Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice

Aims: Humans with inactivating mutations in peroxisomal proliferators activated receptor gamma (PPAR?) typically develop a complex metabolic syndrome characterized by insulin resistance, diabetes, lipodystrophy, hypertension, and dyslipidaemia which is likely to increase their cardiovascular risk. Despite evidence that the activation of PPAR? may prevent cardiac fibrosis and hypertrophy, recent evidence has suggested that pharmacological activation of PPAR? causes increased cardiovascular mortality. In this study, we investigated the effects of defective PPAR? function on the development of cardiac fibrosis and hypertrophy in a murine model carrying a human dominant-negative mutation in PPAR?. Methods and results: Mice with a dominant-negative point mutation in PPAR? (P465L) and their wild-type (WT) littermates were treated with either subcutaneous angiotensin II (AngII) infusion or saline for 2 weeks. Heterozygous P465L and WT mice developed a similar increase in systolic blood pressure, but the mutant mice developed significantly more severe cardiac fibrosis to AngII that correlated with increased expression of profibrotic genes. Both groups similarly increased the heart weight to body weight ratio compared with saline-treated controls. There were no differences in fibrosis between saline-treated WT and P465L mice. Conclusion: These results show synergistic pathogenic effects between the presence of defective PPAR? and AngII-induced hypertension and suggest that patients with PPAR? mutation and hypertension may need more aggressive therapeutic measures to reduce the risk of accelerated cardiac fibrosis. © The Author 2009.

Quantity-setting games with a dominant firm

We consider a possible game-theoretic foundation of Forchheimer's model of dominant-firm price leadership based on quantity-setting games with one large firm and many small firms. If the large firm is the exogenously given first mover, we obtain Forchheimer's model. We also investigate whether the large firm can emerge as a first mover of a timing game.

On Forchheimer's Model of Dominant Firm Price Leadership

We show that in a simple price-setting game with one large firm and many small firms the large firm does not accept the role of the price leader.

Domináns vállalat versenyképességének hatása az ellátási láncban (Effects of competitiveness of the dominant company in the supply chain)

Beszállító, gyártó és vevő vállalatok alkotnak egy ellátási láncot. Optimális esetben a vállalatok integrált rendszerben működnek, az együttműködés bizal mi alapon nyugszik, így a közös stratégiai döntések révén versenyképes lesz a lánc. Az ellátási láncban lehet egy kulcsfontosságú vállalat, amelyik domináns hatalmi pozícióval rendelkezik. A kutatás célja, hogy feltárja a hatalommal rendelkező vállalat szerepét a partnercégek és az ellátási lánc versenyképességének alakulásában. A szakirodalom alapján a hipotézis feltételezi, hogy van kapcsolat a versenyképesség és a domináns vállalat szerepvállalása között. A szerzők elemzése primer kutatáson alapul, a kérdőív válaszait SPSS statisztikai kiértékeléssel végezték. Az eredmények azt mutatták, hogy a domináns vállalat versenyképességétől valóban függ a partnercégek versenyképessége. Szignifikáns kapcsolat megléte bizonyítja a hipotézist. A vizsgálatok kiemelik, hogy a verseny már egy szinttel feljebb, az ellátási lánc szintjén értelmezhető: globális ellátási láncok versenyeznek egymással. _____ Supplier, producer and buyer companies make up a supply chain. In an optimal case the companies are integrated, partnership rests on trust which results in common strategic decisions leading to competitiveness. Each supply chain has a key company with dominant power position. The objective of the research is to analyse how the company with power affects competitiveness of partner firms and the supply chain as a whole. Based on theories hypothesis assumes a link between competitiveness and power position and its influence. Methodology of the analysis is based on primary research; the authors used SPSS statistical analysis to evaluate the answers of questionnaire. Findings include that partner firms’ competitiveness rely on competitiveness of the company with dominant power position. Significant connections prove that the hypothesis is true. Results show that competitiveness is being moved up to supply chain level. Global supply chains compete with each other.

I want out of the labels : how Chuck Palahniuk's characters challenge the dominant discourse

The purpose of this study was to explore postmodern identity in the work of Chuck Palahniuk. The characters within Palahniuk's text Invisible Monsters realize the manner in which identity is a construct, and their response is to oppose and redefine it. In my research, I looked at how postmodern identity is defined by some of the leading critical thinkers in the field, and then I applied their thought to Palahniuk's characters. I showed how these characters come to understand the process by which society defines them, and with that realization, they oppose its totalizing definitions. The characters deconstruct the natural attitudes society has towards identity, and they reveal that it is in some way possible to create a unique identity that is not easily definable by the ruling discourse. I concluded that his attention to identity highlights Palahniuk's concern for the place, identity, and influence of his generation.

Molecular diversity, cultivation, and improved detection by fluorescent in situ hybridization of a dominant group of human gut bacteria related to Roseburia spp. or Eubacterium rectale

Peer reviewed

Explaining Interest Group Interactions with Party Group Members in the European Parliament : Dominant Party Groups and Coalition Formation

Peer reviewed

Molecular diversity, cultivation, and improved detection by fluorescent in situ hybridization of a dominant group of human gut bacteria related to Roseburia spp. or Eubacterium rectale

Peer reviewed

Explaining Interest Group Interactions with Party Group Members in the European Parliament : Dominant Party Groups and Coalition Formation

Peer reviewed

Altered fibrinolysis in autosomal dominant thrombomodulin associated coagulopathy

The NIHR BioResource-Rare Diseases and the ThromboGenomics sequencing projects are supported by the National Institute for Health Research (NIHR; http://www.nihr.ac.uk). KB is an NIHR academic clinical fellow. SKW is supported by a Medical Research Council (MRC) Clinical Training Fellowship (MR/K023489/1). KS and ET are supported by the NIHR BioResource Rare Diseases. CSW and NJM are supported by the British Heart Foundation (FS/11/2/28579). ADM is supported by the NIHR Bristol Cardiovascular Biomedical Research Unit.

Bovine serum albumin as the dominant form of dietary protein reduces subcutaneous fat mass, plasma leptin and plasma corticosterone in high fat-fed C57/BL6J mice

Acknowledgements The authors thank Harriett Schellekens from the University College Cork and Paula O’Connor from Teagasc Moorepark Food Research Centre for their assistance in procuring laboratory space and equipment. The present study was funded by Teagasc. B. L. M. was funded by the Walsh Fellowship Program. J. R. S. was supported by a 1000-talents professorship from the Chinese government. The funding bodies had no input on the design of the study or in the interpretation of the data.

Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver.

A small portion of cellular glycogen is transported to and degraded in lysosomes by acid α-glucosidase (GAA) in mammals, but it is unclear why and how glycogen is transported to the lysosomes. Stbd1 has recently been proposed to participate in glycogen trafficking to lysosomes. However, our previous study demonstrated that knockdown of Stbd1 in GAA knock-out mice did not alter lysosomal glycogen storage in skeletal muscles. To further determine whether Stbd1 participates in glycogen transport to lysosomes, we generated GAA/Stbd1 double knock-out mice. In fasted double knock-out mice, glycogen accumulation in skeletal and cardiac muscles was not affected, but glycogen content in liver was reduced by nearly 73% at 3 months of age and by 60% at 13 months as compared with GAA knock-out mice, indicating that the transport of glycogen to lysosomes was suppressed in liver by the loss of Stbd1. Exogenous expression of human Stbd1 in double knock-out mice restored the liver lysosomal glycogen content to the level of GAA knock-out mice, as did a mutant lacking the Atg8 family interacting motif (AIM) and another mutant that contains only the N-terminal 24 hydrophobic segment and the C-terminal starch binding domain (CBM20) interlinked by an HA tag. Our results demonstrate that Stbd1 plays a dominant role in glycogen transport to lysosomes in liver and that the N-terminal transmembrane region and the C-terminal CBM20 domain are critical for this function.