Regulation of astrocyte metabolism by mitochondrial translocator protein 18 kDa

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The datasets used and analyzed during this study are available from the corresponding author upon receipt of reasonable request.The mitochondrial translocator protein 18 kDa (TSPO) has been linked to functions from steroidogenesis to regulation of cellular metabolism and is an attractive therapeutic target for chronic CNS inflammation. Studies in Leydig cells and microglia indicate that TSPO function may vary between cells depending on their specialized roles. Astrocytes are critical for providing trophic and metabolic support in the brain. Recent work has highlighted that TSPO expression increases in astrocytes under inflamed conditions and may drive astrocyte reactivity. Relatively little is known about the role TSPO plays in regulating astrocyte metabolism and whether this protein is involved in immunometabolic processes in these cells. Using TSPO-deficient (TSPO-/- ) mouse primary astrocytes in vitro (MPAs) and a human astrocytoma cell line (U373 cells), we performed extracellular metabolic flux analyses. We found that TSPO deficiency reduced basal cellular respiration and attenuated the bioenergetic response to glucopenia. Fatty acid oxidation was increased, and lactate production was reduced in TSPO-/- MPAs and U373 cells. Co-immunoprecipitation studies revealed that TSPO forms a complex with carnitine palmitoyltransferase 1a in U373 and MPAs, presenting a mechanism wherein TSPO may regulate FAO in these cells. Compared to TSPO+/+ cells, in TSPO-/- MPAs we observed attenuated tumor necrosis factor release following 3 h lipopolysaccharide (LPS) stimulation, which was enhanced at 24 h post-LPS stimulation. Together these data suggest that while TSPO acts as a regulator of metabolic flexibility, TSPO deficiency does not appear to modulate the metabolic response of MPAs to inflammation, at least in response to the model used in this study.British Society for NeuroendocrinologyResearch EnglandUniversity of Exete

Brain permeable AMP-activated protein kinase activator R481 raises glycaemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycaemia in rats

This is the final version. Available on open access from Frontiers Media via the DOI in this record.Data Availability Statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Aim: We evaluated the efficacy of a novel brain permeable “metformin-like” AMP-activated protein kinase activator, R481, in regulating glucose homeostasis. Materials and Methods: We used glucose sensing hypothalamic GT1-7 neuronal cells and pancreatic αTC1.9 α-cells to examine the effect of R481 on AMPK pathway activation and cellular metabolism. Glucose tolerance tests and hyperinsulinemic-euglycemic and hypoglycemic clamps were used in Sprague-Dawley rats to assess insulin sensitivity and hypoglycemia counterregulation, respectively. Results: In vitro, we demonstrate that R481 increased AMPK phosphorylation in GT1-7 and αTC1.9 cells. In Sprague-Dawley rats, R481 increased peak glucose levels during a glucose tolerance test, without altering insulin levels or glucose clearance. The effect of R481 to raise peak glucose levels was attenuated by allosteric brain permeable AMPK inhibitor SBI-0206965. This effect was also completely abolished by blockade of the autonomic nervous system using hexamethonium. During hypoglycemic clamp studies, R481 treated animals had a significantly lower glucose infusion rate compared to vehicle treated controls. Peak plasma glucagon levels were significantly higher in R481 treated rats with no change to plasma adrenaline levels. In vitro, R481 did not alter glucagon release from αTC1.9 cells, but increased glycolysis. Non brain permeable AMPK activator R419 enhanced AMPK activity in vitro in neuronal cells but did not alter glucose excursion in vivo. Conclusions: These data demonstrate that peripheral administration of the brain permeable “metformin-like” AMPK activator R481 increases blood glucose by activation of the autonomic nervous system and amplifies the glucagon response to hypoglycemia in rats. Taken together, our data suggest that R481 amplifies the counterregulatory response to hypoglycemia by a central rather than a direct effect on the pancreatic α-cell. These data provide proof-of-concept that central AMPK could be a target for future drug development for prevention of hypoglycemia in diabetes.Juvenile Diabetes Research Foundation InternationalDiabetes UKSociety for EndocrinologyBritish Society for NeuroendocrinologyUniversity of Exete

The Impact of Global Warming and Anoxia on Marine Benthic Community Dynamics: an Example from the Toarcian (Early Jurassic)

The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic-rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of “dead zones” in modern oceans

ECG marker of adverse electrical remodeling post-myocardial infarction predicts outcomes in MADIT II study

PMC3522579Background Post-myocardial infarction (MI) structural remodeling is characterized by left ventricular dilatation, fibrosis, and hypertrophy of the non-infarcted myocardium. Objective The goal of our study was to quantify post-MI electrical remodeling by measuring the sum absolute QRST integral (SAI QRST). We hypothesized that adverse electrical remodeling predicts outcomes in MADIT II study participants. Methods Baseline orthogonal ECGs of 750 MADIT II study participants (448 [59.7%] ICD arm) were analyzed. SAI QRST was measured as the arithmetic sum of absolute QRST integrals over all three orthogonal ECG leads. The primary endpoint was defined as sudden cardiac death (SCD) or sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) with appropriate ICD therapies. All-cause mortality served as a secondary endpoint. Results Adverse electrical remodeling in post-MI patients was characterized by wide QRS, increased magnitudes of spatial QRS and T vectors, J-point deviation, and QTc prolongation. In multivariable Cox regression analysis after adjustment for age, QRS duration, atrial fibrillation, New York Heart Association heart failure class and blood urea nitrogen, SAI QRST predicted SCD/VT/VF (HR 1.33 per 100 mV*ms (95%CI 1.11–1.59); P=0.002), and all-cause death (HR 1.27 per 100 mV*ms (95%CI 1.03–1.55), P=0.022) in both arms. No interaction with therapy arm and bundle branch block (BBB) status was found. Conclusions In MADIT II patients, increased SAI QRST is associated with increased risk of sustained VT/VF with appropriate ICD therapies and all-cause death in both ICD and in conventional medical therapy arms, and in patients with and without BBB. Further studies of SAI QRST are warranted.JH Libraries Open Access Fun

Visual adaptation enhances action sound discrimination

Prolonged exposure, or adaptation, to a stimulus in one modality can bias, but also enhance, perception of a subsequent stimulus presented within the same modality. However, recent research has also found that adaptation in one modality can bias perception in another modality. Here we show a novel crossmodal adaptation effect, where adaptation to a visual stimulus enhances subsequent auditory perception. We found that when compared to no adaptation, prior adaptation to visual, auditory or audiovisual hand actions enhanced discrimination between two subsequently presented hand action sounds. Discrimination was most enhanced when the visual action ‘matched’ the auditory action. In addition, prior adaptation to a visual, auditory or audiovisual action caused subsequent ambiguous action sounds to be perceived as less like the adaptor. In contrast, these crossmodal action aftereffects were not generated by adaptation to the names of actions. Enhanced crossmodal discrimination and crossmodal perceptual aftereffects may result from separate mechanisms operating in audiovisual action sensitive neurons within perceptual systems. Adaptation induced crossmodal enhancements cannot be explained by post-perceptual responses or decisions. More generally, these results together indicate that adaptation is a ubiquitous mechanism for optimizing perceptual processing of multisensory stimuli

Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events

Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis

OBJECTIVES: Autoantibodies directed against cytosolic 5'-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5'-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis.MATERIALS AND METHODS: Data from various European inclusion body myositis registries were pooled. Anticytosolic 5'-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression.RESULTS: Data from 311 patients were available for analysis; 102 (33%) had anticytosolic 5'-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients.INTERPRETATION: Differences were observed in clinical and histopathological features between anticytosolic 5'-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5'-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.</p

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Impact of chemogenetic activation of dorsal vagal complex astrocytes in mice on adaptive glucoregulatory responses

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.The dorsal vagal complex (DVC) regulates diverse aspects of physiology including food intake and blood glucose homeostasis. Astrocytes play an active role in regulating DVC function and, by extension, physiological parameters. DVC astrocytes in ex vivo slices respond to low tissue glucose. The response of neurons to low glucose is conditional on intact astrocyte signalling in slice preparations, suggesting astrocytes are primary sensors of glucose deprivation (glucoprivation). Based on these published findings we hypothesised that in vivo DVC astrocyte manipulation with chemogenetics would be sufficient to alter physiological responses that control blood glucose. We found that 2-h after systemic 2-DG-induced glucoprivation there were no observable changes in morphology of glial fibrillary acidic protein (GFAP)-immunoreactive DVC cells, specifically those in the nucleus of the solitary tract (NTS). Chemogenetic activation of DVC astrocytes was sufficient to suppress nocturnal food intake by reducing both meal size and meal number and this manipulation also suppressed 2-DG-induced glucoprivic food intake. Chemogenetic activation of DVC astrocytes did not increase basal blood glucose nor protect against insulin-induced hypoglycaemia. In male mice, chemogenetic DVC astrocyte activation did not alter glucose tolerance. In female mice, the initial glucose excursion was reduced in a glucose tolerance test, suggesting enhanced glucose absorption. Based on our data and published work, we propose that DVC astrocytes may play an indispensable homeostatic role, that is, are necessary to maintain the function of glucoregulatory neuronal circuitry, but alone their bulk activation is not sufficient to result in adaptive glucoregulatory responses. It is possible that there are state-dependent effects and/or DVC astrocyte subsets that have this specialised role, but this was unresolvable using the experimental approaches employed here.Diabetes U