Antioxidant Effect of CoQ(10) on N-nitrosodiethylamine-induced Oxidative Stress in Mice.

PubMed

Song, Ho Sun; Kim, Hee Rae; Park, Tae Wook; Cho, Bong Jae; Choi, Mi Young; Kim, Chang Jong; Sohn, Uy Dong; Sim, Sang Soo

2009-08-01

The antioxidant effect of CoQ(10) on N-nitrosodiethylamine (NDEA)-induced oxidative stress was investigated in mice. Food intake and body weight were similar in both CoQ(10) and control groups during the 3-week experimental period. NDEA significantly increased the activities of typical marker enzymes of liver function (AST, ALT and ALP) both in control and CoQ(10) groups. However, the increase of plasma aminotransferase activity was significantly reduced in the CoQ(10) group. Lipid peroxidation in various tissues, such as heart, lung, liver, kidney, spleen and plasma, was significantly increased by NDEA, but this increase was significantly reduced by 100 mg/kg of CoQ(10). Superoxide dismutase activity increased significantly upon NDEA-induced oxidative stress in both the control and CoQ(10) groups with the effect being less in the CoQ(10) group. Catalase activity decreased significantly in both the control and CoQ(10) groups treated with NDEA, again with the effect being less in the CoQ(10) group. The lesser effect on superoxide dismutase and catalase in the NDEA-treated CoQ(10) group is indicative of the protective effect CoQ(10). Thus, CoQ(10) can offer useful protection against NDEA-induced oxidative stress.

NEWLY DISCOVERED PLANETS ORBITING HD 5319, HD 11506, HD 75784 AND HD 10442 FROM THE N2K CONSORTIUM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giguere, Matthew J.; Fischer, Debra A.; Brewer, John M.

2015-01-20

Initially designed to discover short-period planets, the N2K campaign has since evolved to discover new worlds at large separations from their host stars. Detecting such worlds will help determine the giant planet occurrence at semi-major axes beyond the ice line, where gas giants are thought to mostly form. Here we report four newly discovered gas giant planets (with minimum masses ranging from 0.4 to 2.1 M {sub Jup}) orbiting stars monitored as part of the Next 2000 target stars (N2K) Doppler Survey program. Two of these planets orbit stars already known to host planets: HD 5319 and HD 11506. Themore » remaining discoveries reside in previously unknown planetary systems: HD 10442 and HD 75784. The refined orbital period of the inner planet orbiting HD 5319 is 641 days. The newly discovered outer planet orbits in 886 days. The large masses combined with the proximity to a 4:3 mean motion resonance make this system a challenge to explain with current formation and migration theories. HD 11506 has one confirmed planet, and here we confirm a second. The outer planet has an orbital period of 1627.5 days, and the newly discovered inner planet orbits in 223.6 days. A planet has also been discovered orbiting HD 75784 with an orbital period of 341.7 days. There is evidence for a longer period signal; however, several more years of observations are needed to put tight constraints on the Keplerian parameters for the outer planet. Lastly, an additional planet has been detected orbiting HD 10442 with a period of 1043 days.« less

HttQ111/+ Huntington’s Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction

PubMed Central

Kovalenko, Marina; Milnerwood, Austen; Giordano, James; St. Claire, Jason; Guide, Jolene R.; Stromberg, Mary; Gillis, Tammy; Sapp, Ellen; DiFiglia, Marian; MacDonald, Marcy E.; Carroll, Jeffrey B.; Lee, Jong-Min; Tappan, Susan; Raymond, Lynn; Wheeler, Vanessa C.

2018-01-01

Background: Successful disease-modifying therapy for Huntington’s disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. Objective: To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Methods: Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. Results: B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor-mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. Conclusions: These data show that a single HttQ111 allele is sufficient to elicit brain region-specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life. PMID:29480209

Chemical analysis of three barium stars: HD 51959, HD 88035, and HD 121447

NASA Astrophysics Data System (ADS)

Karinkuzhi, Drisya; Goswami, Aruna; Sridhar, Navin; Masseron, Thomas; Purandardas, Meenakshi

2018-05-01

We present elemental abundance results from high-resolution spectral analysis of three nitrogen-enhanced barium stars. The analysis is based on spectra obtained with the fibre-fed extended range optical spectrograph attached to 1.52 m telescope at European Southern Observatory, Chile. The spectral resolution is R ˜ 48,000 and the spectral coverage spans from 3500 to 9000Å . For the objects HD 51959 and HD 88035, we present the first-time abundance analyses results. Although a few studies are available in literature on the object HD 121447, the results are significantly different from each other. We have therefore carried out a detailed chemical composition study for this object based on a high-resolution spectrum with high S/N ratio, for a better understanding of the origin of the abundance patterns observed in this star. Stellar atmospheric parameters, the effective temperature, surface gravity, microturbulence, and metallicity of the stars are determined from the local thermodynamic equilibrium analysis using model atmospheres. The metallicities of HD 51959 and HD 88035 are found to be near-solar; they exhibit enhanced abundances of neutron-capture elements. HD 121447 is found to be moderately metal-poor with [Fe/H] = -0.65. While carbon is near-solar in the other two objects, HD 121447 shows carbon enhancement at a level, [C/Fe] = 0.82. Neutron-capture elements are highly enhanced with [X/Fe] > 2 (X: Ba, La, Pr, Nd, Sm) in this object. The α- and iron-peak elements show abundances very similar to field giants with the same metallicity. From kinematic analysis all the three objects are found to be members of thin disc population with a high probability of 0.99, 0.99, and 0.92 for HD 51959, HD 88035, and HD 121447, respectively.

Characterization of Behavioral, Neuropathological, Brain Metabolic and Key Molecular Changes in zQ175 Knock-In Mouse Model of Huntington's Disease.

PubMed

Peng, Qi; Wu, Bin; Jiang, Mali; Jin, Jing; Hou, Zhipeng; Zheng, Jennifer; Zhang, Jiangyang; Duan, Wenzhen

2016-01-01

Huntington's disease (HD) is caused by an expansion of the trinucleotide poly (CAG) tract located in exon 1 of the huntingtin (Htt) gene leading to progressive neurodegeneration in selected brain regions, and associated functional impairments in motor, cognitive, and psychiatric domains. Since the discovery of the gene mutation that causes the disease, mouse models have been developed by different strategies. Recently, a new model, the zQ175 knock-in (KI) line, was developed in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. The behavioral phenotype was characterized across the independent laboratories and important features reminiscent of human HD are observed in zQ175 mice. In the current study, we characterized the zQ175 model housed in an academic laboratory under reversed dark-light cycle, including motor function, in vivo longitudinal structural MRI imaging for brain volume, MRS for striatal metabolites, neuropathology, as well as a panel of key disease marker proteins in the striatum at different ages. Our results suggest that homozygous zQ175 mice exhibited significant brain atrophy before the motor deficits and brain metabolite changes. Altered striatal medium spiny neuronal marker, postsynaptic marker protein and complement component C1qC also characterized zQ175 mice. Our results confirmed that the zQ175 KI model is valuable in understanding of HD-like pathophysiology and evaluation of potential therapeutics. Our data also provide suggestions to select appropriate outcome measurements in preclinical studies using the zQ175 mice.

Phosphorodiamidate morpholino oligomers suppress mutant huntingtin expression and attenuate neurotoxicity

PubMed Central

Sun, Xin; Marque, Leonard O.; Cordner, Zachary; Pruitt, Jennifer L.; Bhat, Manik; Li, Pan P.; Kannan, Geetha; Ladenheim, Ellen E.; Moran, Timothy H.; Margolis, Russell L.; Rudnicki, Dobrila D.

2014-01-01

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Disease pathogenesis derives, at least in part, from the long polyglutamine tract encoded by mutant HTT. Therefore, considerable effort has been dedicated to the development of therapeutic strategies that significantly reduce the expression of the mutant HTT protein. Antisense oligonucleotides (ASOs) targeted to the CAG repeat region of HTT transcripts have been of particular interest due to their potential capacity to discriminate between normal and mutant HTT transcripts. Here, we focus on phosphorodiamidate morpholino oligomers (PMOs), ASOs that are especially stable, highly soluble and non-toxic. We designed three PMOs to selectively target expanded CAG repeat tracts (CTG22, CTG25 and CTG28), and two PMOs to selectively target sequences flanking the HTT CAG repeat (HTTex1a and HTTex1b). In HD patient–derived fibroblasts with expanded alleles containing 44, 77 or 109 CAG repeats, HTTex1a and HTTex1b were effective in suppressing the expression of mutant and non-mutant transcripts. CTGn PMOs also suppressed HTT expression, with the extent of suppression and the specificity for mutant transcripts dependent on the length of the targeted CAG repeat and on the CTG repeat length and concentration of the PMO. PMO CTG25 reduced HTT-induced cytotoxicity in vitro and suppressed mutant HTT expression in vivo in the N171-82Q transgenic mouse model. Finally, CTG28 reduced mutant HTT expression and improved the phenotype of HdhQ7/Q150 knock-in HD mice. These data demonstrate the potential of PMOs as an approach to suppressing the expression of mutant HTT. PMID:25035419

Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease.

PubMed

Covey, Dan P; Dantrassy, Hannah M; Zlebnik, Natalie E; Gildish, Iness; Cheer, Joseph F

2016-05-04

Huntington's disease (HD) is a heritable neurodegenerative disorder caused by expansion of CAG (glutamine) repeats in the HTT gene. A prodromal stage characterized by psychiatric disturbances normally precedes primary motor symptoms and suppressed motivation represents one of the earliest and most common psychiatric symptoms. Although dopamine in the nucleus accumbens (NAc) critically regulates motivation and altered dopamine signaling is implicated in HD, the nature of dopaminergic deficits and contribution to symptoms in HD is poorly understood. We therefore tested whether altered NAc dopamine release accompanies motivational deficits in the Q175 knock-in HD mouse model. Q175 mice express a CAG expansion of the human mutant huntingtin allele in the native mouse genome and gradually manifest symptoms late in life, closely mimicking the genotypic context and disease progression in human HD. Sub-second extracellular dopamine release dynamics were monitored using fast-scan cyclic voltammetry, whereas motivation was assessed using a progressive ratio reinforcement schedule. As the response ratio (lever presses per reward) escalated, Q175 mice exerted less effort to earn fewer rewards versus wild-type (WT). Moreover, dopamine released at reward delivery dynamically encoded increasing reward cost in WT but not Q175 mice. Deficits were specific to situations of high effortful demand as no difference was observed in locomotion, free feeding, hedonic processing, or reward seeking when the response requirement was low. This compromised dopaminergic encoding of reward delivery coincident with suppressed motivation to work for reward in Q175 mice provides novel, neurobiological insight into an established and clinically relevant endophenotype of prodromal HD. Psychiatric impairments in Huntington's disease (HD) typically manifest early in disease progression, before motor deficits. However, the neurobiological factors contributing to psychiatric symptoms are poorly understood

Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease.

PubMed

Heikkinen, Taneli; Lehtimäki, Kimmo; Vartiainen, Nina; Puoliväli, Jukka; Hendricks, Susan J; Glaser, Jack R; Bradaia, Amyaouch; Wadel, Kristian; Touller, Chrystelle; Kontkanen, Outi; Yrjänheikki, Juha M; Buisson, Bruno; Howland, David; Beaumont, Vahri; Munoz-Sanjuan, Ignacio; Park, Larry C

2012-01-01

Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, [1]) in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to

Insights into the pathogenesis of GvHD: what mice can teach us about man.

PubMed

Hülsdünker, J; Zeiser, R

2015-01-01

Acute graft-vs-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). Most of the knowledge about the biology of GvHD is derived from mouse models of this disease and therefore a critical analysis of potential advantages and disadvantages of the murine GvHD models is important to classify and understand the findings made in these models. The central events leading up to GvHD were characterized in three phases which includes the tissue damage-phase, the T cell priming-phase and the effector-phase, when the disease becomes clinically overt. The role of individual cytokines, chemokines, transcription factor or receptors was studied in these models by using gene deficient or transgenic mice in the donor or recipient compartments. Besides, numerous studies have been performed in these models to prevent or treat GvHD. Several recent clinical trials were all based on previously reported findings from the mouse model of GvHD such as the trials on CCR5-blockade, donor statin treatment, vorinostat treatment or adoptive transfer of regulatory T cells for GvHD prevention. The different mouse models for GvHD and graft-vs-leukemia effects are critically reviewed and their impact on current clinical practice is discussed. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Longitudinal Motor Characterisation of the HdhQ111 Mouse Model of Huntington's Disease.

PubMed

Yhnell, Emma; Dunnett, Stephen B; Brooks, Simon P

2016-05-31

Huntington's disease (HD) is a rare, incurable neurodegenerative disorder caused by a CAG trinucleotide expansion with the first exon of the huntingtin gene. Numerous knock-in mouse models are currently available for modelling HD. However, before their use in scientific research, these models must be characterised to determine their face and predictive validity as models of the disease and their reliability in recapitulating HD symptoms. Manifest HD is currently diagnosed upon the onset of motor symptoms, thus we sought to longitudinally characterise the progression and severity of motor signs in the HdhQ111 knock-in mouse model of HD, in heterozygous mice. An extensive battery of motor tests including: rotarod, inverted lid test, balance beam, spontaneous locomotor activity and gait analysis were applied longitudinally to a cohort of HdhQ111 heterozygous mice in order to progressively assess motor function. A progressive failure to gain body weight was demonstrated from 11 months of age and motor problems in all measures of balance beam performance were shown in HdhQ111 heterozygous animals in comparison to wild type control animals from 9 months of age. A decreased latency to fall from the rotarod was demonstrated in HdhQ111 heterozygous animals in comparison to wild type animals, although this was not progressive with time. No genotype specific differences were demonstrated in any of the other motor tests included in the test battery. The HdhQ111 heterozygous mouse demonstrates a subtle and progressive motor phenotype that begins at 9 months of age. This mouse model represents an early disease stage and would be ideal for testing therapeutic strategies that require elongated lead-in times, such as viral gene therapies or striatal transplantation.

A Longitudinal Operant Assessment of Cognitive and Behavioural Changes in the HdhQ111 Mouse Model of Huntington’s Disease

PubMed Central

Dunnett, Stephen B.; Brooks, Simon P.

2016-01-01

Huntington’s disease (HD) is characterised by motor symptoms which are often preceded by cognitive and behavioural changes, that can significantly contribute to disease burden for people living with HD. Numerous knock-in mouse models of HD are currently available for scientific research. However, before their use, they must be behaviourally characterised to determine their suitability in recapitulating the symptoms of the human condition. Thus, we sought to longitudinally characterise the nature, severity and time course of cognitive and behavioural changes observed in HdhQ111 heterozygous knock-in mice.To determine changes in cognition and behaviour an extensive battery of operant tests including: fixed ratio, progressive ratio, the five choice serial reaction time task and the serial implicit learning task, were applied longitudinally to HdhQ111 and wild type mice. The operant test battery was conducted at 6, 12 and 18 months of age. Significant deficits were observed in HdhQ111 animals in comparison to wild type animals in all operant tests indicating altered cognition (attentional and executive function) and motivation. However, the cognitive and behavioural deficits observed were not shown to be progressive over time in the longitudinal testing paradigm that was utilised. The results therefore demonstrate that the HdhQ111 mouse model of HD reflects some features of the cognitive and behavioural changes shown in the human condition of HD. Although, the cognitive and behavioural deficits demonstrated were not shown to be progressive over time. PMID:27701442

A comprehensive glycome profiling of Huntington's disease transgenic mice.

PubMed

Gizaw, Solomon T; Koda, Toshiaki; Amano, Maho; Kamimura, Keiko; Ohashi, Tetsu; Hinou, Hiroshi; Nishimura, Shin-Ichiro

2015-09-01

Huntington's disease (HD) is an autosomal, dominantly inherited and progressive neurodegenerative disease, nosologically classified as the presence of intranuclear inclusion bodies and the loss of GABA-containing neurons in the neostriatum and subsequently in the cerebellar cortex. Abnormal processing of neuronal proteins can result in the misfolding of proteins and altered post-translational modification of newly synthesized proteins. Total glycomics, namely, N-glycomics, O-glycomics, and glycosphingolipidomics (GSL-omics) of HD transgenic mice would be a hallmark for central nervous system disorders in order to discover disease specific biomarkers. Glycoblotting method, a high throughput glycomic protocol, and matrix-assisted laser desorption ionization-time of flight/mass spectrometry (MALDI-TOF/MS) were used to study the total glycome expression levels in the brain tissue (3 mice of each sex) and sera (5 mice of each sex) of HD transgenic and control mice. All experiments were performed twice and differences in the expression levels of major glycoforms were compared between HD transgenic and control mice. We estimated the structure and expression levels of 87 and 58N-glycans in brain tissue and sera, respectively, of HD transgenic and control mice. The present results clearly indicated that the brain glycome and their expression levels are significantly gender specific when compared with those of other tissues and serum. Core-fucosylated and bisecting-GlcNAc types of N-glycans were found in increased levels in the brain tissue HD transgenic mice. Accordingly, core-fucosylated and sialic acid (particularly N-glycolylneuraminic acid, NeuGc) for biantennary type glycans were found in increased amounts in the sera of HD transgenic mice compared to that of control mice. Core 3 type O-glycans were found in increased levels in male and in decreased levels in both the striatum and cortexes of female HD transgenic mice. Furthermore, serum levels of core 1 type O

Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111/+ model of Huntington's disease.

PubMed

Bragg, Robert M; Coffey, Sydney R; Weston, Rory M; Ament, Seth A; Cantle, Jeffrey P; Minnig, Shawn; Funk, Cory C; Shuttleworth, Dominic D; Woods, Emily L; Sullivan, Bonnie R; Jones, Lindsey; Glickenhaus, Anne; Anderson, John S; Anderson, Michael D; Dunnett, Stephen B; Wheeler, Vanessa C; MacDonald, Marcy E; Brooks, Simon P; Price, Nathan D; Carroll, Jeffrey B

2017-02-08

We investigated the appearance and progression of disease-relevant signs in the B6.Htt Q111/+ mouse, a genetically precise model of the mutation that causes Huntington's disease (HD). We find that B6.Htt Q111/+ mice are healthy, show no overt signs of central or peripheral inflammation, and no gross motor impairment as late as 12 months of age. Behaviorally, we find that 4-9 month old B6.Htt Q111/+ mice have normal activity levels and show no clear signs of anxiety or depression, but do show clear signs of reduced motivation. The neuronal density, neuronal size, synaptic density and number of glia is normal in B6.Htt Q111/+ striatum, the most vulnerable brain region in HD, up to 12 months of age. Despite this preservation of the synaptic and cellular composition of the striatum, we observe clear progressive, striatal-specific transcriptional dysregulation and accumulation of neuronal intranuclear inclusions (NIIs). Simulation studies suggest these molecular endpoints are sufficiently robust for future preclinical studies, and that B6.Htt Q111/+ mice are a useful tool for modeling disease-modifying or neuroprotective strategies for disease processes before the onset of overt phenotypes.

Serine 421 regulates mutant huntingtin toxicity and clearance in mice

PubMed Central

Kratter, Ian H.; Zahed, Hengameh; Lau, Alice; Daub, Aaron C.; Weiberth, Kurt F.; Gu, Xiaofeng; Humbert, Sandrine; Yang, X. William; Osmand, Alex; Steffan, Joan S.; Masliah, Eliezer

2016-01-01

Huntington’s disease (HD) is a progressive, adult-onset neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the N-terminal region of the protein huntingtin (HTT). There are no cures or disease-modifying therapies for HD. HTT has a highly conserved Akt phosphorylation site at serine 421, and prior work in HD models found that phosphorylation at S421 (S421-P) diminishes the toxicity of mutant HTT (mHTT) fragments in neuronal cultures. However, whether S421-P affects the toxicity of mHTT in vivo remains unknown. In this work, we used murine models to investigate the role of S421-P in HTT-induced neurodegeneration. Specifically, we mutated the human mHTT gene within a BAC to express either an aspartic acid or an alanine at position 421, mimicking tonic phosphorylation (mHTT-S421D mice) or preventing phosphorylation (mHTT-S421A mice), respectively. Mimicking HTT phosphorylation strongly ameliorated mHTT-induced behavioral dysfunction and striatal neurodegeneration, whereas neuronal dysfunction persisted when S421 phosphorylation was blocked. We found that S421 phosphorylation mitigates neurodegeneration by increasing proteasome-dependent turnover of mHTT and reducing the presence of a toxic mHTT conformer. These data indicate that S421 is a potent modifier of mHTT toxicity and offer in vivo validation for S421 as a therapeutic target in HD. PMID:27525439

Q(n) species distribution in K2O.2SiO2 glass by 29Si magic angle flipping NMR.

PubMed

Davis, Michael C; Kaseman, Derrick C; Parvani, Sahar M; Sanders, Kevin J; Grandinetti, Philip J; Massiot, Dominique; Florian, Pierre

2010-05-06

Two-dimensional magic angle flipping (MAF) was employed to measure the Q((n)) distribution in a (29)Si-enriched potassium disilicate glass (K(2)O.2SiO(2)). Relative concentrations of [Q((4))] = 7.2 +/- 0.3%, [Q((3))] = 82.9 +/- 0.1%, and [Q((2))] = 9.8 +/- 0.6% were obtained. Using the thermodynamic model for Q((n)) species disproportionation, these relative concentrations yield an equilibrium constant k(3) = 0.0103 +/- 0.0008, indicating, as expected, that the Q((n)) species distribution is close to binary in the potassium disilicate glass. A Gaussian distribution of isotropic chemical shifts was observed for each Q((n)) species with mean values of -82.74 +/- 0.03, -91.32 +/- 0.01, and -101.67 +/- 0.02 ppm and standard deviations of 3.27 +/- 0.03, 4.19 +/- 0.01, and 5.09 +/- 0.03 ppm for Q((2)), Q((3)), and Q((4)), respectively. Additionally, nuclear shielding anisotropy values of zeta =-85.0 +/- 1.3 ppm, eta = 0.48 +/- 0.02 for Q((2)) and zeta = -74.9 +/- 0.2 ppm, eta = 0.03 +/- 0.01 for Q((3)) were observed in the potassium disilicate glass.

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

PubMed

McGarry, Andrew; McDermott, Michael; Kieburtz, Karl; de Blieck, Elisabeth A; Beal, Flint; Marder, Karen; Ross, Christopher; Shoulson, Ira; Gilbert, Peter; Mallonee, William M; Guttman, Mark; Wojcieszek, Joanne; Kumar, Rajeev; LeDoux, Mark S; Jenkins, Mary; Rosas, H Diana; Nance, Martha; Biglan, Kevin; Como, Peter; Dubinsky, Richard M; Shannon, Kathleen M; O'Suilleabhain, Padraig; Chou, Kelvin; Walker, Francis; Martin, Wayne; Wheelock, Vicki L; McCusker, Elizabeth; Jankovic, Joseph; Singer, Carlos; Sanchez-Ramos, Juan; Scott, Burton; Suchowersky, Oksana; Factor, Stewart A; Higgins, Donald S; Molho, Eric; Revilla, Fredy; Caviness, John N; Friedman, Joseph H; Perlmutter, Joel S; Feigin, Andrew; Anderson, Karen; Rodriguez, Ramon; McFarland, Nikolaus R; Margolis, Russell L; Farbman, Eric S; Raymond, Lynn A; Suski, Valerie; Kostyk, Sandra; Colcher, Amy; Seeberger, Lauren; Epping, Eric; Esmail, Sherali; Diaz, Nancy; Fung, Wai Lun Alan; Diamond, Alan; Frank, Samuel; Hanna, Philip; Hermanowicz, Neal; Dure, Leon S; Cudkowicz, Merit

2017-01-10

To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. These data do not justify use of CoQ as a treatment to slow functional decline in HD. NCT00608881. This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD. © 2016 American Academy of Neurology.

Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111/+ model of Huntington’s disease

PubMed Central

Bragg, Robert M.; Coffey, Sydney R.; Weston, Rory M.; Ament, Seth A.; Cantle, Jeffrey P.; Minnig, Shawn; Funk, Cory C.; Shuttleworth, Dominic D.; Woods, Emily L.; Sullivan, Bonnie R.; Jones, Lindsey; Glickenhaus, Anne; Anderson, John S.; Anderson, Michael D.; Dunnett, Stephen B.; Wheeler, Vanessa C.; MacDonald, Marcy E.; Brooks, Simon P.; Price, Nathan D.; Carroll, Jeffrey B.

2017-01-01

We investigated the appearance and progression of disease-relevant signs in the B6.HttQ111/+ mouse, a genetically precise model of the mutation that causes Huntington’s disease (HD). We find that B6.HttQ111/+ mice are healthy, show no overt signs of central or peripheral inflammation, and no gross motor impairment as late as 12 months of age. Behaviorally, we find that 4–9 month old B6.HttQ111/+ mice have normal activity levels and show no clear signs of anxiety or depression, but do show clear signs of reduced motivation. The neuronal density, neuronal size, synaptic density and number of glia is normal in B6.HttQ111/+ striatum, the most vulnerable brain region in HD, up to 12 months of age. Despite this preservation of the synaptic and cellular composition of the striatum, we observe clear progressive, striatal-specific transcriptional dysregulation and accumulation of neuronal intranuclear inclusions (NIIs). Simulation studies suggest these molecular endpoints are sufficiently robust for future preclinical studies, and that B6.HttQ111/+ mice are a useful tool for modeling disease-modifying or neuroprotective strategies for disease processes before the onset of overt phenotypes. PMID:28176805

Prolonged Incubation Time in Sheep with QK171 Genotype

USDA-ARS?s Scientific Manuscript database

Background: Sheep scrapie susceptibility or resistance is a function of genotype with polymorphisms at codon 171 playing a major role. Glutamine (Q) at 171 contributes to scrapie susceptibility while arginine (R) is associated with resistance. In some breeds, lysine (K) occurs at 171, but its affe...

Early Detection of Apathetic Phenotypes in Huntington's Disease Knock-in Mice Using Open Source Tools.

PubMed

Minnig, Shawn; Bragg, Robert M; Tiwana, Hardeep S; Solem, Wes T; Hovander, William S; Vik, Eva-Mari S; Hamilton, Madeline; Legg, Samuel R W; Shuttleworth, Dominic D; Coffey, Sydney R; Cantle, Jeffrey P; Carroll, Jeffrey B

2018-02-02

Apathy is one of the most prevalent and progressive psychiatric symptoms in Huntington's disease (HD) patients. However, preclinical work in HD mouse models tends to focus on molecular and motor, rather than affective, phenotypes. Measuring behavior in mice often produces noisy data and requires large cohorts to detect phenotypic rescue with appropriate power. The operant equipment necessary for measuring affective phenotypes is typically expensive, proprietary to commercial entities, and bulky which can render adequately sized mouse cohorts as cost-prohibitive. Thus, we describe here a home-built, open-source alternative to commercial hardware that is reliable, scalable, and reproducible. Using off-the-shelf hardware, we adapted and built several of the rodent operant buckets (ROBucket) to test Htt Q111/+ mice for attention deficits in fixed ratio (FR) and progressive ratio (PR) tasks. We find that, despite normal performance in reward attainment in the FR task, Htt Q111/+ mice exhibit reduced PR performance at 9-11 months of age, suggesting motivational deficits. We replicated this in two independent cohorts, demonstrating the reliability and utility of both the apathetic phenotype, and these ROBuckets, for preclinical HD studies.

Comparisons of amino acids, body constituents and antioxidative response between long-time HD and normal HD.

PubMed

Torigoe, Akira; Sato, Emiko; Mori, Takefumi; Ieiri, Norio; Takahashi, Chika; Ishida, Yoko; Hotta, Osamu; Ito, Sadayoshi

2016-10-01

Introduction Oxidative stress is one of the main mediators of progression of chronic kidney diseases (CKD). Nuclear factor E2-related factor 2 (Nrf2) is the transcription factor of antioxidant and detoxifying enzymes and related proteins which play an important role in cellular defense. Long-time hemodialysis (HD) therapy (8 hours) has been considered to be more beneficial compared to normal HD therapy (4 hours). We investigated oxidative response related to Nrf2 in peripheral blood mononuclear cells (PBMCs) of long-time HD and normal HD patients. Methods Eight adult long-time HD therapy patients (44.5 ± 3.0 years) and 10 normal HD therapy patients (68.1 ± 2.7 years) were enrolled. PBMCs were isolated and processed for expression of Nrf2 and its related genes by qRT-PCR. Plasma indoxyl sulfate, amino acids, and body constituents were measured. Findings Plasma indoxyl sulfate was significantly low after long-time HD therapy compare to that of normal HD therapy. Although, skeletal muscle mass, lean body mass, mineral and protein were significantly decreased 2 months in normal HD patients, those in long-time HD patients were significantly increased after 2 months. Almost of amino acids were significantly decreased after HD therapy in both HD therapies. Plasma amino acids were significantly low in long-time HD patients compared to normal HD patients. In PBMCs, the expression of Nrf2 was significantly decreased and hemooxygenase-1 expression was significantly increased in long-time HD compared to normal HD. Conclusion These observations indicate the beneficial effects of in long-time HD in improving oxidative stress in patients. © 2016 International Society for Hemodialysis.

Cellular Models: HD Patient-Derived Pluripotent Stem Cells.

PubMed

Geater, Charlene; Hernandez, Sarah; Thompson, Leslie; Mattis, Virginia B

2018-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded polyglutamine (polyQ)-encoding repeats in the Huntingtin (HTT) gene. Traditionally, HD cellular models consisted of either patient cells not affected by disease or rodent neurons expressing expanded polyQ repeats in HTT. As these models can be limited in their disease manifestation or proper genetic context, respectively, human HD pluripotent stem cells (PSCs) are currently under investigation as a way to model disease in patient-derived neurons and other neural cell types. This chapter reviews embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) models of disease, including published differentiation paradigms for neurons and their associated phenotypes, as well as current challenges to the field such as validation of the PSCs and PSC-derived cells. Highlighted are potential future technical advances to HD PSC modeling, including transdifferentiation, complex in vitro multiorgan/system reconstruction, and personalized medicine. Using a human HD patient model of the central nervous system, hopefully one day researchers can tease out the consequences of mutant HTT (mHTT) expression on specific cell types within the brain in order to identify and test novel therapies for disease.

Metabolic effects of a mitochondrial-targeted coenzyme Q analog in high fat fed obese mice.

PubMed

Fink, Brian D; Guo, Deng Fu; Kulkarni, Chaitanya A; Rahmouni, Kamal; Kerns, Robert J; Sivitz, William I

2017-04-01

We recently reported that mitoquinone (mitoQ, 500  μ mol/L) added to drinking water of C57BL/6J mice attenuated weight gain, decreased food intake, increased hypothalamic orexigenic gene expression, and mitigated oxidative stress when administered from the onset of high-fat (HF) feeding. Here, we examined the effects of mitoQ on pre-existing obesity in C57BL/6J mice first made obese by 107 days of HF feeding. In contrast to our preventative study, we found that already obese mice did not tolerate mitoQ at 500  μ mol/L. Within 4 days of administration, obese mice markedly decreased food and water intake and lost substantial weight necessitating a dose reduction to 250  μ mol/L. Food and water intake then improved. Over the next 4 weeks, body mass of the mitoQ-treated mice increased faster than vehicle-treated controls but did not catch up. Over the subsequent 10 weeks, weights of the mitoQ-treated group remained significantly less than vehicle control, but percent fat and food intake did not differ. Although the mitoQ-treated groups continued to drink less, there was no difference in percent body fluid and no laboratory evidence of dehydration at study end. At the time of killing, hypothalamic NPY gene expression was reduced in the mitoQ-treated mice . Liver fat was markedly increased by HF feeding but did not differ between mitoQ and vehicle groups and, in contrast to our previous preventative study, there was no improvement in plasma alanine amino transferase or liver hydroperoxides. In summary, administration of mitoQ to already obese mice attenuated weight gain, but showed limited overall benefit.

Studies of FCAPT uvby Photometry with Period04: The mCP Stars HD 5797, HD 36792, HD 27309, HD 47913, HD 74521, HD 120198, HD 171263, and HD 215441

NASA Astrophysics Data System (ADS)

Dukes, Robert J., Jr.; Adelman, Saul J.

2018-04-01

We present differential Strömgren uvby Four College Automated Photometric Telescope (FCAPT) observations of eight magnetic chemically peculiar stars: HD 5797, HD 26792, HD 27309, HD 49713, HD 74521, HD 120198, HD 171263, and HD 215441. Our data sets are larger than those of most mCP stars in the literature. These are the first FCAPT observations of HD 5797, HD 26792, HD 49713, and HD 171263. Those for the other four stars substantially extend published FCAPT data sets. The FCAPT has observed some stars for a longer time range and with greater accuracy than other optical region telescopes. We determine very accurate periods and u, v, b, and y amplitudes, as well as if there are any long-term periods. Further, we compare our results with those of magnetic field measurements, when they exist, to help interpret the light curves. For each star, we used the Period04 computer program to analyze the uvby light curves. This program provides errors for the derived quantities. Our derived periods of 68.0457 ± 0.0200 days for HD 5797, 3.80205 ± 0.00015 days for HD 26792, 1.5688908 ± 0.0000046 days for HD 27309, 2.135361 ± 0.000031 days for HD 49713, 7.05053 ± 0.00024 for days HD 74521, 1.3857690 ± 0.0000058 days for HD 120198, 3.99744 ± 0.00015 days for HD 171263, and 9.487792 ± 0.000049 days for HD 215441 are refinements of the last determinations in the literature. We also found a low-frequency term for HD 49713 in all four filters.

Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal Disease

PubMed Central

Haase, Volker H.; King, Rhonda; Polyak, Erzsebet; Selak, Mary; Yudkoff, Marc; Hancock, Wayne W.; Meade, Ray; Saiki, Ryoichi; Lunceford, Adam L.; Clarke, Catherine F.; Gasser, David L.

2008-01-01

Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2kd/kd genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2kd/kd mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2loxP/loxP knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2loxP/loxP knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment. PMID:18437205

Quantitative Electroencephalographic Analysis Provides an Early-Stage Indicator of Disease Onset and Progression in the zQ175 Knock-In Mouse Model of Huntington's Disease.

PubMed

Fisher, Simon P; Schwartz, Michael D; Wurts-Black, Sarah; Thomas, Alexia M; Chen, Tsui-Ming; Miller, Michael A; Palmerston, Jeremiah B; Kilduff, Thomas S; Morairty, Stephen R

2016-02-01

Patients with Huntington's disease (HD) show a high prevalence of sleep disorders that typically occur prior to the onset of motoric symptoms and neurodegeneration. Our understanding of the pathophysiological alterations in premanifest HD is limited, hindering the ability to measure disease modification in response to treatment. We used a full-length knock-in HD model to determine early changes in the electroencephalogram (EEG) and sleep that may predict the onset and progression of the disease. A 10-month longitudinal study was designed to determine the effect of the HD mutation on the EEG and sleep/wake changes in heterozygous (HET) and homozygous (HOM) zQ175 mice and wild-type (WT) littermates from 8 to 48 w of age. Mice were instrumented with tethered headmounts to record EEG/electromyography signals. Telemeters were implanted to continuously measure locomotor activity (LMA) and body temperature (Tb). Sleep deprivation (SDep) was performed at 8, 12, 16, 24, 32, and 48 w of age. The HD mutation disrupted the EEG field potential from 8-12 w in an age- and mutant huntington dose-dependent manner, prior to changes in sleep/wake states, LMA, and Tb. Prominent effects of the HD mutation on the EEG included a progressive reduction in low frequency power, a slowing of rapid eye movement peak theta frequency, and the emergence of state-dependent beta/gamma oscillations. There was no effect of genotype on the relative increase in nonrapid eye movement delta power or sleep time in response to SDep. The expression of the Huntington's disease (HD) mutation results in complex EEG alterations that occur prior to deficits in behavioral measures and are one of the earliest phenotypes uncovered in this mouse model. Despite these EEG changes, homeostatic responses to sleep loss were preserved in HET and HOM zQ175 mice. Greater insight into the localization and response of these EEG alterations to novel therapies may enable early intervention and improve outcomes for patients with

Nanoparticles, [Gd@C82(OH)22]n, induces dendritic cell maturation and activates Th1 immune responses

PubMed Central

Yang, De; Zhao, Yuliang; Guo, Hua; Li, Yana; Tewary, Poonam; Xing, Gengmei; Hou, Wei; Oppenheim, Joost J.; Zhang, Ning

2010-01-01

Dendritic cells play a pivotal role in host immune defense, such as elimination of foreign pathogen and inhibition of tumorigenesis. In this paper, we report that [Gd@C82(OH)22]n could induce phenotypic maturation of dendritic cells by stimulating DC production of cytokines including IL-12p70, upregulating DC costimulatory (CD80, CD83, and CD86) and MHC (HLA-A,B,C and HLA-DR) molecules, and switching DCs from a CCL5-responsive to a CCL19-responsive phenotype. We found that [Gd@C82(OH)22]n can induce dendritic cells to become functionally mature as illustrated by their capacity to activate allogeneic T cells. Mice immunized with ovalbumin in the presence of [Gd@C82(OH)22]n exhibit enhanced ovalbumin-specific Th1-polarized immune response as evidenced by the predominantly increased production of IFNγ, IL-1β, and IL-2. The [Gd@C82(OH)22]n nanoparticle is a potent activator of dendritic cells and Th1 immune responses. These new findings also provide a rational understanding of the potent anticancer activities of [Gd@C82(OH)22]n nanoparticles reported previously. PMID:20121217

Obesity-induced oocyte mitochondrial defects are partially prevented and rescued by supplementation with co-enzyme Q10 in a mouse model

PubMed Central

Boots, C.E.; Boudoures, A.; Zhang, W.; Drury, A.; Moley, K.H.

2016-01-01

observed in the HF/HS mice. Overall, CoQ10 supplementation significantly increased the percentage of normal spindle and chromosome alignment (92.3 versus 80.2%, P= 0.039). In the sub-analysis by diet, the difference did not reach statistical significance. When undergoing IVF, there were no statistically significant differences in the number of mature oocytes, the fertilization rate, blastocyst formation rates, implantation rates, resorption rates or litter size between HF/HS mice receiving CoQ10 or vehicle injections. LIMITATIONS, REASONS FOR CAUTION Experiments were limited to one species and strain of mice. The majority of experiments were performed after ovulation induction, which may not represent natural cycle fertility. WIDER IMPLICATIONS OF THE FINDINGS Improvement in oocyte mitochondrial distribution and function of normal, chow-fed mice and HF/HS-fed mice demonstrates the importance of CoQ10 and the efficiency of the mitochondrial respiratory chain in oocyte competence. Clinical studies are now needed to evaluate the therapeutic potential of CoQ10 in women's reproductive health. STUDY FUNDING/COMPETING INTEREST(S) C.E.B. received support from the National Research Training Program in Reproductive Medicine sponsored by the National Institute of Health (T32 HD040135-13) and the Scientific Advisory Board of Vivere Health. K.H.M received support from the American Diabetes Association and the National Institute of Health (R01 HD083895). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER This study is not a clinical trial. PMID:27432748

A Mitochondrial-Targeted Coenzyme Q Analog Prevents Weight Gain and Ameliorates Hepatic Dysfunction in High-Fat–Fed Mice

PubMed Central

Fink, Brian D.; Herlein, Judith A.; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J.; Yu, Liping; Grobe, Justin L.; Rahmouni, Kamal; Kerns, Robert J.

2014-01-01

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. PMID:25301169

Trehalose rescues glial cell dysfunction in striatal cultures from HD R6/1 mice at early postnatal development.

PubMed

Perucho, Juan; Gómez, Ana; Muñoz, María Paz; de Yébenes, Justo García; Mena, María Ángeles; Casarejos, María José

2016-07-01

The pathological hallmark of Huntington disease (HD) is the intracellular aggregation of mutant huntingtin (mHTT) in striatal neurons and glia associated with the selective loss of striatal medium-sized spiny neurons. Up to the present, the role of glia in HD is poorly understood and has been classically considered secondary to neuronal disorder. Trehalose is a disaccharide known to possess many pharmacological properties, acting as an antioxidant, a chemical chaperone, and an inducer of autophagy. In this study, we analyzed at an early postnatal development stage the abnormalities observed in striatal glial cell cultures of postnatal R6/1 mice (HD glia), under baseline and stressing conditions and the protective effects of trehalose. Our data demonstrate that glial HD alterations already occur at early stages of postnatal development. After 20 postnatal days in vitro, striatal HD glia cultures showed more reactive astrocytes with increased expression of glial fibrillary acidic protein (GFAP) but with less replication capacity, less A2B5(+) glial progenitors and more microglia than wild-type (WT) cultures. HD glia had lower levels of intracellular glutathione (GSH) and was more susceptible to H2O2 and epoxomicin insults. The amount of expressed GDNF and secreted mature-BDNF by HD astrocytes were much lower than by WT astrocytes. In addition, HD glial cultures showed a deregulation of the major proteolytic systems, the ubiquitin-proteasomal system (UPS), and the autophagic pathway. This produces a defective protein quality control, indicated by the elevated levels of ubiquitination and p62 protein. Interestingly, we show that trehalose, through its capacity to induce autophagy, inhibited p62/SQSTM1 accumulation and facilitated the degradation of cytoplasmic aggregates from mHTT and α-synuclein proteins. Trehalose also reduced microglia activation and reversed the disrupted cytoskeleton of astrocytes accompanied with an increase in the replication capacity. In

A mitochondrial-targeted coenzyme q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice.

PubMed

Fink, Brian D; Herlein, Judith A; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J; Yu, Liping; Grobe, Justin L; Rahmouni, Kamal; Kerns, Robert J; Sivitz, William I

2014-12-01

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. U.S. Government work not protected by U.S. copyright.

Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175.

PubMed

Menalled, Liliana B; Kudwa, Andrea E; Miller, Sam; Fitzpatrick, Jon; Watson-Johnson, Judy; Keating, Nicole; Ruiz, Melinda; Mushlin, Richard; Alosio, William; McConnell, Kristi; Connor, David; Murphy, Carol; Oakeshott, Steve; Kwan, Mei; Beltran, Jose; Ghavami, Afshin; Brunner, Dani; Park, Larry C; Ramboz, Sylvie; Howland, David

2012-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric manifestations. Since the mutation responsible for the disease was identified as an unstable expansion of CAG repeats in the gene encoding the huntingtin protein in 1993, numerous mouse models of HD have been generated to study disease pathogenesis and evaluate potential therapeutic approaches. Of these, knock-in models best mimic the human condition from a genetic perspective since they express the mutation in the appropriate genetic and protein context. Behaviorally, however, while some abnormal phenotypes have been detected in knock-in mouse models, a model with an earlier and more robust phenotype than the existing models is required. We describe here for the first time a new mouse line, the zQ175 knock-in mouse, derived from a spontaneous expansion of the CAG copy number in our CAG 140 knock-in colony [1]. Given the inverse relationship typically observed between age of HD onset and length of CAG repeat, since this new mouse line carries a significantly higher CAG repeat length it was expected to be more significantly impaired than the parent line. Using a battery of behavioral tests we evaluated both heterozygous and homozygous zQ175 mice. Homozygous mice showed motor and grip strength abnormalities with an early onset (8 and 4 weeks of age, respectively), which were followed by deficits in rotarod and climbing activity at 30 weeks of age and by cognitive deficits at around 1 year of age. Of particular interest for translational work, we also found clear behavioral deficits in heterozygous mice from around 4.5 months of age, especially in the dark phase of the diurnal cycle. Decreased body weight was observed in both heterozygotes and homozygotes, along with significantly reduced survival in the homozygotes. In addition, we detected an early and significant decrease of striatal gene markers from 12 weeks of age. These data suggest

Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice.

PubMed

Gioscia-Ryan, Rachel A; Battson, Micah L; Cuevas, Lauren M; Eng, Jason S; Murphy, Michael P; Seals, Douglas R

2018-05-01

Aortic stiffening is a major independent risk factor for cardiovascular diseases, cognitive dysfunction, and other chronic disorders of aging. Mitochondria-derived reactive oxygen species are a key source of arterial oxidative stress, which may contribute to arterial stiffening by promoting adverse structural changes-including collagen overabundance and elastin degradation-and enhancing inflammation, but the potential for mitochondria-targeted therapeutic strategies to ameliorate aortic stiffening with primary aging is unknown. We assessed aortic stiffness [pulse-wave velocity (aPWV)], ex vivo aortic intrinsic mechanical properties [elastic modulus (EM) of collagen and elastin regions], and aortic protein expression in young (~6 mo) and old (~27 mo) male C57BL/6 mice consuming normal drinking water (YC and OC) or water containing mitochondria-targeted antioxidant MitoQ (250 µM; YMQ and OMQ) for 4 wk. Both baseline and postintervention aPWV values were higher in OC vs. YC (post: 482 ± 21 vs. 420 ± 5 cm/s, P < 0.05). MitoQ had no effect in young mice but decreased aPWV in old mice (OMQ, 426 ± 20, P < 0.05 vs. OC). MitoQ did not affect age-associated increases in aortic collagen-region EM, collagen expression, or proinflammatory cytokine expression, but partially attenuated age-associated decreases in elastin region EM and elastin expression. Our results demonstrate that MitoQ reverses in vivo aortic stiffness in old mice and suggest that mitochondria-targeted antioxidants may represent a novel, promising therapeutic strategy for decreasing aortic stiffness with primary aging and, possibly, age-related clinical disorders in humans. The destiffening effects of MitoQ treatment may be at least partially mediated by attenuation/reversal of age-related aortic elastin degradation. NEW & NOTEWORTHY We show that 4 wk of treatment with the mitochondria-specific antioxidant MitoQ in mice completely reverses the age-associated elevation in aortic stiffness

Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice

PubMed Central

Gioscia-Ryan, Rachel A.; Battson, Micah L.; Cuevas, Lauren M.; Eng, Jason S.; Murphy, Michael P.

2018-01-01

Aortic stiffening is a major independent risk factor for cardiovascular diseases, cognitive dysfunction, and other chronic disorders of aging. Mitochondria-derived reactive oxygen species are a key source of arterial oxidative stress, which may contribute to arterial stiffening by promoting adverse structural changes—including collagen overabundance and elastin degradation—and enhancing inflammation, but the potential for mitochondria-targeted therapeutic strategies to ameliorate aortic stiffening with primary aging is unknown. We assessed aortic stiffness [pulse-wave velocity (aPWV)], ex vivo aortic intrinsic mechanical properties [elastic modulus (EM) of collagen and elastin regions], and aortic protein expression in young (~6 mo) and old (~27 mo) male C57BL/6 mice consuming normal drinking water (YC and OC) or water containing mitochondria-targeted antioxidant MitoQ (250 µM; YMQ and OMQ) for 4 wk. Both baseline and postintervention aPWV values were higher in OC vs. YC (post: 482 ± 21 vs. 420 ± 5 cm/s, P < 0.05). MitoQ had no effect in young mice but decreased aPWV in old mice (OMQ, 426 ± 20, P < 0.05 vs. OC). MitoQ did not affect age-associated increases in aortic collagen-region EM, collagen expression, or proinflammatory cytokine expression, but partially attenuated age-associated decreases in elastin region EM and elastin expression. Our results demonstrate that MitoQ reverses in vivo aortic stiffness in old mice and suggest that mitochondria-targeted antioxidants may represent a novel, promising therapeutic strategy for decreasing aortic stiffness with primary aging and, possibly, age-related clinical disorders in humans. The destiffening effects of MitoQ treatment may be at least partially mediated by attenuation/reversal of age-related aortic elastin degradation. NEW & NOTEWORTHY We show that 4 wk of treatment with the mitochondria-specific antioxidant MitoQ in mice completely reverses the age-associated elevation in aortic stiffness

A Circumstellar Disk around HD 169142 in the Mid-Infrared (N-Band)

NASA Astrophysics Data System (ADS)

Okamoto, Yoshiko Kataza; Kataza, Hirokazu; Honda, M.; Yamashita, T.; Fujiyoshi, T.; Miyata, T.; Sako, S.; Fujiwara, H.; Sakon, I.; Fukagawa, M.; Momose, M.; Onaka, T.

2017-07-01

The Herbig Ae star HD 169142 is one of the objects that show complex structure, such as multiple (innermost, middle, and outer) disks, gaps, and unresolved sources. We made N-band (8-13 μm) observations of HD 169142 with the Cooled Mid-Infrared Camera and Spectrometer on the 8.2 m Subaru Telescope. The images are spatially resolved out to an ˜1″ radius in all the observed bands. We made a simple disk model composed of an unresolved central source (representing the innermost disk/halo) and the ring at a radius r ˜ 25 au (corresponding to the inner wall or edge of a middle disk at ˜25-40 au). The radial intensity profile within the central region (≲0.″3 or ≲ 40 au) is well reproduced by the model. Furthermore, we subtracted the model image from the observed one to search for additional structures. In the model-subtracted images, we found an unresolved west source separated by 17.0 ± 2.9 au in the direction of position angle 260° ± 5° from the original emission peak, which is supposed to correspond to the position of the central star, and a bright east arc located at r ˜ 60 au. The west source is different from the L‧-band unresolved source recently found in coronagraphic observations. It could be a structure related to planet formation in the disk, such as a circumplanetary disk or clumpy disk structure. The east arc corresponds to the inner wall or edge of the outer disk. Based on data collected at the Subaru Telescope, which is operated by the National Astronomical Observatory of Japan.

Effect of a mitochondrial-targeted coenzyme Q analog on pancreatic β-cell function and energetics in high fat fed obese mice.

PubMed

Imai, Yumi; Fink, Brian D; Promes, Joseph A; Kulkarni, Chaitanya A; Kerns, Robert J; Sivitz, William I

2018-06-01

We recently reported that mitoquinone (mitoQ, 500 μmol/L) added to drinking water of C57BL/6J mice attenuated weight gain and reduced oxidative stress when administered to high-fat (HF) fed mice. Here, we examined the effects of mitoQ administered to HF fed mice on pancreatic islet morphology, dynamics of insulin secretion, and islet mitochondrial metabolism. C57BL/6J mice were fed HF for 130 days while we administered vehicle (cyclodextrin [CD]) or mitoQ added to the drinking water at up to 500 μmol/L. MitoQ-treated mice vs vehicle gained significantly less weight, expended significantly more energy as determined by indirect calorimetry, and trended to consume less (nonsignificant) food. As we and others reported before, mitoQ-treated mice drank less water but showed no difference in percent body fluid by nuclear magnetic resonance. Circulating insulin and glucose-stimulated insulin secretion by isolated islets were decreased in mitoQ-treated mice while insulin sensitivity (plasma insulin x glucose) was greater. Islet respiration as basal oxygen consumption (OCR), OCR directed at ATP synthesis, and maximal uncoupled OCR were also reduced in mitoQ-treated mice. Quantitative morphologic studies revealed that islet size was reduced in the mitoQ-treated mice while visual inspection of histochemically stained sections suggested that mitoQ reduced islet lipid peroxides. MitoQ markedly improved liver function as determined by plasma alanine aminotransferase. In summary, mitoQ treatment reduced the demand for insulin and reduced islet size, likely consequent to the action of mitoQ to mitigate weight gain and improve liver function. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice.

PubMed

Kino, Yoshihiro; Washizu, Chika; Kurosawa, Masaru; Yamada, Mizuki; Doi, Hiroshi; Takumi, Toru; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Hicks, Geoffrey G; Hattori, Nobutaka; Shimogori, Tomomi; Nukina, Nobuyuki

2016-10-14

FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington's disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS. Co-aggregation between FUS/TLS and mutant huntingtin resulted in the depletion of free FUS/TLS protein in HD mice that was detected as a monomer in SDS-PAGE analysis. Recently, we found that FUS/TLS paralogs, TAF15 and EWS, were up-regulated in homozygous FUS/TLS knockout mice. These two proteins were up-regulated in both HD and FUS/TLS heterozygote mice, and were further elevated in HD-TLS +/- double mutant mice, consistent with the functional impairment of FUS/TLS. These results suggest that FUS/TLS sequestration by co-aggregation is a rate-limiting factor of disease phenotypes of HD and that inclusions may have an adverse aspect, rather than being simply benign or protective. In addition, our results highlight inclusions as repositories of potential modifiers of neurodegeneration.

Mitochondria-Targeted Antioxidant SkQ1 Improves Dermal Wound Healing in Genetically Diabetic Mice

PubMed Central

Demyanenko, Ilya A.; Zakharova, Vlada V.; Ilyinskaya, Olga P.; Vasilieva, Tamara V.; Fedorov, Artem V.; Skulachev, Vladimir P.

2017-01-01

Oxidative stress is widely recognized as an important factor in the delayed wound healing in diabetes. However, the role of mitochondrial reactive oxygen species in this process is unknown. It was assumed that mitochondrial reactive oxygen species are involved in many wound-healing processes in both diabetic humans and animals. We have applied the mitochondria-targeted antioxidant 10-(6′-plastoquinonyl)decyltriphenylphosphonium (SkQ1) to explore the role of mitochondrial reactive oxygen species in the wound healing of genetically diabetic mice. Healing of full-thickness excisional dermal wounds in diabetic C57BL/KsJ-db−/db− mice was significantly enhanced after long-term (12 weeks) administration of SkQ1. SkQ1 accelerated wound closure and stimulated epithelization, granulation tissue formation, and vascularization. On the 7th day after wounding, SkQ1 treatment increased the number of α-smooth muscle actin-positive cells (myofibroblasts), reduced the number of neutrophils, and increased macrophage infiltration. SkQ1 lowered lipid peroxidation level but did not change the level of the circulatory IL-6 and TNF. SkQ1 pretreatment also stimulated cell migration in a scratch-wound assay in vitro under hyperglycemic condition. Thus, a mitochondria-targeted antioxidant normalized both inflammatory and regenerative phases of wound healing in diabetic mice. Our results pointed to nearly all the major steps of wound healing as the target of excessive mitochondrial reactive oxygen species production in type II diabetes. PMID:28761623

Mitochondria-Targeted Antioxidant SkQ1 Improves Dermal Wound Healing in Genetically Diabetic Mice.

PubMed

Demyanenko, Ilya A; Zakharova, Vlada V; Ilyinskaya, Olga P; Vasilieva, Tamara V; Fedorov, Artem V; Manskikh, Vasily N; Zinovkin, Roman A; Pletjushkina, Olga Yu; Chernyak, Boris V; Skulachev, Vladimir P; Popova, Ekaterina N

2017-01-01

Oxidative stress is widely recognized as an important factor in the delayed wound healing in diabetes. However, the role of mitochondrial reactive oxygen species in this process is unknown. It was assumed that mitochondrial reactive oxygen species are involved in many wound-healing processes in both diabetic humans and animals. We have applied the mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) to explore the role of mitochondrial reactive oxygen species in the wound healing of genetically diabetic mice. Healing of full-thickness excisional dermal wounds in diabetic C57BL/KsJ-db - /db - mice was significantly enhanced after long-term (12 weeks) administration of SkQ1. SkQ1 accelerated wound closure and stimulated epithelization, granulation tissue formation, and vascularization. On the 7th day after wounding, SkQ1 treatment increased the number of α -smooth muscle actin-positive cells (myofibroblasts), reduced the number of neutrophils, and increased macrophage infiltration. SkQ1 lowered lipid peroxidation level but did not change the level of the circulatory IL-6 and TNF. SkQ1 pretreatment also stimulated cell migration in a scratch-wound assay in vitro under hyperglycemic condition. Thus, a mitochondria-targeted antioxidant normalized both inflammatory and regenerative phases of wound healing in diabetic mice. Our results pointed to nearly all the major steps of wound healing as the target of excessive mitochondrial reactive oxygen species production in type II diabetes.

Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice.

PubMed

Demyanenko, Ilya A; Popova, Ekaterina N; Zakharova, Vlada V; Ilyinskaya, Olga P; Vasilieva, Tamara V; Romashchenko, Valeria P; Fedorov, Artem V; Manskikh, Vasily N; Skulachev, Maxim V; Zinovkin, Roman A; Pletjushkina, Olga Yu; Skulachev, Vladimir P; Chernyak, Boris V

2015-07-01

The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlierin vitro. The Transforming Growth Factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds.

Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice

PubMed Central

Zakharova, Vlada V.; Ilyinskaya, Olga P.; Vasilieva, Tamara V.; Romashchenko, Valeria P.; Fedorov, Artem V.; Manskikh, Vasily N.; Skulachev, Maxim V.; Zinovkin, Roman A.; Pletjushkina, Olga Yu.; Skulachev, Vladimir P.; Chernyak, Boris V.

2015-01-01

The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlier in vitro. The Transforming Growth Factor beta (TGFβ)produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds. PMID:26187706

HdhQ111 Mice Exhibit Tissue Specific Metabolite Profiles that Include Striatal Lipid Accumulation

PubMed Central

Carroll, Jeffrey B.; Deik, Amy; Fossale, Elisa; Weston, Rory M.; Guide, Jolene R.; Arjomand, Jamshid; Kwak, Seung; Clish, Clary B.; MacDonald, Marcy E.

2015-01-01

The HTT CAG expansion mutation causes Huntington’s Disease and is associated with a wide range of cellular consequences, including altered metabolism. The mutant allele is expressed widely, in all tissues, but the striatum and cortex are especially vulnerable to its effects. To more fully understand this tissue-specificity, early in the disease process, we asked whether the metabolic impact of the mutant CAG expanded allele in heterozygous B6.HdhQ111/+ mice would be common across tissues, or whether tissues would have tissue-specific responses and whether such changes may be affected by diet. Specifically, we cross-sectionally examined steady state metabolite concentrations from a range of tissues (plasma, brown adipose tissue, cerebellum, striatum, liver, white adipose tissue), using an established liquid chromatography-mass spectrometry pipeline, from cohorts of 8 month old mutant and wild-type littermate mice that were fed one of two different high-fat diets. The differential response to diet highlighted a proportion of metabolites in all tissues, ranging from 3% (7/219) in the striatum to 12% (25/212) in white adipose tissue. By contrast, the mutant CAG-expanded allele primarily affected brain metabolites, with 14% (30/219) of metabolites significantly altered, compared to wild-type, in striatum and 11% (25/224) in the cerebellum. In general, diet and the CAG-expanded allele both elicited metabolite changes that were predominantly tissue-specific and non-overlapping, with evidence for mutation-by-diet interaction in peripheral tissues most affected by diet. Machine-learning approaches highlighted the accumulation of diverse lipid species as the most genotype-predictive metabolite changes in the striatum. Validation experiments in cell culture demonstrated that lipid accumulation was also a defining feature of mutant HdhQ111 striatal progenitor cells. Thus, metabolite-level responses to the CAG expansion mutation in vivo were tissue specific and most evident

Rotationally resolved photoelectron spectroscopy of n-H/sub 2/, p-H/sub 2/, HD, and D/sub 2/

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pollard, J.E.; Trevor, D.J.; Reutt, J.E.

1982-07-01

The 584 A photoelectron spectra of n-H/sub 2/, p-H/sub 2/, HD, and D/sub 2/ were recorded at a resolution of 11 meV FWHM using a supersonic molecular beam source. Spectra were taken at several stagnation temperatures and pressures in order to vary the rotational population distribution in the beam with a corresponding variation in the relative intensities of the rotational transitions. Many of the Q-branch components were resolved for the first time. ..delta..G(v+1/2) and B/sub v/ values were measured for all observed vibrational states of H/sup +//sub 2/, HD/sup +/, and D/sup +//sub 2/ and were used to determined themore » ionic vibrational and rotational constants: ..omega../sub e/, ..omega../sub e/x/sub e/, ..omega../sub e/y/sub e/, ..omega../sub e/z/sub e/, B/sub e/, and ..cap alpha../sub e/. The results represent a substantial improvement over previous experimental determinations and were found to be consistent with the available theoretical rotation-vibration energy levels. The measurement of the intensity distribution of photoelectrons as a function of vibrational states yielded photoionization cross sections which were in good agreement with the theoretical values calculated by O'Niel and Reinhardt.« less

Long-Term Follow-Up of Contemporary Treatment in Early-Stage Hodgkin Lymphoma: Updated Analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 Trials.

PubMed

Sasse, Stephanie; Bröckelmann, Paul J; Goergen, Helen; Plütschow, Annette; Müller, Horst; Kreissl, Stefanie; Buerkle, Carolin; Borchmann, Sven; Fuchs, Michael; Borchmann, Peter; Diehl, Volker; Engert, Andreas

2017-06-20

Purpose Combined-modality treatment is widely considered the standard of care in early-stage Hodgkin lymphoma (HL), and treatment intensity has been reduced over the last years. Long-term follow-up is important to judge both efficacy and safety of the different therapies used. Patients and Methods We analyzed updated follow-up data on 4,276 patients treated within the German Hodgkin Study Group trials HD7 and HD10 for early-stage favorable HL and HD8 and HD11 for early-stage unfavorable HL between 1993 and 2003. Results In HD7 (N = 627; median follow-up, 120 months), combined-modality treatment was superior to extended-field radiotherapy (RT), with 15-year progression-free survival (PFS) of 73% versus 52% (hazard ratio [HR], 0.5; 95% CI, 0.3 to 0.6; P < .001), without differences in overall survival (OS). In HD10 (N = 1,190; median follow-up, 98 months), noninferiority of two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) plus 20 Gy involved-field (IF)-RT to more intensive four cycles of ABVD plus 30 Gy IF-RT was confirmed with 10-year PFS of 87% each (HR, 1.0; 95%, 0.6 to 1.5) and OS of 94% each (HR, 0.9; 95% CI, 0.5 to 1.6), respectively. In both trials, no differences in second neoplasias were observed. In HD8 (N = 1,064; median follow-up, 153 months), noninferiority of involved-field RT to extended-field RT regarding PFS was confirmed (HR, 1.0; 95% CI, 0.8 to 1.2). In HD11 (N = 1,395; median follow-up, 106 months), superiority of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline over ABVD was not observed. After BEACOPP baseline , 20 Gy IF-RT was noninferior to 30 Gy (10-year PFS, 84% v 84%; HR, 1.0; 95% CI, 0.7 to 1.5). In contrast, PFS was inferior in ABVD-treated patients receiving 20 Gy instead of 30 Gy IF-RT (10-year PFS, 76% v 84%; HR, 1.5; 95% CI, 1.0 to 2.1). No differences in OS or second neoplasias were observed in in both trials. Conclusion Long-term follow-up data of the

Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice.

PubMed

Gioscia-Ryan, Rachel A; LaRocca, Thomas J; Sindler, Amy L; Zigler, Melanie C; Murphy, Michael P; Seals, Douglas R

2014-06-15

Age-related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age-related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria-targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was impaired by ∼30% in old (∼27 months) compared with young (∼8 months) mice as a result of reduced NO bioavailability (P < 0.05). Acute (ex vivo) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on endothelium-independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD). Our results suggest that mitochondria-derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria-targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age-related CVD. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological

Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice

PubMed Central

Gioscia-Ryan, Rachel A; LaRocca, Thomas J; Sindler, Amy L; Zigler, Melanie C; Murphy, Michael P; Seals, Douglas R

2014-01-01

Age-related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age-related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria-targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was impaired by ∼30% in old (∼27 months) compared with young (∼8 months) mice as a result of reduced NO bioavailability (P < 0.05). Acute (ex vivo) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on endothelium-independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD). Our results suggest that mitochondria-derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria-targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age-related CVD. PMID:24665093

Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice.

PubMed

Quinzii, Catarina M; Garone, Caterina; Emmanuele, Valentina; Tadesse, Saba; Krishna, Sindu; Dorado, Beatriz; Hirano, Michio

2013-02-01

Primary human CoQ(10) deficiencies are clinically heterogeneous diseases caused by mutations in PDSS2 and other genes required for CoQ(10) biosynthesis. Our in vitro studies of PDSS2 mutant fibroblasts, with <20% CoQ(10) of control cells, revealed reduced activity of CoQ(10)-dependent complex II+III and ATP synthesis, without amplification of reactive oxygen species (ROS), markers of oxidative damage, or antioxidant defenses. In contrast, COQ2 and ADCK3 mutant fibroblasts, with 30-50% CoQ(10) of controls, showed milder bioenergetic defects but significantly increased ROS and oxidation of lipids and proteins. We hypothesized that absence of oxidative stress markers and cell death in PDSS2 mutant fibroblasts were due to the extreme severity of CoQ(10) deficiency. Here, we have investigated in vivo effects of Pdss2 deficiency in affected and unaffected organs of CBA/Pdss2(kd/kd) mice at presymptomatic, phenotypic-onset, and end-stages of the disease. Although Pdss2 mutant mice manifest widespread CoQ(9) deficiency and mitochondrial respiratory chain abnormalities, only affected organs show increased ROS production, oxidative stress, mitochondrial DNA depletion, and reduced citrate synthase activity, an index of mitochondrial mass. Our data indicate that kidney-specific loss of mitochondria triggered by oxidative stress may be the cause of renal failure in Pdss2(kd/kd) mice.

Prolonged incubation time in sheep with prion protein containing lysine at position 171

USDA-ARS?s Scientific Manuscript database

Sheep scrapie susceptibility or resistance is a function of genotype with polymorphisms at codon 171 in the sheep prion gene playing a major role. Glutamine (Q) at 171 contributes to scrapie susceptibility while arginine (R) is associated with resistance. In some breeds, lysine (K) occurs at codon 1...

Progressive Cl- channel defects reveal disrupted skeletal muscle maturation in R6/2 Huntington's mice.

PubMed

Miranda, Daniel R; Wong, Monica; Romer, Shannon H; McKee, Cynthia; Garza-Vasquez, Gabriela; Medina, Alyssa C; Bahn, Volker; Steele, Andrew D; Talmadge, Robert J; Voss, Andrew A

2017-01-01

Huntington's disease (HD) patients suffer from progressive and debilitating motor dysfunction. Previously, we discovered reduced skeletal muscle chloride channel (ClC-1) currents, inwardly rectifying potassium (Kir) channel currents, and membrane capacitance in R6/2 transgenic HD mice. The ClC-1 loss-of-function correlated with increased aberrant mRNA processing and decreased levels of full-length ClC-1 mRNA (Clcn1 gene). Physiologically, the resulting muscle hyperexcitability may help explain involuntary contractions of HD. In this study, the onset and progression of these defects are investigated in R6/2 mice, ranging from 3 wk old (presymptomatic) to 9-13 wk old (late-stage disease), and compared with age-matched wild-type (WT) siblings. The R6/2 ClC-1 current density and level of aberrantly spliced Clcn1 mRNA remain constant with age. In contrast, the ClC-1 current density increases, and the level of aberrantly spliced Clcn1 mRNA decreases with age in WT mice. The R6/2 ClC-1 properties diverge from WT before the onset of motor symptoms, which occurs at 5 wk of age. The relative decrease in R6/2 muscle capacitance also begins in 5-wk-old mice and is independent of fiber atrophy. Kir current density is consistently lower in R6/2 compared with WT muscle. The invariable R6/2 ClC-1 properties suggest a disruption in muscle maturation, which we confirm by measuring elevated levels of neonatal myosin heavy chain (MyHC) in late-stage R6/2 skeletal muscle. Similar changes in ClC-1 and MyHC isoforms in the more slowly developing Q175 HD mice suggest an altered maturational state is relevant to adult-onset HD. Finally, we find nuclear aggregates of muscleblind-like protein 1 without predominant CAG repeat colocalization in R6/2 muscle. This is unlike myotonic dystrophy, another trinucleotide repeat disorder with similar ClC-1 defects, and suggests a novel mechanism of aberrant mRNA splicing in HD. These early and progressive skeletal muscle defects reveal much needed

Neonatal Iron Supplementation Induces Striatal Atrophy in Female YAC128 Huntington's Disease Mice.

PubMed

Berggren, Kiersten L; Lu, Zhen; Fox, Julia A; Dudenhoeffer, Megan; Agrawal, Sonal; Fox, Jonathan H

2016-01-01

Dysregulation of iron homeostasis is implicated in the pathogenesis of Huntington's disease. We have previously shown that increased iron intake in R6/2 HD neonatal mice, but not adult R6/2 HD mice potentiates disease outcomes at 12-weeks of age corresponding to advanced HD [Redox Biol. 2015;4 : 363-74]. However, whether these findings extend to other HD models is unknown. In particular, it is unclear if increased neonatal iron intake can promote neurodegeneration in mouse HD models where disease onset is delayed to mid-adult life. To determine if increased dietary iron intake in neonatal and adult life-stages potentiates HD in the slowly progressive YAC128 HD mouse model. Female neonatal mice were supplemented daily from days 10-17 with 120μg/g body weight of carbonyl iron. Adult mice were provided diets containing low (50 ppm), medium (150 ppm) and high (500 ppm) iron concentrations from 2-months of age. HD progression was determined using behavioral, brain morphometric and biochemical approaches. Neonatal-iron supplemented YAC128 HD mice had significantly lower striatal volumes and striatal neuronal cell body volumes as compared to control HD mice at 1-year of age. Neonatal-iron supplementation of HD mice had no effect on rota-rod motor endurance and brain iron or glutathione status. Adult iron intake level had no effect on HD progression. YAC128 HD mice had altered peripheral responses to iron intake compared to iron-matched wild-type controls. Female YAC128 HD mice supplemented with nutritionally-relevant levels of iron as neonates demonstrate increased striatal degeneration 1-year later.

Cryogenic Characterization of FBK RGB-HD SiPMs

DOE PAGES

Aalseth, C. E.

2017-09-26

We report on the cryogenic characterization of Red Green Blue - High Density (RGB-HD) SiPMs developed at Fondazione Bruno Kessler (FBK) as part of the DarkSide program of dark matter searches with liquid argon time projection chambers. A dedicated setup was used to measure the primary dark noise, the correlated noise, and the gain of the SiPMs at varying temperatures. A custom-made data acquisition system and analysis software were used to precisely characterize these parameters. We demonstrate that FBK RGB-HD SiPMs with low quenching resistance (RGB-HD-LRmore » $$_q$$) can be operated from 40 K to 300 K with gains in the range $10^5$ to $10^6$ and noise rates on the order of a few Hz/mm$^2$.« less

Infrared spectra of N2O-(ortho-D2)N and N2O-(HD)N clusters trapped in bulk solid parahydrogen.

PubMed

Lorenz, Britney D; Anderson, David T

2007-05-14

High-resolution infrared spectra of the clusters N2O-(ortho-D2)N and N2O-(HD)N, N=1-4, isolated in bulk solid parahydrogen at liquid helium temperatures are studied in the 2225 cm-1 region of the nu3 antisymmetric stretch of N2O. The clusters form during vapor deposition of separate gas streams of a precooled hydrogen mixture (ortho-D2para-H2 or HDpara-H2) and N2O onto a BaF2 optical substrate held at approximately 2.5 K in a sample-in-vacuum liquid helium cryostat. The cluster spectra reveal the N2O nu3 vibrational frequency shifts to higher energy as a function of N, and the shifts are larger for ortho-D2 compared to HD. These vibrational shifts result from the reduced translational zero-point energy for N2O solvated by the heavier hydrogen isotopomers. These spectra allow the N=0 peak at 2221.634 cm-1, corresponding to the nu3 vibrational frequency of N2O isolated in pure solid parahydrogen, to be assigned. The intensity of the N=0 absorption feature displays a strong temperature dependence, suggesting that significant structural changes occur in the parahydrogen solvation environment of N2O in the 1.8-4.9 K temperature range studied.

Q-switched all-fiber laser with short pulse duration based on tungsten diselenide

NASA Astrophysics Data System (ADS)

Li, Wenyi; OuYang, Yuyi; Ma, Guoli; Liu, Mengli; Liu, Wenjun

2018-05-01

Fiber lasers are widely used in industrial processing, sensing, medical and communications applications due to their simple structure, good stability and low cost. With the rapid development of fiber lasers and the sustained improvement of industrial laser quality requirements, researchers in ultrafast optics focus on how to get laser pulses with high output power and narrow pulse duration. Q-switched technology is one of the most effective techniques to generate ultrashort pulses. In this paper, a tungsten diselenide saturable absorber with 16.82% modulation depth is prepared by chemical vapor deposition. Experimental results show that when the pump power changes from 115.7 mW to 630 mW, the all-fiber laser can achieve a stable Q-switched pulse output. The repetition rate of the output pulse varies from 80.32 kHz to 204.2 kHz, the pulse duration is 581 ns, the maximum output power is 17.1 mW and the maximum pulse energy is 83.7 nJ. Results in this paper show that tungsten diselenide can be applied to ultrafast optics, which is a kind of saturable absorption material with excellent properties.

Properties of r-process nuclei near N=82 shell closure

NASA Astrophysics Data System (ADS)

Farhan, A. R.; Sharma, M. M.

2004-10-01

We have studied properties of nuclei in r-process region near N=82 shell closure with the RMF calculations in a deformed basis using the force NL-SV1 that includes vector self-coupling of w meson. It is shown that nuclei above N=82 in several isotopic chains in the r-process region exhibit an onset of deformation beyond the drip line. Consequently, induced by the deformation these nuclei show an extra stability above the shell closure. This stability of nuclei is expected to contribute to the r-process nucleosynthesis of nuclei below the abundance peak at A ˜130. A comparison with the mass formulae shows that our microscopic calculations with NL-SV1 show a decrease of shell strength with increase in isospin. This is in contrast to the strong shell effects shown by FRDM and ETF-SI in going to the drip line. The stiffness of the shell structure with FRDM and ETF-SI is known to lead to a shortfall in the r-process abundances. This shortcoming of the above mass formulae has inspired an ad-hoc inclusion of shell quenching in the mass formula ETF-SI(Q) with a view to better reproduce the r-process abundances. In comparison, our model shows a decrease of the shell strength in going from the r-process path to the drip line. Therefore, this represents a natural behaviour as required by r-process abundances. It may, however, be confirmed in network chain calculations using inputs from our microscopic model.

Progressive Cl− channel defects reveal disrupted skeletal muscle maturation in R6/2 Huntington’s mice

PubMed Central

Miranda, Daniel R.; Wong, Monica; Romer, Shannon H.; McKee, Cynthia; Garza-Vasquez, Gabriela; Medina, Alyssa C.; Bahn, Volker; Steele, Andrew D.; Talmadge, Robert J.

2017-01-01

Huntington’s disease (HD) patients suffer from progressive and debilitating motor dysfunction. Previously, we discovered reduced skeletal muscle chloride channel (ClC-1) currents, inwardly rectifying potassium (Kir) channel currents, and membrane capacitance in R6/2 transgenic HD mice. The ClC-1 loss-of-function correlated with increased aberrant mRNA processing and decreased levels of full-length ClC-1 mRNA (Clcn1 gene). Physiologically, the resulting muscle hyperexcitability may help explain involuntary contractions of HD. In this study, the onset and progression of these defects are investigated in R6/2 mice, ranging from 3 wk old (presymptomatic) to 9–13 wk old (late-stage disease), and compared with age-matched wild-type (WT) siblings. The R6/2 ClC-1 current density and level of aberrantly spliced Clcn1 mRNA remain constant with age. In contrast, the ClC-1 current density increases, and the level of aberrantly spliced Clcn1 mRNA decreases with age in WT mice. The R6/2 ClC-1 properties diverge from WT before the onset of motor symptoms, which occurs at 5 wk of age. The relative decrease in R6/2 muscle capacitance also begins in 5-wk-old mice and is independent of fiber atrophy. Kir current density is consistently lower in R6/2 compared with WT muscle. The invariable R6/2 ClC-1 properties suggest a disruption in muscle maturation, which we confirm by measuring elevated levels of neonatal myosin heavy chain (MyHC) in late-stage R6/2 skeletal muscle. Similar changes in ClC-1 and MyHC isoforms in the more slowly developing Q175 HD mice suggest an altered maturational state is relevant to adult-onset HD. Finally, we find nuclear aggregates of muscleblind-like protein 1 without predominant CAG repeat colocalization in R6/2 muscle. This is unlike myotonic dystrophy, another trinucleotide repeat disorder with similar ClC-1 defects, and suggests a novel mechanism of aberrant mRNA splicing in HD. These early and progressive skeletal muscle defects reveal much needed

Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice.

PubMed

Tong, Xiaoping; Ao, Yan; Faas, Guido C; Nwaobi, Sinifunanya E; Xu, Ji; Haustein, Martin D; Anderson, Mark A; Mody, Istvan; Olsen, Michelle L; Sofroniew, Michael V; Khakh, Baljit S

2014-05-01

Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.

Abundance analysis of the supergiant stars HD 80057 and HD 80404 based on their UVES Spectra

NASA Astrophysics Data System (ADS)

Tanrıverdi, T.; Baştürk, Ö.

2016-08-01

This study presents elemental abundances of the early A-type supergiant HD 80057 and the late A-type supergiant HD 80404. High resolution and high signal-to-noise ratio spectra published by the UVES Paranal Observatory Project (Bagnulo et al., 2003) were analyzed to compute their elemental abundances using ATLAS9 (Kurucz, 1993; 2005; Sbordone et al., 2004). In our analysis we assumed local thermodynamic equilibrium. The atmospheric parameters of HD 80057 used in this study are from Firnstein and Przybilla (2012), and that of HD 80404 are derived from spectral energy distribution, ionization equilibria of Cr I/II and Fe I/II, the fits to the wings of Balmer and Paschen lines as Teff = 7700 ± 150 K and log g = 1.60 ± 0.15 (in cgs). The microturbulent velocities of HD 80057 and HD 80404 have been determined as 4.3 ± 0.1 and 2.2 ± 0.0 km s^-1, respectively. The rotational velocities are 15 ± 1 and 7 ± 2 km s^-1 and their macroturbulence velocities are 24 ± 2 and 2 ± 1 km s^1. We have given the abundances of 25 ions of 19 elements for HD 80057 and 36 ions of 25 elements for HD 80404. The abundances are close to solar values, except for some elements (Na, Sc, Ti, V, Ba, and Sr). We have found the metallicities [M/H] for HD 80057 and HD 80404 as -0.16 ± 0.24 and -0.04 ± 0.16 dex, respectively. The evolutionary status of these stars are discussed and their nitrogen-to-carbon (N/C) and nitrogen-to-oxygen (N/O) ratios show that they are in their blue supergiant phase before the red supergiant region.

Spectrophotometry of Peculiar B-Stars and A-Stars - Part Nine - HD5797 HD12288 9-TAURI HD81009 HD111133 33-LIBRAE and HD216533

NASA Astrophysics Data System (ADS)

Adelman, S. J.

1981-02-01

Optical region spectrophotometry of λλ3300-7100 is presented for seven sharp-lined peculiar A stars: HD 5797, HD 12288, 9 Tauri, HD 81009, HD 111133, 33 Librae, and HD 216533. Many of proposed periods in the literature are questioned. Some of the deviations from the predictions of normal stellar atmospheres suggest that such continua are only remotely related to those of peculiar A stars.

Deuterium-reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the Q140 knock in mouse model of Huntington's disease.

PubMed

Hatami, Asa; Zhu, Chunni; Relaño-Gines, Aroa; Elias, Chris; Galstyan, Arpine; Jun, Michael; Milne, Ginger; Cantor, Charles R; Chesselet, Marie-Francoise; Shchepinov, Mikhail S

2018-06-22

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which has no effective treatment and is characterized by psychiatric disorders, motor alterations, and dementia, with the cognitive deficits representing a devastating aspect of the disorder. Oxidative stress and elevated levels of lipid peroxidation (LPO) products are found in mouse models and patients with HD, suggesting that strategies to reduce LPO may be beneficial in HD. In contrast to traditional antioxidants, substituting hydrogen with deuterium at bis-allylic sites in polyunsaturated fatty acids (D-PUFA) decreases the rate-limiting initiation step of PUFA autoxidation, a strategy that has shown benefits in other neurodegenerative diseases. Here we investigated the effect of D-PUFA treatment in a knock-in mouse model of HD (Q140) which presents motor deficits and neuropathology from a few months of age, and progressive cognitive decline. Q140 knock-in mice were fed a diet containing either D- or H-PUFAs for 5 months starting at one month of age. D-PUFA treatment significantly decreased F 2 -isoprostanes in the striatum by approximately 80% as compared to H-PUFA treatment and improved performance in novel object recognition tests, without significantly changing motor deficits or huntingtin aggregation. Therefore, D-PUFA administration represents a promising new strategy to broadly reduce rates of LPO, and may be useful in improving a subset of the core deficits in HD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Project VeSElkA: abundance analysis of chemical species in HD 41076 and HD 148330

NASA Astrophysics Data System (ADS)

Khalack, V.; Gallant, G.; Thibeault, C.

2017-10-01

A new semi-automatic approach is employed to carry out the abundance analysis of high-resolution spectra of HD 41076 and HD 148330 obtained recently with the spectropolarimetre Echelle SpectroPolarimetric Device for Observations of Stars at the Canada-France-Hawaii Telescope. This approach allows to prepare in a semi-automatic mode the input data for the modified zeeman2 code and to analyse several hundreds of line profiles in sequence during a single run. It also provides more information on abundance distribution for each chemical element at the deeper atmospheric layers. Our analysis of the Balmer profiles observed in the spectra of HD 41076 and HD 148330 has resulted in the estimates of their effective temperature, gravity, metallicity and radial velocity. The respective models of stellar atmosphere have been calculated with the code phoenix and used to carry out abundance analysis employing the modified zeeman2 code. The analysis shows a deficit of the C, N, F, Mg, Ca, Ti, V, Cu, Y, Mo, Sm and Gd, and overabundance of Cr, Mn, Fe, Co, Ni, Sr, Zr, Ba, Ce, Nd and Dy in the stellar atmosphere of HD 41076. In the atmosphere of HD 148330, the C, N and Mo appear to be underabundant, while the Ne, Na, Al, Si, P, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Zn, Sr, Y, Zr, Ba, Ce, Pr, Nd, Sm, Eu, Gd and Dy are overabundant. We also have found signatures of vertical abundance stratification of Fe, Ti, Cr and Mn in HD 41076, and of Fe, Ti, V, Cr, Mn, Y, Zr, Ce, Nd, Sm and Gd in HD 148330.

Neonatal Iron Supplementation Induces Striatal Atrophy in Female YAC128 Huntington’s Disease Mice

PubMed Central

Berggren, Kiersten L.; Lu, Zhen; Fox, Julia A.; Dudenhoeffer, Megan; Agrawal, Sonal; Fox, Jonathan H.

2016-01-01

Background: Dysregulation of iron homeostasis is implicated in the pathogenesis of Huntington’s disease. We have previously shown that increased iron intake in R6/2 HD neonatal mice, but not adult R6/2 HD mice potentiates disease outcomes at 12-weeks of age corresponding to advanced HD [Redox Biol. 2015;4 : 363–74]. However, whether these findings extend to other HD models is unknown. In particular, it is unclear if increased neonatal iron intake can promote neurodegeneration in mouse HD models where disease onset is delayed to mid-adult life. Objective: To determine if increased dietary iron intake in neonatal and adult life-stages potentiates HD in the slowly progressive YAC128 HD mouse model. Methods: Female neonatal mice were supplemented daily from days 10–17 with 120μg/g body weight of carbonyl iron. Adult mice were provided diets containing low (50 ppm), medium (150 ppm) and high (500 ppm) iron concentrations from 2-months of age. HD progression was determined using behavioral, brain morphometric and biochemical approaches. Results: Neonatal-iron supplemented YAC128 HD mice had significantly lower striatal volumes and striatal neuronal cell body volumes as compared to control HD mice at 1-year of age. Neonatal-iron supplementation of HD mice had no effect on rota-rod motor endurance and brain iron or glutathione status. Adult iron intake level had no effect on HD progression. YAC128 HD mice had altered peripheral responses to iron intake compared to iron-matched wild-type controls. Conclusions: Female YAC128 HD mice supplemented with nutritionally-relevant levels of iron as neonates demonstrate increased striatal degeneration 1-year later. PMID:27079948

Early white matter abnormalities, progressive brain pathology and motor deficits in a novel knock-in mouse model of Huntington's disease

PubMed Central

Jin, Jing; Peng, Qi; Hou, Zhipeng; Jiang, Mali; Wang, Xin; Langseth, Abraham J.; Tao, Michael; Barker, Peter B.; Mori, Susumu; Bergles, Dwight E.; Ross, Christopher A.; Detloff, Peter J.; Zhang, Jiangyang; Duan, Wenzhen

2015-01-01

White matter abnormalities have been reported in premanifest Huntington's disease (HD) subjects before overt striatal neuronal loss, but whether the white matter changes represent a necessary step towards further pathology and the underlying mechanism of these changes remains unknown. Here, we characterized a novel knock-in mouse model that expresses mouse HD gene homolog (Hdh) with extended CAG repeat- HdhQ250, which was derived from the selective breeding of HdhQ150 mice. HdhQ250 mice manifest an accelerated and robust phenotype compared with its parent line. HdhQ250 mice exhibit progressive motor deficits, reduction in striatal and cortical volume, accumulation of mutant huntingtin aggregation, decreased levels of DARPP32 and BDNF and altered striatal metabolites. The abnormalities detected in this mouse model are reminiscent of several aspects of human HD. In addition, disturbed myelination was evident in postnatal Day 14 HdhQ250 mouse brain, including reduced levels of myelin regulatory factor and myelin basic protein, and decreased numbers of myelinated axons in the corpus callosum. Thinner myelin sheaths, indicated by increased G-ratio of myelin, were also detected in the corpus callosum of adult HdhQ250 mice. Moreover, proliferation of oligodendrocyte precursor cells is altered by mutant huntingtin both in vitro and in vivo. Our data indicate that this model is suitable for understanding comprehensive pathogenesis of HD in white matter and gray matter as well as developing therapeutics for HD. PMID:25609071

A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington's disease in mice.

PubMed

Acuña, Aníbal I; Esparza, Magdalena; Kramm, Carlos; Beltrán, Felipe A; Parra, Alejandra V; Cepeda, Carlos; Toro, Carlos A; Vidal, René L; Hetz, Claudio; Concha, Ilona I; Brauchi, Sebastián; Levine, Michael S; Castro, Maite A

2013-01-01

Huntington's disease has been associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. Using an electrophysiological approach in R6/2 HD slices, we observe an abnormal ascorbic acid flux from astrocytes to neurons, which is responsible for alterations in neuronal metabolic substrate preferences. Here using striatal neurons derived from knock-in mice expressing mutant huntingtin (STHdhQ cells), we study ascorbic acid transport. When extracellular ascorbic acid concentration increases, as occurs during synaptic activity, ascorbic acid transporter 2 (SVCT2) translocates to the plasma membrane, ensuring optimal ascorbic acid uptake for neurons. In contrast, SVCT2 from cells that mimic HD symptoms (dubbed HD cells) fails to reach the plasma membrane under the same conditions. We reason that an early impairment of ascorbic acid uptake in HD neurons could lead to early metabolic failure promoting neuronal death.

The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice.

PubMed

Mercer, John R; Yu, Emma; Figg, Nichola; Cheng, Kian-Kai; Prime, Tracy A; Griffin, Julian L; Masoodi, Mojgan; Vidal-Puig, Antonio; Murphy, Michael P; Bennett, Martin R

2012-03-01

A number of recent studies suggest that mitochondrial oxidative damage may be associated with atherosclerosis and the metabolic syndrome. However, much of the evidence linking mitochondrial oxidative damage and excess reactive oxygen species (ROS) with these pathologies is circumstantial. Consequently the importance of mitochondrial ROS in the etiology of these disorders is unclear. Furthermore, the potential of decreasing mitochondrial ROS as a therapy for these indications is not known. We assessed the impact of decreasing mitochondrial oxidative damage and ROS with the mitochondria-targeted antioxidant MitoQ in models of atherosclerosis and the metabolic syndrome (fat-fed ApoE(-/-) mice and ATM(+/-)/ApoE(-/-) mice, which are also haploinsufficient for the protein kinase, ataxia telangiectasia mutated (ATM). MitoQ administered orally for 14weeks prevented the increased adiposity, hypercholesterolemia, and hypertriglyceridemia associated with the metabolic syndrome. MitoQ also corrected hyperglycemia and hepatic steatosis, induced changes in multiple metabolically relevant lipid species, and decreased DNA oxidative damage (8-oxo-G) in multiple organs. Although MitoQ did not affect overall atherosclerotic plaque area in fat-fed ATM(+/+)/ApoE(-/-) and ATM(+/-)/ApoE(-/-) mice, MitoQ reduced the macrophage content and cell proliferation within plaques and 8-oxo-G. MitoQ also significantly reduced mtDNA oxidative damage in the liver. Our data suggest that MitoQ inhibits the development of multiple features of the metabolic syndrome in these mice by affecting redox signaling pathways that depend on mitochondrial ROS such as hydrogen peroxide. These findings strengthen the growing view that elevated mitochondrial ROS contributes to the etiology of the metabolic syndrome and suggest a potential therapeutic role for mitochondria-targeted antioxidants. Copyright © 2011 Elsevier Inc. All rights reserved.

Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice

PubMed Central

Tong, Xiaoping; Ao, Yan; Faas, Guido C.; Nwaobi, Sinifunanya E.; Xu, Ji; Haustein, Martin D.; Anderson, Mark A.; Mody, Istvan; Olsen, Michelle L.; Sofroniew, Michael V.; Khakh, Baljit S.

2014-01-01

Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, which display mutant huntingtin in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models is not associated with classical astrogliosis, but is associated with decreased Kir4.1 K+ channel functional expression, leading to elevated in vivo levels of striatal extracellular K+, which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K+, recovered aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte–mediated K+ homeostasis, revealing astrocytes and Kir4.1 channels as novel therapeutic targets. PMID:24686787

A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington’s disease in mice

PubMed Central

Acuña, Aníbal I.; Esparza, Magdalena; Kramm, Carlos; Beltrán, Felipe A.; Parra, Alejandra V.; Cepeda, Carlos; Toro, Carlos A.; Vidal, René L.; Hetz, Claudio; Concha, Ilona I.; Brauchi, Sebastián; Levine, Michael S.; Castro, Maite A.

2013-01-01

Huntington’s disease has been associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. Using an electrophysiological approach in R6/2 HD slices, we observe an abnormal ascorbic acid flux from astrocytes to neurons, which is responsible for alterations in neuronal metabolic substrate preferences. Here using striatal neurons derived from knock-in mice expressing mutant huntingtin (STHdhQ cells), we study ascorbic acid transport. When extracellular ascorbic acid concentration increases, as occurs during synaptic activity, ascorbic acid transporter 2 (SVCT2) translocates to the plasma membrane, ensuring optimal ascorbic acid uptake for neurons. In contrast, SVCT2 from cells that mimic HD symptoms (dubbed HD cells) fails to reach the plasma membrane under the same conditions. We reason that an early impairment of ascorbic acid uptake in HD neurons could lead to early metabolic failure promoting neuronal death. PMID:24336051

A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington’s disease in mice

NASA Astrophysics Data System (ADS)

Acuña, Aníbal I.; Esparza, Magdalena; Kramm, Carlos; Beltrán, Felipe A.; Parra, Alejandra V.; Cepeda, Carlos; Toro, Carlos A.; Vidal, René L.; Hetz, Claudio; Concha, Ilona I.; Brauchi, Sebastián; Levine, Michael S.; Castro, Maite A.

2013-12-01

Huntington’s disease has been associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. Using an electrophysiological approach in R6/2 HD slices, we observe an abnormal ascorbic acid flux from astrocytes to neurons, which is responsible for alterations in neuronal metabolic substrate preferences. Here using striatal neurons derived from knock-in mice expressing mutant huntingtin (STHdhQ cells), we study ascorbic acid transport. When extracellular ascorbic acid concentration increases, as occurs during synaptic activity, ascorbic acid transporter 2 (SVCT2) translocates to the plasma membrane, ensuring optimal ascorbic acid uptake for neurons. In contrast, SVCT2 from cells that mimic HD symptoms (dubbed HD cells) fails to reach the plasma membrane under the same conditions. We reason that an early impairment of ascorbic acid uptake in HD neurons could lead to early metabolic failure promoting neuronal death.

Geometric phase effects in ultracold collisions of H/D with rotationally excited HD

NASA Astrophysics Data System (ADS)

Kendrick, Brian K.; Croft, James F. E.; Hazra, Jisha; Balakrishnan, N.

2017-04-01

Quantum reactive scattering calculations for the H/D + HD(v = 4 , j = 1 , 2) -> H/D + HD(v', j') and H + H2(v = 4 , j = 1 , 2) -> H + H2(v', j') exchange reactions are presented for the ground electronic state of H3. A numerically exact three-dimensional time-independent scattering method based on hyperspherical coordinates is used to compute rotationally resolved reaction cross sections and non-thermal rate coefficients for collision energies between 1 μK and 100 K . The geometric (Berry) phase associated with the D3h conical intersection in H3 is included using a U(1) vector (gauge) potential approach. It is shown that the geometric phase leads to a significant (up to three orders of magnitude) enhancement or suppression of the ultracold reaction rate coefficients depending upon whether the interference between the reaction pathways encircling the conical intersection is constructive or destructive. The nature of the interference is governed by a newly discovered mechanism which leads to an effective quantization of the ultracold scattering phase shifts. Interesting behavior due to rotational excitation of the HD and H2 is observed which might be exploited by experimentalists to control the reaction outcome. This work was supported in part by NSF Grant PHY-1505557 (N.B.) and ARO MURI Grant No. W911NF-12-1-0476 (N.B.), and DOE LDRD Grant No. 20170221ER (B.K.).

The RoPES project with HARPS and HARPS-N. I. A system of super-Earths orbiting the moderately active K-dwarf HD 176986

NASA Astrophysics Data System (ADS)

Suárez Mascareño, A.; González Hernández, J. I.; Rebolo, R.; Velasco, S.; Toledo-Padrón, B.; Udry, S.; Motalebi, F.; Ségrasan, D.; Wyttenbach, A.; Mayor, M.; Pepe, F.; Lovis, C.; Santos, N. C.; Figueira, P.; Esposito, M.

2018-04-01

We report the discovery of a system of two super-Earths orbiting the moderately active K-dwarf HD 176986. This work is part of the RoPES RV program of G- and K-type stars, which combines radial velocities (RVs) from the HARPS and HARPS-N spectrographs to search for short-period terrestrial planets. HD 176986 b and c are super-Earth planets with masses of 5.74 and 9.18 M⊕, orbital periods of 6.49 and 16.82 days, and distances of 0.063 and 0.119 AU in orbits that are consistent with circular. The host star is a K2.5 dwarf, and despite its modest level of chromospheric activity (log10 (RHK' = -4.90 ± 0.04), it shows a complex activity pattern. Along with the discovery of the planets, we study the magnetic cycle and rotation of the star. HD 176986 proves to be suitable for testing the available RV analysis technique and further our understanding of stellar activity. Full Table A.1 is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/612/A41Based on observations made with the Italian Telescopio Nazionale Galileo (TNG), operated on the island of La Palma by the INAF - Fundación Galileo Galilei at the Roche de Los Muchachos Observatory of the Instituto de Astrofísica de Canarias (IAC); observations made with the HARPS instrument on the ESO 3.6-m telescope at La Silla Observatory (Chile).

Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study.

PubMed

Epping, Eric A; Mills, James A; Beglinger, Leigh J; Fiedorowicz, Jess G; Craufurd, David; Smith, Megan M; Groves, Mark; Bijanki, Kelly R; Downing, Nancy; Williams, Janet K; Long, Jeffrey D; Paulsen, Jane S

2013-10-01

Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dynamical Simulations of HD 69830

NASA Astrophysics Data System (ADS)

Payne, Matthew J.; Ford, Eric B.; Wyatt, Mark C.; Booth, Mark

2009-02-01

Previous studies have developed models for the growth and migration of three planets orbiting HD 69830. We perform n-body simulations using MERCURY (Chambers 1999) to explore the implications of these models for: 1) the excitation of planetary orbits via planet-planet interactions, 2) the accretion and clearing of a putative planetesimal disk, 3) the distribution of planetesimal orbits following migration, and 4) the implications for the origin of the observed infrared emission from the HD 69830 system. We report preliminary results that suggest new constraints on the formation of HD 69830.

Fluorescence lifetime dynamics of eGFP in protein aggregates with expanded polyQ

NASA Astrophysics Data System (ADS)

Ghukasyan, Vladimir; Hsu, Chih-Chun; Liu, Chia-Rung; Kao, Fu-Jen; Cheng, Tzu-Hao

2009-02-01

Expanding a polyglutamine (polyQ) stretch at the N-terminus of huntingtin protein is the main cause of the neurodegenerative disorder Huntington's disease (HD). Expansion of polyQ above 39 residues has an inherent propensity to form amyloid-like fibrils and aggregation of the mutant protein is found to be a critical component for abnormal pathology of HD. Using yeast Saccharomyces cerevisiae as a model system, we have observed a decrease in fluorescence lifetime of the enhanced green fluorescence protein (eGFP) fused to 97 successive glutamine residues (97Q). Compared to the sample expressing evenly distributed eGFP, the 97Q-eGFP fusion proteins show the formation of grain-like particles and the reduction of eGFP lifetime by ~250 ps as measured by time-correlated single-photon counting technique (TCSPC). More importantly, this phenomenon does not appear in Hsp104-deficient cells. The gene product of HSP104 is required for the formation of polyQ aggregates in yeast cells; therefore, the cellular 97Q-eGFP become soluble and evenly distributive in the absence of Hsp104. Under this condition, the lifetime value of 97Q-eGFP is close to the one exhibited by eGFP alone. The independence of the effect of the environmental parameters, such as pH and refraction index is demonstrated. These data indicate that the fluorescence lifetime dynamics of eGFP is linked to the process of polyQ protein aggregation per se.

Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival.

PubMed

Nuzzo, Maria Teresa; Fiocchetti, Marco; Totta, Pierangela; Melone, Mariarosa A B; Cardinale, Antonella; Fusco, Francesca R; Gustincich, Stefano; Persichetti, Francesca; Ascenzi, Paolo; Marino, Maria

2017-10-01

Among several mechanisms underlying the well-known trophic and protective effects of 17β-estradiol (E2) in the brain, we recently reported that E2 induces the up-regulation of two anti-apoptotic and neuroprotectant proteins: huntingtin (HTT) and neuroglobin (NGB). Here, we investigate the role of this up-regulation. The obtained results indicate that E2 promotes NGB-HTT association, induces the localization of the complex at the mitochondria, and protects SK-N-BE neuroblastoma cells and murine striatal cells, which express wild-type HTT (i.e., polyQ 7 ), against H 2 O 2 -induced apoptosis. All E2 effects were completely abolished in HTT-knocked out SK-N-BE cells and in striatal neurons expressing the mutated form of HTT (mHTT; i.e., polyQ 111 ) typical of Huntington's disease (HD). As a whole, these data provide a new function of wild-type HTT which drives E2-induced NGB in mitochondria modulating NGB anti-apoptotic activity. This new function is lost by HTT polyQ pathological expansion. These data evidence the existence of a novel E2/HTT/NGB neuroprotective axis that may play a relevant role in the development of HD therapeutics.

Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons

PubMed Central

2012-01-01

Background A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Results Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. Conclusions Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD. PMID:22413862

Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons.

PubMed

Lejeune, François-Xavier; Mesrob, Lilia; Parmentier, Frédéric; Bicep, Cedric; Vazquez-Manrique, Rafael P; Parker, J Alex; Vert, Jean-Philippe; Tourette, Cendrine; Neri, Christian

2012-03-13

A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD. © 2012 Lejeune et al; licensee BioMed Central Ltd.

Characterization of Runella slithyformis HD-Pnk, a bifunctional DNA/RNA end-healing enzyme composed of an N-terminal 2',3' -phosphoesterase HD domain and a C-terminal 5' -OH polynucleotide kinase domain.

PubMed

Munir, Annum; Shuman, Stewart

2016-11-28

5' and 3' end healing are key steps in nucleic acid break repair in which 5' -OH ends are phosphorylated by a polynucleotide kinase and 3' -PO 4 or 2',3' -cyclic-PO 4 ends are hydrolyzed by a phosphoesterase to generate the 5' -PO 4 and 3' -OH termini required for sealing by classic polynucleotide ligases. End healing and sealing enzymes are present in diverse bacterial taxa, often organized as modular units within a single multifunctional polypeptide or as subunits of a repair complex. Here we identify and characterize Runella slithyformis HD-Pnk as a novel bifunctional end-healing enzyme composed of an N-terminal 2',3' -phosphoesterase HD domain and a C-terminal 5' -OH polynucleotide kinase P-loop domain. HD-Pnk phosphorylates 5' -OH polynucleotides (9-mers or longer) in the presence of magnesium and any NTP donor. HD-Pnk dephosphorylates RNA 2',3' -cyclic phosphate, RNA 3' -phosphate, RNA 2' -phosphate, and DNA 3' -phosphate ends in the presence of a transition metal cofactor, which can be nickel, copper or cobalt. HD-Pnkp homologs are present in genera from eleven bacterial phyla and are often encoded in an operon with a putative ATP-dependent polynucleotide ligase. The present study provides insights to the diversity of nucleic acid repair strategies via the characterization of Runella slithyformis HD-Pnkp as the exemplar of a novel clade of dual 5' and 3' end-healing enzymes that phosphorylate 5' -OH termini and dephosphorylate 2',3' -cyclic-PO 4 , 3' -PO 4 , and 2' -PO 4 ends. The distinctive feature of HD-Pnk is its domain composition: a fusion of an N-terminal HD phosphohydrolase module to a C-terminal P-loop polynucleotide kinase module. Homologs of Runella HD-Pnk with the same domain composition, domain order, and similar polypeptide size are distributed widely among genera from eleven bacterial phyla. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1

PubMed Central

Shabalina, Irina G.; Vyssokikh, Mikhail Yu.; Gibanova, Natalia; Csikasz, Robert I.; Edgar, Daniel; Hallden-Waldemarson, Anne; Rozhdestvenskaya, Zinaida; Bakeeva, Lora E.; Vays, Valeria B.; Pustovidko, Antonina V.; Skulachev, Maxim V.; Cannon, Barbara; Skulachev, Vladimir P.; Nedergaard, Jan

2017-01-01

MtDNA mutator mice exhibit marked features of premature aging. We find that these mice treated from age of ≈100 days with the mitochondria-targeted antioxidant SkQ1 showed a delayed appearance of traits of aging such as kyphosis, alopecia, lowering of body temperature, body weight loss, as well as ameliorated heart, kidney and liver pathologies. These effects of SkQ1 are suggested to be related to an alleviation of the effects of an enhanced reactive oxygen species (ROS) level in mtDNA mutator mice: the increased mitochondrial ROS released due to mitochondrial mutations probably interact with polyunsaturated fatty acids in cardiolipin, releasing malondialdehyde and 4-hydroxynonenal that form protein adducts and thus diminishes mitochondrial functions. SkQ1 counteracts this as it scavenges mitochondrial ROS. As the results, the normal mitochondrial ultrastructure is preserved in liver and heart; the phosphorylation capacity of skeletal muscle mitochondria as well as the thermogenic capacity of brown adipose tissue is also improved. The SkQ1-treated mice live significantly longer (335 versus 290 days). These data may be relevant in relation to treatment of mitochondrial diseases particularly and the process of aging in general. PMID:28209927

N*(1535) electroproduction at high Q2

DOE Office of Scientific and Technical Information (OSTI.GOV)

G. Ramalho, M.T. Pena, K. Tsushima

2012-04-01

A covariant spectator quark model is applied to study the {gamma}N {yields} N*(1535) reaction in the large Q{sup 2} region. Starting from the relation between the nucleon and N*(1535) systems, the N*(1535) valence quark wave function is determined without the addition of any parameters. The model is then used to calculate the {gamma}N {yields} N*(1535) transition form factors. A very interesting, useful relation between the A{sub 1/2} and S{sub 1/2} helicity amplitudes for Q{sup 2} > GeV{sup 2}, is also derived.

Rhes suppression enhances disease phenotypes in Huntington's disease mice.

PubMed

Lee, John H; Sowada, Matthew J; Boudreau, Ryan L; Aerts, Andrea M; Thedens, Daniel R; Nopoulos, Peg; Davidson, Beverly L

2014-01-01

In Huntington's disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.

Overexpressing wild-type γ2 subunits rescued the seizure phenotype in Gabrg2+/Q390X Dravet syndrome mice.

PubMed

Huang, Xuan; Zhou, Chengwen; Tian, Mengnan; Kang, Jing-Qiong; Shen, Wangzhen; Verdier, Kelienne; Pimenta, Aurea; MacDonald, Robert L

2017-08-01

The mutant γ-aminobutyric acid type A (GABA A ) receptor γ2(Q390X) subunit (Q351X in the mature peptide) has been associated with the epileptic encephalopathy, Dravet syndrome, and the epilepsy syndrome genetic epilepsy with febrile seizures plus (GEFS+). The mutation generates a premature stop codon that results in translation of a stable truncated and misfolded γ2 subunit that accumulates in neurons, forms intracellular aggregates, disrupts incorporation of γ2 subunits into GABA A receptors, and affects trafficking of partnering α and β subunits. Heterozygous Gabrg2 +/Q390X knock-in (KI) mice had reduced cortical inhibition, spike wave discharges on electroencephalography (EEG), a lower seizure threshold to the convulsant drug pentylenetetrazol (PTZ), and spontaneous generalized tonic-clonic seizures. In this proof-of-principal study, we attempted to rescue these deficits in KI mice using a γ2 subunit gene (GABRG2) replacement therapy. We introduced the GABRG2 allele by crossing Gabrg2 +/Q390X KI mice with bacterial artificial chromosome (BAC) transgenic mice overexpressing HA (hemagglutinin)-tagged human γ2 HA subunits, and compared GABA A receptor subunit expression by Western blot and immunohistochemical staining, seizure threshold by monitoring mouse behavior after PTZ-injection, and thalamocortical inhibition and network oscillation by slice recording. Compared to KI mice, adult mice carrying both mutant allele and transgene had increased wild-type γ2 and partnering α1 and β2/3 subunits, increased miniature inhibitory postsynaptic current (mIPSC) amplitudes recorded from layer VI cortical neurons, reduced thalamocortical network oscillations, and higher PTZ seizure threshold. Based on these results we suggest that seizures in a genetic epilepsy syndrome caused by epilepsy mutant γ2(Q390X) subunits with dominant negative effects could be rescued potentially by overexpression of wild-type γ2 subunits. Wiley Periodicals, Inc. © 2017 International

Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice

PubMed Central

Nakai, Nobuhiro; Nagano, Masatoshi; Saitow, Fumihito; Watanabe, Yasuhito; Kawamura, Yoshinobu; Kawamoto, Akiko; Tamada, Kota; Mizuma, Hiroshi; Onoe, Hirotaka; Watanabe, Yasuyoshi; Monai, Hiromu; Hirase, Hajime; Nakatani, Jin; Inagaki, Hirofumi; Kawada, Tomoyuki; Miyazaki, Taisuke; Watanabe, Masahiko; Sato, Yuka; Okabe, Shigeo; Kitamura, Kazuo; Kano, Masanobu; Hashimoto, Kouichi; Suzuki, Hidenori; Takumi, Toru

2017-01-01

Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms. PMID:28691086

Additive enhancement of wound healing in diabetic mice by low level light and topical CoQ10.

PubMed

Mao, Zhigang; Wu, Jeffrey H; Dong, Tingting; Wu, Mei X

2016-02-02

Diabetes, a highly prevalent disease that affects 9.3% of Americans, often leads to severe complications and slow wound healing. Preclinical studies have suggested that low level light therapy (LLLT) can accelerate wound healing in diabetic subjects, but significant improvements must be made to overcome the absence of persuasive evidence for its clinical use. We demonstrate here that LLLT can be combined with topical Coenzyme Q10 (CoQ10) to heal wounds in diabetic mice significantly faster than LLLT alone, CoQ10 alone, or controls. LLLT followed by topical CoQ10 enhanced wound healing by 68~103% in diabetic mice in the first week and more than 24% in the second week compared with untreated controls. All wounds were fully healed in two weeks following the dual treatment, in contrast to only 50% wounds or a fewer being fully healed for single or sham treatment. The accelerated healing was corroborated by at least 50% higher hydroxyproline levels, and tripling cell proliferation rates in LLLT and CoQ10 treated wounds over controls. The beneficial effects on wound healing were probably attributed to additive enhancement of ATP production by LLLT and CoQ10 treatment. The combination of LLLT and topical CoQ10 is safe and convenient, and merits further clinical study.

Additive enhancement of wound healing in diabetic mice by low level light and topical CoQ10

NASA Astrophysics Data System (ADS)

Mao, Zhigang; Wu, Jeffrey H.; Dong, Tingting; Wu, Mei X.

2016-02-01

Diabetes, a highly prevalent disease that affects 9.3% of Americans, often leads to severe complications and slow wound healing. Preclinical studies have suggested that low level light therapy (LLLT) can accelerate wound healing in diabetic subjects, but significant improvements must be made to overcome the absence of persuasive evidence for its clinical use. We demonstrate here that LLLT can be combined with topical Coenzyme Q10 (CoQ10) to heal wounds in diabetic mice significantly faster than LLLT alone, CoQ10 alone, or controls. LLLT followed by topical CoQ10 enhanced wound healing by 68~103% in diabetic mice in the first week and more than 24% in the second week compared with untreated controls. All wounds were fully healed in two weeks following the dual treatment, in contrast to only 50% wounds or a fewer being fully healed for single or sham treatment. The accelerated healing was corroborated by at least 50% higher hydroxyproline levels, and tripling cell proliferation rates in LLLT and CoQ10 treated wounds over controls. The beneficial effects on wound healing were probably attributed to additive enhancement of ATP production by LLLT and CoQ10 treatment. The combination of LLLT and topical CoQ10 is safe and convenient, and merits further clinical study.

Mutant Huntingtin Inhibits αB-Crystallin Expression and Impairs Exosome Secretion from Astrocytes

PubMed Central

2017-01-01

In the brain, astrocytes secrete diverse substances that regulate neuronal function and viability. Exosomes, which are vesicles produced through the formation of multivesicular bodies and their subsequent fusion with the plasma membrane, are also released from astrocytes via exocytotic secretion. Astrocytic exosomes carry heat shock proteins that can reduce the cellular toxicity of misfolded proteins and prevent neurodegeneration. Although mutant huntingtin (mHtt) affects multiple functions of astrocytes, it remains unknown whether mHtt impairs the production of exosomes from astrocytes. We found that mHtt is not present in astrocytic exosomes, but can decrease exosome secretion from astrocytes in HD140Q knock-in (KI) mice. N-terminal mHtt accumulates in the nuclei and forms aggregates, causing decreased secretion of exosomes from cultured astrocytes. Consistently, there is a significant decrease in secreted exosomes in both female and male HD KI mouse striatum in which abundant nuclear mHtt aggregates are present. Conversely, injection of astrocytic exosomes into the striatum of HD140Q KI mice reduces the density of mHtt aggregates. Further, mHtt in astrocytes decreased the expression of αB-crystallin, a small heat shock protein that is enriched in astrocytes and mediates exosome secretion, by reducing the association of Sp1 with the enhancer of the αB-crystallin gene. Importantly, overexpression of αB-crystallin rescues defective exosome release from HD astrocytes as well as mHtt aggregates in the striatum of HD140Q KI mice. Our results demonstrate that mHtt reduces the expression of αB-crystallin in astrocytes to decrease exosome secretion in the HD brains, contributing to non–cell-autonomous neurotoxicity in HD. SIGNIFICANCE STATEMENT Huntington's disease (HD) is characterized by selective neurodegeneration that preferentially occurs in the striatal medium spiny neurons. Recent studies in different HD mouse models demonstrated that dysfunction of

The effects of either resveratrol or exercise on macrophage infiltration and switching from M1 to M2 in high fat diet mice.

PubMed

Jeong, Jun Hyun; Lee, Young Ran; Park, Hee Geun; Lee, Wang Lok

2015-06-01

The aim of this study was to compare the effectiveness of either resveratrol supplementation or exercise training on macrophage infiltration and switching from M1 to M2 kupffer cells in high fat diet mice. C57BL/6 mice were separated into 5 groups: normal diet (ND; n = 6), high-fat diet (HD; n = 6), high-fat diet with resveratrol (HR; n = 6), high-fat diet with exercise (HE; n = 6) or high-fat diet with resveratrol and exercise (HRE; n = 6). Resveratrol supplementation mice were orally gavaged with resveratrol (25mg/kg of body weight) dissolved in 50% propylene glycol. Exercise mice ran on a treadmill at 12-20 m/min for 30-60 min/day, 5 times/week for 12 weeks. After 12 weeks of intervention, the liver was analyzed. F4/80 expression was evaluated by western blot while CD11c and CD163 mRNA expressions were evaluated by RT-PCR. The weights of the body and liver were significantly increased in the HD and HR group compared to the ND group (p < 0.01). However, the weights were most effectively reduced in the HE and HRE groups compared to the HD group (p < 0.05). The macrophage marker, F4/80 expression was significantly lower in the HE and HRE groups compared to the HD group (p < 0.05). mRNA expression of the M1 macrophage marker, CD11c, in the HD group was significantly increased compared to the ND group (p < 0.01). mRNA expression of the M2 macrophage specific marker, CD163, in the HE and HRE groups were significantly increased compared to the HD group (p < 0.05). The mRNA expressions of TLR4, ICAM-1 and VCAM-1, which induce pro-inflammatory cytokine production, were strongly decreased in the HR, HE, and HRE groups compared to the HD group. These results suggest that moderate exercise training inhibits macrophage infiltration and up regulation of CD163 expression. However, resveratrol supplementation is not enough to ameliorate obesity-induced macrophage infiltration and switching.

Polarized Disk Emission from Herbig Ae/Be Stars Observed Using Gemini Planet Imager: HD 144432, HD 150193, HD 163296, and HD 169142

DOE Office of Scientific and Technical Information (OSTI.GOV)

Monnier, John D.; Aarnio, Alicia; Adams, Fred C.

In order to look for signs of ongoing planet formation in young disks, we carried out the first J -band polarized emission imaging of the Herbig Ae/Be stars HD 150193, HD 163296, and HD 169142 using the Gemini Planet Imager, along with new H band observations of HD 144432. We confirm the complex “double ring” structure for the nearly face-on system HD 169142 first seen in H -band, finding the outer ring to be substantially redder than the inner one in polarized intensity. Using radiative transfer modeling, we developed a physical model that explains the full spectral energy distribution andmore » J - and H -band surface brightness profiles, suggesting that the differential color of the two rings could come from reddened starlight traversing the inner wall and may not require differences in grain properties. In addition, we clearly detect an elongated, off-center ring in HD 163296 (MWC 275), locating the scattering surface to be 18 au above the midplane at a radial distance of 77 au, co-spatial with a ring seen at 1.3 mm by ALMA linked to the CO snow line. Lastly, we report a weak tentative detection of scattered light for HD 150193 (MWC 863) and a non-detection for HD 144432; the stellar companion known for each of these targets has likely disrupted the material in the outer disk of the primary star. For HD 163296 and HD 169142, the prominent outer rings we detect could be evidence for giant planet formation in the outer disk or a manifestation of large-scale dust growth processes possibly related to snow-line chemistry.« less

Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice.

PubMed

Warner, Timothy A; Liu, Zhong; Macdonald, Robert L; Kang, Jing-Qiong

2017-08-01

It has been established that febrile seizures and its extended syndromes like generalized epilepsy with febrile seizures (FS) plus (GEFS+) and Dravet syndrome have been associated with mutations especially in SCN1A and GABRG2 genes. In patients, the onset of FS is likely due to the combined effect of temperature and inflammation in genetically vulnerable individuals because fever is often associated with infection. Much effort has been spent to understand the mechanisms underlying fever induction of seizures. In addition to the role of cytokines in FS, previous studies in Scn1a +/- knockout mice, a model of Dravet syndrome, indicated that temperature elevation alone could result in seizure generation, and the effect of elevated temperature inducing seizures was age-dependent. Here, we report the thermal effect in a different mouse model of Dravet syndrome, the Gabrg2 +/Q390X knockin mouse. We demonstrated age-dependent dysregulated temperature control and that temperature elevation produced myoclonic jerks, generalized tonic clonic seizures (GTCSs) and heightened anxiety-like symptoms in Gabrg2 +/Q390X mice. The study indicated that regardless of other inflammatory factors, brief heat alone increased brain excitability and induced multiple types of seizures in Gabrg2 +/Q390X mice, suggesting that mutations like GABRG2(Q390X) may alter brain thermal regulation and precipitate seizures during temperature elevations. Copyright © 2017 Elsevier B.V. All rights reserved.

NMR studies of double proton transfer in hydrogen bonded cyclic N,N'-diarylformamidine dimers: conformational control, kinetic HH/HD/DD isotope effects and tunneling.

PubMed

Lopez, Juan Miguel; Männle, Ferdinand; Wawer, Iwona; Buntkowsky, Gerd; Limbach, Hans-Heinrich

2007-08-28

Using dynamic NMR spectroscopy, the kinetics of the degenerate double proton transfer in cyclic dimers of polycrystalline (15)N,(15)N'-di-(4-bromophenyl)-formamidine (DBrFA) have been studied including the kinetic HH/HD/DD isotope effects in a wide temperature range. This transfer is controlled by intermolecular interactions, which in turn are controlled by the molecular conformation and hence the molecular structure. At low temperatures, rate constants were determined by line shape analysis of (15)N NMR spectra obtained using cross-polarization (CP) and magic angle spinning (MAS). At higher temperatures, in the microsecond time scale, rate constants and kinetic isotope effects were obtained by a combination of longitudinal (15)N and (2)H relaxation measurements. (15)N CPMAS line shape analysis was also employed to study the non-degenerate double proton transfer of polycrystalline (15)N,(15)N'-diphenyl-formamidine (DPFA). The kinetic results are in excellent agreement with the kinetics of DPFA and (15)N,(15)N'-di-(4-fluorophenyl)-formamidine (DFFA) studied previously for solutions in tetrahydrofuran. Two large HH/HD and HD/DD isotope effects are observed in the whole temperature range which indicates a concerted double proton transfer mechanism in the domain of the reaction energy surface. The Arrhenius curves are non-linear indicating a tunneling mechanism. Arrhenius curve simulations were performed using the Bell-Limbach tunneling model. The role of the phenyl group conformation and hydrogen bond compression on the barrier of the proton transfer is discussed.

Additive enhancement of wound healing in diabetic mice by low level light and topical CoQ10

PubMed Central

Mao, Zhigang; Wu, Jeffrey H.; Dong, Tingting; Wu, Mei X.

2016-01-01

Diabetes, a highly prevalent disease that affects 9.3% of Americans, often leads to severe complications and slow wound healing. Preclinical studies have suggested that low level light therapy (LLLT) can accelerate wound healing in diabetic subjects, but significant improvements must be made to overcome the absence of persuasive evidence for its clinical use. We demonstrate here that LLLT can be combined with topical Coenzyme Q10 (CoQ10) to heal wounds in diabetic mice significantly faster than LLLT alone, CoQ10 alone, or controls. LLLT followed by topical CoQ10 enhanced wound healing by 68~103% in diabetic mice in the first week and more than 24% in the second week compared with untreated controls. All wounds were fully healed in two weeks following the dual treatment, in contrast to only 50% wounds or a fewer being fully healed for single or sham treatment. The accelerated healing was corroborated by at least 50% higher hydroxyproline levels, and tripling cell proliferation rates in LLLT and CoQ10 treated wounds over controls. The beneficial effects on wound healing were probably attributed to additive enhancement of ATP production by LLLT and CoQ10 treatment. The combination of LLLT and topical CoQ10 is safe and convenient, and merits further clinical study. PMID:26830658

Consequences of long-term oral administration of the mitochondria-targeted antioxidant MitoQ to wild-type mice.

PubMed

Rodriguez-Cuenca, Sergio; Cochemé, Helena M; Logan, Angela; Abakumova, Irina; Prime, Tracy A; Rose, Claudia; Vidal-Puig, Antonio; Smith, Anthony C; Rubinsztein, David C; Fearnley, Ian M; Jones, Bruce A; Pope, Simon; Heales, Simon J R; Lam, Brian Y H; Neogi, Sudeshna Guha; McFarlane, Ian; James, Andrew M; Smith, Robin A J; Murphy, Michael P

2010-01-01

The mitochondria-targeted quinone MitoQ protects mitochondria in animal studies of pathologies in vivo and is being developed as a therapy for humans. However, it is unclear whether the protective action of MitoQ is entirely due to its antioxidant properties, because long-term MitoQ administration may alter whole-body metabolism and gene expression. To address this point, we administered high levels of MitoQ orally to wild-type C57BL/6 mice for up to 28 weeks and investigated the effects on whole-body physiology, metabolism, and gene expression, finding no measurable deleterious effects. In addition, because antioxidants can act as pro-oxidants under certain conditions in vitro, we examined the effects of MitoQ administration on markers of oxidative damage. There were no changes in the expression of mitochondrial or antioxidant genes as assessed by DNA microarray analysis. There were also no increases in oxidative damage to mitochondrial protein, DNA, or cardiolipin, and the activities of mitochondrial enzymes were unchanged. Therefore, MitoQ does not act as a pro-oxidant in vivo. These findings indicate that mitochondria-targeted antioxidants can be safely administered long-term to wild-type mice. Copyright 2009 Elsevier Inc. All rights reserved.

Characterization of Runella slithyformis HD-Pnk, a Bifunctional DNA/RNA End-Healing Enzyme Composed of an N-Terminal 2′,3′-Phosphoesterase HD Domain and a C-Terminal 5′-OH Polynucleotide Kinase Domain

PubMed Central

Munir, Annum

2016-01-01

ABSTRACT 5′- and 3′-end-healing reactions are key steps in nucleic acid break repair in which 5′-OH ends are phosphorylated by a polynucleotide kinase (Pnk) and 3′-PO4 or 2′,3′-cyclic-PO4 ends are hydrolyzed by a phosphoesterase to generate the 5′-PO4 and 3′-OH termini required for sealing by classic polynucleotide ligases. End-healing and sealing enzymes are present in diverse bacterial taxa, often organized as modular units within a single multifunctional polypeptide or as subunits of a repair complex. Here we identify and characterize Runella slithyformis HD-Pnk as a novel bifunctional end-healing enzyme composed of an N-terminal 2′,3′-phosphoesterase HD domain and a C-terminal 5′-OH polynucleotide kinase P-loop domain. HD-Pnk phosphorylates 5′-OH polynucleotides (9-mers or longer) in the presence of magnesium and any nucleoside triphosphate donor. HD-Pnk dephosphorylates RNA 2′,3′-cyclic phosphate, RNA 3′-phosphate, RNA 2′-phosphate, and DNA 3′-phosphate ends in the presence of a transition metal cofactor, which can be nickel, copper, or cobalt. HD-Pnk homologs are present in genera from 11 bacterial phyla and are often encoded in an operon with a putative ATP-dependent polynucleotide ligase. IMPORTANCE The present study provides insights regarding the diversity of nucleic acid repair strategies via the characterization of Runella slithyformis HD-Pnk as the exemplar of a novel clade of dual 5′- and 3′-end-healing enzymes that phosphorylate 5′-OH termini and dephosphorylate 2′,3′-cyclic-PO4, 3′-PO4, and 2′-PO4 ends. The distinctive feature of HD-Pnk is its domain composition, i.e., a fusion of an N-terminal HD phosphohydrolase module and a C-terminal P-loop polynucleotide kinase module. Homologs of Runella HD-Pnk with the same domain composition, same domain order, and similar polypeptide sizes are distributed widely among genera from 11 bacterial phyla. PMID:27895092

PB2-Q591K Mutation Determines the Pathogenicity of Avian H9N2 Influenza Viruses for Mammalian Species

PubMed Central

Wang, Congrong; Lee, Horace Hok Yeung; Yang, Zi Feng; Mok, Chris Ka Pun; Zhang, Zhi

2016-01-01

Background Influenza A subtype H9N2 is widespread and prevalent in poultry. It has repeatedly transmitted zoonotically to cause mild influenza-like illness in humans and is regarded as a potential pandemic candidate. In additon, the six internal genes of H7N9 and H10N8 viruses which caused infection in human in China as well as some of the highly pathogenic H5N1 strains are origined from H9N2. Previous studies have shown that the mammalian adaptation PB2-Q591K contributes to the pathogenicity of H5N1 and H7N9 viruses. However, the role of the PB2-Q591K mutation in H9N2 subtype is still not well understood. Methods To define and compare the individual role of PB2-Q591K substitution in the PB2 gene segment of H9N2 in relation to polymerase activity, replication competence and the pathogenicity using in vitro and in vivo models. Results The PB2-Q591K mutation in H9N2 virus enhanced the polymerase activity and virus replication in human NHBE cells when compared to the wild type strain. Mice infected with the PB2 mutant showed significant weight loss, higher virus replication and immune responses in the lungs. Conclusions Our evidences suggest that the PB2-Q591K, in addition to the -E627K mutation in H9N2 enhanced the pathogenicity in mammalian host. PMID:27684944

The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice.

PubMed

Rehman, Hasibur; Liu, Qinlong; Krishnasamy, Yasodha; Shi, Zengdun; Ramshesh, Venkat K; Haque, Khujista; Schnellmann, Rick G; Murphy, Michael P; Lemasters, John J; Rockey, Don C; Zhong, Zhi

2016-01-01

Oxidative stress plays an essential role in liver fibrosis. This study investigated whether MitoQ, an orally active mitochondrial antioxidant, decreases liver fibrosis. Mice were injected with corn oil or carbon tetrachloride (CCl4, 1:3 dilution in corn oil; 1 µl/g, ip) once every 3 days for up to 6 weeks. 4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress. MitoQ attenuated oxidative stress after CCl4. Collagen 1α1 mRNA and hydroxyproline increased markedly after CCl4 treatment, indicating increased collagen formation and deposition. CCl4 caused overt pericentral fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy. MitoQ blunted fibrosis after CCl4. Profibrotic transforming growth factor-β1 (TGF-β1) mRNA and expression of smooth muscle α-actin, an indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-β fibrogenic effects, was also activated after CCl4 treatment. MitoQ blunted HSC activation, TGF-β expression, and Smad2/3 activation after CCl4 treatment. MitoQ also decreased necrosis, apoptosis and inflammation after CCl4 treatment. In cultured HSCs, MitoQ decreased oxidative stress, inhibited HSC activation, TGF-β1 expression, Smad2/3 activation, and extracellular signal-regulated protein kinase activation. Taken together, these data indicate that mitochondrial reactive oxygen species play an important role in liver fibrosis and that mitochondria-targeted antioxidants are promising potential therapies for prevention and treatment of liver fibrosis.

The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice

PubMed Central

Rehman, Hasibur; Liu, Qinlong; Krishnasamy, Yasodha; Shi, Zengdun; Ramshesh, Venkat K; Haque, Khujista; Schnellmann, Rick G; Murphy, Michael P; Lemasters, John J; Rockey, Don C; Zhong, Zhi

2016-01-01

Oxidative stress plays an essential role in liver fibrosis. This study investigated whether MitoQ, an orally active mitochondrial antioxidant, decreases liver fibrosis. Mice were injected with corn oil or carbon tetrachloride (CCl4, 1:3 dilution in corn oil; 1 µl/g, ip) once every 3 days for up to 6 weeks. 4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress. MitoQ attenuated oxidative stress after CCl4. Collagen 1α1 mRNA and hydroxyproline increased markedly after CCl4 treatment, indicating increased collagen formation and deposition. CCl4 caused overt pericentral fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy. MitoQ blunted fibrosis after CCl4. Profibrotic transforming growth factor-β1 (TGF-β1) mRNA and expression of smooth muscle α-actin, an indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-β fibrogenic effects, was also activated after CCl4 treatment. MitoQ blunted HSC activation, TGF-β expression, and Smad2/3 activation after CCl4 treatment. MitoQ also decreased necrosis, apoptosis and inflammation after CCl4 treatment. In cultured HSCs, MitoQ decreased oxidative stress, inhibited HSC activation, TGF-β1 expression, Smad2/3 activation, and extracellular signal-regulated protein kinase activation. Taken together, these data indicate that mitochondrial reactive oxygen species play an important role in liver fibrosis and that mitochondria-targeted antioxidants are promising potential therapies for prevention and treatment of liver fibrosis. PMID:27186319

Therapeutic Effects of Anthocyanins and Environmental Enrichment in R6/1 Huntington's Disease Mice.

PubMed

Kreilaus, Fabian; Spiro, Adena S; Hannan, Anthony J; Garner, Brett; Jenner, Andrew M

2016-10-01

Huntington's disease (HD) is a progressive neurodegenerative disease with no effective treatment or cure. Environmental enrichment has been used to slow processes leading to ageing and neurodegenerative diseases including HD. Phenolic phytochemicals including anthocyanins have also been shown to improve brain function in ageing and neurodegenerative diseases. This study examined the effects of anthocyanin dietary supplementation and environmental enrichment on behavioural phenotypes and brain cholesterol metabolic alterations in the R6/1 mouse model of HD. R6/1 HD mice and their wild-type littermate controls were randomised into the different experimental conditions, involving either environmentally enriched versus standard housing conditions, or anthocyanin versus control diet. Motor dysfunction was assessed from 6 to 26 weeks using the RotaRod and the hind-paw clasping tests. Gas chromatography - tandem mass spectrometry was used to quantify a broad range of sterols in the striatum and cortex of R6/1 HD mice. Anthocyanin dietary supplementation delayed the onset of motor dysfunction in female HD mice. Environmental enrichment improved motor function and the hind paw clasping phenotype in male HD mice only. These mice also had lower levels of cholesterol oxidation products in the cortex compared to standard-housed mice. Both anthocyanin supplementation and environmental enrichment are able to improve the motor dysfunction phenotype of R6/1 mice, however the effectiveness of these interventions was different between the two sexes. The interventions examined did not alter brain cholesterol metabolic deficits that have been reported previously in this mouse model of HD.

Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington's Disease.

PubMed

Valdeolivas, Sara; Sagredo, Onintza; Delgado, Mercedes; Pozo, Miguel A; Fernández-Ruiz, Javier

2017-03-23

Several cannabinoids afforded neuroprotection in experimental models of Huntington's disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆⁸-tetrahydrocannabinol (∆⁸-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex ® , is beneficial in R6/2 mice (a transgenic model of HD), as it was previously shown to have positive effects in neurotoxin-based models of HD. We recorded the progression of neurological deficits and the extent of striatal deterioration, using behavioral, in vivo imaging, and biochemical methods in R6/2 mice and their corresponding wild-type mice. The mice were daily treated, starting at 4 weeks after birth, with a Sativex-like combination of phytocannabinoids (equivalent to 3 mg/kg weight of pure CBD + ∆⁸-THC) or vehicle. R6/2 mice exhibited the characteristic deterioration in rotarod performance that initiated at 6 weeks and progressed up to 10 weeks, and elevated clasping behavior reflecting dystonia. Treatment with the Sativex-like combination of phytocannabinoids did not recover rotarod performance, but markedly attenuated clasping behavior. The in vivo positron emission tomography (PET) analysis of R6/2 animals at 10 weeks revealed a reduced metabolic activity in the basal ganglia, which was partially attenuated by treatment with the Sativex-like combination of phytocannabinoids. Proton nuclear magnetic resonance spectroscopy (H⁺-MRS) analysis of the ex vivo striatum of R6/2 mice at 12 weeks revealed changes in various prognostic markers reflecting events typically found in HD patients and animal models, such as energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/ N -acetylaspartate, and N -acetylaspartate/choline ratios) were completely reversed by treatment with the Sativex-like combination of phytocannabinoids. A Sativex-like combination of phytocannabinoids administered to R6

17 CFR 270.30a-2 - Certification of Form N-CSR and Form N-Q.

Code of Federal Regulations, 2012 CFR

2012-04-01

... and Form N-Q. 270.30a-2 Section 270.30a-2 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... Form N-CSR and Form N-Q. (a) Each report filed on Form N-CSR (§§ 249.331 and 274.128 of this chapter) or Form N-Q (§§ 249.332 and 274.130 of this chapter) by a registered management investment company...

17 CFR 270.30a-2 - Certification of Form N-CSR and Form N-Q.

Code of Federal Regulations, 2013 CFR

2013-04-01

... and Form N-Q. 270.30a-2 Section 270.30a-2 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... Form N-CSR and Form N-Q. (a) Each report filed on Form N-CSR (§§ 249.331 and 274.128 of this chapter) or Form N-Q (§§ 249.332 and 274.130 of this chapter) by a registered management investment company...

17 CFR 270.30a-2 - Certification of Form N-CSR and Form N-Q.

Code of Federal Regulations, 2014 CFR

2014-04-01

... and Form N-Q. 270.30a-2 Section 270.30a-2 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... Form N-CSR and Form N-Q. (a) Each report filed on Form N-CSR (§§ 249.331 and 274.128 of this chapter) or Form N-Q (§§ 249.332 and 274.130 of this chapter) by a registered management investment company...

The regeneration of thermal wound on mice skin (Mus Musculus) after Q-Switch Nd: YAG laser irradiation for cancer therapy candidate

NASA Astrophysics Data System (ADS)

Apsari, R.; Nahdliyatun, E.; Winarni, D.

2017-09-01

The aims of this study are to investigate the regeneration of mice skin tissue (Mus Musculus) irradiated by Q-Switch Nd: YAG laser and morphological change due to Q-Switch Nd: YAG laser irradiation compared to conventional heating (hairdryer). The 2-3 month of twenty-seven mice were used for experimental animals. Mice were incised in the dorsum by the damage effect of laser energy dose (therapeutic dose) of 29.5 J/cm2 with 10 seconds of exposure time, 10 Hz of repetition rate, and 100 pulses of the given single pulse energy. The mice skin tissue was injuried by hairdryer to get burned effect. Mice were divided into three groups, Group I (control) were not treated by anything, Group II were treated by Q-Switch Nd: YAG laser irradiation and sacrificed on (0, 1, 3, 5) days, and Group III were treated by hairdryer then sacrificed on (0, 1, 3, 5) days. Pathology examination showed that the energy of 29,5 J/cm2 dose produced the hole effect (ablation) through the hypodermic layer caused by optical breakdown and collagen coagulation. Thus, the 60 °C temperature of burn showed coagulation necrosis because piknosis discovered in the injured area. The regeneration process showed that the mice skin tissue's ability to regenerate was irradiated by fast laser because of the focus of Q-Switch Nd: YAG laser. It was showed by the scab releases on third day and completely reepithelialization formation on the fifth day. The collagen fibers distribution was same as normal skin tissue on day 5 and so did angiogenesis. Therefore, Q-Switch Nd: YAG laser can be applied for problems of dermatology medical therapies, especially melasma, nevus of ota and tatto therapy. For skin cancer therapy application, energy dose of unregenerated skin tissue is chosen because the death expected effect is permanent.

Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington’s Disease

PubMed Central

Valdeolivas, Sara; Sagredo, Onintza; Delgado, Mercedes; Pozo, Miguel A.; Fernández-Ruiz, Javier

2017-01-01

Several cannabinoids afforded neuroprotection in experimental models of Huntington’s disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆9-tetrahydrocannabinol (∆9-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex®, is beneficial in R6/2 mice (a transgenic model of HD), as it was previously shown to have positive effects in neurotoxin-based models of HD. We recorded the progression of neurological deficits and the extent of striatal deterioration, using behavioral, in vivo imaging, and biochemical methods in R6/2 mice and their corresponding wild-type mice. The mice were daily treated, starting at 4 weeks after birth, with a Sativex-like combination of phytocannabinoids (equivalent to 3 mg/kg weight of pure CBD + ∆9-THC) or vehicle. R6/2 mice exhibited the characteristic deterioration in rotarod performance that initiated at 6 weeks and progressed up to 10 weeks, and elevated clasping behavior reflecting dystonia. Treatment with the Sativex-like combination of phytocannabinoids did not recover rotarod performance, but markedly attenuated clasping behavior. The in vivo positron emission tomography (PET) analysis of R6/2 animals at 10 weeks revealed a reduced metabolic activity in the basal ganglia, which was partially attenuated by treatment with the Sativex-like combination of phytocannabinoids. Proton nuclear magnetic resonance spectroscopy (H+-MRS) analysis of the ex vivo striatum of R6/2 mice at 12 weeks revealed changes in various prognostic markers reflecting events typically found in HD patients and animal models, such as energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/N-acetylaspartate, and N-acetylaspartate/choline ratios) were completely reversed by treatment with the Sativex-like combination of phytocannabinoids. A Sativex-like combination of phytocannabinoids administered to R6/2 mice at

IGF-1 intranasal administration rescues Huntington's disease phenotypes in YAC128 mice.

PubMed

Lopes, Carla; Ribeiro, Márcio; Duarte, Ana I; Humbert, Sandrine; Saudou, Frederic; Pereira de Almeida, Luís; Hayden, Michael; Rego, A Cristina

2014-06-01

Huntington's disease (HD) is an autosomal dominant disease caused by an expansion of CAG repeats in the gene encoding for huntingtin. Brain metabolic dysfunction and altered Akt signaling pathways have been associated with disease progression. Nevertheless, conflicting results persist regarding the role of insulin-like growth factor-1 (IGF-1)/Akt pathway in HD. While high plasma levels of IGF-1 correlated with cognitive decline in HD patients, other data showed protective effects of IGF-1 in HD striatal neurons and R6/2 mice. Thus, in the present study, we investigated motor phenotype, peripheral and central metabolic profile, and striatal and cortical signaling pathways in YAC128 mice subjected to intranasal administration of recombinant human IGF-1 (rhIGF-1) for 2 weeks, in order to promote IGF-1 delivery to the brain. We show that IGF-1 supplementation enhances IGF-1 cortical levels and improves motor activity and both peripheral and central metabolic abnormalities in YAC128 mice. Moreover, decreased Akt activation in HD mice brain was ameliorated following IGF-1 administration. Upregulation of Akt following rhIGF-1 treatment occurred concomitantly with increased phosphorylation of mutant huntingtin on Ser421. These data suggest that intranasal administration of rhIGF-1 ameliorates HD-associated glucose metabolic brain abnormalities and mice phenotype.

Extended Millimeter Emission in the HD 141569 Circumstellar Disk Detected with ALMA

NASA Astrophysics Data System (ADS)

White, Jacob Aaron; Boley, A. C.

2018-06-01

We present archival Atacama Large Millimeter/submillimeter Array (ALMA) observations of the HD 141569 circumstellar disk at 345, 230, and 100 GHz. These data detect extended millimeter emission that is exterior to the inner disk. We find through simultaneous visibility modeling of all three data sets that the system’s morphology is described well by a two-component disk model. The inner disk ranges from approximately 16–45 au with a spectral index of 1.81 (q = 2.95), and the outer disk ranges from 95 to 300 au with a spectral index of 2.28 (q = 3.21). Azimuthally averaged radial emission profiles derived from the continuum images at each frequency show potential emission that is consistent with the visibility modeling. The analysis presented here shows that at ∼5 Myr, HD 141569's grain size distribution is steeper and therefore possibly evolved in the outer disk than in the inner disk.

Mutant Huntingtin Inhibits αB-Crystallin Expression and Impairs Exosome Secretion from Astrocytes.

PubMed

Hong, Yan; Zhao, Ting; Li, Xiao-Jiang; Li, Shihua

2017-09-27

In the brain, astrocytes secrete diverse substances that regulate neuronal function and viability. Exosomes, which are vesicles produced through the formation of multivesicular bodies and their subsequent fusion with the plasma membrane, are also released from astrocytes via exocytotic secretion. Astrocytic exosomes carry heat shock proteins that can reduce the cellular toxicity of misfolded proteins and prevent neurodegeneration. Although mutant huntingtin (mHtt) affects multiple functions of astrocytes, it remains unknown whether mHtt impairs the production of exosomes from astrocytes. We found that mHtt is not present in astrocytic exosomes, but can decrease exosome secretion from astrocytes in HD140Q knock-in (KI) mice. N-terminal mHtt accumulates in the nuclei and forms aggregates, causing decreased secretion of exosomes from cultured astrocytes. Consistently, there is a significant decrease in secreted exosomes in both female and male HD KI mouse striatum in which abundant nuclear mHtt aggregates are present. Conversely, injection of astrocytic exosomes into the striatum of HD140Q KI mice reduces the density of mHtt aggregates. Further, mHtt in astrocytes decreased the expression of αB-crystallin, a small heat shock protein that is enriched in astrocytes and mediates exosome secretion, by reducing the association of Sp1 with the enhancer of the α B-crystallin gene. Importantly, overexpression of αB-crystallin rescues defective exosome release from HD astrocytes as well as mHtt aggregates in the striatum of HD140Q KI mice. Our results demonstrate that mHtt reduces the expression of αB-crystallin in astrocytes to decrease exosome secretion in the HD brains, contributing to non-cell-autonomous neurotoxicity in HD. SIGNIFICANCE STATEMENT Huntington's disease (HD) is characterized by selective neurodegeneration that preferentially occurs in the striatal medium spiny neurons. Recent studies in different HD mouse models demonstrated that dysfunction of

PERFLUOROOCTANOIC ACID AND PERFLUORONONANOIC ACID IN FETAL AND NEONATAL MICE FOLLOWING IN UTERO EXPOSURE TO 8-2 FLUOROTELOMER ALCOHOL

EPA Science Inventory

8-2 fluorotelomer alcohol (FTOH) and its metabolites, perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA), are developmental toxicants, but metabolism and distribution during pregnancy is not known. To examine this, timed-pregnant mice received a single gavage dose (...

Studies of Second Layer Hydrogens on Graphite: Hydrogen/hd/gr and Hd/hd/gr.

NASA Astrophysics Data System (ADS)

Liu, Yuanming

Quasi-adiabatic heat capacity and volumetric vapor pressure isotherm techniques were used to study the thermodynamic properties of monolayer H_2 adsorbed on HD plated graphite (H_2/HD/Gr) and bilayer HD on bare graphite (HD/HD/Gr). Quasielastic neutron scattering (QENS) measurements were performed at the Laboratoire Leon Brillouin (LLB) in Saclay, France, to study the mobility of the bilayer HD films. The three techniques complemented each other. Three types of graphite were used: graphite foam for the heat capacity measurements, more loose and homogeneous graphite 'worms' for the isotherm measurements, and Papyex (similar to Grafoil) with a high surface-to-volume ratio for the QENS measurements. The heat capacity study on the mixture system H_2/HD/Gr is a continuation of the previous study on H_2/D _2/Gr by F. C. Liu et al. The results show three peculiar features which have not been seen in the pure bilayer hydrogen films: a tilted triple line, a distorted liquid(L)-vapor(V) coexistence region, and weak heat capacity anomalies at 10.1K. The triple line tilts backwards, from 6.58K to 6.25K as the H2 coverage increases. The lowest triple point temperature (6.25K) is still higher than both 5.96K of H_2/H _2/Gr (Wiechert et al.) and 5.74K of H_2/D_2/Gr (F. C. Liu et al.). The behavior of the triple line can be semi-quantitatively explained by a model of interlayer mixing which is based on the consideration that interlayer mixing lowers the system's free energy. The distortion of the L-V region and appearance of weak heat capacity anomalies are also believed to be due to interlayer mixing. The heat capacity measurements on HD/HD/Gr show a phase diagram similar to those of H_2 /H_2/MgO, H_2 /H_2/Gr, and 3D van der Waals systems, with the 2D triple and critical points at T _{t} = 8.44K and T_ {c} = 11.45K. The entropy change and heat of fusion at the triple point melting in HD/HD/Gr are comparable with those of H_2/H _2/Gr and D_2/D _2/Gr, but are considerably less

The interstellar N2 abundance towards HD 124314 from far-ultraviolet observations.

PubMed

Knauth, David C; Andersson, B-G; McCandliss, Stephan R; Moos, H Warren

2004-06-10

The abundance of interstellar molecular nitrogen (N2) is of considerable importance: models of steady-state gas-phase interstellar chemistry, together with millimetre-wavelength observations of interstellar N2H+ in dense molecular clouds predict that N2 should be the most abundant nitrogen-bearing molecule in the interstellar medium. Previous attempts to detect N2 absorption in the far-ultraviolet or infrared (ice features) have hitherto been unsuccessful. Here we report the detection of interstellar N2 at far-ultraviolet wavelengths towards the moderately reddened star HD 124314 in the constellation of Centaurus. The N2 column density is larger than expected from models of diffuse clouds and significantly smaller than expected for dense molecular clouds. Moreover, the N2 abundance does not explain the observed variations in the abundance of atomic nitrogen (N I) towards high-column-density sightlines, implying that the models of nitrogen chemistry in the interstellar medium are incomplete.

Accurate effective temperatures of the metal-poor benchmark stars HD 140283, HD 122563, and HD 103095 from CHARA interferometry

NASA Astrophysics Data System (ADS)

Karovicova, I.; White, T. R.; Nordlander, T.; Lind, K.; Casagrande, L.; Ireland, M. J.; Huber, D.; Creevey, O.; Mourard, D.; Schaefer, G. H.; Gilmore, G.; Chiavassa, A.; Wittkowski, M.; Jofré, P.; Heiter, U.; Thévenin, F.; Asplund, M.

2018-03-01

Large stellar surveys of the Milky Way require validation with reference to a set of `benchmark' stars whose fundamental properties are well determined. For metal-poor benchmark stars, disagreement between spectroscopic and interferometric effective temperatures has called the reliability of the temperature scale into question. We present new interferometric measurements of three metal-poor benchmark stars, HD 140283, HD 122563, and HD 103095, from which we determine their effective temperatures. The angular sizes of all the stars were determined from observations with the PAVO beam combiner at visible wavelengths at the CHARA array, with additional observations of HD 103095 made with the VEGA instrument, also at the CHARA array. Together with photometrically derived bolometric fluxes, the angular diameters give a direct measurement of the effective temperature. For HD 140283, we find θLD = 0.324 ± 0.005 mas, Teff = 5787 ± 48 K; for HD 122563, θLD = 0.926 ± 0.011 mas, Teff = 4636 ± 37 K; and for HD 103095, θLD = 0.595 ± 0.007 mas, Teff = 5140 ± 49 K. Our temperatures for HD 140283 and HD 103095 are hotter than the previous interferometric measurements by 253 and 322 K, respectively. We find good agreement between our temperatures and recent spectroscopic and photometric estimates. We conclude some previous interferometric measurements have been affected by systematic uncertainties larger than their quoted errors.

Gelidium amansii extract ameliorates obesity by down-regulating adipogenic transcription factors in diet-induced obese mice.

PubMed

Kang, Ji-Hye; Lee, Hyun-Ah; Kim, Hak-Ju; Han, Ji-Sook

2017-02-01

In this study, we investigated whether Gelidium amansii extract (GAE) ameliorates obesity in diet-induced obese (DIO) mice. The mice were maintained on a high-fat diet (HD) for 5 weeks to generate the DIO mouse model. And then mice fed HD plus 0.5% (GAE1), 1% (GAE2) or 2% (GAE3) for 8 weeks. After the experimental period, GAE-supplemented groups were significantly lower than the HD group in body weight gain and liver weight. GAE supplemented groups were significantly lower than the HD group in both epididymal and mesenteric adipose tissue mass. The plasma leptin level was significantly higher in the HD group than in GAE-supplemented groups. The leptin level of HD+GAE3 group was significantly lower than that of the HD+conjugated linoleic acid (CLA) group. In contrast, plasma adiponectin level of the HD group was significantly lower than those of HD+GAE2 and HD+GAE3 groups. The expression levels of adipogenic proteins such as fatty acid synthase, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor γ, and CCAAT/enhancer binding protein α in the GAE supplemented groups were significantly decreased than those in HD group, respectively. In addition, the expression levels of HD+GAE2 and HD+GAE3 groups are significantly decreased compared to those of HD+CLA group. On the contrary, the expression levels of hormone-sensitive lipase and phospho-AMP-activated protein kinase, proteins associated with lipolysis, were significantly increased in the GAE supplemented groups compared to those in the HD group. HD+GAE3 group showed the highest level among the GAE supplemented groups. These results suggested that GAE supplementation stimulated the expressions of lipid metabolic factors and reduced weight gain in HD-fed C57BL/6J obese mice.

Gelidium amansii extract ameliorates obesity by down-regulating adipogenic transcription factors in diet-induced obese mice

PubMed Central

Kang, Ji-Hye; Lee, Hyun-Ah; Kim, Hak-Ju

2017-01-01

BACKGROUND/OBJECTIVES In this study, we investigated whether Gelidium amansii extract (GAE) ameliorates obesity in diet-induced obese (DIO) mice. MATERIALS/METHODS The mice were maintained on a high-fat diet (HD) for 5 weeks to generate the DIO mouse model. And then mice fed HD plus 0.5% (GAE1), 1% (GAE2) or 2% (GAE3) for 8 weeks. RESULTS After the experimental period, GAE-supplemented groups were significantly lower than the HD group in body weight gain and liver weight. GAE supplemented groups were significantly lower than the HD group in both epididymal and mesenteric adipose tissue mass. The plasma leptin level was significantly higher in the HD group than in GAE-supplemented groups. The leptin level of HD+GAE3 group was significantly lower than that of the HD+conjugated linoleic acid (CLA) group. In contrast, plasma adiponectin level of the HD group was significantly lower than those of HD+GAE2 and HD+GAE3 groups. The expression levels of adipogenic proteins such as fatty acid synthase, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor γ, and CCAAT/enhancer binding protein α in the GAE supplemented groups were significantly decreased than those in HD group, respectively. In addition, the expression levels of HD+GAE2 and HD+GAE3 groups are significantly decreased compared to those of HD+CLA group. On the contrary, the expression levels of hormone-sensitive lipase and phospho-AMP-activated protein kinase, proteins associated with lipolysis, were significantly increased in the GAE supplemented groups compared to those in the HD group. HD+GAE3 group showed the highest level among the GAE supplemented groups. CONCLUSIONS These results suggested that GAE supplementation stimulated the expressions of lipid metabolic factors and reduced weight gain in HD-fed C57BL/6J obese mice. PMID:28194261

A Novel mouse model of enhanced proteostasis: Full-length human heat shock factor 1 transgenic mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pierce, Anson, E-mail: piercea2@uthscsa.edu; Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229; The Department of Veteran's Affairs, South Texas Veterans Health Care System, San Antonio, Texas, 78284

2010-11-05

Research highlights: {yields} Development of mouse overexpressing native human HSF1 in all tissues including CNS. {yields} HSF1 overexpression enhances heat shock response at whole-animal and cellular level. {yields} HSF1 overexpression protects from polyglutamine toxicity and favors aggresomes. {yields} HSF1 overexpression enhances proteostasis at the whole-animal and cellular level. -- Abstract: The heat shock response (HSR) is controlled by the master transcriptional regulator heat shock factor 1 (HSF1). HSF1 maintains proteostasis and resistance to stress through production of heat shock proteins (HSPs). No transgenic model exists that overexpresses HSF1 in tissues of the central nervous system (CNS). We generated a transgenicmore » mouse overexpressing full-length non-mutant HSF1 and observed a 2-4-fold increase in HSF1 mRNA and protein expression in all tissues studied of HSF1 transgenic (HSF1{sup +/0}) mice compared to wild type (WT) littermates, including several regions of the CNS. Basal expression of HSP70 and 90 showed only mild tissue-specific changes; however, in response to forced exercise, the skeletal muscle HSR was more elevated in HSF1{sup +/0} mice compared to WT littermates and in fibroblasts following heat shock, as indicated by levels of inducible HSP70 mRNA and protein. HSF1{sup +/0} cells elicited a significantly more robust HSR in response to expression of the 82 repeat polyglutamine-YFP fusion construct (Q82YFP) and maintained proteasome-dependent processing of Q82YFP compared to WT fibroblasts. Overexpression of HSF1 was associated with fewer, but larger Q82YFP aggregates resembling aggresomes in HSF1{sup +/0} cells, and increased viability. Therefore, our data demonstrate that tissues and cells from mice overexpressing full-length non-mutant HSF1 exhibit enhanced proteostasis.« less

Prevention of diabetic nephropathy in Ins2(+/)⁻(AkitaJ) mice by the mitochondria-targeted therapy MitoQ.

PubMed

Chacko, Balu K; Reily, Colin; Srivastava, Anup; Johnson, Michelle S; Ye, Yaozu; Ulasova, Elena; Agarwal, Anupam; Zinn, Kurt R; Murphy, Michael P; Kalyanaraman, Balaraman; Darley-Usmar, Victor

2010-11-15

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2(+/)⁻(AkitaJ) mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2(+/)⁻(AkitaJ) mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2(+/)⁻(AkitaJ) mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis.

Prevention of diabetic nephropathy in Ins2+/−AkitaJ mice by the mitochondria-targeted therapy MitoQ

PubMed Central

Chacko, Balu K.; Reily, Colin; Srivastava, Anup; Johnson, Michelle S.; Ye, Yaozu; Ulasova, Elena; Agarwal, Anupam; Zinn, Kurt R.; Murphy, Michael P.; Kalyanaraman, Balaraman; Darley-Usmar, Victor

2010-01-01

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2+/−AkitaJ mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2+/−AkitaJ mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2+/−AkitaJ mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis. PMID:20825366

Amyloid Precursor Protein Haploinsufficiency Preferentially Mediates Brain Iron Accumulation in Mice Transgenic for The Huntington's Disease Mutation.

PubMed

Berggren, Kiersten; Agrawal, Sonal; Fox, Julia A; Hildenbrand, Justin; Nelson, Ryan; Bush, Ashley I; Fox, Jonathan H

2017-01-01

Huntington's disease (HD) is an autosomal dominant disorder caused by a CAG expansion in the huntingtin gene that results in expression of mutant huntingtin protein. Iron accumulates in HD brain neurons. Amyloid precursor protein (APP) promotes neuronal iron export. However, the role of APP in brain iron accumulation in HD is unclear. To determine the effects of APP insufficiency on HD in YAC128 mice. We crossed APP hemizygous mice (APP+/-) with YAC128 mice that are transgenic (Tg) for human mutant huntingtin (hmHTT) to generate APP+/+ hmHTT-/-, APP+/- hmHTT-/-, APP+/+ hmHTT+/- and APP+/- hmHTT+/- progeny. Mice were evaluated for behavioral, biochemical and neuropathology HD outcomes at 2-12 months of age. APP heterozygosity decreased cortical APP 25% and 60% in non-Tg and Tg mice, respectively. Cerebral and striatal iron levels were increased by APP knockdown in Tg mice only. Nest-building behavior was decreased in Tg mice; APP knockdown decreased nest building in non-Tg but not Tg mice. Rota-rod endurance was decreased in Tg mice. APP+/- hHTT+/- mice demonstrated additional decreases in rota-rod endurance from 4-10 months of age. Tg mice had smaller striatal volumes and fewer striatal neurons but were not affected by APP knockdown. APP heterozygosity results in greater decreases of cortical APP in Tg versus non-Tg mice. Mutant huntingtin transgenic mice develop brain iron accumulation as a result of greater suppression of APP levels. Elevated brain iron in Tg mice was associated with a decline in motor endurance consistent with a disease promoting effect of iron in the YAC128 model of human HD.

Stages of Huntington's Disease (HD)

MedlinePlus

... HD The Scope of HD Who Is At Risk Genetic Testing & Family Planning Juvenile HD An End to HD? ... hd The Scope of hd Who is at-risk? GENETIC TESTING & FAMILY PLANNING PRENATAL TESTING JHD OVERVIEW AN END ...

What is HD - Huntington's Disease?

MedlinePlus

... HD The Scope of HD Who Is At Risk Genetic Testing & Family Planning Juvenile HD An End to HD? ... hd The Scope of hd Who is at-risk? GENETIC TESTING & FAMILY PLANNING PRENATAL TESTING JHD OVERVIEW AN END ...

Effects of Mitochondrial Antioxidant SkQ1 on Biochemical and Behavioral Parameters in a Parkinsonism Model in Mice.

PubMed

Pavshintsev, V V; Podshivalova, L S; Frolova, O Y; Belopolskaya, M V; Averina, O A; Kushnir, E A; Marmiy, N V; Lovat, M L

2017-12-01

According to one hypothesis, Parkinson's disease pathogenesis is largely caused by dopamine catabolism that is catalyzed on mitochondrial membranes by monoamine oxidase. Reactive oxygen species are formed as a byproduct of these reactions, which can lead to mitochondrial damage followed by cell degeneration and death. In this study, we investigated the effects of administration of the mitochondrial antioxidant SkQ1 on biochemical, immunohistochemical, and behavioral parameters in a Parkinson-like condition caused by protoxin MPTP injections in C57BL/6 mice. SkQ1 administration increased dopamine quantity and decreased signs of sensory-motor deficiency as well as destruction of dopaminergic neurons in the substantia nigra and ventral tegmental area in mice with the Parkinson-like condition.

RNAi-Based GluN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin.

PubMed

Marco, Sonia; Murillo, Alvaro; Pérez-Otaño, Isabel

2018-06-15

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs. Here, we tested the therapeutic potential of silencing GluN3A expression in YAC128 mice, a well-established HD model. Recombinant adeno-associated viruses encoding a short-hairpin RNA against GluN3A (rAAV-shGluN3A) were generated, and the ability of different serotypes to transduce MSNs was compared. A single injection of rAAV9-shGluN3A into the striatum of 1-month-old mice drove potent (>90%) and long-lasting reductions of GluN3A expression in MSNs, prevented dendritic spine loss and improved motor performance in YAC128 mice. Later delivery, when spine pathology is already apparent, was also effective. Our data provide proof-of-concept for GluN3A silencing as a beneficial strategy to prevent or reverse corticostriatal disconnectivity and motor impairment in HD and support the use of RNAi-based or small-molecule approaches for harnessing this therapeutic potential. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

The development of colon innervation in trisomy 16 mice and Hirschsprungs disease

PubMed Central

Li, Ji Cheng; Mi, Kai Hong; Zhou, Ji Lin; Busch, LC; Kuhnel, W

2001-01-01

AIM: To study the colon innervation of trisomy 16 mouse, an animal model for Down’s syndrome, and the expression of protein gene product 9.5 (PGP 9.5) in the stenosed segment of colon in Hirschsprungs disease (HD). METHODS: Trisomy 16 mouse breeding; cytogenetic analysis of trisomy 16 mice; and PGP 9.5 immunohistochemistry of colons of trisomy 16 mice and HD were carried out. RESULTS: Compared with their normal littermates, the nervous system of colon in trisomy 16 mice was abnormally developed. There existed developmental delay of muscular plexuses of colon, no submucosal plexus was found in the colon, and there was 5 mm aganglionic bowel aparting from the anus in trisomy 16 mice. The mesentery nerve fibers were as well developed as shown in their normal littermates. Abundant proliferation of PGP 9.5 positive nerve fibers was evealed in the stenosed segment of HD colon. CONCLUSION: Trisomy 16 mice could serve as an animal model for Hirschsprung’s disease for aganglionic bowel in the distal part of colon. Abundant proliferation of PGP 9.5 positive fibers resulted from extrinsic nerve compensation, since no ganglionic cells were observed in the stenosed segment of the colon in HD. HD has a genetic tendency. PMID:11819726

Modelling of three long-periodic magnetic CP-stars: HD 2453, HD 12288, and HD 200311

NASA Astrophysics Data System (ADS)

Glagolevskij, Yurij V.; Gerth, Ewald

2004-12-01

Using observational data published as phase curves of the effective magnetic field strength Be(P) and the surface field Bs(P), magnetic models of three stars with long rotational periods are calculated by the Magnetic Charge Distribution method. For two of these stars (HD 2453 and HD 12288), the structure of the magnetic field can be described well by a central dipole model. The third star (HD 200311) is better fitted by a model of a displaced dipole, being decentered by triangle r = 0.08 R along the dipole axis.

Depletion-Mode GaN HEMT Q-Spoil Switches for MRI Coils

PubMed Central

Lu, Jonathan Y.; Grafendorfer, Thomas; Zhang, Tao; Vasanawala, Shreyas; Robb, Fraser; Pauly, John M.; Scott, Greig C.

2017-01-01

Q-spoiling is the process of decoupling an MRI receive coil to protect the equipment and patient. Conventionally, Q-spoiling is performed using a PIN diode switch that draws significant current. In this work, a Q-spoiling technique using a depletion-mode Gallium Nitride HEMT device was developed for coil detuning at both 1.5 T and 3 T MRI. The circuits with conventional PIN diode Q-spoiling and the GaN HEMT device were implemented on surface coils. SNR was measured and compared for all surfaces coils. At both 1.5 T and 3 T, comparable SNR was achieved for all coils with the proposed technique and conventional Q-spoiling. The GaN HEMT device has significantly reduced the required power for Q-spoiling. The GaN HEMT device also provides useful safety features by detuning the coil when unpowered. PMID:27362895

Detection of planet candidates around K giants. HD 40956, HD 111591, and HD 113996

NASA Astrophysics Data System (ADS)

Jeong, G.; Lee, B.-C.; Han, I.; Omiya, M.; Izumiura, H.; Sato, B.; Harakawa, H.; Kambe, E.; Mkrtichian, D.

2018-02-01

Aims: The purpose of this paper is to detect and investigate the nature of long-term radial velocity (RV) variations of K-type giants and to confirm planetary companions around the stars. Methods: We have conducted two planet search programs by precise RV measurement using the 1.8 m telescope at Bohyunsan Optical Astronomy Observatory (BOAO) and the 1.88 m telescope at Okayama Astrophysical Observatory (OAO). The BOAO program searches for planets around 55 early K giants. The OAO program is looking for 190 G-K type giants. Results: In this paper, we report the detection of long-period RV variations of three K giant stars, HD 40956, HD 111591, and HD 113996. We investigated the cause of the observed RV variations and conclude the substellar companions are most likely the cause of the RV variations. The orbital analyses yield P = 578.6 ± 3.3 d, m sin i = 2.7 ± 0.6 MJ, a = 1.4 ± 0.1 AU for HD 40956; P = 1056.4 ± 14.3 d, m sin i = 4.4 ± 0.4 MJ, a = 2.5 ± 0.1 AU for HD 111591; P = 610.2 ± 3.8 d, m sin i = 6.3 ± 1.0 MJ, a = 1.6 ± 0.1 AU for HD 113996. Based on observations made with the BOES at BOAO in Korea and HIDES at OAO in Japan.Tables 3-5 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/610/A3

Subthreshold membrane potential oscillations in inferior olive neurons are dynamically regulated by P/Q- and T-type calcium channels: a study in mutant mice.

PubMed

Choi, Soonwook; Yu, Eunah; Kim, Daesoo; Urbano, Francisco J; Makarenko, Vladimir; Shin, Hee-Sup; Llinás, Rodolfo R

2010-08-15

The role of P/Q- and T-type calcium channels in the rhythmic oscillatory behaviour of inferior olive (IO) neurons was investigated in mutant mice. Mice lacking either the CaV2.1 gene of the pore-forming alpha1A subunit for P/Q-type calcium channel, or the CaV3.1 gene of the pore-forming alpha1G subunit for T-type calcium channel were used. In vitro intracellular recording from IO neurons reveals that the amplitude and frequency of sinusoidal subthreshold oscillations (SSTOs) were reduced in the CaV2.1-/- mice. In the CaV3.1-/- mice, IO neurons also showed altered patterns of SSTOs and the probability of SSTO generation was significantly lower (15%, 5 of 34 neurons) than that of wild-type (78%, 31 of 40 neurons) or CaV2.1-/- mice (73%, 22 of 30 neurons). In addition, the low-threshold calcium spike and the sustained endogenous oscillation following rebound potentials were absent in IO neurons from CaV3.1-/- mice. Moreover, the phase-reset dynamics of oscillatory properties of single neurons and neuronal clusters in IO were remarkably altered in both CaV2.1-/- and CaV3.1-/- mice. These results suggest that both alpha1A P/Q- and alpha1G T-type calcium channels are required for the dynamic control of neuronal oscillations in the IO. These findings were supported by results from a mathematical IO neuronal model that incorporated T and P/Q channel kinetics.

Observation of g/u-symmetry mixing in the high-n Rydberg states of HD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sprecher, Daniel; Merkt, Frédéric, E-mail: frederic.merkt@phys.chem.ethz.ch

2014-03-28

The structure and dynamics of high-n Rydberg states belonging to series converging to the (v{sup +} = 0, N{sup +} = 0–2) levels of the X{sup +2}Σ{sub g}{sup +} electronic ground state of HD{sup +} were studied by high-resolution spectroscopy from the GK{sup 1}Σ{sub g}{sup +} (v= 1, N = 1) state under field-free conditions. Three effects of g/u-symmetry breaking were detected: (i) Single-photon transitions from the GK (v = 1, N = 1) state of gerade symmetry to the 30d2{sub 1} and 31g2{sub 2} Rydberg states of gerade symmetry were observed after careful compensation of the stray electric fields. (ii)more » The singlet 61p1{sub 2} Rydberg state of ungerade symmetry was found to autoionize to the N{sup +} = 0, ℓ = 2 ionization continuum of gerade symmetry with a lifetime of 77(10) ns. (iii) Shifts of up to 20 MHz induced by g/u-symmetry mixing were measured for members of the np1{sub 1} Rydberg series which lie close to nd2{sub 1} Rydberg states. These observations were analyzed in the framework of multichannel quantum-defect theory. From the observed level shifts, the off-diagonal eigenquantum-defect element μ{sub pd} of singlet-π symmetry was determined to be 0.0023(3) and the corresponding autoionization dynamics could be characterized. The ionization energy of the GK (v = 1, N = 1) state of HD was determined to be 12 710.544 23(10) cm{sup −1}.« less

Activation pattern of ACE2/Ang-(1-7) and ACE/Ang II pathway in course of heart failure assessed by multiparametric MRI in vivo in Tgαq*44 mice.

PubMed

Tyrankiewicz, Urszula; Olkowicz, Mariola; Skórka, Tomasz; Jablonska, Magdalena; Orzylowska, Anna; Bar, Anna; Gonet, Michal; Berkowicz, Piotr; Jasinski, Krzysztof; Zoladz, Jerzy A; Smolenski, Ryszard T; Chlopicki, Stefan

2018-01-01

Here, we analyzed systemic (plasma) and local (heart/aorta) changes in ACE/ACE-2 balance in Tgαq*44 mice in course of heart failure (HF). Tgαq*44 mice with cardiomyocyte-specific Gαq overexpression and late onset of HF were analyzed at different age for angiotensin pattern in plasma, heart, and aorta using liquid chromatography/mass spectrometry, for progression of HF by in vivo magnetic resonance imaging under isoflurane anesthesia, and for physical activity by voluntary wheel running. Six-month-old Tgαq*44 mice displayed decreased ventricle radial strains and impaired left atrial function. At 8-10 mo, Tgαq*44 mice showed impaired systolic performance and reduced voluntary wheel running but exhibited preserved inotropic reserve. At 12 mo, Tgαq*44 mice demonstrated a severe impairment of basal cardiac performance and modestly compromised inotropic reserve with reduced voluntary wheel running. Angiotensin analysis in plasma revealed an increase in concentration of angiotensin-(1-7) in 6- to 10-mo-old Tgαq*44 mice. However, in 12- to 14-mo-old Tgαq*44 mice, increased angiotensin II was noted with a concomitant increase in Ang III, Ang IV, angiotensin A, and angiotensin-(1-10). The pattern of changes in the heart and aorta was also compatible with activation of ACE2, followed by activation of the ACE pathway. In conclusion, mice with cardiomyocyte Gαq protein overexpression develop HF that is associated with activation of the systemic and the local ACE/Ang II pathway. However, it is counterbalanced by a prominent ACE2/Ang-(1-7) activation, possibly allowing to delay decompensation. NEW & NOTEWORTHY Changes in ACE/ACE-2 balance were analyzed based on measurements of a panel of nine angiotensins in plasma, heart, and aorta of Tgαq*44 mice in relation to progression of heart failure (HF) characterized by multiparametric MRI and exercise performance. The early stage of HF was associated with upregulation of the ACE2/angiotensin-(1-7) pathway, whereas the end

An epidemiologic study of index and family infectious mononucleosis and adult Hodgkin's disease (HD): evidence for a specific association with EBV+ve HD in young adults.

PubMed

Alexander, Freda E; Lawrence, Davia J; Freeland, June; Krajewski, Andrew S; Angus, Brian; Taylor, G Malcolm; Jarrett, Ruth F

2003-11-01

Infectious mononucleosis (IM) is an established risk factor for Hodgkin's disease (HD). A substantial minority (33%) of cases of HD have Epstein-Barr virus (EBV) DNA within the malignant cells (are EBV+ve). It is unclear whether risk after IM applies specifically to EBV+ve HD. We report the results of a population-based case-control study of HD in adults (n = 408 cases of classical HD, 513 controls) aged 16-74 years; the case series included 113 EBV+ve and 243 EBV+ve HD. Analyses compared total HD, EBV+ve HD and EBV-ve HD with the controls and EBV+ve HD with EBV-ve HD cases using, mainly, logistic regression. Regression analyses were adjusted for gender, age-group and socioeconomic status, and were performed for the whole age range and separately for young (< 35 years) and old adults (> or = 35 years); formal tests of effect modification by age were included. For the young adults, reported IM in index or relative was strongly and significantly associated with EBV+ve HD when compared to controls (odds ratio [OR] = 2.94, 95% confidence interval [CI]: 1.08-7.98 and OR = 5.22, 95% CI: 2.15-12.68, respectively). These results may be interpreted as indications that late first exposure to EBV increases risk of HD, especially in young adults; this applies primarily to EBV+ve HD. Copyright 2003 Wiley-Liss, Inc.

High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington's disease CAG knock-in mice across multiple genetic backgrounds.

PubMed

Ament, Seth A; Pearl, Jocelynn R; Grindeland, Andrea; St Claire, Jason; Earls, John C; Kovalenko, Marina; Gillis, Tammy; Mysore, Jayalakshmi; Gusella, James F; Lee, Jong-Min; Kwak, Seung; Howland, David; Lee, Min Young; Baxter, David; Scherler, Kelsey; Wang, Kai; Geman, Donald; Carroll, Jeffrey B; MacDonald, Marcy E; Carlson, George; Wheeler, Vanessa C; Price, Nathan D; Hood, Leroy E

2017-03-01

Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+  mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ethological endophenotypes are altered by elevated stress hormone levels in both Huntington's disease and wildtype mice.

PubMed

Mo, Christina; Renoir, Thibault; Hannan, Anthony J

2014-11-01

Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder with cognitive, psychiatric, motor, neuroendocrine and peripheral dysfunctions. Symptom onset and progression can be closely modeled in HD transgenic mice, which facilitate the search for therapeutics and environmental modulators. In the first investigation of chronic stress in HD, we have previously shown that administering a moderate dose of the stress hormone, corticosterone (CORT) had no effect on short-term memory in wildtype (WT) mice but accelerated the onset of the impairment in male R6/1 HD mice. We now extend this investigation to ethological dysfunctions in HD, which we hypothesized to be more susceptible to CORT treatment compared to the same functions in WT littermates. Both genotypes consumed similar doses of CORT dissolved in drinking water across 6-14 weeks of age and were assessed for olfactory sensitivity, nest-building, saccharin preference as well as vocal responses to sociosexual stimuli. In female HD and WT mice, olfactory sensitivity and saccharin preference were reduced by 2 and 4 weeks of CORT, respectively. In males, there was no effect of CORT on saccharin preference, however the number of vocalizations to a female mouse was transiently increased by CORT-drinking, regardless of genotype. Nest-building was severely impaired in HD mice at an early age, but was unaffected by CORT. Our results suggest that the presence of the HD mutation had no bearing on CORT-induced effects at this dose, suggesting that even moderately elevated stress hormone levels can impair ethological behaviors in both the HD and healthy brain. Copyright © 2014 Elsevier B.V. All rights reserved.

The nature of the late B-type stars HD 67044 and HD 42035

NASA Astrophysics Data System (ADS)

Monier, R.; Gebran, M.; Royer, F.

2016-04-01

While monitoring a sample of apparently slowly rotating superficially normal bright late B and early A stars in the northern hemisphere, we have discovered that HD 67044 and HD 42035, hitherto classified as normal late B-type stars, are actually respectively a new chemically peculiar star and a new spectroscopic binary containing a very slow rotator HD 42035 S with ultra-sharp lines (v_{{e}}sin i= 3.7 km s^{-1}) and a fast rotator HD 42035 B with broad lines. The lines of Ti ii, Cr ii, Mn ii, Sr ii, Y ii, Zr ii and Ba ii are conspicuous features in the high resolution SOPHIE spectrum (R=75000) of HD 67044. The Hg ii line at 3983.93 Å is also present as a weak feature. The composite spectrum of HD 42035 is characterised by very sharp lines formed in HD 42035 S superimposed onto the shallow and broad lines of HD 42035 B. These very sharp lines are mostly due to light elements from C to Ni, the only heavy species definitely present are strontium and barium. Selected lines of 21 chemical elements from He up to Hg have been synthesized using model atmospheres computed with ATLAS9 and the spectrum synthesis code SYNSPEC48 including hyperfine structure of various isotopes when relevant. These synthetic spectra have been adjusted to high resolution high signal-to-noise spectra of HD 67044 and HD 42035 S in order to derive abundances of these key elements. HD 67044 is found to have distinct enhancements of Ti, Cr, Mn, Sr, Y, Zr, Ba and Hg and underabundances in He, C, O, Ca and Sc which shows that this star is not a superficially normal late B-type star, but actually is a new CP star most likely of the HgMn type. HD 42035 S has provisional underabundances of the light elements from C to Ti and overabundances of heavier elements (except for Fe and Sr which are also underabundant) up to barium. These values are lower limits to the actual abundances as we cannot currently place properly the continuum of HD 42035 S. More accurate fundamental parameters and abundances for HD

Subthreshold membrane potential oscillations in inferior olive neurons are dynamically regulated by P/Q- and T-type calcium channels: a study in mutant mice

PubMed Central

Choi, Soonwook; Yu, Eunah; Kim, Daesoo; Urbano, Francisco J; Makarenko, Vladimir; Shin, Hee-Sup; Llinás, Rodolfo R

2010-01-01

The role of P/Q- and T-type calcium channels in the rhythmic oscillatory behaviour of inferior olive (IO) neurons was investigated in mutant mice. Mice lacking either the CaV2.1 gene of the pore-forming α1A subunit for P/Q-type calcium channel, or the CaV3.1 gene of the pore-forming α1G subunit for T-type calcium channel were used. In vitro intracellular recording from IO neurons reveals that the amplitude and frequency of sinusoidal subthreshold oscillations (SSTOs) were reduced in the CaV2.1−/− mice. In the CaV3.1−/− mice, IO neurons also showed altered patterns of SSTOs and the probability of SSTO generation was significantly lower (15%, 5 of 34 neurons) than that of wild-type (78%, 31 of 40 neurons) or CaV2.1−/− mice (73%, 22 of 30 neurons). In addition, the low-threshold calcium spike and the sustained endogenous oscillation following rebound potentials were absent in IO neurons from CaV3.1−/− mice. Moreover, the phase-reset dynamics of oscillatory properties of single neurons and neuronal clusters in IO were remarkably altered in both CaV2.1−/− and CaV3.1−/− mice. These results suggest that both α1A P/Q- and α1G T-type calcium channels are required for the dynamic control of neuronal oscillations in the IO. These findings were supported by results from a mathematical IO neuronal model that incorporated T and P/Q channel kinetics. PMID:20547676

GnRH Neuron-Specific Ablation of Gαq/11 Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: In Vivo Evidence for Kiss1r-Coupled Gαq/11-Independent GnRH Secretion.

PubMed

Babwah, Andy V; Navarro, Víctor M; Ahow, Maryse; Pampillo, Macarena; Nash, Connor; Fayazi, Mehri; Calder, Michele; Elbert, Adrienne; Urbanski, Henryk F; Wettschureck, Nina; Offermanns, Stefan; Carroll, Rona S; Bhattacharya, Moshmi; Tobet, Stuart A; Kaiser, Ursula B

2015-09-16

The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility and kisspeptin (KP) is a potent trigger of GnRH secretion from GnRH neurons. KP signals via KISS1R, a Gαq/11-coupled receptor, and mice bearing a global deletion of Kiss1r (Kiss1r(-/-)) or a GnRH neuron-specific deletion of Kiss1r (Kiss1r(d/d)) display hypogonadotropic hypogonadism and infertility. KISS1R also signals via β-arrestin, and in mice lacking β-arrestin-1 or -2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of Gαq/11 in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that Gαq/11-independent GnRH secretion would be sufficient to maintain fertility. To test this, Gnaq (encodes Gαq) was selectively inactivated in the GnRH neurons of global Gna11 (encodes Gα11)-null mice by crossing Gnrh-Cre and Gnaq(fl/fl);Gna11(-/-) mice. Experimental Gnaq(fl/fl);Gna11(-/-);Gnrh-Cre (Gnaq(d/d)) and control Gnaq(fl/fl);Gna11(-/-) (Gnaq(fl/fl)) littermate mice were generated and subjected to reproductive profiling. This process revealed that testicular development and spermatogenesis, preputial separation, and anogenital distance in males and day of vaginal opening and of first estrus in females were significantly less affected in Gnaq(d/d) mice than in previously characterized Kiss1r(-/-) or Kiss1r(d/d) mice. Additionally, Gnaq(d/d) males were subfertile, and although Gnaq(d/d) females did not ovulate spontaneously, they responded efficiently to a single dose of gonadotropins. Finally, KP stimulation triggered a significant increase in gonadotropins and testosterone levels in Gnaq(d/d) mice. We therefore conclude that the milder reproductive phenotypes and maintained responsiveness to KP and gonadotropins reflect Gαq/11-independent GnRH secretion and activation of the neuroendocrine-reproductive axis in Gnaq(d/d) mice. The gonadotropin-releasing hormone (GnRH) is the master regulator of

A single dose of hypnotic corrects sleep and EEG abnormalities in symptomatic Huntington's disease mice.

PubMed

Kantor, Sandor; Varga, Janos; Morton, A Jennifer

2016-06-01

Sleep and electroencephalogram abnormalities are prominent early features of Huntington's disease (HD) that typically appear before the onset of characteristic motor symptoms. The changes in sleep and electroencephalogram seen in HD patients are largely recapitulated in mouse models of HD such as transgenic R6/2 lines. To test whether or not drugs with hypnotic properties can correct the sleep and electroencephalogram abnormalities seen in HD mice, we treated male wild-type (WT; N = 7) and R6/2 mice (N = 9) acutely with intraperitoneal injections of vehicle, zolpidem (5, 10 or 20 mg/kg) or amitriptyline (5, 10 or 20 mg/kg), and then monitored their sleep-wake behavior. In R6/2 mice, both zolpidem and amitriptyline suppressed the abnormally high REM sleep amount and electroencephalographic gamma (30-46 Hz) oscillations in a dose-dependent manner. Amitriptyline's effect on sleep was similar in both genotypes, whereas zolpidem showed significant genotype differences. Zolpidem exerted a strong hypnotic effect in WT mice by increasing electroencephalographic delta power, doubling the mean bout duration and the total amount of non-rapid eye movement sleep. However, no such effect was seen in R6/2 mice. Our study demonstrates that the pathophysiological changes seen in sleep and electroencephalogram are not 'hard-wired' in HD brain and can be reversed even at late stages of the disease. The diminished hypnotic effect of zolpidem suggests that the GABAergic control of sleep-wake states is impaired in HD mice. A better understanding of the neurochemical basis underlying these abnormalities should lead to more effective and rational therapies for HD. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Search for Planetary Transits of the Star HD 187123 by Spot Filter CCD Differential Photometry

NASA Technical Reports Server (NTRS)

Castellano, T.; DeVincenzi, D. (Technical Monitor)

2000-01-01

A novel method for performing high precision, time series CCD differential photometry of bright stars using a spot filter, is demonstrated. Results for several nights of observing of the 51 Pegasi b-type planet bearing star HD 187123 are presented. Photometric precision of 0.0015 - 0.0023 magnitudes is achieved. No transits are observed at the epochs predicted from the radial velocity observation. If the planet orbiting HD 187123 at 0.0415 AU is an inflated Jupiter similar in radius to HD 209458b it would have been detected at the greater than 6(sigma), level if the orbital inclination is near 90 degrees and at the greater than 3(sigma), level if the orbital inclination is as small as 82.7 degrees.

Red fluorescence and 3-12 micron emission in NGC 2023, HD 44179, M 82, and Lynds 1780

NASA Technical Reports Server (NTRS)

Ryter, Charles; Dhendecourt, Louis B.

1989-01-01

A red excess observed in the Red Rectangle (HD 44179), was attributed to a possible molecular fluorescence mechanism was discovered in NGC 2023 and analyzed in subsequent work in this and other nebulae. An unexpected red light excess was also noticed in a high latitude dark cloud L 1780. The fluorescence was attributed to hydrogenated amorphous carbon by Duley (1985), on the basis of laboratory work. Alternatively, transitions between electronic states of free polycyclic aromatic hydrocarbon molecules, by-passing the cascade along the vibrational states was considered. In L 1780, the red excess was related to the 12 micron emission detected by IRAS. A quantitative comparison of the intensity of the red fluorescence and that of the 3 to 12 micron features is thus warranted in helping assess the physical properties of large interstellar molecules. The red fluorescence radiation, F(R), appears as a bump on the spectra between 0.6 and 0.9 micron. Values were deduced from the spectra for HD 44179, and for the high latitude cloud L 1780. Corrections for the extinction, both interstellar and internal to the nebulae, were included. The 3 to 12 micron brightness, F(IR), was obtained through integration of the spectra for NGC 2023, and for HD 44179 after removal of a smooth continuum due to hot large grains. The values of the ratio of fluorescence flux to the infrared flux, F(R)/F(IR), are summarized. Red fluorescence and infrared radiation are two separate ways to access to the size of the molecules through observation, and it is rewarding that both approaches give similar results. These findings bring a striking coherence into the physical description of the particles, and add further support to the initial attribution of the infrared features to polycyclic aromatic hydrocarbons (PAHs).

q-bosons and the q-analogue quantized field

NASA Technical Reports Server (NTRS)

Nelson, Charles A.

1995-01-01

The q-analogue coherent states are used to identify physical signatures for the presence of a 1-analogue quantized radiation field in the q-CS classical limits where the absolute value of z is large. In this quantum-optics-like limit, the fractional uncertainties of most physical quantities (momentum, position, amplitude, phase) which characterize the quantum field are O(1). They only vanish as O(1/absolute value of z) when q = 1. However, for the number operator, N, and the N-Hamiltonian for a free q-boson gas, H(sub N) = h(omega)(N + 1/2), the fractional uncertainties do still approach zero. A signature for q-boson counting statistics is that (Delta N)(exp 2)/ (N) approaches 0 as the absolute value of z approaches infinity. Except for its O(1) fractional uncertainty, the q-generalization of the Hermitian phase operator of Pegg and Barnett, phi(sub q), still exhibits normal classical behavior. The standard number-phase uncertainty-relation, Delta(N) Delta phi(sub q) = 1/2, and the approximate commutation relation, (N, phi(sub q)) = i, still hold for the single-mode q-analogue quantized field. So, N and phi(sub q) are almost canonically conjugate operators in the q-CS classical limit. The q-analogue CS's minimize this uncertainty relation for moderate (absolute value of z)(exp 2).

The de-ubiquitinating enzyme ataxin-3 does not modulate disease progression in a knock-in mouse model of Huntington disease.

PubMed

Zeng, Li; Tallaksen-Greene, Sara J; Wang, Bo; Albin, Roger L; Paulson, Henry L

2013-01-01

Ataxin-3 is a deubiquitinating enzyme (DUB) that participates in ubiquitin-dependent protein quality control pathways and, based on studies in model systems, may be neuroprotective against toxic polyglutamine proteins such as the Huntington's disease (HD) protein, huntingtin (htt). HD is one of at least nine polyglutamine neurodegenerative diseases in which disease-causing proteins accumulate in ubiquitin-positive inclusions within neurons. In studies crossing mice null for ataxin-3 to an established HD knock-in mouse model (HdhQ200), we tested whether loss of ataxin-3 alters disease progression, perhaps by impairing the clearance of mutant htt or the ubiquitination of inclusions. While loss of ataxin-3 mildly exacerbated age-dependent motor deficits, it did not alter inclusion formation, ubiquitination of inclusions or levels of mutant or normal htt. Ataxin-3, itself a polyglutamine-containing protein with multiple ubiquitin binding domains, was not observed to localize to htt inclusions. Changes in neurotransmitter receptor binding known to occur in HD knock-in mice also were not altered by the loss of ataxin-3, although we unexpectedly observed increased GABAA receptor binding in the striatum of HdhQ200 mice, which has not previously been noted. Finally, we confirmed that CNS levels of hsp70 are decreased in HD mice as has been reported in other HD mouse models, regardless of the presence or absence of ataxin-3. We conclude that while ataxin-3 may participate in protein quality control pathways, it does not critically regulate the handling of mutant htt or contribute to major features of disease pathogenesis in HD.

Shadows and cavities in protoplanetary disks: HD 163296, HD 141569A, and HD 150193A in polarized light

NASA Astrophysics Data System (ADS)

Garufi, A.; Quanz, S. P.; Schmid, H. M.; Avenhaus, H.; Buenzli, E.; Wolf, S.

2014-08-01

Context. The morphological evolution of dusty disks around young (a few Myr old) stars is pivotal for a better understanding of planet formation. Since both dust grains and the global disk geometry evolve on short timescales, high-resolution imaging of a sample of objects may provide important indications about this evolution. Aims: We enlarge the sample of protoplanetary disks imaged in polarized light with high-resolution imaging (≲0.2″) by observing the Herbig Ae/Be stars HD 163296, HD 141569A, and HD 150193A. We combine our data with previous datasets to understand the larger context of their morphology. Methods: Polarimetric differential imaging is an attractive technique with which to image at near-IR wavelengths a significant fraction of the light scattered by the circumstellar material. The unpolarized stellar light is canceled out by combining two simultaneous orthogonal polarization states. This allowed us to achieve an inner working angle and an angular resolution as low as ~0.1″. Results: We report a weak detection of the disk around HD 163296 in the H and KS bands. The disk is resolved as a broken ring structure with a significant surface brightness drop inward of 0.6″. No sign of extended polarized emission is detected from the disk around HD 141569A and HD 150193A. Conclusions: We propose that the absence of scattered light in the inner 0.6″ around HD 163296 and the non-detection of the disk around HD 150193A may be due to similar geometric factors. Since these disks are known to be flat or only moderately flared, self-shadowing by the disk inner wall is the favored explanation. We show that the polarized brightness of a number of disks is indeed related to their flaring angle. Other scenarios (such as dust grain growth or interaction with icy molecules) are also discussed. On the other hand, the non-detection of HD 141569A is consistent with previous datasets that revealed a huge cavity in the dusty disk. Based on observations collected at

Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease.

PubMed

Gratuze, Maud; Noël, Anastasia; Julien, Carl; Cisbani, Giulia; Milot-Rousseau, Philippe; Morin, Françoise; Dickler, Maya; Goupil, Claudia; Bezeau, François; Poitras, Isabelle; Bissonnette, Stéphanie; Whittington, Robert A; Hébert, Sébastien S; Cicchetti, Francesca; Parker, J Alex; Samadi, Pershia; Planel, Emmanuel

2015-01-01

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms. For that purpose, we used the R6/2 mouse, a well-characterized model of HD, and analyzed tau phosphorylation before and after the onset of HD-like symptoms. We found a significant increase in tau hyperphosphorylation at the PHF-1 epitope in pre-symptomatic R6/2 mice, whereas symptomatic mice displayed tau hyperphosphorylation at multiple tau phosphoepitopes (AT8, CP13, PT205 and PHF-1). There was no activation of major tau kinases that could explain this observation. However, when we examined tau phosphatases, we found that calcineurin/PP2B was downregulated by 30% in pre-symptomatic and 50% in symptomatic R6/2 mice, respectively. We observed similar changes in tau phosphorylation and calcineurin expression in Q175 mice, another HD model. Calcineurin was also reduced in Q111 compared with Q7 cells. Finally, pharmacological or genetic inhibition of endogenous calcineurin was sufficient to promote tau hyperphosphorylation in neuronal cells. Taken together, our data suggest that mutant huntingtin can induce abnormal tau hyperphosphorylation in vivo, via the deregulation of calcineurin. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Magnetic biomineralisation in Huntington's disease transgenic mice

NASA Astrophysics Data System (ADS)

Beyhum, W.; Hautot, D.; Dobson, J.; Pankhurst, Q. A.

2005-01-01

The concentration levels of biogenic magnetite nanoparticles in transgenic R6/2 Huntington's disease (HD) mice have been investigated, using seven control and seven HD mice each from an 8 week-old litter and from a 12 week-old litter. Hysteresis and isothermal remnant magnetisation data were collected on a SQUID magnetometer, and analysed using a model comprising dia/paramagnetic, ferrimagnetic and superparamagnetic contributions, to extract the magnetite and ferritin concentrations present. It was found that magnetite was present in both superparamagnetic and blocked states. A larger spread and higher concentration of magnetite levels was found in the diseased mice for both the 8 week-old and 12 week-old batches, compared to the controls.

MGE-derived nNOS+ interneurons promote fear acquisition in nNOS-/- mice.

PubMed

Zhang, Lin; Yuan, Hong-Jin; Cao, Bo; Kong, Cheng-Cheng; Yuan, Fang; Li, Jun; Ni, Huan-Yu; Wu, Hai-Yin; Chang, Lei; Liu, Yan; Luo, Chun-Xia

2017-12-02

Neuronal nitric oxide synthase (nNOS) 1 , mainly responsible for NO release in central nervous system (CNS) 2 , plays a significant role in multiple physiological functions. However, the function of nNOS + interneurons in fear learning has not been much explored. Here we focused on the medial ganglionic eminences (MGE) 3 -derived nNOS + interneurons in fear learning. To determine the origin of nNOS + interneurons, we cultured neurons in vitro from MGE, cortex, lateral ganglionic eminence (LGE) 4 , caudal ganglionic eminences (CGE) 5 and preoptic area (POA) 6 . The results showed that MGE contained the most abundant precursors of nNOS + interneurons. Moreover, donor cells from E12.5 embryos demonstrated the highest positive rate of nNOS + interneurons compared with other embryonic periods (E11.5, E12, E13, E13.5 and E14). Additionally, these cells from E12.5 embryos showed long axonal and abundant dendritic arbors after 10 days culture, indicating the capability to disperse and integrate in host neural circuits after transplantation. To investigate the role of MGE-derived nNOS + interneurons in fear learning, donor MGE cells were transplanted into dentate gyrus (DG) 7 of nNOS knock-out (nNOS -/- ) or wild-type mice. Results showed that the transplantation of MGE cells promoted the acquisition of nNOS -/- but not the wild-type mice, suggesting the importance of nNOS + neurons in fear acquisition. Moreover, we transplanted MGE cells from nNOS -/- mice or wild-type mice into DG of the nNOS -/- mice and found that only MGE cells from wild-type mice but not the nNOS -/- mice rescued the deficit in acquisition of the nNOS -/- mice, further confirming the positive role of nNOS + neurons in fear learning. Copyright © 2017 Elsevier Inc. All rights reserved.

Evidences of extragalactic origin and planet engulfment in the metal-poor twin pair HD 134439/HD 134440

NASA Astrophysics Data System (ADS)

Reggiani, Henrique; Meléndez, Jorge

2018-04-01

Recent studies of chemical abundances in metal-poor halo stars show the existence of different populations, which is important for studies of Galaxy formation and evolution. Here, we revisit the twin pair of chemically anomalous stars HD 134439 and HD 134440, using high resolution (R ˜ 72 000) and high S/N ratio (S/N ˜ 250) HDS/Subaru spectra. We compare them to the well-studied halo star HD 103095, using the line-by-line differential technique to estimate precise stellar parameters and LTE chemical abundances. We present the abundances of C, O, Na, Mg, Si, Ca, Sc, Ti, V, Cr, Mn, Co, Ni, Cu, Zn, Sr, Y, Ba, La, Ce, Nd, and Sm. We compare our results to the precise abundance patterns of Nissen & Schuster (2010) and data from dwarf Spheroidal galaxies (dSphs). We show that the abundance pattern of these stars appears to be closely linked to that of dSphs with [α/Fe] knee below [Fe/H] < -1.5. We also find a systematic difference of 0.06 ± 0.01 dex between the abundances of these twin binary stars, which could be explained by the engulfment of a planet, thus suggesting that planet formation is possible at low metallicities ([Fe/H] = -1.4).

Behavioral Characterization of Knockin Mice with Mutations M287L and Q266I in the Glycine Receptor α1 Subunit

PubMed Central

Blednov, Yuri A.; Benavidez, Jill M.; Homanics, Gregg E.

2012-01-01

We used behavioral pharmacology to characterize heterozygous knockin mice with mutations (Q266I or M287L) in the α1 subunit of the glycine receptor (GlyR) (J Pharmacol Exp Ther 340:304–316, 2012). These mutations were designed to reduce (M287L) or eliminate (Q266I) ethanol potentiation of GlyR function. We asked which behavioral effects of ethanol would be reduced more in the Q266I mutant than the M287L and found rotarod ataxia to be the behavior that fulfilled this criterion. Compared with controls, the mutant mice also differed in ethanol consumption, ethanol-stimulated startle response, signs of acute physical dependence, and duration of loss of righting response produced by ethanol, butanol, ketamine, pentobarbital, and flurazepam. Some of these behavioral changes were mimicked in wild-type mice by acute injections of low, subconvulsive doses of strychnine. Both mutants showed increased acoustic startle response and increased sensitivity to strychnine seizures. Thus, in addition to reducing ethanol action on the GlyRs, these mutations reduced glycinergic inhibition, which may also alter sensitivity to GABAergic drugs. PMID:22037202

Transplantation of umbilical cord-derived mesenchymal stem cells into the striata of R6/2 mice: behavioral and neuropathological analysis

PubMed Central

2013-01-01

Introduction Huntington’s disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat on the short arm of chromosome 4 resulting in cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Neuropathologically, HD is characterized by a specific loss of medium spiny neurons in the caudate and the putamen, as well as subsequent neuronal loss in the cerebral cortex. The transgenic R6/2 mouse model of HD carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops some of the behavioral characteristics that are analogous to the human form of the disease. Mesenchymal stem cells (MSCs) have shown the ability to slow the onset of behavioral and neuropathological deficits following intrastriatal transplantation in rodent models of HD. Use of MSCs derived from umbilical cord (UC) offers an attractive strategy for transplantation as these cells are isolated from a noncontroversial and inexhaustible source and can be harvested at a low cost. Because UC MSCs represent an intermediate link between adult and embryonic tissue, they may hold more pluripotent properties than adult stem cells derived from other sources. Methods Mesenchymal stem cells, isolated from the UC of day 15 gestation pups, were transplanted intrastriatally into 5-week-old R6/2 mice at either a low-passage (3 to 8) or high-passage (40 to 50). Mice were tested behaviorally for 6 weeks using the rotarod task, the Morris water maze, and the limb-clasping response. Following behavioral testing, tissue sections were analyzed for UC MSC survival, the immune response to the transplanted cells, and neuropathological changes. Results Following transplantation of UC MSCs, R6/2 mice did not display a reduction in motor deficits but there appeared to be transient sparing in a spatial memory task when compared to untreated R6/2 mice. However, R6/2 mice receiving either low- or high-passage UC MSCs

Maternal Emotions and Self-Efficacy Beliefs in Relation to Boys and Girls with AD/HD

ERIC Educational Resources Information Center

Maniadaki, Katerina; Sonuga-Barke, Edmund; Kakouros, Efthymios; Karaba, Rania

2005-01-01

This study examined the impact of child gender on mothers' emotional responses to AD/HD, self-efficacy beliefs and perceived severity of AD/HD. Mothers (N = 118) of pre-schoolers were presented with a vignette describing a typical boy or girl with AD/HD and then completed three scales relating to their emotional response to AD/HD behaviour, their…

Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice.

PubMed

Falk, Marni J; Polyak, Erzsebet; Zhang, Zhe; Peng, Min; King, Rhonda; Maltzman, Jonathan S; Okwuego, Ezinne; Horyn, Oksana; Nakamaru-Ogiso, Eiko; Ostrovsky, Julian; Xie, Letian X; Chen, Jia Yan; Marbois, Beth; Nissim, Itzhak; Clarke, Catherine F; Gasser, David L

2011-07-01

Therapy of mitochondrial respiratory chain diseases is complicated by limited understanding of cellular mechanisms that cause the widely variable clinical findings. Here, we show that focal segmental glomerulopathy-like kidney disease in Pdss2 mutant animals with primary coenzyme Q (CoQ) deficiency is significantly ameliorated by oral treatment with probucol (1% w/w). Preventative effects in missense mutant mice are similar whether fed probucol from weaning or for 3 weeks prior to typical nephritis onset. Furthermore, treating symptomatic animals for 2 weeks with probucol significantly reduces albuminuria. Probucol has a more pronounced health benefit than high-dose CoQ(10) supplementation and uniquely restores CoQ(9) content in mutant kidney. Probucol substantially mitigates transcriptional alterations across many intermediary metabolic domains, including peroxisome proliferator-activated receptor (PPAR) pathway signaling. Probucol's beneficial effects on the renal and metabolic manifestations of Pdss2 disease occur despite modest induction of oxidant stress and appear independent of its hypolipidemic effects. Rather, decreased CoQ(9) content and altered PPAR pathway signaling appear, respectively, to orchestrate the glomerular and global metabolic consequences of primary CoQ deficiency, which are both preventable and treatable with oral probucol therapy. Copyright © 2011 EMBO Molecular Medicine.

MitoQ supplementation prevent long-term impact of maternal smoking on renal development, oxidative stress and mitochondrial density in male mice offspring.

PubMed

Sukjamnong, Suporn; Chan, Yik Lung; Zakarya, Razia; Nguyen, Long The; Anwer, Ayad G; Zaky, Amgad A; Santiyanont, Rachana; Oliver, Brian G; Goldys, Ewa; Pollock, Carol A; Chen, Hui; Saad, Sonia

2018-04-26

To investigate the effect of maternal MitoQ treatment on renal disorders caused by maternal cigarette smoke exposure (SE). We have demonstrated that maternal SE during pregnancy increases the risk of developing chronic kidney disease (CKD) in adult offspring. Mitochondrial oxidative damage contributes to the adverse effects of maternal smoking on renal disorders. MitoQ is a mitochondria-targeted antioxidant that has been shown to protect against oxidative damage-related pathologies in many diseases. Female Balb/c mice (8 weeks) were divided into Sham (exposed to air), SE (exposed to cigarette smoke) and SEMQ (exposed to cigarette smoke with MitoQ supplemented from mating) groups. Kidneys from the mothers were collected when the pups weaned and those from the offspring were collected at 13 weeks. Maternal MitoQ supplementation during gestation and lactation significantly reversed the adverse impact of maternal SE on offspring's body weight, kidney mass and renal pathology. MitoQ administration also significantly reversed the impact of SE on the renal cellular mitochondrial density and renal total reactive oxygen species in both the mothers and their offspring in adulthood. Our results suggested that MitoQ supplementation can mitigate the adverse impact of maternal SE on offspring's renal pathology, renal oxidative stress and mitochondrial density in mice offspring.

Mutant Huntingtin Causes a Selective Decrease in the Expression of Synaptic Vesicle Protein 2C.

PubMed

Peng, Chaohua; Zhu, Gaochun; Liu, Xiangqian; Li, He

2018-04-30

Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin (Htt) protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 (SV2s), a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic (TG) mice and Neuro2a mouse neuroblastoma cells (N2a cells) expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not significantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progressively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt-mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.

A natural variant of obestatin, Q90L, inhibits ghrelin's action on food intake and GH secretion and targets NPY and GHRH neurons in mice.

PubMed

Hassouna, Rim; Zizzari, Philippe; Viltart, Odile; Yang, Seung-Kwon; Gardette, Robert; Videau, Catherine; Badoer, Emilio; Epelbaum, Jacques; Tolle, Virginie

2012-01-01

Ghrelin and obestatin are two gut-derived peptides originating from the same ghrelin/obestatin prepropeptide gene (GHRL). While ghrelin stimulates growth hormone (GH) secretion and food intake and inhibits γ-aminobutyric-acid synaptic transmission onto GHRH (Growth Hormone Releasing Hormone) neurons, obestatin blocks these effects. In Humans, GHRL gene polymorphisms have been associated with pathologies linked to an unbalanced energy homeostasis. We hypothesized that one polymorphism located in the obestatin sequence (Q to L substitution in position 90 of the ghrelin/obestatin prepropeptide, rs4684677) may impact on the function of obestatin. In the present study, we tested the activity of native and Q90L obestatin to modulate ghrelin-induced food intake, GH secretion, cFos activity in GHRH and Neuropeptide Y (NPY) neurons and γ-aminobutyric-acid activity onto GHRH neurons. Food intake, GH secretion and electrophysiological recordings were assessed in C57BL/6 mice. cFos activity was measured in NPY-Renilla-GFP and GHRH-eGFP mice. Mice received saline, ghrelin or ghrelin combined to native or Q90L obestatin (30 nmol each) in the early light phase. Ghrelin stimulation of food intake and GH secretion varied considerably among individual mice with 59-77% eliciting a robust response. In these high-responders, ghrelin-induced food intake and GH secretion were reduced equally by native and Q90L obestatin. In contrast to in vivo observations, Q90L was slightly more efficient than native obestatin in inhibiting ghrelin-induced cFos activation within the hypothalamic arcuate nucleus and the nucleus tractus solitarius of the brainstem. After ghrelin injection, 26% of NPY neurons in the arcuate nucleus expressed cFos protein and this number was significantly reduced by co-administration of Q90L obestatin. Q90L was also more potent that native obestatin in reducing ghrelin-induced inhibition of γ-aminobutyric-acid synaptic transmission onto GHRH neurons. These data support

Genome-wide linkage scans for type 2 diabetes mellitus in four ethnically diverse populations-significant evidence for linkage on chromosome 4q in African Americans: the Family Investigation of Nephropathy and Diabetes Research Group.

PubMed

Malhotra, Alka; Igo, Robert P; Thameem, Farook; Kao, W H Linda; Abboud, Hanna E; Adler, Sharon G; Arar, Nedal H; Bowden, Donald W; Duggirala, Ravindranath; Freedman, Barry I; Goddard, Katrina A B; Ipp, Eli; Iyengar, Sudha K; Kimmel, Paul L; Knowler, William C; Kohn, Orly; Leehey, David; Meoni, Lucy A; Nelson, Robert G; Nicholas, Susanne B; Parekh, Rulan S; Rich, Stephen S; Chen, Yii-Der I; Saad, Mohammed F; Scavini, Marina; Schelling, Jeffrey R; Sedor, John R; Shah, Vallabh O; Taylor, Kent D; Thornley-Brown, Denyse; Zager, Philip G; Horvath, Amanda; Hanson, Robert L

2009-11-01

Previous studies have shown that in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations. Phenotypic and genotypic data were obtained from African American (AA; total number of individuals [N] = 1004), American Indian (AI; N = 883), European American (EA; N = 537), and Mexican American (MA; N = 1634) individuals from the Family Investigation of Nephropathy and Diabetes. Non-parametric linkage analysis, using an average of 4404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM. Statistically significant evidence for linkage was observed on chromosome 4q21.1 (LOD = 3.13; genome-wide p = 0.04) in AA. In addition, a total of 11 regions showed suggestive evidence for linkage (estimated at LOD > 1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD = 2.02) and 22q12.3 (LOD = 2.38) in AA, 2p11.1 (LOD = 2.23) in AI, 6p12.3 (LOD = 2.77) in EA, and 13q21.1 (LOD = . 2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD > 1.71 have been identified in previously published studies. The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA; 6p in EA; 2p in AI; and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.

HD-SAO-DM cross index

NASA Technical Reports Server (NTRS)

Nagy, T. A.; Mead, J.

1978-01-01

A table of correspondence SAO-HD-DM-GC was prepared by Morin (1973). The machine-readable version of this cross identification was obtained from the Centre de Donnees Stellaires (Strasbourg, France). The table was sorted at the Goddard Space Flight Center by HD number and all blank HD number records were removed to produce the HD-SAO-DM table presented. There were 258997 entries in the original table; there are 180411 entries after removing the blank HD records. The Boss General Catalogue (GC) numbers were retained on the machine-readable version after the sort.

Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract

PubMed Central

Shen, Koning; Calamini, Barbara; Fauerbach, Jonathan A; Ma, Boxue; Shahmoradian, Sarah H; Serrano Lachapel, Ivana L; Chiu, Wah; Lo, Donald C; Frydman, Judith

2016-01-01

Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington’s disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases. DOI: http://dx.doi.org/10.7554/eLife.18065.001 PMID:27751235

Functional magnetic resonance imaging of working memory in Huntington's disease: cross-sectional data from the IMAGE-HD study.

PubMed

Georgiou-Karistianis, Nellie; Stout, Julie C; Domínguez D, Juan F; Carron, Sarah P; Ando, Ayaka; Churchyard, Andrew; Chua, Phyllis; Bohanna, India; Dymowski, Alicia R; Poudel, Govinda; Egan, Gary F

2014-05-01

We used functional magnetic resonance imaging (fMRI) to investigate spatial working memory (WM) in an N-BACK task (0, 1, and 2-BACK) in premanifest Huntington's disease (pre-HD, n = 35), early symptomatic Huntington's disease (symp-HD, n = 23), and control (n = 32) individuals. Overall, both WM conditions (1-BACK and 2-BACK) activated a large network of regions throughout the brain, common to all groups. However, voxel-wise and time-course analyses revealed significant functional group differences, despite no significant behavioral performance differences. During 1-BACK, voxel-wise blood-oxygen-level-dependent (BOLD) signal activity was significantly reduced in a number of regions from the WM network (inferior frontal gyrus, anterior insula, caudate, putamen, and cerebellum) in pre-HD and symp-HD groups, compared with controls; however, time-course analysis of the BOLD response in the dorsolateral prefrontal cortex (DLPFC) showed increased activation in symp-HD, compared with pre-HD and controls. The pattern of reduced voxel-wise BOLD activity in pre-HD and symp-HD, relative to controls, became more pervasive during 2-BACK affecting the same structures as in 1-BACK, but also incorporated further WM regions (anterior cingulate gyrus, parietal lobe and thalamus). The DLPFC BOLD time-course for 2-BACK showed a reversed pattern to that observed in 1-BACK, with a significantly diminished signal in symp-HD, relative to pre-HD and controls. Our findings provide support for functional brain reorganisation in cortical and subcortical regions in both pre-HD and symp-HD, which are modulated by task difficulty. Moreover, the lack of a robust striatal BOLD signal in pre-HD may represent a very early signature of change observed up to 15 years prior to clinical diagnosis. Copyright © 2013 Wiley Periodicals, Inc.

Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors.

PubMed

Lewis, Alan S; Pittenger, Steven T; Mineur, Yann S; Stout, Dawson; Smith, Philip H; Picciotto, Marina R

2018-05-01

Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the α7 nicotinic acetylcholine receptor (nAChR), and manifest a variable neuropsychiatric phenotype that frequently includes persistent aggression. In mice, nAChR activation by nicotine is anti-aggressive, or 'serenic,' an effect which requires α7 nAChRs and is recapitulated by GTS-21, an α7 nAChR partial agonist. Pharmacotherapies potentiating α7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the α7 nAChR as an important regulator of aggressive behavior, but the underlying neurobiological substrates remain to be determined. We therefore investigated the brain regions and potential neural circuits in which α7 nAChRs regulate aggressive behavior in male mice. As in 15q13.3DS, mice heterozygous for Chrna7 were significantly more aggressive compared to wild-type controls in the resident-intruder test. We subsequently examined the hippocampus, where α7 nAChRs are highly expressed, particularly in GABAergic interneurons. Resident-intruder interactions strongly activated granule cells in the dentate gyrus (DG). In contrast, GTS-21, which reduces aggression in mice, reduced DG granule cell activity during resident-intruder interactions. Short hairpin RNA knockdown of Chrna7 in the DG enhanced baseline aggression and eliminated the serenic effects of both nicotine and GTS-21 on attack latency. These data further implicate α7 nAChRs in regulation of aggression, and demonstrate that hippocampal α7 nAChR signaling is necessary and sufficient to limit aggression. These findings suggest that nAChR-mediated regulation of hippocampal excitatory-inhibitory balance could be a promising therapeutic intervention for aggression arising in certain forms of neuropsychiatric disease.

Highly sensitive and selective determination of redox states of coenzymes Q9 and Q10 in mice tissues: Application of orbitrap mass spectrometry.

PubMed

Pandey, Renu; Riley, Christopher L; Mills, Edward M; Tiziani, Stefano

2018-06-29

Coenzyme Q (CoQ) is a redox active molecule that plays a fundamental role in mitochondrial energy generation and functions as a potent endogenous antioxidant. Redox ratio of CoQ has been suggested as a good marker of mitochondrial dysfunction and oxidative stress. Nevertheless, simultaneous measurement of redox states of CoQ is challenging owing to its hydrophobicity and instability of the reduced form. In order to improve the analytical methodology, paying special attention to this instability, we developed a highly sensitive and selective high-resolution/accurate-mass (HR/AM) UHPLC-MS/MS method for the rapid determination of redox states of CoQ 9 and CoQ 10 by ultra-performance liquid chromatography-hybrid quadrupole-Orbitrap mass spectrometry. CoQs were extracted using hexane with the addition of butylated hydroxytoluene to limit oxidation during sample preparation. Chromatographic separation of the analytes was achieved on a Kinetex C 18 column with the isocratic elution of 5 mM ammonium formate in 2-propanol/methanol (60:40) within 4 min. A full MS/all ion fragmentation (AIF) acquisition mode with mass accuracy < 5 ppm was used for detection and determination of redox states of CoQ 9 and CoQ 10 in healthy mice tissues using reduced and oxidized CoQ 4 as internal standards. The validated method showed good linearity (r 2  ≥ 0.9991), intraday, inter-day precision (CVs ≤ 11.9%) and accuracy (RE ≤±15.2%). In contrast to existing methods, the current method offers enhanced sensitivity (up to 52 fold) with LOD and LOQ ranged from 0.01 to 0.49 ng mL -1 and 0.04-1.48 ng mL -1 , respectively. Moreover, we evaluated various diluents to investigate bench top stability (at 4 °C) of targeted analytes in tissue samples during LC-MS assay up to 24 h. Ethanol was determined to be an optimum diluent without any significant oxidation of reduced CoQ up to 24 h. The developed method offers a rapid, highly sensitive and selective strategy

Genome-wide analysis of soybean HD-Zip gene family and expression profiling under salinity and drought treatments.

PubMed

Chen, Xue; Chen, Zhu; Zhao, Hualin; Zhao, Yang; Cheng, Beijiu; Xiang, Yan

2014-01-01

Homeodomain-leucine zipper (HD-Zip) proteins, a group of homeobox transcription factors, participate in various aspects of normal plant growth and developmental processes as well as environmental responses. To date, no overall analysis or expression profiling of the HD-Zip gene family in soybean (Glycine max) has been reported. An investigation of the soybean genome revealed 88 putative HD-Zip genes. These genes were classified into four subfamilies, I to IV, based on phylogenetic analysis. In each subfamily, the constituent parts of gene structure and motif were relatively conserved. A total of 87 out of 88 genes were distributed unequally on 20 chromosomes with 36 segmental duplication events, indicating that segmental duplication is important for the expansion of the HD-Zip family. Analysis of the Ka/Ks ratios showed that the duplicated genes of the HD-Zip family basically underwent purifying selection with restrictive functional divergence after the duplication events. Analysis of expression profiles showed that 80 genes differentially expressed across 14 tissues, and 59 HD-Zip genes are differentially expressed under salinity and drought stress, with 20 paralogous pairs showing nearly identical expression patterns and three paralogous pairs diversifying significantly under drought stress. Quantitative real-time RT-PCR (qRT-PCR) analysis of six paralogous pairs of 12 selected soybean HD-Zip genes under both drought and salinity stress confirmed their stress-inducible expression patterns. This study presents a thorough overview of the soybean HD-Zip gene family and provides a new perspective on the evolution of this gene family. The results indicate that HD-Zip family genes may be involved in many plant responses to stress conditions. Additionally, this study provides a solid foundation for uncovering the biological roles of HD-Zip genes in soybean growth and development.

Genome-Wide Analysis of Soybean HD-Zip Gene Family and Expression Profiling under Salinity and Drought Treatments

PubMed Central

Chen, Xue; Chen, Zhu; Zhao, Hualin; Zhao, Yang; Cheng, Beijiu; Xiang, Yan

2014-01-01

Background Homeodomain-leucine zipper (HD-Zip) proteins, a group of homeobox transcription factors, participate in various aspects of normal plant growth and developmental processes as well as environmental responses. To date, no overall analysis or expression profiling of the HD-Zip gene family in soybean (Glycine max) has been reported. Methods and Findings An investigation of the soybean genome revealed 88 putative HD-Zip genes. These genes were classified into four subfamilies, I to IV, based on phylogenetic analysis. In each subfamily, the constituent parts of gene structure and motif were relatively conserved. A total of 87 out of 88 genes were distributed unequally on 20 chromosomes with 36 segmental duplication events, indicating that segmental duplication is important for the expansion of the HD-Zip family. Analysis of the Ka/Ks ratios showed that the duplicated genes of the HD-Zip family basically underwent purifying selection with restrictive functional divergence after the duplication events. Analysis of expression profiles showed that 80 genes differentially expressed across 14 tissues, and 59 HD-Zip genes are differentially expressed under salinity and drought stress, with 20 paralogous pairs showing nearly identical expression patterns and three paralogous pairs diversifying significantly under drought stress. Quantitative real-time RT-PCR (qRT-PCR) analysis of six paralogous pairs of 12 selected soybean HD-Zip genes under both drought and salinity stress confirmed their stress-inducible expression patterns. Conclusions This study presents a thorough overview of the soybean HD-Zip gene family and provides a new perspective on the evolution of this gene family. The results indicate that HD-Zip family genes may be involved in many plant responses to stress conditions. Additionally, this study provides a solid foundation for uncovering the biological roles of HD-Zip genes in soybean growth and development. PMID:24498296

Carbon and nitrogen abundances in the supergiants HD 93840 and zeta Per

NASA Technical Reports Server (NTRS)

Massa, Derck; Altner, Bruce; Wynne, David; Lamers, H. J. G. L. M.

1990-01-01

The BN supergiant HD 93840 is shown to have the same temperature and surface gravity as the normal Bi Ib zeta Per. Differential abundance analysis of their C 4 and N 5 wind line profiles are found. The results are independent of the usual model atmosphere analyses and, therefore, a valuable check on them. Ratios for the C and N surface abundances in HD 93840 compared to Per of 1:10 and 4.6:1 are found respectively. By introducing a simple model for the compositions of both atmospheres the fraction of material in each atmosphere which has undergone CNO processing, more than 90 percent for HD 93840 and less than about 15 percent for zeta Per, is derived.

Effects of Combined Treatment with Branched-Chain Amino Acids, Citric Acid, L-Carnitine, Coenzyme Q10, Zinc, and Various Vitamins in Tumor-Bearing Mice.

PubMed

Awa, Hiroko; Futamura, Akihiko; Higashiguchi, Takashi; Ito, Akihiro; Mori, Naoharu; Murai, Miyo; Ohara, Hiroshi; Chihara, Takeshi; Kaneko, Takaaki

2017-03-01

A functional dietary supplement (FDS) containing Coenzyme Q10, branched-chain amino acids and L-carnitine was administered to tumor-bearing mice, investigating its effects on tumor and muscle tissues. Experiment (A): B16 melanoma cells were implanted subcutaneously into the right side of the abdomen of 8- to 9-week-old C57BL/6J mice. The mice were divided into two groups: a FDS group that received oral administration of FDS (n=10), and a control group that received oral administration of glucose (n=10). The moribund condition was used as the endpoint, and median survival time was determined. Experiment (B): On day 21 after tumor implantation, tumors, soleus muscle, gastrocnemius muscle, and suprahyoid muscles were collected. Tumor and muscle weight and other aspects were evaluated in each group: FDS group (n=15) and control group (n=15). The median survival time was comparable (21 d in the FDS group vs. 18 d in the control group, p=0.30). However, cumulative food intake was significantly higher in the FDS group than the control group (p=0.011). Metastasis of melanoma to the lung was observed in the control group but not in the FDS group (p=0.043). The weight of the suprahyoid muscles was significantly higher in the FDS group than in the control group (p=0.0045). The weight of the tumor was significantly lower in the FDS group than in the control group (p=0.013). The results possibly suggest oral administration of FDS in tumor-bearing mice enhances the maintenance of suprahyoid muscles, resulting in an extended feeding period and suppression of tumor growth and metastasis.

Spinal blockage of P/Q- or N-type voltage-gated calcium channels modulates functional and symptomatic changes related to haemorrhagic cystitis in mice

PubMed Central

Silva, R B M; Sperotto, N D M; Andrade, E L; Pereira, T C B; Leite, C E; de Souza, A H; Bogo, M R; Morrone, F B; Gomez, M V; Campos, M M

2015-01-01

Background and Purpose Spinal voltage-gated calcium channels (VGCCs) are pivotal regulators of painful and inflammatory alterations, representing attractive therapeutic targets. We examined the effects of epidural administration of the P/Q- and N-type VGCC blockers Tx3-3 and Phα1β, respectively, isolated from the spider Phoneutria nigriventer, on symptomatic, inflammatory and functional changes allied to mouse cyclophosphamide (CPA)-induced haemorrhagic cystitis (HC). The effects of P. nigriventer-derived toxins were compared with those displayed by MVIIC and MVIIA, extracted from the cone snail Conus magus. Experimental Approach HC was induced by a single i.p. injection of CPA (300 mg·kg–1). Dose- and time-related effects of spinally administered P/Q and N-type VGCC blockers were assessed on nociceptive behaviour and macroscopic inflammation elicited by CPA. The effects of toxins were also evaluated on cell migration, cytokine production, oxidative stress, functional cystometry alterations and TRPV1, TRPA1 and NK1 receptor mRNA expression. Key Results The spinal blockage of P/Q-type VGCC by Tx3-3 and MVIIC or N-type VGCC by Phα1β attenuated nociceptive and inflammatory events associated with HC, including bladder oxidative stress and cytokine production. CPA produced a slight increase in bladder TRPV1 and TRPA1 mRNA expression, which was reversed by all the toxins tested. Noteworthy, Phα1β strongly prevented bladder neutrophil migration, besides HC-related functional alterations, and its effects were potentiated by co-injecting the selective NK1 receptor antagonist CP-96345. Conclusions and Implications Our results shed new light on the role of spinal P/Q and N-type VGCC in bladder dysfunctions, pointing out Phα1β as a promising alternative for treating complications associated with CPA-induced HC. PMID:25298144

Combination of N149S and D171G mutations in Aeromonas caviae polyhydroxyalkanoate synthase and impact on polyhydroxyalkanoate biosynthesis.

PubMed

Tsuge, Takeharu; Watanabe, Shinko; Shimada, Daisuke; Abe, Hideki; Doi, Yoshiharu; Taguchi, Seiichi

2007-12-01

Aeromonas caviae polyhydroxyalkanoate synthase (PhaC(Ac)) is an important biocatalyst for the synthesis of practically useful two-component polyhydroxyalkanoate copolymer, poly[(R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate] [P(3HB-co-3HHx)]. In a previous study, two PhaC(Ac) mutants that have a single amino acid substitution of either asparagine 149 by serine (N149S) or aspartate 171 by glycine (D171G) were isolated as higher active enzymes by means of evolutionary engineering. In this study, the synergistic effects of N149S and D171G double mutation (NSDG) in PhaC(Ac) on polyhydroxyalkanoate biosynthesis were investigated in recombinant Ralstonia eutropha. The PhaC(Ac) NSDG mutant showed enhanced incorporation of longer 3-hydroxyalkanoate (3HA) units into the polyhydroxyalkanoate copolymer from octanoate (3HA fraction: 18.5 mol%) and soybean oil (5.4 mol%) as a carbon source. Besides, the NSDG mutant synthesized P(3HB) homopolymer with a very high molecular weight (M(w)=368 x 10(4)) when fructose was used as a carbon source. Thus, a combination of the beneficial mutations synergistically altered enzymatic properties, leading to synthesis of a polyhydroxyalkanoate copolymer with enhanced 3HA fraction and increased molecular weight.

A Natural Variant of Obestatin, Q90L, Inhibits Ghrelin's Action on Food Intake and GH Secretion and Targets NPY and GHRH Neurons in Mice

PubMed Central

Hassouna, Rim; Zizzari, Philippe; Viltart, Odile; Yang, Seung-Kwon; Gardette, Robert; Videau, Catherine; Badoer, Emilio; Epelbaum, Jacques; Tolle, Virginie

2012-01-01

Background Ghrelin and obestatin are two gut-derived peptides originating from the same ghrelin/obestatin prepropeptide gene (GHRL). While ghrelin stimulates growth hormone (GH) secretion and food intake and inhibits γ-aminobutyric-acid synaptic transmission onto GHRH (Growth Hormone Releasing Hormone) neurons, obestatin blocks these effects. In Humans, GHRL gene polymorphisms have been associated with pathologies linked to an unbalanced energy homeostasis. We hypothesized that one polymorphism located in the obestatin sequence (Q to L substitution in position 90 of the ghrelin/obestatin prepropeptide, rs4684677) may impact on the function of obestatin. In the present study, we tested the activity of native and Q90L obestatin to modulate ghrelin-induced food intake, GH secretion, cFos activity in GHRH and Neuropeptide Y (NPY) neurons and γ-aminobutyric-acid activity onto GHRH neurons. Methodology/Principal findings Food intake, GH secretion and electrophysiological recordings were assessed in C57BL/6 mice. cFos activity was measured in NPY-Renilla-GFP and GHRH-eGFP mice. Mice received saline, ghrelin or ghrelin combined to native or Q90L obestatin (30 nmol each) in the early light phase. Ghrelin stimulation of food intake and GH secretion varied considerably among individual mice with 59–77% eliciting a robust response. In these high-responders, ghrelin-induced food intake and GH secretion were reduced equally by native and Q90L obestatin. In contrast to in vivo observations, Q90L was slightly more efficient than native obestatin in inhibiting ghrelin-induced cFos activation within the hypothalamic arcuate nucleus and the nucleus tractus solitarius of the brainstem. After ghrelin injection, 26% of NPY neurons in the arcuate nucleus expressed cFos protein and this number was significantly reduced by co-administration of Q90L obestatin. Q90L was also more potent that native obestatin in reducing ghrelin-induced inhibition of γ-aminobutyric-acid synaptic

High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington's disease expansion mutation carriers shows normal mitochondrial respiratory function.

PubMed

Buck, Eva; Zügel, Martina; Schumann, Uwe; Merz, Tamara; Gumpp, Anja M; Witting, Anke; Steinacker, Jürgen M; Landwehrmeyer, G Bernhard; Weydt, Patrick; Calzia, Enrico; Lindenberg, Katrin S

2017-01-01

Alterations in mitochondrial respiration are an important hallmark of Huntington's disease (HD), one of the most common monogenetic causes of neurodegeneration. The ubiquitous expression of the disease causing mutant huntingtin gene raises the prospect that mitochondrial respiratory deficits can be detected in skeletal muscle. While this tissue is readily accessible in humans, transgenic animal models offer the opportunity to cross-validate findings and allow for comparisons across organs, including the brain. The integrated respiratory chain function of the human vastus lateralis muscle was measured by high-resolution respirometry (HRR) in freshly taken fine-needle biopsies from seven pre-manifest HD expansion mutation carriers and nine controls. The respiratory parameters were unaffected. For comparison skeletal muscle isolated from HD knock-in mice (HdhQ111) as well as a broader spectrum of tissues including cortex, liver and heart muscle were examined by HRR. Significant changes of mitochondrial respiration in the HdhQ knock-in mouse model were restricted to the liver and the cortex. Mitochondrial mass as quantified by mitochondrial DNA copy number and citrate synthase activity was stable in murine HD-model tissue compared to control. mRNA levels of key enzymes were determined to characterize mitochondrial metabolic pathways in HdhQ mice. We demonstrated the feasibility to perform high-resolution respirometry measurements from small human HD muscle biopsies. Furthermore, we conclude that alterations in respiratory parameters of pre-manifest human muscle biopsies are rather limited and mirrored by a similar absence of marked alterations in HdhQ skeletal muscle. In contrast, the HdhQ111 murine cortex and liver did show respiratory alterations highlighting the tissue specific nature of mutant huntingtin effects on respiration.

Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington's disease

PubMed Central

Yin, Xiangling; Manczak, Maria; Reddy, P. Hemachandra

2016-01-01

The objective of this study was to determine the protective effects of the mitochondria-targeted molecules MitoQ and SS31 in striatal neurons that stably express mutant huntingtin (Htt) (STHDhQ111/Q111) in Huntington's disease (HD). We studied mitochondrial and synaptic activities by measuring mRNA and the protein levels of mitochondrial and synaptic genes, mitochondrial function, and ultra-structural changes in MitoQ- and SS31-treated mutant Htt neurons relative to untreated mutant Htt neurons. We used gene expression analysis, biochemical methods, transmission electron microscopy (TEM) and confocal microscopy methods. In the MitoQ- and SS31-treated mutant Htt neurons, fission genes Drp1 and Fis1 were down-regulated, and fusion genes Mfn1, Mfn2 and Opa1 were up-regulated relative to untreated neurons, suggesting that mitochondria-targeted molecules reduce fission activity. Interestingly, the mitochondrial biogenesis genes PGC1α, PGC1β, Nrf1, Nrf2 and TFAM were up-regulated in MitoQ- and SS31-treated mutant Htt neurons. The synaptic genes synaptophysin and PSD95 were up-regulated, and mitochondrial function was normal in the MitoQ- and SS31-treated mutant Htt neurons. Immunoblotting findings of mitochondrial and synaptic proteins agreed with the mRNA findings. TEM studies revealed decreased numbers of structurally intact mitochondria in MitoQ- and SS31-treated mutant Htt neurons. These findings suggest that mitochondria-targeted molecules MitoQ and SS31 are protective against mutant Htt-induced mitochondrial and synaptic damage in HD neurons, and these mitochondria-targeted molecules are potential therapeutic molecules for the treatment of HD neurons. PMID:26908605

Search for Exoplanets around Northern Circumpolar Stars. II. The Detection of Radial Velocity Variations in M Giant Stars HD 36384, HD 52030, and HD 208742

NASA Astrophysics Data System (ADS)

Lee, Byeong-Cheol; Jeong, Gwanghui; Park, Myeong-Gu; Han, Inwoo; Mkrtichian, David E.; Hatzes, Artie P.; Gu, Shenghong; Bai, Jinming; Lee, Sang-Min; Oh, Hyeong-Il; Kim, Kang-Min

2017-07-01

We present the detection of long-period RV variations in HD 36384, HD 52030, and HD 208742 by using the high-resolution, fiber-fed Bohyunsan Observatory Echelle Spectrograph (BOES) for the precise radial velocity (RV) survey of about 200 northern circumpolar stars. Analyses of RV data, chromospheric activity indicators, and bisector variations spanning about five years suggest that the RV variations are compatible with planet or brown dwarf companions in Keplerian motion. However, HD 36384 shows photometric variations with a period very close to that of RV variations as well as amplitude variations in the weighted wavelet Z-transform (WWZ) analysis, which argues that the RV variations in HD 36384 are from the stellar pulsations. Assuming that the companion hypothesis is correct, HD 52030 hosts a companion with minimum mass 13.3 M Jup orbiting in 484 days at a distance of 1.2 au. HD 208742 hosts a companion of 14.0 M Jup at 1.5 au with a period of 602 days. All stars are located at the asymptotic giant branch (AGB) stage on the H-R diagram after undergoing the helium flash and leaving the giant clump.With stellar radii of 53.0 R ⊙ and 57.2 R ⊙ for HD 52030 and HD 208742, respectively, these stars may be the largest yet, in terms of stellar radius, found to host substellar companions. However, given possible RV amplitude variations and the fact that these are highly evolved stars, the planet hypothesis is not yet certain.

Search for Exoplanets around Northern Circumpolar Stars. II. The Detection of Radial Velocity Variations in M Giant Stars HD 36384, HD 52030, and HD 208742

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Byeong-Cheol; Jeong, Gwanghui; Han, Inwoo

2017-07-20

We present the detection of long-period RV variations in HD 36384, HD 52030, and HD 208742 by using the high-resolution, fiber-fed Bohyunsan Observatory Echelle Spectrograph (BOES) for the precise radial velocity (RV) survey of about 200 northern circumpolar stars. Analyses of RV data, chromospheric activity indicators, and bisector variations spanning about five years suggest that the RV variations are compatible with planet or brown dwarf companions in Keplerian motion. However, HD 36384 shows photometric variations with a period very close to that of RV variations as well as amplitude variations in the weighted wavelet Z-transform (WWZ) analysis, which argues thatmore » the RV variations in HD 36384 are from the stellar pulsations. Assuming that the companion hypothesis is correct, HD 52030 hosts a companion with minimum mass 13.3 M {sub Jup} orbiting in 484 days at a distance of 1.2 au. HD 208742 hosts a companion of 14.0 M {sub Jup} at 1.5 au with a period of 602 days. All stars are located at the asymptotic giant branch (AGB) stage on the H–R diagram after undergoing the helium flash and leaving the giant clump.With stellar radii of 53.0 R {sub ⊙} and 57.2 R {sub ⊙} for HD 52030 and HD 208742, respectively, these stars may be the largest yet, in terms of stellar radius, found to host substellar companions. However, given possible RV amplitude variations and the fact that these are highly evolved stars, the planet hypothesis is not yet certain.« less

HD 285507b: An eccentric hot Jupiter in the hyades open cluster

DOE Office of Scientific and Technical Information (OSTI.GOV)

Quinn, Samuel N.; White, Russel J.; Latham, David W.

We report the discovery of the first hot Jupiter in the Hyades open cluster. HD 285507b orbits a V = 10.47 K4.5V dwarf (M {sub *} = 0.734 M {sub ☉}; R {sub *} = 0.656 R {sub ☉}) in a slightly eccentric (e=0.086{sub −0.019}{sup +0.018}) orbit with a period of 6.0881{sub −0.0018}{sup +0.0019} days. The induced stellar radial velocity corresponds to a minimum companion mass of M {sub P}sin i = 0.917 ± 0.033 M {sub Jup}. Line bisector spans and stellar activity measures show no correlation with orbital phase, and the radial velocity amplitude is independent of wavelength,more » supporting the conclusion that the variations are caused by a planetary companion. Follow-up photometry indicates with high confidence that the planet does not transit. HD 285507b joins a small but growing list of planets in open clusters, and its existence lends support to a planet formation scenario in which a high stellar space density does not inhibit giant planet formation and migration. We calculate the circularization timescale for HD 285507b to be larger than the age of the Hyades, which may indicate that this planet's non-zero eccentricity is the result of migration via interactions with a third body. We also demonstrate a significant difference between the eccentricity distributions of hot Jupiters that have had time to tidally circularize and those that have not, which we interpret as evidence against Type II migration in the final stages of hot Jupiter formation. Finally, the dependence of the circularization timescale on the planetary tidal quality factor, Q {sub P}, allows us to constrain the average value for hot Jupiters to be logQ{sub P}=6.14{sub −0.25}{sup +0.41}.« less

Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex.

PubMed

Palmer, Bradley M; Wang, Yuan; Teekakirikul, Polakit; Hinson, J Travis; Fatkin, Diane; Strouse, Stacy; Vanburen, Peter; Seidman, Christine E; Seidman, J G; Maughan, David W

2008-04-01

Male but not female mice carrying a single R403Q missense allele for cardiac alpha-myosin heavy chain (M-alphaMHC(R403Q/+) and F-alphaMHC(R403Q/+), respectively) develop significant hypertrophic cardiomyopathy (HCM) compared with male and female wild-type mice (M-alphaMHC(+/+) and F-alphaMHC(+/+), respectively) after approximately 30 wk of age. We tested the hypothesis that myofilament mechanical performance differs between M-alphaMHC(R403Q/+) and F-alphaMHC(R403Q/+) at younger ages (10-20 wk) and could account for sex differences in HCM development. The sensitivity of chemically skinned myocardial strips to Ca(2+) activation (pCa(50)) was significantly (P < 0.05) enhanced in male mice independent of genotype (M-alphaMHC(R403Q/+): 5.70 +/- 0.06, M-alphaMHC(+/+): 5.63 +/- 0.05, F-alphaMHC(R403Q/+): 5.57 +/- 0.03, F-alphaMHC(+/+): 5.54 +/- 0.04) by two-way ANOVA, whereas maximum developed tension was significantly enhanced in alpha-MHC(R403Q/+) independent of sex (M-alphaMHC(R403Q/+): 29.3 +/- 2.3, M-alphaMHC(+/+): 26.0 +/- 1.4, F-alphaMHC(R403Q/+): 30.2 +/- 2.1, F-alphaMHC(+/+): 26.2 +/- 1.2 mN/mm(2)). The frequency of maximum work generated by sinusoidal length perturbation was significantly higher in alphaMHC(R403Q/+) mice than in sex-matched controls (M-alphaMHC(R403Q/+): 2.26 +/- 0.47, M-alphaMHC(+/+): 1.29 +/- 0.18, F-alphaMHC(R403Q/+): 3.21 +/- 0.33, F-alphaMHC(+/+): 2.52 +/- 0.36 Hz). Unloaded shortening velocity was significantly enhanced in alphaMHC(R403Q/+) and in female mice (M-alphaMHC(R403Q/+): 2.26 +/- 0.47, M-alphaMHC(+/+): 1.29 +/- 0.18, F-alphaMHC(R403Q/+): 3.21 +/- 0.33, F-alphaMHC(+/+): 2.52 +/- 0.36 muscle lengths/s), and normalized mechanical power, calculated from the tension-velocity relationship, was significantly enhanced in alphaMHC(R403Q/+) independent of sex (M-alphaMHC(R403Q/+): 60 +/- 2 10(-3), M-alphaMHC(+/+): 37 +/- 3 10(-3), F-alphaMHC(R403Q/+): 57 +/- 3 10(-3), F-alphaMHC(+/+) 25 +/- 3 10(-3) muscle lengths/s x normalized tension

The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus replication and pathogenesis in mice.

PubMed

Zaraket, Hassan; Bridges, Olga A; Russell, Charles J

2013-05-01

After receptor binding and internalization during influenza virus entry, the hemagglutinin (HA) protein is triggered by low pH to undergo irreversible conformational changes that mediate membrane fusion. To investigate how mutations that alter the activation pH of the HA protein influence the fitness of an avian H5N1 influenza virus in a mammalian model, we infected C57BL/6J or DBA/2J mice and compared the replication and virulence of recombinant A/chicken/Vietnam/C58/04 (H5N1) HA-Y231H mutant, wild-type, and HA-H241Q and HA-K582I mutant viruses that have HA activation pH values of 6.3, 5.9, 5.6, and 5.4, respectively. The HA-Y231H mutant virus was highly susceptible to acid inactivation in vitro and was attenuated for growth and virulence in mice, suggesting that an H5N1 HA protein triggered at pH 6.3 is too unstable for the virus to remain fit. Wild-type and HA-H241Q viruses were similar in pathogenicity and grew to similar levels in mice, ducks, and cell cultures derived from both avian and mammalian tissues, suggesting that H5N1 HA proteins triggered at pH values in the range of 5.9 to 5.6 broadly support replication. The HA-K582I mutant virus had greater growth and virulence in DBA/2J mice than the wild type did, although the mutant virus was highly attenuated in ducks. The data suggest that adaptation of avian H5N1 influenza virus for infection in mammals is supported by a decrease in the HA activation pH to 5.4. Identification of the HA activation pH as a host-specific infectivity factor is expected to aid in the surveillance and risk assessment of currently circulating H5N1 influenza viruses.

Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype.

PubMed

Ali, Niwa; Flutter, Barry; Sanchez Rodriguez, Robert; Sharif-Paghaleh, Ehsan; Barber, Linda D; Lombardi, Giovanna; Nestle, Frank O

2012-01-01

The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice") are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null)), notably the NOD-scid IL-2Rγ(null) (NSG) and BALB/c-Rag2(null) IL-2Rγ(null) (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+) compartment and higher engraftment levels of CD3(+) T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM)) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM)-cell driven GvHD.

Similar Progression of Morphological and Metabolic Phenotype in R6/2 Mice with Different CAG Repeats Revealed by In Vivo Magnetic Resonance Imaging and Spectroscopy.

PubMed

Sawiak, Stephen J; Wood, Nigel I; Morton, A Jennifer

2016-10-01

Huntington's disease (HD) is caused by an unstable polyglutamine (CAG) repeat in the HD gene, whereby a CAG repeat length greater than ∼36 leads to the disease. In HD patients, longer repeats correlate with more severe disease and earlier death. This is also seen in R6/2 mice carrying repeat lengths up to ∼200. Paradoxically, R6/2 mice with repeat lengths >300 have a less aggressive phenotype and longer lifespan than those with shorter repeats. The mechanism underlying this phenomenon is unknown. To investigate the consequences of longer repeat lengths on structural changes in the brains of R6/2 mice, especially with regard to progressive atrophy. We used longitudinal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) to compare pathological changes in two strains of R6/2 mice, one with a rapidly progressing disease (250 CAG repeats), and the other with a less aggressive phenotype (350 CAG repeats). We found significant progressive brain atrophy in both 250 and 350 CAG repeat mice, as well as changes in metabolites (glutamine/glutamate, choline and aspartate). Although similar in magnitude, atrophy in the brains of 350 CAG R6/2 mice progressed more slowly than that seen in 250 CAG mice, in line with the milder phenotype and longer lifespan. Interestingly, significant atrophy was detectable in 350 CAG mice as early as 8-12 weeks of age, although behavioural abnormalities in these mice are not apparent before 25-30 weeks. This finding fits well with human data from the PREDICT-HD and TRACK-HD project, where reductions in brain volume were found 10 years in advance of the onset of symptoms. The similar brain atrophy with a mismatch between onset of brain atrophy and behavioural phenotype in HD mice with 350 repeats will make this mouse particularly useful for modelling early stages of HD pathology.

A Note on a Sampling Theorem for Functions over GF(q)n Domain

NASA Astrophysics Data System (ADS)

Ukita, Yoshifumi; Saito, Tomohiko; Matsushima, Toshiyasu; Hirasawa, Shigeichi

In digital signal processing, the sampling theorem states that any real valued function ƒ can be reconstructed from a sequence of values of ƒ that are discretely sampled with a frequency at least twice as high as the maximum frequency of the spectrum of ƒ. This theorem can also be applied to functions over finite domain. Then, the range of frequencies of ƒ can be expressed in more detail by using a bounded set instead of the maximum frequency. A function whose range of frequencies is confined to a bounded set is referred to as bandlimited function. And a sampling theorem for bandlimited functions over Boolean domain has been obtained. Here, it is important to obtain a sampling theorem for bandlimited functions not only over Boolean domain (GF(q)n domain) but also over GF(q)n domain, where q is a prime power and GF(q) is Galois field of order q. For example, in experimental designs, although the model can be expressed as a linear combination of the Fourier basis functions and the levels of each factor can be represented by GF(q)n, the number of levels often take a value greater than two. However, the sampling theorem for bandlimited functions over GF(q)n domain has not been obtained. On the other hand, the sampling points are closely related to the codewords of a linear code. However, the relation between the parity check matrix of a linear code and any distinct error vectors has not been obtained, although it is necessary for understanding the meaning of the sampling theorem for bandlimited functions. In this paper, we generalize the sampling theorem for bandlimited functions over Boolean domain to a sampling theorem for bandlimited functions over GF(q)n domain. We also present a theorem for the relation between the parity check matrix of a linear code and any distinct error vectors. Lastly, we clarify the relation between the sampling theorem for functions over GF(q)n domain and linear codes.

34 CFR 668.171 - General.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 34 Education 3 2010-07-01 2010-07-01 false General. 668.171 Section 668.171 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Financial Responsibility § 668.171 General. (a...

Magnetic field geometries of two slowly rotating Ap/Bp stars: HD 12288 and HD 14437

NASA Astrophysics Data System (ADS)

Wade, G. A.; Kudryavtsev, D.; Romanyuk, I. I.; Landstreet, J. D.; Mathys, G.

2000-03-01

In this paper we report magnetic field models and basic physical parameters for the slowly rotating Ap/Bp stars HD 12288 and HD 14437. Using new and previously published mean longitudinal magnetic field, mean magnetic field modulus, and hipparcos photometric measurements, we have inferred the rotational periods of both stars (HD 12288: P_rot=34.9d +/- 0.2d HD 14437: P_rot=26.87d +/- 0.02d). From the magnetic measurements we have determined the best-fit decentred magnetic dipole configurations. For HD 12288, we find that the field geometry is consistent with a centred dipole, while for HD 14437 a large decentring parameter (a=0.23 R_*) is inferred. Both stars show one angle in the ambiguous (i,beta ) couplet which is smaller than about 20degr . This is consistent with the observation of Landstreet & Mathys (2000), who point out that almost all magnetic Ap stars with periods longer than about 30 days exhibit magnetic fields aligned with their rotational axis.

49 CFR 171.4 - Marine pollutants.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 2 2014-10-01 2014-10-01 false Marine pollutants. 171.4 Section 171.4..., AND DEFINITIONS Applicability, General Requirements, and North American Shipments § 171.4 Marine... or transport a marine pollutant, as defined in § 171.8, in intrastate or interstate commerce except...

49 CFR 171.4 - Marine pollutants.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 2 2013-10-01 2013-10-01 false Marine pollutants. 171.4 Section 171.4..., AND DEFINITIONS Applicability, General Requirements, and North American Shipments § 171.4 Marine... or transport a marine pollutant, as defined in § 171.8, in intrastate or interstate commerce except...

49 CFR 171.4 - Marine pollutants.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false Marine pollutants. 171.4 Section 171.4..., AND DEFINITIONS Applicability, General Requirements, and North American Shipments § 171.4 Marine... or transport a marine pollutant, as defined in § 171.8, in intrastate or interstate commerce except...

49 CFR 171.4 - Marine pollutants.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 2 2011-10-01 2011-10-01 false Marine pollutants. 171.4 Section 171.4..., AND DEFINITIONS Applicability, General Requirements, and North American Shipments § 171.4 Marine... or transport a marine pollutant, as defined in § 171.8, in intrastate or interstate commerce except...

49 CFR 171.4 - Marine pollutants.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 2 2012-10-01 2012-10-01 false Marine pollutants. 171.4 Section 171.4..., AND DEFINITIONS Applicability, General Requirements, and North American Shipments § 171.4 Marine... or transport a marine pollutant, as defined in § 171.8, in intrastate or interstate commerce except...

Systematic Analysis of Sequences and Expression Patterns of Drought-Responsive Members of the HD-Zip Gene Family in Maize

PubMed Central

Zhao, Yang; Zhou, Yuqiong; Jiang, Haiyang; Li, Xiaoyu; Gan, Defang; Peng, Xiaojian; Zhu, Suwen; Cheng, Beijiu

2011-01-01

Background Members of the homeodomain-leucine zipper (HD-Zip) gene family encode transcription factors that are unique to plants and have diverse functions in plant growth and development such as various stress responses, organ formation and vascular development. Although systematic characterization of this family has been carried out in Arabidopsis and rice, little is known about HD-Zip genes in maize (Zea mays L.). Methods and Findings In this study, we described the identification and structural characterization of HD-Zip genes in the maize genome. A complete set of 55 HD-Zip genes (Zmhdz1-55) were identified in the maize genome using Blast search tools and categorized into four classes (HD-Zip I-IV) based on phylogeny. Chromosomal location of these genes revealed that they are distributed unevenly across all 10 chromosomes. Segmental duplication contributed largely to the expansion of the maize HD-ZIP gene family, while tandem duplication was only responsible for the amplification of the HD-Zip II genes. Furthermore, most of the maize HD-Zip I genes were found to contain an overabundance of stress-related cis-elements in their promoter sequences. The expression levels of the 17 HD-Zip I genes under drought stress were also investigated by quantitative real-time PCR (qRT-PCR). All of the 17 maize HD-ZIP I genes were found to be regulated by drought stress, and the duplicated genes within a sister pair exhibited the similar expression patterns, suggesting their conserved functions during the process of evolution. Conclusions Our results reveal a comprehensive overview of the maize HD-Zip gene family and provide the first step towards the selection of Zmhdz genes for cloning and functional research to uncover their roles in maize growth and development. PMID:22164299

Systematic analysis of sequences and expression patterns of drought-responsive members of the HD-Zip gene family in maize.

PubMed

Zhao, Yang; Zhou, Yuqiong; Jiang, Haiyang; Li, Xiaoyu; Gan, Defang; Peng, Xiaojian; Zhu, Suwen; Cheng, Beijiu

2011-01-01

Members of the homeodomain-leucine zipper (HD-Zip) gene family encode transcription factors that are unique to plants and have diverse functions in plant growth and development such as various stress responses, organ formation and vascular development. Although systematic characterization of this family has been carried out in Arabidopsis and rice, little is known about HD-Zip genes in maize (Zea mays L.). In this study, we described the identification and structural characterization of HD-Zip genes in the maize genome. A complete set of 55 HD-Zip genes (Zmhdz1-55) were identified in the maize genome using Blast search tools and categorized into four classes (HD-Zip I-IV) based on phylogeny. Chromosomal location of these genes revealed that they are distributed unevenly across all 10 chromosomes. Segmental duplication contributed largely to the expansion of the maize HD-ZIP gene family, while tandem duplication was only responsible for the amplification of the HD-Zip II genes. Furthermore, most of the maize HD-Zip I genes were found to contain an overabundance of stress-related cis-elements in their promoter sequences. The expression levels of the 17 HD-Zip I genes under drought stress were also investigated by quantitative real-time PCR (qRT-PCR). All of the 17 maize HD-ZIP I genes were found to be regulated by drought stress, and the duplicated genes within a sister pair exhibited the similar expression patterns, suggesting their conserved functions during the process of evolution. Our results reveal a comprehensive overview of the maize HD-Zip gene family and provide the first step towards the selection of Zmhdz genes for cloning and functional research to uncover their roles in maize growth and development.

32 CFR 171.4 - Qualifications.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false Qualifications. 171.4 Section 171.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.4 Qualifications. The Secretary of Agriculture...

32 CFR 171.4 - Qualifications.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false Qualifications. 171.4 Section 171.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.4 Qualifications. The Secretary of Agriculture...

32 CFR 171.4 - Qualifications.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 1 2012-07-01 2012-07-01 false Qualifications. 171.4 Section 171.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.4 Qualifications. The Secretary of Agriculture...

32 CFR 171.4 - Qualifications.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Qualifications. 171.4 Section 171.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.4 Qualifications. The Secretary of Agriculture...

10 CFR 171.9 - Communications.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 2 2013-01-01 2013-01-01 false Communications. 171.9 Section 171.9 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) ANNUAL FEES FOR REACTOR LICENSES AND FUEL CYCLE LICENSES AND MATERIALS... APPROVALS AND GOVERNMENT AGENCIES LICENSED BY THE NRC § 171.9 Communications. All communications concerning...

10 CFR 171.9 - Communications.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 2 2014-01-01 2014-01-01 false Communications. 171.9 Section 171.9 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) ANNUAL FEES FOR REACTOR LICENSES AND FUEL CYCLE LICENSES AND MATERIALS... APPROVALS AND GOVERNMENT AGENCIES LICENSED BY THE NRC § 171.9 Communications. All communications concerning...

16 CFR 1.71 - Administration.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Administration. 1.71 Section 1.71 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE GENERAL PROCEDURES Administration of the Fair Credit Reporting Act § 1.71 Administration. The general administration of the Fair...

16 CFR 1.71 - Administration.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Administration. 1.71 Section 1.71 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE GENERAL PROCEDURES Administration of the Fair Credit Reporting Act § 1.71 Administration. The general administration of the Fair...

16 CFR 1.71 - Administration.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Administration. 1.71 Section 1.71 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE GENERAL PROCEDURES Administration of the Fair Credit Reporting Act § 1.71 Administration. The general administration of the Fair...

7 CFR 1.171 - Intervention.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 1 2014-01-01 2014-01-01 false Intervention. 1.171 Section 1.171 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Rules of Practice Governing Cease and Desist Proceedings Under Section 2 of the Capper-Volstead Act § 1.171 Intervention. Intervention under...

7 CFR 1.171 - Intervention.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 1 2011-01-01 2011-01-01 false Intervention. 1.171 Section 1.171 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Rules of Practice Governing Cease and Desist Proceedings Under Section 2 of the Capper-Volstead Act § 1.171 Intervention. Intervention under...

7 CFR 1.171 - Intervention.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Intervention. 1.171 Section 1.171 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Rules of Practice Governing Cease and Desist Proceedings Under Section 2 of the Capper-Volstead Act § 1.171 Intervention. Intervention under...

7 CFR 1.171 - Intervention.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 1 2012-01-01 2012-01-01 false Intervention. 1.171 Section 1.171 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Rules of Practice Governing Cease and Desist Proceedings Under Section 2 of the Capper-Volstead Act § 1.171 Intervention. Intervention under...

7 CFR 1.171 - Intervention.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 1 2013-01-01 2013-01-01 false Intervention. 1.171 Section 1.171 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Rules of Practice Governing Cease and Desist Proceedings Under Section 2 of the Capper-Volstead Act § 1.171 Intervention. Intervention under...

16 CFR 1.71 - Administration.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Administration. 1.71 Section 1.71 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE GENERAL PROCEDURES Administration of the Fair Credit Reporting Act § 1.71 Administration. The general administration of the Fair...

10 CFR 171.9 - Communications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false Communications. 171.9 Section 171.9 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) ANNUAL FEES FOR REACTOR LICENSES AND FUEL CYCLE LICENSES AND MATERIALS... APPROVALS AND GOVERNMENT AGENCIES LICENSED BY THE NRC § 171.9 Communications. All communications concerning...

7 CFR 1.71 - Purpose.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 1 2013-01-01 2013-01-01 false Purpose. 1.71 Section 1.71 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Cooperative Production of Television Films § 1.71... Department of Agriculture requested by producers of films for television use. These procedures are designed...

22 CFR 171.22 - Appeals.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Appeals. 171.22 Section 171.22 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC Executive Order 12958 Provisions § 171.22 Appeals. Any denial of a mandatory declassification review request...

22 CFR 171.22 - Appeals.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Appeals. 171.22 Section 171.22 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC Executive Order 12958 Provisions § 171.22 Appeals. Any denial of a mandatory declassification review request...

22 CFR 171.22 - Appeals.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Appeals. 171.22 Section 171.22 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC Executive Order 12958 Provisions § 171.22 Appeals. Any denial of a mandatory declassification review request...

22 CFR 171.22 - Appeals.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Appeals. 171.22 Section 171.22 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC Executive Order 12958 Provisions § 171.22 Appeals. Any denial of a mandatory declassification review request...

7 CFR 1.71 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 1 2012-01-01 2012-01-01 false Purpose. 1.71 Section 1.71 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Cooperative Production of Television Films § 1.71... Department of Agriculture requested by producers of films for television use. These procedures are designed...

7 CFR 1.71 - Purpose.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 1 2011-01-01 2011-01-01 false Purpose. 1.71 Section 1.71 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Cooperative Production of Television Films § 1.71... Department of Agriculture requested by producers of films for television use. These procedures are designed...

7 CFR 1.71 - Purpose.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 1 2014-01-01 2014-01-01 false Purpose. 1.71 Section 1.71 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Cooperative Production of Television Films § 1.71... Department of Agriculture requested by producers of films for television use. These procedures are designed...

32 CFR 171.2 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false Applicability. 171.2 Section 171.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.2 Applicability. The regulations in this part...

32 CFR 171.2 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Applicability. 171.2 Section 171.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.2 Applicability. The regulations in this part...

32 CFR 171.2 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 1 2012-07-01 2012-07-01 false Applicability. 171.2 Section 171.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.2 Applicability. The regulations in this part...

32 CFR 171.2 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false Applicability. 171.2 Section 171.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.2 Applicability. The regulations in this part...

32 CFR 171.2 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Applicability. 171.2 Section 171.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.2 Applicability. The regulations in this part...

7 CFR 1.71 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Purpose. 1.71 Section 1.71 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Cooperative Production of Television Films § 1.71... Department of Agriculture requested by producers of films for television use. These procedures are designed...

22 CFR 171.31 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Department, including, but not limited to education, financial transactions, medical history, and criminal or... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Definitions. 171.31 Section 171.31 Foreign... Privacy Act Provisions § 171.31 Definitions. As used in this subpart, the following definitions shall...

14 CFR 171.117 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Reports. 171.117 Section 171.117... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Simplified Directional Facility (SDF) § 171.117 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the time...

14 CFR 171.117 - Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Reports. 171.117 Section 171.117... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Simplified Directional Facility (SDF) § 171.117 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the time...

14 CFR 171.117 - Reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Reports. 171.117 Section 171.117... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Simplified Directional Facility (SDF) § 171.117 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the time...

22 CFR 171.22 - Appeals.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Appeals. 171.22 Section 171.22 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC Executive Order 12958 Provisions § 171.22 Appeals. Any denial of a mandatory declassification review request...

N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.

PubMed

Wright, Dean J; Gray, Laura J; Finkelstein, David I; Crouch, Peter J; Pow, David; Pang, Terence Y; Li, Shanshan; Smith, Zoe M; Francis, Paul S; Renoir, Thibault; Hannan, Anthony J

2016-07-15

Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington's disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system x c - In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine-γ-lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transporters, system x c - and GLT-1. We demonstrate that the R6/1 transgenic mouse model of HD has lower basal levels of cystine, and showed depressive-like behaviors in the forced-swim test. Administration of NAC reversed these behaviors. This effect was blocked by co-administration of the system x c - and GLT-1 inhibitors CPG and DHK, showing that glutamate transporter activity was required for the antidepressant effects of NAC. NAC was also able to specifically increase glutamate in HD mice, in a glutamate transporter-dependent manner. These in vivo changes reflect changes in glutamate transporter protein in HD mice and human HD post-mortem tissue. Furthermore, NAC was able to rescue changes in key glutamate receptor proteins related to excitotoxicity in HD, including NMDAR2B. Thus, we have shown that baseline reductions in cysteine underlie glutamatergic dysfunction and depressive-like behavior in HD and these changes can be rescued by treatment with NAC. These findings have implications for the development of new therapeutic approaches for depressive disorders. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

17 CFR 171.12 - Settlement.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Settlement. 171.12 Section 171... RESPONSIBILITY ACTIONS General Provisions § 171.12 Settlement. At any time before the Commission has reached a... settlement agreement. If, in its view, the settlement is consistent with the public interest, the Commission...

32 CFR 171.8 - Expiration.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 1 2012-07-01 2012-07-01 false Expiration. 171.8 Section 171.8 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.8 Expiration. This part expires on 30 September 2005. ...

32 CFR 171.8 - Expiration.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Expiration. 171.8 Section 171.8 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.8 Expiration. This part expires on 30 September 2005. ...

32 CFR 171.8 - Expiration.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Expiration. 171.8 Section 171.8 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.8 Expiration. This part expires on 30 September 2005. ...

32 CFR 171.8 - Expiration.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false Expiration. 171.8 Section 171.8 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.8 Expiration. This part expires on 30 September 2005. ...

32 CFR 171.8 - Expiration.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false Expiration. 171.8 Section 171.8 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.8 Expiration. This part expires on 30 September 2005. ...

14 CFR 171.213 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Reports. 171.213 Section 171.213... FACILITIES NON-FEDERAL NAVIGATION FACILITIES VHF Marker Beacons § 171.213 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times indicated, to the...

14 CFR 171.53 - Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Reports. 171.53 Section 171.53 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Instrument Landing System (ILS) Facilities § 171.53 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times...

14 CFR 171.163 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Reports. 171.163 Section 171.163... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Distance Measuring Equipment (DME) § 171.163 Reports. The owner of each facility to which this subpart applies shall make the following reports on forms furnished by...

14 CFR 171.53 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Reports. 171.53 Section 171.53 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Instrument Landing System (ILS) Facilities § 171.53 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times...

14 CFR 171.163 - Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Reports. 171.163 Section 171.163... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Distance Measuring Equipment (DME) § 171.163 Reports. The owner of each facility to which this subpart applies shall make the following reports on forms furnished by...

14 CFR 171.163 - Reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Reports. 171.163 Section 171.163... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Distance Measuring Equipment (DME) § 171.163 Reports. The owner of each facility to which this subpart applies shall make the following reports on forms furnished by...

14 CFR 171.33 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Reports. 171.33 Section 171.33 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Nondirectional Radio Beacon Facilities § 171.33 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times...

14 CFR 171.33 - Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Reports. 171.33 Section 171.33 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Nondirectional Radio Beacon Facilities § 171.33 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times...

14 CFR 171.53 - Reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Reports. 171.53 Section 171.53 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Instrument Landing System (ILS) Facilities § 171.53 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times...

14 CFR 171.213 - Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Reports. 171.213 Section 171.213... FACILITIES NON-FEDERAL NAVIGATION FACILITIES VHF Marker Beacons § 171.213 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times indicated, to the...

14 CFR 171.213 - Reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Reports. 171.213 Section 171.213... FACILITIES NON-FEDERAL NAVIGATION FACILITIES VHF Marker Beacons § 171.213 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times indicated, to the...

14 CFR 171.33 - Reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Reports. 171.33 Section 171.33 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Nondirectional Radio Beacon Facilities § 171.33 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times...

27 CFR 28.171 - General.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false General. 28.171 Section 28.171 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS EXPORTATION OF ALCOHOL Exportation of Distilled Spirits With Benefit of Drawback § 28.171...

27 CFR 28.171 - General.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false General. 28.171 Section 28.171 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL EXPORTATION OF ALCOHOL Exportation of Distilled Spirits With Benefit of Drawback § 28.171...

27 CFR 28.171 - General.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false General. 28.171 Section 28.171 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS EXPORTATION OF ALCOHOL Exportation of Distilled Spirits With Benefit of Drawback § 28.171...

27 CFR 28.171 - General.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false General. 28.171 Section 28.171 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL EXPORTATION OF ALCOHOL Exportation of Distilled Spirits With Benefit of Drawback § 28.171...

27 CFR 28.171 - General.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false General. 28.171 Section 28.171 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS EXPORTATION OF ALCOHOL Exportation of Distilled Spirits With Benefit of Drawback § 28.171...

7 CFR 1150.171 - Reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 9 2011-01-01 2011-01-01 false Reports. 1150.171 Section 1150.171 Agriculture... Order Reports, Books and Records § 1150.171 Reports. Each producer marketing milk of that producer's own... collection of the assessment under § 1150.152 shall be required to report at the time for remitting...

7 CFR 1150.171 - Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Reports. 1150.171 Section 1150.171 Agriculture... Order Reports, Books and Records § 1150.171 Reports. Each producer marketing milk of that producer's own... collection of the assessment under § 1150.152 shall be required to report at the time for remitting...

7 CFR 1150.171 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 9 2012-01-01 2012-01-01 false Reports. 1150.171 Section 1150.171 Agriculture... Order Reports, Books and Records § 1150.171 Reports. (a) Each producer marketing milk of that producer's... the collection of the assessment under § 1150.152(a) shall be required to report at the time for...

7 CFR 1150.171 - Reports.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 9 2014-01-01 2013-01-01 true Reports. 1150.171 Section 1150.171 Agriculture... Order Reports, Books and Records § 1150.171 Reports. (a) Each producer marketing milk of that producer's... the collection of the assessment under § 1150.152(a) shall be required to report at the time for...

17 CFR 171.10 - Motions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... ACTIONS General Provisions § 171.10 Motions. (a) In general. An application for a form of relief not... modification of the action. (d) Dilatory motions. Frivolous or repetitive motions dealing with the same subject... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Motions. 171.10 Section 171.10...

17 CFR 171.10 - Motions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... ACTIONS General Provisions § 171.10 Motions. (a) In general. An application for a form of relief not... modification of the action. (d) Dilatory motions. Frivolous or repetitive motions dealing with the same subject... 17 Commodity and Securities Exchanges 1 2011-04-01 2011-04-01 false Motions. 171.10 Section 171.10...

The 3H(d,gamma) Reaction and the 3 H(d,gamma)/ 3H(d, n) Branching Ratio for Ec.m. 300 keV

NASA Astrophysics Data System (ADS)

Parker, Cody E.

The 3H(d, gamma)5He reaction and the 3H(d, gamma)/3H(d, n) branching ratio have been measured using a 500-keV pulsed deuteron beam incident on a titanium tritide target of stopping thickness at the Edwards Accelerator Laboratory. The time-of-flight technique has been used to distinguish the gamma-rays from neutrons in the bismuth germinate (BGO) gamma-ray detector. A stilbene scintillator and an NE-213 scintillator have been used to detect the neutrons from the 3H(d, n)alpha reaction using both the pulse-shape discrimination and time-of-flight techniques. A target holder with an ion-implanted silicon detector at a fixed angle of 135° to the beam axis to simultaneously measure alpha-particles as a normalization for the number of neutrons was incorporated to reduce the uncertainty in the neutron yield over the preliminary measurement. The gamma-rays have been measured at laboratory angles of 0°, 4°, 9°, and 15°. Information about the gamma-ray energy distribution for the unbound ground state and first excited state of 5He have been obtained experimentally by comparing the BGO data to Monte Carlo simulations. The reported branching ratios for each angle contain only contributions from the ground-state gamma-ray branch.

Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington's disease.

PubMed

Yin, Xiangling; Manczak, Maria; Reddy, P Hemachandra

2016-05-01

The objective of this study was to determine the protective effects of the mitochondria-targeted molecules MitoQ and SS31 in striatal neurons that stably express mutant huntingtin (Htt) (STHDhQ111/Q111) in Huntington's disease (HD). We studied mitochondrial and synaptic activities by measuring mRNA and the protein levels of mitochondrial and synaptic genes, mitochondrial function, and ultra-structural changes in MitoQ- and SS31-treated mutant Htt neurons relative to untreated mutant Htt neurons. We used gene expression analysis, biochemical methods, transmission electron microscopy (TEM) and confocal microscopy methods. In the MitoQ- and SS31-treated mutant Htt neurons, fission genes Drp1 and Fis1 were down-regulated, and fusion genes Mfn1, Mfn2 and Opa1 were up-regulated relative to untreated neurons, suggesting that mitochondria-targeted molecules reduce fission activity. Interestingly, the mitochondrial biogenesis genes PGC1α, PGC1β, Nrf1, Nrf2 and TFAM were up-regulated in MitoQ- and SS31-treated mutant Htt neurons. The synaptic genes synaptophysin and PSD95 were up-regulated, and mitochondrial function was normal in the MitoQ- and SS31-treated mutant Htt neurons. Immunoblotting findings of mitochondrial and synaptic proteins agreed with the mRNA findings. TEM studies revealed decreased numbers of structurally intact mitochondria in MitoQ- and SS31-treated mutant Htt neurons. These findings suggest that mitochondria-targeted molecules MitoQ and SS31 are protective against mutant Htt-induced mitochondrial and synaptic damage in HD neurons, and these mitochondria-targeted molecules are potential therapeutic molecules for the treatment of HD neurons. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

14 CFR 171.13 - Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Reports. 171.13 Section 171.13 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES VOR Facilities § 171.13 Reports. The owner of each facility to which this subpart applies shall make the following reports on forms furnished by the FAA, at the times...

14 CFR 171.13 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Reports. 171.13 Section 171.13 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES VOR Facilities § 171.13 Reports. The owner of each facility to which this subpart applies shall make the following reports on forms furnished by the FAA, at the times...

14 CFR 171.13 - Reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Reports. 171.13 Section 171.13 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES VOR Facilities § 171.13 Reports. The owner of each facility to which this subpart applies shall make the following reports on forms furnished by the FAA, at the times...

Coenzyme Q10 protects hair cells against aminoglycoside.

PubMed

Sugahara, Kazuma; Hirose, Yoshinobu; Mikuriya, Takefumi; Hashimoto, Makoto; Kanagawa, Eiju; Hara, Hirotaka; Shimogori, Hiroaki; Yamashita, Hiroshi

2014-01-01

It is well known that the production of free radicals is associated with sensory cell death induced by an aminoglycoside. Many researchers have reported that antioxidant reagents protect sensory cells in the inner ear, and coenzyme Q10 (CoQ10) is an antioxidant that is consumed as a health food in many countries. The purpose of this study was to investigate the role of CoQ10 in mammalian vestibular hair cell death induced by aminoglycoside. Cultured utricles of CBA/CaN mice were divided into three groups (control group, neomycin group, and neomycin + CoQ10 group). In the neomycin group, utricles were cultured with neomycin (1 mM) to induce hair cell death. In the neomycin + CoQ10 group, utricles were cultured with neomycin and water-soluble CoQ10 (30-0.3 µM). Twenty-four hours after exposure to neomycin, the cultured tissues were fixed, and vestibular hair cells were labeled using an anti-calmodulin antibody. Significantly more hair cells survived in the neomycin + CoQ10 group than in the neomycin group. These data indicate that CoQ10 protects sensory hair cells against neomycin-induced death in the mammalian vestibular epithelium; therefore, CoQ10 may be useful as a protective drug in the inner ear.

Trisomy 2q11.2-->q21.1 resulting from an unbalanced insertion in two generations.

PubMed Central

Glass, I A; Stormer, P; Oei, P T; Hacking, E; Cotter, P D

1998-01-01

In this communication, we describe two cases of proximal 2q trisomy (2q11.2--> q21.1) resulting from an interchromosomal insertion. The chromosomal origin of the insertion was confirmed by fluorescence in situ hybridisation. An unbalanced karyotype, 46,XX,der(8) ,ins(8;2) (p21.3; q21.1q11.2), was found in the proband and her mother, who both have mild mental retardation, short stature, dysmorphic features, insulin dependent diabetes mellitus, and a psychotic illness. This family is a rare example of direct transmission of a partial autosomal trisomy. Images PMID:9598728

Coenzyme Q as an antiadipogenic factor.

PubMed

Bour, Sandy; Carmona, Maria-Carmen; Galinier, Anne; Caspar-Bauguil, Sylvie; Van Gaal, Luc; Staels, Bart; Pénicaud, Luc; Casteilla, Louis

2011-02-01

Coenzyme Q (CoQ) is not only the single antioxidant synthesized in humans but also an obligatory element of mitochondrial functions. We have previously reported CoQ deficiency in white adipose tissue of ob/ob mice. We sought to determine (i) whether this deficit exists in all species and its relevance in human obesity and (ii) to what extent CoQ could be involved in adipocyte differentiation. Here we identified in rodents as well as in humans a specific very strong nonlinear negative correlation between CoQ content in subcutaneous adipose tissue and obesity indexes. This striking correlation reveals a threshold value similar in both species. This relative deficit in CoQ content in adipose tissue rapidly took place during the time course of high-fat-diet-induced obesity in mice. Adipocyte differentiation was assessed in vitro using the preadipocyte 3T3-F442A cell line. When CoQ synthesis was inhibited by a pharmacological approach using chlorobenzoic acid, this strongly triggered adipose differentiation. In contrast, adipogenesis was strongly inhibited when a long-term increase in CoQ content was obtained by overexpressing human 4-hydroxy benzoate acid polyprenyltransferase gene. Altogether, these data suggest that a strict level of CoQ remains essential for adipocyte differentiation, and its impairment is associated with obesity.

Substance abuse may hasten motor onset of Huntington disease: Evaluating the Enroll-HD database.

PubMed

Schultz, Jordan L; Kamholz, John A; Moser, David J; Feely, Shawna M E; Paulsen, Jane S; Nopoulos, Peg C

2017-02-28

To investigate the relationship between substances of abuse and age at motor onset (AMO) in patients with Huntington disease (HD) in a large and diverse patient population. This was a retrospective, observational study of the Enroll-HD database. Participants were determined to belong to 1 of 3 substance abuse groups: (1) tobacco abusers, (2) alcohol abusers, and (3) drug abusers. A group of participants who had never abused substances served as a control group. The average AMO of patients in the substance abuse groups was compared to the control group. The number of CAG repeats was used as a covariate in all analyses. The average difference in AMOs of participants in the tobacco (n = 566), alcohol (n = 374), and drug abuse groups (n = 217) compared to the control group (n = 692) were 2.3 ( F 1, 1,258 = 33.8, p < 0.0001), 1.0 ( F 1, 1,066 = 4.2, p = 0.04), and 3.3 ( F 1, 909 = 29.7, p < 0.0001) years earlier, respectively. In all substance abuse groups, the AMO was lowered to a greater degree in female participants than it was in male participants. Substances of abuse have a strong effect on the AMO in patients with HD. These effects seem to be amplified in women with HD compared to men. These results may provide a safe intervention capable of adding disease-free years to patients with HD. © 2017 American Academy of Neurology.

Spectrophotometry of peculiar B and A stars. XIV - 56 Arietis, 41 Tauri, 25 Sextantis, HD 170973, HD 205087, and HD 215441

NASA Astrophysics Data System (ADS)

Adelman, S. J.

1983-03-01

Optical region spectrophotometry of six relatively hot Ap stars is presented. Additional scans of 56 Ari extend the results of an earlier paper in this series. The data for 41 Tau, 25 Sex, HD 170973, and HD 215441 are studied as a function of phase. The observations of HD 205087 are inconclusive about its variability although they show spectrophotometrically that it is a definite Ap star. The observations of HD 215441 show a prominent λ5200 broad, continuum feature with an unusual shape. However, when the data are corrected for interstellar reddening, the energy distribution resembles those of other silicon stars. The λ5200 feature is found to be variable in phase with the U-B and B-V colors and with the magnetic field strength. This feature is strongest when the Balmer jump is smallest, the Paschen continuum the bluest according to B-V, and the surface magnetic field strength the largest.

A new family of N dimensional superintegrable double singular oscillators and quadratic algebra Q(3) ⨁ so(n) ⨁ so(N-n)

NASA Astrophysics Data System (ADS)

Fazlul Hoque, Md; Marquette, Ian; Zhang, Yao-Zhong

2015-11-01

We introduce a new family of N dimensional quantum superintegrable models consisting of double singular oscillators of type (n, N-n). The special cases (2,2) and (4,4) have previously been identified as the duals of 3- and 5-dimensional deformed Kepler-Coulomb systems with u(1) and su(2) monopoles, respectively. The models are multiseparable and their wave functions are obtained in (n, N-n) double-hyperspherical coordinates. We obtain the integrals of motion and construct the finitely generated polynomial algebra that is the direct sum of a quadratic algebra Q(3) involving three generators, so(n), so(N-n) (i.e. Q(3) ⨁ so(n) ⨁ so(N-n)). The structure constants of the quadratic algebra itself involve the Casimir operators of the two Lie algebras so(n) and so(N-n). Moreover, we obtain the finite dimensional unitary representations (unirreps) of the quadratic algebra and present an algebraic derivation of the degenerate energy spectrum of the superintegrable model.

Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory Phenotype

PubMed Central

Ali, Niwa; Flutter, Barry; Sanchez Rodriguez, Robert; Sharif-Paghaleh, Ehsan; Barber, Linda D.; Lombardi, Giovanna; Nestle, Frank O.

2012-01-01

The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; “Hu-PBMC mice”) are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγnull), notably the NOD-scid IL-2Rγnull (NSG) and BALB/c-Rag2 null IL-2Rγnull (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45+ compartment and higher engraftment levels of CD3+ T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (TEM) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting TEM-cell driven GvHD. PMID:22937164

Myricetin Reduces Toxic Level of CAG Repeats RNA in Huntington's Disease (HD) and Spino Cerebellar Ataxia (SCAs).

PubMed

Khan, Eshan; Tawani, Arpita; Mishra, Subodh Kumar; Verma, Arun Kumar; Upadhyay, Arun; Kumar, Mohit; Sandhir, Rajat; Mishra, Amit; Kumar, Amit

2018-01-19

Huntington's disease (HD) is a neurodegenerative disorder that is caused by abnormal expansion of CAG repeats in the HTT gene. The transcribed mutant RNA contains expanded CAG repeats that translate into a mutant huntingtin protein. This expanded CAG repeat also causes mis-splicing of pre-mRNA due to sequestration of muscle blind like-1 splicing factor (MBNL1), and thus both of these elicit the pathogenesis of HD. Targeting the onset as well as progression of HD by small molecules could be a potent therapeutic approach. We have screened a set of small molecules to target this transcript and found Myricetin, a flavonoid, as a lead molecule that interacts with the CAG motif and thus prevents the translation of mutant huntingtin protein as well as sequestration of MBNL1. Here, we report the first solution structure of the complex formed between Myricetin and RNA containing the 5'CAG/3'GAC motif. Myricetin interacts with this RNA via base stacking at the AA mismatch. Moreover, Myricetin was also found reducing the proteo-toxicity generated due to the aggregation of polyglutamine, and further, its supplementation also improves neurobehavioral deficits in the HD mouse model. Our study provides the structural and mechanistic basis of Myricetin as an effective therapeutic candidate for HD and other polyQ related disorders.

The qWR star HD 45166 . I. Observations and system parameters

NASA Astrophysics Data System (ADS)

Steiner, J. E.; Oliveira, A. S.

2005-12-01

The binary star HD 45166 has been observed since 1922 but its orbital period has not yet been found. It is considered a peculiar Wolf-Rayet star, and its assigned classification has varied. For this reason we included the object as a candidate V Sge star and performed spectroscopy in order to search for its putative orbital period. High-resolution spectroscopic observations show that the spectrum, in emission and in absorption, is quite rich. The emission lines have great diversity of widths and profiles. The full widths at half maximum vary from 70 km s-1 for the weakest lines up to 370 km s-1 for the most intense ones. The hydrogen and helium lines are systematically broader than the CNO lines. Assuming that HD 45166 is a double-line spectroscopic binary, it presents an orbital period of P = 1.596 ± 0.003 day, with an eccentricity of e = 0.18 ± 0.08. In addition, a search for periodicity using standard techniques reveals that the emission lines present at least two other periods, of 5 and 15 h. The secondary star has a spectral type of B7 V and, therefore, should have a mass of about M2 = 4.8 ~M⊙. Given the radial velocity amplitudes, we determined the mass of the hot (primary) star as M1 = 4.2 ± 0.7~M⊙ and the inclination angle of the system, i = 0.77° ± 0.09°. As the eccentricity of the orbit is non zero, the Roche lobes increase and decrease as a function of the orbital phase. At periastron, the secondary star fills its Roche lobe. The distance to the star has been re-determined as d = 1.3 ± 0.2 kpc and a color excess of E(B-V)=0.155~±~0.007 has been derived. This implies an absolute B magnitude of -0.6 for the primary star and -0.7 for the B7 star. We suggest that the discrete absorption components (DACs) observed in the ultraviolet with a periodicity similar to the orbital period may be induced by periastron events. Based on observations made at the 1.5 m ESO telescope at La Silla, Chile, and at Laboratório Nacional de Astrofísica/CNPq, Brazil

Liposomal gD Ectodomain (gD1-306) Vaccine Protects Against HSV2 Genital or Rectal Infection of Female and Male Mice

PubMed Central

Olson, K.; Macias, P.; Hutton, S.; Ernst, W. A.; Fujii, G.; Adler-Moore, J. P.

2009-01-01

Herpes simplex virus type 2 (HSV2) is the most common causative agent of genital herpes, with infection rates as high as 1 in 6 adults. The present studies were done to evaluate the efficacy of a liposomal HSV2 gD1-306 vaccine (L-gD1-306-HD) in an acute murine HSV2 infection model of intravaginal (female) or intrarectal (male or female) challenge. Two doses of L-gD1-306-HD containing 60μg gD1-306-HD and 15μg monophosphoryl lipid A (MPL) per dose provided protection against HSV2 intravaginal challenge (86-100% survival, P≤0.0003 vs control liposomes; P=0.06 vs L-gD1-306-HD without MPL). Both male and female mice (BALB/c and C57BL/6) immunized with L-gD1-306-HD/MPL were significantly protected against HSV2 intrarectal challenge, with higher survival rates compared to controls (71-100%, P≤0.007). L-gD1-306-HD/MPL also provided increased survival when compared to a liposomal peptide vaccine, L-gD264-285-HD/MPL (male BALB/c, P≤0.001; female BALB/c and male C57BL/6, P=0.06). Mice given L-gD1-306-HD/MPL also had minimal disease signs, reduced viral burden in their spinal cords and elevated neutralizing antibody titers in the females. The vaccine also stimulated gD1-306-HD specific splenocytes of both male and female mice with significantly elevated levels of IFN-γ compared to IL-4 (P≤0.01) indicating that there was an enhanced Th1 response. These results provide the first evidence that the L-gD1-306–HD vaccine can protect both male and female mice against intrarectal HSV2 challenge. PMID:19835825

Liposomal gD ectodomain (gD1-306) vaccine protects against HSV2 genital or rectal infection of female and male mice.

PubMed

Olson, K; Macias, P; Hutton, S; Ernst, W A; Fujii, G; Adler-Moore, J P

2009-12-11

Herpes simplex virus type 2 (HSV2) is the most common causative agent of genital herpes, with infection rates as high as 1 in 6 adults. The present studies were done to evaluate the efficacy of a liposomal HSV2 gD(1-306) vaccine (L-gD(1-306)-HD) in an acute murine HSV2 infection model of intravaginal (female) or intrarectal (male or female) challenge. Two doses of L-gD(1-306)-HD containing 60 microg gD(1-306)-HD and 15 microg monophosphoryl lipid A (MPL) per dose provided protection against HSV2 intravaginal challenge (86-100% survival, P< or =0.0003 vs. control liposomes; P=0.06 vs. L-gD(1-306)-HD without MPL). Both male and female mice (BALB/c and C57BL/6) immunized with L-gD(1-306)-HD/MPL were significantly protected against HSV2 intrarectal challenge, with higher survival rates compared to controls (71-100%, P< or =0.007). L-gD(1-306)-HD/MPL also provided increased survival when compared to a liposomal peptide vaccine, L-gD(264-285)-HD/MPL (male BALB/c, PMice given L-gD(1-306)-HD/MPL also had minimal disease signs, reduced viral burden in their spinal cords and elevated neutralizing antibody titers in the females. The vaccine also stimulated gD(1-306)-HD specific splenocytes of both male and female mice with significantly elevated levels of IFN-gamma compared to IL-4 (P< or =0.01) indicating that there was an enhanced Th1 response. These results provide the first evidence that the L-gD(1-306)-HD vaccine can protect both male and female mice against intrarectal HSV2 challenge.

Prevalence and determinants of fatigue in patients with moderate to severe chronic GvHD.

PubMed

Im, A; Mitchell, S A; Steinberg, S M; Curtis, L; Berger, A; Baird, K; Kuzmina, Z; Joe, G; Comis, L E; Juckett, M; Avila, D; Baruffaldi, J; Masuch, L; Pirsl, F; Pavletic, S Z

2016-05-01

Although fatigue is common after allogeneic hematopoietic cell transplantation, little is known about fatigue in patients with chronic GvHD (cGvHD). The aim of this study was to explore factors associated with fatigue in cGvHD. Data were drawn from a sequentially recruited, cross-sectional study of adults with moderate or severe cGvHD (n=263). Respondents were classified as fatigued or not fatigued based on their response to a single item regarding loss of energy from the Lee cGvHD Symptom Scale. In univariate analysis, factors significantly associated with fatigue included performance status, number of prior cGvHD therapies, cGvHD symptom bother, self-assessed physical and mental health, nutritional status, walk velocity and self-reported physical activity. There were no significant associations between fatigue and disease-related cGvHD variables. Multivariable logistic regression demonstrated that being less active and having pulmonary and/or muscle/joint symptoms were independently associated with fatigue. In conclusion, clinically significant fatigue was prevalent in more than one-third of subjects with cGvHD, and was disabling. Absence of association with measures of cGvHD severity underscores the need to elucidate the pathogenesis of fatigue and its relationship with inflammatory activity. Pulmonary and muscle/joint symptoms and physical inactivity represent potential targets for intervention in clinical studies.

Negative subthreshold psychotic symptoms distinguish 22q11.2 deletion syndrome from other neurodevelopmental disorders: A two-site study.

PubMed

Mekori-Domachevsky, Ehud; Guri, Yael; Yi, James; Weisman, Omri; Calkins, Monica E; Tang, Sunny X; Gross, Raz; McDonald-McGinn, Donna M; Emanuel, Beverly S; Zackai, Elaine H; Zalsman, Gil; Weizman, Abraham; Gur, Ruben C; Gur, Raquel E; Gothelf, Doron

2017-10-01

About one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia. Notably, a full-blown psychotic disorder is usually preceded by subthreshold symptoms. Therefore, it is important to identify early signs of psychosis in this population, a task that is complicated by the intellectual disabilities typically seen in 22q11.2DS. We aimed to identify subthreshold psychotic symptoms that distinguish 22q11.2DS from other neurodevelopmental disorders. The study included two independent cohorts from Tel Aviv and Philadelphia. 22q11.2DS (N=171) and typically developing (TD; N=832) individuals were enrolled at both sites and further compared to two groups with intellectual disabilities: Williams syndrome (WS; N=21) in the Tel Aviv cohort and idiopathic developmental disabilities (IDD; N=129) in the Philadelphia cohort. Participants and their primary caregivers were interviewed with the Structured Interview for Prodromal Symptoms (SIPS) and psychopathologies were assessed using standardized tools; general cognitive abilities were assessed with the Computerized Neurocognitive Battery. Negative/disorganized subthreshold syndrome was significantly more common in the 22q11.2DS group than in the WS (OR=3.90, 95% CI=1.34-11.34) or IDD (OR=5.05, 95% CI=3.01-10.08) groups. The 22q11.2DS group had higher scores than the two intellectual disabilities groups on several SIPS negative items, including avolition and decreased expression of emotion. Overall, there were few significant correlations between level of cognitive deficits and severity of negative symptoms in 22q11.2DS and only in the Tel Aviv cohort. Our findings suggest that 22q11.2DS individuals at the age of risk for developing psychosis should be closely monitored for negative symptoms. Copyright © 2016 Elsevier B.V. All rights reserved.

Beyond the redox imbalance: oxidative stress contributes to an impaired GLUT3 modulation in Huntington's disease

PubMed Central

Covarrubias-Pinto, Adriana; Moll, Pablo; Solís-Maldonado, Macarena; Acuña, Aníbal I.; Riveros, Andrea; Miró, María Paz; Papic, Eduardo; Beltrán, Felipe A.; Cepeda, Carlos; Concha, Ilona I.; Brauchi, Sebastián; Castro, Maite A.

2016-01-01

Failure in energy metabolism and oxidative damage are associated with Huntington’s disease (HD). Ascorbic acid released during synaptic activity inhibits use of neuronal glucose, favouring lactate uptake to sustain brain activity. Here, we observe a decreased expression of GLUT3 in STHdhQ111 cells (HD cells) and R6/2 mice (HD mice). Localisation of GLUT3 is decreased at the plasma membrane in HD cells affecting the modulation of glucose uptake by ascorbic acid. An ascorbic acid analogue without antioxidant activity is able to inhibit glucose uptake in HD cells. The impaired modulation of glucose uptake by ascorbic acid is directly related to ROS levels indicating that oxidative stress sequesters the ability of ascorbic acid to modulate glucose utilisation. Therefore, in HD, a decrease in GLUT3 localisation at the plasma membrane would contribute to an altered neuronal glucose uptake during resting periods while redox imbalance should contribute to metabolic failure during synaptic activity. PMID:26456058

Development of the HD-Teen Inventory

PubMed Central

Driessnack, Martha; Williams, Janet K.; Barnette, J. Jackson; Sparbel, Kathleen J.; Paulsen, Jane S.

2013-01-01

Adolescents, who have a parent with Huntington Disease (HD), not only are at genetic risk for HD but also are witness to its onset and devastating clinical progression as their parent declines. To date, no mechanism has been developed to direct health care providers to the atypical adolescent experiences of these teens. The purpose of this report is to describe the process of developing the HD-Teen Inventory clinical assessment tool. Forty-eight teens and young adults from 19 U.S. states participated in the evaluation of the HD-Teen Inventory tool. Following item analysis, the number of items was reduced and item frequency and reaction scales were combined, based on the strong correlation (r = .94). The resultant tool contains 15 inventory and 2 open-ended response items. The HD-Teen Inventory emerged as a more compact and efficient tool for identifying the most salient concerns of at-risk teens in HD families in research and/or clinical practice. PMID:21632913

Development of the HD-Teen Inventory.

PubMed

Driessnack, Martha; Williams, Janet K; Barnette, J Jackson; Sparbel, Kathleen J; Paulsen, Jane S

2012-05-01

Adolescents, who have a parent with Huntington Disease (HD), not only are at genetic risk for HD but also are witness to its onset and devastating clinical progression as their parent declines. To date, no mechanism has been developed to direct health care providers to the atypical adolescent experiences of these teens. The purpose of this report is to describe the process of developing the HD-Teen Inventory clinical assessment tool. Forty-eight teens and young adults from 19 U.S. states participated in the evaluation of the HD-Teen Inventory tool. Following item analysis, the number of items was reduced and item frequency and reaction scales were combined, based on the strong correlation (r = .94). The resultant tool contains 15 inventory and 2 open-ended response items. The HD-Teen Inventory emerged as a more compact and efficient tool for identifying the most salient concerns of at-risk teens in HD families in research and/or clinical practice.

Nuclear 82-kDa choline acetyltransferase decreases amyloidogenic APP metabolism in neurons from APP/PS1 transgenic mice.

PubMed

Albers, Shawn; Inthathirath, Fatima; Gill, Sandeep K; Winick-Ng, Warren; Jaworski, Ewa; Wong, Daisy Y L; Gros, Robert; Rylett, R Jane

2014-09-01

Alzheimer disease (AD) is associated with increased amyloidogenic processing of amyloid precursor protein (APP) to β-amyloid peptides (Aβ), cholinergic neuron loss with decreased choline acetyltransferase (ChAT) activity, and cognitive dysfunction. Both 69-kDa ChAT and 82-kDa ChAT are expressed in cholinergic neurons in human brain and spinal cord with 82-kDa ChAT localized predominantly to neuronal nuclei, suggesting potential alternative functional roles for the enzyme. By gene microarray analysis, we found that 82-kDa ChAT-expressing IMR32 neural cells have altered expression of genes involved in diverse cellular functions. Importantly, genes for several proteins that regulate APP processing along amyloidogenic and non-amyloidogenic pathways are differentially expressed in 82-kDa ChAT-containing cells. The predicted net effect based on observed changes in expression patterns of these genes would be decreased amyloidogenic APP processing with decreased Aβ production. This functional outcome was verified experimentally as a significant decrease in BACE1 protein levels and activity and a concomitant reduction in the release of endogenous Aβ1-42 from neurons cultured from brains of AD-model APP/PS1 transgenic mice. The expression of 82-kDa ChAT in neurons increased levels of GGA3, which is involved in trafficking BACE1 to lysosomes for degradation. shRNA-induced decreases in GGA3 protein levels attenuated the 82-kDa ChAT-mediated decreases in BACE1 protein and activity and Aβ1-42 release. Evidence that 82-kDa ChAT can enhance GGA3 gene expression is shown by enhanced GGA3 gene promoter activity in SN56 neural cells expressing this ChAT protein. These studies indicate a novel relationship between cholinergic neurons and APP processing, with 82-kDa ChAT acting as a negative regulator of Aβ production. This decreased formation of Aβ could result in protection for cholinergic neurons, as well as protection of other cells in the vicinity that are sensitive to

14 CFR 171.7 - Performance requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Performance requirements. 171.7 Section 171.7 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) NAVIGATIONAL FACILITIES NON-FEDERAL NAVIGATION FACILITIES VOR Facilities § 171.7 Performance requirements. (a...

14 CFR 171.7 - Performance requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Performance requirements. 171.7 Section 171.7 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) NAVIGATIONAL FACILITIES NON-FEDERAL NAVIGATION FACILITIES VOR Facilities § 171.7 Performance requirements. (a...

14 CFR 171.7 - Performance requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Performance requirements. 171.7 Section 171.7 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) NAVIGATIONAL FACILITIES NON-FEDERAL NAVIGATION FACILITIES VOR Facilities § 171.7 Performance requirements. (a...

14 CFR 171.7 - Performance requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Performance requirements. 171.7 Section 171.7 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) NAVIGATIONAL FACILITIES NON-FEDERAL NAVIGATION FACILITIES VOR Facilities § 171.7 Performance requirements. (a...

22 CFR 171.13 - Business information.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Business information. 171.13 Section 171.13... PUBLIC Freedom of Information Act Provisions § 171.13 Business information. (a) Business information... section. (b) Definitions. For purposes of this section: (1) Business information means information...

22 CFR 171.13 - Business information.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Business information. 171.13 Section 171.13... PUBLIC Freedom of Information Act Provisions § 171.13 Business information. (a) Business information... section. (b) Definitions. For purposes of this section: (1) Business information means information...

22 CFR 171.13 - Business information.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Business information. 171.13 Section 171.13... PUBLIC Freedom of Information Act Provisions § 171.13 Business information. (a) Business information... section. (b) Definitions. For purposes of this section: (1) Business information means information...

22 CFR 171.13 - Business information.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Business information. 171.13 Section 171.13... PUBLIC Freedom of Information Act Provisions § 171.13 Business information. (a) Business information... section. (b) Definitions. For purposes of this section: (1) Business information means information...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

46 CFR 171.130 - Specific applicability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Specific applicability. 171.130 Section 171.130 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SUBDIVISION AND STABILITY SPECIAL RULES PERTAINING TO VESSELS CARRYING PASSENGERS Drainage of Weather Decks § 171.130 Specific applicability. (a...

40 CFR 98.171 - Reporting threshold.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Reporting threshold. 98.171 Section 98.171 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Iron and Steel Production § 98.171 Reporting threshold. You must report...

40 CFR 98.171 - Reporting threshold.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 22 2012-07-01 2012-07-01 false Reporting threshold. 98.171 Section 98.171 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Iron and Steel Production § 98.171 Reporting threshold. You must report...

Full Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

PubMed Central

Gray, Michelle; Shirasaki, Dyna I.; Cepeda, Carlos; Andre, Veronique M.; Wilburn, Brian; Lu, Xiao-Hong; Tao, Jifang; Yamazaki, Irene; Li, Shi-Hua; Sun, Yi E.; Li, Xiao-Jiang; Levine, Michael S.; William Yang, X

2008-01-01

To elucidate the pathogenic mechanisms in Huntington’s disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a Bacterial Artificial Chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Further analyses of BACHD mice provide additional insights into how mhtt may elicit neuropathogenesis. First, unlike prior fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e. as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment. PMID:18550760

22 CFR 171.13 - Business information.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Business information. 171.13 Section 171.13 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC Freedom of Information Act Provisions § 171.13 Business information. (a) Business information...

32 CFR 171.7 - Reporting requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false Reporting requirements. 171.7 Section 171.7 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.7 Reporting requirements. Not later...

32 CFR 171.7 - Reporting requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Reporting requirements. 171.7 Section 171.7 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.7 Reporting requirements. Not later...

32 CFR 171.7 - Reporting requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Reporting requirements. 171.7 Section 171.7 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.7 Reporting requirements. Not later...

32 CFR 171.7 - Reporting requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false Reporting requirements. 171.7 Section 171.7 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING IMPLEMENTATION OF WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.7 Reporting requirements. Not later...

50 CFR 217.171 - Effective dates.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 50 Wildlife and Fisheries 9 2011-10-01 2011-10-01 false Effective dates. 217.171 Section 217.171 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION... Liquefied Natural Gas Facility Off Massachusetts § 217.171 Effective dates. Regulations in this subpart are...

22 CFR 171.21 - Declassification review.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Declassification review. 171.21 Section 171.21 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC Executive Order 12958 Provisions § 171.21 Declassification review. (a) Scope. All information...

Early Alterations of Brain Cellular Energy Homeostasis in Huntington Disease Models*

PubMed Central

Mochel, Fanny; Durant, Brandon; Meng, Xingli; O'Callaghan, James; Yu, Hua; Brouillet, Emmanuel; Wheeler, Vanessa C.; Humbert, Sandrine; Schiffmann, Raphael; Durr, Alexandra

2012-01-01

Brain energy deficit has been a suggested cause of Huntington disease (HD), but ATP depletion has not reliably been shown in preclinical models, possibly because of the immediate post-mortem changes in cellular energy metabolism. To examine a potential role of a low energy state in HD, we measured, for the first time in a neurodegenerative model, brain levels of high energy phosphates using microwave fixation, which instantaneously inactivates brain enzymatic activities and preserves in vivo levels of analytes. We studied HD transgenic R6/2 mice at ages 4, 8, and 12 weeks. We found significantly increased creatine and phosphocreatine, present as early as 4 weeks for phosphocreatine, preceding motor system deficits and decreased ATP levels in striatum, hippocampus, and frontal cortex of R6/2 mice. ATP and phosphocreatine concentrations were inversely correlated with the number of CAG repeats. Conversely, in mice injected with 3-nitroproprionic acid, an acute model of brain energy deficit, both ATP and phosphocreatine were significantly reduced. Increased creatine and phosphocreatine in R6/2 mice was associated with decreased guanidinoacetate N-methyltransferase and creatine kinase, both at the protein and RNA levels, and increased phosphorylated AMP-dependent protein kinase (pAMPK) over AMPK ratio. In addition, in 4-month-old knock-in HdhQ111/+ mice, the earliest metabolic alterations consisted of increased phosphocreatine in the frontal cortex and increased the pAMPK/AMPK ratio. Altogether, this study provides the first direct evidence of chronic alteration in homeostasis of high energy phosphates in HD models in the earliest stages of the disease, indicating possible reduced utilization of the brain phosphocreatine pool. PMID:22123819

The nature of dust around the post-asymptotic giant branch objects HD 161796 and HD 179821

NASA Technical Reports Server (NTRS)

Justtanont, K.; Barlow, M. J.; Skinner, C. J.; Tielens, A. G. G. M.

1992-01-01

Ground-based 7.4-24-micron spectra of two post-AGB objects, HD 161796 and HD 179821, are reported, and they are compared to those of other preplanetary nebulae. HD 161796 and HD 17982 show emission features at 10-12 microns and at 10 microns, and they exhibit a very rapid increase in flux between 13 and 15.5 microns. In view of the O-rich photosphere of HD 161796 and the presence of OH maser emission around all three objects, these features are ascribed to various oxides. The observed spectral features are quite different from the canonical silicate features observed in most O-rich giants. It is argued that HD 161796 and the bipolar nebulae Roberts 22 and NGC 6302 have all undergone the third dredge-up, with most of the dredged-up carbon having been converted to nitrogen by envelope-burning. It is concluded that carbon-rich grain material, produced during the interval between the end of the third dredge-up and the moment when envelope burning finally reduced the C/O ratio below unity again, could be responsible for the UIR bands now being excited in Roberts 22 and NGC 6302.

Tracking Advanced Planetary Systems (TAPAS) with HARPS-N. II. Super Li-rich giant HD 107028

NASA Astrophysics Data System (ADS)

Adamów, M.; Niedzielski, A.; Villaver, E.; Wolszczan, A.; Kowalik, K.; Nowak, G.; Adamczyk, M.; Deka-Szymankiewicz, B.

2015-09-01

Context. Lithium-rich giant stars are rare objects. For some of them, Li enrichment exceeds the abundance of this element found in solar system meteorites, suggesting that these stars have gone through a Li enhancement process. Aims: We identified a Li-rich giant HD 107028 with A(Li) > 3.3 in a sample of evolved stars observed within the PennState Toruń Planet Search. In this work we study different enhancement scenarios and we try to identify the one responsible for Li enrichment in HD 107028. Methods: We collected high-resolution spectra with three different instruments, covering different spectral ranges. We determined stellar parameters and abundances of selected elements with both equivalent width measurements and analysis, and spectral synthesis. We also collected multi-epoch high-precision radial velocities in an attempt to detect a companion. Results: Collected data show that HD 107028 is a star at the base of the red giant branch (RGB). Except for high Li abundance, we have not identified any other anomalies in its chemical composition, and there is no indication of a low-mass or stellar companion. We exclude Li production at the luminosity function bump on the RGB as the effective temperature and luminosity suggest that the evolutionary state is much earlier than the RGB bump. We also cannot confirm the Li enhancement by contamination as we do not observe any anomalies that are associated with this scenario. Conclusions: After evaluating various scenarios of Li enhancement we conclude that the Li-overabundance of HD 107028 originates from main-sequence evolution, and may be caused by diffusion processes. Based on observations obtained with the Hobby-Eberly Telescope, which is a joint project of the University of Texas at Austin, the Pennsylvania State University, Stanford University, Ludwig-Maximilians-Universität München, and Georg-August-Universität Göttingen.Based on observations made with the Italian Telescopio Nazionale Galileo (TNG) operated on

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington's Disease.

PubMed

Cabezas-Llobet, N; Vidal-Sancho, L; Masana, M; Fournier, A; Alberch, J; Vaudry, D; Xifró, X

2018-03-10

Deficits in hippocampal synaptic plasticity result in cognitive impairment in Huntington's disease (HD). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts neuroprotective actions, mainly through the PAC1 receptor. However, the role of PACAP in cognition is poorly understood, and no data exists in the context of Huntington's disease (HD). Here, we investigated the ability of PACAP receptor stimulation to enhance memory development in HD. First, we observed a hippocampal decline of all three PACAP receptor expressions, i.e., PAC1, VPAC1, and VPAC2, in two different HD mouse models, R6/1 and HdhQ7/Q111, from the onset of cognitive dysfunction. In hippocampal post-mortem human samples, we found a specific decrease of PAC1, without changes in VPAC1 and VPAC2 receptors. To determine whether activation of PACAP receptors could contribute to improve memory performance, we conducted daily intranasal administration of PACAP38 to R6/1 mice at the onset of cognitive impairment for seven days. We found that PACAP treatment rescued PAC1 level in R6/1 mice, promoted expression of the hippocampal brain-derived neurotrophic factor, and reduced the formation of mutant huntingtin aggregates. Furthermore, PACAP administration counteracted R6/1 mice memory deficits as analyzed by the novel object recognition test and the T-maze spontaneous alternation task. Importantly, the effect of PACAP on cognitive performance was associated with an increase of VGlut-1 and PSD95 immunolabeling in hippocampus of R6/1 mice. Taken together, these results suggest that PACAP, acting through stimulation of PAC1 receptor, may have a therapeutic potential to counteract cognitive deficits induced in HD.

29 CFR 102.171 - Cost shifting.

Code of Federal Regulations, 2010 CFR

2010-07-01

... By Federal Income Tax Refund Offset § 102.171 Cost shifting. Costs incurred by the Agency in... 29 Labor 2 2010-07-01 2010-07-01 false Cost shifting. 102.171 Section 102.171 Labor Regulations... amount of the offset. Such costs may include administrative costs and attorneys fees. ...

7 CFR 3015.171 - Unused supplies.

Code of Federal Regulations, 2010 CFR

2010-01-01

..., DEPARTMENT OF AGRICULTURE UNIFORM FEDERAL ASSISTANCE REGULATIONS Property § 3015.171 Unused supplies. (a) If unused supplies exceeding $1,000 in total aggregate market value are left over upon termination or... 7 Agriculture 15 2010-01-01 2010-01-01 false Unused supplies. 3015.171 Section 3015.171...

Analytical expression for the exit probability of the q -voter model in one dimension

NASA Astrophysics Data System (ADS)

Timpanaro, André M.; Galam, Serge

2015-07-01

We present in this paper an approximation that is able to give an analytical expression for the exit probability of the q -voter model in one dimension. This expression gives a better fit for the more recent data about simulations in large networks [A. M. Timpanaro and C. P. C. do Prado, Phys. Rev. E 89, 052808 (2014), 10.1103/PhysRevE.89.052808] and as such departs from the expression ρ/qρq+(1-ρ ) q found in papers that investigated small networks only [R. Lambiotte and S. Redner, Europhys. Lett. 82, 18007 (2008), 10.1209/0295-5075/82/18007; P. Przybyła et al., Phys. Rev. E 84, 031117 (2011), 10.1103/PhysRevE.84.031117; F. Slanina et al., Europhys. Lett. 82, 18006 (2008), 10.1209/0295-5075/82/18006]. The approximation consists in assuming a large separation on the time scales at which active groups of agents convince inactive ones and the time taken in the competition between active groups. Some interesting findings are that for q =2 we still have ρ/2ρ2+(1-ρ ) 2 as the exit probability and for q >2 we can obtain a lower-order approximation of the form ρ/sρs+(1-ρ ) s with s varying from q for low values of q to q -1/2 for large values of q . As such, this work can also be seen as a deduction for why the exit probability ρ/qρq+(1-ρ ) q gives a good fit, without relying on mean-field arguments or on the assumption that only the first step is nondeterministic, as q and q -1/2 will give very similar results when q →∞ .

The impact of reinforcement contingencies on AD/HD: a review and theoretical appraisal.

PubMed

Luman, Marjolein; Oosterlaan, Jaap; Sergeant, Joseph A

2005-02-01

One of the core deficits in attention deficit/hyperactivity disorder (AD/HD) is thought to be an aberrant sensitivity to reinforcement, such as reward and response cost. Twenty-two studies (N=1181 children) employing AD/HD and reinforcement contingencies are reviewed from vantage points: task performance, motivation, and psychophysiology. Results indicate that reinforcement contingencies have a positive impact on task performance and levels of motivation for both children with AD/HD and normal controls. There is evidence that the effect related to task performance is somewhat more prominent in AD/HD. There is some evidence that a high intensity of reinforcement is highly effective in AD/HD. Children with AD/HD prefer immediate over delayed reward. From a psychophysiological point of view, children with AD/HD seem less sensitive to reinforcement compared to controls. While comorbid disorders are suggested to be confounders of the dependent variables, many studies do not examine the effect of oppositional defiant disorder (ODD) and conduct disorder (CD). We discuss the implications of the findings for five theoretical frameworks, including the model by, the cognitive-energetic model (CEM), the dual-pathway model and the BIS/BAS model. Results show a discrepancy between the theoretical models and the behavioural findings.

Stellar wind variations in HD 45166: The continuing story. [Wolf-Rayet star

NASA Technical Reports Server (NTRS)

Willis, Allan J.; Stickland, David J.; Heap, Sara R.

1988-01-01

High resolution SWP IUE spectra of HD 45166 (qWR+B8V) obtained over a 36 hr continuous run, together with earlier observations, reveal 2 distinct modes of UV variability in this object. Gross, epoch-linked changes are seen in the strengths of the qWR emission lines, accompanied by large changes in its highly ionized photospheric absorption spectrum. Rapid (hours) variability in strong, multiple, high velocity, wind discrete absorption components (DAC), in the CIV lambda 1550 resonance lines, which superpose to give the appearance of a broad P Cygni absorption profile at many epochs is also observed. These multiple DAC's (often at least 3 are seen) propagate in velocity, from 0.6 to 1.0 v inf, on a timescale of 1 day, implying an acceleration of 180 cm/s comparable to that seen in O-type stars.

Real-time PCR to determine transgene copy number and to quantitate the biolocalization of adoptively transferred cells from EGFP-transgenic mice.

PubMed

Joshi, Molishree; Keith Pittman, H; Haisch, Carl; Verbanac, Kathryn

2008-09-01

Quantitative real-time PCR (qPCR) is a sensitive technique for the detection and quantitation of specific DNA sequences. Here we describe a Taqman qPCR assay for quantification of tissue-localized, adoptively transferred enhanced green fluorescent protein (EGFP)-transgenic cells. A standard curve constructed from serial dilutions of a plasmid containing the EGFP transgene was (i) highly reproducible, (ii) detected as few as two copies, and (iii) was included in each qPCR assay. qPCR analysis of genomic DNA was used to determine transgene copy number in several mouse strains. Fluorescent microscopy of tissue sections showed that adoptively transferred vascular endothelial cells (VEC) from EGFP-transgenic mice specifically localized to tissue with metastatic tumors in syngeneic recipients. VEC microscopic enumeration of liver metastases strongly correlated with qPCR analysis of identical sections (Pearson correlation 0.81). EGFP was undetectable in tissue from control mice by qPCR. In another study using intra-tumor EGFP-VEC delivery to subcutaneous tumors, manual cell count and qPCR analysis of alternating sections also strongly correlated (Pearson correlation 0.82). Confocal microscopy of the subcutaneous tumor sections determined that visual fluorescent signals were frequently tissue artifacts. This qPCR methodology offers specific, objective, and rapid quantitation, uncomplicated by tissue autofluorescence, and should be readily transferable to other in vivo models to quantitate the biolocalization of transplanted cells.

nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice.

PubMed

Itzhak, Y; Martin, J L; Ail, S F

2000-09-11

Methamphetamine (METH)-induced dopaminergic neurotoxicity is associated with hyperthermia. We investigated the effect of several neuronal nitric oxide synthase (nNOS) inhibitors on METH-induced hyperthermia and striatal dopaminergic neurotoxicity. Administration of METH (5 mg/kg; q. 3 h x 3) to Swiss Webster mice produced marked hyperthermia and 50-60% depletion of striatal dopaminergic markers 72 h after METH administration. Pretreatment with the nNOS inhibitors S-methylthiocitrulline (SMTC; 10 mg/kg) or 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg) before each METH injection did not affect the persistent hyperthermia produced by METH, but afforded protection against the depletion of dopaminergic markers. A low dose (25 mg/kg) of the nNOS inhibitor 7-nitroindazole (7-NI) did not affect METH-induced hyperthermia, but a high dose (50 mg/kg) produced significant hypothermia. These findings indicate that low dose of selective nNOS inhibitors protect against METH-induced neurotoxicity with no effect on body temperature and support the hypothesis that nitric oxide (NO) and peroxynitrite have a major role in METH-induced dopaminergic neurotoxicity.

Physical Activity Self-Management and Coaching Compared to Social Interaction in Huntington Disease: Results From the ENGAGE-HD Randomized, Controlled Pilot Feasibility Trial

PubMed Central

Quinn, Lori; Drew, Cheney; Kelson, Mark; Trubey, Rob; McEwan, Kirsten; Jones, Carys; Townson, Julia; Dawes, Helen; Tudor-Edwards, Rhiannon; Rosser, Anne; Hood, Kerenza

2017-01-01

Abstract Background. Self-management and self-efficacy for physical activity is not routinely considered in neurologic rehabilitation. Objective. This study assessed feasibility and outcomes of a 14-week physical activity self-management and coaching intervention compared with social contact in Huntington disease (HD) to inform the design of a future full-scale trial. Design. Assessor blind, multisite, randomized pilot feasibility trial. Setting. Participants were recruited and assessed at baseline, 16 weeks following randomization, and then again at 26 weeks in HD specialist clinics with intervention delivery by trained coaches in the participants’ homes. Patients and Intervention. People with HD were allocated to the ENGAGE-HD physical activity coaching intervention or a social interaction intervention. Measurements. Eligibility, recruitment, retention, and intervention participation were determined at 16 weeks. Other outcomes of interest included measures of mobility, self-efficacy, physical activity, and disease-specific measures of motor and cognition. Fidelity and costs for both the physical activity and social comparator interventions were established. Results. Forty percent (n = 46) of eligible patients were enrolled; 22 were randomized to the physical intervention and 24 to social intervention. Retention rates in the physical intervention and social intervention were 77% and 92%, respectively. Minimum participation criteria were achieved by 82% of participants in the physical intervention and 100% in the social intervention. There was no indication of between-group treatment effects on function; however, increases in self-efficacy for exercise and self-reported levels of physical activity in the physical intervention lend support to our predefined intervention logic model. Limitations. The use of self-report measures may have introduced bias. Conclusions. An HD physical activity self-management and coaching intervention is feasible and worthy of further

Copious amounts of hot and cold dust orbiting the main sequence a-type stars HD 131488 and HD 121191

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melis, Carl; Zuckerman, B.; Rhee, Joseph H.

2013-11-20

We report two new dramatically dusty main sequence stars: HD 131488 (A1 V) and HD 121191 (A8 V). HD 131488 is found to have substantial amounts of dust in its terrestrial planet zone (L {sub IR}/L {sub bol} ≈ 4 × 10{sup –3}), cooler dust farther out in its planetary system, and an unusual mid-infrared spectral feature. HD 121191 shows terrestrial planet zone dust (L {sub IR}/L {sub bol} ≈ 2.3 × 10{sup –3}), hints of cooler dust, and shares the unusual mid-infrared spectral shape identified in HD 131488. These two stars belong to sub-groups of the Scorpius-Centaurus OB associationmore » and have ages of ∼10 Myr. HD 131488 and HD 121191 are the dustiest main sequence A-type stars currently known. Early-type stars that host substantial inner planetary system dust are thus far found only within the age range of 5-20 Myr.« less

N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease

PubMed Central

Wright, D J; Renoir, T; Smith, Z M; Frazier, A E; Francis, P S; Thorburn, D R; McGee, S L; Hannan, A J; Gray, L J

2015-01-01

Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy. PMID:25562842

12 CFR 19.171 - Deposition subpoenas.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Deposition subpoenas. 19.171 Section 19.171... PROCEDURE Discovery Depositions and Subpoenas § 19.171 Deposition subpoenas. (a) Issuance. At the request of... at a discovery deposition under paragraph (a) of this section. The attendance of a witness may be...

12 CFR 19.171 - Deposition subpoenas.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 12 Banks and Banking 1 2011-01-01 2011-01-01 false Deposition subpoenas. 19.171 Section 19.171... PROCEDURE Discovery Depositions and Subpoenas § 19.171 Deposition subpoenas. (a) Issuance. At the request of... at a discovery deposition under paragraph (a) of this section. The attendance of a witness may be...

32 CFR 171.5 - Sale procedures.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Sale procedures. 171.5 Section 171.5 National... WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.5 Sale procedures. Disposal of aircraft and... with other pertinent parts of this manual, with the following changes and additions: (a) Sales shall be...

32 CFR 171.5 - Sale procedures.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 1 2012-07-01 2012-07-01 false Sale procedures. 171.5 Section 171.5 National... WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.5 Sale procedures. Disposal of aircraft and... with other pertinent parts of this manual, with the following changes and additions: (a) Sales shall be...

32 CFR 171.5 - Sale procedures.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false Sale procedures. 171.5 Section 171.5 National... WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.5 Sale procedures. Disposal of aircraft and... with other pertinent parts of this manual, with the following changes and additions: (a) Sales shall be...

32 CFR 171.5 - Sale procedures.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Sale procedures. 171.5 Section 171.5 National... WILDFIRE SUPPRESSION AIRCRAFT TRANSFER ACT OF 1996 § 171.5 Sale procedures. Disposal of aircraft and... with other pertinent parts of this manual, with the following changes and additions: (a) Sales shall be...

40 CFR 98.171 - Reporting threshold.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 22 2013-07-01 2013-07-01 false Reporting threshold. 98.171 Section 98.171 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Iron and Steel Production § 98.171 Reporting threshold. You must report GHG emissions under this subpart if your...

40 CFR 98.171 - Reporting threshold.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 21 2011-07-01 2011-07-01 false Reporting threshold. 98.171 Section 98.171 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Iron and Steel Production § 98.171 Reporting threshold. You must report GHG emissions under this subpart if your...

40 CFR 98.171 - Reporting threshold.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 21 2014-07-01 2014-07-01 false Reporting threshold. 98.171 Section 98.171 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Iron and Steel Production § 98.171 Reporting threshold. You must report GHG emissions under this subpart if your...

Search for spectroscopical signatures of transiting HD 209458b's exosphere

NASA Astrophysics Data System (ADS)

Moutou, C.; Coustenis, A.; Schneider, J.; St Gilles, R.; Mayor, M.; Queloz, D.; Kaufer, A.

2001-05-01

Following recent attempts to detect the exosphere of the extra-solar planet 51 Pegb in the infrared (Coustenis et al. \\cite{cou97}, \\cite{cou98}; Rauer et al. \\cite{rau00a}), we discuss here a search for optical spectroscopic signatures from a gaseous extended envelope (called exosphere) surrounding the planet HD 209458b. This planet has a demonstrated photometric transit (Charbonneau et al. \\cite{cha00a}; Henry et al. \\cite{hen00}), thus offering an increased probability for the spectroscopic detection of such an envelope. Therefore it is the best known candidate for probing the exospheric composition of a giant planet, orbiting a Sun-like star at a short distance. The observations were performed with UVES at the VLT and cover most of the 328-669 nm range. We did not detect HD 209458b's exosphere at a level of 1%, a value close to the predictions. We discuss here the first results obtained and their limitations, as well as future prospective. Based on public data from the UVES Commissioning at the ESO 8.2~m Kueyen telescope operated on Paranal Observatory, Chile.

The chemically peculiar double-lined spectroscopic binary HD 90264

NASA Astrophysics Data System (ADS)

Quiroga, C.; Torres, A. F.; Cidale, L. S.

2010-10-01

Context. HD 90264 is a chemically peculiar (CP) double-lined spectroscopic binary system of the type He-weak. Double-lined binaries are unique sources of data for stellar masses, physical properties, and evolutionary aspects of stars. Therefore, the determination of orbital elements is of great importance to study how the physical characteristics of CP stars are affected by a companion. Aims: We carried out a detailed spectral and polarimetric study of the spectroscopic binary system HD 90264 to characterize its orbit, determine the stellar masses, and investigate the spectral variability and possible polarization of the binary components. Methods: We employed medium-resolution échelle spectra and polarimetric data obtained at the 2.15-m telescope at CASLEO Observatory, Argentina. We measured radial velocities and line equivalent widths with IRAF packages. The radial velocity curves of both binary components were obtained combining radial velocity data derived from the single line of Hg II λ3984 Åand the double lines of Mg II λ4481 Å. Polarimetric data were studied by means of the statistical method of Clarke & Stewart and the Welch test. Results: We found that both components of the binary system are chemically peculiar stars, deficient in helium, where the primary is a He variable and the secondary is a Hg-Mn star. We derived for the first time the orbital parameters of the binary system. We found that the system has a quasi-circular orbit (e ~ 0.04) with an orbital period of 15.727 days. Taking into account the circular orbit solution, we derived a mass ratio of q = MHe-w/MHg-Mn = 1.22. We also found a rotational period of around 15-16 days, suggesting a spin-orbit synchronization. Possible signs of intrinsic polarization have also been detected. Conclusions: HD 90264 is the first known binary system comprised of a He variable star as the primary component and a Hg-Mn star as the secondary one. Based on observations taken at Complejo Astronómico El

1p3/2 proton-hole state in 132Sn and the shell structure along N = 82.

PubMed

Taprogge, J; Jungclaus, A; Grawe, H; Nishimura, S; Doornenbal, P; Lorusso, G; Simpson, G S; Söderström, P-A; Sumikama, T; Xu, Z Y; Baba, H; Browne, F; Fukuda, N; Gernhäuser, R; Gey, G; Inabe, N; Isobe, T; Jung, H S; Kameda, D; Kim, G D; Kim, Y-K; Kojouharov, I; Kubo, T; Kurz, N; Kwon, Y K; Li, Z; Sakurai, H; Schaffner, H; Steiger, K; Suzuki, H; Takeda, H; Vajta, Zs; Watanabe, H; Wu, J; Yagi, A; Yoshinaga, K; Benzoni, G; Bönig, S; Chae, K Y; Coraggio, L; Covello, A; Daugas, J-M; Drouet, F; Gadea, A; Gargano, A; Ilieva, S; Kondev, F G; Kröll, T; Lane, G J; Montaner-Pizá, A; Moschner, K; Mücher, D; Naqvi, F; Niikura, M; Nishibata, H; Odahara, A; Orlandi, R; Patel, Z; Podolyák, Zs; Wendt, A

2014-04-04

A low-lying state in 131In82, the one-proton hole nucleus with respect to double magic 132Sn, was observed by its γ decay to the Iπ=1/2- β-emitting isomer. We identify the new state at an excitation energy of Ex=1353  keV, which was populated both in the β decay of 131Cd83 and after β-delayed neutron emission from 132Cd84, as the previously unknown πp3/2 single-hole state with respect to the 132Sn core. Exploiting this crucial new experimental information, shell-model calculations were performed to study the structure of experimentally inaccessible N=82 isotones below 132Sn. The results evidence a surprising absence of proton subshell closures along the chain of N=82 isotones. The consequences of this finding for the evolution of the N=82 shell gap along the r-process path are discussed.

49 CFR 171.3 - Hazardous waste.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false Hazardous waste. 171.3 Section 171.3... waste. (a) No person may offer for transportation or transport a hazardous waste (as defined in § 171.8... waste for which a manifest is required unless that person: (1) Has marked each motor vehicle used to...

17 CFR 270.30a-2 - Certification of Form N-CSR and Form N-Q.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., at the time of filing of the report must sign a certification. (b) Each report on Form N-CSR filed by... company (or equivalent thereof) must sign a certification. This requirement may be satisfied by a single... Form N-CSR and Form N-Q. (a) Each report filed on Form N-CSR (§§ 249.331 and 274.128 of this chapter...

17 CFR 270.30a-2 - Certification of Form N-CSR and Form N-Q.

Code of Federal Regulations, 2011 CFR

2011-04-01

..., at the time of filing of the report must sign a certification. (b) Each report on Form N-CSR filed by... company (or equivalent thereof) must sign a certification. This requirement may be satisfied by a single... Form N-CSR and Form N-Q. (a) Each report filed on Form N-CSR (§§ 249.331 and 274.128 of this chapter...

Precise Ages for the Benchmark Brown Dwarfs HD 19467 B and HD 4747 B

NASA Astrophysics Data System (ADS)

Wood, Charlotte; Boyajian, Tabetha; Crepp, Justin; von Braun, Kaspar; Brewer, John; Schaefer, Gail; Adams, Arthur; White, Tim

2018-01-01

Large uncertainty in the age of brown dwarfs, stemming from a mass-age degeneracy, makes it difficult to constrain substellar evolutionary models. To break the degeneracy, we need ''benchmark" brown dwarfs (found in binary systems) whose ages can be determined independent of their masses. HD~19467~B and HD~4747~B are two benchmark brown dwarfs detected through the TRENDS (TaRgeting bENchmark objects with Doppler Spectroscopy) high-contrast imaging program for which we have dynamical mass measurements. To constrain their ages independently through isochronal analysis, we measured the radii of the host stars with interferometry using the Center for High Angular Resolution Astronomy (CHARA) Array. Assuming the brown dwarfs have the same ages as their host stars, we use these results to distinguish between several substellar evolutionary models. In this poster, we present new age estimates for HD~19467 and HD~4747 that are more accurate and precise and show our preliminary comparisons to cooling models.

Project VeSElkA: results of abundance analysis for HD 53929 and HD 63975

NASA Astrophysics Data System (ADS)

Ndiaye, M. L.; LeBlanc, F.; Khalack, V.

2018-03-01

Project VeSElkA (Vertical Stratification of Element Abundances) has been initiated with the aim to detect and study the vertical stratification of element abundances in the atmosphere of chemically peculiar stars. Abundance stratification occurs in hydrodynamically stable stellar atmospheres due to the migration of the elements caused by atomic diffusion. Two HgMn stars, HD 53929 and HD 63975 were selected from the VeSElkA sample and analysed with the aim to detect some abundance peculiarities employing the ZEEMAN2 code. We present the results of abundance analysis of HD 53929 and HD 63975 observed recently with the spectropolarimeter ESPaDOnS at Canada-France-Hawaii Telescope. Evidence of phosphorus vertical stratification was detected in the atmosphere of these two stars. In both cases, phosphorus abundance increases strongly towards the superficial layers. The strong overabundance of Mn found in stellar atmosphere of both stars confirms that they are HgMn type stars.

The proteome pattern cGvHD_MS14 allows early and accurate prediction of chronic GvHD after allogeneic stem cell transplantation.

PubMed

Weissinger, E M; Human, C; Metzger, J; Hambach, L; Wolf, D; Greinix, H T; Dickinson, A M; Mullen, W; Jonigk, D; Kuzmina, Z; Kreipe, H; Schweier, P; Böhm, O; Türüchanow, I; Ihlenburg-Schwarz, D; Raad, J; Durban, A; Schiemann, M; Könecke, C; Diedrich, H; Holler, E; Beutel, G; Krauter, J; Ganser, A; Stadler, M

2017-03-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be curative, but is associated with significant morbidity and mortality. Chronic graft-versus-host disease (cGvHD), characterized by inflammation and fibrosis of multiple target organs, considerably contributes to the morbidity and mortality even years after allo-HSCT. Diagnosis of cGvHD is based on clinical features and histology of biopsies. Here, we report the generation of a urinary cGvHD-specific proteome-pattern (cGvHD_MS14) established by capillary electrophoresis-mass spectrometry to predict onset and severity of cGvHD as an unbiased laboratory test. cGvHD_MS14 was evaluated on samples from 412 patients collected prospectively in four transplant centers. Sensitivity and specificity was 84 and 76% by cGvHD_MS14 classification. Sensitivity further increased to 93% by combination of cGvHD_MS14 with relevant clinical variables to a logistic regression model. cGvHD was predicted up to 55 days prior to clinical diagnosis. Acute GvHD is not recognized by cGvHD_MS14. cGvHD_MS14 consists of 14 differentially excreted peptides, six of those have been sequenced to date and are fragments from thymosin β-4, eukaryotic translation initiation factor 4γ2, fibrinogen β-chain or collagens. In conclusion, the cGvHD_MS14-pattern allows early, highly sensitive and specific prediction of cGvHD as an independent diagnostic criterion of clinical diagnosis potentially allowing early therapeutic intervention.

Protective effect of mitochondrial-targeted antioxidant MitoQ against iron ion 56Fe radiation induced brain injury in mice.

PubMed

Gan, Lu; Wang, Zhenhua; Si, Jing; Zhou, Rong; Sun, Chao; Liu, Yang; Ye, Yancheng; Zhang, Yanshan; Liu, Zhiyuan; Zhang, Hong

2018-02-15

Exposure to iron ion 56 Fe radiation (IR) during space missions poses a significant risk to the central nervous system and radiation exposure is intimately linked to the production of reactive oxygen species (ROS). MitoQ is a mitochondria-targeted antioxidant that has been shown to decrease oxidative damage and lower mitochondrial ROS in a number of animal models. Therefore, the present study aimed to investigate role of the mitochondrial targeted antioxidant MitoQ against 56 Fe particle irradiation-induced oxidative damage and mitochondria dysfunction in the mouse brains. Increased ROS levels were observed in mouse brains after IR compared with the control group. Enhanced ROS production leads to disruption of cellular antioxidant defense systems, mitochondrial respiration dysfunction, altered mitochondria dynamics and increased release of cytochrome c (cyto c) from mitochondria into cytosol resulting in apoptotic cell death. MitoQ reduced IR-induced oxidative stress (decreased ROS production and increased SOD, CAT activities) with decreased lipid peroxidation as well as reduced protein and DNA oxidation. MitoQ also protected mitochondrial respiration after IR. In addition, MitoQ increased the expression of mitofusin2 (Mfn2) and optic atrophy gene1 (OPA1), and decreased the expression of dynamic-like protein (Drp1). MitoQ also suppressed mitochondrial DNA damage, cyto c release, and caspase-3 activity in IR-treated mice compared to the control group. These results demonstrate that MitoQ may protect against IR-induced brain injury. Copyright © 2018 Elsevier Inc. All rights reserved.

TWO SMALL PLANETS TRANSITING HD 3167

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vanderburg, Andrew; Bieryla, Allyson; Latham, David W.

2016-09-20

We report the discovery of two super-Earth-sized planets transiting the bright (V = 8.94, K = 7.07) nearby late G-dwarf HD 3167, using data collected by the K2 mission. The inner planet, HD 3167 b, has a radius of 1.6 R {sub ⊕} and an ultra-short orbital period of only 0.96 days. The outer planet, HD 3167 c, has a radius of 2.9 R {sub ⊕} and orbits its host star every 29.85 days. At a distance of just 45.8 ± 2.2 pc, HD 3167 is one of the closest and brightest stars hosting multiple transiting planets, making HD 3167more » b and c well suited for follow-up observations. The star is chromospherically inactive with low rotational line-broadening, ideal for radial velocity observations to measure the planets’ masses. The outer planet is large enough that it likely has a thick gaseous envelope that could be studied via transmission spectroscopy. Planets transiting bright, nearby stars like HD 3167 are valuable objects to study leading up to the launch of the James Webb Space Telescope .« less

A synthetic eicosanoid LX-mimetic unravels host-donor interactions in allogeneic BMT-induced GvHD to reveal an early protective role for host neutrophils.

PubMed

Devchand, Pallavi R; Schmidt, Birgitta A; Primo, Valeria C; Zhang, Qing-yin; Arnaout, M Amin; Serhan, Charles N; Nikolic, Boris

2005-02-01

Lipoxin A(4) (LXA(4)) and aspirin-triggered 15-epi-LXA(4) are potent endogenous lipid mediators thought to define the inflammatory set-point. We used single prophylactic administrations of a synthetic aspirin-triggered lipoxin A(4) signal mimetic, ATLa, to probe dynamics of early host-donor interactions in a mouse model for the inflammation-associated multifactorial disease of allogeneic bone marrow transplant (BMT) -induced graft-vs.-host disease (GvHD). We first demonstrated that both host and donor are responsive to the ATLa signals. The simple and restricted regimen of a single prophylactic administration of ATLa [100 ng/mL to donor cells or 1 microg (approximately 50 microg/kg) i.v. to host] was sufficient to delay death. Clinical indicators of weight, skin lesions, diarrhea and eye inflammation were monitored. Histological analyses on day 45 post-BMT showed that the degree of cellular trafficking, particularly neutrophil infiltrate, and protection of end-organ target pathology are different, depending on whether the host or donor was treated with ATLa. Taken together, these results chart some ATLa protective effects on GvHD cellular dynamics over time and identify a previously unrecognized effect of host neutrophils in the early phase post-BMT as important determinants in the dynamics of GvHD onset and progression.-Devchand, P. R., Schmidt, B. A., Primo, V. C., Zhang, Q.-y., Arnaout, M. A., Serhan, C. N., Nikolic, B. A synthetic eicosanoid LX-mimetic unravels host-donor interactions in allogeneic BMT-induced GvHD to reveal an early protective role for host neutrophils.

14 CFR 21.171 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Applicability. 21.171 Section 21.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CERTIFICATION... procedural requirements for the issue of airworthiness certificates. ...

14 CFR 21.171 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Applicability. 21.171 Section 21.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CERTIFICATION... procedural requirements for the issue of airworthiness certificates. ...

14 CFR 21.171 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Applicability. 21.171 Section 21.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CERTIFICATION... procedural requirements for the issue of airworthiness certificates. ...

14 CFR 21.171 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Applicability. 21.171 Section 21.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CERTIFICATION... procedural requirements for the issue of airworthiness certificates. ...

14 CFR 21.171 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Applicability. 21.171 Section 21.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CERTIFICATION... procedural requirements for the issue of airworthiness certificates. ...

Tracking Advanced Planetary Systems (TAPAS) with HARPS-N. V. A Massive Jupiter orbiting the very-low-metallicity giant star BD+03 2562 and a possible planet around HD 103485

NASA Astrophysics Data System (ADS)

Villaver, E.; Niedzielski, A.; Wolszczan, A.; Nowak, G.; Kowalik, K.; Adamów, M.; Maciejewski, G.; Deka-Szymankiewicz, B.; Maldonado, J.

2017-10-01

Context. Evolved stars with planets are crucial to understanding the dependency of the planet formation mechanism on the mass and metallicity of the parent star and to studying star-planet interactions. Aims: We present two evolved stars (HD 103485 and BD+03 2562) from the Tracking Advanced PlAnetary Systems (TAPAS) with HARPS-N project devoted to RV precision measurements of identified candidates within the PennState - Toruń Centre for Astronomy Planet Search. Methods: The paper is based on precise radial velocity (RV) measurements. For HD 103485 we collected 57 epochs over 3317 days with the Hobby-Eberly Telescope (HET) and its high-resolution spectrograph and 18 ultra-precise HARPS-N data over 919 days. For BD+03 2562 we collected 46 epochs of HET data over 3380 days and 19 epochs of HARPS-N data over 919 days. Results: We present the analysis of the data and the search for correlations between the RV signal and stellar activity, stellar rotation, and photometric variability. Based on the available data, we interpret the RV variations measured in both stars as Keplerian motion. Both stars have masses close to Solar (1.11 M⊙ HD 103485 and 1.14 M⊙ BD+03 2562), very low metallicities ([Fe/H] = - 0.50 and - 0.71 for HD 103485 and BD+03 2562), and both have Jupiter planetary mass companions (m2sini = 7 and 6.4 MJ for HD 103485 and BD+03 2562 resp.) in close to terrestrial orbits (1.4 au HD 103485 and 1.3 au BD+03 2562) with moderate eccentricities (e = 0.34 and 0.2 for HD 103485 and BD+03 2562). However, we cannot totally rule-out the possibility that the signal in the case of HD 103485 is due to rotational modulation of active regions. Conclusions: Based on the current data, we conclude that BD+03 2562 has a bona fide planetary companion while for HD 103485 we cannot totally exclude the possibility that the best explanation for the RV signal modulations is not the existence of a planet but stellar activity. If the interpretation remains that both stars have

Tracking Advanced Planetary Systems (TAPAS) with HARPS-N. VI. HD 238914 and TYC 3318-01333-1: two more Li-rich giants with planets

NASA Astrophysics Data System (ADS)

Adamów, M.; Niedzielski, A.; Kowalik, K.; Villaver, E.; Wolszczan, A.; Maciejewski, G.; Gromadzki, M.

2018-05-01

Context. We present the latest results of our search for planets with HARPS-N at the 3.6 m Telescopio Nazionale Galileo under the Tracking Advanced Planetary Systems project: an in-depth study of the 15 most Li abundant giants from the PennState - Toruń Planet Search sample. Aims: Our goals are first, to obtain radial velocities of the most Li-rich giants we identified in our sample to search for possible low-mass substellar companions, and second, to perform an extended spectral analysis to define the evolutionary status of these stars. Methods: This work is based on high-resolution spectra obtained with the Hobby-Eberly Telescope and its High Resolution Spectrograph, and with the HARPS-N spectrograph at the Telescopio Nazionale Galileo. Two stars, HD 181368 and HD 188214, were also observed with UVES at the VLT to determine beryllium abundances. Results: We report i) the discovery of two new planetary systems around the Li-rich giant stars: HD 238914 and TYC 3318-01333-1 (a binary system); ii) reveal a binary Li-rich giant, HD 181368; iii) although our current phase coverage is not complete, we suggest the presence of planetary mass companions around TYC 3663-01966-1 and TYC 3105-00152-1; iv) we confirm the previous result for BD+48 740 and present updated orbital parameters, and v) we find a lack of a relation between the Li enhancement and the Be abundance for the stars HD 181368 and HD 188214, for which we acquired blue spectra. Conclusions: We found seven stars with stellar or potential planetary companions among the 15 Li-rich giant stars. The binary star frequency of the Li-rich giants in our sample appears to be normal, but the planet frequency is twice that of the general sample, which suggests a possible connection between hosting a companion and enhanced Li abundance in giant stars. We also found most of the companions orbits to be highly eccentric. Based on observations obtained with the Hobby-Eberly Telescope, which is a joint project of the

Erythroblast differentiation at spleen in Q137E mutant ribosomal protein S19 gene knock-in C57BL/6J mice.

PubMed

Yamanegi, Koji; Yamada, Naoko; Nakasho, Keiji; Nishiura, Hiroshi

2018-01-01

We recently found that erythroblast-like cells derived from human leukaemia K562 cells express C5a receptor (C5aR) and produce its antagonistic and agonistic ligand ribosomal protein S19 (RP S19) polymer, which is cross-linked between K122 and Q137 by tissue transglutaminases. RP S19 polymer binds to the reciprocal C5aRs on erythroblast-like cells and macrophage-like cells derived from human monocytic THP-1 cells and promotes differentiation into reticulocyte-like cells through enucleation in vitro. To examine the roles of RP S19 polymer in mouse erythropoiesis, we prepared Q137E mutant RP S19 gene knock-in C57BL/6J mice. In contrast to wild-type mice, erythroblast numbers at the preliminary stage (CD71 high /TER119 low ) in spleen based on transferrin receptor (CD71) and glycophorin A (TER119) values and erythrocyte numbers in orbital artery bloods were not largely changed in knock-in mice. Conversely, erythroblast numbers at the early stage (CD71 high /TER119 high ) were significantly decreased in spleen by knock-in mice. The reduction of early erythroblast numbers in spleen was enhanced by the phenylhydrazine-induced pernicious anemia model knock-in mice and was rescued by a functional analogue of RP S19 dimer S-tagged C5a/RP S19. These data indicated that RP S19 polymer plays the roles in the early erythroblast differentiation of C57BL/6J mouse spleen. Copyright © 2017 Elsevier GmbH. All rights reserved.

Adjuvant guided polarization of the immune humoral response against a protective multicomponent antigenic protein (Q) from Leishmania infantum. A CpG + Q mix protects Balb/c mice from infection.

PubMed

Parody, N; Soto, M; Requena, J M; Alonso, C

2004-01-01

It has been shown that vaccination with three doses of the Leishmania infantum poly-protein Q containing five genetically fused antigenic determinants from the Lip2a, Lip2b, H2A and P0 proteins, mixed with BCG induces clearance of parasites in 9 out of 10 Leishmania infantum-infected Beagle dogs, in addition to clinical protection. In the present paper we analysed the immunogenic potential of the poly-protein Q and the specificity and polarization of the response against the antigenic determinants of Q when mixed with various adjuvants. The data showed that the Q protein had high intrinsic immunogenic potential and that it was able to induce a long-lasting IgG response. The IgM immunogenic potential of the poly-protein was mainly due to the LiP2a and LiP2b determinants, whereas the IgG immunogenic potential was mainly due to the LiP2a component. It was observed that the protein itself elicited a mixed IgG2a/IgG1 response and that the determinants of Q were endowed with different IgG2a/IgG1 potential. It was also observed that the adjuvants did not influence the intensity or specificity of the IgM response but that they modulated the intensity, the specificity and the polarization of the IgG response against the determinants of Q. CpG-ODN motifs or double-stranded DNA plasmids containing CpG motifs when mixed with Q induced a predominant IgG2a response mainly observed at early stages post-immunization. The data showed that a CpG + Q mix induced significant protection against L. infantum infection in Balb/c mice.

Identification of Excited States in the N=Z Nucleus 82Nb

NASA Astrophysics Data System (ADS)

Caceres, L. S.; Gorska, M.; Jungclaus, A.; Regan, P. H.; Garnsworthy, A. B.; Pietri, S.; Podolyak, Zs.; Rudolph, D.; Steer, S. J.; Grawe, H.; Balabanski, D. L.; Becker, F.; Bednarczyk, P.; Benzoni, G.; Blank, B.; Brandau, C.; Bruce, A. M.; Camera, F.; Catford, W. N.; Cullen, I. J.; Dombradi, Zs.; Doornenbal, P.; Estevez, E.; Geissel, H.; Gelletly, W.; Gerl, J.; Grebosz, J.; Heinz, A.; Hoischen, R.; Ilie, G.; Jolie, J.; Jones, G. A.; Kmiecik, M.; Kojouharov, I.; Kondev, F. G.; Kurtukian-Nieto, T.; Kurz, N.; Lalkowski, S.; Liu, L.; Maj, A.; Myalski, S.; Montes, F.; Pfuetzner, M.; Prokopowicz, W.; Saito, T.; Schaffner, H.; Schwertel, S.; Shizuma, T.; Simons, A. J.; Tashenov, S.; Walker, P. M.; Werner-Malento, E.; Wieland, O.; Wollersheim, H. J.

2007-04-01

Information on the first excited states in the N=Z=41 nucleus 82Nb sheds light on the competition of isospin T=0 and T=1 states in the A sim 80 region. The measurement was performed at the GSI laboratory using fragmentation of a 107Ag primary beam at 750 MeV/u on a 4 g/cm2 9Be target. The fragments were separated and identified unambiguously in the FRagment Separator. Three excited states were observed and the half-life estimate for the isomeric state was extracted. A tentative spin assignment based on the isobaric analogue states systematics in the Tz=1 nucleus 82Zr, and transition probabilities indicate T=1 character of the first two excited states, and T=0 for the isomeric state.

Three-dimensional (3D) structure prediction and function analysis of the chitin-binding domain 3 protein HD73_3189 from Bacillus thuringiensis HD73.

PubMed

Zhan, Yiling; Guo, Shuyuan

2015-01-01

Bacillus thuringiensis (Bt) is capable of producing a chitin-binding protein believed to be functionally important to bacteria during the stationary phase of its growth cycle. In this paper, the chitin-binding domain 3 protein HD73_3189 from B. thuringiensis has been analyzed by computer technology. Primary and secondary structural analyses demonstrated that HD73_3189 is negatively charged and contains several α-helices, aperiodical coils and β-strands. Domain and motif analyses revealed that HD73_3189 contains a signal peptide, an N-terminal chitin binding 3 domains, two copies of a fibronectin-like domain 3 and a C-terminal carbohydrate binding domain classified as CBM_5_12. Moreover, analysis predicted the protein's associated localization site to be the cell wall. Ligand site prediction determined that amino acid residues GLU-312, TRP-334, ILE-341 and VAL-382 exposed on the surface of the target protein exhibit polar interactions with the substrate.

Cardiovascular disease hospitalizations in relation to exposure to the September 11, 2001 World Trade Center disaster and posttraumatic stress disorder.

PubMed

Jordan, Hannah T; Stellman, Steven D; Morabia, Alfredo; Miller-Archie, Sara A; Alper, Howard; Laskaris, Zoey; Brackbill, Robert M; Cone, James E

2013-10-24

A cohort study found that 9/11-related environmental exposures and posttraumatic stress disorder increased self-reported cardiovascular disease risk. We attempted to replicate these findings using objectively defined cardiovascular disease hospitalizations in the same cohort. Data for adult World Trade Center Health Registry enrollees residing in New York State on enrollment and no cardiovascular disease history (n = 46,346) were linked to a New York State hospital discharge-reporting system. Follow-up began at Registry enrollment (2003-2004) and ended at the first cerebrovascular or heart disease (HD) hospitalization, death, or December 31, 2010, whichever was earliest. We used proportional hazards models to estimate adjusted hazard ratios (AHRs) for HD (n = 1151) and cerebrovascular disease (n = 284) hospitalization during 302,742 person-years of observation (mean follow-up, 6.5 years per person), accounting for other factors including age, race/ethnicity, smoking, and diabetes. An elevated risk of HD hospitalization was observed among women (AHR 1.32, 95% CI 1.01 to 1.71) but not men (AHR 1.16, 95% CI 0.97 to 1.40) with posttraumatic stress disorder at enrollment. A high overall level of World Trade Center rescue and recovery-related exposure was associated with an elevated HD hospitalization risk in men (AHR 1.82, 95% CI 1.06 to 3.13; P for trend = 0.05), but findings in women were inconclusive (AHR 3.29, 95% CI 0.85 to 12.69; P for trend = 0.09). Similar associations were observed specifically with coronary artery disease hospitalization. Posttraumatic stress disorder increased the cerebrovascular disease hospitalization risk in men but not in women. 9/11-related exposures and posttraumatic stress disorder appeared to increase the risk of subsequent hospitalization for HD and cerebrovascular disease. This is consistent with findings based on self-reported outcomes.

14 CFR 23.171 - General.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false General. 23.171 Section 23.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... any condition normally encountered in service, if flight tests show it is necessary for safe operation. ...

14 CFR 23.171 - General.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false General. 23.171 Section 23.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... any condition normally encountered in service, if flight tests show it is necessary for safe operation. ...

19 CFR 201.171-201.999 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false [Reserved] 201.171-201.999 Section 201.171-201.999 Customs Duties UNITED STATES INTERNATIONAL TRADE COMMISSION GENERAL RULES OF GENERAL APPLICATION.... International Trade Commission §§ 201.171-201.999 [Reserved] ...

19 CFR 201.171-201.999 - [Reserved

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 3 2013-04-01 2013-04-01 false [Reserved] 201.171-201.999 Section 201.171-201.999 Customs Duties UNITED STATES INTERNATIONAL TRADE COMMISSION GENERAL RULES OF GENERAL APPLICATION.... International Trade Commission §§ 201.171-201.999 [Reserved] ...

19 CFR 201.171-201.999 - [Reserved

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 3 2011-04-01 2011-04-01 false [Reserved] 201.171-201.999 Section 201.171-201.999 Customs Duties UNITED STATES INTERNATIONAL TRADE COMMISSION GENERAL RULES OF GENERAL APPLICATION.... International Trade Commission §§ 201.171-201.999 [Reserved] ...

19 CFR 201.171-201.999 - [Reserved

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 3 2014-04-01 2014-04-01 false [Reserved] 201.171-201.999 Section 201.171-201.999 Customs Duties UNITED STATES INTERNATIONAL TRADE COMMISSION GENERAL RULES OF GENERAL APPLICATION.... International Trade Commission §§ 201.171-201.999 [Reserved] ...

45 CFR 2301.171-2301.999 - [Reserved

Code of Federal Regulations, 2011 CFR

2011-10-01

... 45 Public Welfare 4 2011-10-01 2011-10-01 false [Reserved] 2301.171-2301.999 Section 2301.171-2301.999 Public Welfare Regulations Relating to Public Welfare (Continued) ARCTIC RESEARCH COMMISSION... STATES ARCTIC RESEARCH COMMISSION §§ 2301.171-2301.999 [Reserved] ...

45 CFR 2301.171-2301.999 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 4 2010-10-01 2010-10-01 false [Reserved] 2301.171-2301.999 Section 2301.171-2301.999 Public Welfare Regulations Relating to Public Welfare (Continued) ARCTIC RESEARCH COMMISSION... STATES ARCTIC RESEARCH COMMISSION §§ 2301.171-2301.999 [Reserved] ...

Analysis of multiple bone responses to graded strains above functional levels, and to disuse, in mice in vivo show that the human Lrp5 G171V High Bone Mass mutation increases the osteogenic response to loading but that lack of Lrp5 activity reduces it

PubMed Central

Saxon, Leanne K.; Jackson, Brendan F.; Sugiyama, Toshihiro; Lanyon, Lance E.; Price, Joanna S.

2011-01-01

Introduction To investigate the role of the low-density lipoprotein receptor-related protein 5 (Lrp5) in bones' responses to loading, we analysed changes in multiple measures of bone architecture in tibias subjected to loading or disuse in male and female mice with the Lrp5 loss of function mutation (Lrp5−/−) or heterozygous for the Lrp5 G171V High Bone Mass (HBM) mutation (Lrp5HBM+). Materials and methods The right tibias of these 17 week old male and female mice and their Wild Type (WT) littermates were subjected to short periods of loading three days a week for two weeks. Each tibia was loaded for 40 cycles, to produce peak strains at the midshaft within the low, medium or high physiological range (~ 1500, 2400 and 3000 microstrain, respectively). In similar groups of mice the right sciatic nerve was severed causing disuse of the right tibia for 3 weeks. Data from microCT of loaded, neurectomised and contra-lateral control tibias were analysed to quantify changes in the cortical and cancellous regions of the bone in the absence of functional strains and in response to graded strains in addition to those derived from function. Results and conclusion Male WT+/+ controls showed significant strain:response curves for cortical area and trabecular thickness, but Lrp5−/− mice showed no detectable strain:response in those same outcomes. Female mice of either WT+/+ or Lrp5−/− genotype did not show significant strain:response curves for cortical or trabecular parameters, the one exception being Tb.Th in Lrp5−/− mice. Since female WT+/+ mice did not respond to loading in a significant dose:responsive manner, the similar lack of responsiveness of the Lrp5−/− females could not be ascribed to their Lrp5 status. Cortical bone loss associated with disuse showed no differences between Lrp5−/− mice and WT+/+ controls, but in cancellous bone of both male and females of these mice, there was a greater loss than in WT+/+ controls. In contrast, the tibias

JUNCTOPHILIN 3 (JPH3) EXPANSION MUTATIONS CAUSING HUNTINGTON DISEASE LIKE 2 (HDL2) ARE COMMON IN SOUTH AFRICAN PATIENTS WITH AFRICAN ANCESTRY AND A HUNTINGTON DISEASE PHENOTYPE

PubMed Central

Krause, A; Mitchell, CL; Essop, F; Tager, S; Temlett, J; Stevanin, G; Ross, CA; Rudnicki, DD; Margolis, RL

2015-01-01

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations. PMID:26079385

36 CFR 909.171-909.999 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false [Reserved] 909.171-909.999 Section 909.171-909.999 Parks, Forests, and Public Property PENNSYLVANIA AVENUE DEVELOPMENT CORPORATION... PENNSYLVANIA AVENUE DEVELOPMENT CORPORATION §§ 909.171-909.999 [Reserved] ...

10 CFR 171.21 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false [Reserved] 171.21 Section 171.21 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) ANNUAL FEES FOR REACTOR LICENSES AND FUEL CYCLE LICENSES AND MATERIALS LICENSES, INCLUDING HOLDERS OF CERTIFICATES OF COMPLIANCE, REGISTRATIONS, AND QUALITY ASSURANCE PROGRAM APPROVALS AND...

14 CFR 25.171 - General.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false General. 25.171 Section 25.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... normally encountered in service, if flight tests show it is necessary for safe operation. [Doc. No. 5066...

14 CFR 25.171 - General.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false General. 25.171 Section 25.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... normally encountered in service, if flight tests show it is necessary for safe operation. [Doc. No. 5066...

Determination of deuteron quadrupole moment from calculations of the electric field gradient in D{sub 2} and HD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pavanello, Michele; Tung Weicheng; Adamowicz, Ludwik

2010-04-15

We have carried out an accurate determination of the quadrupole moment of the deuteron nucleus. The evaluation of the constant is achieved by combining high accuracy Born-Oppenheimer calculations of the electric field gradient at the nucleus in the H{sub 2} molecule with spectroscopic measurements of the quadrupolar splitting in D{sub 2} and HD. The derived value is Q=0.285783(30) fm{sup 2}.

Ultrafast carrier dynamics in a GaN/Al 0.18Ga0.82N superlattice

NASA Astrophysics Data System (ADS)

Mahler, Felix; Tomm, Jens W.; Reimann, Klaus; Woerner, Michael; Elsaesser, Thomas; Flytzanis, Christos; Hoffmann, Veit; Weyers, Markus

2018-04-01

Relaxation processes of photoexcited carriers in a GaN /Al0.18Ga0.82N superlattice are studied in femtosecond spectrally resolved reflectivity measurements at ambient temperature. The transient reflectivity reveals electron trapping into defect states close to the conduction-band minimum with a 150-200 fs time constant, followed by few-picosecond carrier cooling. A second slower trapping process into a different manifold of defect states is observed on a time scale of approximately 10 ps. Our results establish the prominent role of structural defects and disorder for ultrafast carrier dynamics in nitride semiconductor structures.

Interface properties of an O2 annealed Au/Ni/n-Al0.18Ga0.82N Schottky contact

NASA Astrophysics Data System (ADS)

Legodi, M. J.; Meyer, W. E.; Auret, F. D.

2012-05-01

We oxidized a Ni/Au metal bi-layer contact fabricated on HVPE Al0.18Ga0.82N from 373 K to 573 K in 100 K steps. In the range 1 kHz to 2 MHz, the Capacitance-Voltage-Frequency (C-V-f) measurements reveal a frequency dispersion of the capacitance and the presence of an anomalous peak at 0.4 V owing to the presence of interface states in the as deposited contact system. The dispersion was progressively removed by O2 anneals from temperatures as low as 373 K. These changes are accompanied by an improvement in the overall quality of the Schottky system: the ideality factor, n, improves from 2.09 to 1.26; the Schottky barrier height (SBH), determined by the Norde [1] method, increases from 0.72 eV to 1.54 eV. From the Nicollian and Goetzberger model [2], we calculated the energy distribution of the density of interface states, NSS. Around 1 eV above the Al0.18Ga0.82N valence band, NSS, decreases from 2.3×1012 eV-1 cm-2 for the un-annealed diodes to 1.3×1012 eV-1 cm-2 after the 573 K anneal. Our results suggest the formation of an insulating NiO leading to a MIS structure for the oxidized Au/Ni/Al0.18Ga0.82N contact.

The 3 H(d , γ) Reaction at Ec . m . <= 300 keV

NASA Astrophysics Data System (ADS)

Parker, C. E.; Brune, C. R.; Massey, T. N.; O'Donnell, J. E.; Richard, A. L.; Sayre, D. B.

2015-04-01

The 3 H(d , γ) 5He reaction has been measured using a 500-keV pulsed deuteron beam incident on a stopping titanium tritide target at the Edwards Accelerator Laboratory. The time-of-flight technique has been used to distinguish the γ-rays from neutrons in the bismuth germinate (BGO) γ-ray detector. A stilbene scintillator and an NE-213 scintillator have been used to detect the neutrons from the 3 H(d , n) α reaction using both the pulse-shape discrimination and time-of-flight techniques. A newly designed target holder with a silicon surface barrier detector to simultaneously measure α-particles to normalize the number of neutrons, along with a new titanium tritide target, was incorporated for subsequent measurements. The γ-rays have been measured at laboratory angles of 0 °, 45 °, 90 °, and 135 °. Information about the γ-ray energy distribution for the unbound ground state and first excited state of 5He can be obtained experimentally by comparing the BGO data to Monte Carlo simulations. The 3 H(d , γ) /3 H(d , n) branching ratio has also been measured. Data analysis is currently underway for the subsequent measurements. This work is supported in part by Lawrence Livermore National Laboratory and the U.S. D.O.E. (NNSA) through Grant No. DE-NA0001837.

1 CFR 17.1 - Receipt and processing.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 1 General Provisions 1 2011-01-01 2011-01-01 false Receipt and processing. 17.1 Section 17.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER PREPARATION, TRANSMITTAL, AND PROCESSING OF DOCUMENTS FILING FOR PUBLIC INSPECTION AND PUBLICATION SCHEDULES Receipt and Processing § 17.1...

1 CFR 17.1 - Receipt and processing.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 1 General Provisions 1 2010-01-01 2010-01-01 false Receipt and processing. 17.1 Section 17.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER PREPARATION, TRANSMITTAL, AND PROCESSING OF DOCUMENTS FILING FOR PUBLIC INSPECTION AND PUBLICATION SCHEDULES Receipt and Processing § 17.1...

22 CFR 171.16 - Miscellaneous fee provisions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Miscellaneous fee provisions. 171.16 Section 171.16 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC Freedom of Information Act Provisions § 171.16 Miscellaneous fee provisions. (a...

14 CFR 125.171 - Fire-detector systems.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Fire-detector systems. 125.171 Section 125.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Requirements § 125.171 Fire-detector systems. Enough quick-acting fire detectors must be provided in each...

14 CFR 125.171 - Fire-detector systems.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Fire-detector systems. 125.171 Section 125.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Requirements § 125.171 Fire-detector systems. Enough quick-acting fire detectors must be provided in each...

14 CFR 125.171 - Fire-detector systems.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Fire-detector systems. 125.171 Section 125.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Requirements § 125.171 Fire-detector systems. Enough quick-acting fire detectors must be provided in each...

14 CFR 125.171 - Fire-detector systems.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Fire-detector systems. 125.171 Section 125.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Requirements § 125.171 Fire-detector systems. Enough quick-acting fire detectors must be provided in each...

14 CFR 125.171 - Fire-detector systems.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Fire-detector systems. 125.171 Section 125.171 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Requirements § 125.171 Fire-detector systems. Enough quick-acting fire detectors must be provided in each...

17 CFR 171.3 - Business address; hours.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 17 Commodity and Securities Exchanges 1 2011-04-01 2011-04-01 false Business address; hours. 171.3 Section 171.3 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION RULES RELATING TO... MEMBER RESPONSIBILITY ACTIONS General Provisions § 171.3 Business address; hours. The principal office of...

17 CFR 171.3 - Business address; hours.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 17 Commodity and Securities Exchanges 1 2012-04-01 2012-04-01 false Business address; hours. 171.3 Section 171.3 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION RULES RELATING TO... MEMBER RESPONSIBILITY ACTIONS General Provisions § 171.3 Business address; hours. The principal office of...

45 CFR 2490.171-2490.999 - [Reserved

Code of Federal Regulations, 2013 CFR

2013-10-01

... 45 Public Welfare 4 2013-10-01 2013-10-01 false [Reserved] 2490.171-2490.999 Section 2490.171-2490.999 Public Welfare Regulations Relating to Public Welfare (Continued) JAMES MADISON MEMORIAL... CONDUCTED BY THE JAMES MADISON MEMORIAL FELLOWSHIP FOUNDATION §§ 2490.171-2490.999 [Reserved] ...

45 CFR 2490.171-2490.999 - [Reserved

Code of Federal Regulations, 2014 CFR

2014-10-01

... 45 Public Welfare 4 2014-10-01 2014-10-01 false [Reserved] 2490.171-2490.999 Section 2490.171-2490.999 Public Welfare Regulations Relating to Public Welfare (Continued) JAMES MADISON MEMORIAL... CONDUCTED BY THE JAMES MADISON MEMORIAL FELLOWSHIP FOUNDATION §§ 2490.171-2490.999 [Reserved] ...

45 CFR 2490.171-2490.999 - [Reserved

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 4 2012-10-01 2012-10-01 false [Reserved] 2490.171-2490.999 Section 2490.171-2490.999 Public Welfare Regulations Relating to Public Welfare (Continued) JAMES MADISON MEMORIAL... CONDUCTED BY THE JAMES MADISON MEMORIAL FELLOWSHIP FOUNDATION §§ 2490.171-2490.999 [Reserved] ...

45 CFR 2490.171-2490.999 - [Reserved

Code of Federal Regulations, 2011 CFR

2011-10-01

... 45 Public Welfare 4 2011-10-01 2011-10-01 false [Reserved] 2490.171-2490.999 Section 2490.171-2490.999 Public Welfare Regulations Relating to Public Welfare (Continued) JAMES MADISON MEMORIAL... CONDUCTED BY THE JAMES MADISON MEMORIAL FELLOWSHIP FOUNDATION §§ 2490.171-2490.999 [Reserved] ...

46 CFR 171.095 - Machinery space bulkhead.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Machinery space bulkhead. 171.095 Section 171.095... PERTAINING TO VESSELS CARRYING PASSENGERS Additional Subdivision Requirements § 171.095 Machinery space... transverse watertight bulkheads to separate the machinery space from the remainder of the vessel. All...

46 CFR 171.095 - Machinery space bulkhead.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Machinery space bulkhead. 171.095 Section 171.095... PERTAINING TO VESSELS CARRYING PASSENGERS Additional Subdivision Requirements § 171.095 Machinery space... transverse watertight bulkheads to separate the machinery space from the remainder of the vessel. All...

46 CFR 171.095 - Machinery space bulkhead.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Machinery space bulkhead. 171.095 Section 171.095... PERTAINING TO VESSELS CARRYING PASSENGERS Additional Subdivision Requirements § 171.095 Machinery space... transverse watertight bulkheads to separate the machinery space from the remainder of the vessel. All...

46 CFR 171.095 - Machinery space bulkhead.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Machinery space bulkhead. 171.095 Section 171.095... PERTAINING TO VESSELS CARRYING PASSENGERS Additional Subdivision Requirements § 171.095 Machinery space... transverse watertight bulkheads to separate the machinery space from the remainder of the vessel. All...

46 CFR 171.095 - Machinery space bulkhead.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Machinery space bulkhead. 171.095 Section 171.095... PERTAINING TO VESSELS CARRYING PASSENGERS Additional Subdivision Requirements § 171.095 Machinery space... transverse watertight bulkheads to separate the machinery space from the remainder of the vessel. All...

1 CFR 17.1 - Receipt and processing.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 1 General Provisions 1 2012-01-01 2012-01-01 false Receipt and processing. 17.1 Section 17.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER PREPARATION, TRANSMITTAL, AND PROCESSING OF DOCUMENTS FILING FOR PUBLIC INSPECTION AND PUBLICATION SCHEDULES Receipt and Processing § 17.1...

1 CFR 17.1 - Receipt and processing.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 1 General Provisions 1 2014-01-01 2012-01-01 true Receipt and processing. 17.1 Section 17.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER PREPARATION, TRANSMITTAL, AND PROCESSING OF DOCUMENTS FILING FOR PUBLIC INSPECTION AND PUBLICATION SCHEDULES Receipt and Processing § 17.1...

1 CFR 17.1 - Receipt and processing.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 1 General Provisions 1 2013-01-01 2012-01-01 true Receipt and processing. 17.1 Section 17.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER PREPARATION, TRANSMITTAL, AND PROCESSING OF DOCUMENTS FILING FOR PUBLIC INSPECTION AND PUBLICATION SCHEDULES Receipt and Processing § 17.1...

17 CFR 171.3 - Business address; hours.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Business address; hours. 171.3 Section 171.3 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION RULES RELATING TO... MEMBER RESPONSIBILITY ACTIONS General Provisions § 171.3 Business address; hours. The principal office of...

45 CFR 2490.171-2490.999 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 4 2010-10-01 2010-10-01 false [Reserved] 2490.171-2490.999 Section 2490.171-2490.999 Public Welfare Regulations Relating to Public Welfare (Continued) JAMES MADISON MEMORIAL... CONDUCTED BY THE JAMES MADISON MEMORIAL FELLOWSHIP FOUNDATION §§ 2490.171-2490.999 [Reserved] ...

14 CFR 171.275 - Reports.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Reports. 171.275 Section 171.275... Reports. The owner of the ISMLS facility or his maintenance representative must make the following reports... the need for periodic maintenance visits to the facility, monthly reports from the remote monitoring...

14 CFR 171.275 - Reports.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Reports. 171.275 Section 171.275... Reports. The owner of the ISMLS facility or his maintenance representative must make the following reports... the need for periodic maintenance visits to the facility, monthly reports from the remote monitoring...