Temperature development in the leakage flow of screw extruders

Temperature distribution at the exit of the leakage gap is of interest for a number of problems. For the calculation of temperatures, the leakage flow may be considered to be a pure drag flow to a good approximation. In the Newtonian case, thermal development length may be expressed in terms of gap height as L ≈ 3/8Pe ·δ ;usually this is less than the available gap length. Pe is the Peclet number and δ the height of leakage gap. Therefore the existing flow may be considered fully developed. For power law fluids, numerical calculations lead to results of the same order. Martin's results therefore may be applied to the flow at the exit of the leakage gap

Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes

BACKGROUND: Altered neuronal connectivity in peri-infarct tissue is an important contributor to both the spontaneous recovery of neurological function that commonly develops after stroke and improvements in recovery that have been induced by experimental treatments in animal models. Microglia and astrocytes are primary determinants of the environment in peri-infarct tissue and hence strongly influence the potential for neuronal plasticity. However, the specific roles of these cells and the timing of critical changes in their function are not well understood. Minocycline can protect against ischemic damage and promote recovery. These effects are usually attributed, at least partially, to the ability of this drug to suppress microglial activation. This study tested the ability of minocycline treatment early after stroke to modify reactive responses in microglia and astrocytes and improve recovery. METHODS: Stroke was induced by photothrombosis in the forelimb sensorimotor cortex of Sprague-Dawley rats. Minocycline was administered for 2 days after stroke induction and the effects on forelimb function assessed up to 28 days. The responses of peri-infarct Iba1-positive cells and astrocytes were evaluated using immunohistochemistry and Western blots. RESULTS: Initial characterization showed that the numbers of Iba1-positive microglia and macrophages decreased in peri-infarct tissue at 24 h then increased markedly over the next few days. Morphological changes characteristic of activation were readily apparent by 3 h and increased by 24 h. Minocycline treatment improved the rate of recovery of motor function as measured by a forelimb placing test but did not alter infarct volume. At 3 days, there were only minor effects on core features of peri-infarct microglial reactivity including the morphological changes and increased density of Iba1-positive cells. The treatment caused a decrease of 57% in the small subpopulation of cells that expressed CD68, a marker of phagocytosis. At 7 days, the expression of glial fibrillary acidic protein and vimentin was markedly increased by minocycline treatment, indicating enhanced reactive astrogliosis. CONCLUSIONS: Early post-stroke treatment with minocycline improved recovery but had little effect on key features of microglial activation. Both the decrease in CD68-positive cells and the increased activation of astrogliosis could influence neuronal plasticity and contribute to the improved recovery.Wai Ping Yew, Natalia D. Djukic, Jaya S. P. Jayaseelan, Frederick R. Walker, Karl A. A. Roos, Timothy K. Chataway, Hakan Muyderman and Neil R. Sim

Glutathione monoethyl ester prevents TDP-43 pathology in motor neuronal NSC-34 cells

© 2017 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (August 2017) in accordance with the publisher’s archiving policyOxidative stress is recognised as central in a range of neurological diseases including Amyotrophic lateral sclerosis (ALS), a disease characterised by fast progressing death of motor neurons in the brain and spinal cord. Cellular pathology includes cytosolic protein aggregates in motor neurons and glia of which potentially cytotoxic hyper-phosphorylated fragments of the Transactive response DNA Binding Protein 43 kDa (TDP-43) constitute a major component. This is closely associated with an additional loss of nuclear TDP-43 expression indicating a “loss of function” mechanism, accelerating motor neuron (MN) loss. Furthermore, mutations in TDP-43 cause familial ALS and ALS-like disease in animal models. In this study, we investigated the role of glutathione (GSH) in modulating oxidative stress responses in TDP-43 pathology in motor neuron NSC-34 cells. Results demonstrate that depletion of GSH produces pathology similar to that of mutant TDP-43, including occurrence of cytosolic aggregates, TDP-43 phosphorylation and nuclear clearing of endogenous TDP-43. We also demonstrate that introduction of mutant TDP-43A315T and silencing of endogenous TDP-43, but not overexpression of wild-type TDP-43, result in similar pathology, including depletion of intracellular GSH, possibly resulting from a decreased expression of a regulatory subunit of ɣ-glutamylcysteine ligase (GCLM), a rate limiting enzyme in GSH synthesis. Importantly, treatment of mutant cells with GSH monoethyl ester (GSHe) that directly increases intracellular GSH and bypasses the need for GSH synthesis, protected against mutant-induced TDP-43 pathology, including reducing aggregate formation, nuclear clearance, reactive oxygen species (ROS) production and cell death. Our data strongly suggest that oxidative stress is central to TDP-43 pathology and may result from a loss of function affecting GSH synthesis and that treatments directly aimed at restoring cellular GSH content may be beneficial in preventing cell death in TDP-43-mediated ALS

RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells

Copyright © 2014 Heshan Peiris et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer’s disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochondrial function and that RCAN1 may itself regulate neuronal ROS production. In this study, we have utilized mice overexpressing RCAN1 and demonstrate an increased susceptibility of neurons from these mice to oxidative stress. Mitochondria from these mice are more numerous and smaller, indicative of mitochondrial dysfunction, and mitochondrial membrane potential is altered under conditions of oxidative stress. We also generated a PC12 cell line overexpressing RCAN1 . Similar to neurons, cells have an increased susceptibility to oxidative stress and produce more mitochondrial ROS. This study demonstrates that increasing RCAN1 expression alters mitochondrial function and increases the susceptibility of neurons to oxidative stress in mammalian cells. These findings further contribute to our understanding of RCAN1 and its potential role in the pathogenesis of neurodegenerative disorders such as AD and DS

Alteration in Superoxide Dismutase 1 Causes Oxidative Stress and p38 MAPK Activation Following RVFV Infection

Rift Valley fever (RVF) is a zoonotic disease caused by Rift Valley fever virus (RVFV). RVFV is a category A pathogen that belongs to the genus Phlebovirus, family Bunyaviridae. Understanding early host events to an infectious exposure to RVFV will be of significant use in the development of effective therapeutics that not only control pathogen multiplication, but also contribute to cell survival. In this study, we have carried out infections of human cells with a vaccine strain (MP12) and virulent strain (ZH501) of RVFV and determined host responses to viral infection. We demonstrate that the cellular antioxidant enzyme superoxide dismutase 1 (SOD1) displays altered abundances at early time points following exposure to the virus. We show that the enzyme is down regulated in cases of both a virulent (ZH501) and a vaccine strain (MP12) exposure. Our data demonstrates that the down regulation of SOD1 is likely to be due to post transcriptional processes and may be related to up regulation of TNFα following infection. We also provide evidence for extensive oxidative stress in the MP12 infected cells. Concomitantly, there is an increase in the activation of the p38 MAPK stress response, which our earlier published study demonstrated to be an essential cell survival strategy. Our data suggests that the viral anti-apoptotic protein NSm may play a role in the regulation of the cellular p38 MAPK response. Alterations in the host protein SOD1 following RVFV infection appears to be an early event that occurs in multiple cell types. Activation of the cellular stress response p38 MAPK pathway can be observed in all cell types tested. Our data implies that maintaining oxidative homeostasis in the infected cells may play an important role in improving survival of infected cells

Calcium signaling in astroglial cells. Noradrenergic effects and regulation

Astroglial cells are the most common cell type in the central nervous system and express a wide array of ion channels and neurotransmitter receptors. The cells organize into multicellular networks and exhibit a calcium-based excitability in which receptor-mediated calcium elevations propagate as intercellular waves over considerable distances. Astrocytes greatly contribute to the maintenance of extracellular homeostasis and have the ability to release neurotransmitter substances in response to neuronal activity. This bi-directional communication between neurons and astrocytes may lead to profound changes in neuronal excitability and synaptic transmission. The astrocytes also constitute major targets for noradrenergic signaling, which mediates events such as increased glucose metabolism, glutamate uptake and metabolism and the secretion of neurotrophins. The overall aim of this thesis was to evaluate the effects of noradrenergic stimulation on astrocytes concerning intracellular calcium and potassium dynamics, calcium-based cell-to-cell communication and glutamate-mediated glutamate release. The results demonstrate distinct differences between neurons and astrocytes in regard to changes in intracellular calcium and potassium concentrations. They further show that b-adrenoceptor activation opens calcium-dependent potassium channels in astrocytes, which implies a dynamic role for noradrenaline in the control of the astroglial buffering of extracellular potassium. Further, a1-adrenergic activation was shown to modify astroglial calcium waves, which in turn indicates a noradrenergic regulation of cellular coordination within the astroglial syncytium. The results also show that the nature of calcium responses is diverse after a1-adrenoceptor and metabotropic glutamate receptor activation, suggesting that astrocytes are capable of discriminating between excitatory inputs. Furthermore, the synchronization of calcium release sites is suggested to determine the properties of oscillatory changes in intracellular calcium. The present study also demonstrates that glutamate-induced oscillatory calcium changes are regulated and modulated by the interplay between the glutamatergic and noradrenergic systems. Further, the results provide evidence for receptor specificity in astroglial glutamate-induced glutamate release and describe how a1-adrenergic activation impairs the release. In summary, the results indicate that activation of noradrenergic astroglial receptors can modify astroglial-neuronal interactions. The findings also provide additional evidence that supports the upcoming hypothesis by which astroglial cells are considered active participants in signal processing in the brain

Mitochondrial dysfunction in amyotrophic lateral sclerosis - a valid pharmacological target?

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective death of upper and lower motor neurons which ultimately leads to paralysis and ultimately death. Pathological changes in ALS are closely associated with pronounced and progressive changes in mitochondrial morphology, bioenergetics and calcium homeostasis. Converging evidence suggests that impaired mitochondrial function could be pivotal in the rapid neurodegeneration of this condition. In this review, we provide an update of recent advances in understanding mitochondrial biology in the pathogenesis of ALS and highlight the therapeutic value of pharmacologically targeting mitochondrial biology to slow disease progression.H Muyderman and T Che

Highly selective and prolonged depletion of mitochondrial glutathione in astrocytes markedly increases sensitivity to peroxynitrite

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Mitochondria, oxidative metabolism and cell death in stroke

AbstractStroke most commonly results from occlusion of a major artery in the brain and typically leads to the death of all cells within the affected tissue. Mitochondria are centrally involved in the development of this tissue injury due to modifications of their major role in supplying ATP and to changes in their properties that can contribute to the development of apoptotic and necrotic cell death. In animal models of stroke, the limited availability of glucose and oxygen directly impairs oxidative metabolism in severely ischemic regions of the affected tissue and leads to rapid changes in ATP and other energy-related metabolites. In the less-severely ischemic “penumbral” tissue, more moderate alterations develop in these metabolites, associated with near normal glucose use but impaired oxidative metabolism. This tissue remains potentially salvageable for at least the first few hours following stroke onset. Early restoration of blood flow can result in substantial recovery of energy-related metabolites throughout the affected tissue. However, glucose oxidation is markedly decreased due both to lower energy requirements in the post-ischemic tissue and limitations on the mitochondrial oxidation of pyruvate. A secondary deterioration of mitochondrial function subsequently develops that may contribute to progression to cell loss. Mitochondrial release of multiple apoptogenic proteins has been identified in ischemic and post-ischemic brain, mostly in neurons. Pharmacological interventions and genetic modifications in rodent models strongly implicate caspase-dependent and caspase-independent apoptosis and the mitochondrial permeability transition as important contributors to tissue damage, particularly when induced by short periods of temporary focal ischemia