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Mine water geothermal energy's potential for decarbonization of heating and cooling in the UK has led to increased national interest and development of new projects. In this study, mine water geothermal exploration has been coupled with ground investigation techniques to assess ground stability alongside seasonal mine water hydrogeology and geochemistry. Drilling operations in late 2020 at Dollar Colliery, Clackmannanshire, Scotland, encountered mined coal seams with varying conditions (void, intact, waste, etc.), reflecting different techniques used throughout a protracted mining history. We found that time and resources spent grouting casing through worked mine seams (ensuring hydraulic separation) can be saved by accessing deeper seams where those above are unworked. Continued assessment of existing water discharges and completion of boreholes with slotted liners into mined coal seams and fractured roof strata allowed chemical and water level changes to be monitored across a 1 year period. Mine water heads and mine discharge flow rates vary seasonally and are elevated between late autumn and early spring. The mine water has a low dissolved solute content. Dissolved sulfate- 34 S isotope data suggest increased pyrite oxidation during lower water levels. These findings can inform future building decisions, whereby housing developments on site could use the mine water for heating. Supplementary material: Borehole data and completion diagrams are available at https://doi.org/10.6084/m9.figshare.22188801 Thematic collection: This article is part of the Early Career Research collection available at: https://www.lyellcollection.org/topic/collections/early-career-research

Prospective and operational mine water geothermal projects worldwide have faced challenges created by mine water chemistry (e.g., iron scaling, corrosion) and high expenditure costs (e.g., drilling or pumping costs) among others. Gravity fed or actively pumped drainages can be cheaper sources of low-carbon mine water heating when coupled with adequately sized heat exchanger and heat pump hardware. They also provide valuable chemical data to indicate mine water quality of associated coalfields. Field collection of temperature and flow rate data from mine water discharges across the Midland Valley of Scotland, combined with existing data for Coal Authority treatment schemes suggest that mine water heat pumps could provide a total of up to 48 MW of heat energy. Chemical characterisation of mine waters across the research area has created a valuable hydrochemical database for project stakeholders investigating mine water geothermal systems using boreholes or mine water discharges for heating or cooling purposes. Hydrochemical analytical assessment of untreated gravity discharges found that most are circumneutral, non-saline waters with an interquartile range for total iron of 2.0–11.6 mg/L. Stable isotope analysis indicates that the discharges are dominated by recent meteoric waters, but the origin of sulphate in mine waters is not as simple as coal pyrite oxidation, rather a more complex, mixed origin. Untreated gravity discharges contribute 595 kg/day of iron to Scottish watercourses; thus, it is recommended that when treatment schemes for mine water discharges are constructed, they are co-designed with mine water geothermal heat networks.

A flexible, practical, and stereoselective synthesis of enantiomerically pure

Impaired liver function may lead to hyperammonemia and risk for hepatic encephalopathy. In brain, detoxification of ammonia is mediated mainly by glutamine synthetase (GS) in astrocytes. This requires a continuous de novo synthesis of glutamate, likely involving the action of both pyruvate carboxylase (PC) and glutamate dehydrogenase (GDH). An increased PC activity upon ammonia exposure and the importance of PC activity for glutamine synthesis has previously been demonstrated while the importance of GDH for generation of glutamate as precursor for glutamine synthesis has received little attention. We therefore investigated the functional importance of GDH for brain metabolism during hyperammonemia. To this end, brain slices were acutely isolated from transgenic CNS-specific GDH null or litter mate control mice and incubated in aCSF containing [U-13C]glucose in the absence or presence of 1 or 5 mM ammonia. In another set of experiments, brain slices were incubated in aCSF containing 1 or 5 mM 15N-labeled NH4Cl and 5 mM unlabeled glucose. Tissue extracts were analyzed for isotopic labeling in metabolites and for total amounts of amino acids. As a novel finding, we reveal a central importance of GDH function for cerebral ammonia fixation and as a prerequisite for de novo synthesis of glutamate and glutamine during hyperammonemia. Moreover, we demonstrated an important role of the concerted action of GDH and alanine aminotransferase in hyperammonemia; the products alanine and α-ketoglutarate serve as an ammonia sink and as a substrate for ammonia fixation via GDH, respectively. The role of this mechanism in human hyperammonemic states remains to be studied.

Primary brain cells cultured on flat surfaces, i.e., in a two-dimensional fashion, have a long history of use as an experimental model system in neuroscience research. However, it is questionable to which extent these cultured brain cells resemble their in vivo counterparts. Mainly, it has been claimed that the non-oxidative glucose metabolism reflected by lactate production is unphysiologically high. Furthermore, it is known that culturing in 2D alters the phenotype of cells. Here we present diphenylalanine peptide nanowires (PNWs) as a culturing substrate for primary neocortical neurons from mice. The topology of the PNWs leads to neuronal cultures developing in 2.5D environment and hence improved culturing conditions. We investigate the effect of different concentrations of PNWs and different cell densities of neurons on the culturing conditions. The neocortical neurons were examined through scanning electron microscopy in order to study the effect of PNW concentrations and neuron densities on the structural appearance of the cells. Then employing the optimal combination of neuron density and PNW concentration, the neurons were evaluated functionally and metabolically by comparison with neocortical neurons standard culturing methods in 2D. Specifically, we tested neuronal viability, capacity for vesicular release of neurotransmitter GABA, as well as oxidative and non-oxidative glucose metabolism. It was evident that neurons cultured on PNWs exhibited increased viability combined with an increased capacity for neurotransmitter release and a lower fraction of non-oxidative metabolism than neurons cultured in 2D. Hence, neocortical neurons cultured in 2.5D on PNWs appear to be healthier and less glycolytic than neurons cultured in 2D.

The Spectral Imaging of the Coronal Environment (SPICE) instrument is a high-resolution imaging spectrometer operating at extreme ultraviolet (EUV) wavelengths. In this paper, we present the concept, design, and pre-launch performance of this facility instrument on the ESA/NASA Solar Orbiter mission. The goal of this paper is to give prospective users a better understanding of the possible types of observations, the data acquisition, and the sources that contribute to the instrument's signal. The paper discusses the science objectives, with a focus on the SPICE-specific aspects, before presenting the instrument's design, including optical, mechanical, thermal, and electronics aspects. This is followed by a characterisation and calibration of the instrument's performance. The paper concludes with descriptions of the operations concept and data processing. The performance measurements of the various instrument parameters meet the requirements derived from the mission's science objectives. The SPICE instrument is ready to perform measurements that will provide vital contributions to the scientific success of the Solar Orbiter mission., Comment: A&A, accepted 19 August 2019; 26 pages, 25 figures

A fundamental understanding of glycogen structure, concentration, polydispersity and turnover is critical to qualify the role of glycogen in the brain. These molecular and metabolic features are under the control of neuronal activity through the interdependent action of neuromodulatory tone, ionic homeostasis and availability of metabolic substrates, all variables that concur to define the state of the system. In this chapter, we briefly describe how glycogen responds to selected behavioral, nutritional, environmental, hormonal, developmental and pathological conditions. We argue that interpreting glycogen metabolism through the lens of brain state is an effective approach to establish the relevance of energetics in connecting molecular and cellular neurophysiology to behavior.

The brain contains a fairly low amount of glycogen, mostly located in astrocytes, a fact that has prompted the suggestion that glycogen does not have a significant physiological role in the brain. However, glycogen metabolism in astrocytes is essential for several key physiological processes and is adversely affected in disease. For instance, diminished ability to break down glycogen impinges on learning, and epilepsy, Alzheimer's disease, and type 2 diabetes are all associated with abnormal astrocyte glycogen metabolism. Glycogen metabolism supports astrocytic K(+) and neurotransmitter glutamate uptake and subsequent glutamine synthesis—three fundamental steps in excitatory signaling at most brain synapses. Thus, there is abundant evidence for a key role of glycogen in brain function. Here, we summarize the physiological brain functions that depend on glycogen, discuss glycogen metabolism in disease, and investigate how glycogen breakdown is regulated at the cellular and molecular levels.

Introduction La radiotherapie dans les carcinomes a cellules de Merkel metastatiques n’est indiquee qu’a visee palliative. L’avelumab a transforme la survie de certains patients, avec un taux de reponse global modere a 33 %, mais une survie prolongee chez les repondeurs. De nouveaux schemas therapeutiques semblent necessaires afin d’augmenter les taux de reponse. Nous rapportons l’observation d’un carcinome de Merkel en hyper-progression locoregionale initiale sous avelumab pour lequel une reponse spectaculaire a ete obtenue apres adjonction de radiotherapie. Observations Un patient de 59 ans, opere avec des marges non saines d’un carcinome de Merkel du bras gauche, developpait une recidive locale rapide avec extension ganglionnaire axillaire (stade T4N1M0). La progression tres rapide se poursuivait sous chimiotherapie (carboplatine + etoposide : 2 cures) puis avelumab (4 cures), et se compliquait d’une anemie par saignement tumoral requerant des transfusions iteratives. Une radiotherapie a visee hemostatique etait alors proposee. Le patient recevait sur la tumeur une dose totale de 20 Gy en 5 fractions de 4 Gy. Au decours survenait une regression tumorale rapide. A 3 mois de la radiotherapie, on notait une reponse clinique et metabolique complete de la tumeur primitive et une regression partielle des adenopathies axillaires. Cette reponse se maintenait a 6 mois sous avelumab, avec une poursuite de la diminution en taille des adenopathies. Discussion L’avelumab est une immunotherapie anti-PD-L1 dont le mode d’action est de supprimer les effets inhibiteurs du PD-L1 sur les lymphocytes T CD8+ cytotoxiques, retablissant ainsi la reponse anti-tumorale. Il a obtenu une AMM en 2e ligne apres chimiotherapie suite a un essai de phase 2. L’effet abscopal est le phenomene de regression d’une metastase a distance du volume irradie. Il a ete initialement decrit de maniere sporadique avec la radiotherapie en monotherapie, mais sa frequence semble augmenter lorsque la radiotherapie est combinee a l’immunotherapie (effet synergique), la liberation d’antigenes tumoraux augmentant alors l’identification des cellules tumorales par les lymphocytes T qui, actives, peuvent induire une reponse anti-tumorale a distance du site irradie. Notre observation suggere une potentialisation de l’avelumab par la radiotherapie, avec une reponse spectaculaire de la lesion primitive apres une faible dose, associee a une regression de sites ganglionnaires non irradies. Cette observation de carcinome a cellules de Merkel de stade III en hyper-progression sous avelumab, suivie d’une reponse quasi complete apres adjonction d’une radiotherapie palliative suggere l’interet et la synergie de l’association avelumab–radiotherapie.

Introduction L’incidence des carcinomes cutanes et lesions pre-cancereuses ne cesse d’augmenter en raison notamment de l’esperance de vie et de l’exposition solaire. Les carcinomes basocellulaires et keratoses actiniques representent respectivement 1 et 5 % des consultations de dermatologie. Differents traitements existent dont la phototherapie dynamique (PDT), utilisant l’activation d’un photosensibilisant par la lumiere pour induire une necrose tumorale. Le laser CO2 permet une destruction cellulaire en agissant sur l’eau intracellulaire, potentialisant ainsi la PDT. Le laser CO2 associe a la PDT a ete etudie dans differents essais suggerant une augmentation d’efficacite, mais aucune etude francaise en vie reelle n’a ete rapportee a notre connaissance. Materiel et methodes Etude retrospective monocentrique des patients traites par laser CO2 et PDT pour un carcinome basocellulaire (CBC), un carcinome epidermoide micro-invasif (CSC), une maladie de Bowen (MB) ou des keratoses actiniques/champs de cancerisations (KA/CC). Chaque lesion a ete traitee par laser CO2 suivi de l’application de methyl amino levulinate sous occlusion pendant 3 heures, puis d’une seance d’illumination avec la lampe Aktilite CL 128®. Selon l’appreciation du medecin 1 a 3 sessions etaient realisees. Un traitement antalgique adapte etait propose (paracetamol, meopa, tramadol). La douleur etait evaluee sur une echelle visuelle analogique (EVA). L’efficacite clinique etait evaluee lors de la consultation de suivi a 3 mois, si necessaire une biopsie etait realisee. Le critere principal etait le taux de reponse complete (RC : avec disparition des lesions). Une reponse partielle (RP) etait definie par une diminution de 25 a 99 %, et un echec par une diminution Resultats 42 patients (30 hommes et 12 femmes) d’âge moyen 79 ans (extremes : 54–92) ont ete inclus et 71 lesions traitees. 5 patients ont ete perdus de vue, le plus souvent en raison d’un âge tres avance ou du deces. Les lesions traitees etaient 2 CSC, 13 MB, 24 KA/CC, 25 CBC. Du fait de l’inclusion jusqu’en mai 2020, le critere principal n’a pu etre evalue a la date de soumission de l’abstract que pour 40 lesions. Une RC a 3 mois etait obtenue pour 11/13 CBC superficiels (1 RP et 1 echec en zone irradiee), 2/4 CBC nodulaires (2 echecs), 8/13 KA/CC (5 RP et 2 echecs avec biopsie montrant un CSC micro infiltrant), 9/10 MB (1 RP). L’EVA de douleur etait disponible pour 20 patients avec une moyenne de 5,4, plus elevee pour les lesions du visage. Discussion Malgre des donnees partielles, on note de bons resultats pour l’association laser CO2–PDT, concordant avec ceux de la litterature, mais incluant aussi des reponses totales pour des carcinomes parfois tres etendus ou plus epais que ceux recommandes par l’AMM. Cette association parait etre plus efficace que la PDT classique et plus simple dans certaines situations que la chirurgie.

Glycogen is the main storage form of glucose in the brain. In contrast with previous beliefs, brain glycogen has recently been shown to play important roles in several brain functions. A fraction of metabolized glucose molecules are being shunted through glycogen before reentering the glycolytic pathway, a phenomenon known as the glycogen shunt. The significance of glycogen in astrocyte energetics is underlined by high activity of the glycogen shunt and the finding that inhibition of glycogen degradation, under some conditions leads to a disproportional increase in glycolytic activity, so-called glycolytic supercompensation. Glycogen phosphorylase, the key enzyme in glycogen degradation, is expressed in two different isoforms in brain, the muscle and the brain isoform. Recent studies have illustrated how these are differently regulated. In the present study, we investigate the role of the two isoforms in glycolytic supercompensation in cultured astrocytes with the expression of either one of the isoforms silenced by siRNA knockdown. When reintroducing glucose to glucose-starved astrocytes, glycolytic activity increased dramatically. Interestingly, the increase was 30% higher in astrocytes not expressing the muscle isoform of glycogen phosphorylase. Based on these results and previously published data we couple the muscle isoform of glycogen phosphorylase to glycolytic supercompensation and glycogen shunt activity, giving insights to the underlying mechanistic of these phenomena.

A large body of evidence suggests that the neuropeptide galanin plays an important role in seizure control. In line with this, it was demonstrated that the galanin analogue, NAX-5055, exerts a potent anticonvulsant activity in animal seizure models. We recently found that the NAX-5055-mediated anticonvulsant action involves modulation of both excitatory and inhibitory neurotransmission. Since homeostasis of neurotransmitters and cerebral energy metabolism are intimately linked, it was investigated whether the effects of NAX-5055 on neurotransmission involve changes in energy metabolism and in particular glucose- and amino acid metabolism. With this aim, cultured neurons from mouse brain were incubated with [U-13 C]glucose in absence or presence of NAX-5055. Since effects of NAX-5055 on neurotransmission were detected during repetitive stimulation, we tested potential metabolic effects while mimicking repetitive bursts of neurotransmitter release as occurring in the intact brain. The metabolic pathways were mapped using gas-chromatography coupled to mass-spectrometry. We found that NAX-5055 does not modify glucose metabolism in glutamatergic and GABAergic neurons. Furthermore, the effect of NAX-5055 on astrocyte-neuron metabolic interactions was investigated by incubating co-cultures of astrocytes and either glutamatergic or GABAergic neurons with [U-13 C]glucose or the glial-selective substrate [1,2-13 C]acetate, with or without NAX-5055. In the presence of NAX-5055, no changes in the metabolic landscape were traced. The findings suggest that the anticonvulsant action of NAX-5055 and the accompanying changes in neurotransmission do not involve alterations in energy and amino acid metabolism. Hence, NAX-5055 appears to be an anti-seizure drug candidate displaying no unwanted side effects concerning brain energy and amino acid homeostasis. © 2017 Wiley Periodicals, Inc.

Brain slice preparations from rats, mice and guinea pigs have served as important tools for studies of neurotransmission and metabolism. While hippocampal slices routinely have been used for electrophysiology studies, metabolic processes have mostly been studied in cerebral cortical slices. Few comparative characterization studies exist for acute hippocampal and cerebral cortical slices, hence, the aim of the current study was to characterize and compare glucose and acetate metabolism in these slice preparations in a newly established incubation design. Cerebral cortical and hippocampal slices prepared from 16 to 18-week-old mice were incubated for 15–90 min with unlabeled glucose in combination with [U-13C]glucose or [1,2-13C]acetate. Our newly developed incubation apparatus allows accurate control of temperature and is designed to avoid evaporation of the incubation medium. Subsequent to incubation, slices were extracted and extracts analyzed for 13C-labeling (%) and total amino acid contents (µmol/mg protein) using gas chromatography–mass spectrometry and high performance liquid chromatography, respectively. Release of lactate from the slices was quantified by analysis of the incubation media. Based on the measured 13C-labeling (%), total amino acid contents and relative activity of metabolic enzymes/pathways, we conclude that the slice preparations in the current incubation apparatus exhibited a high degree of metabolic integrity. Comparison of 13C-labeling observed with [U-13C]glucose in slices from cerebral cortex and hippocampus revealed no significant regional differences regarding glycolytic or total TCA cycle activities. On the contrary, results from the incubations with [1,2-13C]acetate suggest a higher capacity of the astrocytic TCA cycle in hippocampus compared to cerebral cortex. Finally, we propose a new approach for assessing compartmentation of metabolite pools between astrocytes and neurons using 13C-labeling (%) data obtained from mass spectrometry. Based on this approach we suggest that cellular metabolic compartmentation in hippocampus and cerebral cortex is very similar.

A fundamental understanding of glycogen structure, concentration, polydispersity and turnover is critical to qualify the role of glycogen in the brain. These molecular and metabolic features are under the control of neuronal activity through the interdependent action of neuromodulatory tone, ionic homeostasis and availability of metabolic substrates, all variables that concur to define the state of the system. In this chapter, we briefly describe how glycogen responds to selected behavioral, nutritional, environmental, hormonal, developmental and pathological conditions. We argue that interpreting glycogen metabolism through the lens of brain state is an effective approach to establish the relevance of energetics in connecting molecular and cellular neurophysiology to behavior.

Introduction L’association encorafenib et binimetinib (ENCO/BINI) est autorisee depuis juin 2019 pour le traitement du melanome non resecable ou metastatique mute BRAF V600. Les toxicites, notamment renales, sont peu decrites. Materiel et methodes Il s’agit d’une etude retrospective, monocentrique, incluant tous les patients traites par ENCO/BINI dans un service de dermatologie oncologique entre octobre 2019 et juin 2020 pour un melanome. Resultats Douze patients, dont 8 femmes, ont ete traites par ENCO/BINI pour un melanome de stade III inoperable ou IV. L’âge moyen etait de 57 ans, 4 avaient une hypertension arterielle, dont 3 sous antihypertenseur nephrotoxique ou diuretique, 1 etait diabetique, aucun n’avait d’insuffisance renale chronique. Une insuffisance renale aigue (IRA) apparaissait chez 7 patients (58 %), apres un delai median de 13 jours (4 a 30), de grade 2 (3 cas), 3 (3 cas) ou 4 (1 cas). Ce dernier patient necessitait une hospitalisation en reanimation pour fievre, rhabdomyolyse et choc hypovolemique associes. Il s’agissait dans 3 cas d’une IRA organique avec une proteinurie moderee entre 27 et 330 mg/mmol de creatinine, de profil tubulaire associe a une composante fonctionnelle. L’IRA etait uniquement fonctionnelle dans un cas. On notait un cas d’IRA progressive sur 4 mois, sans proteinurie. Il n’y avait pas d’hematurie ni de leucocyturie. Deux cas rapidement resolutifs n’ont pas ete explores. Aucun patient n’a eu de biopsie renale. La resolution de l’IRA sans sequelles a ete obtenue par la suspension d’ENCO/BINI dans 6 cas, associee a une hydratation par voie IV dans 4 cas. La poursuite a la meme posologie ou une reprise a dose reduite ont ete possibles pour 2 patients sans recidive de l’IRA. Cinq patients ont eu un changement de therapie ciblee sans recidive de l’IRA. Discussion Les toxicites renales sont peu decrites avec les inhibiteurs de BRAF et MEK. Nous rapportons une frequence elevee de toxicite renale sous ENCO/BINI, chez environ 60 % de nos patients, necessitant une prise en charge hospitaliere dans les 2/3 des cas, ce qui n’avait pas ete rapporte dans les etudes de phase 2 et 3 (COLOMBUS), une IRA de grade 3 ou 4 n’etant notee que dans 0,7 % des cas de la population COMBO450. Une etude retrospective sur 57 patients a en revanche revele une IRA dans 26 % des cas, dont 3 de toxicite tubulaire, sans proteinurie superieure a 0,3 g/24 h, toujours resolutive. Comparativement aux autres associations anti-BRAK/MEK, la toxicite renale semble etre plus frequente sous ENCO/BINI et vemurafenib/cobimetinib (12 a 14 %) que sous dabrafenib/trametinib (4 %). Conclusion La frequence de la toxicite renale sous ENCO/BINI apparait elevee dans notre experience en vie reelle, atteignant deux tiers des patients sur un faible effectif. Une surveillance renale etroite et un controle strict des facteurs nephrotoxiques associes paraissent importants.

An accurate model for simulating the transient turn-ON performance of thyristor-type switches is desirable for the development of solid-state pulse generators. The existing thyristor models are not suitable since they are either impractical to implement in an SPICE simulator, do not accurately model transient turn-ON performance, or are dependent on external circuit parameters that may not be known during the design phase, such as the load and discharge capacitance. An empirical model is developed and presented for Silicon Power’s CCS SC 14N40 thyristor. The process of model determination is detailed, and waveforms obtained from the experiment and an SPICE circuit simulation that implements the thyristor model are discussed.

The endogenous neuropeptide galanin is ubiquitously expressed throughout the mammalian brain. Through the galanin receptors GalR1-3, galanin has been demonstrated to modulate both glutamatergic and GABAergic neurotransmission, and this appears to be important in epilepsy and seizure activity. Accordingly, galanin analogues are likely to provide a new approach to seizure management. However, since peptides are generally poor candidates for therapeutic agents due to their poor metabolic stability and low brain bioavailability, a search for alternative strategies for the development of galanin-based anti-convulsant drugs was prompted. Based on this, a rationally designed GalR1 preferring galanin analogue, NAX-5055, was synthesized. This compound demonstrates anti-convulsant actions in several animal models of epilepsy. However, the alterations at the cellular level leading to this anti-convulsant action of NAX-5055 are not known. Here we investigate the action of NAX-5055 at the cellular level by determining its effects on excitatory and inhibitory neurotransmission, i.e. vesicular release of glutamate and GABA, respectively, in cerebellar, neocortical and hippocampal preparations. In addition, its effects on cell viability and neurotransmitter transporter capacity were examined to evaluate potential cell toxicity mediated by NAX-5055. It was found that vesicular release of glutamate was reduced concentration-dependently by NAX-5055 in the range from 0.1 to 1000 nM. Moreover, exposure to 1 μM NAX-5055 led to a reduction in the extracellular level of glutamate and an elevation of the extracellular level of GABA. Altogether these findings may at least partly explain the anti-convulsant effect of NAX-5055 observed in vivo.

SPICE is an imaging spectrometer operating at vacuum ultraviolet (VUV) wavelengths, 70.4 – 79.0 nm and 97.3 - 104.9 nm. It is a facility instrument on the Solar Orbiter mission, which carries 10 science instruments in all, to make observations of the Sun’s atmosphere and heliosphere, at close proximity to the Sun, i.e to 0.28 A.U. at perihelion. SPICE’s role is to make VUV measurements of plasma in the solar atmosphere. SPICE is designed to achieve spectral imaging at spectral resolution >1500, spatial resolution of several arcsec, and two-dimensional FOV of 11 x16arcmins. The many strong constraints on the instrument design imposed by the mission requirements prevent the imaging performance from exceeding those of previous instruments, but by being closer to the sun there is a gain in spatial resolution. The price which is paid is the harsher environment, particularly thermal. This leads to some novel features in the design, which needed to be proven by ground test programs. These include a dichroic solar-transmitting primary mirror to dump the solar heat, a high in-flight temperature (60deg.C) and gradients in the optics box, and a bespoke variable-line-spacing grating to minimise the number of reflective components used. The tests culminate in the systemlevel test of VUV imaging performance and pointing stability. We will describe how our dedicated facility with heritage from previous solar instruments, is used to make these tests, and show the results, firstly on the Engineering Model of the optics unit, and more recently on the Flight Model. For the keywords, select up to 8 key terms for a search on your manuscript's subject.

A 37-year-old Japanese woman with a past medical history of aortic valve replacement secondary to a congenital aortic aneurysm and presumed Takayasu's arteritis treated with prednisone (60 mg daily) presented to the inpatient service with shortness of breath, abdominal pain, and leg and foot pain.

GABA is the major inhibitory neurotransmitter in mammalian brain. GABA is synthesized from glutamate and degraded to succinate in a bypath of the tricarboxylic acid cycle known as the GABA shunt. In rodent neocortex, GABAergic neurons comprise ∼15%–30% of neurons and consume ∼18% of the glucose oxidized by neurons. GABA produced in neurons by glutamic acid decarboxylase (GAD) and released by exocytosis is cleared from the synapse by reuptake into the terminal and also by uptake and metabolism in the glia via specialized GABA transporter proteins. GABA degraded in the astroglia is replenished by glial precursors mainly as glutamine in the glutamate/GABA–glutamine cycle, although other precursors may be involved as well. Different pools of cytoplasmic and vesicular GABA exist in the cell, and their synthesis may involve separate isoforms of GAD.

Glycogen phosphorylase (GP) is activated to degrade glycogen in response to different stimuli, to support both the astrocyte's own metabolic demand and the metabolic needs of neurons. The regulatory mechanism allowing such a glycogenolytic response to distinct triggers remains incompletely understood. In the present study, we used siRNA-mediated differential knockdown of the two isoforms of GP expressed in astrocytes, muscle isoform (GPMM), and brain isoform (GPBB), to analyze isoform-specific regulatory characteristics in a cellular setting. Subsequently, we tested the response of each isoform to phosphorylation, triggered by incubation with norepinephrine (NE), and to AMP, increased by glucose deprivation in cells in which expression of one GP isoform had been silenced. Successful knockdown was demonstrated on the protein level by Western blot, and on a functional level by determination of glycogen content showing an increase in glycogen levels following knockdown of either GPMM or GPBB. NE triggered glycogenolysis within 15 min in control cells and after GPBB knockdown. However, astrocytes in which expression of GPMM had been silenced showed a delay in response to NE, with glycogen levels significantly reduced only after 60 min. In contrast, allosteric activation of GP by AMP, induced by glucose deprivation, seemed to mainly affect GPBB, as only knockdown of GPBB, but not of GPMM, delayed the glycogenolytic response to glucose deprivation. Our results indicate that the two GP isoforms expressed in astrocytes respond to different physiological triggers, therefore conferring distinct metabolic functions of brain glycogen. GLIA 2015;63:154–162

A central task of the tricarboxylic acid (TCA, Krebs, citric acid) cycle in brain is to provide precursors for biosynthesis of glutamate, GABA, aspartate and glutamine. Three of these amino acids are the partners in the intricate interaction between astrocytes and neurons and form the so-called glutamine-glutamate (GABA) cycle. The ketoacids α-ketoglutarate and oxaloacetate are removed from the cycle for this process. When something is removed from the TCA cycle it must be replaced to permit the continued function of this essential pathway, a process termed anaplerosis. This anaplerotic process in the brain is mainly carried out by pyruvate carboxylation performed by pyruvate carboxylase. The present book chapter gives an introduction and overview into this carboxylation and additionally anaplerosis mediated by propionyl-CoA carboxylase under physiological conditions in the adult and in the developing rodent brain. Furthermore, examples are given about pathological conditions in which anaplerosis is disturbed.

A large body of evidence suggests that the neuropeptide galanin plays an important role in seizure control. In line with this, it was demonstrated that the galanin analogue, NAX-5055, exerts a potent anticonvulsant activity in animal seizure models. We recently found that the NAX-5055-mediated anticonvulsant action involves modulation of both excitatory and inhibitory neurotransmission. Since homeostasis of neurotransmitters and cerebral energy metabolism are intimately linked, it was investigated whether the effects of NAX-5055 on neurotransmission involve changes in energy metabolism and in particular glucose- and amino acid metabolism. With this aim, cultured neurons from mouse brain were incubated with [U

Instrument development for the 24m Giant Magellan Telescope (GMT) is described: current activities, progress, status, and schedule. One instrument team has completed its preliminary design and is currently beginning its final design (GCLEF, an optical 350-950 nm, high-resolution and precision radial velocity echelle spectrograph). A second instrument team is in its conceptual design phase (GMACS, an optical 350-950 nm, medium resolution, 6-10 arcmin field, multi-object spectrograph). A third instrument team is midway through its preliminary design phase (GMTIFS, a near-IR YJHK diffraction-limited imager/integral-field-spectrograph), focused on risk reduction prototyping and design optimization. A fourth instrument team is currently fabricating the 5 silicon immersion gratings needed to begin its preliminary design phase (GMTNIRS, a simultaneous JHKLM high-resolution, AO-fed, echelle spectrograph). And, another instrument team is focusing on technical development and prototyping (MANIFEST, a facility robotic, multifiber feed, with a 20 arcmin field of view). In addition, a medium-field (6 arcmin, 0.06 arcsec/pix) optical imager will support telescope and AO commissioning activities, and will excel at narrow-band imaging. In the spirit of advancing synergies with other groups, the challenges of running an ELT instrument program and opportunities for cross-ELT collaborations are discussed.

Brain slice preparations from rats, mice and guinea pigs have served as important tools for studies of neurotransmission and metabolism. While hippocampal slices routinely have been used for electrophysiology studies, metabolic processes have mostly been studied in cerebral cortical slices. Few comparative characterization studies exist for acute hippocampal and cerebral cortical slices, hence, the aim of the current study was to characterize and compare glucose and acetate metabolism in these slice preparations in a newly established incubation design. Cerebral cortical and hippocampal slices prepared from 16 to 18-week-old mice were incubated for 15-90 min with unlabeled glucose in combination with [U

The trend toward small-sized spacecraft continues in government applications and is even increasing in commercial space endeavors that are funded by venture capital. Small spacecraft, including nanosatellites, microsatellites, and small satellites (smallsats), are an attractive alternative to traditional, larger spacecraft due to reduced development costs, decreased launch costs, and increased launch opportunities. A significant disadvantage, however, of a small spacecraft is its reduced or limited capabilities. The physical size of the small spacecraft reduces the size of the payload and/or the number of payloads that it can host, its propulsion capabilities, and its power. Small spacecraft are most commonly used in low Earth orbit, limiting the number of observation opportunities for a particular area of the Earth or space and the number of ground station downlink opportunities for stored data. These constraints affect the complexity and types of applications that small spacecraft can serve. Using multiple spacecraft that work together can overcome many of these limitations and expand the utility of small spacecraft. Two concepts for cooperative groups of spacecraft are constellations and clusters. A key technical challenge for small spacecraft, constellations, and clusters is communication of data. Communication challenges exist for accommodating varying numbers of users, serving high user densities in a given geographical area, and providing a consistent quality of service for different types of applications (e.g., Internet access, voice communication, machine-to-machine). This paper explores concepts for emerging communication technologies for space-ground and inter-satellite communication, while citing examples of existing and new constellation and cluster concepts. Several aspects of the communication systems are examined in terms of frequency bands, data rates, multiple access methods, and accommodation on spacecraft.

A central task of the tricarboxylic acid (TCA, Krebs, citric acid) cycle in brain is to provide precursors for biosynthesis of glutamate, GABA, aspartate and glutamine. Three of these amino acids are the partners in the intricate interaction between astrocytes and neurons and form the so-called glutamine–glutamate (GABA) cycle. The ketoacids α-ketoglutarate and oxaloacetate are removed from the cycle for this process. When something is removed from the TCA cycle it must be replaced to permit the continued function of this essential pathway, a process termed anaplerosis. This anaplerotic process in the brain is mainly carried out by pyruvate carboxylation performed by pyruvate carboxylase. The present book chapter gives an introduction and overview into this carboxylation and additionally anaplerosis mediated by propionyl-CoA carboxylase under physiological conditions in the adult and in the developing rodent brain. Furthermore, examples are given about pathological conditions in which anaplerosis is disturbed.

GABA is synthesized from glutamate by glutamate decarboxylase (GAD), which exists in two isoforms, that is, GAD65 and GAD67. In line with GAD65 being located in the GABAergic synapse, several studies have demonstrated that this isoform is important during sustained synaptic transmission. In contrast, the functional significance of GAD65 in the maintenance of GABA destined for extrasynaptic tonic inhibition is less well studied. Using GAD65-/- and wild type GAD65+/+ mice, this was examined employing the cortical wedge preparation, a model suitable for investigating extrasynaptic GABA(A) receptor activity. An impaired tonic inhibition in GAD65-/- mice was revealed demonstrating a significant role of GAD65 in the synthesis of GABA acting extrasynaptically. The correlation between an altered tonic inhibition and metabolic events as well as the functional and metabolic role of GABA synthesized by GAD65 was further investigated in vivo. Tonic inhibition and the demand for biosynthesis of GABA were augmented by injection of kainate into GAD65-/- and GAD65+/+ mice. Moreover, [1-(13) C]glucose and [1,2-(13) C]acetate were administered to study neuronal and astrocytic metabolism concomitantly. Subsequently, cortical and hippocampal extracts were analyzed by NMR spectroscopy and mass spectrometry, respectively. Although seizure activity was induced by kainate, neuronal hypometabolism was observed in GAD65+/+ mice. In contrast, kainate evoked hypermetabolism in GAD65-/- mice exhibiting deficiencies in tonic inhibition. These findings underline the importance of GAD65 for synthesis of GABA destined for extrasynaptic tonic inhibition, regulating epileptiform activity.

Hidradenitis suppurativa (HS) is a frustrating disease to treat for both the patient and the practitioner. In severe cases, aggressive management will often have a more tolerable outcome. We present the case of a 46-year-old gentleman with a long-standing history of severe HS, who was treated successfully with wide surgical excision, followed by a full-thickness skin graft and negative pressure wound therapy (both pre- and post-operatively). A review of the literature revealed few reports of HS treatment using these sequential steps

γ-Aminobutyric acid (GABA) synthesis from glutamate is catalyzed by glutamate decarboxylase (GAD) of which two isoforms, GAD65 and GAD67, have been identified. The GAD65 has repeatedly been shown to be important during intensified synaptic activity. To specifically elucidate the significance of GAD65 for maintenance of the highly compartmentalized intracellular and intercellular GABA homeostasis, GAD65 knockout and corresponding wild-type mice were injected with [1-13C]glucose and the astrocyte-specific substrate [1,2-13C]acetate. Synthesis of GABA from glutamine in the GABAergic synapses was further investigated in GAD65 knockout and wild-type mice using [1,2-13C]acetate and in some cases c-vinylGABA (GVG, Vigabatrin), an inhibitor of GABA degradation. A detailed metabolic mapping was obtained by nuclear magnetic resonance (NMR) spectroscopic analysis of tissue extracts of cerebral cortex and hippocampus. The GABA content in both brain regions was reduced by ~20%. Moreover, it was revealed that GAD65 is crucial for maintenance of biosynthesis of synaptic GABA particularly by direct synthesis from astrocytic glutamine via glutamate. The GAD67 was found to be important for synthesis of GABA from glutamine both via direct synthesis and via a pathway involving mitochondrial metabolism. Furthermore, a severe neuronal hypometabolism, involving glycolysis and tricarboxylic acid (TCA) cycle activity, was observed in cerebral cortex of GAD65 knockout mice.

α7 nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartate receptors (NMDARs) are key mediators of central cholinergic and glutamatergic neurotransmission, respectively. In addition to numerous well-established functional interactions between α7 nAChRs and NMDARs, the two receptors have been proposed to form a multimeric complex, and in the present study we have investigated this putative α7 nAChR/NMDAR assembly in human and murine brain tissues. By α-bungarotoxin (BGT) affinity purification, α7 and NMDAR subunits were co-purified from human and murine cortical and hippocampal homogenates, substantiating the notion that the receptors are parts of a multimeric complex in the human and rodent brain. Interestingly, the ratios between GluN1 and α7 levels in BGT pull-downs from cortical homogenates from Alzheimer's disease (AD) brains were significantly lower than those in pull-downs from non-AD controls, indicating a reduced degree of α7 nAChR/NMDAR complex formation in the diseased tissue. A similar difference in GluN1/α7 ratios was observed between pull-downs from cortical homogenates from adult 3xTg-AD and age-matched wild type (WT) mice, whereas the GluN1/α7 ratios determined in pull-downs from young 3xTg-AD and age-matched WT mice did not differ significantly. The observation that pretreatment with oligomeric amyloid-β1-42 reduced GluN1/α7 ratios in BGT pull-downs from human cortical homogenate in a concentration-dependent manner provided a plausible molecular mechanism for this observed reduction. In conclusion, while it will be important to further challenge the existence of the putative α7 nAChR/NMDAR complex in future studies applying other methodologies than biochemical assays and to investigate the functional implications of this complex for cholinergic and glutamatergic neurotransmission, this work supports the formation of the complex and presents new insights into its regulation in healthy and diseased brain tissue.

The involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present unclear. The significance of glycogen in fueling glutamate uptake into astrocytes was specifically addressed in cultured astrocytes. Moreover, the objective was to elucidate whether glycogen derived energy is important for maintaining glutamatergic neurotransmission, induced by repetitive exposure to NMDA in co-cultures of cerebellar neurons and astrocytes. In the astrocytes it was shown that uptake of the glutamate analogue D-[3H]aspartate was impaired when glycogen degradation was inhibited irrespective of the presence of glucose, signifying that energy derived from glycogen degradation is important for the astrocytic compartment. By inhibiting glycogen degradation in co-cultures it was evident that glycogen provides energy to sustain glutamatergic neurotransmission, i.e. release and uptake of glutamate. The relocation of glycogen derived lactate to the neuronal compartment was investigated by employing d-lactate, a competitive substrate for the monocarboxylate transporters. Neurotransmitter release was affected by the presence of d-lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment.

The significance and functional roles of glycogen shunt activity in the brain are largely unknown. It represents the fraction of metabolized glucose that passes through glycogen molecules prior to entering the glycolytic pathway. The present study was aimed at elucidating this pathway in cultured astrocytes from mouse exposed to agents such as a high [K+], D-aspartate and norepinephrine (NE) known to affect energy metabolism in response to neurotransmission. Glycogen shunt activity was assessed employing [1,6-13C]glucose, and the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) to block glycogen degradation. The label intensity in lactate, reflecting glycolytic activity, was determined by mass spectrometry. In the presence of NE a substantial glycogen shunt activity was observed, accounting for almost 40% of overall glucose metabolism. Moreover, when no metabolic stimulant was applied, a compensatory increase in glycolytic activity was seen when the shunt was inhibited by DAB. Actually the labeling in lactate exceeded that obtained when glycolysis and glycogen shunt both were operational, i.e. supercompensation. A similar phenomenon was seen when astrocytes were exposed to D-aspartate. In addition to glycolysis, tricarboxylic acid (TCA) cycle activity was monitored, analyzing labeling by mass spectrometry in glutamate which equilibrates with alpha-ketoglutarate. Both an elevated [K+] and D-aspartate induced an increased TCA cycle activity, which was altered when glycogen degradation was inhibited. Thus, the present study provides evidence that manipulation of glycogen metabolism affects both glycolysis and TCA cycle metabolism. Altogether, the results reveal a highly complex interaction between glycogenolysis and glycolysis, with the glycogen shunt playing a significant role in astrocytic energy metabolism.

Neuronal activity is tightly coupled with brain energy metabolism. Numerous studies have suggested that lactate is equally important as an energy substrate for neurons as glucose. Lactate production is reportedly triggered by glutamate uptake, and independent of glutamate receptor activation. Here we show that climbing fibre stimulation of cerebellar Purkinje cells increased extracellular lactate by 30% within 30 s of stimulation, but not for briefer stimulation periods. To explore whether lactate production was controlled by pre- or postsynaptic events we silenced AMPA receptors with CNQX. This blocked all evoked rises in postsynaptic activity, blood flow, and glucose and oxygen consumption. CNQX also abolished rises in lactate concomitantly with marked reduction in postsynaptic currents. Rises in lactate were unaffected by inhibition of glycogen phosphorylase, suggesting that lactate production was independent of glycogen breakdown. Stimulated lactate production in cerebellum is derived directly from glucose uptake, and coupled to neuronal activity via AMPA receptor activation.

The Marx pulse generator topology has been widely used in pulsed power applications1,2. Another pulse generator topology, the linear transformer driver (LTD), has been developed3 that may serve as a viable alternative to the Marx generator. LTDs utilize inductively added stages to achieve high voltages and currents. Unlike a Marx generator, each stage in an LTD features multiple bricks, all of which are ground referenced and allow current to be distributed amongst an arbitrary number of switches. This allows for LTDs that utilize solid-state switches, potentially resulting in more compact and reliable pulse generators. A solid-state, >10 kA peak current, multiple-stage LTD is developed. The generator's performance will be analyzed for viability as a replacement for driving a high power microwave generator.