Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.

Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility. Rather, MPC inhibition rewires mitochondrial substrate metabolism to preferentially increase reliance on glutamate to fuel energetics and anaplerosis. Mobilizing the neuronal glutamate pool for oxidation decreases the quantity of glutamate released upon depolarization and, in turn, limits the positive-feedback cascade of excitotoxic neuronal injury. The finding links mitochondrial pyruvate metabolism to glutamatergic neurotransmission and establishes the MPC as a therapeutic target to treat neurodegenerative diseases characterized by excitotoxicity

Commercial production of fresh market tomatoes

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Application of Appropriateness Criteria to Stress Single-Photon Emission Computed Tomography Sestamibi Studies and Stress Echocardiograms in an Academic Medical Center

ObjectivesThe purpose of this study was to apply published appropriateness criteria for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in a single academic medical center.BackgroundThe American College of Cardiology Foundation (ACCF) and the American Society of Nuclear Cardiology (ASNC) have developed appropriateness criteria for stress SPECT MPI to address concern about the growth in cardiac imaging studies.MethodsWe retrospectively examined 284 patients who underwent stress SPECT MPI and 298 patients who underwent stress echocardiography before publication of these criteria.ResultsThe overall level of agreement in characterizing appropriateness between 2 experienced cardiovascular nurse abstractors was modest (kappa = 0.56), but noticeably poorer (kappa = 0.27) for patients with previous SPECT or echo studies. Similar percentages of each imaging modality were assigned to the 3 appropriateness categories: 64% of stress SPECT and 64% of stress echo studies were classified appropriate; 11% of stress SPECT and 9% of stress echo were of uncertain appropriateness; and 14% of stress SPECT and 18% of stress echo were inappropriate. Of the inappropriate studies, 88% were performed for 1 of 4 indications. Approximately 10% of the patients were unclassifiable.ConclusionsApplication of existing SPECT MPI appropriateness criteria is demanding and requires an established database or detailed data collection, as well as a number of assumptions. Fourteen percent of stress SPECT studies and 18% of stress echo studies were performed for inappropriate reasons. Quality improvement efforts directed at reducing the number of these inappropriate studies may improve efficiency in the health care system

Motor onset and diagnosis in Huntington disease using the diagnostic confidence level

Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments. Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine-adenine-guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington's Disease Rating Scale. HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, was associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11% (95% CI 7-15%) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47% (95% CI 27-69%). Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models

Bioprocessing of High-sulfur Crudes Via Appliaction of Critical Fluid Biocatalysis

This experimental research project investigated protein-based biocatalysis in supercritical fluid solvents as an integrated process approach to catalyze the removal of sulfur atoms from crude oils and fuels. The work focused on the oxidation of model sulfur-containing compounds in supercritical reaction media and included three major tasks: microbiological induction experiments, proteincatalyzed biooxidation in supercritical solvents, and a work-in-kind cooperative research and development agreement (CRADA). This work demonstrated that the biooxidation reaction could be improved by an order-of-magnitude by carrying out the reaction in emulsions in supercritical fluids

Altered Regulation of Striatal Neuronal N-Methyl-D-Aspartate Receptor Trafficking by Palmitoylation in Huntington Disease Mouse Model

N-methyl-D-aspartate receptors (NMDARs) play a critical role in synaptic signaling, and alterations in the synaptic/extrasynaptic NMDAR balance affect neuronal survival. Studies have shown enhanced extrasynaptic GluN2B-type NMDAR (2B-NMDAR) activity in striatal neurons in the YAC128 mouse model of Huntington disease (HD), resulting in increased cell death pathway activation contributing to striatal vulnerability to degeneration. However, the mechanism(s) of altered GluN2B trafficking remains unclear. Previous work shows that GluN2B palmitoylation on two C-terminal cysteine clusters regulates 2B-NMDAR trafficking to the surface membrane and synapses in cortical neurons. Notably, two palmitoyl acyltransferases (PATs), zDHHC17 and zDHHC13, also called huntingtin-interacting protein 14 (HIP14) and HIP14-like (HIP14L), directly interact with the huntingtin protein (Htt), and mutant Htt disrupts this interaction. Here, we investigated whether GluN2B palmitoylation is involved in enhanced extrasynaptic surface expression of 2B-NMDARs in YAC128 striatal neurons and whether this process is regulated by HIP14 or HIP14L. We found reduced GluN2B palmitoylation in YAC128 striatum, specifically on cysteine cluster II. Consistent with that finding, the palmitoylation-deficient GluN2B Cysteine cluster II mutant exhibited enhanced, extrasynaptic surface expression in striatal neurons from wild-type mice, mimicking increased extrasynaptic 2B-NMDAR observed in YAC128 cultures. We also found that HIP14L palmitoylated GluN2B cysteine cluster II. Moreover, GluN2B palmitoylation levels were reduced in striatal tissue from HIP14L-deficient mice, and siRNA-mediated HIP14L knockdown in cultured neurons enhanced striatal neuronal GluN2B surface expression and susceptibility to NMDA toxicity. Thus, altered regulation of GluN2B palmitoylation levels by the huntingtin-associated PAT HIP14L may contribute to the cell death-signaling pathways underlying HD

NASA Image eXchange (NIX)

This paper discusses the technical aspects of and the project background for the NASA Image exchange (NIX). NIX, which provides a single entry point to search selected image databases at the NASA Centers, is a meta-search engine (i.e., a search engine that communicates with other search engines). It uses these distributed digital image databases to access photographs, animations, and their associated descriptive information (meta-data). NIX is available for use at the following URL: http://nix.nasa.gov./NIX, which was sponsored by NASAs Scientific and Technical Information (STI) Program, currently serves images from seven NASA Centers. Plans are under way to link image databases from three additional NASA Centers. images and their associated meta-data, which are accessible by NIX, reside at the originating Centers, and NIX utilizes a virtual central site that communicates with each of these sites. Incorporated into the virtual central site are several protocols to support searches from a diverse collection of database engines. The searches are performed in parallel to ensure optimization of response times. To augment the search capability, browse functionality with pre-defined categories has been built into NIX, thereby ensuring dissemination of 'best-of-breed' imagery. As a final recourse, NIX offers access to a help desk via an on-line form to help locate images and information either within the scope of NIX or from available external sources

Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice

SummaryN-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative disease. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice

Legitimating space: art and the politics of place

Rock art, graffiti, and other emplaced works of art bring people together at specific places. This type of art allows for encounters between people in their absence, and thus presents a range of possibilities for making statements about specific places and those who occupy or visit. This opens the possibility for issues of legitimation to become implicitly or explicitly articulated. However, the legitimate use of space, and the legitimate employment of art, can vary drastically across different contexts. Here, the paper discusses a range of different strategies of art and legitimation in three case studies from India, California, and Spai