Differential levels of glutamate dehydrogenase 1 (GLUD1) in Balb/c and C57BL/6 mice and the effects of overexpression of the Glud1 gene on glutamate release in striatum

We have previously shown that overexpression of the Glud1 (glutamate dehydrogenase 1) gene in neurons of C57BL/6 mice results in increased depolarization-induced glutamate release that eventually leads to selective neuronal injury and cell loss by 12 months of age. However, it is known that isogenic lines of Tg (transgenic) mice produced through back-crossing with one strain may differ in their phenotypic characteristics from those produced using another inbred mouse strain. Therefore, we decided to introduce the Glud1 transgene into the Balb/c strain that has endogenously lower levels of GLUD1 (glutamate dehydrogenase 1) enzyme activity in the brain as compared with C57BL/6. Using an enzyme-based MEA (microelectrode array) that is selective for measuring glutamate in vivo, we measured depolarization-induced glutamate release. Within a discrete layer of the striatum, glutamate release was significantly increased in Balb/c Tg mice compared with wt (wild-type) littermates. Furthermore, Balb/c mice released approx. 50–60% of the amount of glutamate compared with C57BL/6 mice. This is similar to the lower levels of endogenous GLUD1 protein in Balb/c compared with C57BL/6 mice. The development of these Glud1-overexpressing mice may allow for the exploration of key molecular events produced by chronic exposure of neurons to moderate, transient increases in glutamate release, a process hypothesized to occur in neurodegenerative disorders.This work was supported by the NSF (National Science Foundation) [grant number EEC-0310723]; NIH/NIDA (National Institutes of Health/National Institute on Drug Abuse) [grant number DA017186]; CEBRA, Phase II, NIA, [grant number AG12993]; NIAAA (National Institute of Alcohol Abuse and Alcoholism) [grant numbers AA11419, AA04732, AA12276]; NSF [grant numbers DBI-9987807, DBI-0352848]; NIDA [grant number DA017186]; NINDS (National Institute of Neurological Disorders and Strokes) [grant number NS39787]; NIMH (National Institute of Mental Health) [grant number MH58414]; NIDA Training [grant number DA022738]; NIDA [grant number DA015088], The Kansas Technology Enterprise Corporation, The Miller, Hedwig and Wilbur Fund, and The University of Kansas Research Development Fund

Differential Levels of Glutamate Dehydrogenase 1 (GLUD1) in Balb/c and C57BL/6 Mice and the Effects of Overexpression of the \u3cem\u3eGlud1\u3c/em\u3e Gene on Glutamate Release in Striatum

We have previously shown that overexpression of the Glud1 (glutamate dehydrogenase 1) gene in neurons of C57BL/6 mice results in increased depolarization-induced glutamate release that eventually leads to selective neuronal injury and cell loss by 12 months of age. However, it is known that isogenic lines of Tg (transgenic) mice produced through back-crossing with one strain may differ in their phenotypic characteristics from those produced using another inbred mouse strain. Therefore, we decided to introduce the Glud1 transgene into the Balb/c strain that has endogenously lower levels of GLUD1 (glutamate dehydrogenase 1) enzyme activity in the brain as compared with C57BL/6. Using an enzyme-based MEA (microelectrode array) that is selective for measuring glutamate in vivo, we measured depolarization-induced glutamate release. Within a discrete layer of the striatum, glutamate release was significantly increased in Balb/c Tg mice compared with wt (wild-type) littermates. Furthermore, Balb/c mice released approx. 50-60% of the amount of glutamate compared with C57BL/6 mice. This is similar to the lower levels of endogenous GLUD1 protein in Balb/c compared with C57BL/6 mice. The development of these Glud1-overexpressing mice may allow for the exploration of key molecular events produced by chronic exposure of neurons to moderate, transient increases in glutamate release, a process hypothesized to occur in neurodegenerative disorders

Transgenic Expression of Glud1 (Glutamate Dehydrogenase 1) in Neurons: In Vivo Model of Enhanced Glutamate Release, Altered Synaptic Plasticity, and Selective Neuronal Vulnerability

This is the published version. Copyright 2009 Society for Neuroscience.The effects of lifelong, moderate excess release of glutamate (Glu) in the CNS have not been previously characterized. We created a transgenic (Tg) mouse model of lifelong excess synaptic Glu release in the CNS by introducing the gene for glutamate dehydrogenase 1 (Glud1) under the control of the neuron-specific enolase promoter. Glud1 is, potentially, an important enzyme in the pathway of Glu synthesis in nerve terminals. Increased levels of GLUD protein and activity in CNS neurons of hemizygous Tg mice were associated with increases in the in vivo release of Glu after neuronal depolarization in striatum and in the frequency and amplitude of miniature EPSCs in the CA1 region of the hippocampus. Despite overexpression of Glud1 in all neurons of the CNS, the Tg mice suffered neuronal losses in select brain regions (e.g., the CA1 but not the CA3 region). In vulnerable regions, Tg mice had decreases in MAP2A labeling of dendrites and in synaptophysin labeling of presynaptic terminals; the decreases in neuronal numbers and dendrite and presynaptic terminal labeling increased with advancing age. In addition, the Tg mice exhibited decreases in long-term potentiation of synaptic activity and in spine density in dendrites of CA1 neurons. Behaviorally, the Tg mice were significantly more resistant than wild-type mice to induction and duration of anesthesia produced by anesthetics that suppress Glu neurotransmission. The Glud1 mouse might be a useful model for the effects of lifelong excess synaptic Glu release on CNS neurons and for age-associated neurodegenerative processes

Differential levels of glutamate dehydrogenase 1 (GLUD1) in Balb/c and C57BL/6 mice and the effects of overexpression of the Glud1 gene on glutamate release in striatum

We have previously shown that overexpression of the Glud1 (glutamate dehydrogenase 1) gene in neurons of C57BL/6 mice results in increased depolarization-induced glutamate release that eventually leads to selective neuronal injury and cell loss by 12 months of age. However, it is known that isogenic lines of Tg (transgenic) mice produced through back-crossing with one strain may differ in their phenotypic characteristics from those produced using another inbred mouse strain. Therefore, we decided to introduce the Glud1 transgene into the Balb/c strain that has endogenously lower levels of GLUD1 (glutamate dehydrogenase 1) enzyme activity in the brain as compared with C57BL/6. Using an enzyme-based MEA (microelectrode array) that is selective for measuring glutamate in vivo, we measured depolarization-induced glutamate release. Within a discrete layer of the striatum, glutamate release was significantly increased in Balb/c Tg mice compared with wt (wild-type) littermates. Furthermore, Balb/c mice released approx. 50–60% of the amount of glutamate compared with C57BL/6 mice. This is similar to the lower levels of endogenous GLUD1 protein in Balb/c compared with C57BL/6 mice. The development of these Glud1-overexpressing mice may allow for the exploration of key molecular events produced by chronic exposure of neurons to moderate, transient increases in glutamate release, a process hypothesized to occur in neurodegenerative disorders

The effect of neighborhood social environment on prostate cancer development in black and white men at high risk for prostate cancer

INTRODUCTION: Neighborhood socioeconomic (nSES) factors have been implicated in prostate cancer (PCa) disparities. In line with the Precision Medicine Initiative that suggests clinical and socioenvironmental factors can impact PCa outcomes, we determined whether nSES variables are associated with time to PCa diagnosis and could inform PCa clinical risk assessment. MATERIALS AND METHODS: The study sample included 358 high risk men (PCa family history and/or Black race), aged 35-69 years, enrolled in an early detection program. Patient variables were linked to 78 nSES variables (employment, income, etc.) from previous literature via geocoding. Patient-level models, including baseline age, prostate specific antigen (PSA), digital rectal exam, as well as combined models (patient plus nSES variables) by race/PCa family history subgroups were built after variable reduction methods using Cox regression and LASSO machine-learning. Model fit of patient and combined models (AIC) were compared; p-values RESULTS: In combined models, nSES variables were significantly associated with time to PCa diagnosis. Workers mode of transportation and low income were significant in White men with a PCa family history. Homeownership (%owner-occupied houses with \u3e3 bedrooms) and unemployment were significant in Black men with and without a PCa family history, respectively. The 5-year predicted probability of PCa was higher in men with a high neighborhood score (weighted combination of significant nSES variables) compared to a low score (e.g., Baseline PSA level of 4ng/mL for men with PCa family history: White-26.7% vs 7.7%; Black-56.2% vs 29.7%). DISCUSSION: Utilizing neighborhood data during patient risk assessment may be useful for high risk men affected by disparities. However, future studies with larger samples and validation/replication steps are needed

Relational happiness through recognition and redistribution:Emotion and inequality

This article develops a model of relational happiness that challenges popular individualized definitions and emphasizes how it can enhance the sociological analysis of inequality. Many studies of happiness suggest that social inequalities are closely associated with distributions of happiness at the national level, but happiness research continues to favour individual-level analyses. Limited attention has been given to the intersubjective aspects of happiness and the correlations between it and higher social equality. Conversely, key theoretical debates about inequalities, such as Axel Honneth and Nancy Fraser\u27s exchanges, have only indirectly touched on happiness. A relational approach to happiness is not new, but what this article offers is a new combination of a relational understanding of happiness as an intersubjectively, culturally experienced complex of emotions with discussions about recognition of marginalized groups and redistribution of material resources. This combined approach can further debates about understanding and remedying social inequalities. It argues that theories and measurements of happiness must consider how it can be achieved collectively through working at mutual respect as well as greater material equality

Antihyperlipidemic effects of Pleurotus ostreatus (oyster mushrooms) in HIV-infected individuals taking antiretroviral therapy

<p>Abstract</p> <p>Background</p> <p>Antiretroviral treatment (ART) regimens in HIV patients commonly cause significant lipid elevations, including increases in both triglycerides and cholesterol. Standard treatments for hypercholesterolemia include the HMG CoA reductase inhibitors, or "statins." Because many ART agents and statins share a common metabolic pathway that uses the cytochrome P450 enzyme system, coadministration of ART with statins could increase statin plasma levels significantly. The oyster mushroom, <it>Pleurotus ostreatus</it>, has been shown in animal models to decrease lipid levels - a finding that has been supported by preliminary data in a small human trial.</p> <p>Methods</p> <p>To assess the safety and efficacy of <it>P. ostreatus </it>in patients with HIV and ART-induced hyperlipidemia, a single-arm, open-label, proof-of-concept study of 8 weeks' duration with a target enrollment of 20 subjects was conducted. Study patients with ART-induced elevated non-HDL cholesterol levels (> 160 mg/dL) were enrolled. Participants received packets of freeze-dried <it>P. ostreatus </it>(15 gm/day) to be administered orally for the 8 week trial period. Lipid levels were drawn every two weeks to assess efficacy. Safety assessments included self-reported incidence of muscle aches and measurement of liver and muscle enzymes. Mean within-person change in lipid levels were estimated using generalized estimating equations to account for repeated observations on individuals. A 30 mg/dL decrease in non-HDL cholesterol was deemed clinically significant.</p> <p>Results</p> <p>126 patients were screened to enroll 25, of which 20 completed the 8-week study. The mean age was 46.4 years (36-60). Patients had a mean 13.7 yrs of HIV infection. Mean non-HDL cholesterol was 204.5 mg/dL at day 0 and 200.2 mg/dL at day 56 (mean within-person change = -1.70; 95% confidence interval (CI) = -17.4, 14.0). HDL cholesterol levels increased from 37.8 mg/dL at day 0 to 40.4 mg/dL on day 56 (mean within-person change = 2.6; 95% CI = -0.1, 5.2). Triglycerides dropped from 336.4 mg/dL on day 0 to 273.4 mg/dL on day 56 (mean within-person change = -63.0; 95% CI = -120.9, -5.1). Only 3 individuals achieved a sustained clinically significant (30 mg/dL) decline in non-HDL cholesterol after 8 weeks of therapy. There were no adverse experiences reported other than patients' distaste for the preparation. Liver function tests and muscle enzymes were not affected by the 8 weeks of treatment.</p> <p>Conclusions</p> <p><it>Pleurotus ostreatus </it>as administered in this experiment did not lower non-HDL cholesterol in HIV patients with ART-induced hypercholesterolemia. Small changes in HDL and triglycerides were not of a clinical magnitude to warrant further study.</p> <p>Trial Registration</p> <p>clinicaltrials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00069524">NCT00069524</a></p

Metabolomics applied to maternal and perinatal health: a review of new frontiers with a translation potential

The prediction or early diagnosis of maternal complications is challenging mostly because the main conditions, such as preeclampsia, preterm birth, fetal growth restriction, and gestational diabetes mellitus, are complex syndromes with multiple underlying mechanisms related to their occurrence. Limited advances in maternal and perinatal health in recent decades with respect to preventing these disorders have led to new approaches, and "omics" sciences have emerged as a potential field to be explored. Metabolomics is the study of a set of metabolites in a given sample and can represent the metabolic functioning of a cell, tissue or organism. Metabolomics has some advantages over genomics, transcriptomics, and proteomics, as metabolites are the final result of the interactions of genes, RNAs and proteins. Considering the recent "boom" in metabolomic studies and their importance in the research agenda, we here review the topic, explaining the rationale and theory of the metabolomic approach in different areas of maternal and perinatal health research for clinical practitioners. We also demonstrate the main exploratory studies of these maternal complications, commenting on their promising findings. The potential translational application of metabolomic studies, especially for the identification of predictive biomarkers, is supported by the current findings, although they require external validation in larger datasets and with alternative methodologies.74CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESSem informação88881.134095/2016-01; 8881.134512/2016-0

The \u3cem\u3eChlamydomonas\u3c/em\u3e Genome Reveals the Evolution of Key Animal and Plant Functions

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the ∼120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella

Incidence and risk factors for Preeclampsia in a cohort of healthy nulliparous pregnant women: a nested case-control study

The objective of this study is to determine the incidence, socio-demographic and clinical risk factors for preeclampsia and associated maternal and perinatal adverse outcomes. This is a nested case-control derived from the multicentre cohort study Preterm SAMBA, in five different centres in Brazil, with nulliparous healthy pregnant women. Clinical data were prospectively collected, and risk factors were assessed comparatively between PE cases and controls using risk ratio (RR) (95% CI) plus multivariate analysis. Complete data were available for 1,165 participants. The incidence of preeclampsia was 7.5%. Body mass index determined at the first medical visit and diastolic blood pressure over 75 mmHg at 20 weeks of gestation were independently associated with the occurrence of preeclampsia. Women with preeclampsia sustained a higher incidence of adverse maternal outcomes, including C-section (3.5 fold), preterm birth below 34 weeks of gestation (3.9 fold) and hospital stay longer than 5 days (5.8 fold) than controls. They also had worse perinatal outcomes, including lower birthweight (a mean 379 g lower), small for gestational age babies (RR 2.45 [1.52-3.95]), 5-minute Apgar score less than 7 (RR 2.11 [1.03-4.29]), NICU admission (RR 3.34 [1.61-6.9]) and Neonatal Near Miss (3.65 [1.78-7.49]). Weight gain rate per week, obesity and diastolic blood pressure equal to or higher than 75 mmHg at 20 weeks of gestation were shown to be associated with preeclampsia. Preeclampsia also led to a higher number of C-sections and prolonged hospital admission, in addition to worse neonatal outcomes9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ401636/2013-5Bill and Melinda Gates FoundationGates Foundation [OPP1107597]; CNPqNational Council for Scientific and Technological Development (CNPq) [401636/2013-5