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Central Role (central + role)
Kinds of Central Role Selected AbstractsCentral role for Cdc45 in establishing an initiation complex of DNA replication in Xenopus egg extractsGENES TO CELLS, Issue 6 2000Satoru Mimura Background In eukaryotes, chromosomal DNA is licensed to be replicated through the sequential loading of the origin recognition complex, Cdc6 and mini-chromosome maintenance protein complex (MCM) onto chromatin. However, how the replication machinery is assembled onto the licensed chromatin during initiation of replication is poorly understood. Results Using Xenopus egg extracts, we have investigated the role of Cdc45 in the loading of various replication proteins onto chromatin at the onset of S phase, and found that Cdc45, which required MCM for its loading, was essential for the sequential loading of replication protein A (RPA), DNA polymerase , and proliferating cell nuclear antigen (PCNA) onto chromatin. The assembly of DNA polymerase , onto chromatin required Cdc45 but did not require DNA polymerase ,. Analysis of nuclease-digested chromatin fractions shows that Cdc45 formed a stable complex with either MCM or DNA polymerase , on chromatin. Conclusions These results demonstrate a central role for Cdc45 in activation of the licensed chromatin to form replication complexes at the onset of S phase, and suggest that Cdc45 has a dual role in the initiation of DNA replication: the unwinding of DNA and the recruiting of DNA polymerases onto DNA. [source] Dendritic cells: biology of the skinCONTACT DERMATITIS, Issue 1 2009Mascha J. Toebak Allergic contact dermatitis results from a T-cell-mediated, delayed-type hypersensitivity immune response induced by allergens. Skin dendritic cells (DCs) play a central role in the initiation of allergic skin responses. Following encounter with an allergen, DCs become activated and undergo maturation and differentiate into immunostimulatory DCs and are able to present antigens effectively to T cells. The frequency of allergic skin disorders has increased in the past decades. Therefore, the identification of potential sensitizing chemicals is important for skin safety. Traditionally, predictive testing for allergenicity has been conducted in animal models. For regulatory reasons, animal use for sensitization testing of compounds for cosmetic purposes is shortly to be prohibited in Europe. Therefore, new non-animal-based test methods need to be developed. Several DC-based assays have been described to discriminate allergens from irritants. Unfortunately, current in vitro methods are not sufficiently resilient to identify allergens and therefore need refinement. Here, we review the immunobiology of skin DCs (Langerhans' cells and dermal dendritic cells) and their role in allergic and irritant contact dermatitis and then explore the possible use of DC-based models for discriminating between allergens and irritants. [source] GENDER, STREETLIFE AND CRIMINAL RETALIATION,CRIMINOLOGY, Issue 4 2004CHRISTOPHER W. MULLINS Recent work in criminology has highlighted the central role of retaliation in shaping criminal violence in America's inner cities. Most of this work, however, has been based on male offenders. It has also failed to consider whether and how gender structures payback in real-life settings and circumstances. In this paper, we analyze in-depth, semi-structured interviews with forty men and twelve women who recently engaged in one or more episodes of retaliatory violence to examine the ways in which gender shapes vengeance. We hope to provide an insider's view of how gender frames the context and dynamics of retaliatory events for both men and women. [source] Ideological Representations of Taiwan's History: An Analysis of Elementary Social Studies Textbooks, 1978,1995CURRICULUM INQUIRY, Issue 3 2007YA-CHEN SU ABSTRACT Textbooks play a central role in Taiwanese education. In the wake of the political reform and social protest movements of the 1970s and 1980s that led to Taiwanese educational reform, critics assert that traditional textbooks reinforce the dominant national Chinese cultural identity without considering the specific perspectives and voices of different gender, cultural, and ethnic groups. The study's purpose is to examine how political and ideological issues were represented in nationally standardized grade-four social studies textbooks from 1978 to 1995; how the textbook portrayed the history of cultural and ethnic groups as well as both genders in Taiwan; and whether the ideology changed because of political and socioeconomic pressures. In order to explore this question, two series of textbooks were examined. The first series was published between 1978 and 1989, the second between 1989 and 1995. Two social studies textbooks from each series were examined. The study's theoretic framework centers on the relationship between legitimated knowledge and the textbooks, employing the methodology of textbook analysis. Three themes were examined: (1) Taiwan's historical development, (2) national identity and nationalism, and (3) ethnic and gender studies. Two analyses were applied in each theme: (1) story-line analysis and (2) language analysis. [source] Diagnostic accuracy of cytology and immunocytology in carcinomatous effusionsCYTOPATHOLOGY, Issue 4 2008G. Metzgeroth Background:, Immunocytology substantially improves the diagnostic accuracy of conventional cytology in the diagnosis of carcinomatous effusions. Due to the unequivocal characterization of the various cell populations, a sensitivity of 92% and specificity of 100% was achieved by immunocytology, examining samples of 1234 serous effusions. Objective:, Cytology plays a central role in the aetiological clarification of serous effusions. The sensitivity of this method for the diagnosis of carcinomatous effusions varies between 40% and 80%. The aim of the present study was to investigate whether immunocytology substantially improves the diagnostic quality of the cytological examination in the diagnosis of carcinomatous effusions. Method:, Consecutive serous effusions were examined by conventional cytology and by immunocytology. The immunocytological examination was performed on smears, using a standard panel of three antibodies against pancytokeratin, human epithelial antigen 125 and calretinin. Results:, Altogether, 1234 effusion samples were examined. A total of 603 effusions were caused by carcinomas, five by malignant mesotheliomas, 11 by malignant lymphomas and 615 by non-malignant disorders. In conventional cytology, carcinomatous effusions were correctly diagnosed in 314 samples, corresponding to a sensitivity of 52%. In 31 specimens (5%) tumour cells without further specification were described and in 161 samples (27%) the presence of tumour cells was suspected (84% overall sensitivity). A total of 97 carcinomatous effusions (16%) were diagnosed false-negatively and 50 (8%) of the 615 non-malignant effusions false-positively (92% specificity). In immunocytology, 561 carcinomatous samples were correctly diagnosed, representing a sensitivity of 93%. In six cases (1%) the presence of tumour cells was suspected. A total of 36 carcinomatous effusions (6%) were diagnosed false-negatively (94% over-all sensitivity). Out of the 615 non-malignant specimens, there were no false-positive diagnoses (100% specificity). Conclusion:, Immunocytology is a simple, cost-effective, routinely practicable method which substantially improves the diagnostic accuracy of conventional cytology in the diagnosis of carcinomatous effusions. Therefore, we recommend the use of immunocytology in all those cases where cytology on its own is not completely unequivocal. [source] Delayed embryonic development and impaired cell growth and survival in Actg1 null mice,CYTOSKELETON, Issue 9 2010Tina M. Bunnell Abstract Actins are among the most highly expressed proteins in eukaryotes and play a central role in nearly all aspects of cell biology. While the intricate process of development undoubtedly requires a properly regulated actin cytoskeleton, little is known about the contributions of different actin isoforms during embryogenesis. Of the six actin isoforms, only the two cytoplasmic actins, ,cyto - and ,cyto -actin, are ubiquitously expressed. We found that ,cyto -actin null (Actg1,/,) mice were fully viable during embryonic development, but most died within 48 h of birth due to respiratory failure and cannibalization by the parents. While no morphogenetic defects were identified, Actg1,/, mice exhibited stunted growth during embryonic and postnatal development as well as delayed cardiac outflow tract formation that resolved by birth. Using primary mouse embryonic fibroblasts, we confirm that ,cyto -actin is not required for cell migration. The Actg1,/, cells, however, exhibited growth impairment and reduced cell viability, defects which perhaps contribute to the stunted growth and developmental delays observed in Actg1,/, embryos. Since the total amount of actin protein was maintained in Actg1,/, cells, our data suggests a distinct requirement for ,cyto -actin in cell growth and survival. © 2010 Wiley-Liss, Inc. [source] The heel and toe of the cell's foot: A multifaceted approach for understanding the structure and dynamics of focal adhesionsCYTOSKELETON, Issue 11 2009Haguy Wolfenson Abstract Focal adhesions (FAs) are large clusters of transmembrane receptors of the integrin family and a multitude of associated cytoplasmic "plaque" proteins, which connect the extracellular matrix-bound receptors with the actin cytoskeleton. The formation of nearly stationary FAs defines a boundary between the dense and highly dynamic actin network in lamellipodium and the sparser and more diverse cytoskeletal organization in the lamella proper, creating a template for the organization of the entire actin network. The major "mechanical" and "sensory" functions of FAs; namely, the nucleation and regulation of the contractile, myosin-II-containing stress fibers and the mechanosensing of external surfaces depend, to a major extent, on the dynamics of molecular components within FAs. A central element in FA regulation concerns the positive feedback loop, based on the most intriguing feature of FAs; that is, their dependence on mechanical tension developing by the growing stress fibers. FAs grow in response to such tension, and rapidly disassemble upon its relaxation. In this article, we address the mechanistic relationships between the process of FA development, maturation and dissociation and the dynamic molecular events, which take place in different regions of the FA, primarily in the distal end of this structure (the "toe") and the proximal "heel," and discuss the central role of local mechanical forces in orchestrating the complex interplay between FAs and the actin system. Cell Motil. Cytoskeleton 66: 1017,1029, 2009. © 2009 Wiley-Liss, Inc. [source] Rho plays a central role in regulating local cell-matrix mechanical interactions in 3D cultureCYTOSKELETON, Issue 6 2007N. Lakshman Abstract The purpose of this study was to assess quantitatively the role of the small GTPase Rho on cell morphology, f-actin organization, and cell-induced matrix remodeling in 3D culture. Human corneal fibroblasts (HTK) were infected with adenoviruses that express green fluorescent protein (GFP) or GFP-N19Rho (dominant negative Rho). One day later cells were plated inside collagen matrices and allowed to spread for 24 h. Cells were fixed and stained for f-actin. Fluorescent (for f-actin) and reflected light (for collagen fibrils) images were acquired using confocal microscopy. Fourier transform analysis was used to assess local collagen fibril alignment, and changes in cell morphology and collagen density were measured using MetaMorph. The decrease in matrix height was used as an indicator of global matrix contraction. HTK and HTK-GFP cells induced significant global matrix contraction; this was inhibited by N19Rho. HTK and HTK-GFP fibroblasts generally had a bipolar morphology and occasional intracellular stress fibers. Collagen fibrils were compacted and aligned parallel to stress fibers and pseudopodia. In contrast, HTK-GFPN19 cells were elongated, and had a more cortical f-actin distribution. Numerous small extensions were also observed along the cell body. In addition, both local collagen fibril density and alignment were significantly reduced. Rho plays a key role in regulating both the morphology and mechanical behavior of corneal fibroblasts in 3D culture. Overall, the data suggest that Rho-kinase dependent cell contractility contributes to global and local matrix remodeling, whereas Rho dependent activation of mDia and/or other downstream effectors regulates the structure and number of cell processes. Cell Motil. Cytoskeleton 2007. © 2007 Wiley-Liss, Inc. [source] Manufacturing Practices and Strategy Integration: Effects on Cost Efficiency, Flexibility, and Market-Based PerformanceDECISION SCIENCES, Issue 3 2005Morgan Swink ABSTRACT Manufacturing plant managers have sought performance improvements through implementing best practices discussed in World Class Manufacturing literature. However, our collective understanding of linkages between practices and performance remains incomplete. This study seeks a more complete theory, advancing the idea that strategy integration and enhanced manufacturing capabilities such as cost efficiency and flexibility serve as intermediaries by which practices affect performance. Hypotheses related to this thesis are tested using data from 57 North American manufacturing plants that are past winners and finalists in Industry Week's"America's Best" competition (Drickhamer, 2001). The results suggest that strategy integration plays a strong, central role in the creation of manufacturing cost efficiency and new product flexibility capabilities. Furthermore, strategy integration moderates the influences of product-process development, supplier relationship management, workforce development, just-in-time flow, and process quality management practices on certain manufacturing capabilities. In turn, manufacturing cost efficiency and new product flexibility capabilities mediate the influence of strategy integration on market-based performance. These findings have implications for practice and for future research. [source] Externalities, Learning and Governance: New Perspectives on Local Economic DevelopmentDEVELOPMENT AND CHANGE, Issue 2 2001Bert Helmsing In spite of growing mobility of production and production factors, economic development is increasingly localized in economic agglomerations. This article reviews three partially overlapping perspectives on local economic development, which derive from three factors intensifying the localized nature of economic development: externalities, learning and governance. Externalities play a central role in the new geographical economics of Krugman and in new economic geography of clusters and industrial districts. The dynamics of local economic development are increasingly associated with evolutionary economic thinking in general and with collective learning in particular. Inter-firm and extra-firm organization has experienced considerable innovation in the last few decades. New institutional devices are based on the notions of commodity chain, cluster and milieu. These innovations introduce new issues of economic governance both at the level of industry and of territory. [source] The subjective experience of taking antipsychotic medication: a content analysis of Internet dataACTA PSYCHIATRICA SCANDINAVICA, Issue 2 2009J. Moncrieff Objective:, We explored the subjective effects associated with olanzapine, risperidone and older antipsychotics. Method:, We conducted a content analysis of an Internet database of comments about prescribed medications. Results:, We analysed 223 comments on risperidone, 170 on olanzapine and 46 relating to three older antipsychotics. The predominant subjective effects produced by all drugs consisted of sedation, cognitive impairment and emotional flattening or indifference. Connections appeared between these effects and Parkinsonian-like symptoms with the older drugs, sexual impairment with risperidone and metabolic effects with olanzapine. The experience of akathisia was frequently linked to suicidal thoughts. Some respondents described how the drugs' subjective effects helped to reduce symptoms of mania, psychosis and anxiety. Conclusion:, The generalisability of Internet data is uncertain. However, the data suggest that adverse subjective effects play a central role in the experience of taking antipsychotic drugs and may be related to the drugs' desired benefits. [source] Androgen receptor gene expression in the developing and adult zebrafish brainDEVELOPMENTAL DYNAMICS, Issue 10 2008Daniel A. Gorelick Abstract Androgens play a central role in the regulation of male sexual differentiation and behavior in many vertebrates, including zebrafish. Their signaling is mediated by activation of the androgen receptor. A single androgen receptor (ar) gene was recently identified in zebrafish, which encodes a protein that binds androgens in vitro. However, the tissue-specific expression pattern of this receptor in vivo has not been described. Using whole-mount RNA in situ hybridization, we characterized expression of the ar gene in developing zebrafish and in the adult brain. In embryos, transcripts were found in the presumptive pronephros and in olfactory placodes. By 3,5 days postfertilization, ar transcripts were also detected in the pineal organ anlage and the retina. In the adult brain, ar was expressed in discrete regions of the telencephalon, in the preoptic area, and throughout the periventricular hypothalamus, regions previously implicated in the regulation of sexually dimorphic behaviors in mammals. Developmental Dynamics 237:2987,2995, 2008. © 2008 Wiley-Liss, Inc. [source] Coordination of development and metabolism in the pre-midblastula transition zebrafish embryoDEVELOPMENTAL DYNAMICS, Issue 7 2008Bryce A. Mendelsohn Abstract To define the mechanisms that coordinate early embryonic development and metabolism, we have examined the response of zebrafish embryos to anoxia before the midblastula transition. Our findings reveal that anoxic pre-midblastula transition embryos slow the cell cycle, arrest before the midblastula transition and can recover normally if restored to a normoxic environment. Analyses of respiratory rates reveal that pre-midblastula transition embryos are less reliant on oxidative phosphorylation than older embryos. Interestingly, arrest in anoxia occurs despite inhibition of zygotic transcription, revealing a central role for maternal factors in the response to energy limitation. Consistent with this concept, we demonstrate that the posttranslational energy-sensing AMP-activated protein kinase pathway is activated in anoxia in pre-midblastula transition embryos. Taken together, these findings demonstrate a maternal program capable of coordinating developmental rate and metabolism in the absence of transcription-based pathways or cell cycle checkpoints. Developmental Dynamics 237:1789,1798, 2008. © 2008 Wiley-Liss, Inc. [source] Tissue surface tensions guide in vitro self-assembly of rodent pancreatic islet cellsDEVELOPMENTAL DYNAMICS, Issue 8 2007Dongxuan Jia Abstract The organization of endocrine cells in pancreatic islets is established through a series of morphogenetic events involving cell sorting, migration, and re-aggregation processes for which intercellular adhesion is thought to play a central role. In animals, these morphogenetic events result in an islet topology in which insulin-secreting cells form the core, while glucagon, somatostatin, and pancreatic polypeptide-secreting cells segregate to the periphery. Isolated pancreatic islet cells self-assemble in vitro into pseudoislets with the same cell type organization as native islets. It is widely held that differential adhesion between cells of the pancreatic islets generates this specific topology. However, this differential adhesion has never been rigorously quantified. In this manuscript, we use tissue surface tensiometry to measure the cohesivity of spherical aggregates from three immortalized mouse pancreatic islet cell lines. We show that, as predicted by the differential adhesion hypothesis, aggregates of the internally segregating INS-1 and MIN6 beta-cell lines are substantially more cohesive than those of the externally segregating ,-TC line. Furthermore, we show that forced overexpression of P-cadherin by ,-TC cells significantly perturbs the sorting process. Collectively, the data indicate that differential adhesion can drive the in vitro organization of immortalized rodent pancreatic islet cells. Developmental Dynamics 236:2039,2049, 2007. © 2007 Wiley-Liss, Inc. [source] The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticityDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2010Eero Castrén Abstract Recent evidence suggests that neuronal plasticity plays an important role in the recovery from depression. Antidepressant drugs and electroconvulsive shock treatment increase the expression of several molecules, which are associated with neuronal plasticity, in particular the neurotrophin BDNF and its receptor TrkB. Furthermore, these treatments increase neurogenesis and synaptic numbers in several brain areas. Conversely, depression, at least in its severe form, is associated with reduced volumes of the hippocampus and prefrontal cortex and in at least some cases these neurodegenerative signs can be attenuated by successful treatment. Such observations suggest a central role for neuronal plasticity in depression and the antidepressant effect, and also implicate BDNF signaling as a mediator of this plasticity. The antidepressant fluoxetine can reactivate developmental-like neuronal plasticity in the adult visual cortex, which, under appropriate environmental guidance, leads to the rewiring of a developmentally dysfunctional neural network. These observations suggest that the simple form of the neurotrophic hypothesis of depression, namely, that deficient levels of neurotrophic support underlies mood disorders and increases in these neurotrophic factors to normal levels brings about mood recovery, may not sufficiently explain the complex process of recovery from depression. This review discusses recent data on the role of BDNF and its receptors in depression and the antidepressant response and suggests a model whereby the effects of antidepressant treatments could be explained by a reactivation of activity-dependent and BDNF-mediated cortical plasticity, which in turn leads to the adjustment of neuronal networks to better adapt to environmental challenges. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 2010 [source] Phosphatidylinositol-3-OH kinase regulatory subunits are differentially expressed during development of the rat cerebellumDEVELOPMENTAL NEUROBIOLOGY, Issue 1 2001José L. Trejo Abstract Recent evidence implicates a central role for PI3K signalling in mediating cell survival during the process of neuronal differentiation. Although PI3K activity is stimulated by a wide range of growth factors and cytokines in different cell lines and tissues, activation of this pathway by insulin-like growth factor I (IGF-I) most likely represents the main survival signal during neuronal differentiation. IGF-I is highly expressed during development of the central nervous system, and thus is a critical factor for the development and maturation of the cerebellum. Upon ligand binding, the IGF-I receptor phosphorylates tyrosine residues in SHC and insulin receptor substrates (IRSs) initiating two main signalling cascades, the MAP kinase and the phosphatidylinositol 3-kinase (PI3K) pathways. Activated PI3K is composed of a catalytic subunit (p110, or ,) associated with one of a large family of regulatory subunits (p85,, p85,, p55,, p55,, and p50,). To evaluate the contributions of these various regulatory subunits to neuronal differentiation, we have used antibodies specific for each of the PI3K subunits. Using these antisera, we now demonstrate that PI3K subunits are differentially regulated in cerebellar development, and that the expression level of the p55, regulatory subunit reaches a maximum during postnatal development, decreasing thereafter to low levels in the adult cerebellum. Furthermore, our studies reveal that the distribution of the various PI3K regulatory subunits varies during development of the cerebellum. Interestingly, p55, is expressed in both glial and neuronal cells; moreover, in Purkinje neurones, this subunit colocalises with the IGF-IR. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 39,50, 2001 [source] Free fatty acids , do they play a central role in type 2 diabetes?DIABETES OBESITY & METABOLISM, Issue 2001Peter Arner First page of article [source] Inflamed adipose tissue, insulin resistance and vascular injuryDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 8 2008Christian X. Andersson Abstract Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system. Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall. Copyright © 2008 John Wiley & Sons, Ltd. [source] Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseasesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2006Eugenio Cersosimo Abstract Cardiovascular disease affects approximately 60% of the adult population over the age of 65 and represents the number one cause of death in the United States. Coronary atherosclerosis is responsible for the vast majority of the cardiovascular events, and a number of cardiovascular risk factors have been identified. In recent years, it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the metabolic syndrome. Endothelial dysfunction is an important component of the metabolic or insulin resistance syndrome and this is demonstrated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release nitric oxide (NO). Deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and endothelial dysfunction. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen (ROS) and nitrogen (RNS) species, which are produced by cellular disturbances in glucose and lipid metabolism. Endothelial dysfunction contributes to impaired insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of insulin-stimulated glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance. Vascular damage, which results from lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of chemoattractants and cytokines worsens the insulin resistance and endothelial dysfunction. From the clinical standpoint, much experimental evidence supports the concept that therapies that improve insulin resistance and endothelial dysfunction reduce cardiovascular morbidity and mortality. Moreover, interventional strategies that reduce insulin resistance ameliorate endothelial dysfunction, while interventions that improve tissue sensitivity to insulin enhance vascular endothelial function. There is general agreement that aggressive therapy aimed simultaneously at improving insulin-mediated glucose/lipid metabolism and endothelial dysfunction represents an important strategy in preventing/delaying the appearance of atherosclerosis. Interventions that 1 correct carbohydrate and lipid metabolism, 2 improve insulin resistance, 3 reduce blood pressure and restore vascular reactivity, and 4 attenuate procoagulant and inflammatory responses in adults with a high risk of developing cardiovascular disease reduce cardiovascular morbidity and mortality. Whether these benefits hold when the same prevention strategies are applied to younger, high-risk individuals remains to be determined. Copyright © 2006 John Wiley & Sons, Ltd. [source] An adipocentric view of signaling and intracellular traffickingDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2002Silvia Mora Abstract Adipocytes have traditionally been considered to be the primary site for whole body energy storage mainly in the form of triglycerides and fatty acids. This occurs through the ability of insulin to markedly stimulate both glucose uptake and lipogenesis. Conventional wisdom held that defects in fuel partitioning into adipocytes either because of increased adipose tissue mass and/or increased lipolysis and circulating free fatty acids resulted in dyslipidemia, obesity, insulin resistance and perhaps diabetes. However, it has become increasingly apparent that loss of adipose tissue (lipodystrophies) in both animal models and humans also leads to metabolic disorders that result in severe states of insulin resistance and potential diabetes. These apparently opposite functions can be resolved by the establishment of adipocytes not only as a fuel storage depot but also as a critical endocrine organ that secretes a variety of signaling molecules into the circulation. Although the molecular function of these adipocyte-derived signals are poorly understood, they play a central role in the maintenance of energy homeostasis by regulating insulin secretion, insulin action, glucose and lipid metabolism, energy balance, host defense and reproduction. The diversity of these secretory factors include enzymes (lipoprotein lipase (LPL) and adipsin), growth factors [vascular endothelial growth factor (VEGF)], cytokines (tumor necrosis factor-,, interleukin 6) and several other hormones involved in fatty acid and glucose metabolism (leptin, Acrp30, resistin and acylation stimulation protein). Despite the large number of molecules secreted by adipocytes, our understanding of the pathways and mechanisms controlling intracellular trafficking and exocytosis in adipocytes is poorly understood. In this article, we will review the current knowledge of the trafficking and secretion processes that take place in adipocytes, focusing our attention on two of the best characterized adipokine molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter. Copyright © 2002 John Wiley & Sons, Ltd. [source] Heparan sulfate proteoglycans in experimental models of diabetes: a role for perlecan in diabetes complicationsDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2001Karin Conde-Knape Abstract Proteoglycans are ubiquitous extracellular proteins that serve a variety of functions throughout the organism. Unlike other glycoproteins, proteoglycans are classified based on the structure of the glycosaminoglycan carbohydrate chains, not the core proteins. Perlecan, a member of the heparan sulfate proteoglycan (HSPG) family, has been implicated in many complications of diabetes. Decreased levels of perlecan have been observed in the kidney and in other organs, both in patients with diabetes and in animal models. Perlecan has an important role in the maintenance of the glomerular filtration barrier. Decreased perlecan in the glomerular basement membrane has a central role in the development of diabetic albuminuria. The involvement of this proteoglycan in diabetic complications and the possible mechanisms underlying such a role have been addressed using a variety of models. Due to the importance of nephropathy among diabetic patients most of the studies conducted so far relate to diabetes effects on perlecan in different types of kidney cells. The various diabetic models used have provided information on some of the mechanisms underlying perlecan's role in diabetes as well as on possible factors affecting its regulation. However, many other aspects of perlecan metabolism still await full elucidation. The present review provides a description of the models that have been used to study HSPG and in particular perlecan metabolism in diabetes and some of the factors that have been found to be important in the regulation of perlecan. Copyright © 2001 John Wiley & Sons, Ltd. [source] Metformin action on AMP-activated protein kinase: a translational research approach to understanding a potential new therapeutic targetDIABETIC MEDICINE, Issue 10 2010J. G. Boyle Diabet. Med. 27, 1097,1106 (2010) Abstract Clinical studies in Type 2 diabetes mellitus have shown that the effects of metformin go beyond improving HbA1c and include reductions in cardiovascular endpoints. Metformin therapy has been widely used in the treatment of Type 2 diabetes for many years, yet the precise mode of action remains uncertain. It has recently been proposed that metformin-mediated stimulation of hepatic AMP-activated protein kinase (AMPK) underlies the hypoglycaemic effects of metformin. AMPK is a heterotrimeric enzyme that is expressed in many tissues and plays a central role in the regulation of energy homoeostasis. Furthermore, there is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. The generation of more specific and potent activators of AMPK, however, could have additional metabolic and vascular benefits for patients with Type 2 diabetes. [source] Animal models of diabetes mellitusDIABETIC MEDICINE, Issue 4 2005D. A. Rees Abstract Animal models have been used extensively in diabetes research. Early studies used pancreatectomised dogs to confirm the central role of the pancreas in glucose homeostasis, culminating in the discovery and purification of insulin. Today, animal experimentation is contentious and subject to legal and ethical restrictions that vary throughout the world. Most experiments are carried out on rodents, although some studies are still performed on larger animals. Several toxins, including streptozotocin and alloxan, induce hyperglycaemia in rats and mice. Selective inbreeding has produced several strains of animal that are considered reasonable models of Type 1 diabetes, Type 2 diabetes and related phenotypes such as obesity and insulin resistance. Apart from their use in studying the pathogenesis of the disease and its complications, all new treatments for diabetes, including islet cell transplantation and preventative strategies, are initially investigated in animals. In recent years, molecular biological techniques have produced a large number of new animal models for the study of diabetes, including knock-in, generalized knock-out and tissue-specific knockout mice. [source] Genetic variants of insulin receptor substrate-1 (IRS-1) in syndromes of severe insulin resistance.DIABETIC MEDICINE, Issue 10 2002Functional analysis of Ala513Pro, Gly1158Glu IRS- Abstract Aims To define further the role of IRS-1 mutations in human syndromes of severe insulin resistance. Methods The IRS-1 gene was scanned for mutations in 83 unrelated affected subjects and 47 unaffected individuals using fluorescent single-strand conformation polymorphism (fSSCP) analysis. A novel heterozygous mutation, Gly1158Glu, was found in one affected subject. Four and two subjects were heterozygous for the previously reported variants Gly972Arg and Ala513Pro, respectively. The previously identified variant Gly819Arg was found in one affected and one unaffected subject. While Gly972Arg has been described to alter the signalling properties of IRS-1, no functional studies of Ala513Pro or Gly1158Glu have been reported. Results Chinese hamster ovary (CHO) cells stably over-expressing the insulin receptor were transiently transfected with vectors expressing either wild-type, Glu1158 or Pro513 IRS-1. A modest increase in insulin-stimulated tyrosine phosphorylation of Glu1158 IRS-1 was observed. However, this did not result in any significant change in the association of Grb2 or the p85, subunit of PI3-kinase or of PI3-kinase activity. In parallel studies, the Pro513 IRS-1 variant was indistinguishable from wild-type IRS-1. Conclusions While subtle effects of these variants cannot be excluded in this system, it is unlikely that these variants are responsible for the extreme insulin resistance seen in the subjects harbouring them. Although IRS proteins play a central role in insulin signalling, functionally significant mutations in the IRS-1 gene are a rare cause of human syndromes of severe insulin resistance. [source] An Essay on the Role of Language in Collegiate Foreign Language Programmatic Reform,DIE UNTERRICHTSPRAXIS/TEACHING GERMAN, Issue 2 2009Hiram Maxim This position paper argues that collegiate foreign language (FL) education has lost sight of the central role that language plays in the profession. Regardless of one's sub-field within foreign language education (i.e., linguistic, literary, or cultural studies), the profession shares the common focus of exploring how to make and interpret meaning in and through language. The paper therefore recommends that an acknowledgement of and re-commitment to this foundational principle provides common ground to effect the types of change within departments that have long been called: the integration of upper- and lower-level instruction; the reform of graduate student teacher education to foster curricular thinking; the explicit and systematic attention to the development of advanced language abilities; and the establishment of a collaborative departmental culture centered around publicly shared beliefs and concerns. [source] Evaluation of a training program to improve clinicians' assessment of patient stabilityDRUG AND ALCOHOL REVIEW, Issue 4 2009ADAM R. WINSTOCK Abstract Introduction and Aims. Public clinics in New South Wales (NSW), Australia play a central role in inducting and stabilising opioid dependent clients onto treatment before transfer to a community pharmacy. Clinical assessment of stability is a vital skill in ensuring that clients are appropriately and effectively transferred. A two-hour clinical training program was delivered to staff at 31 public clinics, that aimed to improve staff confidence in assessing client stability, and skills in negotiating the transfer of clients to community pharmacies. Design and Methods. Pre- and post-training evaluation was conducted examining self-ratings of confidence and ability in the assessment of client stability, and the perceived utility of a clinical algorithm to improve assessments. Follow-up was conducted 3 to 6 months post-training assessing individual and clinic level changes in clinical practice. Results. 205 staff completed pre- and post-training questionnaires. Staff demonstrated a moderate level of self-reported baseline knowledge and skills in assessing client stability (mean = 6.5; 1 = poor; 10 = excellent) that improved when re-assessed following the training (mean = 8.0). 76 staff responded to the follow-up questionnaire. , 75% reported some level of improvement in their approach to clinical practice regarding stability assessment, and 59% reported being more effective in identifying clients appropriate for community pharmacy transfer. Of 19 public clinics, 14 reported an increased focus on stability assessment. Nine clinics reported barriers to achieving changes in clinical practice. Discussion and Conclusions. This evaluation demonstrates that it is possible to implement a targeted clinical training package to staff that translates into positive changes in clinical practice.[Winstock AR, Lea T. Evaluation of a training program to improve clinicians' assessment of patient stability. Drug Alcohol Rev 2009;28:353,359] [source] The role of the family in preventing and intervening with substance use and misuse: a comprehensive review of family interventions, with a focus on young peopleDRUG AND ALCOHOL REVIEW, Issue 2 2005RICHARD D. B. VELLEMAN PhD Abstract The family plays a key part in both preventing and intervening with substance use and misuse, both through inducing risk, and/or encouraging and promoting protection and resilience. This review examines a number of family processes and structures that have been associated with young people commencing substance use and later misuse, and concludes that there is significant evidence for family involvement in young people's taking up, and later misusing, substances. Given this family involvement, the review explores and appraises interventions aimed at using the family to prevent substance use and misuse amongst young people. The review concludes that there is a dearth of methodologically highly sound research in this area, but the research that has been conducted does suggest strongly that the family can have a central role in preventing substance use and later misuse amongst young people. [source] Torture and truth in late antique martyrologyEARLY MEDIEVAL EUROPE, Issue 4 2002Lucy Grig This article looks at descriptions of torture in hagiographical texts, analysing the significance of representations of violence and suffering in late antique Christian discourse. Seemingly redundant descriptions of torture in texts such as Prudentius's Peristephanon can be contextualized within a broader late antique concern with violence and pain. These descriptions should also be seen as playing a central role in constructing the power of the martyr, and that of his or her church. Close readings of several martyr acts show how the torture process (the quaestio) was rewritten to suit the needs of a new era: that of the Church Triumphant. [source] Lesions of the Mitral Valve as a Cause of Central Retinal Artery Occlusion: Presentation and Discussion of Two CasesECHOCARDIOGRAPHY, Issue 1 2010Maryam Ayati M.D. We present two cases of mitral valve lesions that manifested with unilateral blindness caused by central retinal artery occlusion (CRAO): Case 1. A 68-year-old woman was admitted to our clinic for sudden blindness. Retinal artery angiogram showed CRAO. Transthoracic and transesophageal echocardiography (TEE) documented a mass attached to the ventricular side of the posterior mitral leaflet, which at pathology was identified as a blood cyst. Case 2. A 67-year-old man was admitted for a sudden unilateral painless loss of vision. Retinal angiogram documented CRAO, and TEE showed a highly mobile, spherical, lesion on the atrial side of anterior mitral leaflet. In this case, the pathological finding was a degenerated calcified thrombosis. We report on two cases of very rare abnormalities of the mitral valve presenting with a very rare embolic complication, i.e., CRAO. Like for cryptogenic stroke, transesophageal echocardiography plays a central role in the diagnosis of cardiogenic embolic sources. (Echocardiography 2010;27:E1-E3) [source] The interpretation, assessment and conservation of ecological communitiesECOLOGICAL MANAGEMENT & RESTORATION, Issue 2009David A. Keith Summary Ecological communities are assemblages of species that occur together in space and time. Their properties include composition, structure, habitat, distribution, biological interactions and ecosystem functions. The community concept has a central role in conservation planning, and is a key approach for biodiversity conservation above the species level. The relatively recent application of risk assessment and regulatory systems to conservation of ecological communities has highlighted a number of challenges related to intrinsic uncertainties in the definition, diagnosis and assessment of ecological communities. In this review, I aim to elucidate some key conceptual issues essential to the interpretation of communities. Effective description, diagnosis and assessment of communities rests on an understanding of community theory in relation to environmental gradients and ecosystem dynamics. Continuum and discrete models can both contribute to interpretation of communities for conservation. Different sources of uncertainty are inherent in the key properties that characterize communities. Although some of these are reducible, remaining uncertainty must be incorporated into assessments and decision-making processes for conservation. Protocols for assessing extinction risks of communities address rates of decline in distribution, size of distribution and rates of decline in ecological functions. Some protocols assess these factors in a manner that may be inconsistent with equivalent methods for assessing species. Communities may be viewed in a framework that distinguishes thematic, spatial and temporal scales. These scales influence the outcomes of risk assessment, the benefits and limitations of maps and how well communities perform their function in conservation planning. When applied effectively, ecological communities can be powerful tools for delivering cost-effective outcomes for land-use planning and biodiversity conservation. [source] | |||||||||||||||||||||||||||||||||||||||||||