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Item does not contain fulltext, It is estimated that the human mitochondrial proteome consists of 1000-1500 distinct proteins. The majority of these support the various biochemical pathways that are active in these organelles. Individuals with an oxidative phosphorylation disorder of unknown cause provide a unique opportunity to identify novel genes implicated in mitochondrial biology. We identified a homozygous deletion of CEP89 in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems. CEP89 is a ubiquitously expressed and highly conserved gene of unknown function. Immunocytochemistry and cellular fractionation experiments showed that CEP89 is present both in the cytosol and in the mitochondrial intermembrane space. Furthermore, we ascertained in vitro that downregulation of CEP89 resulted in a severe decrease in complex IV in-gel activity and altered mobility, suggesting that the complex is aberrantly formed. Two-dimensional BN-SDS gel analysis revealed that CEP89 associates with a high-molecular weight complex. Together, these data confirm a role for CEP89 in mitochondrial metabolism. In addition, we modeled CEP89 loss of function in Drosophila. Ubiquitous knockdown of fly Cep89 decreased complex IV activity and resulted in complete lethality. Furthermore, Cep89 is required for mitochondrial integrity, membrane depolarization and synaptic transmission of photoreceptor neurons, and for (sub)synaptic organization of the larval neuromuscular junction. Finally, we tested neuronal Cep89 knockdown flies in the light-off jump reflex habituation assay, which revealed its role in learning. We conclude that CEP89 proteins play an important role in mitochondrial metabolism, especially complex IV activity, and are required for neuronal and cognitive function across evolution.

Analyse of problem In the fall of 2008 the credit crunch started in The Netherlands. The financial sector in The Netherlands deteriorated with serious consequences for the Dutch real estate market. After years of increases in real estate investment, the investment volume in Dutch real estate decreased in the second half of 2008 (Debenham Thouard Zadel-hoff (DTZ), 2010 in Mierlo, Y.C.M., 2010). Until now the market conditions are extra-ordinary because few transactions take place. (Mierlo, Y.C.M., 2010) The crisis hits the area development, the real estate sector and municipal development com-panies hard. In many projects, progress is coming to a standstill and the cooperation between public and private is under pressure. Due to the economic and financial crisis, financing of projects has become difficult for both private and public parties. The government is withdrawing grants and banks are critical. This applies to both consumers and the investing parties. Banks only look at projects without risk and with a guaranteed positive return. Even then it is not certain that investments are made and buyers in the market let it fail. This provides the market limited space to invest and investors can take less risk. However, area developments in cities are really necessary. The cities must continue to adapt to new social needs and demands. Stagnation often means (relative) decline. (van ‘t Verlaat, 2007) The necessary redevelopments are especially needed in what is sometimes called ‘problem districts’. In these districts multiple problems exist, actually there is a con-centration of problems. In these districts there are additional questions to solve prob-lems with regard to living, working, learning, integration and security. When nothing is done, these problem areas will elapse even further. The (bad) per-formance of such a district presents many social problems (and costs). To maintain the residents of these districts, to preserve the people in a healthy and liveable envi, CREM, Real Estate & Housing, Architecture

Begin 2011 is de situatie in het Midden-Oosten continu in het nieuws. In de 'Arabische Lente' is Tunesië in opstand gekomen tegen de heersende macht en volgens de media is de 'Facebookrevolutie' losgebarsten in Egypte. Spoedig wordt er gedebatteerd over de vraag wat de invloed van social media is in de revolutiegolf die het Midden-Oosten in zijn greep heeft? Menigeen meent er iets over te kunnen zeggen al dan niet met gefundeerde argumenten... In deze discoursanalyse reduceer ik het debat rond de invloed van social media op de revolutiegolf in het Midden-Oosten tot een binair (these versus antithese) debat en hef ik deze dialectische tegenstelling op in een synthese middels een comparatieve, empirische reflectie.

Een kwalitatief onderzoek naar de betekenissen die betrokkenen aan het topsportklimaat geven en de wijze waarop de gemeente het klimaat kan verbeteren. Onder betrokkenen vallen beleidsmedewerkers van de gemeente 's-Hertogenbosch, bestuurders van topsportorganisaties, topsporters, bestuurders van breedtesportverenigingen en medewerkers van het Olympisch Netwerk Brabant.

Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide Melanin-Concentrating Hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH-precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch(-/-) rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch(-/-) rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e. the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet-dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development, and indicate that the MCH-Melanin-Concentrating Hormone Receptor 1-system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries., Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide Melanin-Concentrating Hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH-precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch(-/-) rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch(-/-) rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e. the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet-dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development, and indicate that the MCH-Melanin-Concentrating Hormone Receptor 1-system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries.

Contains fulltext : 49646.pdf (publisher's version ) (Closed access), We report on a female patient with severe mental retardation, dysmorphic features, deafness, spasticity, and behavioural problems in whom a 2.3 Mb duplication of 12q24.21q24.23 was detected by genome-wide tiling-path resolution array-based comparative genomic hybridization. Mental retardation, microcephaly, short stature, recurrent infections, hypotonia and facial features, such as hypertelorism, epicanthal folds, and a broad nasal bridge, were also described in patients with larger duplications overlapping the 12q24.21q24.23 region. The duplicated region contains 16 genes, of which several genes, such as thyroid hormone receptor associated protein 2, replication factor C5 and nitric oxide synthase 1, are expressed in the brain and/or are involved in embryogenesis. The current case shows that microduplications might be a more frequent cause of mental retardation and human malformation than previously appreciated.

Glucose is one of the most important energy sources for the body in general, and the brain in particular. It is essential for survival to keep glucose levels within strict boundaries. Acute disturbances of glucose homeostasis are rapidly corrected by hormonal and neuronal mechanisms. Furthermore, changes in energy expenditure associated with the light-dark cycle induce variations in the plasma glucose concentration that are more gradual. Organisms take advantage of adapting their internal physiology to the predictable daily changes in energy expenditure, because it enables them to anticipate these changes and to prevent unnecessary disturbance of homeostasis. The hypothalamic biological clock, located in the suprachiasmatic nucleus (SCN), receives light information from the eyes and transmits this information to the rest of the body to synchronize physiology to the environment. Here we review several studies providing evidence for biological clock control of the daily variation in several aspects of glucose metabolism. Although both hormones and the autonomic nervous system can stimulate glucose uptake or production by organs in the periphery, we have shown that the biological clock control of glucose metabolism mostly occurs through the autonomic nervous system. The critical involvement of the biological clock is also indicated by several studies, indicating that disturbance of the biological clock is often associated with metabolic diseases, such as obesity, diabetes mellitus and hypertension., Glucose is one of the most important energy sources for the body in general, and the brain in particular. It is essential for survival to keep glucose levels within strict boundaries. Acute disturbances of glucose homeostasis are rapidly corrected by hormonal and neuronal mechanisms. Furthermore, changes in energy expenditure associated with the light-dark cycle induce variations in the plasma glucose concentration that are more gradual. Organisms take advantage of adapting their internal physiology to the predictable daily changes in energy expenditure, because it enables them to anticipate these changes and to prevent unnecessary disturbance of homeostasis. The hypothalamic biological clock, located in the suprachiasmatic nucleus (SCN), receives light information from the eyes and transmits this information to the rest of the body to synchronize physiology to the environment. Here we review several studies providing evidence for biological clock control of the daily variation in several aspects of glucose metabolism. Although both hormones and the autonomic nervous system can stimulate glucose uptake or production by organs in the periphery, we have shown that the biological clock control of glucose metabolism mostly occurs through the autonomic nervous system. The critical involvement of the biological clock is also indicated by several studies, indicating that disturbance of the biological clock is often associated with metabolic diseases, such as obesity, diabetes mellitus and hypertension.

ICSLP 2002, 16 september 2002, Contains fulltext : 76211.pdf (author's version ) (Open Access)

Vascular endothelial cadherin, VE-cadherin, mediates adhesion between endothelial cells and may affect vascular morphogenesis via intracellular signaling, but the nature of these signals remains unknown. Here, targeted inactivation (VEC-/-) or truncation of the beta-catenin-binding cytosolic domain (VECdeltaC/deltaC) of the VE-cadherin gene was found not to affect assembly of endothelial cells in vascular plexi, but to impair their subsequent remodeling and maturation, causing lethality at 9.5 days of gestation. Deficiency or truncation of VE-cadherin induced endothelial apoptosis and abolished transmission of the endothelial survival signal by VEGF-A to Akt kinase and Bcl2 via reduced complex formation with VEGF receptor-2, beta-catenin, and phosphoinositide 3 (PI3)-kinase. Thus, VE-cadherin/ beta-catenin signaling controls endothelial survival.

Contains fulltext : 10204.pdf (publisher's version ) (Open Access)

Promotores : C. van der Staak en C. Hosman, Contains fulltext : mmubn000001_254042589.pdf (publisher's version ) (Open Access)

Item does not contain fulltext