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ER Stress Induces Anabolic Resistance in Muscle Cells through PKB-Induced Blockade of mTORC1
Louise Deldicque,Luc Bertrand,Amy Patton,Marc Francaux,Keith Baar
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020993
Abstract: Anabolic resistance is the inability to increase protein synthesis in response to an increase in amino acids following a meal. One potential mediator of anabolic resistance is endoplasmic reticulum (ER) stress. The purpose of the present study was to test whether ER stress impairs the response to growth factors and leucine in muscle cells.
A Limited Role for PI(3,4,5)P3 Regulation in Controlling Skeletal Muscle Mass in Response to Resistance Exercise
D. Lee Hamilton,Andrew Philp,Matthew G. MacKenzie,Keith Baar
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011624
Abstract: Since activation of the PI3K/(protein kinase B; PKB/akt) pathway has been shown to alter muscle mass and growth, the aim of this study was to determine whether resistance exercise increased insulin like growth factor (IGF) I/phosphoinositide 3-kinase (PI3K) signalling and whether altering PI(3,4,5)P3 metabolism genetically would increase load induced muscle growth.
Prolonged activation of S6K1 does not suppress IRS or PI-3 kinase signaling during muscle cell differentiation
D Lee Hamilton, Andrew Philp, Matthew G MacKenzie, Keith Baar
BMC Cell Biology , 2010, DOI: 10.1186/1471-2121-11-37
Abstract: S6K1 activity increased in a linear fashion following plating and was more than 3-fold higher after Day 3 of differentiation (subconfluent = 11.09 ± 3.05, Day 3 = 29.34 ± 3.58). IRS-1 levels tended to increase upon serum withdrawal but decreased approximately 2-fold (subconfluent = 0.88 ± 0.10, Day 3 = 0.42 ± 0.06) 3 days following differentiation whereas IRS-2 protein remained stable. IRS-1 associated p85 was significantly reduced upon serum withdrawal (subconfluent = 0.86 ± 0.07, Day 0 = 0.31 ± 0.05), remaining low through day 1. IRS-2 associated p85 decreased following serum withdrawal (subconfluent = 0.96 ± 0.05, Day 1 = 0.56 ± 0.08) and remained suppressed up to Day 3 following differentiation (0.56 ± 0.05). Phospho-tyrosine associated p85 increased significantly from subconfluent to Day 0 and remained elevated throughout differentiation. siRNA directed against S6K1 and S6K2 did not result in changes in IRS-1 levels after either 48 or 96 hrs. Furthermore, neither 48 nor 96 hrs of S6K1 knockdown caused a change in myotube formation.Even though S6K1 activity increases throughout muscle cell differentiation and IRS-1 levels decrease over this period, siRNA suggests that S6K1 is not mediating the decrease in IRS-1. The decrease in IRS-1/2 associated p85 together with the increase in phospho-tyrosine associated p85 suggests that PI3K associates primarily with scaffolds other than IRS-1/2 during muscle cell differentiation.During development, multinucleated muscle fibers form from the terminal differentiation and fusion of individual myogenic progenitors, or myoblasts [1]. This process is recapitulated during the process of skeletal muscle regeneration in response to trauma, disease, or contraction mediated injury [2]. As a result of the importance of this process, the regulation of myoblast differentiation and fusion has been widely studied in tissue culture using both primary and transformed myoblasts. In 2-dimensional cell culture, myoblasts are maintained in a pr
Beneficial Effects of Resistance Exercise on Glycemic Control Are Not Further Improved by Protein Ingestion
Leigh Breen, Andrew Philp, Christopher S. Shaw, Asker E. Jeukendrup, Keith Baar, Kevin D. Tipton
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020613
Abstract: Purpose To investigate the mechanisms underpinning modifications in glucose homeostasis and insulin sensitivity 24 h after a bout of resistance exercise (RE) with or without protein ingestion. Methods Twenty-four healthy males were assigned to a control (CON; n = 8), exercise (EX; n = 8) or exercise plus protein condition (EX+PRO; n = 8). Muscle biopsy and blood samples were obtained at rest for all groups and immediately post-RE (75% 1RM, 8×10 repetitions of leg-press and extension exercise) for EX and EX+PRO only. At 24 h post-RE (or post-resting biopsy for CON), a further muscle biopsy was obtained. Participants then consumed an oral glucose load (OGTT) containing 2 g of [U-13C] glucose during an infusion of 6, 6-[2H2] glucose. Blood samples were obtained every 10 min for 2 h to determine glucose kinetics. EX+PRO ingested an additional 25 g of intact whey protein with the OGTT. A final biopsy sample was obtained at the end of the OGTT. Results Fasted plasma glucose and insulin were similar for all groups and were not different immediately post- and 24 h post-RE. Following RE, muscle glycogen was 26±8 and 19±6% lower in EX and EX+PRO, respectively. During OGTT, plasma glucose AUC was lower for EX and EX+PRO (75.1±2.7 and 75.3±2.8 mmol·L?1:120 min, respectively) compared with CON (90.6±4.1 mmol·L?1:120 min). Plasma insulin response was 13±2 and 21±4% lower for EX and CON, respectively, compared with EX+PRO. Glucose disappearance from the circulation was ~12% greater in EX and EX+PRO compared with CON. Basal 24 h post-RE and insulin-stimulated PAS-AS160/TBC1D4 phosphorylation was greater for EX and EX+PRO. Conclusions Prior RE improves glycemic control and insulin sensitivity through an increase in the rate at which glucose is disposed from the circulation. However, co-ingesting protein during a high-glucose load does not augment this response at 24 h post-exercise in healthy, insulin-sensitive individuals.
Inhibition of Myostatin Signaling through Notch Activation following Acute Resistance Exercise
Matthew G. MacKenzie, David Lee Hamilton, Mark Pepin, Amy Patton, Keith Baar
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068743
Abstract: Myostatin is a TGFβ family member and negative regulator of muscle size. Due to the complexity of the molecular pathway between myostatin mRNA/protein and changes in transcription, it has been difficult to understand whether myostatin plays a role in resistance exercise-induced skeletal muscle hypertrophy. To circumvent this problem, we determined the expression of a unique myostatin target gene, Mighty, following resistance exercise. Mighty mRNA increased by 6 h (82.9±24.21%) and remained high out to 48 h (56.5±19.67%) after resistance exercise. Further examination of the soleus, plantaris and tibialis anterior muscles showed that the change in Mighty mRNA at 6 h correlated with the increase in muscle size associated with this protocol (R2 = 0.9996). The increase in Mighty mRNA occurred both independent of Smad2 phosphorylation and in spite of an increase in myostatin mRNA (341.8±147.14% at 3 h). The myostatin inhibitor SKI remained unchanged. However, activated Notch, another potential inhibitor of TGFβ signaling, increased immediately following resistance exercise (83±11.2%) and stayed elevated out to 6 h (78±16.6%). Electroportion of the Notch intracellular domain into the tibialis anterior resulted in an increase in Mighty mRNA (63±13.4%) that was equivalent to the canonical Notch target HES-1 (94.4±7.32%). These data suggest that acute resistance exercise decreases myostatin signaling through the activation of the TGFβ inhibitor Notch resulting in a decrease in myostatin transcriptional activity that correlates well with muscle hypertrophy.
Glycogen Content Regulates Peroxisome Proliferator Activated Receptor-? (PPAR-?) Activity in Rat Skeletal Muscle
Andrew Philp, Matthew G. MacKenzie, Micah Y. Belew, Mhairi C. Towler, Alan Corstorphine, Angela Papalamprou, D. Grahame Hardie, Keith Baar
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077200
Abstract: Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial β-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR) coactivator-1α (PGC-1α) and the transcription factor/nuclear receptor PPAR-?. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1α and PPAR-? function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4): control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]). Gastrocnemius (GTN) muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-? activity via chromatin immunoprecipitation (ChIP) assays, AMPK α1/α2 kinase activity, and the localization of AMPK and PGC-1α. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E) finished with higher AMPK-α2 activity (147%, p<0.05), nuclear AMPK-α2 and PGC-1α, but no difference in AMPK-α1 activity compared to CON. In addition, PPAR-? binding to the CPT1 promoter was significantly increased only in the LG-E group. Finally, cell reporter studies in contracting C2C12 myotubes indicated that PPAR-? activity following contraction is sensitive to glucose availability, providing mechanistic insight into the association between PPAR-? and glycogen content/substrate availability. The present study is the first to examine PPAR-? activity in skeletal muscle in response to an acute bout of endurance exercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-? and initiates AMPK translocation in skeletal muscle in response to exercise.
Conflicting Discourses on Female Dissent in the Early Modern Period: The Case of Antoinette Bourignon (1616-1680)
Mirjam de?Baar
Atelier du Centre de Recherches Historiques , 2009, DOI: 10.4000/acrh.1399
Abstract: Quelles sont donc les bases de l'identification plus ou moins évidente d'un certain type – considéré comme acceptable et reconnu au début des Temps modernes – de religiosité au fanatisme, voire à l'hystérie, qui semble d'autant plus évidente lorsqu'il s'agit d'un prophète féminin ? La prophétesse du dix-septième siècle Antoinette Bourignon est à cet égard un cas très intéressant, parce que, immédiatement après sa mort en 1680, une lutte acharnée éclata entre deux intellectuels de premier plan, Pierre Poiret et Pierre Bayle, tous les deux théologiens, sur la question de la signification qu'il fallait attribuer à sa vie et à son uvre. Poiret faisait partie des disciples les plus fidèles de Bourignon et il se battit, après la mort de celle-ci, pour publier un recueil de ses uvres et inscrire son ancien guide spirituel dans une tradition mystico-théologique. L'accent était mis chez lui sur la femme pieuse qui était si réceptive à l'illumination divine et qui pouvait apporter un soutien spirituel aux ames craignant Dieu grace à sa connaissance et à son amour de Dieu. Bayle par contre ne pouvait voir en Bourignon qu'un charlatan et la traiter qu'avec défiance et suspicion. En fait, il s'agissait ici de deux discours diamétralement opposés sur la dissidence féminine . L'un (la vision de Poiret) finit à terme par avoir le dessous au profit de l'autre (le jugement de Bayle). Le fait que Bayle a pu explicitement marquer de son empreinte la perception historique de Bourignon, peut être attribué à l'autorité qui fut accordée à son Dictionnaire au sein de l'histoire intellectuelle. Mais ce fut justement aussi l'identification d'auteurs éclairés ultérieurs avec l'aversion de Bayle pour ce qu'il qualifiait d' enthousiasme et avec ses normes implicites de la féminité, qui fit que son jugement ou plus exactement son préjugé contre Bourignon continua à se répercuter également à long terme sur la perception historique autour de sa personne. La conséquence de tout cela fut que, jusqu'à une période avancée du vingtième siècle, Bourignon eut la réputation d'être une illuminée et une hystérique. Des termes qui négligent complètement son influence, car en la disqualifiant sur la base de son sexe ou de la structure de sa personnalité, la question de savoir pourquoi à l'époque un groupe de chrétiens appartenant à des sectes diverses fut prêt à reconna tre Bourignon comme un guide religieux, dispara t complètement à l'arrière-plan. Cette question a formé pour moi le point de départ de l'écriture d'une nouvelle biographie de Bourignon ( Ik moet spreken. Het spiritueel le
Dutch-Book Arguments against using Conditional Probabilities for Conditional Bets  [PDF]
Keith Hutchison
Open Journal of Philosophy (OJPP) , 2012, DOI: 10.4236/ojpp.2012.23030
Abstract: We consider here an important family of conditional bets, those that proceed to settlement if and only if some agreed evidence is received that a condition has been met. Despite an opinion widespread in the literature, we observe that when the evidence is strong enough to generate certainty as to whether the condition has been met or not, using traditional conditional probabilities for such bets will NOT preserve a gambler from having a synchronic Dutch Book imposed upon him. On the contrary (I show) the gambler can be Dutch-Booked if his betting ratios ever depart from a rather different probability, one that involves the probability of the agreed evidence being provided. We note furthermore that this same alternative probability assessment is necessary if the evidence is weaker (i.e. if it fails to provide knowledge whether or not the condition has been met.) By contrast, some of the (rather different) probability assessments proposed by Jeffrey, precisely for such situations, still expose the gambler to a Dutch-Book.
T.J. Saxby, The quest for the New Jerusalem, Jean de Labadie and the Labadists, 1610-1744
M.P.A. de Baar
BMGN : Low Countries Historical Review , 1989,
A.W.G. Jaakke, E.W. Tuinstra, Om een verstaanbare bijbel. Nederlandse vertalingen na de Statenbijbel
M.P.A. de Baar
BMGN : Low Countries Historical Review , 1992,
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