EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010
Akihiro Kimura
Abstract IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses. IL-6 induces the development of Th17 cells from naïve T cells together with TGF-,; in contrast, IL-6 inhibits TGF-,-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL-6 in regulating Th17/Treg balance and describe the critical functions of IL-6 and Th17 in immunity and immune-pathology. [source]

Some ideas for QFT research

INTERNATIONAL JOURNAL OF ROBUST AND NONLINEAR CONTROL, Issue 7 2003
Isaac Horowitz
Feedback theory is much less popular now than 5 years ago. However, there is little question that the problem of achieving desired system tolerances from uncertain plants, at minimum cost of feedback, will remain an important, enduring one for many future generations. Although much progress has been made, it is minuscule in comparison with the extent of the problem. The purpose here is to suggest some significant QFT research problems, some tantalizingly on the boundary of the unknown. There have been in the past many suggestions for improvements in feedback synthesis. Most e.g. the Smith Regulator (Int. J. Control 1983;38:977) have been illusory, because they were formulated in a qualitative context, without the disciplines of quantitative uncertainty and performance specifications, degrees of freedom, sensor noise, plant modification, etc. Without such disciplines, it is impossible to properly evaluate competing techniques. The reader is referred to the 1991 Survey paper for some background, Horowitz (Int. J. Control 1991;53(2):255). Copyright © 2003 John Wiley & Sons, Ltd. [source]

FGF-23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate Homeostasis,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2004
Takashi Shimada
Abstract We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. Introduction: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. Materials and Methods: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. Results: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1,-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. Conclusions: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis. [source]

Calorie restriction effects on silencing and recombination at the yeast rDNA

AGING CELL, Issue 6 2009
Daniel L. Smith Jr
Summary Aging research has developed rapidly over the past decade, identifying individual genes and molecular mechanisms of the aging process through the use of model organisms and high throughput technologies. Calorie restriction (CR) is the most widely researched environmental manipulation that extends lifespan. Activation of the NAD+ -dependent protein deacetylase Sir2 (Silent Information Regulator 2) has been proposed to mediate the beneficial effects of CR in the budding yeast Saccharomyces cerevisiae, as well as other organisms. Here, we show that in contrast to previous reports, Sir2 is not stimulated by CR to strengthen silencing of multiple reporter genes in the rDNA of S. cerevisiae. CR does modestly reduce the frequency of rDNA recombination, although in a SIR2 -independent manner. CR-mediated repression of rDNA recombination also does not correlate with the silencing of Pol II-transcribed noncoding RNAs derived from the rDNA intergenic spacer, suggesting that additional silencing-independent pathways function in lifespan regulation. [source]

RGS9-2 mediates specific inhibition of agonist-induced internalization of D2 -dopamine receptors

JOURNAL OF NEUROCHEMISTRY, Issue 3 2010
Jeremy Celver
J. Neurochem. (2010) 114, 739,749. Abstract Regulator of G protein signaling 9-2 (RGS9-2), a member of the RGS family of GTPase accelerating proteins, is expressed specifically in the striatum, a brain region involved in controlling movement, motivation, mood and addiction. RGS9-2 can be found co-localized with D2 -class dopamine receptors in medium spiny striatal neurons and altered functioning of both RGS9-2 and D2 -like dopamine receptors have been implicated in schizophrenia, movement disorders and reward responses. Previously we showed that RGS9-2 can specifically co-localize with D2 -dopamine receptors (D2R). Here we provide further evidence of the specificity of RGS9-2 for regulating D2R cellular functions: the expression of RGS9-2 inhibits dopamine-mediated cellular internalization of D2R, while the expression of another RGS protein, RGS4, had no effect. In addition, the agonist-mediated internalization of the G protein coupled delta opioid receptor was unaffected by RGS9-2 expression. We utilized mutant constructs of RGS9-2 to show that the RGS9-2 DEP (for Disheveled, EGL-10, Pleckstrin homology) domain and the GTPase accelerating activity of RGS9-2 were necessary for mediating specific inhibition of D2R internalization. [source]

RGS7 Is Palmitoylated and Exists as Biochemically Distinct Forms

JOURNAL OF NEUROCHEMISTRY, Issue 5 2000
Jeremy J. Rose
Abstract:Regulator of G protein signaling (RGS) proteins are GTPase-activating proteins that modulate neurotransmitter and G protein signaling. RGS7 and its binding partners G, and G,5 are enriched in brain, but biochemical mechanisms governing RGS7/G,/G,5 interactions and membrane association are poorly defined. We report that RGS7 exists as one cytosolic and three biochemically distinct membrane-bound fractions (salt-extractable, detergent-extractable, and detergent-insensitive) in brain. To define factors that determine RGS7 membrane attachment, we examined the biochemical properties of recombinant RGS7 and G,5 synthesized in Spodoptera frugiperda insect cells. We have found that membrane-bound but not cytosolic RGS7 is covalently modified by the fatty acid palmitate. G,5 is not palmitoylated. Both unmodified (cytosolic) and palmitoylated (membrane-derived) forms of RGS7, when complexed with G,5, are equally effective stimulators of G,o GTPase activity, suggesting that palmitoylation does not prevent RGS7/G,o interactions. The isolated core RGS domain of RGS7 selectively binds activated G,i/o in brain extracts and is an effective stimulator of both G,o and G,i1 GTPase activities in vitro. In contrast, the RGS7/G,5 complex selectively interacts with G,o only, suggesting that features outside the RGS domain and/or G,5 association dictate RGS7-G, interactions. These findings define previously unrecognized biochemical properties of RGS7, including the first demonstration that RGS7 is palmitoylated. [source]

Kisspeptin: A Novel Regulator of Reproductive Function

JOURNAL OF NEUROENDOCRINOLOGY, Issue 8 2008
W. S. Dhillo
Young Neuroendocrinologists Prize Reviews Michael Harbuz Young Investigator Prize Lecture The UK and international neuroendocrine community was deeply shocked and saddened the unbelievably premature death of Michael Harbuz in Bristol in 2006. Mick was a superb friend and colleague, and played a huge part in the development and activities of the British Neuroendocrine Group/British Society for Neuroendocrinology (BSN), serving as both Membership Secretary and Treasurer between 1999 and 2004. Mick was a leader in the field of neuroendocrine,immune interactions, and brought a great deal of charisma, humour and ability to meetings and conferences. He was also a passionate and committed supporter of the progress of young researchers and of their participation in neuroendocrine events. He recognised that today's postgraduate students and postdoctoral research fellows are tomorrow's neuroendocrine researchers, be it in academia, the health services or industry. To recognise Mick's great commitment to and enthusiasm for postgraduate education both in the University of Bristol and in the BSN, we decided to honour and remember him by instituting the ,Michael Harbuz Young Investigator Prize Lecture' to be delivered annually. Dr Waljit Dhillo from Imperial College London was the inaugural recipient of this award, and presented his lecture at the Annual Meeting of the BSN in Nottingham in September 2007, upon which this review is based. Recent evidence demonstrates that the neuropeptide kisspeptin and its receptor, GPR54, have a fundamental role in initiating the onset of puberty and are important in regulating reproductive function. This review discusses the evidence available from animals and humans demonstrating that kisspeptin potently stimulates the release of gonadotrophins by stimulating the release of gonadotrophin-releasing hormone and that a lack of kisspeptin or GPR54 results in reproductive failure. [source]

Evidence That Gonadotropin-Releasing Hormone II Is Not a Physiological Regulator of Gonadotropin Secretion in Mammals

JOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2003
P. M. Gault
Abstract Gonadotropin-releasing hormone (GnRH)-II stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion when administered at high doses in mammals, and this effect has been assumed to be mediated through the GnRH-II receptor expressed on gonadotropes. This study used two selective GnRH-I receptor antagonists to test the alternative hypothesis that GnRH-II acts through the GnRH-I receptor to elicit gonadotropin secretion. The antagonist, antide, was used to characterize the receptor-relay because it was a pure antagonist in vitro based on inositol phosphate responses in COS-7 cells transfected with either mammalian GnRH-I and GnRH-II receptors and, in vivo, potently antagonized the gonadotropin-releasing effect of a single injection of 250 ng GnRH-I in our sexually inactive sheep model. In a series of studies in sheep, antide (i) blocked the acute LH response to a single injection of GnRH-II (20 µg antide: 10 µg GnRH-II); (ii) blocked both the acute, pulsatile LH response and the FSH priming response to 2-hourly injections of GnRH-II over 36 h (100 µg antide/8 h: 4 µg GnRH-II/2 h); and (iii) chronically blocked both the pulsatile LH response and the marked FSH priming response to 4-hourly injections of GnRH-II over 10 days (75 µg antide/8 h: 4 µg GnRH-II/4 h). In two final experiments, the GnRH-I antagonist 135-18, shown previously to agonize the mammalian GnRH-II receptor, blocked the gonadotropin-releasing effects of GnRH-I (250 ng) but failed to elicit an LH response when given alone, and simultaneous administration of GnRH-II (250 ng) failed to alter the LH-releasing effect of GnRH-I (50,500 ng). These data thus support our hypothesis. Based on additional literature, it is unlikely that the GnRH-II decapeptide is a native regulator of the gonadotrope in mammals. [source]

GDNF is an Endogenous Negative Regulator of Ethanol-Mediated Reward and of Ethanol Consumption After a Period of Abstinence

ALCOHOLISM, Issue 6 2009
Sebastien Carnicella
Background:, We previously found that activation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the ventral tegmental area (VTA) reduces ethanol-drinking behaviors. In this study, we set out to assess the contribution of endogenous GDNF or its receptor GFR,1 to the regulation of ethanol-related behaviors. Methods:, GDNF and GFR,1 heterozygote mice (HET) and their wild-type littermate controls (WT) were used for the studies. Ethanol-induced hyperlocomotion, sensitization, and conditioned place preference (CPP), as well as ethanol consumption before and after a period of abstinence were evaluated. Blood ethanol concentration (BEC) was also measured. Results:, We observed no differences between the GDNF HET and WT mice in the level of locomotor activity or in sensitization to ethanol-induced hyperlocomotion after systemic injection of a nonhypnotic dose of ethanol and in BEC. However, GDNF and GFR,1 mice exhibited increased place preference to ethanol as compared with their WT littermates. The levels of voluntary ethanol or quinine consumption were similar in the GDNF HET and WT mice, however, a small but significant increase in saccharin intake was observed in the GDNF HET mice. No changes were detected in voluntary ethanol, saccharin or quinine consumption of GFR,1 HET mice as compared with their WT littermates. Interestingly, however, both the GDNF and GFR,1 HET mice consumed much larger quantities of ethanol after a period of abstinence from ethanol as compared with their WT littermates. Furthermore, the increase in ethanol consumption after abstinence was found to be specific for ethanol as similar levels of saccharin intake were measured in the GDNF and GFR,1 HET and WT mice after abstinence. Conclusions:, Our results suggest that endogenous GDNF negatively regulates the rewarding effect of ethanol and ethanol-drinking behaviors after a period of abstinence. [source]

Molecular Diversity of VEGF-A as a Regulator of Its Biological Activity

MICROCIRCULATION, Issue 7 2009
Jeanette Woolard
ABSTRACT The vascular endothelial growth factor (VEGF) family of proteins regulates blood flow, growth, and function in both normal physiology and disease processes. VEGF-A is alternatively spliced to form multiple isoforms, in two subfamilies, that have specific, novel functions. Alternative splicing of exons 5,7 of the VEGF gene generates forms with differing bioavailability and activities, whereas alternative splice-site selection in exon 8 generates proangiogenic, termed VEGFxxx, or antiangiogenic proteins, termed VEGFxxxb. Despite its name, emerging roles for VEGF isoforms on cell types other than endothelium have now been identified. Although VEGF-A has conventionally been considered to be a family of proangiogenic, propermeability vasodilators, the identification of effects on nonendothelial cells, and the discovery of the antiangiogenic subfamily of splice isoforms, has added further complexity to their regulation of microvascular function. The distally spliced antiangiogenic isoforms are expressed in normal human tissue, but downregulated in angiogenic diseases, such as cancer and proliferative retinopathy, and in developmental pathologies, such as Denys Drash syndrome and preeclampsia. Here, we examine the molecular diversity of VEGF-A as a regulator of its biological activity and compare the role of the pro- and antiangiogenic VEGF-A splice isoforms in both normal and pathophysiological processes. [source]

NF-,B in Photodynamic Therapy: Discrepancies of a Master Regulator

PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2006
Jean-Yves Matroule
ABSTRACT Tumor eradication by photodynamic therapy (PDT) results from the onset of distinct killing processes. In addition to the well-known necrotic and apoptotic mechanisms, PDT initiates an inflammatory response that will indirectly contribute to tumor clearance. The NF-,B transcription factor is a major regulator of inflammation modulating the expression of cyto-kines, chemokines, and adhesion molecules in various cell types in response to a large number of stimuli. Besides, NF-,B regulates the expression of antiapoptotic genes, cyclooxygenases (COXs) and metalloproteinases (MMPs) as well, thereby favoring tumor cell proliferation and dissemination. In the present review, we aim to summarize the current knowledge on NF-,B status following photosensitization of cancer cells and endothelial cells. In order to unravel the NF-,B impact in PDT tumorigenicity and recurrences, we will stress the discrepancies of this major transcription factor relative to the signaling cascades underlying its activation and the cellular effects triggered by its translocation into the nucleus and its binding to its target genes. [source]

Novel missense polymorphism in the regulator of G-protein signaling 10 gene: analysis of association with schizophrenia

PSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 5 2004
AKITOYO HISHIMOTO md
ABSTRACT, Dysfunction of neuronal signal transduction via G-protein has previously been speculated to be involved in the pathophysiology of schizophrenia. Regulator of G-protein signaling (RGS) is a protein that acts as a GTPase-activator for G, protein. A total of 33 Japanese patients with schizophrenia were screened for mutations in the coding region of the RGS10 gene, and a novel missense polymorphism (Val38Met) in the RGS domain was detected. A case-control study did not reveal a significant association between this polymorphism and schizophrenia. The results do not provide evidence that the RGS10 gene is involved in biological vulnerability to schizophrenia. [source]

ORIGINAL ARTICLE: Calcineurin/NFAT Pathway: A Novel Regulator of Parturition

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009
Chisa Tabata
Problem, The oxytocin (OT),oxytocin receptor (OTR) system plays an important role in mammalian parturition. However, we found OTR-deficient (OTRKO) mice are fertile and deliver at term without birth defects, thus alternative pathways inducing parturition can be hypothesized. Methods of study, We tested the gene expression profile of OTRKO mice using suppressive subtractive hybridization, and focused on the calcineurin/nuclear factor of activated T cells (NFAT) pathway. We examined the expression and localization of this pathway in mouse parturition. Results, Calcineurin and NFATc1 were detected in the decidua of pregnant uteri at term using immunohistochemistry (IHC). We identified higher activation levels of NFATc1 in wild type (WT) than in OTRKO mice and increased calcineurin A and NFATc1 mRNA levels during pregnancy. Moreover, injection of FK506, the inhibitor of this pathway, prolonged the delivery of the first pup. Conclusion, Our findings suggested that the calcineurin/NFAT pathway might play a substantial role in initiation of labor. [source]

Leukemia Inhibitory Factor: An Important Regulator of Endometrial Function

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2004
Zdzis, awa Kondera-Anasz
Problem:, Leukemia inhibitory factor (LIF) is multifunctional cytokine that displays biological activities in different cells, including endometrial cells. The aim of this study is to describe implications of LIF on a physiological function of endometrium. Method of study:, The role of LIF in the endometrial function is reviewed and summarized from the available literature. Results:, LIF plays an important role in a physiological function of endometrium. In human endometrial LIF expression depends on cellular localizations, steroid hormones, menstrual stages and a local cytokine network. Stronger LIF expression exists in an endometrial epithelium during a luteal phase of the menstrual cycle, which coincides with the time of an implantation. The impairments of the endometrial LIF expression may play a significant role in the pathological processes involving implantation and the infertility. Conclusions:, There is a substantial evidence that LIF is a potential regulator of the endometrial function and might be one of the factors that play a key role in human reproduction. [source]

Transplantation Oversight,Finding the Right Balance Between the Layperson, the Transplant Professional and the Regulator

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009
G. B. G. Klintmalm
Is UNOS the right body to make recommendations for standards for medical evaluation and care? The authors, who were involved in the development of the recent rule, suggest that it would be more appropriately done by the professional societies. See also article by Brown, Jr. et al in this issue on page 31. [source]

RE,Coil: An Antimicrobial Peptide Regulator

ANGEWANDTE CHEMIE, Issue 51 2009
Maxim
Mal aktiv, mal inaktiv: Ein Peptidsystem, das für die Regulierung antimikrobieller Wirkungen entwickelt wurde, schaltet zwischen antimikrobiellen und inaktiven Formen um. Der Regulator besteht aus zwei ,-helicalen Sequenzen: Eine, das R-Knäuel, bindet an Mikroben-Membranen, fungiert als antimikrobielle Komponente und wird durch die andere, das E-Knäuel, ein membraninaktives Peptid, desaktiviert (siehe Bild). [source]

Identification of RGS1 as a candidate biomarker for undifferentiated spondylarthritis by genome-wide expression profiling and real-time polymerase chain reaction

ARTHRITIS & RHEUMATISM, Issue 11 2009
Jieruo Gu
Objective To compare gene expression profiles between ankylosing spondylitis (AS) and undifferentiated spondylarthritis (uSpA) patients with inflammatory low back pain. Methods Peripheral blood mononuclear cells (PBMCs) from patients with AS, patients with uSpA, and healthy subjects were screened using genome-wide microarrays, followed by validation by real-time polymerase chain reaction (PCR). Results Microarray profiling and real-time PCR assays showed only minor differences between AS patients and healthy subjects. In contrast, 20 genes were strikingly more highly expressed in uSpA patients. Regulator of G protein signaling 1 (RGS1) was identified as the most useful biomarker for distinguishing uSpA patients, and to a lesser extent AS patients, from control subjects (P = 2.3 × 10,7 and 6.7 × 10,3, respectively). These findings were verified in an independent cohort that also included patients with rheumatoid arthritis and patients with mechanical low back pain. The receiver operating characteristic area under the curve values in the first and second cohorts of uSpA patients were 0.99 and 0.93, respectively (P = 1 × 10,4). To evaluate the possible derivation of RGS1, we cultured a monocyte-derived cell line with a panel of cytokines and chemokines. RGS1 was significantly induced either by tumor necrosis factor , (TNF,) or by interleukin-17 (IL-17). Conclusion Our findings indicate that uSpA PBMCs carry strikingly more highly expressed genes compared with PBMCs from AS patients or healthy subjects, and that TNF,- and IL-17,inducible RGS1 is a potential biomarker for uSpA, and to a lesser extent for AS, with inflammatory low back pain. [source]

Gene expression in the efferent ducts, epididymis, and vas deferens during embryonic development of the mouse

DEVELOPMENTAL DYNAMICS, Issue 9 2010
Elizabeth M. Snyder
Abstract The tissues of the male reproductive tract are characterized by distinct morphologies, from highly coiled to un-coiled. Global gene expression profiles of efferent ducts, epididymis, and vas deferens were generated from embryonic day 14.5 to postnatal day 1 as tissue-specific morphologies emerge. Expression of homeobox genes, potential mediators of tissue-specific morphological development, was assessed. Twenty homeobox genes were identified as either tissue-enriched, developmentally regulated, or both. Additionally, ontology analysis demonstrated cell adhesion to be highly regulated along the length of the reproductive tract. Regulators of cell adhesion with variable expression between the three tissues were identified including Alcam, various cadherins, and multiple integrins. Immunofluorescence localization of the cell adhesion regulators POSTN and CDH2 demonstrated cell adhesion in the epithelium and mesenchyme of the epididymis may change throughout development. These results suggest cell adhesion may be modulated in a tissue-specific manner, playing an important role in establishing each tissue's final morphology. Developmental Dynamics 239:2479,2491, 2010. © 2010 Wiley-Liss, Inc. [source]

Bush Appointments of Regulators

GLOBAL BUSINESS AND ORGANIZATIONAL EXCELLENCE, Issue 1 2001
Thomas J. Knapp Esq.
[source]

Profit and Price Effects of Multi-species Individual Transferable Quotas

JOURNAL OF AGRICULTURAL ECONOMICS, Issue 1 2005
Diane P. Dupont
Regulators in many countries have adopted individual transferable quotas as a means of dealing with the open access problem inherent in fisheries. Using individual vessel data prior to and after the introduction of ITQs in Canada's multi-species Scotia-Fundy mobile gear fishery, the paper uses an index number profit decomposition to compare vessel performance over time and across individual vessels. The approach allows us to undertake both an ex post evaluation of short-term impacts of ITQs and an ex ante evaluation of longer term impacts. With respect to short-term impacts, the results suggest that larger vessels have benefited the most from the introduction of ITQs, but that all vessels have enjoyed increases in the prices received for those fish species that are included in the quota program. With respect to longer-term impacts, the transferability provisions of the ITQ program have encouraged exit and more efficient operations to prevail. [source]

Identification of Novel Regulators Associated With Early-Phase Osteoblast Differentiation,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2004
Diana S de Jong
Abstract Key regulatory components of the BMP-induced osteoblast differentiation cascade remain to be established. Microarray and subsequent expression analyses in mice identified two transcription factors, Hey1 and Tcf7, with in vitro and in vivo expression characteristics very similar to Cbfa1. Transfection studies suggest that Tcf7 modulates BMP2-induced osteoblast differentiation. This study contributes to a better definition of the onset of BMP-induced osteoblast differentiation. Introduction: Elucidation of the genetic cascade guiding mesenchymal stem cells to become osteoblasts is of extreme importance for improving the treatment of bone-related diseases such as osteoporosis. The aim of this study was to identify regulators of the early phases of bone morphogenetic protein (BMP)2-induced osteoblast differentiation. Materials and Methods: Osteoblast differentiation of mouse C2C12 cells was induced by treatment with BMP2, and regulation of gene expression was studied during the subsequent 24 h using high-density microarrays. The regulated genes were grouped by means of model-based clustering, and protein functions were assigned. Real-time quantitative RT-PCR analysis was used to validate BMP2-induced gene expression patterns in C2C12 cells. Osteoblast specificity was studied by comparing these expression patterns with those in C3H10T1/2 and NIH3T3 cells under similar conditions. In situ hybridization of mRNA in embryos at embryonic day (E)14.5 and E16.5 of gestation and on newborn mouse tails were used to study in vivo expression patterns. Cells constitutively expressing the regulated gene Tcf7 were used to investigate its influence on BMP-induced osteoblast differentiation. Results and Conclusions: A total of 184 genes and expressed sequence tags (ESTs) were differentially expressed in the first 24 h after BMP2 treatment and grouped in subsets of immediate early, intermediate early, and late early response genes. Signal transduction regulatory factors mainly represented the subset of immediate early genes. Regulation of expression of these genes was direct, independent of de novo protein synthesis and independent of the cell type studied. The intermediate early and late early genes consisted primarily of genes related to processes that modulate morphology, basement membrane formation, and synthesis of extracellular calcified matrix. The late early genes require de novo protein synthesis and show osteoblast specificity. In vivo and in vitro experiments showed that the transcription factors Hey1 and Tcf7 exhibited expression characteristics and cell type specificity very similar to those of the osteoblast specific transcription factor Cbfa1, and constitutive expression of Tcf7 in C2C12 cells differentially regulated osteoblast differentiation marker genes. [source]

Auditors on the hot seat

JOURNAL OF CORPORATE ACCOUNTING & FINANCE, Issue 4 2006
Robert W. Rouse
Regulators continue to look at auditors with a suspicious eye. The authors look at current developments, including the recent AICPA SEC/PCAOB conference, a PCAOB report, and more © 2006 Wiley Periodicals, Inc. [source]

A Class of Transpose Jacobian-based NPID Regulators for Robot Manipulators with an Uncertain Kinematics

JOURNAL OF FIELD ROBOTICS (FORMERLY JOURNAL OF ROBOTIC SYSTEMS), Issue 11 2002
C. Q. Huang
Transpose Jacobian-based controllers present an attractive approach to robot set-point control in Cartesian space that derive the end-effector posture to a specified desired position and orientation with neither solving the inverse kinematics nor computing the inverse Jacobian. By a Lyapunov function with virtual artificial potential energy, a class of complete transpose Jacobian-based Nonlinear proportional-integral-derivative regulators is proposed in this paper for robot manipulators with uncertain kinematics on the basis of the set of all continuous differentiable increasing functions. It shows globally asymptotic stability for the result closed-loop system on the condition of suitable feedback gains and suitable parameter selection for the corresponding function set as well as artificial potential function, and only upper bound on Jacobian matrix error and Cartesian dynamics parameters are needed. The existing linear PID (LPID) regulators are the special cases of it. Nevertheless, in the case of LPID regulators, only locally asymptotic stability is guaranteed if the corresponding conditions are satisfied. Simulations demonstrate the result and robustness of transpose Jacobian-based NPID regulators. © 2002 Wiley Periodicals, Inc. [source]

Regulators of G Protein Signaling

JOURNAL OF NEUROCHEMISTRY, Issue 4 2000
A Bestiary of Modular Protein Binding Domains
Abstract: Members of the newly discovered regulator of G protein signaling (RGS) families of proteins have a common RGS domain. This RGS domain is necessary for conferring upon RGS proteins the capacity to regulate negatively a variety of G, protein subunits. However, RGS proteins are more than simply negative regulators of signaling. RGS proteins can function as effector antagonists, and recent evidence suggests that RGS proteins can have positive effects on signaling as well. Many RGS proteins possess additional C- and N-terminal modular protein-binding domains and motifs. The presence of these additional modules within the RGS proteins provides for multiple novel regulatory interactions performed by these molecules. These regions are involved in conferring regulatory selectivity to specific G,-coupled signaling pathways, enhancing the efficacy of the RGS domain, and the translocation or targeting of RGS proteins to intracellular membranes. In other instances, these domains are involved in cross-talk between different G,-coupled signaling pathways and, in some cases, likely serve to integrate small GTPases with these G protein signaling pathways. This review discusses these C- and N-terminal domains and their roles in the biology of the brain-enriched RGS proteins. Methods that can be used to investigate the function of these domains are also discussed. [source]

Differential Effects of Restricted Versus Unlimited High-Fat Feeding in Rats on Fat Mass, Plasma Hormones and Brain Appetite Regulators

JOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2009
T. Shiraev
The rapid rise in obesity has been linked to altered food consumption patterns. There is increasing evidence that, in addition to total energy intake, the macronutrient composition of the diet may influence the development of obesity. The present study aimed to examine the impact of high dietary fat content, under both isocaloric and hypercaloric conditions, compared with a low fat diet, on adiposity, glucose and lipid metabolism, and brain appetite regulators in rats. Male Sprague,Dawley rats were exposed to one of three diets: control (14% fat), ad lib high-fat palatable (HFD, 35% fat) or high-fat palatable restricted (HFD-R, matched to the energy intake of control) and were killed in the fasting state 11 weeks later. Body weight was increased by 28% in unrestricted HFD fed rats, with an almost tripling of caloric intake and fat mass (P < 0.001) and double the plasma triglycerides of controls. Glucose intolerance and increased insulin levels were observed. HFD-R animals calorie matched to control had double their fat mass, plasma insulin and triglycerides (P < 0.05). Only ad lib consumption of the HFD increased the hypothalamic mRNA expression of the appetite-regulating peptides, neuropeptide Y and pro-opiomelanocortin. Although restricted consumption of palatable HFD had no significant impact on hypothalamic appetite regulators or body weight, it increased adiposity and circulating triglycerides, suggesting that the proportion of dietary fat, independent of caloric intake, affects fat deposition and the metabolic profile. [source]

A New Information Exchange System for Nursing Professionals to Enhance Patient Safety Across Europe

JOURNAL OF NURSING SCHOLARSHIP, Issue 4 2009
Dr. Alessandro Stievano RN
Abstract Purpose: Ensuring safe healthcare services is one of today's most challenging issues, especially in light of the increasing mobility of health professionals and patients. In the last few years, nursing research has contributed to the creation of a culture of safety that is an integral part of clinical care and a cornerstone of healthcare systems. Organizing Constructs: European institutions continue to discuss methods and tools that would best contribute to ensuring safe and high-quality care, as well as ensuring access to healthcare services. According to the European Commission between 8% and 12% of patients admitted to hospitals in the European Union member states suffer from adverse events while receiving care, although some of these events are part of the intrinsic risk linked to receiving care. However, most of these adverse events are caused by such avoidable healthcare errors as, for instance, diagnosis mistakes, inability to act on the results of tests, medication errors, failures of healthcare equipment and hospital infections. Nosocomial infections alone are estimated to affect 4.1 million inpatients, that is, about 1 of every 20 inpatients, causing avoidable suffering and mortality, as well as an enormous loss of financial resources (at least ,5.48 billion a year). Conclusions: The Internal Market Information (IMI) System, developed by the European Commission, aims at contributing to patient safety by means of a timely and updated exchange of information among nursing regulatory bodies on the good standing and scope of practice of their registrants. Through the IMI System, the European Federation of Nursing Regulators will improve its electronic database on nurses to allow national nursing regulatory bodies to exchange the information needed to recognize the nurses' educational and professional qualifications and competencies. This process both facilitates the mobility of professionals and ensures high-quality nursing practice in an even and consistent way across the European Union. Clinical Relevance: On a national basis, nursing regulatory bodies play an important role in ensuring patient safety through high standards of nursing education and competence, whereas on an international basis, patient safety can assured by a better exchange of information between national regulatory bodies on the good professional standing of nurses. [source]

MicroRNAs: Master Regulators of Ethanol Abuse and Toxicity?

ALCOHOLISM, Issue 4 2010
Rajesh C. Miranda
Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders. [source]

A chimeric activator of transcription that uses two DNA-binding domains to make simultaneous contact with pairs of recognition sites

MOLECULAR MICROBIOLOGY, Issue 4 2001
Robert C. Langdon
Many well-known transcriptional regulatory proteins are composed of at least two independently folding domains and, typically, only one of these is a DNA-binding domain. However, some transcriptional regulators have been described that have more than one DNA-binding domain. Regulators with a single DNA-binding domain often bind co-operatively to the DNA in homotypic or heterotypic combinations, and two or more DNA-binding domains of a single regulatory protein can also bind co-operatively to suitably positioned recognition sequences. Here, we examine the behaviour of a chimeric activator of transcription with two different DNA-binding domains, that of the bacteriophage , cI protein and that of the Escherichia coli cyclic AMP receptor protein. We show that these two DNA-binding moieties, when present in the same molecule, can bind co-operatively to a pair of cognate recognition sites located upstream of a test promoter, thereby permitting the chimera to function as a particularly strong activator of transcription from this promoter. Our results show how such a bivalent DNA-binding protein can be used to regulate transcription differentially from promoters that bear either one or both recognition sites. [source]

Current Awareness in Phytochemical Analysis

PHYTOCHEMICAL ANALYSIS, Issue 1 2008
Article first published online: 30 JAN 200
In order to keep subscribers up-to-date with the latest developments in their field, John Wiley &Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of phytochemical analysis. Each bibliography is divided into 13 sections: 1 Reviews; 2 General; 3 Nucleic Acids; 4 Amino Acids, Proteins &Enzymes; 5 Carbohydrates; 6 Lipids; 7 Secondary Products; 8 Growth Regulators; 9 Industrially-Important Products; 10 Toxins/Allergens; 11 Pigments; 12 Vitamins; 13 Others. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted. [source]

REVIEW ARTICLE: B7 Family Molecules as Regulators of the Maternal Immune System in Pregnancy

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2010
Margaret G. Petroff
Citation Petroff MG, Perchellet A. B7 family molecules as regulators of the maternal immune system in pregnancy. Am J Reprod Immunol 2010 Placental and fetal growth and development are associated with chronic exposure of the maternal immune system to fetally derived, paternally inherited antigens. Because maternal lymphocytes are aware of fetal antigens, active tolerance mechanisms are required to ensure unperturbed progression of pregnancy and delivery of a healthy newborn. These mechanisms of tolerance may include deletion, receptor downregulation, and anergy of fetal antigen-specific cells in lymphoid tissues, as well as regulation at the maternal,fetal interface by a variety of locally expressed immunoregulatory molecules. The B7 family of costimulatory molecules comprises one group of immunoregulatory molecules present in the decidua and placenta. B7 family members mediate both inhibitory and stimulatory effects on T-cell activation and effector functions and may play a critical role in maintaining tolerance to the fetus. Here, we review the known functions of the B7 family proteins in pregnancy. [source]