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991.
This study covers a fifty-year period between 1953 and 2005 and looks at secular trends in stature, weight and sitting height sizes among French boys and girls between the ages of 3 and 11. A special modelling in function to the age and variable for each child was established so that a comparison could be made in the kinetic growth patterns over these same two periods. Statistical analysis shows a significant increase in growth, of 0.8cm per decade in stature, characterised by a certain increase in the lower limbs and the weight (0.8kg per decade) together with a proportional increase on the body mass index. Positive secular trends of this anthropometric nature are generally thanks to improved eating and sanitary habits and this study enables us to build and elaborate new standards in growth patterns essential for monitoring auxological development in 3 to 11-year-old children in the years 2000 and onwards. 相似文献
992.
The phosphorylation of a substrate at multiple sites is a common protein modification that can give rise to important structural and electrostatic changes. Scaffold proteins can enhance protein phosphorylation by facilitating an interaction between a protein kinase enzyme and its target substrate. In this work we consider a simple mathematical model of a scaffold protein and show that under specific conditions, the presence of the scaffold can substantially raise the likelihood that the resulting system will exhibit bistable behavior. This phenomenon is especially pronounced when the enzymatic reactions have sufficiently large K(M), compared to the concentration of the target substrate. We also find for a closely related model that bistable systems tend to have a specific kinetic conformation. Using deficiency theory and other methods, we provide a number of necessary conditions for bistability, such as the presence of multiple phosphorylation sites and the dependence of the scaffold binding/unbinding rates on the number of phosphorylated sites. 相似文献
993.
Banoglu E Çalişkan B Luderer S Eren G Özkan Y Altenhofen W Weinigel C Barz D Gerstmeier J Pergola C Werz O 《Bioorganic & medicinal chemistry》2012,20(12):3728-3741
Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC(50)=0.31 μM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC(50)=0.12-0.19 μM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents. 相似文献
994.
Prader-Willi syndrome(PWS) is an important,wellrecognized syndromic form of neurodevelopmental disorder. The incidence is about 1 in 15,000-25,000 live births,and it affects both males and females(Vogels et al.,2004).The underlying genetic defects occur at an imprinted region on chromosome 15q11-13.Within this region,some genes only express on the maternally inherited chromosome 15,like UBE3A and ATP10C;while other genes only express on the paternally inherited chromosome 15,like MKRN3,MAGEL2, NDN,C15orf2,SNURF-SNRPN,and a number of small 相似文献
995.
996.
Daisy?Rymen Liesbeth?Keldermans Valérie?Race Luc?Régal Nicolas?Deconinck Carlo?Dionisi-Vici Cheuk-wing?Fung Luisa?Sturiale Claire?Rosnoblet Fran?ois?Foulquier Gert?Matthijs Jaak?JaekenEmail author 《Orphanet journal of rare diseases》2012,7(1):94
Background
The Conserved Oligomeric Golgi (COG) complex is involved in the retrograde trafficking of Golgi components, thereby affecting the localization of Golgi glycosyltransferases. Deficiency of a COG-subunit leads to defective protein glycosylation, and thus Congenital Disorders of Glycosylation (CDG). Mutations in subunits 1, 4, 5, 6, 7 and 8 have been associated with CDG-II. The first patient with COG5-CDG was recently described (Paesold-Burda et al. Hum Mol Genet 2009; 18:4350–6). Contrary to most other COG-CDG cases, the patient presented a mild/moderate phenotype, i.e. moderate psychomotor retardation with language delay, truncal ataxia and slight hypotonia.Methods
CDG-IIx patients from our database were screened for mutations in COG5. Clinical data were compared. Brefeldin A treatment of fibroblasts and immunoblotting experiments were performed to support the diagnosis.Results and conclusion
We identified five new patients with proven COG5 deficiency. We conclude that the clinical picture is not always as mild as previously described. It rather comprises a broad spectrum with phenotypes ranging from mild to very severe. Interestingly, on a clinical basis some of the patients present a significant overlap with COG7-CDG, a finding which can probably be explained by subunit interactions at the protein level.997.
998.
Wen Guo Siu Wong Michelle Li Wentao Liang Marc Liesa Carlo Serra Ravi Jasuja Andrzej Bartke James L. Kirkland Orian Shirihai Shalender Bhasin 《PloS one》2012,7(12)
Testosterone supplementation increases muscle mass in older men but has not been shown to consistently improve physical function and activity. It has been hypothesized that physical exercise is required to induce the adaptations necessary for translation of testosterone-induced muscle mass gain into functional improvements. However, the effects of testosterone plus low intensity physical exercise training (T/PT) on functional performance and bioenergetics are unknown. In this pilot study, we tested the hypothesis that combined administration of T/PT would improve functional performance and bioenergetics in male mice late in life more than low-intensity physical training alone. 28-month old male mice were randomized to receive T/PT or vehicle plus physical training (V/PT) for 2 months. Compare to V/PT control, administration of T/PT was associated with improvements in muscle mass, grip strength, spontaneous physical movements, and respiratory activity. These changes were correlated with increased mitochondrial DNA copy number and expression of markers for mitochondrial biogenesis. Mice receiving T/PT also displayed increased expression of key elements for mitochondrial quality control, including markers for mitochondrial fission-and-fusion and mitophagy. Concurrently, mice receiving T/PT also displayed increased expression of markers for reduced tissue oxidative damage and improved muscle quality. Conclusion: Testosterone administered with low-intensity physical training improves grip strength, spontaneous movements, and respiratory activity. These functional improvements were associated with increased muscle mitochondrial biogenesis and improved mitochondrial quality control. 相似文献
999.
Anne-Cecile Huby Panagiotis Kavvadas Carlo Alfieri Ahmed Abed Julie Toubas Maria-Pia Rastaldi Jean-Claude Dussaule Christos Chatziantoniou Christos E. Chadjichristos 《PloS one》2012,7(12)
Background
Several studies have shown that activation of the renin-angiotensin system may lead to hypertension, a major risk factor for the development of chronic kidney disease (CKD). The existing hypertension-induced CDK mouse models are quite fast and consequently away from the human pathology. Thus, there is an urgent need for a mouse model that can be used to delineate the pathogenic process leading to progressive renal disease. The objective of this study was dual: to investigate whether mice overexpressing renin could mimic the kinetics and the physiopathological characteristics of hypertension-induced renal disease and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD.Methodology/Principal Findings
We used a novel transgenic strain, the RenTg mice harboring a genetically clamped renin transgene. At 3 months, heterozygous mice are hypertensive and slightly albuminuric. The expression of adhesion markers such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 are increased in the renal vasculature indicating initiation of endothelial dysfunction. At 5 months, perivascular and periglomerular infiltrations of macrophages are observed. These early renal vascular events are followed at 8 months by leukocyte invasion, decreased expression of nephrin, increased expression of KIM-1, a typical protein of tubular cell stress, and of several pro-fibrotic agents of the TGFβ family. At 12 months, mice display characteristic structural alterations of hypertensive renal disease such as glomerular ischemia, glomerulo- and nephroangio-sclerosis, mesangial expansion and tubular dilation.Conclusions/Significance
The RenTg strain develops CKD progressively. In this model, endothelial dysfunction is an early event preceding the structural and fibrotic alterations which ultimately lead to the development of CKD. This model can provide new insights into the mechanisms of chronic renal failure and help to identify new targets for arresting and/or reversing the development of the disease. 相似文献1000.
Mehdi Najafzadeh Carlo A. Marra Larry D. Lynd Mohsen Sadatsafavi J. Mark FitzGerald Bruce McManus Don Sin 《PloS one》2012,7(10)