperatures between $T \sim 1$ GeV and $T\sim 160$ GeV. The computation has been performed by means of Monte Carlo simulations of lattice QCD with $N_f=3$ flavors of $O(a)$-improved Wilson fermions: we exploit a novel strategy which has recently allowed to determine for the first time non-singlet mesonic screening masses up to extremely high temperatures. The baryonic screening masses are measured with a few per-mille precision in the continuum limit, and percent deviations from the free theory result $3\pi T$ are clearly visible even at the highest temperatures. The observed degeneracy of the positive and negative parity state's screening mass, expected from Ward identities associated to non-singlet axial transformations, provides further evidence for the restoration of chiral symmetry in the high temperature regime of QCD.Comment: 7 pages, 4 figures, Proceedings of the 40th International Symposium on Lattice Field Theory (Lattice 2023

CIN++: Enhancing Topological Message Passing

Graph Neural Networks (GNNs) have demonstrated remarkable success in learning from graph-structured data. However, they face significant limitations in expressive power, struggling with long-range interactions and lacking a principled approach to modeling higher-order structures and group interactions. Cellular Isomorphism Networks (CINs) recently addressed most of these challenges with a message passing scheme based on cell complexes. Despite their advantages, CINs make use only of boundary and upper messages which do not consider a direct interaction between the rings present in the underlying complex. Accounting for these interactions might be crucial for learning representations of many real-world complex phenomena such as the dynamics of supramolecular assemblies, neural activity within the brain, and gene regulation processes. In this work, we propose CIN++, an enhancement of the topological message passing scheme introduced in CINs. Our message passing scheme accounts for the aforementioned limitations by letting the cells to receive also lower messages within each layer. By providing a more comprehensive representation of higher-order and long-range interactions, our enhanced topological message passing scheme achieves state-of-the-art results on large-scale and long-range chemistry benchmarks.Comment: 21 pages, 9 figure

Exotic atoms at extremely high magnetic fields: the case of neutron star atmosphere

The presence of exotic states of matter in neutron stars (NSs) is currently an open issue in physics. The appearance of muons, kaons, hyperons, and other exotic particles in the inner regions of the NS, favored by energetic considerations, is considered to be an effective mechanism to soften the equation of state (EoS). In the so-called two-families scenario, the softening of the EoS allows for NSs characterized by very small radii, which become unstable and convert into a quark stars (QSs). In the process of conversion of a NS into a QS material can be ablated by neutrinos from the surface of the star. Not only neutron-rich nuclei, but also more exotic material, such as hypernuclei or deconfined quarks, could be ejected into the atmosphere. In the NS atmosphere, atoms like H, He, and C should exist, and attempts to model the NS thermal emission taking into account their presence, with spectra modified by the extreme magnetic fields, have been done. However, exotic atoms, like muonic hydrogen $(p\,\mu^-)$ or the so-called Sigmium $(\Sigma^+\,e^-)$, could also be present during the conversion process or in its immediate aftermath. At present, analytical expressions of the wave functions and eigenvalues for these atoms have been calculated only for H. In this work, we extend the existing solutions and parametrizations to the exotic atoms $(p\,\mu^-)$ and $(\Sigma^+\,e^-)$, making some predictions on possible transitions. Their detection in the spectra of NS would provide experimental evidence for the existence of hyperons in the interior of these stars.Comment: 10 pages, 6 figures, proceedings of the "International Conference on Exotic Atoms and Related Topics - EXA2017", Austrian Academy of Sciences, Austria, September 11-15, 201