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  • 1
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    Oxidative metabolism in YAC128 mouse model of Huntington's disease (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-07
    Description: Alterations in oxidative metabolism are considered to be one of the major contributors to Huntington's disease (HD) pathogenesis. However, existing data about oxidative metabolism in HD are contradictory. Here, we investigated the effect of mutant huntingtin (mHtt) on oxidative metabolism in YAC128 mice. Both mHtt and wild-type huntingtin (Htt) were associated with mitochondria and the amount of bound Htt was four-times higher than the amount of bound mHtt. Percoll gradient-purified brain synaptic and non-synaptic mitochondria as well as unpurified brain, liver and heart mitochondria, isolated from 2- and 10-month-old YAC128 mice and age-matched WT littermates had similar respiratory rates. There was no difference in mitochondrial membrane potential or ADP and ATP levels. Expression of selected nuclear-encoded mitochondrial proteins in 2- and 10-month-old YAC128 and WT mice was similar. Cultured striatal and cortical neurons from YAC128 and WT mice had similar respiratory and glycolytic activities as measured with Seahorse XF24 analyzer in medium containing 10 m m glucose and 15 m m pyruvate. In the medium with 2.5 m m glucose, YAC128 striatal neurons had similar respiration, but slightly lower glycolytic activity. Striatal neurons had lower maximal respiration compared with cortical neurons. In vivo experiments with YAC128 and WT mice showed similar O 2 consumption, CO 2 release, physical activity, food consumption and fasted blood glucose. However, YAC128 mice were heavier and had more body fat compared with WT mice. Overall, our data argue against respiratory deficiency in YAC128 mice and, consequently, suggest that mitochondrial respiratory dysfunction is not essential for HD pathogenesis.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus (2015)
    The American Physiological Society (APS)
    Details
    Publication Date: 2015-03-02
    Description: Leptin receptors (ObRs) in the forebrain and hindbrain have been independently recognized as important mediators of leptin responses. We recently used low-dose leptin infusions to show that chronic activation of both hypothalamic and hindbrain ObRs is required to reduce body fat. The objective of the present study was to identify the brain nuclei that are selectively activated in rats that received chronic infusion of leptin in both the forebrain and hindbrain. Either saline or leptin was infused into third and fourth ventricles (0.1 μg/24 h in the third ventricle and 0.6 μg/24 h in the fourth ventricle) of male Sprague-Dawley rats for 6 days using Alzet pumps. Rats infused with leptin into both ventricles (LL rats) showed a significant increase in phosphorylated (p)STAT3 immunoreactivity in the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and posterior hypothalamus compared with other groups. No differences in pSTAT3 immunoreactivity were observed in midbrain or hindbrain nuclei despite a sixfold higher infusion of leptin into the fourth ventricle than the third ventricle. FosB immunoreactivity, a marker of chronic neuronal activation, showed that multiple brain nuclei were chronically activated due to the process of infusion, but only the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and ventral tuberomamillary nucleus showed a significant increase in LL rats compared with other groups. These data demonstrate that low-dose leptin in the hindbrain increases pSTAT3 in areas of the hypothalamus known to respond to leptin, supporting the hypothesis that leptin-induced weight loss requires an integrated response from both the hindbrain and forebrain.
    Print ISSN: 0193-1849
    Electronic ISSN: 1522-1555
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 3
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    Pillars Article: AID Mutates E. coli Suggesting a DNA Deamination Mechanism for Antibody Diversification. Nature. 2002. 418: 99-103 [PILLARS OF IMMUNOLOGY] (2015)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2015-02-25
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 4
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    Long-term temperature records following the Mw 7.9 Wenchuan (China) earthquake are consistent with low friction (2015)
    Geological Society of America (GSA)
    In: Geology
    Details
    Publication Date: 2015-01-21
    Description: Knowledge of the shear stress on a fault during slip is necessary for a physically-based understanding of earthquakes. Borehole temperature measurements inside the fault zone immediately after an earthquake can record the energy dissipated by this stress. In the first Wenchuan Earthquake Fault Zone Scientific Drilling Project hole (Sichuan province, China) we repeatedly measured temperature profiles from 1.3 to 5.3 yr after the 12 May 2008, M w 7.9 Wenchuan earthquake. The previously identified candidate for the principal slip surface had only a small local temperature increase of at most 0.02 °C with no obvious decay. The small amplitude of the temperature increase provides an upper bound for the frictional heat–generated coseismic slip, but is unlikely to be a frictionally generated signal. Two larger temperature anomalies are located above and within the fault zone. However, neither anomaly evolves as expected from a frictional transient. We conclude that the frictional heat from the Wenchuan earthquake remains elusive and the total heat generated at this location is much less than 29 MJ/m 2 . Low friction during slip is consistent with the temperature data.
    Print ISSN: 0091-7613
    Electronic ISSN: 1943-2682
    Topics: Geosciences
    Published by Geological Society of America (GSA)
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  • 5
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    More than Skin Deep: Functional Genomic Basis for Resistance to Amphibian Chytridiomycosis (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-31
    Description: The amphibian-killing chytrid fungus Batrachochytrium dendrobatidis ( Bd ) is one of the most generalist pathogens known, capable of infecting hundreds of species globally and causing widespread population declines and extinctions. However, some host species are seemingly unaffected by Bd , tolerating or clearing infections without clinical signs of disease. Variation in host immune responses is commonly evoked for these resistant or tolerant species, yet to date, we have no direct comparison of amphibian species responses to infection at the level of gene expression. In this study, we challenged four Central American frog species that vary in Bd susceptibility, with a sympatric virulent strain of the pathogen. We compared skin and spleen orthologous gene expression using differential expression tests and coexpression gene network analyses. We found that resistant species have reduced skin inflammatory responses and increased expression of genes involved in skin integrity. In contrast, only highly susceptible species exhibited suppression of splenic T-cell genes. We conclude that resistance to chytridiomycosis may be related to a species’ ability to escape the immunosuppressive activity of the fungus. Moreover, our results indicate that within-species differences in splenic proteolytic enzyme gene expression may contribute to intraspecific variation in survival. This first comparison of amphibian functional immunogenomic architecture in response to Bd provides insights into key genetic mechanisms underlying variation in disease outcomes among amphibian species.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Requisite Role for Nck Adaptors in Cardiovascular Development, Endothelial-to-Mesenchymal Transition, and Directed Cell Migration [Articles] (2015)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2015-04-07
    Description: Development of the cardiovascular system is critically dependent on the ability of endothelial cells (ECs) to reorganize their intracellular actin architecture to facilitate migration, adhesion, and morphogenesis. Nck family cytoskeletal adaptors function as key mediators of actin dynamics in numerous cell types, though their role in EC biology remains largely unexplored. Here, we demonstrate an essential requirement for Nck within ECs. Mouse embryos lacking endothelial Nck1/2 expression develop extensive angiogenic defects that result in lethality at about embryonic day 10. Mutant embryos show immature vascular networks, with decreased vessel branching, aberrant perivascular cell recruitment, and reduced cardiac trabeculation. Strikingly, embryos deficient in endothelial Nck also fail to undergo the endothelial-to-mesenchymal transition (EnMT) required for cardiac valve morphogenesis, with loss of Nck disrupting expression of major EnMT markers, as well as suppressing mesenchymal outgrowth. Furthermore, we show that Nck-null ECs are unable to migrate downstream of vascular endothelial growth factor and angiopoietin-1, and they exhibit profound perturbations in cytoskeletal patterning, with disorganized cellular projections, impaired focal adhesion turnover, and disrupted actin-based signaling. Our collective findings thereby reveal a crucial role for Nck as a master regulator within the endothelium to control actin cytoskeleton organization, vascular network remodeling, and EnMT during cardiovascular development.
    Print ISSN: 0270-7306
    Electronic ISSN: 1098-5549
    Topics: Biology , Medicine
    Published by The American Society for Microbiology (ASM)
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  • 7
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    In vivo and in vitro evidence that chronic activation of the hexosamine biosynthetic pathway interferes with leptin-dependent STAT3 phosphorylation (2015)
    The American Physiological Society (APS)
    Details
    Publication Date: 2015-03-16
    Description: We previously reported that a 2-day peripheral infusion of glucosamine caused leptin resistance in rats, suggesting a role for the hexosamine biosynthetic pathway (HBP) in the development of leptin resistance. Here we tested leptin responsiveness in mice in which HBP activity was stimulated by offering 30% sucrose solution in addition to chow and water or by infusing glucosamine. Mice were leptin resistant after 33 days of access to sucrose. Resistance was associated with increased activity of the HBP and with phosphorylation of transcription factor signal transducer and activator of transcription-3 Tyr705 [pSTAT3(Y705)] but inhibition of suppressor of cytokine signaling 3 in the liver and hypothalamus. Intravenous infusion of glucosamine for 3 h stimulated pSTAT3(Y705) but prevented leptin-induced phosphorylation of STAT3(S727). In an in vitro system, glucose, glucosamine, and leptin each dose dependently increased O -linked β- N -acetylglucosamine ( O -GlcNAc) protein and pSTAT3(Y705) in HepG2 cells. To test the effect of glucose on leptin responsiveness cells were incubated in 5.5 mM (LG) or 20 mM (HG) glucose for 18 h and were treated with 0 or 50 ng/ml leptin for 15 min. HG alone and LG + leptin produced similar increases in O -GlcNAc protein, glutamine fructose-6-phosphate amidotransferase (GFAT), and pSTAT3(Y705) compared with LG media. Leptin did not stimulate these proteins in HG cells, suggesting leptin resistance. Leptin-induced pSTAT3(S727) was prevented by HG media. Inhibition of GFAT with azaserine prevented LG + leptin and HG stimulation of pSTAT3. These data demonstrate development of leptin resistance in sucrose-drinking mice and provide new evidence of leptin-induced stimulation of the HBP.
    Print ISSN: 0363-6119
    Electronic ISSN: 1522-1490
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 8
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    Glycine Receptors Containing {alpha}2 or {alpha}3 Subunits Regulate Specific Ethanol-Mediated Behaviors [Behavioral Pharmacology] (2015)
    The American Society for Pharmacology and Experimental Therapeutics
    Details
    Publication Date: 2015-03-05
    Description: Glycine receptors (GlyRs) are broadly expressed in the central nervous system. Ethanol enhances the function of brain GlyRs, and the GlyR α 1 subunit is associated with some of the behavioral actions of ethanol, such as loss of righting reflex. The in vivo role of GlyR α 2 and α 3 subunits in alcohol responses has not been characterized despite high expression levels in the nucleus accumbens and amygdala, areas that are important for the rewarding properties of drugs of abuse. We used an extensive panel of behavioral tests to examine ethanol actions in mice lacking Glra2 (the gene encoding the glycine receptor alpha 2 subunit) or Glra3 (the gene encoding the glycine receptor alpha 3 subunit). Deletion of Glra2 or Glra3 alters specific ethanol-induced behaviors. Glra2 knockout mice demonstrate reduced ethanol intake and preference in the 24-hour two-bottle choice test and increased initial aversive responses to ethanol and lithium chloride. In contrast, Glra3 knockout mice show increased ethanol intake and preference in the 24-hour intermittent access test and increased development of conditioned taste aversion to ethanol. Mutants and wild-type mice consumed similar amounts of ethanol in the limited access drinking in the dark test. Other ethanol effects, such as anxiolysis, motor incoordination, loss of righting reflex, and acoustic startle response, were not altered in the mutants. The behavioral changes in mice lacking GlyR α 2 or α 3 subunits were distinct from effects previously observed in mice with knock-in mutations in the α 1 subunit. We provide evidence that GlyR α 2 and α 3 subunits may regulate ethanol consumption and the aversive response to ethanol.
    Print ISSN: 0022-3565
    Electronic ISSN: 1521-0103
    Topics: Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics
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  • 9
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    APOBEC3B Upregulation by PKC/NF-{kappa}B (2015)
    The American Association for Cancer Research (AACR)
    Details
    Publication Date: 2015-11-03
    Description: Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in many cancers. Human papillomavirus infection accounts for APOBEC3B upregulation in cervical and head/neck cancers, but the mechanisms underlying nonviral malignancies are unclear. In this study, we investigated the signal transduction pathways responsible for APOBEC3B upregulation. Activation of protein kinase C (PKC) by the diacylglycerol mimic phorbol-myristic acid resulted in specific and dose-responsive increases in APOBEC3B expression and activity, which could then be strongly suppressed by PKC or NF-κB inhibition. PKC activation caused the recruitment of RELB, but not RELA, to the APOBEC3B promoter, implicating noncanonical NF-κB signaling. Notably, PKC was required for APOBEC3B upregulation in cancer cell lines derived from multiple tumor types. By revealing how APOBEC3B is upregulated in many cancers, our findings suggest that PKC and NF-κB inhibitors may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes, such as drug resistance and metastasis. Cancer Res; 75(21); 4538–47. ©2015 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 10
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    In vivo evidence for unidentified leptin-induced circulating factors that control white fat mass (2015)
    The American Physiological Society (APS)
    Details
    Publication Date: 2015-12-17
    Description: Fat transplants increase body fat mass without changing the energy status of an animal and provide a tool for investigating control of total body fat. Early transplant studies found that small pieces of transplanted fat took on the morphology of the transplant recipient. Experiments described here tested whether this response was dependent upon expression of leptin receptors in either transplanted fat or the recipient mouse. Fat from leptin receptor deficient db/db mice or wild-type mice was placed subcutaneously in db/db mice. After 12 wk, cell size distribution in the transplant was the same as in endogenous fat of the recipient. Thus, wild-type fat cells, which express leptin receptors, were enlarged in a hyperleptinemic environment, indicating that leptin does not directly control adipocyte size. By contrast, db/db or wild-type fat transplanted into wild-type mice decreased in size, suggesting that a functional leptin system in the recipient is required for body fat mass to be controlled. In the final experiment, wild-type fat was transplanted into a db/db mouse parabiosed to either another db/db mouse to an ob/ob mouse or in control pairs in which both parabionts were ob/ob mice. Transplants increased in size in db/db–db/db pairs, decreased in db/db–ob/ob pairs and did not change in ob/ob-ob/ob pairs. We propose that leptin from db/db parabionts activated leptin receptors in their ob/ob partners. This, in turn, stimulated release of unidentified circulating factors, which travelled back to the db/db partner and acted on the transplant to reduce fat cell size.
    Print ISSN: 0363-6119
    Electronic ISSN: 1522-1490
    Topics: Medicine
    Published by The American Physiological Society (APS)
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