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      Multiple Oxygen Tension Environments Reveal Diverse Patterns of Transcriptional Regulation in Primary Astrocytes

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          Abstract

          The central nervous system normally functions at O 2 levels which would be regarded as hypoxic by most other tissues. However, most in vitro studies of neurons and astrocytes are conducted under hyperoxic conditions without consideration of O 2-dependent cellular adaptation. We analyzed the reactivity of astrocytes to 1, 4 and 9% O 2 tensions compared to the cell culture standard of 20% O 2, to investigate their ability to sense and translate this O 2 information to transcriptional activity. Variance of ambient O 2 tension for rat astrocytes resulted in profound changes in ribosomal activity, cytoskeletal and energy-regulatory mechanisms and cytokine-related signaling. Clustering of transcriptional regulation patterns revealed four distinct response pattern groups that directionally pivoted around the 4% O 2 tension, or demonstrated coherent ascending/decreasing gene expression patterns in response to diverse oxygen tensions. Immune response and cell cycle/cancer-related signaling pathway transcriptomic subsets were significantly activated with increasing hypoxia, whilst hemostatic and cardiovascular signaling mechanisms were attenuated with increasing hypoxia. Our data indicate that variant O 2 tensions induce specific and physiologically-focused transcript regulation patterns that may underpin important physiological mechanisms that connect higher neurological activity to astrocytic function and ambient oxygen environments. These strongly defined patterns demonstrate a strong bias for physiological transcript programs to pivot around the 4% O 2 tension, while uni-modal programs that do not, appear more related to pathological actions. The functional interaction of these transcriptional ‘programs’ may serve to regulate the dynamic vascular responsivity of the central nervous system during periods of stress or heightened activity.

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          Most cited references 72

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          Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

          Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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            Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction.

            Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, worms and flies. Mammals contain seven homologs of yeast Sir2, SIRT1-7. Here, we review recent findings demonstrating the role of these mammalian sirtuins as regulators of physiology, calorie restriction, and aging. The current findings sharpen our understanding of sirtuins as potential pharmacological targets to treat the major diseases of aging.
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              Glial regulation of the cerebral microvasculature.

              The brain is a heterogeneous organ with regionally varied and constantly changing energetic needs. Blood vessels in the brain are equipped with control mechanisms that match oxygen and glucose delivery through blood flow with the local metabolic demands that are imposed by neural activity. However, the cellular bases of this mechanism have remained elusive. A major advance has been the demonstration that astrocytes, cells with extensive contacts with both synapses and cerebral blood vessels, participate in the increases in flow evoked by synaptic activity. Their organization in nonoverlapping spatial domains indicates that they are uniquely positioned to shape the spatial distribution of the vascular responses that are evoked by neural activity. Astrocytic calcium is an important determinant of microvascular function and may regulate flow independently of synaptic activity. The involvement of astrocytes in neurovascular coupling has broad implications for the interpretation of functional imaging signals and for the understanding of brain diseases that are associated with neurovascular dysfunction.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                27 June 2011
                : 6
                : 6
                Affiliations
                [1 ]Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
                [2 ]Institute for Cardiovascular Research, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, West Yorkshire, United Kingdom
                [3 ]Metabolism Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
                [4 ]Gene Expression and Genomics Unit, Research Resources Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
                Universidade Federal do Rio de Janeiro, Brazil
                Author notes

                Conceived and designed the experiments: WC JPB CP SM. Performed the experiments: WC JPB Y. Zhou LW S-SP BM RW KGB WHW Y. Zhang. Analyzed the data: KGB Y. Zhang BM RW SM. Contributed reagents/materials/analysis tools: WC JPB CP SM. Wrote the paper: WC JPB BM CP SM. Assisted in data acquisition: Y. Zhou.

                ¶ These authors also contributed equally to this work.

                Article
                PONE-D-11-04059
                10.1371/journal.pone.0021638
                3124552
                21738745
                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
                Page count
                Pages: 20
                Categories
                Research Article
                Biology
                Biochemistry
                Genomics
                Functional Genomics
                Genome Expression Analysis
                Pharmacogenomics
                Molecular Cell Biology
                Signal Transduction
                Signaling Pathways
                Cellular Stress Responses
                Neuroscience
                Molecular Neuroscience
                Signaling Pathways
                Neurophysiology
                Central Nervous System
                Cellular Neuroscience
                Neurobiology of Disease and Regeneration
                Neurochemistry
                Systems Biology

                Uncategorized

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