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Sample records for expansion mechanisms regulating

  1. Load regulating expansion fixture

    International Nuclear Information System (INIS)

    Wagner, L.M.; Strum, M.J.

    1998-01-01

    A free standing self contained device for bonding ultra thin metallic films, such as 0.001 inch beryllium foils is disclosed. The device will regulate to a predetermined load for solid state bonding when heated to a bonding temperature. The device includes a load regulating feature, whereby the expansion stresses generated for bonding are regulated and self adjusting. The load regulator comprises a pair of friction isolators with a plurality of annealed copper members located there between. The device, with the load regulator, will adjust to and maintain a stress level needed to successfully and economically complete a leak tight bond without damaging thin foils or other delicate components. 1 fig

  2. Regulation of gas infrastructure expansion

    International Nuclear Information System (INIS)

    De Joode, J.

    2012-01-01

    The topic of this dissertation is the regulation of gas infrastructure expansion in the European Union (EU). While the gas market has been liberalised, the gas infrastructure has largely remained in the regulated domain. However, not necessarily all gas infrastructure facilities - such as gas storage facilities, LNG import terminals and certain gas transmission pipelines - need to be regulated, as there may be scope for competition. In practice, the choice of regulation of gas infrastructure expansion varies among different types of gas infrastructure facilities and across EU Member States. Based on a review of economic literature and on a series of in-depth case studies, this study explains these differences in choices of regulation from differences in policy objectives, differences in local circumstances and differences in the intrinsic characteristics of the infrastructure projects. An important conclusion is that there is potential for a larger role for competition in gas infrastructure expansion.

  3. Thermal Expansion Anomaly Regulated by Entropy

    Science.gov (United States)

    Liu, Zi-Kui; Wang, Yi; Shang, Shunli

    2014-11-01

    Thermal expansion, defined as the temperature dependence of volume under constant pressure, is a common phenomenon in nature and originates from anharmonic lattice dynamics. However, it has been poorly understood how thermal expansion can show anomalies such as colossal positive, zero, or negative thermal expansion (CPTE, ZTE, or NTE), especially in quantitative terms. Here we show that changes in configurational entropy due to metastable micro(scopic)states can lead to quantitative prediction of these anomalies. We integrate the Maxwell relation, statistic mechanics, and first-principles calculations to demonstrate that when the entropy is increased by pressure, NTE occurs such as in Invar alloy (Fe3Pt, for example), silicon, ice, and water, and when the entropy is decreased dramatically by pressure, CPTE is expected such as in anti-Invar cerium, ice and water. Our findings provide a theoretic framework to understand and predict a broad range of anomalies in nature in addition to thermal expansion, which may include gigantic electrocaloric and electromechanical responses, anomalously reduced thermal conductivity, and spin distributions.

  4. Space Creation Mechanism during the Expansion of Universe

    Directory of Open Access Journals (Sweden)

    Emre Dil

    2016-01-01

    Full Text Available We propose a novel mechanism related to the expansion of universe. Recently Verlinde’s proposal has been applied to the deformed bosons being a candidate for the dark energy constituents, since the negative pressure of the deformed bosons. The expansion of universe is dependent on the dark energy and implies a creation of space; we admit that the space creation mechanism is related to the deformed bosons and so is the dark energy. In order to relate the dark energy and the mechanism for creation of space, we consider Verlinde’s proposal including the Holographic principle for emergence of space, which was recently applied to the deformed bosons. To check the validity of our mechanism, we calculate the ratio of the size of universe before and after the expansion and compare the results with the observational data. We find that the results are consistent with each other and infer that the proposed mechanism works correctly.

  5. Effect of high thermal expansion glass infiltration on mechanical ...

    Indian Academy of Sciences (India)

    This work studies the effect on the mechanical properties of alumina-10 wt% zirconia (3 mol% yttria stabilized) composite by infiltrating glass of a higher thermal expansion (soda lime glass) on the surface at high temperature. The glass improved the strength of composite at room temperature as well as at high temperature.

  6. ERK Regulates Renal Cell Proliferation and Renal Cyst Expansion in inv Mutant Mice

    International Nuclear Information System (INIS)

    Okumura, Yasuko; Sugiyama, Noriyuki; Tanimura, Susumu; Nishida, Masashi; Hamaoka, Kenji; Kohno, Michiaki; Yokoyama, Takahiko

    2009-01-01

    Nephronophthisis (NPHP) is the most frequent genetic cause of end-stage kidney disease in children and young adults. Inv mice are a model for human nephronophthisis type 2 (NPHP2) and characterized by multiple renal cysts and situs inversus. Renal epithelial cells in inv cystic kidneys show increased cell proliferation. We studied the ERK pathway to understand the mechanisms that induce cell proliferation and renal cyst progression in inv kidneys. We studied the effects of ERK suppression by administering PD184352, an oral mitogen-activated protein kinase kinase (MEK) inhibitor on renal cyst expansion, extracellular signal-regulated protein kinase (ERK) activity, bromo-deoxyuridine (BrdU) incorporation and expression of cell-cycle regulators in invΔC kidneys. Phosphorylated ERK (p-ERK) level increased along with renal cyst enlargement. Cell-cycle regulators showed a high level of expression in invΔC kidneys. PD184352 successfully decreased p-ERK level and inhibited renal cyst enlargement. The inhibitor also decreased expression of cell-cycle regulators and BrdU incorporation in renal epithelial cells. The present results showed that ERK regulated renal cell proliferation and cyst expansion in inv mutants

  7. Molecular Mechanisms of Appetite Regulation

    Directory of Open Access Journals (Sweden)

    Ji Hee Yu

    2012-12-01

    Full Text Available The prevalence of obesity has been rapidly increasing worldwide over the last several decades and has become a major health problem in developed countries. The brain, especially the hypothalamus, plays a key role in the control of food intake by sensing metabolic signals from peripheral organs and modulating feeding behaviors. To accomplish these important roles, the hypothalamus communicates with other brain areas such as the brainstem and reward-related limbic pathways. The adipocyte-derived hormone leptin and pancreatic β-cell-derived insulin inform adiposity to the hypothalamus. Gut hormones such as cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1, and oxyntomodulin transfer satiety signals to the brain and ghrelin relays hunger signals. The endocannabinoid system and nutrients are also involved in the physiological regulation of food intake. In this article, we briefly review physiological mechanisms of appetite regulation.

  8. Mechanism of actuation in conducting polymers: Osmotic expansion

    DEFF Research Database (Denmark)

    Bay, Lasse; Jacobsen, Torben; West, Keld

    2001-01-01

    Conducting polymers expand or contract when their redox state is changed. This expansion/contraction effect can be separated in an intrinsic part because of changes of the polymer backbone on reduction/oxidation and a part depending on the surrounding electrolyte phase, because of osmotic expansion...... is compared with measurements on PPy(DBS) films. The experiments show that the expansion decreases as the electrolyte concentration is increased. This means that a considerable part of the total expansion is due to the osmotic effect. The osmotic effect should be taken into account when interpreting...

  9. On distributive effects of optimal regulation for power grid expansion

    International Nuclear Information System (INIS)

    Herrera, Luis Ángel; Rosellón, Juan

    2014-01-01

    To date, the distributive implications of incentive regulation on electricity transmission networks have not been explicitly studied in the literature. More specifically, the parameters that a regulator might use to achieve distributive efficiency under price-cap regulation have not yet been identified. To discern these parameters is the motivation for the research presented in this paper. We study how different weight parameters affect the distributive characteristics of optimal price-cap incentive regulation for electricity transmission. We find that a regulator's use of ideal (Laspeyres) weights tends to be more beneficial for the Transco (consumers) than for consumers (the Transco). - Highlights: • Distributive implications of incentive regulation on transmission networks have not been studied in the literature. • The parameters that a regulator might use to achieve distributive efficiency have so far not been explicitly analyzed. • Analyze how different weights affect the distributive characteristics of price-cap regulation in electricity transmission. • Results: ideal (Laspeyres) weights tend to be more beneficial for the Transco (consumers) than for consumers (the Transco)

  10. Light-regulated leaf expansion in two Populus species: dependence on developmentally controlled ion transport.

    Science.gov (United States)

    Stiles, Kari A; Van Volkenburgh, Elizabeth

    2002-07-01

    Leaf growth responses to light have been compared in two species of Populus, P. deltoides and P. trichocarpa. These species differ markedly in morphology, anatomy, and dependence on light during leaf expansion. Light stimulates the growth rate and acidification of cell walls in P. trichocarpa but not in P. deltoides, whereas leaves of P. deltoides maintain growth in the dark. Light-induced growth is promoted in P. deltoides when cells are provided 50-100 mM KCl. In both species, light initially depolarizes, then hyperpolarizes mesophyll plasma membranes. However, in the dark, the resting E(m) of mesophyll cells in P. deltoides, but not in P. trichocarpa, is relatively insensitive to decade changes in external [K+]. Results suggest that light-stimulated leaf growth depends on developmentally regulated cellular mechanisms controlling ion fluxes across the plasma membrane. These developmental differences underlie species-level differences in growth and physiological responses to the photoenvironment.

  11. Student understanding of Taylor series expansions in statistical mechanics

    Directory of Open Access Journals (Sweden)

    Trevor I. Smith

    2013-08-01

    Full Text Available One goal of physics instruction is to have students learn to make physical meaning of specific mathematical expressions, concepts, and procedures in different physical settings. As part of research investigating student learning in statistical physics, we are developing curriculum materials that guide students through a derivation of the Boltzmann factor using a Taylor series expansion of entropy. Using results from written surveys, classroom observations, and both individual think-aloud and teaching interviews, we present evidence that many students can recognize and interpret series expansions, but they often lack fluency in creating and using a Taylor series appropriately, despite previous exposures in both calculus and physics courses.

  12. Student understanding of Taylor series expansions in statistical mechanics

    Science.gov (United States)

    Smith, Trevor I.; Thompson, John R.; Mountcastle, Donald B.

    2013-12-01

    One goal of physics instruction is to have students learn to make physical meaning of specific mathematical expressions, concepts, and procedures in different physical settings. As part of research investigating student learning in statistical physics, we are developing curriculum materials that guide students through a derivation of the Boltzmann factor using a Taylor series expansion of entropy. Using results from written surveys, classroom observations, and both individual think-aloud and teaching interviews, we present evidence that many students can recognize and interpret series expansions, but they often lack fluency in creating and using a Taylor series appropriately, despite previous exposures in both calculus and physics courses.

  13. Asymptotic expansions of Mathieu functions in wave mechanics

    International Nuclear Information System (INIS)

    Hunter, G.; Kuriyan, M.

    1976-01-01

    Solutions of the radial Schroedinger equation containing a polarization potential r -4 are expanded in a form appropriate for large values of r. These expansions of the Mathieu functions are used in association with the numerical solution of the Schroedinger equation to impose the asymptotic boundary condition in the case of bound states, and to extract phase shifts in the case of scattering states

  14. Atypical PKC-iota Controls Stem Cell Expansion via Regulation of the Notch Pathway

    Directory of Open Access Journals (Sweden)

    In Kyoung Mah

    2015-11-01

    Full Text Available The number of stem/progenitor cells available can profoundly impact tissue homeostasis and the response to injury or disease. Here, we propose that an atypical PKC, Prkci, is a key player in regulating the switch from an expansion to a differentiation/maintenance phase via regulation of Notch, thus linking the polarity pathway with the control of stem cell self-renewal. Prkci is known to influence symmetric cell division in invertebrates; however a definitive role in mammals has not yet emerged. Using a genetic approach, we find that loss of Prkci results in a marked increase in the number of various stem/progenitor cells. The mechanism used likely involves inactivation and symmetric localization of NUMB, leading to the activation of NOTCH1 and its downstream effectors. Inhibition of atypical PKCs may be useful for boosting the production of pluripotent stem cells, multipotent stem cells, or possibly even primordial germ cells by promoting the stem cell/progenitor fate.

  15. An incentive mechanism for electricity transmission expansion in Mexico

    International Nuclear Information System (INIS)

    Rosellon, Juan

    2007-01-01

    This study proposes an incentive regulatory framework for expanding electricity transmission in Mexico. A two-part pricing model is implemented within a combined merchant-regulatory structure. Three cases are considered. In the first, a monopolist with 'postage stamp tariffs' serves the whole country using uniform prices. In the second case, one firm holds a regional monopoly in each of the five electricity areas. In the third, a monopolist operates in all areas of the national electricity system and discriminates in the prices it charges in each of the regions. This approach is described and then applied to the Mexican electricity transmission network. Using real data, the study compares all three cases in terms of profits, capacity increases, and network expansion. The results are found to depend on two effects: the 'economies-of-scale effect', in which the maximum level is reached with a single network; and the 'discriminatory effect' that results when a firm can discriminate among types of consumers. The economies-of-scale effect produces greater capacity and network expansion, whereas the discriminatory effect increases profits

  16. An incentive mechanism for electricity transmission expansion in Mexico

    Energy Technology Data Exchange (ETDEWEB)

    Rosellon, Juan [Division de Economia, Centro de Investigacion y Docencia Economicas (CIDE), Carret. Mexico-Toluca 3655, Lomas de Santa Fe, C.P. 01210, Mexico DF (Mexico)

    2007-05-15

    This study proposes an incentive regulatory framework for expanding electricity transmission in Mexico. A two-part pricing model is implemented within a combined merchant-regulatory structure. Three cases are considered. In the first, a monopolist with ''postage stamp tariffs'' serves the whole country using uniform prices. In the second case, one firm holds a regional monopoly in each of the five electricity areas. In the third, a monopolist operates in all areas of the national electricity system and discriminates in the prices it charges in each of the regions. This approach is described and then applied to the Mexican electricity transmission network. Using real data, the study compares all three cases in terms of profits, capacity increases, and network expansion. The results are found to depend on two effects: the ''economies-of-scale effect'', in which the maximum level is reached with a single network; and the ''discriminatory effect'' that results when a firm can discriminate among types of consumers. The economies-of-scale effect produces greater capacity and network expansion, whereas the discriminatory effect increases profits. (author)

  17. High-tension electricity network expansions in Argentina: decision mechanisms and willingness-to-pay revelation

    International Nuclear Information System (INIS)

    Chisari, O.O.; Dal-Bo, P.; Romero, C.A.

    2001-01-01

    This paper describes the procedures established by the present regulation for high-tension network expansions, studies its optimality and points its main problems. According to the present regulatory scheme, the decision to expand the high-tension network system is on the hands of the private sector. A simple model of the Argentine electricity system and its regulation allowed the simulation of cases in which the present 'Public Contest' method could result in the rejection of socially desirable projects and the acceptance of undesirable ones. Three main reasons for the existence of wrong incentives to investment are found. First, since consumers are not included in the mechanism, they have no way to reveal their willingness-to-pay for the investment. Second, the approximation of the future use of the line is done in such a way that it leaves important nodes under represented, thereby affecting the optimality of the mechanism. Third, the profit agents obtain from a line may not be related to their use, e.g. the generators profits depend also on generation costs

  18. High-tension electricity network expansions in Argentina: decision mechanisms and willingness-to-pay revelation

    Energy Technology Data Exchange (ETDEWEB)

    Chisari, O.O. [Departamento de Economia y Finanzas, Universidad Argentina de la Empresa, Chile 1142 lo piso, 1073 Buenos Aires (Argentina); Dal-Bo, P. [Department of Economics, University of California, Los Angeles, CA (United States); Romero, C.A. [Departamento de Economia y Finanzas and Centro de Estudios Economicos de la Regulacion, Universidad Argentina de la Empresa, Buenos Aires (Argentina)

    2001-11-01

    This paper describes the procedures established by the present regulation for high-tension network expansions, studies its optimality and points its main problems. According to the present regulatory scheme, the decision to expand the high-tension network system is on the hands of the private sector. A simple model of the Argentine electricity system and its regulation allowed the simulation of cases in which the present 'Public Contest' method could result in the rejection of socially desirable projects and the acceptance of undesirable ones. Three main reasons for the existence of wrong incentives to investment are found. First, since consumers are not included in the mechanism, they have no way to reveal their willingness-to-pay for the investment. Second, the approximation of the future use of the line is done in such a way that it leaves important nodes under represented, thereby affecting the optimality of the mechanism. Third, the profit agents obtain from a line may not be related to their use, e.g. the generators profits depend also on generation costs.

  19. Multiple sclerosis : Mechanisms of myelin phagocytosis and lesion expansion

    NARCIS (Netherlands)

    Hendrickx, D.A.E.

    2018-01-01

    Multiple sclerosis (MS) is characterized by immune activation and focal demyelination in the central nervous system. The aim of this thesis was to gain more insight into the mechanisms of myelin phagocytosis by resident microglia and infiltrating macrophages. We first evaluated the expression of the

  20. Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass

    Directory of Open Access Journals (Sweden)

    Vivas Yurena

    2011-12-01

    Full Text Available Abstract Background The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion Results Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell. Conclusions Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

  1. Mechanism of economic regulation of land relations

    OpenAIRE

    Mykhaylo Stupen'; Svitlana Rogach; Ivan Riy

    2015-01-01

    In the article the mechanism of economic regulation of land relations is revealed. The main functions of the economic evaluation of land resources are: registration of land resources and environment; choices of resources and conditions usage. The author proves that the proper economic regulation needs governmental support which is to preserve the land as a natural resource.

  2. Regulative mechanisms of chondrocyte adhesion

    DEFF Research Database (Denmark)

    Schmal, Hagen; Mehlhorn, Alexander T; Fehrenbach, Miriam

    2006-01-01

    Interaction between chondrocytes and extracellular matrix is considered a key factor in the generation of grafts for matrix-associated chondrocyte transplantation. Therefore, our objective was to study the influence of differentiation status on cellular attachment. Adhesion of chondrocytes...... to collagen type II increased after removal from native cartilage up to the third day in monolayer in a dose-dependent manner. Following dedifferentiation after the second passage, adhesion to collagen types I (-84%) and II (-46%) decreased, whereas adhesion to fibrinogen (+59%) and fibronectin (+43......%) increased. A cartilage construct was developed based on a clinically established collagen type I scaffold. In this matrix, more than 80% of the cells could be immobilized by mechanisms of adhesion, filtration, and cell entrapment. Confocal laser microscopy revealed focal adhesion sites as points of cell...

  3. Differential response of cell-cycle and cell-expansion regulators to heat stress in apple (Malus domestica) fruitlets.

    Science.gov (United States)

    Flaishman, Moshe A; Peles, Yuval; Dahan, Yardena; Milo-Cochavi, Shira; Frieman, Aviad; Naor, Amos

    2015-04-01

    Temperature is one of the most significant factors affecting physiological and biochemical aspects of fruit development. Current and progressing global warming is expected to change climate in the traditional deciduous fruit tree cultivation regions. In this study, 'Golden Delicious' trees, grown in a controlled environment or commercial orchard, were exposed to different periods of heat treatment. Early fruitlet development was documented by evaluating cell number, cell size and fruit diameter for 5-70 days after full bloom. Normal activities of molecular developmental and growth processes in apple fruitlets were disrupted under daytime air temperatures of 29°C and higher as a result of significant temporary declines in cell-production and cell-expansion rates, respectively. Expression screening of selected cell cycle and cell expansion genes revealed the influence of high temperature on genetic regulation of apple fruitlet development. Several core cell-cycle and cell-expansion genes were differentially expressed under high temperatures. While expression levels of B-type cyclin-dependent kinases and A- and B-type cyclins declined moderately in response to elevated temperatures, expression of several cell-cycle inhibitors, such as Mdwee1, Mdrbr and Mdkrps was sharply enhanced as the temperature rose, blocking the cell-cycle cascade at the G1/S and G2/M transition points. Moreover, expression of several expansin genes was associated with high temperatures, making them potentially useful as molecular platforms to enhance cell-expansion processes under high-temperature regimes. Understanding the molecular mechanisms of heat tolerance associated with genes controlling cell cycle and cell expansion may lead to the development of novel strategies for improving apple fruit productivity under global warming. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Dynein-Based Accumulation of Membranes Regulates Nuclear Expansion in Xenopus laevis Egg Extracts.

    Science.gov (United States)

    Hara, Yuki; Merten, Christoph A

    2015-06-08

    Nuclear size changes dynamically during development and has long been observed to correlate with the space surrounding the nucleus, as well as with the volume of the cell. Here we combine an in vitro cell-free system of Xenopus laevis egg extract with microfluidic devices to systematically analyze the effect of spatial constraints. The speed of nuclear expansion depended on the available space surrounding the nucleus up to a threshold volume in the nanoliter range, herein referred to as the nuclear domain. Under spatial constraints smaller than this nuclear domain, the size of microtubule-occupied space surrounding the nucleus turned out to be limiting for the accumulation of membranes around the nucleus via the motor protein dynein, therefore determining the speed of nuclear expansion. This mechanism explains how spatial information surrounding the nucleus, such as the positioning of the nucleus inside the cell, can control nuclear expansion. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Mechanical feedback coordinates cell wall expansion and assembly in yeast mating morphogenesis

    Science.gov (United States)

    2018-01-01

    The shaping of individual cells requires a tight coordination of cell mechanics and growth. However, it is unclear how information about the mechanical state of the wall is relayed to the molecular processes building it, thereby enabling the coordination of cell wall expansion and assembly during morphogenesis. Combining theoretical and experimental approaches, we show that a mechanical feedback coordinating cell wall assembly and expansion is essential to sustain mating projection growth in budding yeast (Saccharomyces cerevisiae). Our theoretical results indicate that the mechanical feedback provided by the Cell Wall Integrity pathway, with cell wall stress sensors Wsc1 and Mid2 increasingly activating membrane-localized cell wall synthases Fks1/2 upon faster cell wall expansion, stabilizes mating projection growth without affecting cell shape. Experimental perturbation of the osmotic pressure and cell wall mechanics, as well as compromising the mechanical feedback through genetic deletion of the stress sensors, leads to cellular phenotypes that support the theoretical predictions. Our results indicate that while the existence of mechanical feedback is essential to stabilize mating projection growth, the shape and size of the cell are insensitive to the feedback. PMID:29346368

  6. The possibility of clean development mechanism in a nuclear power expansion in Brazil

    International Nuclear Information System (INIS)

    Paris, Alexandre G.; Oliveira, Wagner S.

    2009-01-01

    The nuclear power expansion is a very controversial topic in Brazil, which needs to be carefully addressed, especially because the national energy supply system is becoming more carbon-intensive. Although most of the electricity generated in Brazil is by hydropower plants, the country's electricity matrix expansion is moving towards a larger participation of fossil fuel thermo power generation which is contrarily the global objects of climate change mitigation. Climate change is a reality and the choice facing this problem is between action and delay. There will be needed a huge international mobilization, associated with a great amount of financial, political and engineering resources interested for preventing the aggravation of the greenhouse effect. This article analyses, in the possibility of including nuclear power in the Clean Development Mechanism (CDM) criteria, the revenue that could be generated from the trading of Certified Emission Reduction (CER) in different scenarios of nuclear power expansion in Brazil. (author)

  7. Expansion mechanisms for indigenously developed horizontal honing machines (Paper No. 06)

    International Nuclear Information System (INIS)

    Murthy, G.S.K.; Devarajan, N.

    1987-02-01

    Coolant channel components for nuclear reactors require scratch free and smooth interior surfaces in addition to control on size. This calls for finish machining by honing process. At the time when these were required to be made, there were no manufacturers in India who were making honing machines especially of horizontal type. In order to meet this requirement, Central Workshops of Bhabha Atomic Research Centre developed and manufactured two horizontal honing machines which can handle tubes upto three metres in length. One of the machines has been so made to accommodate jobs upto six metres in length. Stone expansion mechanisms used in these machines were of automatic hydraulic type combined with a mechanical expansion device. Details of these mechanisms have been discussed in this paper. (author). 3 figs

  8. Mechanisms regulating skin immunity and inflammation.

    Science.gov (United States)

    Pasparakis, Manolis; Haase, Ingo; Nestle, Frank O

    2014-05-01

    Immune responses in the skin are important for host defence against pathogenic microorganisms. However, dysregulated immune reactions can cause chronic inflammatory skin diseases. Extensive crosstalk between the different cellular and microbial components of the skin regulates local immune responses to ensure efficient host defence, to maintain and restore homeostasis, and to prevent chronic disease. In this Review, we discuss recent findings that highlight the complex regulatory networks that control skin immunity, and we provide new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation.

  9. Regulation Mechanism of HBV cccDNA

    Directory of Open Access Journals (Sweden)

    Cheng Jun

    2012-06-01

    Full Text Available Covalently closed circular (ccc DNA of hepatitis B virus (HBV existed in the nuclei of HBV infected hepatocytes with a half-life time of 14.3 years in a mathematic model. Viral protein feedback regulation in HBV life cycle to maintain vital viral replication is an important mechanism. Interleukin-6, epithelial growth factor, heme oxygenase-1, histones, and hepatocyte nuclear factors are demonstrated as the key regulators for HBV life cycle. CpG island structure and methylation status are involved in the regulation of HBV DNA replication. Nucleos(tide analogues are widely used in the clinical practice for the treatment of chronic hepatitis B patients, although no evidence indicating a direct inhibiton of HBV cccDNA. In the future, along with the study of HBV life cycle, new drugs including RNA interference technique, will pave the way to eliminate the HBV cccDNA from infected hepatocytes resulting final cure of chronic hepatitis B.

  10. Some exactly solvable models in quantum mechanics and the low energy expansions

    International Nuclear Information System (INIS)

    Albeverio, S.; Hoeegh-Krohn, R.; Holden, H.; Gesztesy, F.

    We give an overview of recent results on exactly solvable models in quantum mechanics. In particular we discuss point interactions located at finitely or infinitely many centers, in one and three dimensions. Results about the resolvent, energy eigenvalues and resonances, scattering quantitites as well as eigenfunctions and corresponding low energy expansions are mentioned, with particular attention to the case of three-dimensional crystals. (orig.)

  11. Evolution of context dependent regulation by expansion of feast/famine regulatory proteins.

    Science.gov (United States)

    Plaisier, Christopher L; Lo, Fang-Yin; Ashworth, Justin; Brooks, Aaron N; Beer, Karlyn D; Kaur, Amardeep; Pan, Min; Reiss, David J; Facciotti, Marc T; Baliga, Nitin S

    2014-11-14

    Expansion of transcription factors is believed to have played a crucial role in evolution of all organisms by enabling them to deal with dynamic environments and colonize new environments. We investigated how the expansion of the Feast/Famine Regulatory Protein (FFRP) or Lrp-like proteins into an eight-member family in Halobacterium salinarum NRC-1 has aided in niche-adaptation of this archaeon to a complex and dynamically changing hypersaline environment. We mapped genome-wide binding locations for all eight FFRPs, investigated their preference for binding different effector molecules, and identified the contexts in which they act by analyzing transcriptional responses across 35 growth conditions that mimic different environmental and nutritional conditions this organism is likely to encounter in the wild. Integrative analysis of these data constructed an FFRP regulatory network with conditionally active states that reveal how interrelated variations in DNA-binding domains, effector-molecule preferences, and binding sites in target gene promoters have tuned the functions of each FFRP to the environments in which they act. We demonstrate how conditional regulation of similar genes by two FFRPs, AsnC (an activator) and VNG1237C (a repressor), have striking environment-specific fitness consequences for oxidative stress management and growth, respectively. This study provides a systems perspective into the evolutionary process by which gene duplication within a transcription factor family contributes to environment-specific adaptation of an organism.

  12. Ring-Expansion/Contraction Radical Crossover Reactions of Cyclic Alkoxyamines: A Mechanism for Ring Expansion-Controlled Radical Polymerization

    Directory of Open Access Journals (Sweden)

    Atsushi Narumi

    2018-06-01

    Full Text Available Macrocyclic polymers present an important class of macromolecules, displaying the reduced radius of gyration or impossibility to entangle. A rare approach for their synthesis is the ring expansion-controlled radical “vinyl” polymerization, starting from a cyclic alkoxyamine. We here describe ring-expansion radical crossover reactions of cyclic alkoxyamines which run in parallel to chain-propagation reactions in the polymerization system. The radical crossover reactions extensively occurred at 105–125 °C, eventually producing high molecular weight polymers with multiple inherent dynamic covalent bonds (NOC bonds. A subsequent ring-contraction radical crossover reaction and the second ring-expansion radical crossover reaction are also described. The major products for the respective three stages were shown to possess cyclic morphologies by the molecular weight profiles and the residual ratios for the NOC bonds (φ in %. In particular, the high φ values ranging from ca. 80% to 98% were achieved for this cyclic alkoxyamine system. This result verifies the high availability of this system as a tool demonstrating the ring-expansion “vinyl” polymerization that allows them to produce macrocyclic polymers via a one-step vinyl polymerization.

  13. Uniaxial Negative Thermal Expansion and Mechanical Properties of a Zinc-Formate Framework

    Directory of Open Access Journals (Sweden)

    Hongqiang Gao

    2017-02-01

    Full Text Available The thermal expansion behavior of a metal-formate framework, Zn(HCOO2·2(H2O (1, has been systematically studied via variable temperature single-crystal X-ray diffraction. Our results demonstrate that this formate exhibits significant negative thermal expansion (NTE, −26(2 MK−1 along its c-axis. Detailed structural analyses reveal that the large NTE response is attributed to the ‘hinge-strut’ like framework motion. In addition, the fundamental mechanical properties of framework 1 have been explored via nanoindentation experiments. The measured elastic modulus and hardness properties on the (00-2/(100/(110 facets are 35.5/35.0/27.1 and 2.04/1.83/0.47 GPa, respectively. The stiffness and hardness anisotropy can be correlated well with the underlying framework structure, like its thermoelastic behavior.

  14. Mechanical homeostasis regulating adipose tissue volume

    Directory of Open Access Journals (Sweden)

    Svedman Paul

    2007-09-01

    Full Text Available Abstract Background The total body adipose tissue volume is regulated by hormonal, nutritional, paracrine, neuronal and genetic control signals, as well as components of cell-cell or cell-matrix interactions. There are no known locally acting homeostatic mechanisms by which growing adipose tissue might adapt its volume. Presentation of the hypothesis Mechanosensitivity has been demonstrated by mesenchymal cells in tissue culture. Adipocyte differentiation has been shown to be inhibited by stretching in vitro, and a pathway for the response has been elucidated. In humans, intermittent stretching of skin for reconstructional purposes leads to thinning of adipose tissue and thickening of epidermis – findings matching those observed in vitro in response to mechanical stimuli. Furthermore, protracted suspension of one leg increases the intermuscular adipose tissue volume of the limb. These findings may indicate a local homeostatic adipose tissue volume-regulating mechanism based on movement-induced reduction of adipocyte differentiation. This function might, during evolution, have been of importance in confined spaces, where overgrowth of adipose tissue could lead to functional disturbance, as for instance in the turtle. In humans, adipose tissue near muscle might in particular be affected, for instance intermuscularly, extraperitoneally and epicardially. Mechanical homeostasis might also contribute to protracted maintainment of soft tissue shape in the face and neck region. Testing of the hypothesis Assessment of messenger RNA-expression of human adipocytes following activity in adjacent muscle is planned, and study of biochemical and volumetric adipose tissue changes in man are proposed. Implications of the hypothesis The interpretation of metabolic disturbances by means of adipose tissue might be influenced. Possible applications in the head and neck were discussed.

  15. Molecular biological mechanism II. Molecular mechanisms of cell cycle regulation

    International Nuclear Information System (INIS)

    Jung, T.

    2000-01-01

    The cell cycle in eukaryotes is regulated by central cell cycle controlling protein kinase complexes. These protein kinase complexes consist of a catalytic subunit from the cyclin-dependent protein kinase family (CDK), and a regulatory subunit from the cyclin family. Cyclins are characterised by their periodic cell cycle related synthesis and destruction. Each cell cycle phase is characterised by a specific set of CDKs and cyclins. The activity of CDK/cyclin complexes is mainly regulated on four levels. It is controlled by specific phosphorylation steps, the synthesis and destruction of cyclins, the binding of specific inhibitor proteins, and by active control of their intracellular localisation. At several critical points within the cell cycle, named checkpoints, the integrity of the cellular genome is monitored. If damage to the genome or an unfinished prior cell cycle phase is detected, the cell cycle progression is stopped. These cell cycle blocks are of great importance to secure survival of cells. Their primary importance is to prevent the manifestation and heritable passage of a mutated genome to daughter cells. Damage sensing, DNA repair, cell cycle control and apoptosis are closely linked cellular defence mechanisms to secure genome integrity. Disregulation in one of these defence mechanisms are potentially correlated with an increased cancer risk and therefore in at least some cases with an increased radiation sensitivity. (orig.) [de

  16. High Density Polyethylene Composites Reinforced with Hybrid Inorganic Fillers: Morphology, Mechanical and Thermal Expansion Performance

    Directory of Open Access Journals (Sweden)

    Birm-June Kim

    2013-09-01

    Full Text Available The effect of individual and combined talc and glass fibers (GFs on mechanical and thermal expansion performance of the filled high density polyethylene (HDPE composites was studied. Several published models were adapted to fit the measured tensile modulus and strength of various composite systems. It was shown that the use of silane-modified GFs had a much larger effect in improving mechanical properties and in reducing linear coefficient of thermal expansion (LCTE values of filled composites, compared with the use of un-modified talc particles due to enhanced bonding to the matrix, larger aspect ratio, and fiber alignment for GFs. Mechanical properties and LCTE values of composites with combined talc and GF fillers varied with talc and GF ratio at a given total filler loading level. The use of a larger portion of GFs in the mix can lead to better composite performance, while the use of talc can help lower the composite costs and increase its recyclability. The use of 30 wt % combined filler seems necessary to control LCTE values of filled HDPE in the data value range generally reported for commercial wood plastic composites. Tensile modulus for talc-filled composite can be predicted with rule of mixture, while a PPA-based model can be used to predict the modulus and strength of GF-filled composites.

  17. High Density Polyethylene Composites Reinforced with Hybrid Inorganic Fillers: Morphology, Mechanical and Thermal Expansion Performance.

    Science.gov (United States)

    Huang, Runzhou; Xu, Xinwu; Lee, Sunyoung; Zhang, Yang; Kim, Birm-June; Wu, Qinglin

    2013-09-17

    The effect of individual and combined talc and glass fibers (GFs) on mechanical and thermal expansion performance of the filled high density polyethylene (HDPE) composites was studied. Several published models were adapted to fit the measured tensile modulus and strength of various composite systems. It was shown that the use of silane-modified GFs had a much larger effect in improving mechanical properties and in reducing linear coefficient of thermal expansion (LCTE) values of filled composites, compared with the use of un-modified talc particles due to enhanced bonding to the matrix, larger aspect ratio, and fiber alignment for GFs. Mechanical properties and LCTE values of composites with combined talc and GF fillers varied with talc and GF ratio at a given total filler loading level. The use of a larger portion of GFs in the mix can lead to better composite performance, while the use of talc can help lower the composite costs and increase its recyclability. The use of 30 wt % combined filler seems necessary to control LCTE values of filled HDPE in the data value range generally reported for commercial wood plastic composites. Tensile modulus for talc-filled composite can be predicted with rule of mixture, while a PPA-based model can be used to predict the modulus and strength of GF-filled composites.

  18. HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

    Science.gov (United States)

    Hong, Peng; Chen, Kang; Huang, Bihui; Liu, Min; Cui, Miao; Rozenberg, Inna; Chaqour, Brahim; Pan, Xiaoyue; Barton, Elisabeth R.; Jiang, Xian-Cheng; Siddiqui, M.A.Q.

    2012-01-01

    The native capacity of adult skeletal muscles to regenerate is vital to the recovery from physical injuries and dystrophic diseases. Currently, the development of therapeutic interventions has been hindered by the complex regulatory network underlying the process of muscle regeneration. Using a mouse model of skeletal muscle regeneration after injury, we identified hexamethylene bisacetamide inducible 1 (HEXIM1, also referred to as CLP-1), the inhibitory component of the positive transcription elongation factor b (P-TEFb) complex, as a pivotal regulator of skeletal muscle regeneration. Hexim1-haplodeficient muscles exhibited greater mass and preserved function compared with those of WT muscles after injury, as a result of enhanced expansion of satellite cells. Transplanted Hexim1-haplodeficient satellite cells expanded and improved muscle regeneration more effectively than WT satellite cells. Conversely, HEXIM1 overexpression restrained satellite cell proliferation and impeded muscle regeneration. Mechanistically, dissociation of HEXIM1 from P-TEFb and subsequent activation of P-TEFb are required for satellite cell proliferation and the prevention of early myogenic differentiation. These findings suggest a crucial role for the HEXIM1/P-TEFb pathway in the regulation of satellite cell–mediated muscle regeneration and identify HEXIM1 as a potential therapeutic target for degenerative muscular diseases. PMID:23023707

  19. The local quantum-mechanical stress tensor in Thomas-Fermi approximation and gradient expansion method

    International Nuclear Information System (INIS)

    Kaschner, R.; Graefenstein, J.; Ziesche, P.

    1988-12-01

    From the local momentum balance using density functional theory an expression for the local quantum-mechanical stress tensor (or stress field) σ(r) of non-relativistic Coulomb systems is found out within the Thomas-Fermi approximation and its generalizations including gradient expansion method. As an illustration the stress field σ(r) is calculated for the jellium model of the interface K-Cs, containing especially the adhesive force between the two half-space jellia. (author). 23 refs, 1 fig

  20. The Tec kinase ITK regulates thymic expansion, emigration, and maturation of γδ NKT cells.

    Science.gov (United States)

    Yin, Catherine C; Cho, Ok Hyun; Sylvia, Katelyn E; Narayan, Kavitha; Prince, Amanda L; Evans, John W; Kang, Joonsoo; Berg, Leslie J

    2013-03-15

    The Tec family tyrosine kinase, Itk, regulates signaling downstream of the TCR. The absence of Itk in CD4(+) T cells results in impaired Th2 responses along with defects in maturation, cytokine production, and survival of iNKT cells. Paradoxically, Itk(-/-) mice have spontaneously elevated serum IgE levels, resulting from an expansion of the Vγ1.1(+)Vδ6.3(+) subset of γδ T cells, known as γδ NKT cells. Comparisons between γδ NKT cells and αβ iNKT cells showed convergence in the pattern of cell surface marker expression, cytokine profiles, and gene expression, suggesting that these two subsets of NKT cells undergo similar differentiation programs. Hepatic γδ NKT cells have an invariant TCR and are derived predominantly from fetal progenitors that expand in the thymus during the first weeks of life. The adult thymus contains these invariant γδ NKT cells plus a heterogeneous population of Vγ1.1(+)Vδ6.3(+) T cells with diverse CDR3 sequences. This latter population, normally excluded from the liver, escapes the thymus and homes to the liver when Itk is absent. In addition, Itk(-/-) γδ NKT cells persistently express high levels of Zbtb16 (PLZF) and Il4, genes that are normally downregulated in the most mature subsets of NKT cells. These data indicate that Itk signaling is required to prevent the expansion of γδ NKT cells in the adult thymus, to block their emigration, and to promote terminal NKT cell maturation.

  1. Research Resource: A Dual Proteomic Approach Identifies Regulated Islet Proteins During β-Cell Mass Expansion In Vivo

    DEFF Research Database (Denmark)

    Horn, Signe; Kirkegaard, Jeannette S.; Hoelper, Soraya

    2016-01-01

    to be up regulated as a response to pregnancy. These included several proteins, not previously associated with pregnancy-induced islet expansion, such as CLIC1, STMN1, MCM6, PPIB, NEDD4, and HLTF. Confirming the validity of our approach, we also identified proteins encoded by genes known to be associated...

  2. TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells.

    Science.gov (United States)

    Tsagaratou, Ageliki; González-Avalos, Edahí; Rautio, Sini; Scott-Browne, James P; Togher, Susan; Pastor, William A; Rothenberg, Ellen V; Chavez, Lukas; Lähdesmäki, Harri; Rao, Anjana

    2017-01-01

    TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4 + CD8 + double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR).

  3. Chemical and mechanical changes during leaf expansion of four woody species of dry Restinga woodland.

    Science.gov (United States)

    Schlindwein, C C D; Fett-Neto, A G; Dillenburg, L R

    2006-07-01

    Young leaves are preferential targets for herbivores, and plants have developed different strategies to protect them. This study aimed to evaluate different leaf attributes of presumed relevance in protection against herbivory in four woody species (Erythroxylum argentinum, Lithrea brasiliensis, Myrciaria cuspidata, and Myrsine umbellata), growing in a dry restinga woodland in southern Brazil. Evaluation of leaf parameters was made through single-point sampling of leaves (leaf mass per area and leaf contents of nitrogen, carbon, and pigments) at three developmental stages and through time-course sampling of expanding leaves (area and strength). Leaves of M. umbellata showed the highest leaf mass per area (LMA), the largest area, and the longest expansion period. On the other extreme, Myrc. cuspidata had the smallest LMA and leaf size, and the shortest expansion period. Similarly to L. brasiliensis, it displayed red young leaves. None of the species showed delayed-greening, which might be related to the high-irradiance growth conditions. Nitrogen contents reduced with leaf maturity and reached the highest values in the young leaves of E. argentinum and Myrc. cuspidata and the lowest in M. umbellata. Each species seems to present a different set of protective attributes during leaf expansion. Myrciaria cuspidata appears to rely mostly on chemical defences to protect its soft leaves, and anthocyanins might play this role at leaf youth, while M. umbellata seems to invest more on mechanical defences, even at early stages of leaf growth, as well as on a low allocation of nitrogen to the leaves. The other species display intermediate characteristics.

  4. A non-uniform expansion mechanical safety model of the stent.

    Science.gov (United States)

    Yang, J; Huang, N; Du, Q

    2009-01-01

    Stents have a serial unstable structure that readily leads to non-uniform expansion. Non-uniform expansion in turn creates a stent safety problem. We explain how a stent may be simplified to a serial unstable structure, and present a method to calculate the non-uniform expansion of the stent on the basis of the serial unstable structure. We propose a safety criterion based on the expansion displacement instead of the strain, and explain that the parameter Rd, the ratio of the maximum displacement of the elements to normal displacement, is meaningful to assess the safety level of the stent. We also examine how laser cutting influences non-uniform expansion. The examples illustrate how to calculate the parameter Rd to assess non-uniform expansion of the stent, and demonstrate how the laser cutting offset and strengthening coefficient of the material influence the stent expansion behaviour. The methods are valuable for assessing stent safety due to non-uniform expansion.

  5. The Development of Expansion Plug Wedge Test for Clad Tubing Structure Mechanical Property Evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jy-An John [ORNL; Jiang, Hao [ORNL

    2016-01-12

    To determine the tensile properties of irradiated fuel cladding in a hot cell, a simple test was developed at the Oak Ridge National Laboratory (ORNL) and is described fully in US Patent Application 20060070455, “Expanded plug method for developing circumferential mechanical properties of tubular materials.” This method is designed for testing fuel rod cladding ductility in a hot cell using an expandable plug to stretch a small ring of irradiated cladding material. The specimen strain is determined using the measured diametrical expansion of the ring. This method removes many complexities associated with specimen preparation and testing. The advantages are the simplicity of measuring the test component assembly in the hot cell and the direct measurement of the specimen’s strain. It was also found that cladding strength could be determined from the test results.

  6. A structure-based extracellular matrix expansion mechanism of fibrous tissue growth.

    Science.gov (United States)

    Kalson, Nicholas S; Lu, Yinhui; Taylor, Susan H; Starborg, Tobias; Holmes, David F; Kadler, Karl E

    2015-05-20

    Embryonic growth occurs predominately by an increase in cell number; little is known about growth mechanisms later in development when fibrous tissues account for the bulk of adult vertebrate mass. We present a model for fibrous tissue growth based on 3D-electron microscopy of mouse tendon. We show that the number of collagen fibrils increases during embryonic development and then remains constant during postnatal growth. Embryonic growth was explained predominately by increases in fibril number and length. Postnatal growth arose predominately from increases in fibril length and diameter. A helical crimp structure was established in embryogenesis, and persisted postnatally. The data support a model where the shape and size of tendon is determined by the number and position of embryonic fibroblasts. The collagen fibrils that these cells synthesise provide a template for postnatal growth by structure-based matrix expansion. The model has important implications for growth of other fibrous tissues and fibrosis.

  7. Mechanical confinement regulates cartilage matrix formation by chondrocytes

    Science.gov (United States)

    Lee, Hong-Pyo; Gu, Luo; Mooney, David J.; Levenston, Marc E.; Chaudhuri, Ovijit

    2017-12-01

    Cartilage tissue equivalents formed from hydrogels containing chondrocytes could provide a solution for replacing damaged cartilage. Previous approaches have often utilized elastic hydrogels. However, elastic stresses may restrict cartilage matrix formation and alter the chondrocyte phenotype. Here we investigated the use of viscoelastic hydrogels, in which stresses are relaxed over time and which exhibit creep, for three-dimensional (3D) culture of chondrocytes. We found that faster relaxation promoted a striking increase in the volume of interconnected cartilage matrix formed by chondrocytes. In slower relaxing gels, restriction of cell volume expansion by elastic stresses led to increased secretion of IL-1β, which in turn drove strong up-regulation of genes associated with cartilage degradation and cell death. As no cell-adhesion ligands are presented by the hydrogels, these results reveal cell sensing of cell volume confinement as an adhesion-independent mechanism of mechanotransduction in 3D culture, and highlight stress relaxation as a key design parameter for cartilage tissue engineering.

  8. MicroRNA Cluster miR-17-92 Regulates Neural Stem Cell Expansion and Transition to Intermediate Progenitors in the Developing Mouse Neocortex

    Directory of Open Access Journals (Sweden)

    Shan Bian

    2013-05-01

    Full Text Available During development of the embryonic neocortex, tightly regulated expansion of neural stem cells (NSCs and their transition to intermediate progenitors (IPs are critical for normal cortical formation and function. Molecular mechanisms that regulate NSC expansion and transition remain unclear. Here, we demonstrate that the microRNA (miRNA miR-17-92 cluster is required for maintaining proper populations of cortical radial glial cells (RGCs and IPs through repression of Pten and Tbr2 protein. Knockout of miR-17-92 and its paralogs specifically in the developing neocortex restricts NSC proliferation, suppresses RGC expansion, and promotes transition of RGCs to IPs. Moreover, Pten and Tbr2 protectors specifically block silencing activities of endogenous miR-17-92 and control proper numbers of RGCs and IPs in vivo. Our results demonstrate a critical role for miRNAs in promoting NSC proliferation and modulating the cell-fate decision of generating distinct neural progenitors in the developing neocortex.

  9. Fat metabolism during exercise: mechanisms of regulation

    Directory of Open Access Journals (Sweden)

    Monique da Silva Gevaerd

    2006-12-01

    Full Text Available Fats are important energetic fuel to exercise. However, the regulation of fat uptake during exercise is unclear. The main objective of this review was to focus on physiological control mechanisms of mobilization, transport and fat uptake during exercise. The articles of fat metabolism were searched in Pubmed and Lilacs indexes. Classical and current papers were preferred. Evidence suggests that transport of fatty acids (FA from extracellular to intracellular spaces could be the main factor to limit fatty acid uptake. Future studies on fat uptake during exercise can focus on this mechanism. In intense exercise, the lower blood fl ow in the adipose tissue and higher fatty acid reesterifi cation rate impairs fat uptake during exercise. Supplementation of the FA has been used, however, the ideal quantities and forms to prevent gastrointestinal discomfort were not yet determined. In the biological point of view, intramuscular reserve of FA could be more effi cient, because is not necessary to FA to cross the cell membrane. RESUMO Os lipídios são considerados importantes fontes energéticas para a realização de exercícios físicos. Entretanto, os mecanismos de regulação do consumo desse substrato durante o exercício não estão totalmente esclarecidos. O objetivo principal da presente revisão foi abordar mecanismos fisiológicos de controle da mobilização, transporte e utilização de gordura durante o exercício. Os trabalhos indexados no banco de dados Pubmed e Lilacs sobre metabolismo de gordura, foram analisados e os clássicos e recentes foram preferencialmente utilizados. A partir dos dados recentes da literatura, especula-se que o transporte de ácidos graxos do meio extracelular para o meio intracelular pode constituir um dos principais mecanismos limitantes no consumo desse substrato. Estudos sobre o consumo de lipídios durante o exercício devem ser focados sobre esse mecanismo. Em exercício intenso, o menor fl uxo de sangue

  10. Mechanical and thermal expansion properties of β-eucryptite prepared by sol-gel methods and hot pressing

    International Nuclear Information System (INIS)

    Xia, L.; Wen, G.W.; Qin, C.L.; Wang, X.Y.; Song, L.

    2011-01-01

    Research highlights: → Dense LAS glass-ceramics were fabricated by sol-gel and hot pressing technique. → The LAS glass-ceramics have relative good mechanical properties. → The negative thermal expansion behavior of LAS glass-ceramics was investigated. -- Abstract: The microstructures, mechanical properties and thermal expansion behavior of monolithic lithium aluminosilicate glass-ceramics, prepared by sol-gel method and hot pressing, were investigated by using X-ray diffraction, scanning and transmission electron microscopies, three-point bend tests and dilatometry. β-eucryptite appeared as main phase in the monolithic lithium aluminosilicate glass-ceramics. The glass ceramics exhibited high relative densities and the average flexural strength and fracture toughness values were 154 MPa and 2.46 MPa m 1/2 , respectively. The lithium aluminosilicate glass-ceramics hot pressed 1300 and 1350 o C demonstrated negative coefficient of thermal expansion, which was affected by amount and type of crystalline phases.

  11. Comparative population genetics of two invading ticks: Evidence of the ecological mechanisms underlying tick range expansions.

    Science.gov (United States)

    Nadolny, Robyn; Gaff, Holly; Carlsson, Jens; Gauthier, David

    2015-10-01

    Two species of ixodid tick, Ixodes affinis Neumann and Amblyomma maculatum Koch, are simultaneously expanding their ranges throughout the mid-Atlantic region of the US. Although we have some understanding of the ecology and life history of these species, the ecological mechanisms governing where and how new populations establish and persist are unclear. To assess population connectivity and ancestry, we sequenced a fragment of the 16S mitochondrial rRNA gene from a representative sample of individuals of both species from populations throughout the eastern US. We found that despite overlapping host preferences throughout ontogeny, each species exhibited very different genetic and geographic patterns of population establishment and connectivity. I. affinis was of two distinct mitochondrial clades, with a clear geographic break separating northern and southern populations. Both I. affinis populations showed evidence of recent expansion, although the southern population was more genetically diverse, indicating a longer history of establishment. A. maculatum exhibited diverse haplotypes that showed no significant relationship with geographic patterns and little apparent connectivity between sites. Heteroplasmy was also observed in the 16S mitochondrial rRNA gene in 3.5% of A. maculatum individuals. Genetic evidence suggests that these species rely on different key life stages to successfully disperse into novel environments, and that host vagility, habitat stability and habitat connectivity all play critical roles in the establishment of new tick populations. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Tc1-mediated contact sensitivity reaction, its mechanism and regulation

    Directory of Open Access Journals (Sweden)

    Magdalena Zemelka-Wiącek

    2014-07-01

    Full Text Available The contact hypersensitivity reaction (CHS to haptens is a classic example of cell-mediated immune response. In the effector phase, two stages can be distinguished: an early component, that appears only 2 hours after subsequent contact with the hapten, and the late component that develops approximately 24 hours later which is mediated by TCRαβ+ cells. The effector lymphocytes may be CD4+ T helper 1 (Th1 cells or CD8+ T cytotoxic 1 (Tc1 cells, which depends on the employed hapten and/or mice strain. NKT lymphocytes play the crucial role in the CHS initiation, by supporting B1 cells in the antigen-specific IgM antibodies production. The development of an early component is essential for the recruitment of T effector (Teff cells to the side of hapten deposition and for the complete expansion of inflammatory reaction. The CHS reaction is under T regulatory (Treg cells control, both in the induction phase as well as in the effector phase. A new view of a negative regulation of the Tc1 mediated CHS response is based on the suppression induced by epicutaneous (EC application of protein antigen. The DNP-BSA skin application, on a gauze patch, leads to a state of immunosuppression. This maneuver results in rising the population of Treg cells with TCRαβ+CD4+CD25+Foxp3+ phenotype. The mechanism of suppression requires direct contact between Treg cells and Teff cells and the participation of CTLA-4 molecule is also necessary. The described method of evoking immune tolerance via EC immunization may contribute to elaborate a new method of allergic contact dermatitis therapy. This is because of its effectiveness, ease of induction and non-invasive protein antigen application.

  13. Theoretical study of negative thermal expansion mechanism of ZnF{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Lei [Center for Clean Energy and Quantum Structures, Zhengzhou University, Zhengzhou 450001 (China); Yuan, Peng-Fei; Wang, Fei; Sun, Qiang [Center for Clean Energy and Quantum Structures, Zhengzhou University, Zhengzhou 450001 (China); School of Physics and Engineering, Zhengzhou University, Zhengzhou 450052 (China); Liang, Er-Jun, E-mail: ejliang@zzu.edu.cn [Center for Clean Energy and Quantum Structures, Zhengzhou University, Zhengzhou 450001 (China); School of Physics and Engineering, Zhengzhou University, Zhengzhou 450052 (China); Jia, Yu, E-mail: jiay@zzu.edu.cn [Center for Clean Energy and Quantum Structures, Zhengzhou University, Zhengzhou 450001 (China); School of Physics and Engineering, Zhengzhou University, Zhengzhou 450052 (China)

    2012-05-15

    Graphical abstract: ZnF{sub 2} owns open-framework structure and its negative thermal expansion (NTE) properties have been confirmed using a first-principles calculation. According to the phonon eigenvectors and group theory analysis, the lowest frequency (48.9 cm{sup -1}, B{sub 1g} mode) rigid unit mode (RUM) of ZnF{sub 6} causes a rotary coupling between two adjacent octahedrons and makes the Zn-Zn distance shorter, which is considered to be most responsible for the NTE properties of ZnF{sub 2}. Highlights: Black-Right-Pointing-Pointer The NTE properties of ZnF{sub 2} are confirmed using a first-principles calculation. Black-Right-Pointing-Pointer Phonon mode classification and Grueneisen parameters are systematically presented. Black-Right-Pointing-Pointer The rigid unit mode causes a rotary coupling and makes the Zn-Zn distance shorter. Black-Right-Pointing-Pointer The optical branch with the lowest frequency is most responsible for the NTE. -- Abstract: ZnF{sub 2} is reported to exhibit negative thermal expansion (NTE) at lower temperatures very recently. In this article, we present the electronic and NTE properties of ZnF{sub 2} using a first-principles calculation. Our results show that ZnF{sub 2} is an insulator with a direct band gap and a strong hybridization occurs between Zn-3p, 4s and F-2p states. The related calculations on NTE properties are obtained within the quasi-harmonic approximation. The resulting relationship between volume and temperature confirms the NTE properties. Besides, we discuss the NTE mechanism in accordance to phonon vibrational modes. The phonon vibrational modes contributing to the NTE are singled out by Grueneisen parameters and all these modes are low-frequency optical phonons. The lowest frequency rigid unit mode (RUM) of ZnF{sub 6} causes a rotary coupling between two adjacent octahedrons and makes the Zn-Zn distance shorter, which is most responsible for the NTE properties of ZnF{sub 2}.

  14. Oil pollution control mechanisms - statutes and regulations

    International Nuclear Information System (INIS)

    1978-04-01

    The purpose of this analysis is to provide a detailed picture of federal statutes and regulations, as well as case law, bearing on oil spill prevention and control. Emphasis has been placed on federal action occurring after a spill, although some effort is directed toward review of prevention statutes and regulations. In-depth consideration is given the control of oil pollution under the Federal Water Pollution Control Act but this analysis also touches lightly upon acts that have a lesser effect on oil pollution control. These acts being: The Refuse Act; The Ports and Waterways Safety Act of 1972; The Outer Continental Shelf Lands Act; The Oil Pollution Act of 1961; The Deepwater Port Act of 1974, and The Fish and Wildlife Coordination Act

  15. Thermal expansion

    International Nuclear Information System (INIS)

    Yun, Y.

    2015-01-01

    Thermal expansion of fuel pellet is an important property which limits the lifetime of the fuels in reactors, because it affects both the pellet and cladding mechanical interaction and the gap conductivity. By fitting a number of available measured data, recommended equations have been presented and successfully used to estimate thermal expansion coefficient of the nuclear fuel pellet. However, due to large scatter of the measured data, non-consensus data have been omitted in formulating the equations. Also, the equation is strongly governed by the lack of appropriate experimental data. For those reasons, it is important to develop theoretical methodologies to better describe thermal expansion behaviour of nuclear fuel. In particular, first-principles and molecular dynamics simulations have been certainly contributed to predict reliable thermal expansion without fitting the measured data. Furthermore, the two theoretical techniques have improved on understanding the change of fuel dimension by describing the atomic-scale processes associated with lattice expansion in the fuels. (author)

  16. Investigation of Reactivity Feedback Mechanism of Axial and Radial Expansion Effect of Metal-Fueled Sodium-Cooled Fast Reactor

    International Nuclear Information System (INIS)

    Seong, Seung-Hwan; Choi, Chi-Woong; Jeong, Tae-Kyung; Ha, Gi-Seok

    2015-01-01

    The major inherent reactivity feedback models for a ceramic fuel used in a conventional light water reactor are Doppler feedback and moderator feedback. The metal fuel has these two reactivity feedback mechanisms previously mentioned. In addition, the metal fuel has two more reactivity feedback models related to the thermal expansion phenomena of the metal fuel. Since the metal fuel has a good capability to expand according to the temperature changes of the core, two more feedback mechanisms exist. These additional two feedback mechanism are important to the inherent safety of metal fuel and can make metal-fueled SFR safer than oxide-fueled SFR. These phenomena have already been applied to safety analysis on design extended condition. In this study, the effect of these characteristics on power control capability was examined through a simple load change operation. The axial expansion mechanism is induced from the change of the fuel temperature according to the change of the power level of PGSFR. When the power increases, the fuel temperatures in the metal fuel will increase and then the reactivity will decrease due to the axial elongation of the metal fuel. To evaluate the expansion effect, 2 cases were simulated with the same scenario by using MMS-LMR code developed at KAERI. The first simulation was to analyze the change of the reactor power according to the change of BOP power without the reactivity feedback model of the axial and radial expansion of the core during the power transient event. That is to say, the core had only two reactivity feedback mechanism of Doppler and coolant temperature

  17. Nutrient regulation by continuous feeding removes limitations on cell yield in the large-scale expansion of Mammalian cell spheroids.

    Directory of Open Access Journals (Sweden)

    Bradley P Weegman

    Full Text Available Cellular therapies are emerging as a standard approach for the treatment of several diseases. However, realizing the promise of cellular therapies across the full range of treatable disorders will require large-scale, controlled, reproducible culture methods. Bioreactor systems offer the scale-up and monitoring needed, but standard stirred bioreactor cultures do not allow for the real-time regulation of key nutrients in the medium. In this study, β-TC6 insulinoma cells were aggregated and cultured for 3 weeks as a model of manufacturing a mammalian cell product. Cell expansion rates and medium nutrient levels were compared in static, stirred suspension bioreactors (SSB, and continuously fed (CF SSB. While SSB cultures facilitated increased culture volumes, no increase in cell yields were observed, partly due to limitations in key nutrients, which were consumed by the cultures between feedings, such as glucose. Even when glucose levels were increased to prevent depletion between feedings, dramatic fluctuations in glucose levels were observed. Continuous feeding eliminated fluctuations and improved cell expansion when compared with both static and SSB culture methods. Further improvements in growth rates were observed after adjusting the feed rate based on calculated nutrient depletion, which maintained physiological glucose levels for the duration of the expansion. Adjusting the feed rate in a continuous medium replacement system can maintain the consistent nutrient levels required for the large-scale application of many cell products. Continuously fed bioreactor systems combined with nutrient regulation can be used to improve the yield and reproducibility of mammalian cells for biological products and cellular therapies and will facilitate the translation of cell culture from the research lab to clinical applications.

  18. Nutrient Regulation by Continuous Feeding Removes Limitations on Cell Yield in the Large-Scale Expansion of Mammalian Cell Spheroids

    Science.gov (United States)

    Weegman, Bradley P.; Nash, Peter; Carlson, Alexandra L.; Voltzke, Kristin J.; Geng, Zhaohui; Jahani, Marjan; Becker, Benjamin B.; Papas, Klearchos K.; Firpo, Meri T.

    2013-01-01

    Cellular therapies are emerging as a standard approach for the treatment of several diseases. However, realizing the promise of cellular therapies across the full range of treatable disorders will require large-scale, controlled, reproducible culture methods. Bioreactor systems offer the scale-up and monitoring needed, but standard stirred bioreactor cultures do not allow for the real-time regulation of key nutrients in the medium. In this study, β-TC6 insulinoma cells were aggregated and cultured for 3 weeks as a model of manufacturing a mammalian cell product. Cell expansion rates and medium nutrient levels were compared in static, stirred suspension bioreactors (SSB), and continuously fed (CF) SSB. While SSB cultures facilitated increased culture volumes, no increase in cell yields were observed, partly due to limitations in key nutrients, which were consumed by the cultures between feedings, such as glucose. Even when glucose levels were increased to prevent depletion between feedings, dramatic fluctuations in glucose levels were observed. Continuous feeding eliminated fluctuations and improved cell expansion when compared with both static and SSB culture methods. Further improvements in growth rates were observed after adjusting the feed rate based on calculated nutrient depletion, which maintained physiological glucose levels for the duration of the expansion. Adjusting the feed rate in a continuous medium replacement system can maintain the consistent nutrient levels required for the large-scale application of many cell products. Continuously fed bioreactor systems combined with nutrient regulation can be used to improve the yield and reproducibility of mammalian cells for biological products and cellular therapies and will facilitate the translation of cell culture from the research lab to clinical applications. PMID:24204645

  19. Development of Cone Wedge Ring Expansion Test to Evaluate Mechanical Properties of Clad Tubing Structure

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jy-An John [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-10-01

    To determine the hoop tensile properties of irradiated fuel cladding in a hot cell, a cone wedge ring expansion test method was developed. A four-piece wedge insert was designed with tapered angles matched to the cone shape of a loading piston. The ring specimen was expanded in the radial direction by the lateral expansion of the wedges under the downward movement of the piston. The advantages of the proposed method are that implementation of the test setup in a hot cell is simple and easy, and that it enables a direct strain measurement of the test specimen from the piston’s vertical displacement soon after the wedge-clad contact resistance is initiated.

  20. Impact of Casing Expansion on the Mechanical and Petro-Physical Properties of Wellbore Cements

    Science.gov (United States)

    Oyibo, A. E.

    2014-12-01

    The main objective of this research is to investigate the applicability of expandable casing technology as a remediation technique for leaky wells resulting in gas migration problems. Micro annulus is usually created at the cement-formation/cement-casing interface or within the cement matrix either due to poor primary cementing or as a result of activities such as temperature and pressure variation or fracturing operations. Recent reports on gas migration in hydraulically fractured wellbores, has raised concerns on the contamination of fresh water aquifers resulting from fluid migration though this flow path. A unique bench-scale physical model which utilizes expandable tubulars in the remediation of micro annular gas flow has been used to simulate expansion of a previously-cemented casing under field-like conditions. Three different designs of cement slurry: regular 16.4 lb. /gal, 16.4 lb. /gal base slurry foamed to 13 lb. /gal and 16.4 lb. /gal cement slurry with 10% salt concentration. Gas flow path (microannulus) was artificially created at the pipe-cement interface by rotating the inner pipe in a pipe inside pipe assembly with cement in the annulus within the first few hours of hydration to create debonding at the cement-casing interface. Nitrogen gas flow-through experiments were performed before and after the expansion to confirm the sealing of the microannulus. The results obtained confirmed the effectiveness of this technique in the complete closure of gas leakage path, providing seal-tight cement-formation interface free of microannulus. The manipulation of the cement sheath during the casing expansion resulted in improved porosity, permeability and the strength of the cement sheath. SEM micrographs revealed decrease in pore size and fracturing of unhydrated cement grains within the cement matrix. This technology has great potential to become one of the leading cement remediation techniques for leaks behind the casing if implemented. Keywords: Wellbore

  1. Elucidating the mechanism responsible for anomalous thermal expansion in a metal-organic framework.

    Science.gov (United States)

    van Heerden, Dewald P; Esterhuysen, Catharine; Barbour, Leonard J

    2016-03-14

    The previously reported anisotropic thermal expansion of a three-dimensional metal-organic framework (MOF) is examined by means of theoretical calculations. Inspection of the 100, 190, 280 and 370 K single crystal X-ray diffraction (SCD) structures indicated a concerted change in the coordination sphere of the zinc centre leading to elongation of the coordination helix in the crystallographic c direction (the Zn-O(H)-Zn angle expands), while the largely unaltered ligands (the ZnLZn distance remains constant) are pulled closer together in the ab plane. This study develops and evaluates a mechanistic model at the DFT level of theory that reproduces the convergent expansion of the coordination helix of the material. The linear increase in energy calculated for extension of a model consisting of six zinc centres and truncated ligands compares favourably with results obtained from a periodic DFT evaluation of the SCD structures. It was also found that the anisotropic thermal expansion trend could be reproduced qualitatively by Molecular Dynamics (MD) simulations in the NPT ensemble.

  2. Mindful Emotion Regulation: Exploring the Neurocognitive Mechanisms behind Mindfulness

    Directory of Open Access Journals (Sweden)

    Alessandro Grecucci

    2015-01-01

    Full Text Available The purpose of this paper is to review some of the psychological and neural mechanisms behind mindfulness practice in order to explore the unique factors that account for its positive impact on emotional regulation and health. After reviewing the mechanisms of mindfulness and its effects on clinical populations we will consider how the practice of mindfulness contributes to the regulation of emotions. We argue that mindfulness has achieved effective outcomes in the treatment of anxiety, depression, and other psychopathologies through the contribution of mindfulness to emotional regulation. We consider the unique factors that mindfulness meditation brings to the process of emotion regulation that may account for its effectiveness. We review experimental evidence that points towards the unique effects of mindfulness specifically operating over and above the regulatory effects of cognitive reappraisal mechanisms. A neuroanatomical circuit that leads to mindful emotion regulation is also suggested. This paper thereby aims to contribute to proposed models of mindfulness for research and theory building by proposing a specific model for the unique psychological and neural processes involved in mindful detachment that account for the effects of mindfulness over and above the effects accounted for by other well-established emotional regulation processes such as cognitive reappraisal.

  3. CLE-CLAVATA1 peptide-receptor signaling module regulates the expansion of plant root systems in a nitrogen-dependent manner.

    Science.gov (United States)

    Araya, Takao; Miyamoto, Mayu; Wibowo, Juliarni; Suzuki, Akinori; Kojima, Soichi; Tsuchiya, Yumiko N; Sawa, Shinichiro; Fukuda, Hiroo; von Wirén, Nicolaus; Takahashi, Hideki

    2014-02-04

    Morphological plasticity of root systems is critically important for plant survival because it allows plants to optimize their capacity to take up water and nutrients from the soil environment. Here we show that a signaling module composed of nitrogen (N)-responsive CLE (CLAVATA3/ESR-related) peptides and the CLAVATA1 (CLV1) leucine-rich repeat receptor-like kinase is expressed in the root vasculature in Arabidopsis thaliana and plays a crucial role in regulating the expansion of the root system under N-deficient conditions. CLE1, -3, -4, and -7 were induced by N deficiency in roots, predominantly expressed in root pericycle cells, and their overexpression repressed the growth of lateral root primordia and their emergence from the primary root. In contrast, clv1 mutants showed progressive outgrowth of lateral root primordia into lateral roots under N-deficient conditions. The clv1 phenotype was reverted by introducing a CLV1 promoter-driven CLV1:GFP construct producing CLV1:GFP fusion proteins in phloem companion cells of roots. The overaccumulation of CLE2, -3, -4, and -7 in clv1 mutants suggested the amplitude of the CLE peptide signals being feedback-regulated by CLV1. When CLE3 was overexpressed under its own promoter in wild-type plants, the length of lateral roots was negatively correlated with increasing CLE3 mRNA levels; however, this inhibitory action of CLE3 was abrogated in the clv1 mutant background. Our findings identify the N-responsive CLE-CLV1 signaling module as an essential mechanism restrictively controlling the expansion of the lateral root system in N-deficient environments.

  4. Mechanism for automatic regulation of combustion. Regolazione automatica della combustione

    Energy Technology Data Exchange (ETDEWEB)

    Borelli, L.; Tagliaferro, B.; Cossalter, V.; Da Lio, M. (Padua Univ. (Italy))

    1993-09-01

    The article describes an original application of a mechanism for the automatic regulation of burners. The aim is to maintain a constant air-fuel ratio even with variations occurring in ambient temperature and fuel supply. To obtain the correct mixture, the air damper is opened with a double mechanism by an ambient temperature transducer and by a screw for the setting up of the rate of fuel supply.

  5. Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel.

    Science.gov (United States)

    He, Li; Si, Guangwei; Huang, Jiuhong; Samuel, Aravinthan D T; Perrimon, Norbert

    2018-03-01

    Somatic stem cells constantly adjust their self-renewal and lineage commitment by integrating various environmental cues to maintain tissue homeostasis. Although numerous chemical and biological signals have been identified that regulate stem-cell behaviour, whether stem cells can directly sense mechanical signals in vivo remains unclear. Here we show that mechanical stress regulates stem-cell differentiation in the adult Drosophila midgut through the stretch-activated ion channel Piezo. We find that Piezo is specifically expressed in previously unidentified enteroendocrine precursor cells, which have reduced proliferation ability and are destined to become enteroendocrine cells. Loss of Piezo activity reduces the generation of enteroendocrine cells in the adult midgut. In addition, ectopic expression of Piezo in all stem cells triggers both cell proliferation and enteroendocrine cell differentiation. Both the Piezo mutant and overexpression phenotypes can be rescued by manipulation of cytosolic Ca 2+ levels, and increases in cytosolic Ca 2+ resemble the Piezo overexpression phenotype, suggesting that Piezo functions through Ca 2+ signalling. Further studies suggest that Ca 2+ signalling promotes stem-cell proliferation and differentiation through separate pathways. Finally, Piezo is required for both mechanical activation of stem cells in a gut expansion assay and the increase of cytosolic Ca 2+ in response to direct mechanical stimulus in a gut compression assay. Thus, our study demonstrates the existence of a specific group of stem cells in the fly midgut that can directly sense mechanical signals through Piezo.

  6. Quantum-statistical mechanics of an atom-dimer mixture: Lee-Yang cluster expansion approach

    International Nuclear Information System (INIS)

    Ohkuma, Takahiro; Ueda, Masahito

    2006-01-01

    We use the Lee-Yang cluster expansion method to study quantum-statistical properties of a mixture of interconvertible atoms and dimers, where the dimers form in a two-body bound state of the atoms. We point out an infinite series of cluster diagrams whose summation leads to the Bose-Einstein condensation of the dimers below a critical temperature. Our theory captures some important features of a cold atom-dimer mixture such as interconversion of atoms and dimers and properties of the mixture at the unitarity limit

  7. An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.

    Directory of Open Access Journals (Sweden)

    Jason E Shoemaker

    2015-06-01

    Full Text Available Influenza viruses present major challenges to public health, evident by the 2009 influenza pandemic. Highly pathogenic influenza virus infections generally coincide with early, high levels of inflammatory cytokines that some studies have suggested may be regulated in a strain-dependent manner. However, a comprehensive characterization of the complex dynamics of the inflammatory response induced by virulent influenza strains is lacking. Here, we applied gene co-expression and nonlinear regression analysis to time-course, microarray data developed from influenza-infected mouse lung to create mathematical models of the host inflammatory response. We found that the dynamics of inflammation-associated gene expression are regulated by an ultrasensitive-like mechanism in which low levels of virus induce minimal gene expression but expression is strongly induced once a threshold virus titer is exceeded. Cytokine assays confirmed that the production of several key inflammatory cytokines, such as interleukin 6 and monocyte chemotactic protein 1, exhibit ultrasensitive behavior. A systematic exploration of the pathways regulating the inflammatory-associated gene response suggests that the molecular origins of this ultrasensitive response mechanism lie within the branch of the Toll-like receptor pathway that regulates STAT1 phosphorylation. This study provides the first evidence of an ultrasensitive mechanism regulating influenza virus-induced inflammation in whole lungs and provides insight into how different virus strains can induce distinct temporal inflammation response profiles. The approach developed here should facilitate the construction of gene regulatory models of other infectious diseases.

  8. Osmosensory mechanisms in cellular and systemic volume regulation

    DEFF Research Database (Denmark)

    Pedersen, Stine Helene Falsig; Kapus, András; Hoffmann, Else K

    2011-01-01

    Perturbations of cellular and systemic osmolarity severely challenge the function of all organisms and are consequently regulated very tightly. Here we outline current evidence on how cells sense volume perturbations, with particular focus on mechanisms relevant to the kidneys and to extracellular...

  9. New Nanocomposite Materials with Improved Mechanical Strength and Tailored Coefficient of Thermal Expansion for Electro-Packaging Applications

    Directory of Open Access Journals (Sweden)

    Abdollah Saboori

    2017-12-01

    Full Text Available In this research, copper nanocomposites reinforced by graphene nanoplatelets (GNPs were fabricated using a wet mixing method followed by a classical powder metallurgy route. In order to find the best dispersion technique, ball milling and wet mixing were chosen. Qualitative evaluation of the structure of the graphene after mixing indicated that the wet mixing is an appropriate technique to disperse the GNPs. Thereafter, the influence of graphene content on microstructure, density, hardness, elastic modulus, and thermal expansion coefficient of composites was investigated. It was shown that by increasing the graphene content the aggregation of graphene is more obvious and, thus, these agglomerates affect the final properties adversely. In comparison with the unreinforced Cu, Cu–GNP composites were lighter, and their hardness and Young’s modulus were higher as a consequence of graphene addition. According to the microstructural observation of pure copper and its composites after sintering, it was concluded that grain refinement is the main mechanism of strengthening in this research. Apart from the mechanical characteristics, the coefficient of thermal expansion of composites decreased remarkably and the combination of this feature with appropriate mechanical properties can make them a promising candidate for use in electronic packaging applications.

  10. Mechanical Regulation in Cell Division and in Neurotransmitter Release

    Science.gov (United States)

    Thiyagarajan, Sathish

    During their lifecycle, cells must produce forces which play important roles in several subcellular processes. Force-producing components are organized into macromolecular assemblies of proteins that are often dynamic, and are constructed or disassembled in response to various signals. The forces themselves may directly be involved in subcellular mechanics, or they may influence mechanosensing proteins either within or outside these structures. These proteins play different roles: they may ensure the stability of the force-producing structure, or they may send signals to a coupled process. The generation and sensing of subcellular forces is an active research topic, and this thesis focusses on the roles of these forces in two key areas: cell division and neurotransmitter release. The first part of the thesis deals with the effect of force on cell wall growth regulation during division in the fission yeast Schizosaccharomyces pombe, a cigar-shaped, unicellular organism. During cytokinesis, the last stage of cell division in which the cell physically divides into two, a tense cytokinetic ring anchored to the cellular membrane assembles and constricts, accompanied by the inward centripetal growth of new cell wall, called septum, in the wake of the inward-moving membrane. The contour of the septum hole maintains its circularity as it reduces in size--an indication of regulated growth. To characterize the cell wall growth process, we performed image analysis on contours of the leading edge of the septum obtained via fluorescence microscopy in the labs of our collaborators. We quantified the deviations from circularity using the edge roughness. The roughness was spatially correlated, suggestive of regulated growth. We hypothesized that the cell wall growers are mechanosensitive and respond to the force exerted by the ring. A mathematical model based on this hypothesis then showed that this leads to corrections of roughness in a curvature-dependent fashion. Thus, one of

  11. KCNK10, a Tandem Pore Domain Potassium Channel, Is a Regulator of Mitotic Clonal Expansion during the Early Stage of Adipocyte Differentiation

    Directory of Open Access Journals (Sweden)

    Makoto Nishizuka

    2014-12-01

    Full Text Available KCNK10, a member of tandem pore domain potassium channel family, gives rise to leak K+ currents. It plays important roles in stabilizing the negative resting membrane potential and in counterbalancing depolarization. We previously demonstrated that kcnk10 expression is quickly elevated during the early stage of adipogenesis of 3T3-L1 cells and that reduction of kcnk10 expression inhibits adipocyte differentiation. However, the molecular mechanism of KCNK10 in adipocyte differentiation remains unclear. Here we revealed that kcnk10 is induced by 3-isobutyl-1-methylxanthine, a cyclic nucleotide phosphodiesterase inhibitor and a potent inducer of adipogenesis, during the early stage of adipocyte differentiation. We also demonstrated that KCNK10 functions as a positive regulator of mitotic clonal expansion (MCE, a necessary process for terminal differentiation. The reduction of kcnk10 expression repressed the expression levels of CCAAT/enhancer-binding protein β (C/EBPβ and C/EBPδ as well as the phosphorylation level of Akt during the early phase of adipogenesis. In addition, knockdown of kcnk10 expression suppressed insulin-induced Akt phosphorylation. These results indicate that KCNK10 contributes to the regulation of MCE through the control of C/EBPβ and C/EBPδ expression and insulin signaling.

  12. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.

    Science.gov (United States)

    Parrish-Novak, J; Dillon, S R; Nelson, A; Hammond, A; Sprecher, C; Gross, J A; Johnston, J; Madden, K; Xu, W; West, J; Schrader, S; Burkhead, S; Heipel, M; Brandt, C; Kuijper, J L; Kramer, J; Conklin, D; Presnell, S R; Berry, J; Shiota, F; Bort, S; Hambly, K; Mudri, S; Clegg, C; Moore, M; Grant, F J; Lofton-Day, C; Gilbert, T; Rayond, F; Ching, A; Yao, L; Smith, D; Webster, P; Whitmore, T; Maurer, M; Kaushansky, K; Holly, R D; Foster, D

    2000-11-02

    Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.

  13. Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers.

    Science.gov (United States)

    Tanimoto, Ryuta; Lu, Kuojung G; Xu, Shi-Qiong; Buraschi, Simone; Belfiore, Antonino; Iozzo, Renato V; Morrione, Andrea

    2016-01-01

    The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias, and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate, and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells. In this review, we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors.

  14. Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers

    Directory of Open Access Journals (Sweden)

    Ryuta Tanimoto

    2016-07-01

    Full Text Available The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells.In this review we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors.

  15. Mechanical, electrical, and thermal expansion properties of carbon nanotube-based silver and silver-palladium alloy composites

    Science.gov (United States)

    Pal, Hemant; Sharma, Vimal

    2014-11-01

    The mechanical, electrical, and thermal expansion properties of carbon nanotube (CNT)-based silver and silver-palladium (10:1, w/w) alloy nanocomposites are reported. To tailor the properties of silver, CNTs were incorporated into a silver matrix by a modified molecular level-mixing process. CNTs interact weakly with silver because of their non-reactive nature and lack of mutual solubility. Therefore, palladium was utilized as an alloying element to improve interfacial adhesion. Comparative microstructural characterizations and property evaluations of the nanocomposites were performed. The structural characterizations revealed that decorated type-CNTs were dispersed, embedded, and anchored into the silver matrix. The experimental results indicated that the modification of the silver and silver-palladium nanocomposite with CNT resulted in increases in the hardness and Young's modulus along with concomitant decreases in the electrical conductivity and the coefficient of thermal expansion (CTE). The hardness and Young's modulus of the nanocomposites were increased by 30%-40% whereas the CTE was decreased to 50%-60% of the CTE of silver. The significantly improved CTE and the mechanical properties of the CNT-reinforced silver and silver-palladium nanocomposites are correlated with the intriguing properties of CNTs and with good interfacial adhesion between the CNTs and silver as a result of the fabrication process and the contact action of palladium as an alloying element.

  16. Regulation of gene expression and pain states by epigenetic mechanisms.

    Science.gov (United States)

    Géranton, Sandrine M; Tochiki, Keri K

    2015-01-01

    The induction of inflammatory or neuropathic pain states is known to involve molecular activity in the spinal superficial dorsal horn and dorsal root ganglia, including intracellular signaling events which lead to changes in gene expression. These changes ultimately cause alterations in macromolecular synthesis, synaptic transmission, and structural architecture which support central sensitization, a process required for the establishment of long-term pain states. Epigenetic mechanisms are essential for long-term synaptic plasticity and modulation of gene expression. This is because epigenetic modifications are known to regulate gene transcription by aiding the physical relaxation or condensation of chromatin. These processes are therefore potential regulators of the molecular changes underlying permanent pain states. A handful of studies have emerged in the field of pain epigenetics; however, the field is still very much in its infancy. This chapter draws upon other specialities which have extensively investigated epigenetic mechanisms, such as learning and memory and oncology. After defining epigenetics as well as the recent field of "neuroepigenetics" and the main molecular mechanisms involved, this chapter describes the role of these mechanisms in the synaptic plasticity seen in learning and memory, and address those epigenetic mechanisms that have been linked with the development of acute and prolonged pain states. Finally, the idea that long-lasting epigenetic modifications could contribute to the transition from acute to chronic pain states by supporting maladaptive molecular changes is discussed. © 2015 Elsevier Inc. All rights reserved.

  17. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock.

    Science.gov (United States)

    Narasimamurthy, Rajesh; Virshup, David M

    2017-01-01

    An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep-wake cycle, feeding-fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

  18. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

    Directory of Open Access Journals (Sweden)

    David M. Virshup

    2017-04-01

    Full Text Available An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

  19. Molecular mechanisms of platelet P2Y(12) receptor regulation.

    Science.gov (United States)

    Cunningham, Margaret R; Nisar, Shaista P; Mundell, Stuart J

    2013-02-01

    Platelets are critical for haemostasis, however inappropriate activation can lead to the development of arterial thrombosis, which can result in heart attack and stroke. ADP is a key platelet agonist that exerts its actions via stimulation of two surface GPCRs (G-protein-coupled receptors), P2Y(1) and P2Y(12). Similar to most GPCRs, P2Y receptor activity is tightly regulated by a number of complex mechanisms including receptor desensitization, internalization and recycling. In the present article, we review the molecular mechanisms that underlie P2Y(1) and P2Y(12) receptor regulation, with particular emphasis on the structural motifs within the P2Y(12) receptor, which are required to maintain regulatory protein interaction. The implications of these findings for platelet responsiveness are also discussed.

  20. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

    OpenAIRE

    David M. Virshup; Rajesh Narasimamurthy

    2017-01-01

    An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entr...

  1. Neural mechanisms of emotional regulation and decision making

    OpenAIRE

    Gospic, Katarina

    2011-01-01

    Emotions influence our perception and decision making. It is of great importance to understand the neurophysiology behind these processes as they influence human core functions. Moreover, knowledge within this field is required in order to develop new medical therapies for pathological conditions that involve dysregulation of emotions. In this thesis the neural mechanisms of emotional regulation and decision making were investigated using different pharmacological manipul...

  2. Mechanical and thermal-expansion characteristics of Ca10(PO46(OH2-Ca3(PO42 composites

    Directory of Open Access Journals (Sweden)

    Ruseska G.

    2006-01-01

    Full Text Available Three types of composites consisting of Ca10(PO46(OH2 and Ca3(PO42 with composition: 75% (wt Ca10(PO46(OH2: 25%(wt Ca3(PO42; 50%(wt Ca10(PO46(OH2: 50%(wtCa3(PO42 and 25 %(wt Ca10(PO46(OH2: 75%(wt Ca3(PO42 were the subject of our investigation. Sintered compacts were in thermal equilibrium, which was proved by the absence of hysteresis effect of the dependence ΔL/L=f(T during heating /cooling in the temperature interval 20-1000-200C. Sintered compacts with the previously mentioned composition possess 26-50% higher values of the E-modulus, G-modulus and K-modulus indicating the presence of a synergism effect. Several proposed model equations for predicting the thermal expansion coefficient in dependence of the thermal and elastic properties of the constitutive phases and their volume fractions, given by: Turner, Kerner, Tummala and Friedberg, Thomas and Taya, were used for making correlations between mechanical and thermal-expansion characteristics of the Ca10(PO46(OH2 - Ca3(PO42 composites. Application of the previously mentioned model equations to all kinds of composites leads to the conclusion that the experimentally obtained results for the thermal expansion coefficient are in an excellent agreement with the theoretical calculated values on account of the volume fraction of each constitutive phase and with all applied model equations, with a coefficient of correlation from 98.16-99.86 %.

  3. Role and mechanism of arsenic in regulating angiogenesis.

    Directory of Open Access Journals (Sweden)

    Ling-Zhi Liu

    Full Text Available Arsenic is a wide spread carcinogen associated with several kinds of cancers including skin, lung, bladder, and liver cancers. Lung is one of the major targets of arsenic exposure. Angiogenesis is the pivotal process during carcinogenesis and chronic pulmonary diseases, but the role and mechanism of arsenic in regulating angiogenesis remain to be elucidated. In this study we show that short time exposure of arsenic induces angiogenesis in both human immortalized lung epithelial cells BEAS-2B and adenocarcinoma cells A549. To study the molecular mechanism of arsenic-inducing angiogenesis, we find that arsenic induces reactive oxygen species (ROS generation, which activates AKT and ERK1/2 signaling pathways and increases the expression of hypoxia-inducible factor 1 (HIF-1 and vascular endothelial growth factor (VEGF. Inhibition of ROS production suppresses angiogenesis by decreasing AKT and ERK activation and HIF-1 expression. Inhibition of ROS, AKT and ERK1/2 signaling pathways is sufficient to attenuate arsenic-inducing angiogenesis. HIF-1 and VEGF are downstream effectors of AKT and ERK1/2 that are required for arsenic-inducing angiogenesis. These results shed light on the mechanism of arsenic in regulating angiogenesis, and are helpful to develop mechanism-based intervention to prevent arsenic-induced carcinogenesis and angiogenesis in the future.

  4. The signaling lipid sphingosine 1-phosphate regulates mechanical pain

    Science.gov (United States)

    Hill, Rose Z; Hoffman, Benjamin U; Morita, Takeshi; Campos, Stephanie M; Lumpkin, Ellen A; Brem, Rachel B

    2018-01-01

    Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds. PMID:29561262

  5. Effect Mechanism of Penstock on Stability and Regulation Quality of Turbine Regulating System

    Directory of Open Access Journals (Sweden)

    Wencheng Guo

    2014-01-01

    Full Text Available This paper studies the effect mechanism of water inertia and head loss of penstock on stability and regulation quality of turbine regulating system with surge tank or not and proposes the construction method of equivalent model of regulating system. Firstly, the complete linear mathematical model of regulating system is established. Then, the free oscillation equation and time response of the frequency that describe stability and regulation quality, respectively, are obtained. Finally, the effects of penstock are analysed by using stability region and response curves. The results indicate that the stability and regulation quality of system without surge tank are determined by time response of frequency which only depends on water hammer wave in penstock, while, for system with surge tank, the time response of frequency depending on water hammer wave in penstock and water-level fluctuation in surge tank jointly determines the stability and regulation quality. Water inertia of penstock mainly affects the stability and time response of frequency of system without surge tank as well as the stability and head wave of time response of frequency with surge tank. Head loss of penstock mainly affects the stability and tail wave of time response of frequency with surge tank.

  6. Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation.

    Science.gov (United States)

    Tanaka, Leonardo Y; Laurindo, Francisco R M

    2017-08-01

    Vascular remodeling, i.e. whole-vessel structural reshaping, determines lumen caliber in (patho)physiology. Here we review mechanisms underlying vessel remodeling, with emphasis in redox regulation. First, we discuss confusing terminology and focus on strictu sensu remodeling. Second, we propose a mechanobiological remodeling paradigm based on the concept of tensional homeostasis as a setpoint regulator. We first focus on shear-mediated models as prototypes of remodeling closely dominated by highly redox-sensitive endothelial function. More detailed discussions focus on mechanosensors, integrins, extracellular matrix, cytoskeleton and inflammatory pathways as potential of mechanisms potentially coupling tensional homeostasis to redox regulation. Further discussion of remodeling associated with atherosclerosis and injury repair highlights important aspects of redox vascular responses. While neointima formation has not shown consistent responsiveness to antioxidants, vessel remodeling has been more clearly responsive, indicating that despite the multilevel redox signaling pathways, there is a coordinated response of the whole vessel. Among mechanisms that may orchestrate redox pathways, we discuss roles of superoxide dismutase activity and extracellular protein disulfide isomerase. We then discuss redox modulation of aneurysms, a special case of expansive remodeling. We propose that the redox modulation of vascular remodeling may reflect (1) remodeling pathophysiology is dominated by a particularly redox-sensitive cell type, e.g., endothelial cells (2) redox pathways are temporospatially coordinated at an organ level across distinct cellular and acellular structures or (3) the tensional homeostasis setpoint is closely connected to redox signaling. The mechanobiological/redox model discussed here can be a basis for improved understanding of remodeling and helps clarifying mechanisms underlying prevalent hard-to-treat diseases. Copyright © 2017 Elsevier Inc. All

  7. Density-dependent hydro-mechanical behaviour of a compacted expansive soil

    International Nuclear Information System (INIS)

    NOWAMOOZ, Hossein; MASROURI, Farimah

    2010-01-01

    Document available in extended abstract form only. Clayey soils are widely used in geotechnical engineering for dam cores, barriers in waste landfills and for engineered barriers in nuclear waste storage facilities. In the latter case, the used materials contain a large amount of smectite which is a highly swelling clay. On site, they can be submitted to complex suction/ stress/temperature variations that could change dramatically their hydro-mechanical behavior, meaning their saturated and unsaturated mechanical characteristics. To further our knowledge of the coupling between the hydraulic and mechanical behaviour of the swelling soils, this paper presents an experimental study on a swelling bentonite/silt mixture using osmotic odometers. A loading/unloading cycle was applied to samples with different initial dry densities (1.27, 1.48, and 1.55 Mg.m -3 ) at different constant suctions (0, 2, and 8 MPa). These experimental results provided a sufficient database to analytically model the mechanical behavior of the swelling soil and define three yielding surfaces: - the Suction Limit between Micro- and Macrostructure (s m/M ) and the Suction Limit between Nano- and Microstructure (s n/m ), which depend completely on the soil fabrics and the diameter separating the nano-, micro-, and macrostructure, - the Loading Collapse (LC) curve, representing the pre-consolidation stress variation as a function of suction, - the Saturation Curve (SC), representing the variation of the saturation stress (P sat ) as a function of suction. In general, we can state that the increase of compaction pressure unified the LC and SC surfaces and decreased the (s m/M ) value without modifying the (s n/m ) value. (authors)

  8. Remote sensing of impervious surface growth: A framework for quantifying urban expansion and re-densification mechanisms

    Science.gov (United States)

    Shahtahmassebi, Amir Reza; Song, Jie; Zheng, Qing; Blackburn, George Alan; Wang, Ke; Huang, Ling Yan; Pan, Yi; Moore, Nathan; Shahtahmassebi, Golnaz; Sadrabadi Haghighi, Reza; Deng, Jing Song

    2016-04-01

    A substantial body of literature has accumulated on the topic of using remotely sensed data to map impervious surfaces which are widely recognized as an important indicator of urbanization. However, the remote sensing of impervious surface growth has not been successfully addressed. This study proposes a new framework for deriving and summarizing urban expansion and re-densification using time series of impervious surface fractions (ISFs) derived from remotely sensed imagery. This approach integrates multiple endmember spectral mixture analysis (MESMA), analysis of regression residuals, spatial statistics (Getis_Ord) and urban growth theories; hence, the framework is abbreviated as MRGU. The performance of MRGU was compared with commonly used change detection techniques in order to evaluate the effectiveness of the approach. The results suggested that the ISF regression residuals were optimal for detecting impervious surface changes while Getis_Ord was effective for mapping hotspot regions in the regression residuals image. Moreover, the MRGU outputs agreed with the mechanisms proposed in several existing urban growth theories, but importantly the outputs enable the refinement of such models by explicitly accounting for the spatial distribution of both expansion and re-densification mechanisms. Based on Landsat data, the MRGU is somewhat restricted in its ability to measure re-densification in the urban core but this may be improved through the use of higher spatial resolution satellite imagery. The paper ends with an assessment of the present gaps in remote sensing of impervious surface growth and suggests some solutions. The application of impervious surface fractions in urban change detection is a stimulating new research idea which is driving future research with new models and algorithms.

  9. [Immune regulation activity and mechanism of Tibetan Kefir exopolysaccharide fractions].

    Science.gov (United States)

    Meng, Li; Zhang, Lanwei

    2009-12-01

    To investigate the effects and mechanism on immune regulation activity in mice of two Tibetan Kefir exoploysaccharides (EPS) with different molecular weight of 0.1 x 10(5) - 3 x 10(5) (fraction 1) and 1.8 x 10(3) (fraction 2). The immune regulation activity experiment was carried out in vitro based on the Functional Assessment Procedure and Test Methods of Health Food, which was issued by Ministry of Health of China. First, we treated mice subjects with EPS at doses of 40 mg/kg, 80 mg/kg, 120 mg/kg through ig. Then we detected the index of immune organs, the ability of antibody production (tested by HC50), activity of NK cell, delayed type hypersensitivity (DTH) and phagocytosis of macrophage in mice. Finally, we examined the expression of Erk protein in Macrophages by Western Blot assay. Fraction 1 could promote HC50, activity of NK cell and DTH in mice which low dose showed better. Fraction 2 could promote DTH, phagocytosis of macrophage which high dose showed better. The expression of Erk and COX-2 had the same trend with Phagocytic index. We verified the two fractions of Tibetan Kefir EPS could enhance immune functions in mice. Fraction 1 regulated immune function through NK cell and B cell while fraction 2 through macrophage cell and T cell. The effects to macrophage of Tibetan Kefir EPS in mice may realize through extra cellular signal-regulated kinase Erk pathway.

  10. FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.

    Directory of Open Access Journals (Sweden)

    Jeremy A Sullivan

    2012-02-01

    Full Text Available CD8 T cell responses have three phases: expansion, contraction, and memory. Dynamic alterations in proliferation and apoptotic rates control CD8 T cell numbers at each phase, which in turn dictate the magnitude of CD8 T cell memory. Identification of signaling pathways that control CD8 T cell memory is incomplete. The PI3K/Akt signaling pathway controls cell growth in many cell types by modulating the activity of FOXO transcription factors. But the role of FOXOs in regulating CD8 T cell memory remains unknown. We show that phosphorylation of Akt, FOXO and mTOR in CD8 T cells occurs in a dynamic fashion in vivo during an acute viral infection. To elucidate the potentially dynamic role for FOXO3 in regulating homeostasis of activated CD8 T cells in lymphoid and non-lymphoid organs, we infected global and T cell-specific FOXO3-deficient mice with Lymphocytic Choriomeningitis Virus (LCMV. We found that FOXO3 deficiency induced a marked increase in the expansion of effector CD8 T cells, preferentially in the spleen, by T cell-intrinsic mechanisms. Mechanistically, the enhanced accumulation of proliferating CD8 T cells in FOXO3-deficient mice was not attributed to an augmented rate of cell division, but instead was linked to a reduction in cellular apoptosis. These data suggested that FOXO3 might inhibit accumulation of growth factor-deprived proliferating CD8 T cells by reducing their viability. By virtue of greater accumulation of memory precursor effector cells during expansion, the numbers of memory CD8 T cells were strikingly increased in the spleens of both global and T cell-specific FOXO3-deficient mice. The augmented CD8 T cell memory was durable, and FOXO3 deficiency did not perturb any of the qualitative attributes of memory T cells. In summary, we have identified FOXO3 as a critical regulator of CD8 T cell memory, and therapeutic modulation of FOXO3 might enhance vaccine-induced protective immunity against intracellular pathogens.

  11. Distinct mechanisms regulate Lck spatial organization in activated T cells

    Directory of Open Access Journals (Sweden)

    Natasha eKapoor-Kaushik

    2016-03-01

    Full Text Available Phosphorylation of the T cell receptor (TCR by the kinase Lck is the first detectable signaling event upon antigen engagement. The distribution of Lck within the plasma membrane, its conformational state, kinase activity and protein interactions all contribute to determine how efficiently Lck phosphorylates the engaged TCR. Here we used cross-correlation raster image spectroscopy (ccRICS and photoactivated localization microscopy (PALM to identify two mechanisms of Lck clustering: an intrinsic mechanism of Lck clustering induced by locking Lck in its open conformation, and an extrinsic mechanism of clustering controlled by the phosphorylation of tyrosine 192, which regulates the affinity of Lck SH2 domain. Both mechanisms of clustering were differently affected by the absence of the kinase Zap70 or the adaptor Lat. We further observed that the adaptor TSAd bound to and promoted the diffusion of Lck when it is phosphorylated on tyrosine 192. Our data suggest that while Lck open conformation drives aggregation and clustering, the spatial organization of Lck is further controlled by signaling events downstream of TCR phosphorylation.

  12. MECHANISMS OF STATE REGULATION OF SMALL AND MEDIUM BUSINESSES

    Directory of Open Access Journals (Sweden)

    Valerii Marenichenko

    2016-11-01

    Full Text Available Subject of research is the mechanisms of state regulation of small and medium businesses in Ukraine. The purpose of the research is effective mechanisms development of state regulation of small and medium enterprises (SMEs. Methodology. The article uses general and special methods of investigation: empirical research methods (observation, comparison; methods used empirically and theoretically study (abstraction, analysis and synthesis; methods of theoretical research (ascent from the abstract to the concrete, systemic and structural approach. The article highlighted the priority areas of activity in Ukraine, such as agriculture, IT-sector and tourism. In particular, we have analyzed data of the State Statistics Service of Ukraine and international surveys such as Enabling the Business of Agriculture, DOU, Deloitte (Global Survey of R&D Incentives 2015, International SOS and Control Risks, WTTC, UPS, Consulting integrated, Organic Monitor and other. We determined that agriculture must use consistent increasing areas under food crops; introduction of modern technology and innovation; gradual increase in the level of mechanization of agricultural production. Scientific research preparation and training of local staff employed in the agriculture and food industry must become the main aspects of quality development. The article defines that IT market requires quality of the state regulation in readiness for a permanent dialogue with government and comprehensive support for sector as a strategic development of the country; development strategy and projects for development of the sector; effective fight against corruption at all levels. The relevance of government regulation in the development of green international tourism is determined. Modern historical and cultural features of Ukraine can allow providing a range of services for international tourism community. There is analyzed an impact of export orientation for small and medium business in the

  13. Regulation mechanisms of the FLT3-ligand after irradiation

    International Nuclear Information System (INIS)

    Prat-Lepesant, M.

    2005-06-01

    The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

  14. Analysis of barosensitive mechanisms in yeast for Pressure Regulated Fermentation

    Science.gov (United States)

    Nomura, Kazuki; Iwahashi, Hitoshi; Iguchi, Akinori; Shigematsu, Toru

    2013-06-01

    Introduction: We are intending to develop a novel food processing technology, Pressure Regulated Fermentation (PReF), using pressure sensitive (barosensitive) fermentation microorganisms. Objectives of our study are to clarify barosensitive mechanisms for application to PReF technology. We isolated Saccharomyces cerevisiae barosensitive mutant a924E1 that was derived from the parent KA31a. Methods: Gene expression levels were analyzed by DNA microarray. The altered genes of expression levels were classified according to the gene function. Mutated genes were estimated by mating and producing diploid strains and confirmed by PCR of mitochondrial DNA (mtDNA). Results and Discussion: Gene expression profiles showed that genes of `Energy' function and that of encoding protein localized in ``Mitochondria'' were significantly down regulated in the mutant. These results suggest the respiratory deficiency and relationship between barosensitivity and respiratory deficiency. Since the respiratory functions of diploids showed non Mendelian inheritance, the respiratory deficiency was indicated to be due to mtDNA mutation. PCR analysis showed that the region of COX1 locus was deleted. COX1 gene encodes the subunit 1 of cytochrome c oxidase. For this reason, barosensitivity is strongly correlated with mitochondrial functions.

  15. Mechanism and Regulation of Nucleocytoplasmic Trafficking of Smad

    Directory of Open Access Journals (Sweden)

    Chen Xiaochu

    2011-12-01

    Full Text Available Abstract Smad proteins are the intracellular mediators of transforming growth factor β (TGF-β signaling. Smads function as transcription factors and their activities require carboxyl-terminal phosphorylation by TGF-β receptor kinases which are embedded in the cell membrane. Therefore, the translocation of activated Smads from the cytoplasm into the nucleus is a rate-limiting step in TGF-β signal transduction into the nucleus. On the other hand, the export of Smads out of the nucleus turns off TGF-β effect. Such spatial control of Smad ensures a tight regulation of TGF-β target genes. Several cross-talk pathways have been shown to affect TGF-β signaling by impairing nuclear translocation of Smad, exemplifying the biological importance of the nuclear transport process. Many laboratories have investigated the underlying molecular mechanism of Smad nucleocytoplasmic translocation, combining genetics, biochemistry and sophisticated live cell imaging approaches. The last few years have witnessed the elucidation of several key players in Smad nuclear transport, most importantly the karyopherins that carry Smads across the nuclear envelope and nuclear pore proteins that facilitate the trans-nuclear envelope movement. The foundation is now set to further elucidate how the nuclear transport process is regulated and exploit such knowledge to manipulate TGF-β signaling. In this review we will discuss the current understanding of the molecular machinery responsible for nuclear import and export of Smads.

  16. Mechanisms and regulation of DNA replication initiation in eukaryotes.

    Science.gov (United States)

    Parker, Matthew W; Botchan, Michael R; Berger, James M

    2017-04-01

    Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and facilitate duplex DNA melting within these regions. In a typical cell cycle, initiation occurs only once per origin and each round of replication is tightly coupled to cell division. To avoid aberrant origin firing and re-replication, eukaryotes tightly regulate two events in the initiation process: loading of the replicative helicase, MCM2-7, onto chromatin by the origin recognition complex (ORC), and subsequent activation of the helicase by its incorporation into a complex known as the CMG. Recent work has begun to reveal the details of an orchestrated and sequential exchange of initiation factors on DNA that give rise to a replication-competent complex, the replisome. Here, we review the molecular mechanisms that underpin eukaryotic DNA replication initiation - from selecting replication start sites to replicative helicase loading and activation - and describe how these events are often distinctly regulated across different eukaryotic model organisms.

  17. Research on Wetting-Drying Cycles’ Effect on the Physical and Mechanical Properties of Expansive Soil Improved by OTAC-KCl

    Directory of Open Access Journals (Sweden)

    Bao-tian Wang

    2015-01-01

    Full Text Available Expansive soil experiences periodic swelling and shrinkage during the alternate wet and dry environments, which will result in severe damage to the slope stability. In this study, a promising modifier OTAC-KCl is introduced, which has a good diffusivity and is soluble in water or other solvents easily. Firstly, a reasonable combination of ameliorant 0.3% STAC and 3% KCl is chosen referring to the free swell test. Then, the best curing period, 14 days, is gotten from UCS tests. The effect of wetting and drying cycles on engineering properties of expansive soil improved by OTAC-KCl admixtures after 14-day curing is also studied accordingly. Both treated and untreated expansive soil samples are prepared for the cyclic wetting-drying tests which mainly include cyclic swelling potential and cyclic strength tests. Experimental results show that the swelling potential of expansive soil samples stabilized with OTAC-KCl is suppressed efficiently, and the untreated soil specimens will collapse when immersed in water while the treated specimens keep in good conditions. Moreover, expansive soil samples modified with 0.3% OTAC + 3% KCl show enough durability on the swelling ability, shear strength, and unconfined compressive strength, which means, that both the physical and the mechanical properties of stabilized expansive soil have been improved effectively.

  18. Fork stalling and template switching as a mechanism for polyalanine tract expansion affecting the DYC mutant of HOXD13, a new murine model of synpolydactyly.

    Science.gov (United States)

    Cocquempot, Olivier; Brault, Véronique; Babinet, Charles; Herault, Yann

    2009-09-01

    Polyalanine expansion diseases are proposed to result from unequal crossover of sister chromatids that increases the number of repeats. In this report we suggest an alternative mechanism we put forward while we investigated a new spontaneous mutant that we named "Dyc" for "Digit in Y and Carpe" phenotype. Phenotypic analysis revealed an abnormal limb patterning similar to that of the human inherited congenital disease synpolydactyly (SPD) and to the mouse mutant model Spdh. Both human SPD and mouse Spdh mutations affect the Hoxd13 gene within a 15-residue polyalanine-encoding repeat in the first exon of the gene, leading to a dominant negative HOXD13. Genetic analysis of the Dyc mutant revealed a trinucleotide expansion in the polyalanine-encoding region of the Hoxd13 gene resulting in a 7-alanine expansion. However, unlike the Spdh mutation, this expansion cannot result from a simple duplication of a short segment. Instead, we propose the fork stalling and template switching (FosTeS) described for generation of nonrecurrent genomic rearrangements as a possible mechanism for the Dyc polyalanine extension, as well as for other polyalanine expansions described in the literature and that could not be explained by unequal crossing over.

  19. Molecular mechanisms of aging and immune system regulation in Drosophila.

    Science.gov (United States)

    Eleftherianos, Ioannis; Castillo, Julio Cesar

    2012-01-01

    Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span.

  20. Co-Transcriptional Folding and Regulation Mechanisms of Riboswitches

    Directory of Open Access Journals (Sweden)

    Sha Gong

    2017-07-01

    Full Text Available Riboswitches are genetic control elements within non-coding regions of mRNA. These self-regulatory elements have been found to sense a range of small metabolites, ions, and other physical signals to exert regulatory control of transcription, translation, and splicing. To date, more than a dozen riboswitch classes have been characterized that vary widely in size and secondary structure. Extensive experiments and theoretical studies have made great strides in understanding the general structures, genetic mechanisms, and regulatory activities of individual riboswitches. As the ligand-dependent co-transcriptional folding and unfolding dynamics of riboswitches are the key determinant of gene expression, it is important to investigate the thermodynamics and kinetics of riboswitches both in the presence and absence of metabolites under the transcription. This review will provide a brief summary of the studies about the regulation mechanisms of the pbuE, SMK, yitJ, and metF riboswitches based on the ligand-dependent co-transcriptional folding of the riboswitches.

  1. Policies for Evaluation and Regulation of Higher Education in Brazil (1995-2010), Supporting the Expansion of Private Higher Education

    Science.gov (United States)

    Barreyro, Gladys Beatriz; Rothen, José Carlos; Santana, Andréia da Cunha Malheiros

    2014-01-01

    This paper analyzes the routes of the evaluation of higher education in Brazil, from 1995 until 2010. In 1995, during Fernando Henrique Cardoso's administration, higher education began a process of expansion through private enterprise. At that time, evaluation had a key role. The focus was the evaluation of courses conducted by the Ministry of…

  2. RhNAC2 and RhEXPA4 Are Involved in the Regulation of Dehydration Tolerance during the Expansion of Rose Petals1[C][W][OA

    Science.gov (United States)

    Dai, Fanwei; Zhang, Changqing; Jiang, Xinqiang; Kang, Mei; Yin, Xia; Lü, Peitao; Zhang, Xiao; Zheng, Yi; Gao, Junping

    2012-01-01

    Dehydration inhibits petal expansion resulting in abnormal flower opening and results in quality loss during the marketing of cut flowers. We constructed a suppression subtractive hybridization library from rose (Rosa hybrida) flowers containing 3,513 unique expressed sequence tags and analyzed their expression profiles during cycles of dehydration. We found that 54 genes were up-regulated by the first dehydration, restored or even down-regulated by rehydration, and once again up-regulated by the second dehydration. Among them, we identified a putative NAC family transcription factor (RhNAC2). With transactivation activity of its carboxyl-terminal domain in yeast (Saccharomyces cerevisiae) cell and Arabidopsis (Arabidopsis thaliana) protoplast, RhNAC2 belongs to the NAC transcription factor clade related to plant development in Arabidopsis. A putative expansin gene named RhEXPA4 was also dramatically up-regulated by dehydration. Silencing RhNAC2 or RhEXPA4 in rose petals by virus-induced gene silencing significantly decreased the recovery of intact petals and petal discs during rehydration. Overexpression of RhNAC2 or RhEXPA4 in Arabidopsis conferred strong drought tolerance in the transgenic plants. RhEXPA4 expression was repressed in RhNAC2-silenced rose petals, and the amino-terminal binding domain of RhNAC2 bound to the RhEXPA4 promoter. Twenty cell wall-related genes, including seven expansin family members, were up-regulated in Arabidopsis plants overexpressing RhNAC2. These data indicate that RhNAC2 and RhEXPA4 are involved in the regulation of dehydration tolerance during the expansion of rose petals and that RhEXPA4 expression may be regulated by RhNAC2. PMID:23093360

  3. Negative thermal expansion materials

    International Nuclear Information System (INIS)

    Evans, J.S.O.

    1997-01-01

    The recent discovery of negative thermal expansion over an unprecedented temperature range in ZrW 2 O 8 (which contracts continuously on warming from below 2 K to above 1000 K) has stimulated considerable interest in this unusual phenomenon. Negative and low thermal expansion materials have a number of important potential uses in ceramic, optical and electronic applications. We have now found negative thermal expansion in a large new family of materials with the general formula A 2 (MO 4 ) 3 . Chemical substitution dramatically influences the thermal expansion properties of these materials allowing the production of ceramics with negative, positive or zero coefficients of thermal expansion, with the potential to control other important materials properties such as refractive index and dielectric constant. The mechanism of negative thermal expansion and the phase transitions exhibited by this important new class of low-expansion materials will be discussed. (orig.)

  4. Mechanisms involved in regulation of osteoclastic differentiation by mechanical stress-loaded osteoblasts

    International Nuclear Information System (INIS)

    Kaneuji, Takeshi; Ariyoshi, Wataru; Okinaga, Toshinori; Toshinaga, Akihiro; Takahashi, Tetsu; Nishihara, Tatsuji

    2011-01-01

    Highlights: → Effect of compressive force on osteoblasts were examined. → Compressive force induced OPG expression and suppressed osteoclastogenesis. → This enhancement of OPG is dependent on Wnt/Ca2+ signal pathway. -- Abstract: Mechanical stress is known to be important for regulation of bone turnover, though the detailed mechanisms are not fully understood. In the present study, we examined the effect of mechanical stress on osteoblasts using a novel compression model. Mouse osteoblastic MC3T3-E1 cells were embedded in three-dimensional (3D) gels and cultured with continuous compressive force (0-10.0 g/cm 2 ) for 48 h, and the conditioned medium were collected. RAW264.7 cells were then incubated with the conditioned medium for various times in the presence of receptor activator of nuclear factor-κB ligand (RANKL). Conditioned medium was found to inhibit the differentiation of RAW264.7 cells into osteoclasts induced by RANKL via down-regulation of the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of IκBα, and nuclear translocation of p50 and p65. Interestingly, the conditioned medium also had a high level of binding activity to RANKL and blocked the binding of RANK to RANKL. Furthermore, the binding activity of conditioned medium to RANKL was reduced when the 3D gel was supplemented with KN-93, an inhibitor of non-canonical Wnt/Ca 2+ pathway. In addition, expression level of osteoprotegerin (OPG) mRNA was increased in time- and force-dependent manners, and remarkably suppressed by KN-93. These results indicate that osteoblastic cells subjected to mechanical stress produce OPG, which binds to RANKL. Furthermore, this binding activity strongly inhibited osteoclastogenesis through suppression of TRAF6 and the nuclear factor-kappa B (NF-κB) signaling pathway, suggesting that enhancement of OPG expression induced by mechanical stress is dependent on non-canonical Wnt/Ca 2+ pathway.

  5. Circuits Regulating Pleasure and Happiness-Mechanisms of Depression.

    Science.gov (United States)

    Loonen, Anton J M; Ivanova, Svetlana A

    2016-01-01

    According to our model of the regulation of appetitive-searching vs. distress-avoiding behaviors, the motivation to display these essential conducts is regulated by two parallel cortico-striato-thalamo-cortical, re-entry circuits, including the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side, to the centromedial amygdala on the other side, controls the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure). Hyperactive motivation to exhibit behavior related to avoidance of misery results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. In clinical depression, a mismatch exists between the activities of these two circuits: the balance is shifted to the misery-avoiding side. Five theories have been developed to explain the mechanism of depressive mood disorders, including the monoamine, biorhythm, neuro-endocrine, neuro-immune, and kindling/neuroplasticity theories. This paper describes these theories in relationship to the model (described above) of the regulation of reward-seeking vs. misery-avoiding behaviors. Chronic stress that leads to structural changes may induce the mismatch between the two systems. This mismatch leads to lack of pleasure, low energy, and indecisiveness, on one hand, and dysphoria, continuous worrying, and negative expectations on the other hand. The neuroplastic effects of monoamines, cortisol, and cytokines may mediate the induction of these structural alterations. Long-term exposure to stressful situations (particularly experienced during childhood) may lead to increased susceptibility for developing this condition. This hypothesis opens up the possibility of treating depression with

  6. Circuits regulating pleasure and happiness – mechanisms of depression

    Directory of Open Access Journals (Sweden)

    Anton J.M. Loonen

    2016-11-01

    Full Text Available According to our model of the regulation of appetitive-searching versus distress-avoiding behaviors, the motivation to display these essential conducts is regulated by two parallel cortico-striato-thalamo-cortical, re-entry circuits, including the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side, to the centromedial amygdala on the other side, controls the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (prefrontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure. Hyperactive motivation to exhibit behavior related to avoidance of misery results in dysphoria (relief leads to happiness. These two systems collaborate in a reciprocal fashion. In clinical depression, a mismatch exists between the activities of these two circuits: the balance is shifted to the misery-avoiding side. Five theories have been developed to explain the mechanism of depressive mood disorders, including the monoamine, biorhythm, neuro-endocrine, neuro-immune, and kindling/neuroplasticity theories. This paper describes these theories in relationship to the model (described above of the regulation of reward-seeking versus misery-avoiding behaviors. Chronic stress that leads to structural changes may induce the mismatch between the two systems. This mismatch leads to lack of pleasure, low energy, and indecisiveness, on one hand, and dysphoria, continuous worrying, and negative expectations on the other hand. The neuroplastic effects of monoamines, cortisol, and cytokines may mediate the induction of these structural alterations. Long-term exposure to stressful situations (particularly experienced during childhood may lead to increased susceptibility for developing this condition. This hypothesis opens up the possibility of treating

  7. The C. elegans engrailed homolog ceh-16 regulates the self-renewal expansion division of stem cell-like seam cells.

    Science.gov (United States)

    Huang, Xinxin; Tian, E; Xu, Yanhua; Zhang, Hong

    2009-09-15

    Stem cells undergo symmetric and asymmetric division to maintain the dynamic equilibrium of the stem cell pool and also to generate a variety of differentiated cells. The homeostatic mechanism controlling the choice between self-renewal and differentiation of stem cells is poorly understood. We show here that ceh-16, encoding the C. elegans ortholog of the transcription factor Engrailed, controls symmetric and asymmetric division of stem cell-like seam cells. Loss of function of ceh-16 causes certain seam cells, which normally undergo symmetric self-renewal expansion division with both daughters adopting the seam cell fate, to divide asymmetrically with only one daughter retaining the seam cell fate. The human engrailed homolog En2 functionally substitutes the role of ceh-16 in promoting self-renewal expansion division of seam cells. Loss of function of apr-1, encoding the C. elegans homolog of the Wnt signaling component APC, results in transformation of self-renewal maintenance seam cell division to self-renewal expansion division, leading to seam cell hyperplasia. The apr-1 mutation suppresses the seam cell division defect in ceh-16 mutants. Our study reveals that ceh-16 interacts with the Wnt signaling pathway to control the choice between self-renewal expansion and maintenance division and also demonstrates an evolutionarily conserved function of engrailed in promoting cell proliferation.

  8. Regulation of ribonucleotide reductase by Spd1 involves multiple mechanisms

    DEFF Research Database (Denmark)

    Nestoras, Konstantinos; Mohammed, Asma Hadi; Schreurs, Ann-Sofie

    2010-01-01

    The correct levels of deoxyribonucleotide triphosphates and their relative abundance are important to maintain genomic integrity. Ribonucleotide reductase (RNR) regulation is complex and multifaceted. RNR is regulated allosterically by two nucleotide-binding sites, by transcriptional control, and...

  9. mechanisms of drought resistance in grain ii:.stomatal regulation

    African Journals Online (AJOL)

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    STOMATAL REGULATION AND ROOT GROWTH ... maintenance of high plant water potential in common bean under stress was the function of stomatal regulation and/or root ... disadvantage since it will reduce CO2 fixation and hence may ...

  10. Membrane mechanisms and intracellular signalling in cell volume regulation

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay; Dunham, Philip B.

    1995-01-01

    Volume regulation, Signal transduction, Calcium-calmodulin, Stretch-activated channels, Eicosanoids, Macromolecular crowding, Cytoskeleton, Protein phosphorylation, dephosphorylation.......Volume regulation, Signal transduction, Calcium-calmodulin, Stretch-activated channels, Eicosanoids, Macromolecular crowding, Cytoskeleton, Protein phosphorylation, dephosphorylation....

  11. TIS21/(BTG2) negatively regulates estradiol-stimulated expansion of hematopoietic stem cells by derepressing Akt phosphorylation and inhibiting mTOR signal transduction.

    Science.gov (United States)

    Kim, Bong Cho; Ryu, Min Sook; Oh, S Paul; Lim, In Kyoung

    2008-09-01

    It has been known that 12-O-tetradecanoyl phorbol-13-acetate-inducible sequence 21 (TIS21), ortholog of human B-cell translocation gene 2, regulates expansions of stage-specific thymocytes and hematopoietic progenitors. In the present study, lineage-negative (Lin(-))/stem cell antigen-1-positive (Sca-1+)/c-Kit+ (LSK) cell content was significantly elevated in bone marrow (BM) of TIS21-knockout (TIS21(-/-)) female mice, suggesting 17beta-estradiol (E(2))-regulated progenitor expansion. E(2) induced DNA synthesis and cell proliferation of mouse embryonic fibroblasts (MEFs) isolated from TIS21(-/-) mice, but not wild type (WT). In contrast to WT, E(2) failed to activate protein kinase B (Akt) in the TIS21(-/-) MEFs, independent of extracellular signal-regulated kinase 1/2 (Erk1/2) activation. Despite attenuation of Akt activation, mammalian target of rapamycin (mTOR) was constitutively activated in the TIS21(-/-) MEFs. Furthermore, mitogen-activated protein kinase 1/2 inhibitor or knockdown of Erk1 could restore activation of Akt and downregulate mTOR. Immunoprecipitation showed Akt preferentially bound to phosphorylated Erk1/2 (p-Erk1/2) in TIS21(-/-) cells, but reconstitution of TIS21 inhibited their interaction. E(2)-injected TIS21(-/-) male mice also increased LSK cells in BM. Taken together, expansion of hematopoietic progenitors in TIS21(-/-) female mice might be through inhibition of Akt activation, and constitutive activation of mTOR via preferential binding of TIS21 to E(2)-induced p-Erk1/2, compared with that of Akt. Our results suggest that TIS21 plays a pivotal role in maintaining the hematopoietic stem cell compartment and hematopoiesis.

  12. Stiff mutant genes of Phycomyces target turgor pressure and wall mechanical properties to regulate elongation growth rate

    Directory of Open Access Journals (Sweden)

    Joseph K. E. Ortega

    2012-05-01

    Full Text Available Regulation of cell growth is paramount to all living organisms. In plants, algae and fungi, regulation of expansive growth of cells is required for development and morphogenesis. Also, many sensory responses of stage IVb sporangiophores of Phycomyces blakesleeanus are produced by regulating elongation growth rate (growth responses and differential elongation growth rate (tropic responses. Stiff mutant sporangiophores exhibit diminished tropic responses and are found to be defective in at least four genes; madD, madE, madF and madG. Prior experimental research suggests that the defective genes affect growth regulation, but this was not verified. All the growth of the single-celled stalk of the stage IVb sporangiophore occurs in a short region termed the growth zone. Prior experimental and theoretical research indicates that elongation growth rate of the stage IVb sporangiophore can be regulated by controlling the cell wall mechanical properties within the growth zone and the magnitude of the turgor pressure. A quantitative biophysical model for elongation growth rate is required to elucidate the relationship between wall mechanical properties and turgor pressure during growth regulation. In this study, it is hypothesized that the mechanical properties of the wall within the growth zone of stiff mutant sporangiophores are different compared to wild type. A biophysical equation for elongation growth rate is derived for fungal and plant cells with a growth zone. Two strains of stiff mutants are studied, C149 madD120 (- and C216 geo- (-. Experimental results demonstrate that turgor pressure is larger but irreversible deformation rates of the wall within the growth zone and growth zone length are smaller for stiff mutant sporangiophores compared to wild type. These findings explain the diminished tropic responses of the stiff mutant sporangiophores and suggest that the defective genes affect the amount of wall-building material delivered to the inner

  13. Mechanisms Down-Regulating Sprouty1, a Growth Inhibitor in Prostate Cancer

    National Research Council Canada - National Science Library

    Kwabi-Addo, Bernard

    2006-01-01

    .... I have demonstrated that Sprouty1 is down-regulated in human prostate cancer (PCa). The purpose of the present study is to characterize the molecular mechanisms regulating Sprouty1 expression in the human PCa. Results...

  14. Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination

    Directory of Open Access Journals (Sweden)

    JEROME A ROTH

    2006-01-01

    Full Text Available This review attempts to summarize and clarify our basic knowledge as to the various factors that potentially influence the risks imposed from chronic exposure to high atmospheric levels of manganese (Mn. The studies describe the interrelationship of the different systems in the body that regulate Mn homeostasis by characterizing specific, biological components involved in its systemic and cellular uptake and its elimination from the body. A syndrome known as manganism occurs when individuals are exposed chronically to high levels of Mn, consisting of reduced response speed, intellectual deficits, mood changes, and compulsive behaviors in the initial stages of the disorder to more prominent and irreversible extrapyramidal dysfunction resembling Parkinson's disease upon protracted exposure. Mn intoxication is most often associated with occupations in which abnormally high atmospheric concentrations prevail, such as in welding and mining. There are three potentially important routes by which Mn in inspired air can gain access the body to: 1 direct uptake into the CNS via uptake into the olfactory or trigeminal presynaptic nerve endings located in the nasal mucosa and the subsequent retrograde axonal transport directly into the CNS; 2 transport across the pulmonary epithelial lining and its subsequent deposition into lymph or blood; and/or 3 mucocilliary elevator clearance from the lung and the subsequent ingestion of the metal in the gastrointestinal tract. Each of these processes and their overall contribution to the uptake of Mn in the body is discussed in this review as well as a description of the various mechanisms that have been proposed for the transport of Mn across the blood-brain barrier which include both a transferrin-dependent and a transferrin-independent process that may involve store-operated Ca channels.

  15. Mechanisms of acid-base regulation in peritoneal dialysis.

    Science.gov (United States)

    Sow, Amadou; Morelle, Johann; Hautem, Nicolas; Bettoni, Carla; Wagner, Carsten A; Devuyst, Olivier

    2017-11-22

    Peritoneal dialysis (PD) contributes to restore acid-base homeostasis in patients with end-stage renal disease. The transport pathways for buffers and carbon dioxide (CO2) across the peritoneal membrane remain poorly understood. Combining well-established PD protocols, whole-body plethysmography and renal function studies in mice, we investigated molecular mechanisms of acid-base regulation in PD, including the potential role of the water channel aquaporin-1 (AQP1). After instillation in peritoneal cavity, the pH of acidic dialysis solutions increased within minutes to rapidly equilibrate with blood pH, whereas the neutral pH of biocompatible solutions remained constant. Predictions from the three-pore model of peritoneal transport suggested that local production of HCO3- accounts at least in part for the changes in intraperitoneal pH observed with acidic solutions. Carbonic anhydrase (CA) isoforms were evidenced in the peritoneal membrane and their inhibition with acetazolamide significantly decreased local production of HCO3- and delayed changes in intraperitoneal pH. On the contrary, genetic deletion of AQP1 had no effect on peritoneal transport of buffers and diffusion of CO2. Besides intraperitoneal modifications, the use of acidic dialysis solutions enhanced acid excretion both at pulmonary and renal levels. These findings suggest that changes in intraperitoneal pH during PD are mediated by bidirectional buffer transport and by CA-mediated production of HCO3- in the membrane. The use of acidic solutions enhances acid excretion through respiratory and renal responses, which should be considered in patients with renal failure. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  16. Mechanisms involved in regulation of osteoclastic differentiation by mechanical stress-loaded osteoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Kaneuji, Takeshi [Division of Oral and Maxillofacial Reconstructive Surgery, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Ariyoshi, Wataru; Okinaga, Toshinori; Toshinaga, Akihiro [Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Takahashi, Tetsu [Division of Oral and Maxillofacial Reconstructive Surgery, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Oral Bioresearch Center, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Nishihara, Tatsuji, E-mail: tatsujin@kyu-dent.ac.jp [Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Oral Bioresearch Center, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan)

    2011-04-29

    Highlights: {yields} Effect of compressive force on osteoblasts were examined. {yields} Compressive force induced OPG expression and suppressed osteoclastogenesis. {yields} This enhancement of OPG is dependent on Wnt/Ca2+ signal pathway. -- Abstract: Mechanical stress is known to be important for regulation of bone turnover, though the detailed mechanisms are not fully understood. In the present study, we examined the effect of mechanical stress on osteoblasts using a novel compression model. Mouse osteoblastic MC3T3-E1 cells were embedded in three-dimensional (3D) gels and cultured with continuous compressive force (0-10.0 g/cm{sup 2}) for 48 h, and the conditioned medium were collected. RAW264.7 cells were then incubated with the conditioned medium for various times in the presence of receptor activator of nuclear factor-{kappa}B ligand (RANKL). Conditioned medium was found to inhibit the differentiation of RAW264.7 cells into osteoclasts induced by RANKL via down-regulation of the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of I{kappa}B{alpha}, and nuclear translocation of p50 and p65. Interestingly, the conditioned medium also had a high level of binding activity to RANKL and blocked the binding of RANK to RANKL. Furthermore, the binding activity of conditioned medium to RANKL was reduced when the 3D gel was supplemented with KN-93, an inhibitor of non-canonical Wnt/Ca{sup 2+} pathway. In addition, expression level of osteoprotegerin (OPG) mRNA was increased in time- and force-dependent manners, and remarkably suppressed by KN-93. These results indicate that osteoblastic cells subjected to mechanical stress produce OPG, which binds to RANKL. Furthermore, this binding activity strongly inhibited osteoclastogenesis through suppression of TRAF6 and the nuclear factor-kappa B (NF-{kappa}B) signaling pathway, suggesting that enhancement of OPG expression induced by mechanical stress is dependent on non-canonical Wnt

  17. Effects of volumetric expansion in molecular crystals: A quantum mechanical investigation on aspirin and paracetamol most stable polymorphs

    Science.gov (United States)

    Adhikari, Kapil; Flurchick, Kenneth M.; Valenzano, Loredana

    2015-02-01

    This work reports a study performed at hybrid semi-empirical density functional level (B3LYP-D2*) of the physico-chemical properties of aspirin (acetylsalicylic acid) and paracetamol (acetaminophen) in their most stable crystalline forms. It is shown how effects arising from volumetric expansions influence the properties of the materials. Structural, energetic, and vibrational properties are in good agreement with experimental values reported at temperatures far from 0 K. Results show that the proposed approach is reliable enough to reproduce effects of volumetric expansion on lattice energies and other measurable physico-chemical observables related to inter-molecular forces.

  18. A combined stretching-tilting mechanism produces negative, zero and positive linear thermal expansion in a semi-flexible Cd(II)-MOF.

    Science.gov (United States)

    Lama, Prem; Das, Raj Kumar; Smith, Vincent J; Barbour, Leonard J

    2014-06-21

    A novel semi-flexible Cd(II)-MOF has been synthesized and characterized by variable temperature powder and single-crystal X-ray diffraction. The material displays an unusual combination of thermal expansion (TE) i.e. negative, zero and positive, which is an extremely rare finding, especially for metal-organic frameworks as a result of a combined stretching-tilting mechanism.

  19. Whole transcriptome analysis for T cell receptor-affinity and IRF4-regulated clonal expansion of T cells

    Directory of Open Access Journals (Sweden)

    Wei Shi

    2014-12-01

    Full Text Available Clonal population expansion of T cells during an immune response is dependent on the affinity of the T cell receptor (TCR for its antigen [1]. However, there is little understanding of how this process is controlled transcriptionally. We found that the transcription factor IRF4 was induced in a manner dependent on TCR-affinity and was critical for the clonal expansion and maintenance of effector function of antigen-specific CD8+ T cells. We performed a genome-wide expression profiling experiment using RNA sequencing technology (RNA-seq to interrogate global expression changes when IRF4 was deleted in CD8+ T cells activated with either a low or high affinity peptide ligand. This allowed us not only to determine IRF4-dependent transcriptional changes but also to identify transcripts dependent on TCR-affinity [2]. Here we describe in detail the analyses of the RNA-seq data, including quality control, read mapping, quantification, normalization and assessment of differential gene expression. The RNA-seq data can be accessed from Gene Expression Omnibus database (accession number GSE49929.

  20. Circuits Regulating Pleasure and Happiness-Mechanisms of Depression

    NARCIS (Netherlands)

    Loonen, Anton J.M.; Ivanova, Svetlana A.

    2016-01-01

    According to our model of the regulation of appetitive-searching vs. distress-avoiding behaviors, the motivation to display these essential conducts is regulated by two parallel cortico-striato-thalamo-cortical, re-entry circuits, including the core and the shell parts of the nucleus accumbens,

  1. Quantifying the mechanical micro-environment during three-dimensional cell expansion on microbeads by means of individual cell-based modelling.

    Science.gov (United States)

    Smeets, Bart; Odenthal, Tim; Tijskens, Engelbert; Ramon, Herman; Van Oosterwyck, Hans

    2013-10-01

    Controlled in vitro three-dimensional cell expansion requires culture conditions that optimise the biophysical micro-environment of the cells during proliferation. In this study, we propose an individual cell-based modelling platform for simulating the mechanics of cell expansion on microcarriers. The lattice-free, particle-based method considers cells as individual interacting particles that deform and move over time. The model quantifies how the mechanical micro-environment of individual cells changes during the time of confluency. A sensitivity analysis is performed, which shows that changes in the cell-specific properties of cell-cell adhesion and cell stiffness cause the strongest change in the mechanical micro-environment of the cells. Furthermore, the influence of the mechanical properties of cells and microbead is characterised. The mechanical micro-environment is strongly influenced by the adhesive properties and the size of the microbead. Simulations show that even in the absence of strong biological heterogeneity, a large heterogeneity in mechanical stresses can be expected purely due to geometric properties of the culture system.

  2. Nitric oxide, prostaglandins and angiotensin II in the regulation of renal medullary blood flow during volume expansion.

    Science.gov (United States)

    Moreno, Carol; Llinás, María T; Rodriguez, Francisca; Moreno, Juan M; Salazar, F Javier

    2016-03-01

    Regulation of medullary blood flow (MBF) is essential in maintaining renal function and blood pressure. However, it is unknown whether outer MBF (OMBF) and papillary blood flow (PBF) are regulated independently when extracellular volume (ECV) is enhanced. The aim of this study was to determine whether OMBF and PBF are differently regulated and whether there is an interaction between nitric oxide (NO), prostaglandins (PGs) and angiotensin II (Ang II) in regulating OMBF and PBF when ECV is enhanced. To achieve these goals, OMBF and PBF were measured by laser-Doppler in volume-expanded rats treated with a cyclooxygenase inhibitor (meclofenamate, 3 mg/kg) and/or a NO synthesis inhibitor (L-nitro-arginine methyl ester (L-NAME), 3 μg/kg/min) and/or Ang II (10 ng/kg/min). OMBF was unchanged by NO or PGs synthesis inhibition but decreased by 36 % (P blood flows to the outer medulla and renal papilla are differently regulated and showing that there is a complex interaction between NO, PGs and Ang II in regulating OMBF and PBF when ECV is enhanced.

  3. Neural mechanisms of emotion regulation in childhood anxiety

    NARCIS (Netherlands)

    Hum, K.M.; Manassis, K.; Lewis, M.D.

    2013-01-01

    Background:: The present study was designed to examine the cortical processes that mediate cognitive regulation in response to emotion-eliciting stimuli in anxious children. Methods:: Electroencephalographic (EEG) activity was recorded from clinically anxious children (n = 29) and typically

  4. Measurement of Mechanical Property and Thermal Expansion Coefficient of Carbon-Nano tube-Reinforced Epoxy Composites

    International Nuclear Information System (INIS)

    Ku, Min Ye; Kim, Jung Hyun; Kang, Hee Yong; Lee, Gyo Woo

    2013-01-01

    By using shear mixing and ultrasonication, we fabricated specimens of well-dispersed multi-walled carbon nano tube composites. To confirm the proper dispersion of the filler, we used scanning electron microscopy images for quantitative evaluation and a tensile test for qualitative assessment. Furthermore, the coefficients of thermal expansion of several specimens having different filler contents were calculated from the measured thermal strains and temperatures of the specimens. Based on the microscopy images of the well-dispersed fillers and the small deviations in the measurements of the tensile strength and stiffness, we confirmed the proper dispersion of absentee in the epoxy. As the filler contents were increased, the values of tensile strength increased from 58.33 to 68.81 MPa, and those of stiffness increased from 2.93 to 3.27 GPa. At the same time, the coefficients of thermal expansion decreased. This implies better thermal stability of the specimen

  5. MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice

    NARCIS (Netherlands)

    J.C.M. Meenhuis (Annemarie); P. van Veelen (Peter); H. de Looper (Hans); N. van Boxtel (Nicole); I.J. van den Berge (Iris); S.M. Sun; E. Taskesen (Erdogan); P. Stern (Patrick); A. de Ru (Arnoud); A.J. van Adrichem (Arjan); J.A.A. Demmers (Jeroen); M. Jongen-Lavrencic (Mojca); B. Löwenberg (Bob); I.P. Touw (Ivo); P.A. Sharp (Phillip); S.J. Erkeland (Stefan)

    2011-01-01

    textabstractMicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain largely unknown. Here, we show that ectopic expression of miR-17, -20,-93 and -106, all AAAGUGC seed-containing miRNAs, increases proliferation, colony outgrowth and replating capacity of

  6. A new mechanism for periodic bursting of the recirculation region in the flow through a sudden expansion in a circular pipe

    Science.gov (United States)

    Lebon, Benoit; Nguyen, Minh Quan; Peixinho, Jorge; Shadloo, Mostafa Safdari; Hadjadj, Abdellah

    2018-03-01

    We report the results of a combined experimental and numerical study of specific finite-amplitude disturbances for transition to turbulence in the flow through a circular pipe with a sudden expansion. The critical amplitude thresholds for localized turbulent patch downstream of the expansion scale with the Reynolds number with a power law exponent of -2.3 for experiments and -2.8 for simulations. A new mechanism for the periodic bursting of the recirculation region is uncovered where the asymmetric recirculation flow develops a periodic dynamics: a secondary recirculation breaks the symmetry along the pipe wall and bursts into localized turbulence, which travels downstream and relaminarises. Flow visualizations show a simple flow pattern of three waves forming, growing, and bursting.

  7. Vitamin K2-enhanced liver regeneration is associated with oval cell expansion and up-regulation of matrilin-2 expression in 2-AAF/PH rat model.

    Science.gov (United States)

    Lin, M; Sun, P; Zhang, G; Xu, X; Liu, G; Miao, H; Yang, Y; Xu, H; Zhang, L; Wu, P; Li, M

    2014-03-01

    Normal liver has a great potential of regenerative capacity after partial hepatectomy. In clinic, however, most patients receiving partial hepatectomy are usually suffering from chronic liver diseases with severely damaged hepatocyte population. Under these conditions, activation of hepatic progenitor cell (oval cell in rodents) population might be considered as an alternative mean to enhance liver functional recovery. Vitamin K2 has been shown to promote liver functional recovery in patients with liver cirrhosis. In this study, we explored the possibility of vitamin K2 treatment in activating hepatic oval cell for liver regeneration with the classic 2-acetamido-fluorene/partial hepatectomy (2-AAF/PH) model in Sprague-Dawley rats. In 2-AAF/PH animals, vitamin K2 treatment induced a dose-dependent increase of liver regeneration as assessed by the weight ratio of remnant liver versus whole body and by measuring serum albumin level. In parallel, a drastic expansion of oval cell population as assessed by anti-OV6 and anti-CK19 immunostaining was noticed in the periportal zone of the remnant liver. Since matrilin-2 was linked to oval cell proliferation and liver regeneration after partial hepatectomy, we assessed its expression at both the mRNA and protein levels. The results revealed a significant increase after vitamin K2 treatment in parallel with the expansion of oval cell population. Consistently, knocking down matrilin-2 expression in vivo largely reduced vitamin K2-induced liver regeneration and oval cell proliferation in 2-AAF/PH animals. In conclusion, these data suggest that vitamin K2 treatment enhances liver regeneration after partial hepatectomy, which is associated with oval cell expansion and matrilin-2 up-regulation.

  8. The autoregulatory loop: A common mechanism of regulation of key ...

    Indian Academy of Sciences (India)

    2016-08-26

    Aug 26, 2016 ... The genes involved in the sex determination cascade such as Sex-lethal (Sxl) in Drosophila melanogaster, transformer (tra) in many other dipterans, coleopterans and hymenopterans, Feminizer (fem) in Apis mellifera, and IGF-II mRNA-binding protein (Bmimp) in Bombyx mori are reported to be regulated ...

  9. Goal setting as a self-regulation mechanism

    NARCIS (Netherlands)

    Suvorov, A.; van de Ven, J.

    2009-01-01

    We develop a theory of self-regulation based on goal setting for an agent with present-biased preferences. Preferences are assumed to be reference-dependent and exhibit loss aversion, as in prospect theory. The reference point is determined endogenously as an optimal self-sustaining goal. The

  10. Goal setting as a self-regulation mechanism

    NARCIS (Netherlands)

    Suvorov, A.; van de Ven, J.

    2008-01-01

    We develop a theory of self-regulation based on goal setting for an agent with present-biased preferences. Preferences are assumed to be reference-dependent and exhibit loss aversion, as in prospect theory. The reference point is determined endogenously as an optimal self-sustaining goal. The

  11. Neural Mechanisms of Emotion Regulation in Autism Spectrum Disorder

    Science.gov (United States)

    Richey, J. Anthony; Damiano, Cara R.; Sabatino, Antoinette; Rittenberg, Alison; Petty, Chris; Bizzell, Josh; Voyvodic, James; Heller, Aaron S.; Coffman, Marika C.; Smoski, Moria; Davidson, Richard J.; Dichter, Gabriel S.

    2015-01-01

    Autism spectrum disorder (ASD) is characterized by high rates of comorbid internalizing and externalizing disorders. One mechanistic account of these comorbidities is that ASD is characterized by impaired emotion regulation (ER) that results in deficits modulating emotional responses. We assessed neural activation during cognitive reappraisal of…

  12. [Expansive development of the French regulation of the genetic print files after the recent reforms (Part I)].

    Science.gov (United States)

    Etxeberria Guridi, José Francisco

    2003-01-01

    French regulations related to "genetic prints" and its later incorporation to an automatized file in the frame of the penal process, initially deserved (1998) a positive judgement due to the guarantees surrounding such techniques, considering that with its use an interference was made with the freedom and rights of the individual. This primary regulation is watching a legislative evolution that brings serious doubts about the current guarantee system. A couple of legal reforms with security as their main axis (2001 and 2003) give more importance to the "genetic print" file by extending the causes in which it starts functioning going against the proportionality that must be observed when freedoms and rights of the individual can be affected.

  13. Genome-Wide Phylogenetic Comparative Analysis of Plant Transcriptional Regulation: A Timeline of Loss, Gain, Expansion, and Correlation with Complexity

    OpenAIRE

    Lang, Daniel; Weiche, Benjamin; Timmerhaus, Gerrit; Richardt, Sandra; Ria?o-Pach?n, Diego M.; Corr?a, Luiz G. G.; Reski, Ralf; Mueller-Roeber, Bernd; Rensing, Stefan A.

    2010-01-01

    Evolutionary retention of duplicated genes encoding transcription-associated proteins (TAPs, comprising transcription factors and other transcriptional regulators) has been hypothesized to be positively correlated with increasing morphological complexity and paleopolyploidizations, especially within the plant kingdom. Here, we present the most comprehensive set of classification rules for TAPs and its application for genome-wide analyses of plants and algae. Using a dated species tree and phy...

  14. MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1–regulated pathways in mice

    Science.gov (United States)

    Meenhuis, Annemarie; van Veelen, Peter A.; de Looper, Hans; van Boxtel, Nicole; van den Berge, Iris J.; Sun, Su M.; Taskesen, Erdogan; Stern, Patrick; de Ru, Arnoud H.; van Adrichem, Arjan J.; Demmers, Jeroen; Jongen-Lavrencic, Mojca; Löwenberg, Bob; Touw, Ivo P.; Sharp, Phillip A.

    2011-01-01

    MicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain largely unknown. Here, we show that ectopic expression of miR-17, -20,-93 and -106, all AAAGUGC seed-containing miRNAs, increases proliferation, colony outgrowth and replating capacity of myeloid progenitors and results in enhanced P-ERK levels. We found that these miRNAs are endogenously and abundantly expressed in myeloid progenitors and down-regulated in mature neutrophils. Quantitative proteomics identified sequestosome 1 (SQSTM1), an ubiquitin-binding protein and regulator of autophagy-mediated protein degradation, as a major target for these miRNAs in myeloid progenitors. In addition, we found increased expression of Sqstm1 transcripts during CSF3-induced neutrophil differentiation of 32D-CSF3R cells and an inverse correlation of SQSTM1 protein levels and miR-106 expression in AML samples. ShRNA-mediated silencing of Sqstm1 phenocopied the effects of ectopic miR-17/20/93/106 expression in hematopoietic progenitors in vitro and in mice. Further, SQSTM1 binds to the ligand-activated colony-stimulating factor 3 receptor (CSF3R) mainly in the late endosomal compartment, but not in LC3 positive autophagosomes. SQSTM1 regulates CSF3R stability and ligand-induced mitogen-activated protein kinase signaling. We demonstrate that AAAGUGC seed-containing miRNAs promote cell expansion, replating capacity and signaling in hematopoietic cells by interference with SQSTM1-regulated pathways. PMID:21628417

  15. Up-regulating the abscisic acid inactivation gene ZmABA8ox1b contributes to seed germination heterosis by promoting cell expansion.

    Science.gov (United States)

    Li, Yangyang; Wang, Cheng; Liu, Xinye; Song, Jian; Li, Hongjian; Sui, Zhipeng; Zhang, Ming; Fang, Shuang; Chu, Jinfang; Xin, Mingming; Xie, Chaojie; Zhang, Yirong; Sun, Qixin; Ni, Zhongfu

    2016-04-01

    Heterosis has been widely used in agriculture, but the underlying molecular principles are still largely unknown. During seed germination, we observed that maize (Zea mays) hybrid B73/Mo17 was less sensitive than its parental inbred lines to exogenous abscisic acid (ABA), and endogenous ABA content in hybrid embryos decreased more rapidly than in the parental inbred lines. ZmABA8ox1b, an ABA inactivation gene, was consistently more highly up-regulated in hybrid B73/Mo17 than in its parental inbred lines at early stages of seed germination. Moreover, ectopic expression of ZmABA8ox1b obviously promoted seed germination in Arabidopsis Remarkably, microscopic observation revealed that cell expansion played a major role in the ABA-mediated maize seed germination heterosis, which could be attributed to the altered expression of cell wall-related genes. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  16. Fibroblast Growth Factor signaling regulates the expansion of A6-expressing hepatocytes in association with AKT-dependent β-catenin activation

    Science.gov (United States)

    Utley, Sarah; James, David; Mavila, Nirmala; Nguyen, Marie V.; Vendryes, Christopher; Salisbury, S. Michael; Phan, Jennifer; Wang, Kasper S.

    2014-01-01

    Background & Aims Fibroblast Growth Factors (FGFs) promote the proliferation and survival of hepatic progenitor cells (HPCs) via AKT-dependent β-catenin activation. Moreover, the emergence of hepatocytes expressing the HPC marker A6 during 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury is mediated partly by FGF and β-catenin signaling. Herein, we investigate the role of FGF signaling and AKT-mediated β-catenin activation in acute DDC liver injury. Methods Transgenic mice were fed DDC chow for 14 days concurrent with either Fgf10 over-expression or inhibition of FGF signaling via expression of soluble dominant-negative FGF Receptor (R)-2IIIb. Results After 14 days of DDC treatment, there was an increase in periportal cells expressing FGFR1, FGFR2, and AKT-activated phospho-Serine 552 (pSer552) β-CATENIN in association with up-regulation of genes encoding FGFR2IIIb ligands, Fgf7, Fgf10, and Fgf22. In response to Fgf10 over-expression, there was an increase in the number of pSer552-β-CATENIN(positive)+ive periportal cells as well as cells co-positive for A6 and hepatocyte marker, Hepatocyte Nuclear Factor-4α (HNF4α). A similar expansion of A6+ive cells was observed after Fgf10 over-expression with regular chow and after partial hepatectomy during ethanol toxicity. Inhibition of FGF signaling increased the periportal A6+iveHNF4α+ive cell population while reducing centrolobular A6+ive HNF4α+ive cells. AKT inhibition with Wortmannin attenuated FGF10-mediated A6+iveHNF4α+ive cell expansion. In vitro analyses using FGF10 treated HepG2 cells demonstrated AKT-mediated β-CATENIN activation but not enhanced cell migration. Conclusion During acute DDC treatment, FGF signaling promotes the expansion of A6-expressing liver cells partly via AKT-dependent activation of β-CATENIN expansion of A6+ive periportal cells and possibly by reprogramming of centrolobular hepatocytes. PMID:24365171

  17. Basic mechanisms of iron metabolism regulation and their clinical significance

    Directory of Open Access Journals (Sweden)

    L. M. Meshсheryakova

    2014-01-01

    Full Text Available This article is а composition of literature and experimental data of iron metabolism. There were studied the level of DMT-1, ferroportin, hepcidin at different stages of anemia and hemochromatosis. It is clear that the level of DMT-1 regulates by the hepcidin. Increaseing of the hepcidin concentration and decreasing DMT-1 level in patients with hemochromatosis explained good results of treatment.

  18. Basic mechanisms of iron metabolism regulation and their clinical significance

    Directory of Open Access Journals (Sweden)

    L. M. Meshсheryakova

    2015-01-01

    Full Text Available This article is а composition of literature and experimental data of iron metabolism. There were studied the level of DMT-1, ferroportin, hepcidin at different stages of anemia and hemochromatosis. It is clear that the level of DMT-1 regulates by the hepcidin. Increaseing of the hepcidin concentration and decreasing DMT-1 level in patients with hemochromatosis explained good results of treatment.

  19. Mechanism and regulation of epithelial–mesenchymal transition in cancer

    Directory of Open Access Journals (Sweden)

    Guttilla Reed IK

    2015-08-01

    Full Text Available Irene K Guttilla ReedDepartment of Biology, University of Saint Joseph, West Hartford, CT, USAAbstract: During development and the pathogenesis of certain diseases, including cancer, the epithelial–mesenchymal transition (EMT program is activated. It is hypothesized that EMT plays a major role in tumor invasion and the establishment of distant metastases. Metastatic disease is responsible for the vast majority of cancer-related deaths, which provides a precedent for elucidating pathways that regulate EMT. EMT is defined as the transition of cells with an epithelial phenotype into cells with a mesenchymal phenotype through a series of genetic and environmental events. This leads to the repression of epithelial-associated markers, upregulation of mesenchymal-associated markers, a loss of cell polarity and adhesion, and increased cell motility and invasiveness. EMT is a reversible and dynamic process, and can be regulated by signals from the microenvironment such as inflammation, hypoxia, and growth factors or epigenetically via microRNAs. These signals modulate key EMT-associated transcription factors and effector proteins that control cellular phenotype and regulate tumor plasticity in response to changing conditions in the microenvironment and the progressive nature of cancer. Understanding the complex regulatory networks controlling EMT can provide insight into tumor progression and metastasis.Keywords: EMT, metastasis, microRNA, transcription factor, growth factor, tumor progression

  20. The role of focal adhesion kinase in the regulation of cellular mechanical properties

    International Nuclear Information System (INIS)

    Mierke, Claudia Tanja

    2013-01-01

    The regulation of mechanical properties is necessary for cell invasion into connective tissue or intra- and extravasation through the endothelium of blood or lymph vessels. Cell invasion is important for the regulation of many healthy processes such as immune response reactions and wound healing. In addition, cell invasion plays a role in disease-related processes such as tumor metastasis and autoimmune responses. Until now the role of focal adhesion kinase (FAK) in regulating mechanical properties of cells and its impact on cell invasion efficiency is still not well known. Thus, this review focuses on mechanical properties regulated by FAK in comparison to the mechano-regulating protein vinculin. Moreover, it points out the connection between cancer cell invasion and metastasis and FAK by showing that FAK regulates cellular mechanical properties required for cellular motility. Furthermore, it sheds light on the indirect interaction of FAK with vinculin by binding to paxillin, which then impairs the binding of paxillin to vinculin. In addition, this review emphasizes whether FAK fulfills regulatory functions similar to vinculin. In particular, it discusses the differences and the similarities between FAK and vinculin in regulating the biomechanical properties of cells. Finally, this paper highlights that both focal adhesion proteins, vinculin and FAK, synergize their functions to regulate the mechanical properties of cells such as stiffness and contractile forces. Subsequently, these mechanical properties determine cellular invasiveness into tissues and provide a source sink for future drug developments to inhibit excessive cell invasion and hence, metastases formation. (paper)

  1. The role of focal adhesion kinase in the regulation of cellular mechanical properties

    Science.gov (United States)

    Mierke, Claudia Tanja

    2013-12-01

    The regulation of mechanical properties is necessary for cell invasion into connective tissue or intra- and extravasation through the endothelium of blood or lymph vessels. Cell invasion is important for the regulation of many healthy processes such as immune response reactions and wound healing. In addition, cell invasion plays a role in disease-related processes such as tumor metastasis and autoimmune responses. Until now the role of focal adhesion kinase (FAK) in regulating mechanical properties of cells and its impact on cell invasion efficiency is still not well known. Thus, this review focuses on mechanical properties regulated by FAK in comparison to the mechano-regulating protein vinculin. Moreover, it points out the connection between cancer cell invasion and metastasis and FAK by showing that FAK regulates cellular mechanical properties required for cellular motility. Furthermore, it sheds light on the indirect interaction of FAK with vinculin by binding to paxillin, which then impairs the binding of paxillin to vinculin. In addition, this review emphasizes whether FAK fulfills regulatory functions similar to vinculin. In particular, it discusses the differences and the similarities between FAK and vinculin in regulating the biomechanical properties of cells. Finally, this paper highlights that both focal adhesion proteins, vinculin and FAK, synergize their functions to regulate the mechanical properties of cells such as stiffness and contractile forces. Subsequently, these mechanical properties determine cellular invasiveness into tissues and provide a source sink for future drug developments to inhibit excessive cell invasion and hence, metastases formation.

  2. Mechanisms for the environmental regulation of gene expression

    Indian Academy of Sciences (India)

    2005-01-07

    Jan 7, 2005 ... The environment can play a significant role in the production of phenotypes. However, the developmental mechanisms by which the environmental agents effect normal development are just becoming known. At least three paths have been found through which the environment can modify gene activity.

  3. Rapid regulation of leaf photosynthesis, carbohydrate status and leaf area expansion to maintain growth in irregular light environments

    DEFF Research Database (Denmark)

    Kjær, Katrine Heinsvig

    2012-01-01

    to maintain carbohydrate status and growth in unpredictable light environments. Our recent results show rapid regulation of photosynthesis and leaf carbohydrate status to maintain growth and light interception in dynamic light environments when campanula, rose and chrysanthemum were grown in a cost......-efficient light control system. Plant dry matter production was in all cases linear related to DLI, despite changes in daily light duration and light intensity of supplemental light suggesting that DLI is the main limiting factor for the prediction of production time in optimal temperature conditions. The results......Protected plant productions in northern latitudes rely heavily on supplemental light use to extend the number of light hours during the day. To conserve electricity and lower costs, a low-energy input system use supplemental lights preferable during less expensive off-peak hours and turn lighting...

  4. Neurohumoral mechanisms of keratinocytes regulation in diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Ekaterina Viktorovna Artemova

    2016-12-01

    Full Text Available The extent of damage to the nervous, vascular and microcirculatory systems in diabetic patients determine the regulation of physiological events that lead to the formation of chronic wounds, reduction of patient quality of life and increase of the financial value of medical care. Successful physiological repair is impossible without the successive phases of inflammation, proliferation and wound healing. Keratinocytes are the major cellular barrier components of the epidermis. These cells play an important role in physiological repair, as suggested by recent research, with many cells able to secrete steroid hormones de novo. Damage to the integrity of the skin leads to keratinocyte activation, triggering a cascade of reactions that contribute to changes in epidermal cell phenotype and lead to their proliferation and migration, analogous to changes in cellular adhesion and configuration of the cytoskeleton. An open question remains as to how the keratinocyte cell cycle, which is altered under conditions of hyperglycemia, and neurotransmitter metabolism during different stages of physiological repair are regulated. Understanding these processes will provide a scientific basis for the development of new targets for pharmacotherapies.

  5. Sexual polyploidization in plants--cytological mechanisms and molecular regulation.

    Science.gov (United States)

    De Storme, Nico; Geelen, Danny

    2013-05-01

    In the plant kingdom, events of whole genome duplication or polyploidization are generally believed to occur via alterations of the sexual reproduction process. Thereby, diploid pollen and eggs are formed that contain the somatic number of chromosomes rather than the gametophytic number. By participating in fertilization, these so-called 2n gametes generate polyploid offspring and therefore constitute the basis for the establishment of polyploidy in plants. In addition, diplogamete formation, through meiotic restitution, is an essential component of apomixis and also serves as an important mechanism for the restoration of F1 hybrid fertility. Characterization of the cytological mechanisms and molecular factors underlying 2n gamete formation is therefore not only relevant for basic plant biology and evolution, but may also provide valuable cues for agricultural and biotechnological applications (e.g. reverse breeding, clonal seeds). Recent data have provided novel insights into the process of 2n pollen and egg formation and have revealed multiple means to the same end. Here, we summarize the cytological mechanisms and molecular regulatory networks underlying 2n gamete formation, and outline important mitotic and meiotic processes involved in the ectopic induction of sexual polyploidization. © 2013 Ghent University. New Phytologist © 2013 New Phytologist Trust.

  6. Nuclear deformation and expression change of cartilaginous genes during in vitro expansion of chondrocytes

    International Nuclear Information System (INIS)

    Hoshiba, Takashi; Yamada, Tomoe; Lu, Hongxu; Kawazoe, Naoki; Tateishi, Tetsuya; Chen, Guoping

    2008-01-01

    Cartilaginous gene expression decreased when chondrocytes were expanded on cell-culture plates. Understanding the dedifferentiation mechanism may provide valuable insight into cartilage tissue engineering. Here, we demonstrated the relationship between the nuclear shape and gene expression during in vitro expansion culture of chondrocytes. Specifically, the projected nuclear area increased and cartilaginous gene expressions decreased during in vitro expansion culture. When the nuclear deformation was recovered by cytochalasin D treatment, aggrecan expression was up-regulated and type I collagen (Col1a2) expression was down-regulated. These results suggest that nuclear deformation may be one of the mechanisms for chondrocyte dedifferentiation during in vitro expansion culture

  7. Stem cell aging: mechanisms, regulators and therapeutic opportunities

    Science.gov (United States)

    Oh, Juhyun; Lee, Yang David; Wagers, Amy J

    2014-01-01

    Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic ‘memory’ that is indelibly written or one that can be reset. PMID:25100532

  8. Mechanical stress as a regulator of cell motility

    Science.gov (United States)

    Putelat, T.; Recho, P.; Truskinovsky, L.

    2018-01-01

    The motility of a cell can be triggered or inhibited not only by an applied force but also by a mechanically neutral force couple. This type of loading, represented by an applied stress and commonly interpreted as either squeezing or stretching, can originate from extrinsic interaction of a cell with its neighbors. To quantify the effect of applied stresses on cell motility we use an analytically transparent one-dimensional model accounting for active myosin contraction and induced actin turnover. We show that stretching can polarize static cells and initiate cell motility while squeezing can symmetrize and arrest moving cells. We show further that sufficiently strong squeezing can lead to the loss of cell integrity. The overall behavior of the system depends on the two dimensionless parameters characterizing internal driving (chemical activity) and external loading (applied stress). We construct a phase diagram in this parameter space distinguishing between static, motile, and collapsed states. The obtained results are relevant for the mechanical understanding of contact inhibition and the epithelial-to-mesenchymal transition.

  9. Preventing Cartilage Degeneration in Warfighters by Elucidating Novel Mechanisms Regulating Osteocyte-Mediated Perilacunar Bone Remodeling

    Science.gov (United States)

    2016-10-01

    hypothesis using mouse models and human PTOA tissue. We aim to determine: 1) the extent to which mechanical loading regulates PLR in a TGFβ- dependent manner ...the major goals of the project? Major Goals Aim 1: Determine the extent to which mechanical loading regulates PLR in a TGFβ- dependent manner . Aim...dependent manner . Overview: We conducted all of the analyses proposed in Aim 1. As described below, these studies convincingly demonstrate that PLR

  10. Circadian mechanisms of 24-hour blood pressure regulation and patterning.

    Science.gov (United States)

    Smolensky, Michael H; Hermida, Ramón C; Portaluppi, Francesco

    2017-06-01

    In most persons, blood pressure (BP) rises slowly during late sleep, increases rapidly upon morning awakening and commencement of diurnal activity, exhibits two - morning and afternoon/early evening - daytime peaks, shows a minor midday nadir, and undergoes a decline during nighttime sleep by 10-20% in systolic BP and somewhat lesser amount in diastolic BP relative to wake-time means. Nyctohemeral cycles of ambient temperature, light, noise and behaviorally driven temporal patterns in food, liquid, salt, and stimulant consumption, mental/emotional stress, posture, and physical activity intensity plus circadian rhythms of wake/sleep, pineal gland melatonin synthesis, autonomic and central nervous, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, renin-angiotensin-aldosterone, renal hemodynamic, endothelial, vasoactive peptide, and opioid systems constitute the key regulators and determinants of the BP 24 h profile. Environmental and behavioral cycles are believed to be far more influential than circadian ones. However, the facts that the: i) BP 24 h pattern of secondary hypertension, e.g., diabetes and renal disease, is characterized by absence of BP fall during sleep, and ii) scheduling of conventional long-acting medications at bedtime, rather than morning, results in much better hypertension control and vascular risk reduction, presumably because highest drug concentration coincides closely with the peak of most key circadian determinants of the BP 24 h profile, indicate endogenous rhythmic influences are of greater importance than previously appreciated. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Structure of the transcriptional regulator LmrR and its mechanism of multidrug recognition

    NARCIS (Netherlands)

    Madoori, Pramod Kumar; Agustiandari, Herfita; Driessen, Arnold J. M.; Thunnissen, Andy-Mark W. H.

    2009-01-01

    LmrR is a PadR-related transcriptional repressor that regulates the production of LmrCD, a major multidrug ABC transporter in Lactococcus lactis. Transcriptional regulation is presumed to follow a drug-sensitive induction mechanism involving the direct binding of transporter ligands to LmrR. Here,

  12. Participatory Democracy: Mechanism of Better Regulation in Europe

    Directory of Open Access Journals (Sweden)

    Neliana RODEAN

    2011-08-01

    Full Text Available This paper aims at analyzing the concept of participatory democracy in the European context. In the era of globalization, tools such as Internet filled the gap between civil society and political institutions. The new information and communication technologies contribute to the involvement of citizens in decision-making process. The democratic deficit is bridged through increasingly active participation of civil society at various levels of policy. Through e-democracy tools is realized a direct action of citizens, or even certain categories, which for various reasons do not have the possibility to be informed or have voice on political decisions. In addition, the European institutions, through mechanisms of “better regulation”, promote processes of simplification rules to find a remedy for an excessive law-making.

  13. Mechanisms and Regulation of Mitotic Recombination in Saccharomyces cerevisiae

    Science.gov (United States)

    Symington, Lorraine S.; Rothstein, Rodney; Lisby, Michael

    2014-01-01

    Homology-dependent exchange of genetic information between DNA molecules has a profound impact on the maintenance of genome integrity by facilitating error-free DNA repair, replication, and chromosome segregation during cell division as well as programmed cell developmental events. This chapter will focus on homologous mitotic recombination in budding yeast Saccharomyces cerevisiae. However, there is an important link between mitotic and meiotic recombination (covered in the forthcoming chapter by Hunter et al. 2015) and many of the functions are evolutionarily conserved. Here we will discuss several models that have been proposed to explain the mechanism of mitotic recombination, the genes and proteins involved in various pathways, the genetic and physical assays used to discover and study these genes, and the roles of many of these proteins inside the cell. PMID:25381364

  14. Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition.

    Directory of Open Access Journals (Sweden)

    Chin-Tong Ong

    2008-07-01

    Full Text Available Recent reports suggested that Delta1, 4 and Jagged1, 2 possessed the ability to instruct CD4(+ T cell into selection of Th1 or Th2 fates, respectively, although the underlying mechanism endowing the cleaved Notch receptor with memory of ligand involved in its activation remains elusive. To examine this, we prepared artificial antigen-presenting cells expressing either DLL1 or Jag1. Although both ligands were efficient in inducing Notch2 cleavage and activation in CD4(+ T or reporter cells, the presence of Lunatic Fringe in CD4(+ T cells inhibited Jag1 activation of Notch1 receptor. Neither ligand could induce Th1 or Th2 fate choice independently of cytokines or redirect cytokine-driven Th1 or Th2 development. Instead, we find that Notch ligands only augment cytokine production during T cell differentiation in the presence of polarizing IL-12 and IL-4. Moreover, the differentiation choices of naïve CD4(+ T cells lacking gamma-secretase, RBP-J, or both in response to polarizing cytokines revealed that neither presenilin proteins nor RBP-J were required for cytokine-induced Th1/Th2 fate selection. However, presenilins facilitate cellular proliferation and cytokine secretion in an RBP-J (and thus, Notch independent manner. The controversies surrounding the role of Notch and presenilins in Th1/Th2 polarization may reflect their role as genetic modifiers of T-helper cells differentiation.

  15. Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms.

    Science.gov (United States)

    DePina, Ana S; Iser, Wendy B; Park, Sung-Soo; Maudsley, Stuart; Wilson, Mark A; Wolkow, Catherine A

    2011-07-12

    Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS). We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+) sperm. However, yolk protein (YP) levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.

  16. Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms

    Directory of Open Access Journals (Sweden)

    Wilson Mark A

    2011-07-01

    Full Text Available Abstract Background Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. Results In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS. We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+ sperm. However, yolk protein (YP levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. Conclusions C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.

  17. Mechanisms regulating osteoblast response to surface microtopography and vitamin D

    Science.gov (United States)

    Bell, Bryan Frederick, Jr.

    A comprehensive understanding of the interactions between orthopaedic and dental implant surfaces with the surrounding host tissue is essential in the design of advanced biomaterials that better promote bone growth and osseointegration of implants. Dental implants with roughened surfaces and high surface energy are well known to promote osteoblast differentiation in vitro and promote increased bone-to-implant contact in vivo. In addition, increased surface roughness increases osteoblasts response to the vitamin D metabolite 1alpha,25(OH)2D3. However, the exact mechanisms mediating cell response to surface properties and 1alpha,25(OH)2D3 are still being elucidated. The central aim of the thesis is to investigate whether integrin signaling in response to rough surface microtopography enhances osteoblast differentiation and responsiveness to 1alpha,25(OH)2D3. The hypothesis is that the integrin alpha5beta1 plays a role in osteoblast response to surface microtopography and that 1alpha,25(OH) 2D3 acts through VDR-independent pathways involving caveolae to synergistically enhance osteoblast response to surface roughness and 1alpha,25(OH) 2D3. To test this hypothesis the objectives of the studies performed in this thesis were: (1) to determine if alpha5beta 1 signaling is required for osteoblast response to surface microstructure; (2) to determine if increased responsiveness to 1alpha,25(OH)2D 3 requires the vitamin D receptor, (3) to determine if rough titanium surfaces functionalized with the peptides targeting integrins (RGD) and transmembrane proteoglycans (KRSR) will enhance both osteoblast proliferation and differentiation, and (4) to determine whether caveolae, which are associated with integrin and 1alpha,25(OH)2D3 signaling, are required for enhance osteogenic response to surface microstructure and 1alpha,25(OH)2D 3. The results demonstrate that integrins, VDR, and caveolae play important roles in mediating osteoblast response to surface properties and 1alpha,25

  18. Phosphodiesterase 1 regulation is a key mechanism in vascular aging

    DEFF Research Database (Denmark)

    Niño, Paula K Bautista; Durik, Matej; Danser, A H Jan

    2015-01-01

    Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role...... in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d...... in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated...

  19. Mechanisms for regulating oxygen toxicity in phytophagous insects.

    Science.gov (United States)

    Ahmad, S; Pardini, R S

    1990-01-01

    The antioxidant enzymatic defense of insects for the regulation of oxygen toxicity was investigated. Insect species examined were lepidopterous larvae of the cabbage looper (Trichoplusia ni), southern armyworm (Spodoptera eridania), and black swallowtail (Papilio polyxenes). These phytophagous species are subject to both endogenous and exogenous sources of oxidative stress from toxic oxygen radicals, hydrogen peroxide (H2O2) and lipid peroxides (LOOH). In general, the constitutive levels of the enzymes superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GT), and its peroxidase activity (GTpx), and glutathione reductase (GR), correlate well with natural feeding habits of these insects and their relative susceptibility to prooxidant plant allelochemicals, quercetin (a flavonoid), and xanthotoxin (a photoactive furanocoumarin). Induction of SOD activity which rapidly destroys superoxide radicals, appears to be the main response to dietary prooxidant exposure. A unique observation includes high constitutive activity of CAT and a broader subcellular distribution in all three insects than observed in most mammalian species. These attributes of CAT appear to be important in the prevention of excessive accumulation of cytotoxic H2O2. Unlike mammalian species, insects possess very low levels of a GPOX-like activity toward H2O2. Irrefutable proof that this activity is due to a selenium-dependent GPOX found in mammals, is lacking at this time. However, the activity of selenium-independent GTpx is unusually high in insects, suggesting that GTpx and not GPOX plays a prominent role in scavenging deleterious LOOHs. The GSSG generated from the GPOX and GTpx reactions may be reduced to GSH by GR activity. A key role of SOD in protecting insects from prooxidant toxicity was evident when its inhibition resulted in enhanced toxicity towards prooxidants. The role of antioxidant compounds in protecting these insects from toxic forms of oxygen has not been explored in

  20. Diapause and quiescence: dormancy mechanisms that contribute to the geographical expansion of mosquitoes and their evolutionary success.

    Science.gov (United States)

    Diniz, Diego Felipe Araujo; de Albuquerque, Cleide Maria Ribeiro; Oliva, Luciana Oliveira; de Melo-Santos, Maria Alice Varjal; Ayres, Constância Flávia Junqueira

    2017-06-26

    Mosquitoes are insects belonging to the order Diptera and family Culicidae. They are distributed worldwide and include approximately 3500 species, of which about 300 have medical and veterinary importance. The evolutionary success of mosquitoes, in both tropical and temperate regions, is due to the various survival strategies these insects have developed throughout their life histories. Of the many adaptive mechanisms, diapause and quiescence, two different types of dormancy, likely contribute to the establishment, maintenance and spread of natural mosquito populations. This review seeks to objectively and coherently describe the terms diapause and quiescence, which can be confused in the literature because the phenotypic effects of these mechanisms are often similar.

  1. Spatial distribution of sequential ventilation during mechanical ventilation of the uninjured lung: an argument for cyclical airway collapse and expansion

    Directory of Open Access Journals (Sweden)

    Altemeier William A

    2010-05-01

    Full Text Available Abstract Background Ventilator-induced lung injury (VILI is a recognized complication of mechanical ventilation. Although the specific mechanism by which mechanical ventilation causes lung injury remains an active area of study, the application of positive end expiratory pressure (PEEP reduces its severity. We have previously reported that VILI is spatially heterogeneous with the most severe injury in the dorsal-caudal lung. This regional injury heterogeneity was abolished by the application of PEEP = 8 cm H2O. We hypothesized that the spatial distribution of lung injury correlates with areas in which cyclical airway collapse and recruitment occurs. Methods To test this hypothesis, rabbits were mechanically ventilated in the supine posture, and regional ventilation distribution was measured under four conditions: tidal volumes (VT of 6 and 12 ml/kg with PEEP levels of 0 and 8 cm H2O. Results We found that relative ventilation was sequentially redistributed towards dorsal-caudal lung with increasing tidal volume. This sequential ventilation redistribution was abolished with the addition of PEEP. Conclusions These results suggest that cyclical airway collapse and recruitment is regionally heterogeneous and spatially correlated with areas most susceptible to VILI.

  2. Roles of Transcriptional and Translational Control Mechanisms in Regulation of Ribosomal Protein Synthesis in Escherichia coli.

    Science.gov (United States)

    Burgos, Hector L; O'Connor, Kevin; Sanchez-Vazquez, Patricia; Gourse, Richard L

    2017-11-01

    Bacterial ribosome biogenesis is tightly regulated to match nutritional conditions and to prevent formation of defective ribosomal particles. In Escherichia coli , most ribosomal protein (r-protein) synthesis is coordinated with rRNA synthesis by a translational feedback mechanism: when r-proteins exceed rRNAs, specific r-proteins bind to their own mRNAs and inhibit expression of the operon. It was recently discovered that the second messenger nucleotide guanosine tetra and pentaphosphate (ppGpp), which directly regulates rRNA promoters, is also capable of regulating many r-protein promoters. To examine the relative contributions of the translational and transcriptional control mechanisms to the regulation of r-protein synthesis, we devised a reporter system that enabled us to genetically separate the cis -acting sequences responsible for the two mechanisms and to quantify their relative contributions to regulation under the same conditions. We show that the synthesis of r-proteins from the S20 and S10 operons is regulated by ppGpp following shifts in nutritional conditions, but most of the effect of ppGpp required the 5' region of the r-protein mRNA containing the target site for translational feedback regulation and not the promoter. These results suggest that most regulation of the S20 and S10 operons by ppGpp following nutritional shifts is indirect and occurs in response to changes in rRNA synthesis. In contrast, we found that the promoters for the S20 operon were regulated during outgrowth, likely in response to increasing nucleoside triphosphate (NTP) levels. Thus, r-protein synthesis is dynamic, with different mechanisms acting at different times. IMPORTANCE Bacterial cells have evolved complex and seemingly redundant strategies to regulate many high-energy-consuming processes. In E. coli , synthesis of ribosomal components is tightly regulated with respect to nutritional conditions by mechanisms that act at both the transcription and translation steps. In

  3. Expansion dynamics

    International Nuclear Information System (INIS)

    Knoll, J.

    1985-10-01

    A quantum dynamical model is suggested which describes the expansion and disassembly phase of highly excited compounds formed in energetic heavy-ion collisions. First applications in two space and one time dimensional model world are discussed and qualitatively compared to standard freeze-out concepts. (orig.)

  4. expansion method

    Indian Academy of Sciences (India)

    of a system under investigation is to model the system in terms of some ... The organization of the paper is as follows: In §2, a brief account of the (G /G)- expansion ...... It is interesting to note that from the general results, one can easily recover.

  5. Mechanical Reaction of Facial Skeleton to Rapid Palatal Expansion Devices using Laser Holography: An in vitro Study

    Directory of Open Access Journals (Sweden)

    Revathi Peddu

    2013-01-01

    Conclusion: Hyrax appliance activation produced mechanical reactions on the teeth, alveolar bone, maxilla and the circum-maxillary bones and sutures. The displacement and fringes increased progressively with two, four and eight turns activation of hyrax. The pattern of the fringes was more circular around the nasomaxillary complex and zygomaticomaxillary sutures, suggesting rotational displacement of the maxilla. The number and pattern of fringes produced by the Spring jet appliances suggest that it produces only dentoalveolar changes and minimal orthopedic affects.

  6. Cultural differences and similarities in beliefs, practices, and neural mechanisms of emotion regulation.

    Science.gov (United States)

    Qu, Yang; Telzer, Eva H

    2017-01-01

    The current research examined whether culture shapes the beliefs, practices, and neural basis of emotion regulation. Twenty-nine American and Chinese participants reported their implicit theory of emotion and frequency of reappraisal use. They also underwent an fMRI scan while completing an emotion regulation task. Chinese (vs. American) participants reported more frequent use of reappraisal, which was mediated by their higher incremental theory of emotion (i.e., believing that emotion is changeable through effort). Although there were some cultural similarities in neural activation during emotion regulation, Chinese participants showed less ventrolateral prefrontal cortex (VLPFC) activation than American participants when regulating negative emotions. Lower VLPFC activation was associated with higher incremental theory of emotion and more frequent use of cognitive reappraisal. Findings suggest that culture may shape how individuals perceive and engage in emotion regulation, and ultimately, the neural mechanisms underlying emotion regulation. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  7. Early Family Relationships Predict Children’s Emotion Regulation and Defense Mechanisms

    Directory of Open Access Journals (Sweden)

    Jallu Lindblom

    2016-12-01

    Full Text Available Early family relationships have been suggested to influence the development of children’s affect regulation, involving both emotion regulation and defense mechanisms. However, we lack research on the specific family predictors for these two forms of affect regulation, which have been conceptualized to differ in their functions and accessibility to consciousness. Accordingly, we examine how the (a quality and (b timing of family relationships during infancy predict child’s later emotion regulation and defense mechanisms. Parents (N = 703 reported autonomy and intimacy in marital and parenting relationships at the child’s ages of 2 and 12 months, and the child’s use of emotion regulation and immature and neurotic defenses at 7 to 8 years. As hypothesized, the results showed that functional early family relationships predicted children’s efficient emotion regulation, whereas dysfunctional relationships predicted reliance on defense mechanisms in middle childhood. Further, results showed a timing effect for neurotic defenses, partially confirming our hypothesis of early infancy being an especially important period for the development of defense mechanisms. The findings are discussed from the viewpoints of attachment and family dynamics, emotional self-awareness, and sense of security.

  8. Advance in the Study of the Mechanisms Regulated by Sphingosine-1-Phosphate

    Science.gov (United States)

    Ye, Fei; Kong, Xiangqian; Luo, Cheng

    2010-09-01

    Sphingosine-1-phosphate (S1P) is a bioactive lipid messenger in the cells that regulate gene expression and NF-KB signal pathway through unknown mechanisms. Recently, Cheng Luo, associate professor of DDDC in Shanghai Institute of Materia Medica, whose project was funded by the National Natural Science Foundation of China, joined in a research team led by Professor Sarah Spiegel of Virginia Commonwealth University. The team continuously made significant breakthroughs in understanding the regulation mechanism of Sphingosine-1-Phosphate. In September 2009, in a paper published on SCIENCE magazine (Science 2009, 325: 1254-7), they firstly demonstrated that S1P is a physiologically important regulator of histone deacetylases (HDACs), HDACs are direct intracellular targets of S1P. Furthermore, they identified the mechanism that S1P regulates gene expression through regulating the activity of HDACs. In June 24th, 2010, in another paper to be published on NATURE magazine (Nature 2010, June 24th, advance online publication) which reports the regulation of NF-KB signaling pathway by S1P. They demonstrate that S1P is the missing cofactor for TRAF2 (tumour-necrosis factor receptor-associated factor 2) and indicate a new paradigm for the regulation of lysine-63-linked poly-ubiquitination. The study also highlight the key role of SphK1 and its product S1P in TNF-α signalling and the canonical NF-KB activation pathway, and then play crucial role in inflammatory, antiapoptotic and immune processes. The identification of new mechanisms by which S1P regulates gene expression and TNF and NF-KB signaling pathway will light up the road to develop novel inhibitors that might be useful for treatment of cancer and inflammatory diseases.

  9. Notch1-Dll4 signaling and mechanical force regulate leader cell formation during collective cell migration

    OpenAIRE

    Riahi, Reza; Sun, Jian; Wang, Shue; Long, Min; Zhang, Donna D.; Wong, Pak Kin

    2015-01-01

    At the onset of collective cell migration, a subset of cells within an initially homogenous population acquires a distinct “leader” phenotype with characteristic morphology and motility. However, the factors driving leader cell formation as well as the mechanisms regulating leader cell density during the migration process remain to be determined. Here, we use single cell gene expression analysis and computational modeling to show that leader cell identity is dynamically regulated by Dll4 sign...

  10. Modeling generation expansion in the context of a security of supply mechanism based on long-term auctions. Application to the Colombian case

    International Nuclear Information System (INIS)

    Rodilla, P.; Batlle, C.; Salazar, J.; Sanchez, J.J.

    2011-01-01

    In an attempt to provide electricity generation investors with appropriate economic incentives so as to maintain quality of supply at socially optimal levels, a growing number of electricity market regulators have opted for implementing a security of supply mechanism based on long-term auctions. In this context, the ability to analyze long-term investment dynamics is a key issue not only for market agents, but also for regulators. This paper describes a model developed to serve this purpose. A general system-dynamics-inspired methodology has been designed to be able to simulate these long-term auction mechanisms in the formats presently in place. A full-scale simulation based on the Colombian system was conducted to illustrate model capabilities. (author)

  11. Modeling generation expansion in the context of a security of supply mechanism based on long-term auctions. Application to the Colombian case

    Energy Technology Data Exchange (ETDEWEB)

    Rodilla, P.; Batlle, C. [Institute for Research in Technology, University Pontificia Comillas, Sta. Cruz de Marcenado 26, 28015 Madrid (Spain); Salazar, J. [Empresas Publicas de Medellin, Carrera 58 No. 42-125 Edificio Inteligente, Medellin (Colombia); Sanchez, J.J. [Secretaria de Estado de Cambio Climatico, Ministerio de Medio Ambiente, Rural y Marino. Plaza San Juan de la Cruz, 28071 Madrid (Spain)

    2011-01-15

    In an attempt to provide electricity generation investors with appropriate economic incentives so as to maintain quality of supply at socially optimal levels, a growing number of electricity market regulators have opted for implementing a security of supply mechanism based on long-term auctions. In this context, the ability to analyze long-term investment dynamics is a key issue not only for market agents, but also for regulators. This paper describes a model developed to serve this purpose. A general system-dynamics-inspired methodology has been designed to be able to simulate these long-term auction mechanisms in the formats presently in place. A full-scale simulation based on the Colombian system was conducted to illustrate model capabilities. (author)

  12. Interferon Regulator Factor 8 (IRF8 Limits Ocular Pathology during HSV-1 Infection by Restraining the Activation and Expansion of CD8+ T Cells.

    Directory of Open Access Journals (Sweden)

    Lin Sun

    Full Text Available Interferon Regulatory Factor-8 (IRF8 is constitutively expressed in monocytes and B cell lineages and plays important roles in immunity to pathogens and cancer. Although IRF8 expression is induced in activated T cells, the functional relevance of IRF8 in T cell-mediated immunity is not well understood. In this study, we used mice with targeted deletion of Irf8 in T-cells (IRF8KO to investigate the role of IRF8 in T cell-mediated responses during herpes simplex virus 1 (HSV-1 infection of the eye. In contrast to wild type mice, HSV-1-infected IRF8KO mice mounted a more robust anti-HSV-1 immune response, which included marked expansion of HSV-1-specific CD8+ T cells, increased infiltration of inflammatory cells into the cornea and trigeminal ganglia (TG and enhanced elimination of virus within the trigeminal ganglion. However, the consequence of the enhanced immunological response was the development of ocular inflammation, limbitis, and neutrophilic infiltration into the cornea of HSV-1-infected IRF8KO mice. Surprisingly, we observed a marked increase in virus-specific memory precursor effector cells (MPEC in IRF8KO mice, suggesting that IRF8 might play a role in regulating the differentiation of effector CD8+ T cells to the memory phenotype. Together, our data suggest that IRF8 might play a role in restraining excess lymphocyte proliferation. Thus, modulating IRF8 levels in T cells can be exploited therapeutically to prevent immune-mediated ocular pathology during autoimmune and infectious diseases of the eye.

  13. Development of maternal seed tissue in barley is mediated by regulated cell expansion and cell disintegration and coordinated with endosperm growth.

    Science.gov (United States)

    Radchuk, Volodymyr; Weier, Diana; Radchuk, Ruslana; Weschke, Winfriede; Weber, Hans

    2011-01-01

    After fertilization, filial grain organs are surrounded by the maternal nucellus embedded within the integuments and pericarp. Rapid early endosperm growth must be coordinated with maternal tissue development. Parameters of maternal tissue growth and development were analysed during early endosperm formation. In the pericarp, cell proliferation is accomplished around the time of fertilization, followed by cell elongation predominantly in longitudinal directions. The rapid cell expansion coincides with endosperm cellularization. Distribution of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling)-positive nuclei reveals distinct patterns starting in the nucellus at anthesis and followed later by the inner cell rows of the pericarp, then spreading to the whole pericarp. The pattern suggests timely and spatially regulated programmed cell death (PCD) processes in maternal seed tissues. When the endosperm is coenocytic, PCD events are only observed within the nucellus. Thereby, remobilization of nucellar storage compounds by PCD could nourish the early developing endosperm when functional interconnections are absent between maternal and filial seed organs. Specific proteases promote PCD events. Characterization of the barley vacuolar processing enzyme (VPE) gene family identified seven gene members specifically expressed in the developing grain. HvVPE2a (known as nucellain) together with closely similar HvVPE2b and HvVPE2d might be involved in nucellar PCD. HvVPE4 is strongly cell specific for pericarp parenchyma. Correlative evidence suggests that HvVPE4 plays a role in PCD events in the pericarp. Possible functions of PCD in the maternal tissues imply a potential nutritive role or the relief of a physical restraint for endosperm growth. PCD could also activate post-phloem transport functions.

  14. DMPD: Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15331118 Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. Wu...e-associated up-regulation in macrophage PGE2 synthesis. PubmedID 15331118 Title Mechanism of age-associated... up-regulation in macrophage PGE2 synthesis. Authors Wu D, Meydani SN. Publicatio

  15. Virial Expansion Bounds

    Science.gov (United States)

    Tate, Stephen James

    2013-10-01

    In the 1960s, the technique of using cluster expansion bounds in order to achieve bounds on the virial expansion was developed by Lebowitz and Penrose (J. Math. Phys. 5:841, 1964) and Ruelle (Statistical Mechanics: Rigorous Results. Benjamin, Elmsford, 1969). This technique is generalised to more recent cluster expansion bounds by Poghosyan and Ueltschi (J. Math. Phys. 50:053509, 2009), which are related to the work of Procacci (J. Stat. Phys. 129:171, 2007) and the tree-graph identity, detailed by Brydges (Phénomènes Critiques, Systèmes Aléatoires, Théories de Jauge. Les Houches 1984, pp. 129-183, 1986). The bounds achieved by Lebowitz and Penrose can also be sharpened by doing the actual optimisation and achieving expressions in terms of the Lambert W-function. The different bound from the cluster expansion shows some improvements for bounds on the convergence of the virial expansion in the case of positive potentials, which are allowed to have a hard core.

  16. A contextual model of self-regulation change mechanisms among individuals with addictive disorders.

    Science.gov (United States)

    Roos, Corey R; Witkiewitz, Katie

    2017-11-01

    Numerous behavioral treatments for addictive disorders include components explicitly aimed at targeting self-regulation (e.g., coping and emotion regulation). We first provide a summary of key findings to date among studies that have examined self-regulation as a mechanism of behavior change (MOBC) in behavioral treatments for addictive disorders. Based on our review, we conclude that the role of self-regulation as a MOBC across behavioral treatments for addictive disorders is not well-characterized and findings are inconsistent across studies. For example, our review indicates that there is still inconsistent evidence that coping is a unique MOBC in cognitive-behavioral approaches for addictive behaviors. We propose that there has been slow progress in understanding self-regulation as a MOBC in addiction treatment because of a lack of attention to contextual factors. Accordingly, in the second half of this paper, we propose a contextual model of self-regulation change mechanisms, which emphasizes that the role of various facets of self-regulation as MOBC may depend on contextual factors in the immediate situational context (e.g., fluctuating internal and external cues) and in the broader context in which an individual is embedded (e.g., major life stressors, environmental conditions, dispositions). Additionally, we provide specific recommendations to guide future research for understanding both between-person and within-person self-regulation MOBC in addiction treatment. In particular, we provide key recommendations for how to capitalize on intensive longitudinal measurement methods (e.g., ecological momentary assessment) when bringing a contextual perspective to the study of self-regulation as MOBC in various addiction treatments. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Mechanisms of the Regulation of the Intestinal Na+/H+ Exchanger NHE3

    Directory of Open Access Journals (Sweden)

    Peijian He

    2010-01-01

    Full Text Available A major of Na+ absorptive process in the proximal part of intestine and kidney is electroneutral exchange of Na+ and H+ by Na+/H+ exchanger type 3 (NHE3. During the past decade, significant advance has been achieved in the mechanisms of NHE3 regulation. A bulk of the current knowledge on Na+/H+ exchanger regulation is based on heterologous expression of mammalian Na+/H+ exchangers in Na+/H+ exchanger deficient fibroblasts, renal epithelial, and intestinal epithelial cells. Based on the reductionist's approach, an understanding of NHE3 regulation has been greatly advanced. More recently, confirmations of in vitro studies have been made using animals deficient in one or more proteins but in some cases unexpected findings have emerged. The purpose of this paper is to provide a brief overview of recent progress in the regulation and functions of NHE3 present in the luminal membrane of the intestinal tract.

  18. The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System.

    Science.gov (United States)

    Cholewa-Waclaw, Justyna; Bird, Adrian; von Schimmelmann, Melanie; Schaefer, Anne; Yu, Huimei; Song, Hongjun; Madabhushi, Ram; Tsai, Li-Huei

    2016-11-09

    Neuroepigenetics is a newly emerging field in neurobiology that addresses the epigenetic mechanism of gene expression regulation in various postmitotic neurons, both over time and in response to environmental stimuli. In addition to its fundamental contribution to our understanding of basic neuronal physiology, alterations in these neuroepigenetic mechanisms have been recently linked to numerous neurodevelopmental, psychiatric, and neurodegenerative disorders. This article provides a selective review of the role of DNA and histone modifications in neuronal signal-induced gene expression regulation, plasticity, and survival and how targeting these mechanisms could advance the development of future therapies. In addition, we discuss a recent discovery on how double-strand breaks of genomic DNA mediate the rapid induction of activity-dependent gene expression in neurons. Copyright © 2016 the authors 0270-6474/16/3611427-08$15.00/0.

  19. The heart as a self-regulating system: integration of homeodynamic mechanisms.

    Science.gov (United States)

    Kresh, J Y; Armour, J A

    1997-04-01

    In the past the study of mechanical and electrical properties of the heart has been disjointed with minimal overlap and unification. The fact remains that these features are tightly coupled and central to the functioning heart. The maintenance of adequate cardiac output relies upon the highly integrated autoregulatory mechanisms and modulation of cardiac myocyte function. Regional ventricular mechanics and energetics are dependent upon muscle fiber stress-strain rate, the passive properties of myocardial collagen matrix, adequate vascular perfusion, transcapillary transport and electrical activation pattern. Intramural hydraulic "loading" is regulated by coronary arterial and venous dynamics. All of these components are under the constant influence of intrinsic cardiac and extracardiac autonomic neurons, as well as circulating hormones. A brief overview of the putative regulation of these various components is presented in this paper.

  20. Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

    International Nuclear Information System (INIS)

    Brady, Robert T.; O'Brien, Fergal J.; Hoey, David A.

    2015-01-01

    Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

  1. Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Brady, Robert T. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); O' Brien, Fergal J. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Hoey, David A., E-mail: david.hoey@ul.ie [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); The Centre for Applied Biomedical Engineering Research, University of Limerick (Ireland); Materials & Surface Science Institute, University of Limerick (Ireland)

    2015-03-27

    Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

  2. Proteomic Analysis Reveals the Leaf Color Regulation Mechanism in Chimera Hosta "Gold Standard" Leaves.

    Science.gov (United States)

    Yu, Juanjuan; Zhang, Jinzheng; Zhao, Qi; Liu, Yuelu; Chen, Sixue; Guo, Hongliang; Shi, Lei; Dai, Shaojun

    2016-03-08

    Leaf color change of variegated leaves from chimera species is regulated by fine-tuned molecular mechanisms. Hosta "Gold Standard" is a typical chimera Hosta species with golden-green variegated leaves, which is an ideal material to investigate the molecular mechanisms of leaf variegation. In this study, the margin and center regions of young and mature leaves from Hosta "Gold Standard", as well as the leaves from plants after excess nitrogen fertilization were studied using physiological and comparative proteomic approaches. We identified 31 differentially expressed proteins in various regions and development stages of variegated leaves. Some of them may be related to the leaf color regulation in Hosta "Gold Standard". For example, cytosolic glutamine synthetase (GS1), heat shock protein 70 (Hsp70), and chloroplastic elongation factor G (cpEF-G) were involved in pigment-related nitrogen synthesis as well as protein synthesis and processing. By integrating the proteomics data with physiological results, we revealed the metabolic patterns of nitrogen metabolism, photosynthesis, energy supply, as well as chloroplast protein synthesis, import and processing in various leaf regions at different development stages. Additionally, chloroplast-localized proteoforms involved in nitrogen metabolism, photosynthesis and protein processing implied that post-translational modifications were crucial for leaf color regulation. These results provide new clues toward understanding the mechanisms of leaf color regulation in variegated leaves.

  3. Mechanism and the origins of stereospecificity in copper-catalyzed ring expansion of vinyl oxiranes: a traceless dual transition-metal-mediated process.

    Science.gov (United States)

    Mustard, Thomas J L; Mack, Daniel J; Njardarson, Jon T; Cheong, Paul Ha-Yeon

    2013-01-30

    Density functional theory computations of the Cu-catalyzed ring expansion of vinyloxiranes is mediated by a traceless dual Cu(I)-catalyst mechanism. Overall, the reaction involves a monomeric Cu(I)-catalyst, but a single key step, the Cu migration, requires two Cu(I)-catalysts for the transformation. This dual-Cu step is found to be a true double Cu(I) transition state rather than a single Cu(I) transition state in the presence of an adventitious, spectator Cu(I). Both Cu(I) catalysts are involved in the bond forming and breaking process. The single Cu(I) transition state is not a stationary point on the potential energy surface. Interestingly, the reductive elimination is rate-determining for the major diastereomeric product, while the Cu(I) migration step is rate-determining for the minor. Thus, while the reaction requires dual Cu(I) activation to proceed, kinetically, the presence of the dual-Cu(I) step is untraceable. The diastereospecificity of this reaction is controlled by the Cu migration step. Suprafacial migration is favored over antarafacial migration due to the distorted Cu π-allyl in the latter.

  4. Study of ytterbium doping effects on structural, mechanical and opto-thermal properties of sprayed ZnO thin films using the Boubaker Polynomials Expansion Scheme (BPES)

    Energy Technology Data Exchange (ETDEWEB)

    Amlouk, A. [Unite de physique des dispositifs a semi-conducteurs, Faculte des sciences de Tunis, Universite de Tunis El Manar, 2092 Tunis (Tunisia); Boubaker, K., E-mail: mmbb11112000@yahoo.f [Unite de physique des dispositifs a semi-conducteurs, Faculte des sciences de Tunis, Universite de Tunis El Manar, 2092 Tunis (Tunisia); Amlouk, M. [Unite de physique des dispositifs a semi-conducteurs, Faculte des sciences de Tunis, Universite de Tunis El Manar, 2092 Tunis (Tunisia); Bouhafs, M. [Unite de Recherche MA2I, Ecole Nationale d' Ingenieurs de Tunis, B.P. 37 Le Belvedere, 1002 Tunis (Tunisia)

    2009-10-19

    In this work, ZnO thin films have been grown on glass substrates by using a solution of propanol (C{sub 3}H{sub 8}O), water (H{sub 2}O) and zinc acetate (Z{sub n}(CH{sub 3}CO{sub 2}){sub 2}) in acidified medium (pH 5). The obtained films were n doped with ytterbium (Yb) at the rates of 100, 200 and 300 ppm. The structural features of the doped films were investigated using XRD, atomic force microscopy and scanning electronic microscopy techniques. XRD analysis shows a strong (0 0 2) X-ray diffraction line for increasing Yb-doping amounts. This c-axis preferential orientation of ZnO crystallites is naturally required to use this oxide as transparent conductor in optoelectronic applications. Atomic force microscopy (AFM) analysis shows an enhancement in the surface roughness of the doped ZnO:Yb thin films. Optical measurements were performed in 300-1800 nm domain via transmittance T(lambda) and reflectance R(lambda) spectra. Conjoint optical and thermal properties were deduced from the optical measurements in reference to the Amlouk-Boubaker opto-thermal expansivity psi{sub AB}. Optically relevant ytterbium doping effects have been discussed. Finally, mechanical measurements have been carried out using Vickers standard disposal. The results confirmed the structural and functional changes that several recent studies attributed to ytterbium doping.

  5. Regulation of Nox enzymes expression in vascular pathophysiology: Focusing on transcription factors and epigenetic mechanisms

    Directory of Open Access Journals (Sweden)

    Simona-Adriana Manea

    2015-08-01

    Full Text Available NADPH oxidases (Nox represent a family of hetero-oligomeric enzymes whose exclusive biological function is the generation of reactive oxygen species (ROS. Nox-derived ROS are essential modulators of signal transduction pathways that control key physiological activities such as cell growth, proliferation, migration, differentiation, and apoptosis, immune responses, and biochemical pathways. Enhanced formation of Nox-derived ROS, which is generally associated with the up-regulation of different Nox subtypes, has been established in various pathologies, namely cardiovascular diseases, diabetes, obesity, cancer, and neurodegeneration. The detrimental effects of Nox-derived ROS are related to alterations in cell signalling and/or direct irreversible oxidative damage of nucleic acids, proteins, carbohydrates, and lipids. Thus, understanding of transcriptional regulation mechanisms of Nox enzymes have been extensively investigated in an attempt to find ways to counteract the excessive formation of Nox-derived ROS in various pathological states. Despite the numerous existing data, the molecular pathways responsible for Nox up-regulation are not completely understood. This review article summarizes some of the recent advances and concepts related to the regulation of Nox expression in the vascular pathophysiology. It highlights the role of transcription factors and epigenetic mechanisms in this process. Identification of the signalling molecules involved in Nox up-regulation, which is associated with the onset and development of cardiovascular dysfunction may contribute to the development of novel strategies for the treatment of cardiovascular diseases.

  6. The Mechanisms of Virulence Regulation by Small Noncoding RNAs in Low GC Gram-Positive Pathogens

    Directory of Open Access Journals (Sweden)

    Stephanie Pitman

    2015-12-01

    Full Text Available The discovery of small noncoding regulatory RNAs (sRNAs in bacteria has grown tremendously recently, giving new insights into gene regulation. The implementation of computational analysis and RNA sequencing has provided new tools to discover and analyze potential sRNAs. Small regulatory RNAs that act by base-pairing to target mRNAs have been found to be ubiquitous and are the most abundant class of post-transcriptional regulators in bacteria. The majority of sRNA studies has been limited to E. coli and other gram-negative bacteria. However, examples of sRNAs in gram-positive bacteria are still plentiful although the detailed gene regulation mechanisms behind them are not as well understood. Strict virulence control is critical for a pathogen’s survival and many sRNAs have been found to be involved in that process. This review outlines the targets and currently known mechanisms of trans-acting sRNAs involved in virulence regulation in various gram-positive pathogens. In addition, their shared characteristics such as CU interaction motifs, the role of Hfq, and involvement in two-component regulators, riboswitches, quorum sensing, or toxin/antitoxin systems are described.

  7. Signal transduction mechanisms of K+-Cl- cotransport regulation and relationship to disease.

    Science.gov (United States)

    Adragna, N C; Ferrell, C M; Zhang, J; Di Fulvio, M; Temprana, C F; Sharma, A; Fyffe, R E W; Cool, D R; Lauf, P K

    2006-01-01

    The K+-Cl- cotransport (COT) regulatory pathways recently uncovered in our laboratory and their implication in disease state are reviewed. Three mechanisms of K+-Cl- COT regulation can be identified in vascular cells: (1) the Li+-sensitive pathway, (2) the platelet-derived growth factor (PDGF)-sensitive pathway and (3) the nitric oxide (NO)-dependent pathway. Ion fluxes, Western blotting, semi-quantitative RT-PCR, immunofluorescence and confocal microscopy were used. Li+, used in the treatment of manic depression, stimulates volume-sensitive K+-Cl- COT of low K+ sheep red blood cells at cellular concentrations 3 mM, causes cell swelling, and appears to regulate K+-Cl- COT through a protein kinase C-dependent pathway. PDGF, a potent serum mitogen for vascular smooth muscle cells (VSMCs), regulates membrane transport and is involved in atherosclerosis. PDGF stimulates VSM K+-Cl- COT in a time- and concentration-dependent manner, both acutely and chronically, through the PDGF receptor. The acute effect occurs at the post-translational level whereas the chronic effect may involve regulation through gene expression. Regulation by PDGF involves the signalling molecules phosphoinositides 3-kinase and protein phosphatase-1. Finally, the NO/cGMP/protein kinase G pathway, involved in vasodilation and hence cardiovascular disease, regulates K+-Cl- COT in VSMCs at the mRNA expression and transport levels. A complex and diverse array of mechanisms and effectors regulate K+-Cl- COT and thus cell volume homeostasis, setting the stage for abnormalities at the genetic and/or regulatory level thus effecting or being affected by various pathological conditions.

  8. Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages.

    Directory of Open Access Journals (Sweden)

    Fattah Sotoodehnejadnematalahi

    Full Text Available Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM, and, intriguingly, show that versican mRNA is up-regulated much more highly (>600 fold by long term hypoxia (5 days than by 1 day of hypoxia (48 fold. We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K, LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression.

  9. Regulation mechanisms of the FLT3-ligand after irradiation; Mecanismes de regulation du FLT3-ligand apres irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Prat-Lepesant, M

    2005-06-15

    The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

  10. Epigenetic Regulation of Adipokines

    Directory of Open Access Journals (Sweden)

    Tho X. Pham

    2017-08-01

    Full Text Available Adipose tissue expansion in obesity leads to changes in the expression of adipokines, adipocyte-specific hormones that can regulate whole body energy metabolism. Epigenetic regulation of gene expression is a mechanism by which cells can alter gene expression through the modifications of DNA and histones. Epigenetic mechanisms, such as DNA methylation and histone modifications, are intimately tied to energy metabolism due to their dependence on metabolic intermediates such as S-adenosylmethionine and acetyl-CoA. Altered expression of adipokines in obesity may be due to epigenetic changes. The goal of this review is to highlight current knowledge of epigenetic regulation of adipokines.

  11. Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

    Science.gov (United States)

    Beck, Michael W; Derrick, Jeffrey S; Kerr, Richard A; Oh, Shin Bi; Cho, Woo Jong; Lee, Shin Jung C; Ji, Yonghwan; Han, Jiyeon; Tehrani, Zahra Aliakbar; Suh, Nayoung; Kim, Sujeong; Larsen, Scott D; Kim, Kwang S; Lee, Joo-Yong; Ruotolo, Brandon T; Lim, Mi Hee

    2016-10-13

    The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

  12. Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

    DEFF Research Database (Denmark)

    Manna, Moutusi; Niemelä, Miia; Tynkkynen, Joona

    2016-01-01

    ) - a prototypical G protein-coupled receptor - is modulated by cholesterol in an allosteric fashion. Extensive atomistic simulations show that cholesterol regulates b2AR by limiting its conformational variability. The mechanism of action is based on the binding of cholesterol at specific high-affinity sites located...... near the transmembrane helices 5-7 of the receptor. The alternative mechanism, where the β2AR conformation would be modulated by membrane-mediated interactions, plays only a minor role. Cholesterol analogues also bind to cholesterol binding sites and impede the structural flexibility of β2AR, however...... cholesterol generates the strongest effect. The results highlight the capacity of lipids to regulate the conformation of membrane receptors through specific interactions....

  13. Studies on the mechanism of quinone action on hormonal regulation of metabolism in the rat liver

    International Nuclear Information System (INIS)

    Cheng, E.Y.

    1989-01-01

    The mechanism of quinone actions in liver cell metabolism had been investigated using menadione as a model compound. Previous reports suggested that quinones and free radicals could produce perturbations in cellular calcium homeostasis. Since calcium plays an important role in the regulation of cellular metabolic processes, then regulation of cytosolic calcium concentrations, and thus of cellular metabolism, by calcium-mobilizing hormones such as phenylephrine and vasopressin could possibly be modified by quinones such as menadione. Methods used to approach this hypothesis included the assay for activation of glycogen phosphorylase, an indirect index of calcium mobilization; the determination of calcium mobilization with 45 Ca efflux exchange and with fluorescent calcium indicator fura-2; and the measurement of phosphatidylinositides, an important link in the membrane-associated receptor-mediated signal transduction mechanism

  14. The effect of natural whey proteins on mechanisms of blood pressure regulation

    Directory of Open Access Journals (Sweden)

    Halina Car

    2014-02-01

    Full Text Available Whey is a rich natural source of peptides and amino acids. It has been reported in numerous studies that biological active peptides isolated from cow’s milk whey may affect blood pressure regulation. Studies on animals and humans have shown that α-lactalbumin and β-lactoglobulin obtained from enzymatically hydrolysed whey inhibit angiotensin converting enzyme (ACE, while lactorphins lower blood pressure by normalizing endothelial function or by opioid receptors dependent mechanism. Whey proteins or their bioactive fragments decrease total cholesterol, LDL fraction and triglycerides, thus reducing the risk factors of cardiovascular diseases. The aim of this review is to discuss the effects of whey proteins on the mechanisms of blood pressure regulation.

  15. Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation

    Science.gov (United States)

    Niessen, Carien M.; Leckband, Deborah; Yap, Alpha S.

    2013-01-01

    This review addresses the cellular and molecular mechanisms of cadherin-based tissue morphogenesis. Tissue physiology is profoundly influenced by the distinctive organizations of cells in organs and tissues. In metazoa, adhesion receptors of the classical cadherin family play important roles in establishing and maintaining such tissue organization. Indeed, it is apparent that cadherins participate in a range of morphogenetic events that range from support of tissue integrity to dynamic cellular rearrangements. A comprehensive understanding of cadherin-based morphogenesis must then define the molecular and cellular mechanisms that support these distinct cadherin biologies. Here we focus on four key mechanistic elements: the molecular basis for adhesion through cadherin ectodomains; the regulation of cadherin expression at the cell surface; cooperation between cadherins and the actin cytoskeleton; and regulation by cell signaling. We discuss current progress and outline issues for further research in these fields. PMID:21527735

  16. A rho scaffold integrates the secretory system with feedback mechanisms in regulation of auxin distribution.

    Directory of Open Access Journals (Sweden)

    Ora Hazak

    2010-01-01

    Full Text Available Development in multicellular organisms depends on the ability of individual cells to coordinate their behavior by means of small signaling molecules to form correctly patterned tissues. In plants, a unique mechanism of directional transport of the signaling molecule auxin between cells connects cell polarity and tissue patterning and thus is required for many aspects of plant development. Direction of auxin flow is determined by polar subcellular localization of PIN auxin efflux transporters. Dynamic PIN polar localization results from the constitutive endocytic cycling to and from the plasma membrane, but it is not well understood how this mechanism connects to regulators of cell polarity. The Rho family small GTPases ROPs/RACs are master regulators of cell polarity, however their role in regulating polar protein trafficking and polar auxin transport has not been established. Here, by analysis of mutants and transgenic plants, we show that the ROP interactor and polarity regulator scaffold protein ICR1 is required for recruitment of PIN proteins to the polar domains at the plasma membrane. icr1 mutant embryos and plants display an a array of severe developmental aberrations that are caused by compromised differential auxin distribution. ICR1 functions at the plasma membrane where it is required for exocytosis but does not recycle together with PINs. ICR1 expression is quickly induced by auxin but is suppressed at the positions of stable auxin maxima in the hypophysis and later in the embryonic and mature root meristems. Our results imply that ICR1 is part of an auxin regulated positive feedback loop realized by a unique integration of auxin-dependent transcriptional regulation into ROP-mediated modulation of cell polarity. Thus, ICR1 forms an auxin-modulated link between cell polarity, exocytosis, and auxin transport-dependent tissue patterning.

  17. Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability

    OpenAIRE

    Wan, Ruiqian; Weigand, Letitia A.; Bateman, Ryan; Griffioen, Kathleen; Mendelowitz, David; Mattson, Mark P.

    2014-01-01

    Autonomic control of heart rate is mediated by cardioinhibitory parasympathetic cholinergic neurons located in the brainstem and stimulatory sympathetic noradrenergic neurons. During embryonic development the survival and cholinergic phenotype of brainstem autonomic neurons is promoted by brain-derived neurotrophic factor (BDNF). We now provide evidence that BDNF regulates heart rate by a mechanism involving increased brainstem cardioinhibitory parasympathetic activity. Mice with a BDNF haplo...

  18. Mechanisms of regulation in the interferon factor 3 (IRF- 3) pathway

    OpenAIRE

    Limmer, Kirsten

    2008-01-01

    Interferon regulatory factor 3 (IRF-3) plays a critical role in the host cell response to both bacterial and viral infection. IRF-3 is activated by Toll-like receptors (TLRs) and cytoplasmic nucleic acid sensors, and serves to upregulate interferon beta and interferon stimulated genes (ISGs), thereby providing a quick and effective response to infection. In this work, two novel mechanisms of regulation in the IRF-3 pathway are revealed. The first part of this thesis work shows that upon bindi...

  19. Afferent nerves regulating the cough reflex: Mechanisms and Mediators of Cough in Disease

    Science.gov (United States)

    Canning, Brendan J.

    2010-01-01

    Bronchopulmonary C-fibers and acid-sensitive, capsaicin-insensitive mechanoreceptors innervating the larynx, trachea and large bronchi regulate the cough reflex. These vagal afferent nerves may interact centrally with sensory input arising from afferent nerves innervating the intrapulmonary airways or even extrapulmonary afferents such as those innervating the nasal mucosa and esophagus to produce chronic cough or enhanced cough responsiveness. The mechanisms of cough initiation in health and in disease are briefly described. PMID:20172253

  20. Development of neural mechanisms of conflict and error processing during childhood: implications for self-regulation.

    Science.gov (United States)

    Checa, Purificación; Castellanos, M C; Abundis-Gutiérrez, Alicia; Rosario Rueda, M

    2014-01-01

    Regulation of thoughts and behavior requires attention, particularly when there is conflict between alternative responses or when errors are to be prevented or corrected. Conflict monitoring and error processing are functions of the executive attention network, a neurocognitive system that greatly matures during childhood. In this study, we examined the development of brain mechanisms underlying conflict and error processing with event-related potentials (ERPs), and explored the relationship between brain function and individual differences in the ability to self-regulate behavior. Three groups of children aged 4-6, 7-9, and 10-13 years, and a group of adults performed a child-friendly version of the flanker task while ERPs were registered. Marked developmental changes were observed in both conflict processing and brain reactions to errors. After controlling by age, higher self-regulation skills are associated with smaller amplitude of the conflict effect but greater amplitude of the error-related negativity. Additionally, we found that electrophysiological measures of conflict and error monitoring predict individual differences in impulsivity and the capacity to delay gratification. These findings inform of brain mechanisms underlying the development of cognitive control and self-regulation.

  1. Development of neural mechanisms of conflict and error processing during childhood: Implications for self-regulation

    Directory of Open Access Journals (Sweden)

    Purificación eCheca

    2014-04-01

    Full Text Available Regulation of thoughts and behavior requires attention, particularly when there is conflict between alternative responses or when errors are to be prevented or corrected. Conflict monitoring and error processing are functions of the executive attention network, a neurocognitive system that greatly matures during childhood. In this study, we examined the development of brain mechanisms underlying conflict and error processing with event-related potentials (ERPs, and explored the relationship between brain function and individual differences in the ability to self-regulate behavior. Three groups of children aged 4 to 6, 7 to 9, and 10 to 13 years, and a group of adults performed a child-friendly version of the flanker task while ERPs were registered. Marked developmental changes were observed in both conflict processing and brain reactions to errors. After controlling by age, higher self-regulation skills are associated with smaller amplitude of the conflict effect but greater amplitude of the error-related negativity. Additionally, we found that electrophysiological measures of conflict and error monitoring predict individual differences in impulsivity and the capacity to delay gratification. These findings inform of brain mechanisms underlying the development of cognitive control and self-regulation.

  2. Development of neural mechanisms of conflict and error processing during childhood: implications for self-regulation

    Science.gov (United States)

    Checa, Purificación; Castellanos, M. C.; Abundis-Gutiérrez, Alicia; Rosario Rueda, M.

    2014-01-01

    Regulation of thoughts and behavior requires attention, particularly when there is conflict between alternative responses or when errors are to be prevented or corrected. Conflict monitoring and error processing are functions of the executive attention network, a neurocognitive system that greatly matures during childhood. In this study, we examined the development of brain mechanisms underlying conflict and error processing with event-related potentials (ERPs), and explored the relationship between brain function and individual differences in the ability to self-regulate behavior. Three groups of children aged 4–6, 7–9, and 10–13 years, and a group of adults performed a child-friendly version of the flanker task while ERPs were registered. Marked developmental changes were observed in both conflict processing and brain reactions to errors. After controlling by age, higher self-regulation skills are associated with smaller amplitude of the conflict effect but greater amplitude of the error-related negativity. Additionally, we found that electrophysiological measures of conflict and error monitoring predict individual differences in impulsivity and the capacity to delay gratification. These findings inform of brain mechanisms underlying the development of cognitive control and self-regulation. PMID:24795676

  3. Staying cool when things get hot: Emotion regulation modulates neural mechanisms of memory encoding

    Directory of Open Access Journals (Sweden)

    Jasmeet P Hayes

    2010-12-01

    Full Text Available During times of emotional stress, individuals often engage in emotion regulation to reduce the experiential and physiological impact of negative emotions. Interestingly, emotion regulation strategies also influence memory encoding of the event. Cognitive reappraisal is associated with enhanced memory while expressive suppression is associated with impaired explicit memory of the emotional event. However, the mechanism by which these emotion regulation strategies affect memory is unclear. We used event-related fMRI to investigate the neural mechanisms that give rise to memory formation during emotion regulation. Twenty-five participants viewed negative pictures while alternately engaging in cognitive reappraisal, expressive suppression, or passive viewing. As part of the subsequent memory design, participants returned to the laboratory two weeks later for a surprise memory test. Behavioral results showed a reduction in negative affect and a retention advantage for reappraised stimuli relative to the other conditions. Imaging results showed that successful encoding during reappraisal was uniquely associated with greater co-activation of the left inferior frontal gyrus, amygdala and hippocampus, suggesting a possible role for elaborative encoding of negative memories. This study provides neurobehavioral evidence that engaging in cognitive reappraisal is advantageous to both affective and mnemonic processes.

  4. A generalized allosteric mechanism for cis-regulated cyclic nucleotide binding domains.

    Directory of Open Access Journals (Sweden)

    Alexandr P Kornev

    2008-04-01

    Full Text Available Cyclic nucleotides (cAMP and cGMP regulate multiple intracellular processes and are thus of a great general interest for molecular and structural biologists. To study the allosteric mechanism of different cyclic nucleotide binding (CNB domains, we compared cAMP-bound and cAMP-free structures (PKA, Epac, and two ionic channels using a new bioinformatics method: local spatial pattern alignment. Our analysis highlights four major conserved structural motifs: 1 the phosphate binding cassette (PBC, which binds the cAMP ribose-phosphate, 2 the "hinge," a flexible helix, which contacts the PBC, 3 the beta(2,3 loop, which provides precise positioning of an invariant arginine from the PBC, and 4 a conserved structural element consisting of an N-terminal helix, an eight residue loop and the A-helix (N3A-motif. The PBC and the hinge were included in the previously reported allosteric model, whereas the definition of the beta(2,3 loop and the N3A-motif as conserved elements is novel. The N3A-motif is found in all cis-regulated CNB domains, and we present a model for an allosteric mechanism in these domains. Catabolite gene activator protein (CAP represents a trans-regulated CNB domain family: it does not contain the N3A-motif, and its long range allosteric interactions are substantially different from the cis-regulated CNB domains.

  5. Agonist-induced down-regulation of endogenous protein kinase c α through an endolysosomal mechanism.

    Science.gov (United States)

    Lum, Michelle A; Pundt, Krista E; Paluch, Benjamin E; Black, Adrian R; Black, Jennifer D

    2013-05-03

    Protein kinase C (PKC) isozymes undergo down-regulation upon sustained stimulation. Previous studies have pointed to the existence of both proteasome-dependent and -independent pathways of PKCα processing. Here we demonstrate that these down-regulation pathways are engaged in different subcellular compartments; proteasomal degradation occurs mainly at the plasma membrane, whereas non-proteasomal processing occurs in the perinuclear region. Using cholesterol depletion, pharmacological inhibitors, RNA interference, and dominant-negative mutants, we define the mechanisms involved in perinuclear accumulation of PKCα and identify the non-proteasomal mechanism mediating its degradation. We show that intracellular accumulation of PKCα involves at least two clathrin-independent, cholesterol/lipid raft-mediated pathways that do not require ubiquitination of the protein; one is dynamin-dependent and likely involves caveolae, whereas the other is dynamin- and small GTPase-independent. Internalized PKCα traffics through endosomes and is delivered to the lysosome for degradation. Supportive evidence includes (a) detection of the enzyme in EEA1-positive early endosomes, Rab7-positive late endosomes/multivesicular bodies, and LAMP1-positive lysosomes and (b) inhibition of its down-regulation by lysosome-disrupting agents and leupeptin. Only limited dephosphorylation of PKCα occurs during trafficking, with fully mature enzyme being the main target for lysosomal degradation. These studies define a novel and widespread mechanism of desensitization of PKCα signaling that involves endocytic trafficking and lysosome-mediated degradation of the mature, fully phosphorylated protein.

  6. Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization.

    Science.gov (United States)

    Kim, Jung; Bilder, David; Neufeld, Thomas P

    2018-01-15

    Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the Drosophila larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in Drosophila fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism. © 2018 Kim et al.; Published by Cold Spring Harbor Laboratory Press.

  7. Concise Review: Plasma and Nuclear Membranes Convey Mechanical Information to Regulate Mesenchymal Stem Cell Lineage.

    Science.gov (United States)

    Uzer, Gunes; Fuchs, Robyn K; Rubin, Janet; Thompson, William R

    2016-06-01

    Numerous factors including chemical, hormonal, spatial, and physical cues determine stem cell fate. While the regulation of stem cell differentiation by soluble factors is well-characterized, the role of mechanical force in the determination of lineage fate is just beginning to be understood. Investigation of the role of force on cell function has largely focused on "outside-in" signaling, initiated at the plasma membrane. When interfaced with the extracellular matrix, the cell uses integral membrane proteins, such as those found in focal adhesion complexes to translate force into biochemical signals. Akin to these outside-in connections, the internal cytoskeleton is physically linked to the nucleus, via proteins that span the nuclear membrane. Although structurally and biochemically distinct, these two forms of mechanical coupling influence stem cell lineage fate and, when disrupted, often lead to disease. Here we provide an overview of how mechanical coupling occurs at the plasma and nuclear membranes. We also discuss the role of force on stem cell differentiation, with focus on the biochemical signals generated at the cell membrane and the nucleus, and how those signals influence various diseases. While the interaction of stem cells with their physical environment and how they respond to force is complex, an understanding of the mechanical regulation of these cells is critical in the design of novel therapeutics to combat diseases associated with aging, cancer, and osteoporosis. Stem Cells 2016;34:1455-1463. © 2016 AlphaMed Press.

  8. LORETA Neurofeedback in the Precuneus: Operant Conditioning in Basic Mechanisms of Self-Regulation.

    Science.gov (United States)

    Cannon, Rex L; Baldwin, Debora R; Diloreto, Dominic J; Phillips, Sherman T; Shaw, Tiffany L; Levy, Jacob J

    2014-10-01

    Low-resolution brain electomagnetic tomography (LORETA) neurofeedback provides a mechanism to influence the electrical activity of the brain in intracranial space. The aim of this study was to determine the effects of LORETA neurofeedback (LNFB) in the precuneus as a mechanism for improving self-regulation in controls and a heterogeneous diagnostic group (DX). Thirteen participants completed between 10 and 20 sessions of LNFB training in a 3-voxel cluster in the left precuneus. The participants included 5 nonclinical university students, and 8 adults with heterogeneous psychiatric diagnoses. We assessed the effects of LNFB with neurophysiological measures as well as pre- and post-Personality Assessment Inventory (PAI) subscales and selected subtests from the Delis-Kaplan Executive Function System (DKEFS). There was a significant total relative power increase at the precuneus for baseline contrasts for the control group. The DX group did not reach significant levels. All participants showed improvements in executive functions and tended to report significantly less psychopathology. The basic neural mechanisms of self-regulation are poorly understood. The data obtained in this study demonstrate that LNFB in a heterogeneous population enhances executive functions while concordantly decreasing endorsement of psychological symptoms. The alpha frequency in the brain may represent integrative functioning relative to operant efficiency and self-regulatory mechanisms. © EEG and Clinical Neuroscience Society (ECNS) 2014.

  9. AGC kinases, mechanisms of regulation ‎and innovative drug development.

    Science.gov (United States)

    Leroux, Alejandro E; Schulze, Jörg O; Biondi, Ricardo M

    2018-02-01

    The group of AGC kinases consists of 63 evolutionarily related serine/threonine protein kinases comprising PDK1, PKB/Akt, SGK, PKC, PRK/PKN, MSK, RSK, S6K, PKA, PKG, DMPK, MRCK, ROCK, NDR, LATS, CRIK, MAST, GRK, Sgk494, and YANK, while two other families, Aurora and PLK, are the most closely related to the group. Eight of these families are physiologically activated downstream of growth factor signalling, while other AGC kinases are downstream effectors of a wide range of signals. The different AGC kinase families share aspects of their mechanisms of inhibition and activation. In the present review, we update the knowledge of the mechanisms of regulation of different AGC kinases. The conformation of the catalytic domain of many AGC kinases is regulated allosterically through the modulation of the conformation of a regulatory site on the small lobe of the kinase domain, the PIF-pocket. The PIF-pocket acts like an ON-OFF switch in AGC kinases with different modes of regulation, i.e. PDK1, PKB/Akt, LATS and Aurora kinases. In this review, we make emphasis on how the knowledge of the molecular mechanisms of regulation can guide the discovery and development of small allosteric modulators. Molecular probes stabilizing the PIF-pocket in the active conformation are activators, while compounds stabilizing the disrupted site are allosteric inhibitors. One challenge for the rational development of allosteric modulators is the lack of complete structural information of the inhibited forms of full-length AGC kinases. On the other hand, we suggest that the available information derived from molecular biology and biochemical studies can already guide screening strategies for the identification of innovative mode of action molecular probes and the development of selective allosteric drugs for the treatment of human diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Stat3 inhibition attenuates mechanical allodynia through transcriptional regulation of chemokine expression in spinal astrocytes.

    Directory of Open Access Journals (Sweden)

    Xiaodong Liu

    Full Text Available BACKGROUND: Signal transducer and activator of transcription 3 (Stat3 is known to induce cell proliferation and inflammation by regulating gene transcription. Recent studies showed that Stat3 modulates nociceptive transmission by reducing spinal astrocyte proliferation. However, it is unclear whether Stat3 also contributes to the modulation of nociceptive transmission by regulating inflammatory response in spinal astrocytes. This study aimed at investigating the role of Stat3 on neuroinflammation during development of pain in rats after intrathecal injection of lipopolysaccharide (LPS. METHODS: Stat3 specific siRNA oligo and synthetic selective inhibitor (Stattic were applied to block the activity of Stat3 in primary astrocytes or rat spinal cord, respectively. LPS was used to induce the expression of proinflammatory genes in all studies. Immunofluorescence staining of cells and slices of spinal cord was performed to monitor Stat3 activation. The impact of Stat3 inhibition on proinflammatory genes expression was determined by cytokine antibody array, enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mechanical allodynia, as determined by the threshold pressure that could induce hind paw withdrawal after application of standardized von Frey filaments, was used to detect the effects of Stat3 inhibition after pain development with intrathecal LPS injection. RESULTS: Intrathecal injection of LPS activated Stat3 in reactive spinal astrocytes. Blockade of Stat3 activity attenuated mechanical allodynia significantly and was correlated with a lower number of reactive astrocytes in the spinal dorsal horn. In vitro study demonstrated that Stat3 modulated inflammatory response in primary astrocytes by transcriptional regulation of chemokine expression including Cx3cl1, Cxcl5, Cxcl10 and Ccl20. Similarly, inhibition of Stat3 reversed the expression of these chemokines in the spinal dorsal horn. CONCLUSIONS: Stat3 acted as a

  11. An APC:WNT counter-current-like mechanism regulates cell division along the colonic crypt axis: a mechanism that explains how APC mutations induce proliferative abnormalities that drive colon cancer development.

    Directory of Open Access Journals (Sweden)

    Bruce M Boman

    2013-11-01

    Full Text Available APC normally down-regulates WNT signaling in human colon, and APC mutations cause proliferative abnormalities in premalignant crypts leading to colon cancer, but the mechanisms are unclear at the level of spatial and functional organization of the crypt. Accordingly, we postulated a counter-current-like mechanism based on gradients of factors (APC;WNT that regulate colonocyte proliferation along the crypt axis. During crypt renewal, stem cells (SCs at the crypt bottom generate non-SC daughter cells that proliferate and differentiate while migrating upwards. The APC concentration is low at the crypt bottom and high at the top (where differentiated cells reside. WNT signaling, in contrast, is high at the bottom (where SCs reside and low at the top. Given that WNT and APC gradients are counter to one another, we hypothesized that a counter-current-like mechanism exists. Since both APC and WNT signaling components (e.g. survivin are required for mitosis, this mechanism establishes a zone in the lower crypt where conditions are optimal for maximal cell division and mitosis orientation (symmetric versus asymmetric. APC haploinsufficiency diminishes the APC gradient, shifts the proliferative zone upwards, and increases symmetric division, which causes SC overpopulation. In homozygote mutant crypts, these changes are exacerbated. Thus, APC-mutation-induced changes in the counter-current-like mechanism cause expansion of proliferative populations (SCs, rapidly-proliferating cells during tumorigenesis. We propose this mechanism also drives crypt fission, functions in the crypt cycle, and underlies adenoma development. Novel chemoprevention approaches designed to normalize the two gradients and readjust the proliferative zone downwards, might thwart progression of these premalignant changes.

  12. An APC:WNT Counter-Current-Like Mechanism Regulates Cell Division Along the Human Colonic Crypt Axis: A Mechanism That Explains How APC Mutations Induce Proliferative Abnormalities That Drive Colon Cancer Development

    Science.gov (United States)

    Boman, Bruce M.; Fields, Jeremy Z.

    2013-01-01

    APC normally down-regulates WNT signaling in human colon, and APC mutations cause proliferative abnormalities in premalignant crypts leading to colon cancer, but the mechanisms are unclear at the level of spatial and functional organization of the crypt. Accordingly, we postulated a counter-current-like mechanism based on gradients of factors (APC;WNT) that regulate colonocyte proliferation along the crypt axis. During crypt renewal, stem cells (SCs) at the crypt bottom generate non-SC daughter cells that proliferate and differentiate while migrating upwards. The APC concentration is low at the crypt bottom and high at the top (where differentiated cells reside). WNT signaling, in contrast, is high at the bottom (where SCs reside) and low at the top. Given that WNT and APC gradients are counter to one another, we hypothesized that a counter-current-like mechanism exists. Since both APC and WNT signaling components (e.g., survivin) are required for mitosis, this mechanism establishes a zone in the lower crypt where conditions are optimal for maximal cell division and mitosis orientation (symmetric versus asymmetric). APC haploinsufficiency diminishes the APC gradient, shifts the proliferative zone upwards, and increases symmetric division, which causes SC overpopulation. In homozygote mutant crypts, these changes are exacerbated. Thus, APC-mutation-induced changes in the counter-current-like mechanism cause expansion of proliferative populations (SCs, rapidly proliferating cells) during tumorigenesis. We propose this mechanism also drives crypt fission, functions in the crypt cycle, and underlies adenoma development. Novel chemoprevention approaches designed to normalize the two gradients and readjust the proliferative zone downwards, might thwart progression of these premalignant changes. PMID:24224156

  13. The Role of Adaptation in Body Load-Regulating Mechanisms During Locomotion

    Science.gov (United States)

    Ruttley, Tara; Holt, Christopher; Mulavara, Ajitkumar; Bloomberg, Jacob

    2010-01-01

    Body loading is a fundamental parameter that modulates motor output during locomotion, and is especially important for controlling the generation of stepping patterns, dynamic balance, and termination of locomotion. Load receptors that regulate and control posture and stance in locomotion include the Golgi tendon organs and muscle spindles at the hip, knee, and ankle joints, and the Ruffini endings and the Pacinian corpuscles in the soles of the feet. Increased body weight support (BWS) during locomotion results in an immediate reorganization of locomotor control, such as a reduction in stance and double support duration and decreased hip, ankle, and knee angles during the gait cycle. Previous studies on the effect during exposure to increased BWS while walking showed a reduction in lower limb joint angles and gait cycle timing that represents a reorganization of locomotor control. Until now, no studies have investigated how locomotor control responds after a period of exposure to adaptive modification in the body load sensing system. The goal of this research was to determine the adaptive properties of body load-regulating mechanisms in locomotor control during locomotion. We hypothesized that body load-regulating mechanisms contribute to locomotor control, and adaptive changes in these load-regulating mechanisms require reorganization to maintain forward locomotion. Head-torso coordination, lower limb movement patterns, and gait cycle timing were evaluated before and after a 30-minute adaptation session during which subjects walked on a treadmill at 5.4 km/hr with 40% body weight support (BWS). Before and after the adaptation period, head-torso and lower limb 3D kinematic data were obtained while performing a goal directed task during locomotion with 0% BWS using a video-based motion analysis system, and gait cycle timing parameters were collected by foot switches positioned under the heel and toe of the subjects shoes. Subjects showed adaptive modification in

  14. Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D.

    Science.gov (United States)

    Wei, Ran; Christakos, Sylvia

    2015-09-24

    Non-classical actions of vitamin D were first suggested over 30 years ago when receptors for the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), were detected in various tissues and cells that are not associated with the regulation of calcium homeostasis, including activated human inflammatory cells. The question that remained was the biological significance of the presence of vitamin D receptors in the different tissues and cells and, with regard to the immune system, whether or not vitamin D plays a role in the normal immune response and in modifying immune mediated diseases. In this article findings indicating that vitamin D is a key factor regulating both innate and adaptive immunity are reviewed with a focus on the molecular mechanisms involved. In addition, the physiological significance of vitamin D action, as suggested by in vivo studies in mouse models is discussed. Together, the findings indicate the importance of 1,25(OH)2D3 as a regulator of key components of the immune system. An understanding of the mechanisms involved will lead to potential therapeutic applications for the treatment of immune mediated diseases.

  15. Mechanisms regulating brain docosahexaenoic acid uptake: what is the recent evidence?

    Science.gov (United States)

    Chouinard-Watkins, Raphaël; Lacombe, R J Scott; Bazinet, Richard P

    2018-03-01

    To summarize recent advances pertaining to the mechanisms regulating brain docosahexaenoic acid (DHA) uptake. DHA is an omega-3 polyunsaturated fatty acid highly enriched in neuronal membranes and it is implicated in several important neurological processes. However, DHA synthesis is extremely limited within the brain. There are two main plasma pools that supply the brain with DHA: the nonesterified pool and the lysophosphatidylcholine (lysoPtdCho) pool. Quantitatively, plasma nonesterified-DHA (NE-DHA) is the main contributor to brain DHA. Fatty acid transport protein 1 (FATP1) in addition to fatty acid-binding protein 5 (FABP5) are key players that regulate brain uptake of NE-DHA. However, the plasma half-life of lysoPtdCho-DHA and its brain partition coefficient are higher than those of NE-DHA after intravenous administration. The mechanisms regulating brain DHA uptake are more complicated than once believed, but recent advances provide some clarity notably by suggesting that FATP1 and FABP5 are key contributors to cellular uptake of DHA at the blood-brain barrier. Elucidating how DHA enters the brain is important as we might be able to identify methods to better deliver DHA to the brain as a potential therapeutic.

  16. Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix.

    Science.gov (United States)

    Kubow, Kristopher E; Vukmirovic, Radmila; Zhe, Lin; Klotzsch, Enrico; Smith, Michael L; Gourdon, Delphine; Luna, Sheila; Vogel, Viola

    2015-08-14

    Despite the crucial role of extracellular matrix (ECM) in directing cell fate in healthy and diseased tissues--particularly in development, wound healing, tissue regeneration and cancer--the mechanisms that direct the assembly and regulate hierarchical architectures of ECM are poorly understood. Collagen I matrix assembly in vivo requires active fibronectin (Fn) fibrillogenesis by cells. Here we exploit Fn-FRET probes as mechanical strain sensors and demonstrate that collagen I fibres preferentially co-localize with more-relaxed Fn fibrils in the ECM of fibroblasts in cell culture. Fibre stretch-assay studies reveal that collagen I's Fn-binding domain is responsible for the mechano-regulated interaction. Furthermore, we show that Fn-collagen interactions are reciprocal: relaxed Fn fibrils act as multivalent templates for collagen assembly, but once assembled, collagen fibres shield Fn fibres from being stretched by cellular traction forces. Thus, in addition to the well-recognized, force-regulated, cell-matrix interactions, forces also tune the interactions between different structural ECM components.

  17. A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation.

    Science.gov (United States)

    Wei, Jia; Zhang, Yixiao; Yu, Tai-Yuan; Sadre-Bazzaz, Kianoush; Rudolph, Michael J; Amodeo, Gabriele A; Symington, Lorraine S; Walz, Thomas; Tong, Liang

    2016-01-01

    Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and attractive targets for drug discovery. Eukaryotic acetyl-CoA carboxylases are 250 kDa single-chain, multi-domain enzymes and function as dimers and higher oligomers. Their catalytic activity is tightly regulated by phosphorylation and other means. Here we show that yeast ACC is directly phosphorylated by the protein kinase SNF1 at residue Ser1157, which potently inhibits the enzyme. Crystal structure of three ACC central domains (AC3-AC5) shows that the phosphorylated Ser1157 is recognized by Arg1173, Arg1260, Tyr1113 and Ser1159. The R1173A/R1260A double mutant is insensitive to SNF1, confirming that this binding site is crucial for regulation. Electron microscopic studies reveal dramatic conformational changes in the holoenzyme upon phosphorylation, likely owing to the dissociation of the biotin carboxylase domain dimer. The observations support a unified molecular mechanism for the regulation of ACC by phosphorylation as well as by the natural product soraphen A, a potent inhibitor of eukaryotic ACC. These molecular insights enhance our understanding of acetyl-CoA carboxylase regulation and provide a basis for drug discovery.

  18. [Molecular mechanisms of autophagy in regulating renal aging and interventional effects of Chinese herbal medicine].

    Science.gov (United States)

    Tu, Yue; Sun, Wei; Chen, Di-Ping; Wan, Yi-Gang; Wu, Wei; Yao, Jian

    2016-11-01

    Aging is the gradual functional recession of the living tissues or organs caused by a variety of genetic and environmental factors together. Autophagy is a process of degrading cytoplasmic components mediated by lysosomes in eukaryotic cells. Kidney is a typical target organ of aging. Autophagy regulates renal aging. Decrease in autophagy can accelerate renal aging,whereas,increase in autophagy can delay renal aging. During the process of regulating renal aging,the mammalian target of rapamycin (mTOR) and its related signaling pathways including the adenosine monophosphate activated protein kinase (AMPK)/mTOR,the phosphatidylinositol 3-kinase (PI3K)/ serine-threonine kinase(Akt)/mTOR,the AMPK/silent information regulation 1 (Sirt1) and transforming growth factor β (TGF-β) play the important roles in renal aging. Regulating the key signaling molecules in these pathways in vivo can control renal aging. Some Chinese herbal medicine (CHM) and their extracts with the effects of nourishing kidney or activating stasis, such as Cordyceps sinensis, curcumin and resveratrol have the beneficial effects on renal aging and/or autophagy. Therefore,revealing the pharmacological effects of CHM in anti-renal aging based on the molecular mechanisms of autophagy will become one of the development trends in the future study. Copyright© by the Chinese Pharmaceutical Association.

  19. A palmitoylation switch mechanism regulates Rac1 function and membrane organization

    Science.gov (United States)

    Navarro-Lérida, Inmaculada; Sánchez-Perales, Sara; Calvo, María; Rentero, Carles; Zheng, Yi; Enrich, Carlos; Del Pozo, Miguel A

    2012-01-01

    The small GTPase Rac1 plays important roles in many processes, including cytoskeletal reorganization, cell migration, cell-cycle progression and gene expression. The initiation of Rac1 signalling requires at least two mechanisms: GTP loading via the guanosine triphosphate (GTP)/guanosine diphosphate (GDP) cycle, and targeting to cholesterol-rich liquid-ordered plasma membrane microdomains. Little is known about the molecular mechanisms governing this specific compartmentalization. We show that Rac1 can incorporate palmitate at cysteine 178 and that this post-translational modification targets Rac1 for stabilization at actin cytoskeleton-linked ordered membrane regions. Palmitoylation of Rac1 requires its prior prenylation and the intact C-terminal polybasic region and is regulated by the triproline-rich motif. Non-palmitoylated Rac1 shows decreased GTP loading and lower association with detergent-resistant (liquid-ordered) membranes (DRMs). Cells expressing no Rac1 or a palmitoylation-deficient mutant have an increased content of disordered membrane domains, and markers of ordered membranes isolated from Rac1-deficient cells do not correctly partition in DRMs. Importantly, cells lacking Rac1 palmitoylation show spreading and migration defects. These data identify palmitoylation as a mechanism for Rac1 function in actin cytoskeleton remodelling by controlling its membrane partitioning, which in turn regulates membrane organization. PMID:22157745

  20. Research on Double Price Regulations and Peak Shaving Reserve Mechanism in Coal-Electricity Supply Chain

    Directory of Open Access Journals (Sweden)

    Hongjun Peng

    2013-01-01

    Full Text Available The game models were used to study the mechanism of coal-electricity price conflict under conditions of double price regulations of coal and electricity. Based on this, the peak shaving reserve mechanism was designed to probe into the countermeasures against the coal-electricity price conflicts. The study revealed that in the boom seasons of coal demand, the initiatives of the coal enterprises to supply thermal coal and the electricity enterprises to order thermal coal are reduced under conditions of double price regulations. However, under the circumstances of coal price marketization, in the boom seasons of coal demand the thermal coal price may go up obviously, the initiatives of the coal enterprises to supply thermal coal are increased, and meanwhile the initiatives of the power enterprises to order thermal coal are decreased dramatically. The transportation capacity constraint of coal supply leads to the evident decrease of the initiatives of coal enterprises for the thermal coal supply. The mechanism of peak shaving reserve of thermal coal may not only reduce the price of coal market but also increase the enthusiasm of the power enterprises to order more thermal coal and the initiatives of the coal enterprises to supply more thermal coal.

  1. The Government Incentive Regulation Model and Pricing Mechanism in Power Transmission and Distribution Market

    Directory of Open Access Journals (Sweden)

    Huan Zhang

    2016-01-01

    Full Text Available The power transmission and distribution (T&D market’s natural monopoly and individual information have been the impediment to improving the energy efficiency in the whole T&D market. In order to improve the whole social welfare, T&D market should be controlled by government. An incentive regulation model with the target of maximizing social welfare has been studied. A list of contracts with transferring payment and quantity of T&D are given to motivate the corporation to reveal the true technical parameter and input the optimal investment. The corporate revenue, optimal investment, and effort are proved to depend on its own technical parameter. The part of incentive regulation model ends with the optimal pricing mechanism of T&D market. At the end of this paper, we give a numerical example to explain our research and confirm its function graphically.

  2. RecA: Regulation and Mechanism of a Molecular Search Engine.

    Science.gov (United States)

    Bell, Jason C; Kowalczykowski, Stephen C

    2016-06-01

    Homologous recombination maintains genomic integrity by repairing broken chromosomes. The broken chromosome is partially resected to produce single-stranded DNA (ssDNA) that is used to search for homologous double-stranded DNA (dsDNA). This homology driven 'search and rescue' is catalyzed by a class of DNA strand exchange proteins that are defined in relation to Escherichia coli RecA, which forms a filament on ssDNA. Here, we review the regulation of RecA filament assembly and the mechanism by which RecA quickly and efficiently searches for and identifies a unique homologous sequence among a vast excess of heterologous DNA. Given that RecA is the prototypic DNA strand exchange protein, its behavior affords insight into the actions of eukaryotic RAD51 orthologs and their regulators, BRCA2 and other tumor suppressors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Ca2+-Dependent Regulations and Signaling in Skeletal Muscle: From Electro-Mechanical Coupling to Adaptation

    Science.gov (United States)

    Gehlert, Sebastian; Bloch, Wilhelm; Suhr, Frank

    2015-01-01

    Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca2+ is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction. Furthermore and among others, Ca2+ regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca2+-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca2+ ions for the integrity of skeletal muscle tissue. In this review, we address the major functions of Ca2+ ions in adult muscle but also highlight recent findings of critical Ca2+-dependent mechanisms essential for skeletal muscle-regulation and maintenance. PMID:25569087

  4. Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xiaoling [Iowa State Univ., Ames, IA (United States)

    2010-01-01

    My research is on the synergistic regulation of PAI-1 by EGF and TGF-β. The mechanism of synergistic regulation of PAI-1 by EGF and TGF-β are addressed. Methods are described for effective identification of RNA accessible sites for antisense oligodexoxynucleotides (ODNs) and siRNA. In this study effective AS-ODN sequences for both Lcn2 and Bcl2 were identified by in vitro tiled microarray studies. Our results suggest that hybridization of ODN arrays to a target mRNA under physiological conditions might be used as a rapid and reliable in vitro method to accurately identify targets on mRNA molecules for effective antisense and potential siRNA activity in vivo.

  5. Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

    Directory of Open Access Journals (Sweden)

    Zhen-Ye Zhang

    2017-09-01

    Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

  6. An Age-Related Mechanism of Emotion Regulation: Regulating Sadness Promotes Children's Learning by Broadening Information Processing

    Science.gov (United States)

    Davis, Elizabeth L.

    2016-01-01

    Emotion regulation predicts positive academic outcomes like learning, but little is known about "why". Effective emotion regulation likely promotes learning by broadening the scope of what may be attended to after an emotional event. One hundred twenty-six 6- to 13-year-olds' (54% boys) regulation of sadness was examined for changes in…

  7. Estrogen Regulates Protein Synthesis and Actin Polymerization in Hippocampal Neurons through Different Molecular Mechanisms

    Science.gov (United States)

    Briz, Victor; Baudry, Michel

    2014-01-01

    Estrogen rapidly modulates hippocampal synaptic plasticity by activating selective membrane-associated receptors. Reorganization of the actin cytoskeleton and stimulation of mammalian target of rapamycin (mTOR)-mediated protein synthesis are two major events required for the consolidation of hippocampal long-term potentiation and memory. Estradiol regulates synaptic plasticity by interacting with both processes, but the underlying molecular mechanisms are not yet fully understood. Here, we used acute rat hippocampal slices to analyze the mechanisms underlying rapid changes in mTOR activity and actin polymerization elicited by estradiol. Estradiol-induced mTOR phosphorylation was preceded by rapid and transient activation of both extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) and by phosphatase and tensin homolog (PTEN) degradation. These effects were prevented by calpain and ERK inhibitors. Estradiol-induced mTOR stimulation did not require activation of classical estrogen receptors (ER), as specific ERα and ERβ agonists (PPT and DPN, respectively) failed to mimic this effect, and ER antagonists could not block it. Estradiol rapidly activated both RhoA and p21-activated kinase (PAK). Furthermore, a specific inhibitor of RhoA kinase (ROCK), H1152, and a potent and specific PAK inhibitor, PF-3758309, blocked estradiol-induced cofilin phosphorylation and actin polymerization. ER antagonists also blocked these effects of estrogen. Consistently, both PPT and DPN stimulated PAK and cofilin phosphorylation as well as actin polymerization. Finally, the effects of estradiol on actin polymerization were insensitive to protein synthesis inhibitors, but its stimulation of mTOR activity was impaired by latrunculin A, a drug that disrupts actin filaments. Taken together, our results indicate that estradiol regulates local protein synthesis and cytoskeletal reorganization via different molecular mechanisms and signaling pathways. PMID:24611062

  8. Spontaneous regulating mechanisms that may have led to the origin of life

    International Nuclear Information System (INIS)

    Chela Flores, J.

    1992-07-01

    According to Salam condensation may be relevant in biochemistry, as a factor contributing to the homochirality of amino acids. We attempt to show that DNA packaging may be modelled, by interpreting chromatin as a form of soft matter, in which a phase transition has induced chromatin into a condensed mode. In the context of the origin of life we show the relevance of simultaneous discussion of DNA packaging, transcription, and DNA replication. Beyond a certain critical length of the protogenome (RNA), physical properties of inert condensed matter may have given rise to a spontaneous regulating mechanism of certain significance for the evolution of life on Earth. (author). 31 refs, 1 tab

  9. Mindfulness meditation-related pain relief: Evidence for unique brain mechanisms in the regulation of pain

    Science.gov (United States)

    Zeidan, F.; Grant, J.A.; Brown, C.A.; McHaffie, J.G.; Coghill, R.C.

    2013-01-01

    The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain. PMID:22487846

  10. Measurement of thermal expansion for a Li2TiO3 pebble bed

    International Nuclear Information System (INIS)

    Hisashi Tanigawa; Mikio Enoeda; Masato Akiba

    2006-01-01

    In the current design of the blanket with ceramic breeders, pebbles of breeding materials are packed into a container and used as a pebble bed. Thermal and mechanical conditions externally loaded on the bed affect thermal and mechanical properties of the bed. It is necessary to analyze thermo-mechanical properties of the bed under controlled thermal and mechanical conditions. In the present paper, thermal expansion of a Li 2 TiO 3 pebble bed was investigated. Our apparatus consists of a tensile test-apparatus and a measurement chamber. Pebbles of Li 2 TiO 3 with 2 mm diameter were used. They were packed into a container made of alumina. At first, thermal expansion of the apparatus was calibrated because the measured deformation included thermal expansions of the load rods and the container. Instead of the pebble bed, a column made of copper was installed and thermal expansion of the system was measured for the calibration. Taking into account the estimated thermal expansion of the column, thermal expansion of the rods and the container could be analyzed. Based on the correction, thermal expansion of the pebble bed was measured under compression of 0.1 MPa. Temperature of the bed was regulated from room temperature to 973 K. From the measured expansion of the bed, average thermal expansion coefficient was estimated. For the beds with different packing factors ranging from 65.5 to 68.5 %, thermal expansion coefficients were 1.4 ± 0. 10-5 K -1 . In the first measurement of the beds without pre-loading, expansion coefficients were larger for the cooling process than heating. When the beds were successively heated and cooled, the difference decreased. This means that relocation of the pebbles arises in the first heat treatment and progress of compaction is larger in the cooling process than heating. After a few heat treatments, packing states of the beds reach stable and expansion coefficients for both heat and cooling processes are close. In the case of the beds that

  11. Thermal expansion of doped lanthanum gallates

    Indian Academy of Sciences (India)

    Administrator

    Since the components are in intimate mechanical contact, any stress generated due to their thermal expansion mis- match during thermal cycling could lead to catastrophic failure of the cell. The functional materials must have similar thermal expansions to avoid mechanical stresses. Hence it is useful to study the thermal ...

  12. Regulation of mRNA Translation Is a Novel Mechanism for Phthalate Toxicity.

    Directory of Open Access Journals (Sweden)

    Jun Ling

    Full Text Available Phthalates are a group of plasticizers that are widely used in many consumer products and medical devices, thus generating a huge burden to human health. Phthalates have been known to cause a number of developmental and reproductive disorders functioning as endocrine modulators. They are also involved in carcinogenesis with mechanisms less understood. To further understand the molecular mechanisms of phthalate toxicity, in this study we reported a new effect of phthalates on mRNA translation/protein synthesis, a key regulatory step of gene expression. Butyl benzyl phthalate (BBP was found to directly inhibit mRNA translation in vitro but showed a complicated pattern of affecting mRNA translation in cells. In human kidney embryonic cell (HEK-293T, BBP increased cap-dependent mRNA translation at lower concentrations but showed inhibitory effect at higher concentrations. Cap-independent translation was not affected. On the other hand, mono (2-ethylhexyl phthalate (MEHP as a major metabolite of another important phthalate di (2-ethylhexyl phthalate (DEHP inhibited both can-dependent and -independent mRNA translation in vivo. In contrast, BBP and MEHP exhibited an overall promoting effect on mRNA translation in cancer cells. Mechanistic studies identified that the level and phosphorylation of eIF4E-BP (eIF4E binding protein and the amount of eIF4GI in eIF4F complex were altered in accordance with the effect of BBP on translation. BBP was also identified to directly bind to eIF4E, providing a further mechanism underlying the regulation of mRNA by phthalate. At the cellular level BBP inhibited normal cell growth but slightly promoted cancer cells (HT29 growth. Overall, this study provides the first evidence that phthalates can directly regulate mRNA translation as a novel mechanism to mediate their biological toxicities.

  13. Mechanical loading regulates human MSC differentiation in a multi-layer hydrogel for osteochondral tissue engineering.

    Science.gov (United States)

    Steinmetz, Neven J; Aisenbrey, Elizabeth A; Westbrook, Kristofer K; Qi, H Jerry; Bryant, Stephanie J

    2015-07-01

    A bioinspired multi-layer hydrogel was developed for the encapsulation of human mesenchymal stem cells (hMSCs) as a platform for osteochondral tissue engineering. The spatial presentation of biochemical cues, via incorporation of extracellular matrix analogs, and mechanical cues, via both hydrogel crosslink density and externally applied mechanical loads, were characterized in each layer. A simple sequential photopolymerization method was employed to form stable poly(ethylene glycol)-based hydrogels with a soft cartilage-like layer of chondroitin sulfate and low RGD concentrations, a stiff bone-like layer with high RGD concentrations, and an intermediate interfacial layer. Under a compressive load, the variation in hydrogel stiffness within each layer produced high strains in the soft cartilage-like layer, low strains in the stiff bone-like layer, and moderate strains in the interfacial layer. When hMSC-laden hydrogels were cultured statically in osteochondral differentiation media, the local biochemical and matrix stiffness cues were not sufficient to spatially guide hMSC differentiation after 21 days. However dynamic mechanical stimulation led to differentially high expression of collagens with collagen II in the cartilage-like layer, collagen X in the interfacial layer and collagen I in the bone-like layer and mineral deposits localized to the bone layer. Overall, these findings point to external mechanical stimulation as a potent regulator of hMSC differentiation toward osteochondral cellular phenotypes. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  14. Distributed force feedback in the spinal cord and the regulation of limb mechanics.

    Science.gov (United States)

    Nichols, T Richard

    2018-03-01

    This review is an update on the role of force feedback from Golgi tendon organs in the regulation of limb mechanics during voluntary movement. Current ideas about the role of force feedback are based on modular circuits linking idealized systems of agonists, synergists, and antagonistic muscles. In contrast, force feedback is widely distributed across the muscles of a limb and cannot be understood based on these circuit motifs. Similarly, muscle architecture cannot be understood in terms of idealized systems, since muscles cross multiple joints and axes of rotation and further influence remote joints through inertial coupling. It is hypothesized that distributed force feedback better represents the complex mechanical interactions of muscles, including the stresses in the musculoskeletal network born by muscle articulations, myofascial force transmission, and inertial coupling. Together with the strains of muscle fascicles measured by length feedback from muscle spindle receptors, this integrated proprioceptive feedback represents the mechanical state of the musculoskeletal system. Within the spinal cord, force feedback has excitatory and inhibitory components that coexist in various combinations based on motor task and integrated with length feedback at the premotoneuronal and motoneuronal levels. It is concluded that, in agreement with other investigators, autogenic, excitatory force feedback contributes to propulsion and weight support. It is further concluded that coexistent inhibitory force feedback, together with length feedback, functions to manage interjoint coordination and the mechanical properties of the limb in the face of destabilizing inertial forces and positive force feedback, as required by the accelerations and changing directions of both predator and prey.

  15. Sun-mediated mechanical LINC between nucleus and cytoskeleton regulates βcatenin nuclear access.

    Science.gov (United States)

    Uzer, Gunes; Bas, Guniz; Sen, Buer; Xie, Zhihui; Birks, Scott; Olcum, Melis; McGrath, Cody; Styner, Maya; Rubin, Janet

    2018-06-06

    βcatenin acts as a primary intracellular signal transducer for mechanical and Wnt signaling pathways to control cell function and fate. Regulation of βcatenin in the cytoplasm has been well studied but βcatenin nuclear trafficking and function remains unclear. In a previous study we showed that, in mesenchymal stem cells (MSC), mechanical blockade of adipogenesis relied on inhibition of βcatenin destruction complex element GSK3β (glycogen synthase kinase 3β) to increase nuclear βcatenin as well as the function of Linker of Cytoskeleton and Nucleoskeleton (LINC) complexes, suggesting that these two mechanisms may be linked. Here we show that shortly after inactivation of GSK3β due to either low intensity vibration (LIV), substrate strain or pharmacologic inhibition, βcatenin associates with the nucleoskeleton, defined as the insoluble nuclear fraction that provides structure to the integrated nuclear envelope, nuclear lamina and chromatin. Co-depleting LINC elements Sun-1 and Sun-2 interfered with both nucleoskeletal association and nuclear entry of βcatenin, resulting in decreased nuclear βcatenin levels. Our findings reveal that the insoluble structural nucleoskeleton actively participates in βcatenin dynamics. As the cytoskeleton transmits applied mechanical force to the nuclear surface to influence the nucleoskeleton and its LINC mediated interaction, our results suggest a pathway by which LINC mediated connectivity may play a role in signaling pathways that depend on nuclear access of βcatenin. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Status, Antimicrobial Mechanism, and Regulation of Natural Preservatives in Livestock Food Systems.

    Science.gov (United States)

    Lee, Na-Kyoung; Paik, Hyun-Dong

    2016-01-01

    This review discusses the status, antimicrobial mechanisms, application, and regulation of natural preservatives in livestock food systems. Conventional preservatives are synthetic chemical substances including nitrates/nitrites, sulfites, sodium benzoate, propyl gallate, and potassium sorbate. The use of artificial preservatives is being reconsidered because of concerns relating to headache, allergies, and cancer. As the demand for biopreservation in food systems has increased, new natural antimicrobial compounds of various origins are being developed, including plant-derived products (polyphenolics, essential oils, plant antimicrobial peptides (pAMPs)), animal-derived products (lysozymes, lactoperoxidase, lactoferrin, ovotransferrin, antimicrobial peptide (AMP), chitosan and others), and microbial metabolites (nisin, natamycin, pullulan, ε-polylysine, organic acid, and others). These natural preservatives act by inhibiting microbial cell walls/membranes, DNA/RNA replication and transcription, protein synthesis, and metabolism. Natural preservatives have been recognized for their safety; however, these substances can influence color, smell, and toxicity in large amounts while being effective as a food preservative. Therefore, to evaluate the safety and toxicity of natural preservatives, various trials including combinations of other substances or different food preservation systems, and capsulation have been performed. Natamycin and nisin are currently the only natural preservatives being regulated, and other natural preservatives will have to be legally regulated before their widespread use.

  17. Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms.

    Science.gov (United States)

    Royston, Kendra J; Paul, Bidisha; Nozell, Susan; Rajbhandari, Rajani; Tollefsbol, Trygve O

    2018-07-01

    Little is known about the effects of combinatorial dietary compounds on the regulation of epigenetic mechanisms involved in breast cancer prevention. The human diet consists of a multitude of components, and there is a need to elucidate how certain compounds interact in collaboration. Withaferin A (WA), found in the Indian winter cherry and documented as a DNA methyltransferase (DNMT) inhibitor, and sulforaphane (SFN), a well-known histone deacetylase (HDAC) inhibitor found in cruciferous vegetables, are two epigenetic modifying compounds that have only recently been studied in conjunction. The use of DNMT and HDAC inhibitors to reverse the malignant expression of certain genes in breast cancer has shown considerable promise. Previously, we found that SFN + WA synergistically promote breast cancer cell death. Herein, we determined that these compounds inhibit cell cycle progression from S to G2 phase in MDA-MB-231 and MCF-7 breast cancer. Furthermore, we demonstrate that this unique combination of epigenetic modifying compounds down-regulates the levels of Cyclin D1 and CDK4, and pRB; conversely, the levels of E2F mRNA and tumor suppressor p21 are increased independently of p53. We find these events coincide with an increase in unrestricted histone methylation. We propose SFN + WA-induced breast cancer cell death is attributed, in part, to epigenetic modifications that result in the modulated expression of key genes responsible for the regulation of cancer cell senescence. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase.

    Directory of Open Access Journals (Sweden)

    Kara R Barber

    2017-02-01

    Full Text Available Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.

  19. Structure of the transcriptional regulator LmrR and its mechanism of multidrug recognition.

    Science.gov (United States)

    Madoori, Pramod Kumar; Agustiandari, Herfita; Driessen, Arnold J M; Thunnissen, Andy-Mark W H

    2009-01-21

    LmrR is a PadR-related transcriptional repressor that regulates the production of LmrCD, a major multidrug ABC transporter in Lactococcus lactis. Transcriptional regulation is presumed to follow a drug-sensitive induction mechanism involving the direct binding of transporter ligands to LmrR. Here, we present crystal structures of LmrR in an apo state and in two drug-bound states complexed with Hoechst 33342 and daunomycin. LmrR shows a common topology containing a typical beta-winged helix-turn-helix domain with an additional C-terminal helix involved in dimerization. Its dimeric organization is highly unusual with a flat-shaped hydrophobic pore at the dimer centre serving as a multidrug-binding site. The drugs bind in a similar manner with their aromatic rings sandwiched in between the indole groups of two dimer-related tryptophan residues. Multidrug recognition is facilitated by conformational plasticity and the absence of drug-specific hydrogen bonds. Combined analyses using site-directed mutagenesis, fluorescence-based drug binding and protein-DNA gel shift assays reveal an allosteric coupling between the multidrug- and DNA-binding sites of LmrR that most likely has a function in the induction mechanism.

  20. A review of visual perception mechanisms that regulate rapid adaptive camouflage in cuttlefish.

    Science.gov (United States)

    Chiao, Chuan-Chin; Chubb, Charles; Hanlon, Roger T

    2015-09-01

    We review recent research on the visual mechanisms of rapid adaptive camouflage in cuttlefish. These neurophysiologically complex marine invertebrates can camouflage themselves against almost any background, yet their ability to quickly (0.5-2 s) alter their body patterns on different visual backgrounds poses a vexing challenge: how to pick the correct body pattern amongst their repertoire. The ability of cuttlefish to change appropriately requires a visual system that can rapidly assess complex visual scenes and produce the motor responses-the neurally controlled body patterns-that achieve camouflage. Using specifically designed visual backgrounds and assessing the corresponding body patterns quantitatively, we and others have uncovered several aspects of scene variation that are important in regulating cuttlefish patterning responses. These include spatial scale of background pattern, background intensity, background contrast, object edge properties, object contrast polarity, object depth, and the presence of 3D objects. Moreover, arm postures and skin papillae are also regulated visually for additional aspects of concealment. By integrating these visual cues, cuttlefish are able to rapidly select appropriate body patterns for concealment throughout diverse natural environments. This sensorimotor approach of studying cuttlefish camouflage thus provides unique insights into the mechanisms of visual perception in an invertebrate image-forming eye.

  1. An autocrine ATP release mechanism regulates basal ciliary activity in airway epithelium.

    Science.gov (United States)

    Droguett, Karla; Rios, Mariana; Carreño, Daniela V; Navarrete, Camilo; Fuentes, Christian; Villalón, Manuel; Barrera, Nelson P

    2017-07-15

    Extracellular ATP, in association with [Ca 2+ ] i regulation, is required to maintain basal ciliary beat frequency. Increasing extracellular ATP levels increases ciliary beating in airway epithelial cells, maintaining a sustained response by inducing the release of additional ATP. Extracellular ATP levels in the millimolar range, previously associated with pathophysiological conditions of the airway epithelium, produce a transient arrest of ciliary activity. The regulation of ciliary beat frequency is dependent on ATP release by hemichannels (connexin/pannexin) and P2X receptor activation, the blockage of which may even stop ciliary movement. The force exerted by cilia, measured by atomic force microscopy, is reduced following extracellular ATP hydrolysis. This result complements the current understanding of the ciliary beating regulatory mechanism, with special relevance to inflammatory diseases of the airway epithelium that affect mucociliary clearance. Extracellular nucleotides, including ATP, are locally released by the airway epithelium and stimulate ciliary activity in a [Ca 2+ ] i -dependent manner after mechanical stimulation of ciliated cells. However, it is unclear whether the ATP released is involved in regulating basal ciliary activity and mediating changes in ciliary activity in response to chemical stimulation. In the present study, we evaluated ciliary beat frequency (CBF) and ciliary beating forces in primary cultures from mouse tracheal epithelium, using videomicroscopy and atomic force microscopy (AFM), respectively. Extracellular ATP levels and [Ca 2+ ] i were measured by luminometric and fluorimetric assays, respectively. Uptake of ethidium bromide was measured to evaluate hemichannel functionality. We show that hydrolysis of constitutive extracellular ATP levels with apyrase (50 U ml -1 ) reduced basal CBF by 45% and ciliary force by 67%. The apyrase effect on CBF was potentiated by carbenoxolone, a hemichannel inhibitor, and oxidized ATP, an

  2. A framework for modelling gene regulation which accommodates non-equilibrium mechanisms.

    Science.gov (United States)

    Ahsendorf, Tobias; Wong, Felix; Eils, Roland; Gunawardena, Jeremy

    2014-12-05

    Gene regulation has, for the most part, been quantitatively analysed by assuming that regulatory mechanisms operate at thermodynamic equilibrium. This formalism was originally developed to analyse the binding and unbinding of transcription factors from naked DNA in eubacteria. Although widely used, it has made it difficult to understand the role of energy-dissipating, epigenetic mechanisms, such as DNA methylation, nucleosome remodelling and post-translational modification of histones and co-regulators, which act together with transcription factors to regulate gene expression in eukaryotes. Here, we introduce a graph-based framework that can accommodate non-equilibrium mechanisms. A gene-regulatory system is described as a graph, which specifies the DNA microstates (vertices), the transitions between microstates (edges) and the transition rates (edge labels). The graph yields a stochastic master equation for how microstate probabilities change over time. We show that this framework has broad scope by providing new insights into three very different ad hoc models, of steroid-hormone responsive genes, of inherently bounded chromatin domains and of the yeast PHO5 gene. We find, moreover, surprising complexity in the regulation of PHO5, which has not yet been experimentally explored, and we show that this complexity is an inherent feature of being away from equilibrium. At equilibrium, microstate probabilities do not depend on how a microstate is reached but, away from equilibrium, each path to a microstate can contribute to its steady-state probability. Systems that are far from equilibrium thereby become dependent on history and the resulting complexity is a fundamental challenge. To begin addressing this, we introduce a graph-based concept of independence, which can be applied to sub-systems that are far from equilibrium, and prove that history-dependent complexity can be circumvented when sub-systems operate independently. As epigenomic data become increasingly

  3. Central and peripheral mechanisms of the NPY system in the regulation of bone and adipose tissue.

    Science.gov (United States)

    Shi, Yan-Chuan; Baldock, Paul A

    2012-02-01

    Skeletal research is currently undergoing a period of marked expansion. The boundaries of "bone" research are being re-evaluated and with this, a growing recognition of a more complex and interconnected biology than previously considered. One aspect that has become the focus of particular attention is the relationship between bone and fat homeostasis. Evidence from a number of avenues indicates that bone and adipose regulation are both related and interdependent. This review examines the neuropeptide Y (NPY) system, known to exert powerful control over both bone and fat tissue. The actions of this system are characterized by signaling both within specific nuclei of the hypothalamus and also the target tissues, mediated predominantly through two G-protein coupled receptors (Y1 and Y2). In bone tissue, elevated NPY levels act consistently to repress osteoblast activity. Moreover, both central Y2 receptor and osteoblastic Y1 receptor signaling act similarly to repress bone formation. Conversely, loss of NPY expression or receptor signaling induces increased osteoblast activity and bone mass in both cortical and cancellous envelopes. In fat tissue, NPY action is more complex. Energy homeostasis is powerfully altered by elevations in hypothalamic NPY, resulting in increases in fat accretion and body-wide energy conservation, through the action of locally expressed Y1 receptors, while local Y2 receptors act to inhibit NPY-ergic tone. Loss of central NPY expression has a markedly reduced effect, consistent with a physiological drive to promote fat accretion. In fat tissue, NPY and Y1 receptors act to promote lipogenesis, consistent with their roles in the brain. Y2 receptors expressed in adipocytes also act in this manner, showing an opposing action to their role in the hypothalamus. While direct investigation of these processes has yet to be completed, these responses appear to be interrelated to some degree. The starvation-based signal of elevated central NPY inducing

  4. Probing molecular mechanisms of the Hsp90 chaperone: biophysical modeling identifies key regulators of functional dynamics.

    Directory of Open Access Journals (Sweden)

    Anshuman Dixit

    Full Text Available Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based "conformational selection" of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected

  5. Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran.

    Science.gov (United States)

    Fisher, Katherine H; Stec, Wojciech; Brown, Stephen; Zeidler, Martin P

    2016-02-01

    Transmembrane receptors interact with extracellular ligands to transduce intracellular signaling cascades, modulate target gene expression, and regulate processes such as proliferation, apoptosis, differentiation, and homeostasis. As a consequence, aberrant signaling events often underlie human disease. Whereas the vertebrate JAK/STAT signaling cascade is transduced via multiple receptor combinations, the Drosophila pathway has only one full-length signaling receptor, Domeless (Dome), and a single negatively acting receptor, Eye Transformer/Latran (Et/Lat). Here we investigate the molecular mechanisms underlying Et/Lat activity. We demonstrate that Et/Lat negatively regulates the JAK/STAT pathway activity and can bind to Dome, thus reducing Dome:Dome homodimerization by creating signaling-incompetent Dome:Et/Lat heterodimers. Surprisingly, we find that Et/Lat is able to bind to both JAK and STAT92E but, despite the presence of putative cytokine-binding motifs, does not detectably interact with pathway ligands. We find that Et/Lat is trafficked through the endocytic machinery for lysosomal degradation but at a much slower rate than Dome, a difference that may enhance its ability to sequester Dome into signaling-incompetent complexes. Our data offer new insights into the molecular mechanism and regulation of Et/Lat in Drosophila that may inform our understanding of how short receptors function in other organisms. © 2016 Fisher et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  6. Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation.

    Science.gov (United States)

    Gomez-Pinilla, F; Zhuang, Y; Feng, J; Ying, Z; Fan, G

    2011-02-01

    We have evaluated the possibility that the action of voluntary exercise on the regulation of brain-derived neurotrophic factor (BDNF), a molecule important for rat hippocampal learning, could involve mechanisms of epigenetic regulation. We focused the studies on the Bdnf promoter IV, as this region is highly responsive to neuronal activity. We have found that exercise stimulates DNA demethylation in Bdnf promoter IV, and elevates levels of activated methyl-CpG-binding protein 2, as well as BDNF mRNA and protein in the rat hippocampus. Chromatin immunoprecipitation assay showed that exercise increases acetylation of histone H3, and protein assessment showed that exercise elevates the ratio of acetylated :total for histone H3 but had no effects on histone H4 levels. Exercise also reduces levels of the histone deacetylase 5 mRNA and protein implicated in the regulation of the Bdnf gene [N.M. Tsankova et al. (2006)Nat. Neurosci., 9, 519-525], but did not affect histone deacetylase 9. Exercise elevated the phosphorylated forms of calcium/calmodulin-dependent protein kinase II and cAMP response element binding protein, implicated in the pathways by which neural activity influences the epigenetic regulation of gene transcription, i.e. Bdnf. These results showing the influence of exercise on the remodeling of chromatin containing the Bdnf gene emphasize the importance of exercise on the control of gene transcription in the context of brain function and plasticity. Reported information about the impact of a behavior, inherently involved in the daily human routine, on the epigenome opens exciting new directions and therapeutic opportunities in the war against neurological and psychiatric disorders. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  7. Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms.

    Science.gov (United States)

    Martin, Lee J; Wong, Margaret

    2013-10-01

    Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS

  8. Theoretical study of Beloussov's hyper-restoration hypothesis for mechanical regulation of morphogenesis.

    Science.gov (United States)

    Taber, Larry A

    2008-12-01

    Computational models were used to explore the idea that morphogenesis is regulated, in part, by feedback from mechanical stress according to Beloussov's hyper-restoration (HR) hypothesis. According to this hypothesis, active tissue responses to stress perturbations tend to restore, but overshoot, the original (target) stress. To capture this behavior, the rate of growth or contraction is assumed to depend on the difference between the current and target stresses. Stress overshoot is obtained by letting the target stress change at a rate proportional to the same stress difference. The feasibility of the HR hypothesis is illustrated by models for stretching of epithelia, cylindrical bending of plates, invagination of cylindrical and spherical shells, and early amphibian development. In each case, an initial perturbation leads to an active mechanical response that changes the form of the tissue. The results show that some morphogenetic processes can be entirely self-driven by HR responses once they are initiated (possibly by genetic activity). Other processes, however, may require secondary mechanisms or perturbations to proceed to completion.

  9. Viral and cellular SOS-regulated motor proteins: dsDNA translocation mechanisms with divergent functions.

    Science.gov (United States)

    Wolfe, Annie; Phipps, Kara; Weitao, Tao

    2014-01-01

    DNA damage attacks on bacterial cells have been known to activate the SOS response, a transcriptional response affecting chromosome replication, DNA recombination and repair, cell division and prophage induction. All these functions require double-stranded (ds) DNA translocation by ASCE hexameric motors. This review seeks to delineate the structural and functional characteristics of the SOS response and the SOS-regulated DNA translocases FtsK and RuvB with the phi29 bacteriophage packaging motor gp16 ATPase as a prototype to study bacterial motors. While gp16 ATPase, cellular FtsK and RuvB are similarly comprised of hexameric rings encircling dsDNA and functioning as ATP-driven DNA translocases, they utilize different mechanisms to accomplish separate functions, suggesting a convergent evolution of these motors. The gp16 ATPase and FtsK use a novel revolution mechanism, generating a power stroke between subunits through an entropy-DNA affinity switch and pushing dsDNA inward without rotation of DNA and the motor, whereas RuvB seems to employ a rotation mechanism that remains to be further characterized. While FtsK and RuvB perform essential tasks during the SOS response, their roles may be far more significant as SOS response is involved in antibiotic-inducible bacterial vesiculation and biofilm formation as well as the perspective of the bacteria-cancer evolutionary interaction.

  10. Closed-form solutions for linear regulator design of mechanical systems including optimal weighting matrix selection

    Science.gov (United States)

    Hanks, Brantley R.; Skelton, Robert E.

    1991-01-01

    Vibration in modern structural and mechanical systems can be reduced in amplitude by increasing stiffness, redistributing stiffness and mass, and/or adding damping if design techniques are available to do so. Linear Quadratic Regulator (LQR) theory in modern multivariable control design, attacks the general dissipative elastic system design problem in a global formulation. The optimal design, however, allows electronic connections and phase relations which are not physically practical or possible in passive structural-mechanical devices. The restriction of LQR solutions (to the Algebraic Riccati Equation) to design spaces which can be implemented as passive structural members and/or dampers is addressed. A general closed-form solution to the optimal free-decay control problem is presented which is tailored for structural-mechanical system. The solution includes, as subsets, special cases such as the Rayleigh Dissipation Function and total energy. Weighting matrix selection is a constrained choice among several parameters to obtain desired physical relationships. The closed-form solution is also applicable to active control design for systems where perfect, collocated actuator-sensor pairs exist.

  11. Intra-hydrogel culture prevents transformation of mesenchymal stem cells induced by monolayer expansion.

    Science.gov (United States)

    Jiang, Tongmeng; Liu, Junting; Ouyang, Yiqiang; Wu, Huayu; Zheng, Li; Zhao, Jinmin; Zhang, Xingdong

    2018-05-01

    In this study, we report that the intra-hydrogel culture system mitigates the transformation of mesenchymal stem cells (MSCs) induced by two-dimensional (2D) expansion. MSCs expanded in monolayer culture prior to encapsulation in collagen hydrogels (group eMSCs-CH) featured impaired stemness in chondrogenesis, comparing with the freshly isolated bone marrow mononuclear cells seeded directly in collagen hydrogels (group fMSCs-CH). The molecular mechanism of the in vitro expansion-triggered damage to MSCs was detected through genome-wide microarray analysis. Results indicated that pathways such as proteoglycans in cancer and pathways in cancer expansion were highly enriched in eMSCs-CH. And multiple up-regulated oncoma-associated genes were verified in eMSCs-CH compared with fMSCs-CH, indicating that expansion in vitro triggered cellular transformation was associated with signaling pathways related to tumorigenicity. Besides, focal adhesion (FA) and mitogen-activated protein kinase (MAPK) signaling pathways were also involved in in vitro expansion, indicating restructuring of the cell architecture. Thus, monolayer expansion in vitro may contribute to vulnerability of MSCs through the regulation of FA and MAPK. This study indicates that intra-hydrogel culture can mitigate the monolayer expansion induced transformation of MSCs and maintain the uniformity of the stem cells, which is a viable in vitro culture system for stem cell therapy.

  12. Epigenetic mechanisms regulate MHC and antigen processing molecules in human embryonic and induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Beatriz Suárez-Alvarez

    2010-04-01

    Full Text Available Human embryonic stem cells (hESCs are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored.We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM components and NKG2D ligands (NKG2D-L in hESCs, induced pluripotent stem cells (iPSCs and NTera2 (NT2 teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1 and tapasin (TPN components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of beta2-microglobulin (beta2m light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and beta2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs. Absence of HLA-DR and HLA-G expression was regulated by DNA methylation.Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance.

  13. Epigenetic Mechanisms Regulate MHC and Antigen Processing Molecules in Human Embryonic and Induced Pluripotent Stem Cells

    Science.gov (United States)

    Suárez-Álvarez, Beatriz; Rodriguez, Ramón M.; Calvanese, Vincenzo; Blanco-Gelaz, Miguel A.; Suhr, Steve T.; Ortega, Francisco; Otero, Jesus; Cibelli, Jose B.; Moore, Harry; Fraga, Mario F.; López-Larrea, Carlos

    2010-01-01

    Background Human embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored. Methodology/Principal Findings We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM) components and NKG2D ligands (NKG2D-L) in hESCs, induced pluripotent stem cells (iPSCs) and NTera2 (NT2) teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP) assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1) and tapasin (TPN) components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of β2-microglobulin (β2m) light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB) were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and β2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs). Absence of HLA-DR and HLA-G expression was regulated by DNA methylation. Conclusions/Significance Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance

  14. [New theory of holistic integrative physiology and medicine. I: New insight of mechanism of control and regulation of breathing].

    Science.gov (United States)

    Sun, Xing-guo

    2015-07-01

    The modern systemic physiology, based on limit-understand functional classification, has significant limitation and one-sidedness. Human being is organic; we should approach the mechanism of control and regulation of breathing integrating all the systems. We use new theory of holistic integrative physiology and medicine to explain the mechanism of control and regulation of breathing. Except the mean level information, the up-down "W" waveform information of arterial blood gas (ABG) is core signal to control and regulate breathing. In order to do so, we must integrate all systems together. New theory will help to explain some unanswered questions in physiology and medicine, for example: fetal does not breathing; how first breath generate; how respiratory rhythm and frequency generate, etc. Breathing is the sign of life. Mechanism of control and regulation of breathing has to integrate respiration, circulation, nerves, metabolism, exercise, sleep and digestion, absorption and elimination and etc altogether.

  15. The Prospects of Modernization of the Mechanism for Budgetary Regulation of the Socio-Economic Development of Lviv City

    Directory of Open Access Journals (Sweden)

    Pidkhomnyi Oleg M.

    2017-11-01

    Full Text Available The socio-economic development of country and its individual territories depends on the efficiency of both accumulation and allocation of financial resources, which is determined by the effectiveness of budget process. Therefore the purpose of the article is theoretical and practical substantiation of prospects for modernization of the mechanism for budgetary regulation of the socio-economic development on the example of Lviv. Features and the main instruments of budgetary regulation of the socio-economic development of the city were researched. The efficiency of allocation and accumulation of budgetary funds, including through tax policy and the inter-budget transfers, was analyzed. Tendencies of changes of indicators of the socio-economic condition of Lviv and influence on them of three main elements of the budget regulation mechanism have been determined. Shortcomings of the existing mechanism for budgetary regulation of socio-economic development of the city have been defined, prospective directions of its modernization have been suggested.

  16. BMPs regulate msx gene expression in the dorsal neuroectoderm of Drosophila and vertebrates by distinct mechanisms.

    Science.gov (United States)

    Esteves, Francisco F; Springhorn, Alexander; Kague, Erika; Taylor, Erika; Pyrowolakis, George; Fisher, Shannon; Bier, Ethan

    2014-09-01

    In a broad variety of bilaterian species the trunk central nervous system (CNS) derives from three primary rows of neuroblasts. The fates of these neural progenitor cells are determined in part by three conserved transcription factors: vnd/nkx2.2, ind/gsh and msh/msx in Drosophila melanogaster/vertebrates, which are expressed in corresponding non-overlapping patterns along the dorsal-ventral axis. While this conserved suite of "neural identity" gene expression strongly suggests a common ancestral origin for the patterning systems, it is unclear whether the original regulatory mechanisms establishing these patterns have been similarly conserved during evolution. In Drosophila, genetic evidence suggests that Bone Morphogenetic Proteins (BMPs) act in a dosage-dependent fashion to repress expression of neural identity genes. BMPs also play a dose-dependent role in patterning the dorsal and lateral regions of the vertebrate CNS, however, the mechanism by which they achieve such patterning has not yet been clearly established. In this report, we examine the mechanisms by which BMPs act on cis-regulatory modules (CRMs) that control localized expression of the Drosophila msh and zebrafish (Danio rerio) msxB in the dorsal central nervous system (CNS). Our analysis suggests that BMPs act differently in these organisms to regulate similar patterns of gene expression in the neuroectoderm: repressing msh expression in Drosophila, while activating msxB expression in the zebrafish. These findings suggest that the mechanisms by which the BMP gradient patterns the dorsal neuroectoderm have reversed since the divergence of these two ancient lineages.

  17. BMPs regulate msx gene expression in the dorsal neuroectoderm of Drosophila and vertebrates by distinct mechanisms.

    Directory of Open Access Journals (Sweden)

    Francisco F Esteves

    2014-09-01

    Full Text Available In a broad variety of bilaterian species the trunk central nervous system (CNS derives from three primary rows of neuroblasts. The fates of these neural progenitor cells are determined in part by three conserved transcription factors: vnd/nkx2.2, ind/gsh and msh/msx in Drosophila melanogaster/vertebrates, which are expressed in corresponding non-overlapping patterns along the dorsal-ventral axis. While this conserved suite of "neural identity" gene expression strongly suggests a common ancestral origin for the patterning systems, it is unclear whether the original regulatory mechanisms establishing these patterns have been similarly conserved during evolution. In Drosophila, genetic evidence suggests that Bone Morphogenetic Proteins (BMPs act in a dosage-dependent fashion to repress expression of neural identity genes. BMPs also play a dose-dependent role in patterning the dorsal and lateral regions of the vertebrate CNS, however, the mechanism by which they achieve such patterning has not yet been clearly established. In this report, we examine the mechanisms by which BMPs act on cis-regulatory modules (CRMs that control localized expression of the Drosophila msh and zebrafish (Danio rerio msxB in the dorsal central nervous system (CNS. Our analysis suggests that BMPs act differently in these organisms to regulate similar patterns of gene expression in the neuroectoderm: repressing msh expression in Drosophila, while activating msxB expression in the zebrafish. These findings suggest that the mechanisms by which the BMP gradient patterns the dorsal neuroectoderm have reversed since the divergence of these two ancient lineages.

  18. Activity-dependent astrocyte swelling is mediated by pH-regulating mechanisms.

    Science.gov (United States)

    Larsen, Brian Roland; MacAulay, Nanna

    2017-10-01

    During neuronal activity in the mammalian brain, the K + released into the synaptic space is initially buffered by the astrocytic compartment. In parallel, the extracellular space (ECS) shrinks, presumably due to astrocytic cell swelling. With the Na + /K + /2Cl - cotransporter and the Kir4.1/AQP4 complex not required for the astrocytic cell swelling in the hippocampus, the molecular mechanisms underlying the activity-dependent ECS shrinkage have remained unresolved. To identify these molecular mechanisms, we employed ion-sensitive microelectrodes to measure changes in ECS, [K + ] o and [H + ] o /pH o during electrical stimulation of rat hippocampal slices. Transporters and receptors responding directly to the K + and glutamate released into the extracellular space (the K + /Cl - cotransporter, KCC, glutamate transporters and G protein-coupled receptors) did not modulate the extracellular space dynamics. The HCO3--transporting mechanism, which in astrocytes mainly constitutes the electrogenic Na + / HCO3- cotransporter 1 (NBCe1), is activated by the K + -mediated depolarization of the astrocytic membrane. Inhibition of this transporter reduced the ECS shrinkage by ∼25% without affecting the K + transients, pointing to NBCe1 as a key contributor to the stimulus-induced astrocytic cell swelling. Inhibition of the monocarboxylate cotransporters (MCT), like-wise, reduced the ECS shrinkage by ∼25% without compromising the K + transients. Isosmotic reduction of extracellular Cl - revealed a requirement for this ion in parts of the ECS shrinkage. Taken together, the stimulus-evoked astrocytic cell swelling does not appear to occur as a direct effect of the K + clearance, as earlier proposed, but partly via the pH-regulating transport mechanisms activated by the K + -induced astrocytic depolarization and the activity-dependent metabolism. © 2017 Wiley Periodicals, Inc.

  19. Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sangsoo Daniel; Antenos, Monica [Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Squires, E. James [Department of Animal and Poultry Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Kirby, Gordon M., E-mail: gkirby@uoguelph.ca [Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada)

    2013-07-15

    Bilirubin (BR) has recently been identified as the first endogenous substrate for cytochrome P450 2A5 (CYP2A5) and it has been suggested that CYP2A5 plays a major role in BR clearance as an alternative mechanism to BR conjugation by uridine-diphosphate glucuronyltransferase 1A1. This study investigated the mechanisms of Cyp2a5 gene regulation by BR and the cytoprotective role of CYP2A5 in BR hepatotoxicity. BR induced CYP2A5 expression at the mRNA and protein levels in a dose-dependent manner in primary mouse hepatocytes. BR treatment also caused nuclear translocation of Nuclear factor-E2 p45-related factor 2 (Nrf2) in hepatocytes. In reporter assays, BR treatment of primary hepatocytes transfected with a Cyp2a5 promoter-luciferase reporter construct resulted in a 2-fold induction of Cyp2a5 reporter activity. Furthermore, cotransfection of the hepatocytes with a Nrf2 expression vector without BR treatment resulted in an increase in Cyp2a5 reporter activity of approximately 2-fold and BR treatment of Nrf2 cotransfectants further increased reporter activity by 4-fold. In addition, site-directed mutation of the ARE in the reporter construct completely abolished both the BR- and Nrf2-mediated increases in reporter activity. The cytoprotective role of CYP2A5 against BR-mediated apoptosis was also examined in Hepa 1–6 cells that lack endogenous CYP2A5. Transient overexpression of CYP2A5 partially blocked BR-induced caspase-3 cleavage in Hepa 1–6 cells. Furthermore, in vitro degradation of BR was increased by microsomes from Hepa 1–6 cells overexpressing CYP2A5 compared to control cells transfected with an empty vector. Collectively, these results suggest that Nrf2-mediated CYP2A5 transactivation in response to BR may provide an additional mechanism for adaptive cytoprotection against BR hepatotoxicity. - Highlights: • The mechanism of Cyp2a5 gene regulation by BR was investigated. • The cytoprotective role of CYP2A5 in BR hepatotoxicity was determined. • BR

  20. [Study of Chinese herbal medicine in treating ascites and their mechanism in regulating lymphatic stomata].

    Science.gov (United States)

    Wu, Y; Li, J C; Mao, L G

    2001-09-01

    To study the therapeutic effect of Chinese herbal medicines (CHM) in treating ascites to elucidate its mechanism in regulating the lymphatic stomata and promoting the absorption of ascites from the peritoneal cavity. Using scanning electron microscope (SEM) and computerized image processing and quantitative analysis assays, the CHM extract consisting of Atractylodes macrocephala, Salvia miltiorrhiza, Codonopsis pilosula, Alismatis orientale and Leonurus heterophyllus were studied. Intraperitoneal injection of nitric oxide (NO) supplier or CHM administration could cause the average area of lymphatic stomata obviously enlarged (P inverted obviously, i.e. the average area and the density of lymphatic stomata were markedly reduced (P < 0.01). CHM might treat ascites through increasing the endogenous NO concentration to open the lymphatic stomata and in turn to conduct the peritoneal water through lymphatic path.

  1. Caulobacter crescentus Cell Cycle-Regulated DNA Methyltransferase Uses a Novel Mechanism for Substrate Recognition.

    Science.gov (United States)

    Woodcock, Clayton B; Yakubov, Aziz B; Reich, Norbert O

    2017-08-01

    Caulobacter crescentus relies on DNA methylation by the cell cycle-regulated methyltransferase (CcrM) in addition to key transcription factors to control the cell cycle and direct cellular differentiation. CcrM is shown here to efficiently methylate its cognate recognition site 5'-GANTC-3' in single-stranded and hemimethylated double-stranded DNA. We report the K m , k cat , k methylation , and K d for single-stranded and hemimethylated substrates, revealing discrimination of 10 7 -fold for noncognate sequences. The enzyme also shows a similar discrimination against single-stranded RNA. Two independent assays clearly show that CcrM is highly processive with single-stranded and hemimethylated DNA. Collectively, the data provide evidence that CcrM and other DNA-modifying enzymes may use a new mechanism to recognize DNA in a key epigenetic process.

  2. Hunger and Satiety Mechanisms and Their Potential Exploitation in the Regulation of Food Intake.

    Science.gov (United States)

    Amin, Tehmina; Mercer, Julian G

    2016-03-01

    Effective strategies to combat recent rises in obesity levels are limited. The accumulation of excess body fat results when energy intake exceeds that expended. Energy balance is controlled by hypothalamic responses, but these can be overridden by hedonic/reward brain systems. This override, combined with unprecedented availability of cheap, energy-dense, palatable foods, may partly explain the increase in overweight and obesity. The complexity of the processes that regulate feeding behaviour has driven the need for further fundamental research. Full4Health is an EU-funded project conceived to advance our understanding of hunger and satiety mechanisms. Food intake has an impact on and is also affected by the gut-brain signalling which controls hunger and appetite. This review describes selected recent research from Full4Health and how new mechanistic findings could be exploited to adapt and control our physiological responses to food, potentially providing an alternative solution to addressing the global problems related to positive energy balance.

  3. Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes.

    Science.gov (United States)

    Gao, Song; Carson, James A

    2016-01-01

    Mechanical stretch can activate muscle and myotube protein synthesis through mammalian target of rapamycin complex 1 (mTORC1) signaling. While it has been established that tumor-derived cachectic factors can induce myotube wasting, the effect of this catabolic environment on myotube mechanical signaling has not been determined. We investigated whether media containing cachectic factors derived from Lewis lung carcinoma (LLC) can regulate the stretch induction of myotube protein synthesis. C2C12 myotubes preincubated in control or LLC-derived media were chronically stretched. Protein synthesis regulation by anabolic and catabolic signaling was then examined. In the control condition, stretch increased mTORC1 activity and protein synthesis. The LLC treatment decreased basal mTORC1 activity and protein synthesis and attenuated the stretch induction of protein synthesis. LLC media increased STAT3 and AMP-activated protein kinase phosphorylation in myotubes, independent of stretch. Both stretch and LLC independently increased ERK1/2, p38, and NF-κB phosphorylation. In LLC-treated myotubes, the inhibition of ERK1/2 and p38 rescued the stretch induction of protein synthesis. Interestingly, either leukemia inhibitory factor or glycoprotein 130 antibody administration caused further inhibition of mTORC1 signaling and protein synthesis in stretched myotubes. AMP-activated protein kinase inhibition increased basal mTORC1 signaling activity and protein synthesis in LLC-treated myotubes, but did not restore the stretch induction of protein synthesis. These results demonstrate that LLC-derived cachectic factors can dissociate stretch-induced signaling from protein synthesis through ERK1/2 and p38 signaling, and that glycoprotein 130 signaling is associated with the basal stretch response in myotubes. Copyright © 2016 the American Physiological Society.

  4. Mechanisms regulating amphipod population density within macroalgal communities with low predator impact

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    Hartvig Christie

    2004-04-01

    Full Text Available In eight mesocosms (land based basins macroalgae communities with associated fauna were transplanted from the sea and established during two years. Then, different doses of nutrients (N and P were added to the basins throughout the following three years. During the period of nutrient addition, macroinvertebrate grazers showed seasonal fluctuations with densities usually between 500,000 and 1 million individuals per mesocosm during summer and to a level of about 100,000 during winter. The macroinvertebrate grazers mainly consisted of about 10 species of amphipods and isopods, among which the amphipod Gammarus locusta dominated strongly by biomass. Although the number of predators was very low, the grazer populations never reached a density where considerable grazing impact could be found on the macroalgae. No increase in grazer density was found in the basins with improved nutrient conditions. Thus food quality may be insufficient for further population growth, or density dependant regulation mechanisms may have prevented the grazers from flourishing and overgrazing the system. In aquarium experiments we showed that G. locusta could grow and reproduce on Fucus serratus, Ulva lactuca, periphyton and detritus, and that cannibalism by adult G. locusta on juveniles may have great impact on the population growth. The basins were run with a water flow through system. Nets were placed in front of the inflow and outflow tubes to measure immigration and emigration. Only few individuals (and no Gammarus sp. were recorded in the inflowing water, while high numbers of both amphipods and isopods were found in the outflowing water. Emigration reached peak values during night-time, and it was then two to three times as high as during day-time. Emigration of mobile grazers from the basins amounted to 1-2% of the standing stock daily. These mechanisms that regulate grazers do contribute to maintenance of the seaweed dominance and thus the stability of the seaweed

  5. Structure, signaling mechanism and regulation of the natriuretic peptide receptor guanylate cyclase.

    Energy Technology Data Exchange (ETDEWEB)

    Misono, K. S.; Philo, J. S.; Arakawa, T.; Ogata, C. M.; Qiu, Y.; Ogawa, H.; Young, H. S. (Biosciences Division); (Univ. of Nevada); (Alliance Protein Labs.)

    2011-06-01

    Atrial natriuretic peptide (ANP) and the homologous B-type natriuretic peptide are cardiac hormones that dilate blood vessels and stimulate natriuresis and diuresis, thereby lowering blood pressure and blood volume. ANP and B-type natriuretic peptide counterbalance the actions of the renin-angiotensin-aldosterone and neurohormonal systems, and play a central role in cardiovascular regulation. These activities are mediated by natriuretic peptide receptor-A (NPRA), a single transmembrane segment, guanylyl cyclase (GC)-linked receptor that occurs as a homodimer. Here, we present an overview of the structure, possible chloride-mediated regulation and signaling mechanism of NPRA and other receptor GCs. Earlier, we determined the crystal structures of the NPRA extracellular domain with and without bound ANP. Their structural comparison has revealed a novel ANP-induced rotation mechanism occurring in the juxtamembrane region that apparently triggers transmembrane signal transduction. More recently, the crystal structures of the dimerized catalytic domain of green algae GC Cyg12 and that of cyanobacterium GC Cya2 have been reported. These structures closely resemble that of the adenylyl cyclase catalytic domain, consisting of a C1 and C2 subdomain heterodimer. Adenylyl cyclase is activated by binding of G{sub s}{alpha} to C2 and the ensuing 7{sup o} rotation of C1 around an axis parallel to the central cleft, thereby inducing the heterodimer to adopt a catalytically active conformation. We speculate that, in NPRA, the ANP-induced rotation of the juxtamembrane domains, transmitted across the transmembrane helices, may induce a similar rotation in each of the dimerized GC catalytic domains, leading to the stimulation of the GC catalytic activity.

  6. Calcineurin signaling and membrane lipid homeostasis regulates iron mediated multidrug resistance mechanisms in Candida albicans.

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    Saif Hameed

    2011-04-01

    Full Text Available We previously demonstrated that iron deprivation enhances drug susceptibility of Candida albicans by increasing membrane fluidity which correlated with the lower expression of ERG11 transcript and ergosterol levels. The iron restriction dependent membrane perturbations led to an increase in passive diffusion and drug susceptibility. The mechanisms underlying iron homeostasis and multidrug resistance (MDR, however, are not yet resolved. To evaluate the potential mechanisms, we used whole genome transcriptome and electrospray ionization tandem mass spectrometry (ESI-MS/MS based lipidome analyses of iron deprived Candida cells to examine the new cellular circuitry of the MDR of this pathogen. Our transcriptome data revealed a link between calcineurin signaling and iron homeostasis. Among the several categories of iron deprivation responsive genes, the down regulation of calcineurin signaling genes including HSP90, CMP1 and CRZ1 was noteworthy. Interestingly, iron deprived Candida cells as well as iron acquisition defective mutants phenocopied molecular chaperone HSP90 and calcineurin mutants and thus were sensitive to alkaline pH, salinity and membrane perturbations. In contrast, sensitivity to above stresses did not change in iron deprived DSY2146 strain with a hyperactive allele of calcineurin. Although, iron deprivation phenocopied compromised HSP90 and calcineurin, it was independent of protein kinase C signaling cascade. Notably, the phenotypes associated with iron deprivation in genetically impaired calcineurin and HSP90 could be reversed with iron supplementation. The observed down regulation of ergosterol (ERG1, ERG2, ERG11 and ERG25 and sphingolipid biosynthesis (AUR1 and SCS7 genes followed by lipidome analysis confirmed that iron deprivation not only disrupted ergosterol biosynthesis, but it also affected sphingolipid homeostasis in Candida cells. These lipid compositional changes suggested extensive remodeling of the membranes in iron

  7. Food and Natural Materials Target Mechanisms to Effectively Regulate Allergic Responses.

    Science.gov (United States)

    Shin, Hee Soon; Shon, Dong-Hwa

    2015-01-01

    An immune hypersensitivity disorder called allergy is caused by diverse allergens entering the body via skin contact, injection, ingestion, and/or inhalation. These allergic responses may develop into allergic disorders, including inflammations such as atopic dermatitis, asthma, anaphylaxis, food allergies, and allergic rhinitis. Several drugs have been developed to treat these allergic disorders; however, long-term intake of these drugs could have adverse effects. As an alternative to these medicines, food and natural materials that ameliorate allergic disorder symptoms without producing any side effects can be consumed. Food and natural materials can effectively regulate successive allergic responses in an allergic chain-reaction mechanism in the following ways: [1] Inhibition of allergen permeation via paracellular diffusion into epithelial cells, [2] suppression of type 2 T-helper (Th) cell-related cytokine production by regulating Th1/Th2 balance, [3] inhibition of pathogenic effector CD4(+) T cell differentiation by inducing regulatory T cells (Treg), and [4] inhibition of degranulation in mast cells. The immunomodulatory effects of food and natural materials on each target mechanism were scientifically verified and shown to alleviate allergic disorder symptoms. Furthermore, consumption of certain food and natural materials such as fenugreek, skullcap, chitin/chitosan, and cheonggukjang as anti-allergics have merits such as safety (no adverse side effects), multiple suppressive effects (as a mixture would contain various components that are active against allergic responses), and ease of consumption when required. These merits and anti-allergic properties of food and natural materials help control various allergic disorders.

  8. Mechanism research of miR-181 regulating human lens epithelial cell apoptosis

    Directory of Open Access Journals (Sweden)

    Yu Qin

    2015-05-01

    Full Text Available AIM: To investigate the expression of miR-181 in the lens tissue of cataract and the regulating mechanism of miR-181 on apoptosis of human lens epithelial cell.METHODS:Real time q-PCR was used to measure the expression of miR-181 in the anterior lens capsules of age-related cataract and human lens epithelial cell apoptosis model. miR-181 mimic and inhibitor were transfected using Lipofectamine 2 000 to regulate the expression of miR-181, and then Real time q-PCR was used to verify transfection efficiency. Flow cytometry was used to detect the change of cell apoptosis rate. RESULTS: Compared with control group, the expression of miR-181 was significantly higher in both the anterior lens capsules of age-related cataract and human lens epithelial cell apoptosis model; the relative expression of miR-181 in lens epithelial cells transfected with miR-181 mimic was increased, whereas decreased in cells transfected with miR-181 inhibitor; the apoptosis rate of cells transfected with miR-181 mimic was increased, while reduced in miR-181 inhibitor group. Each result was statistically significant(PCONCLUSION: High expression of miR-181 is detected in anterior lens capsule of age-related cataract. miR-181 might play a certain role in the pathogenesis of cataract via promoting human lens epithelial cell apoptosis. miR-181 probably becomes a new approach for the nonoperative treatment of cataract, but the concrete mechanism still needs to be further studied.

  9. Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer

    Directory of Open Access Journals (Sweden)

    Chen Hairu

    2010-10-01

    Full Text Available Abstract Background Activated leukocyte cell adhesion molecule (ALCAM is implicated in the prognosis of multiple cancers with low level expression associated with metastasis and early death in breast cancer. Despite this significance, mechanisms that regulate ALCAM gene expression and ALCAM's role in adhesion of pre-metastatic circulating tumor cells have not been defined. We studied ALCAM expression in 20 tumor cell lines by real-time PCR, western blot and immunochemistry. Epigenetic alterations of the ALCAM promoter were assessed using methylation-specific PCR and bisulfite sequencing. ALCAM's role in adhesion of tumor cells to the vascular wall was studied in isolated perfused lungs. Results A common site for transcription initiation of the ALCAM gene was identified and the ALCAM promoter sequenced. The promoter contains multiple cis-active elements including a functional p65 NF-κB motif, and it harbors an extensive array of CpG residues highly methylated exclusively in ALCAM-negative tumor cells. These CpG residues were modestly demethylated after 5-aza-2-deoxycytidine treatment. Restoration of high-level ALCAM expression using an ALCAM cDNA increased clustering of MDA-MB-435 tumor cells perfused through the pulmonary vasculature of ventilated rat lungs. Anti-ALCAM antibodies reduced the number of intravascular tumor cell clusters. Conclusion Our data suggests that loss of ALCAM expression, due in part to DNA methylation of extensive segments of the promoter, significantly impairs the ability of circulating tumor cells to adhere to each other, and may therefore promote metastasis. These findings offer insight into the mechanisms for down-regulation of ALCAM gene expression in tumor cells, and for the positive prognostic value of high-level ALCAM in breast cancer.

  10. Discrete β-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia.

    Science.gov (United States)

    Hasan, Shirin; Mosier, Michael J; Szilagyi, Andrea; Gamelli, Richard L; Muthumalaiappan, Kuzhali

    2017-10-01

    Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by β1/β2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of β1/β2, β-2, or β-3 blockade in burn mediated erythropoietin-resistant anemia. Burn mice were randomized to receive daily injections of propranolol (nonselective β1/β2 antagonist), nadolol (long-acting β1/β2 antagonist), butoxamine (selective β2 antagonist), or SR59230A (selective β3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells. Although propranolol improved early and late erythroblasts, only butoxamine and selective β3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, β1/β2 antagonism increased the early erythroblasts through commitment stages via β2 specific MafB regulation. β3 antagonism was more effective in improving overall red blood cells through late maturation stages. The study unfolds novel β2 and β3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively. Copyright © 2017

  11. Cytological, molecular mechanisms and temperature stress regulating production of diploid male gametes in Dianthus caryophyllus L.

    Science.gov (United States)

    Zhou, Xuhong; Mo, Xijun; Gui, Min; Wu, Xuewei; Jiang, Yalian; Ma, Lulin; Shi, Ziming; Luo, Ying; Tang, Wenru

    2015-12-01

    In plant evolution, because of its key role in sexual polyploidization or whole genome duplication events, diploid gamete formation is considered as an important component in diversification and speciation. Environmental stress often triggers unreduced gamete production. However, the molecular, cellular mechanisms and adverse temperature regulating diplogamete production in carnation remain poorly understood. Here, we investigate the cytological basis for 2n male gamete formation and describe the isolation and characterization of the first gene, DcPS1 (Dianthus Caryophyllus Parallel Spindle 1). In addition, we analyze influence of temperature stress on diploid gamete formation and transcript levels of DcPS1. Cytological evidence indicated that 2n male gamete formation is attributable to abnormal spindle orientation at male meiosis II. DcPS1 protein is conserved throughout the plant kingdom and carries domains suggestive of a regulatory function. DcPS1 expression analysis show DcPS1 gene probably have a role in 2n pollen formation. Unreduced pollen formation in various cultivation was sensitive to high or low temperature which was probably regulated by the level of DcPS1 transcripts. In a broader perspective, these findings can have potential applications in fundamental polyploidization research and plant breeding programs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  12. RhoG regulates anoikis through a phosphatidylinositol 3-kinase-dependent mechanism

    International Nuclear Information System (INIS)

    Yamaki, Nao; Negishi, Manabu; Katoh, Hironori

    2007-01-01

    In normal epithelial cells, cell-matrix interaction is required for cell survival and proliferation, whereas disruption of this interaction causes epithelial cells to undergo apoptosis called anoikis. Here we show that the small GTPase RhoG plays an important role in the regulation of anoikis. HeLa cells are capable of anchorage-independent cell growth and acquire resistance to anoikis. We found that RNA interference-mediated knockdown of RhoG promoted anoikis in HeLa cells. Previous studies have shown that RhoG activates Rac1 and induces several cellular functions including promotion of cell migration through its effector ELMO and the ELMO-binding protein Dock180 that function as a Rac-specific guanine nucleotide exchange factor. However, RhoG-induced suppression of anoikis was independent of the ELMO- and Dock180-mediated activation of Rac1. On the other hand, the regulation of anoikis by RhoG required phosphatidylinositol 3-kinase (PI3K) activity, and constitutively active RhoG bound to the PI3K regulatory subunit p85α and induced the PI3K-dependent phosphorylation of Akt. Taken together, these results suggest that RhoG protects cells from apoptosis caused by the loss of anchorage through a PI3K-dependent mechanism, independent of its activation of Rac1

  13. Ironing Out the Unconventional Mechanisms of Iron Acquisition and Gene Regulation in Chlamydia

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    Nick D. Pokorzynski

    2017-09-01

    Full Text Available The obligate intracellular pathogen Chlamydia trachomatis, along with its close species relatives, is known to be strictly dependent upon the availability of iron. Deprivation of iron in vitro induces an aberrant morphological phenotype termed “persistence.” This persistent phenotype develops in response to various immunological and nutritional insults and may contribute to the development of sub-acute Chlamydia-associated chronic diseases in susceptible populations. Given the importance of iron to Chlamydia, relatively little is understood about its acquisition and its role in gene regulation in comparison to other iron-dependent bacteria. Analysis of the genome sequences of a variety of chlamydial species hinted at the involvement of unconventional mechanisms, being that Chlamydia lack many conventional systems of iron homeostasis that are highly conserved in other bacteria. Herein we detail past and current research regarding chlamydial iron biology in an attempt to provide context to the rapid progress of the field in recent years. We aim to highlight recent discoveries and innovations that illuminate the strategies involved in chlamydial iron homeostasis, including the vesicular mode of acquiring iron from the intracellular environment, and the identification of a putative iron-dependent transcriptional regulator that is synthesized as a fusion with a ABC-type transporter subunit. These recent findings, along with the noted absence of iron-related homologs, indicate that Chlamydia have evolved atypical approaches to the problem of iron homeostasis, reinvigorating research into the iron biology of this pathogen.

  14. Antibody-independent mechanisms regulate the establishment of chronic Plasmodium infection

    Science.gov (United States)

    Lin, Jingwen; Cunningham, Deirdre; Tumwine, Irene; Kushinga, Garikai; McLaughlin, Sarah; Spence, Philip; Böhme, Ulrike; Sanders, Mandy; Conteh, Solomon; Bushell, Ellen; Metcalf, Tom; Billker, Oliver; Duffy, Patrick E.; Newbold, Chris; Berriman, Matthew; Langhorne, Jean

    2017-01-01

    Malaria is caused by parasites of the genus Plasmodium. All human-infecting Plasmodium species can establish long-lasting chronic infections1–5, creating an infectious reservoir to sustain transmission1,6. It is widely accepted that maintenance of chronic infection involves evasion of adaptive immunity by antigenic variation7. However, genes involved in this process have been identified in only two of five human-infecting species: P. falciparum and P. knowlesi. Furthermore, little is understood about the early events in establishment of chronic infection in these species. Using a rodent model we demonstrate that only a minority of parasites from among the infecting population, expressing one of several clusters of virulence-associated pir genes, establishes a chronic infection. This process occurs in different species of parasite and in different hosts. Establishment of chronicity is independent of adaptive immunity and therefore different from the mechanism proposed for maintainance of chronic P. falciparum infections7–9. Furthermore, we show that the proportions of parasites expressing different types of pir genes regulate the time taken to establish a chronic infection. Since pir genes are common to most, if not all, species of Plasmodium10, this process may be a common way of regulating the establishment of chronic infections. PMID:28165471

  15. Self-Regulation and Mechanisms of Action in Psychotherapy: A Theory-Based Translational Perspective

    Science.gov (United States)

    Strauman, Timothy J.; Goetz, Elena L.; Detloff, Allison M.; MacDuffie, Katherine E.; Zaunmüller, Luisa; Lutz, Wolfgang

    2012-01-01

    Psychotherapy is a complex, multi-layered process with the potential to bring about changes at multiple levels of functioning, from the neurobiology of the brain to the individual’s role in the social world. Although studies of the mechanisms by which psychotherapy leads to change continue to appear, there remains much to be learned about how psychological interventions work. To guide explorations of how and for whom particular treatment approaches lead to change, researchers can rely on theory to identify potential loci for change and on translational research methods to integrate basic behavioral science and neuroscience with clinical science. In this article, we describe research linking individual differences in the self-regulation of personal goal pursuit with the etiology and treatment of mood disorders. The research draws upon regulatory focus theory as a model of self-regulation and on microintervention designs – controlled laboratory investigations of a specific therapeutic technique – to generate and test hypotheses about how psychological interventions can help to reverse maladaptive self-regulatory processes. PMID:23072383

  16. Real-time transient stabilization and voltage regulation of power generators with unknown mechanical power input

    International Nuclear Information System (INIS)

    Kenne, Godpromesse; Goma, Raphael; Nkwawo, Homere; Lamnabhi-Lagarrigue, Francoise; Arzande, Amir; Vannier, Jean Claude

    2010-01-01

    A nonlinear adaptive excitation controller is proposed to enhance the transient stability and voltage regulation of synchronous generators with unknown power angle and mechanical power input. The proposed method is based on a standard third-order model of a synchronous generator which requires only information about the physical available measurements of relative angular speed, active electric power, infinite bus and generator terminal voltages. The operating conditions are computed online using the above physical available measurements, the terminal voltage reference value and the estimate of the mechanical power input. The proposed design is therefore capable of providing satisfactory voltage in the presence of unknown variations of the power system operating conditions. Using the concept of sliding mode equivalent control techniques, a robust decentralized adaptive controller which insures the exponential convergence of the outputs to the desired ones, is obtained. Real-time experimental results are reported, comparing the performance of the proposed adaptive nonlinear control scheme to one of the conventional AVR/PSS controller. The high simplicity of the overall adaptive control scheme and its robustness with respect to line impedance variation including critical unbalanced operating condition and temporary turbine fault, constitute the main positive features of the proposed approach.

  17. Fc-receptor-mediated phagocytosis is regulated by mechanical properties of the target

    Science.gov (United States)

    Beningo, Karen A.; Wang, Yu-li

    2002-01-01

    Phagocytosis is an actin-based process used by macrophages to clear particles greater than 0.5 microm in diameter. In addition to its role in immunological responses, phagocytosis is also necessary for tissue remodeling and repair. To prevent catastrophic autoimmune reactions, phagocytosis must be tightly regulated. It is commonly assumed that the recognition/selection of phagocytic targets is based solely upon receptor-ligand binding. Here we report an important new criterion, that mechanical parameters of the target can dramatically affect the efficiency of phagocytosis. When presented with particles of identical chemical properties but different rigidity, macrophages showed a strong preference to engulf rigid objects. Furthermore, phagocytosis of soft particles can be stimulated with the microinjection of constitutively active Rac1 but not RhoA, and with lysophosphatidic acid, an agent known to activate the small GTP-binding proteins of the Rho family. These data suggest a Rac1-dependent mechanosensory mechanism for phagocytosis, which probably plays an important role in a number of physiological and pathological processes from embryonic development to autoimmune diseases.

  18. Past matrix stiffness primes epithelial cells and regulates their future collective migration through a mechanical memory.

    Science.gov (United States)

    Nasrollahi, Samila; Walter, Christopher; Loza, Andrew J; Schimizzi, Gregory V; Longmore, Gregory D; Pathak, Amit

    2017-11-01

    During morphogenesis and cancer metastasis, grouped cells migrate through tissues of dissimilar stiffness. Although the influence of matrix stiffness on cellular mechanosensitivity and motility are well-recognized, it remains unknown whether these matrix-dependent cellular features persist after cells move to a new microenvironment. Here, we interrogate whether priming of epithelial cells by a given matrix stiffness influences their future collective migration on a different matrix - a property we refer to as the 'mechanical memory' of migratory cells. To prime cells on a defined matrix and track their collective migration onto an adjoining secondary matrix of dissimilar stiffness, we develop a modular polyacrylamide substrate through step-by-step polymerization of different PA compositions. We report that epithelial cells primed on a stiff matrix migrate faster, display higher actomyosin expression, form larger focal adhesions, and retain nuclear YAP even after arriving onto a soft secondary matrix, as compared to their control behavior on a homogeneously soft matrix. Priming on a soft ECM causes a reverse effect. The depletion of YAP dramatically reduces this memory-dependent migration. Our results present a previously unidentified regulation of mechanosensitive collective cell migration by past matrix stiffness, in which mechanical memory depends on YAP activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Real-time transient stabilization and voltage regulation of power generators with unknown mechanical power input

    Energy Technology Data Exchange (ETDEWEB)

    Kenne, Godpromesse, E-mail: gokenne@yahoo.co [Laboratoire d' Automatique et d' Informatique Appliquee (LAIA), Departement de Genie Electrique, Universite de Dschang, B.P. 134 Bandjoun (Cameroon); Goma, Raphael, E-mail: raphael.goma@lss.supelec.f [Laboratoire des Signaux et Systemes (L2S), CNRS-SUPELEC, Universite Paris XI, 3 Rue Joliot Curie, 91192 Gif-sur-Yvette (France); Nkwawo, Homere, E-mail: homere.nkwawo@iutv.univ-paris13.f [Departement GEII, Universite Paris XIII, 99 Avenue Jean Baptiste Clement, 93430 Villetaneuse (France); Lamnabhi-Lagarrigue, Francoise, E-mail: lamnabhi@lss.supelec.f [Laboratoire des Signaux et Systemes (L2S), CNRS-SUPELEC, Universite Paris XI, 3 Rue Joliot Curie, 91192 Gif-sur-Yvette (France); Arzande, Amir, E-mail: Amir.arzande@supelec.f [Departement Energie, Ecole Superieure d' Electricite-SUPELEC, 3 Rue Joliot Curie, 91192 Gif-sur-Yvette (France); Vannier, Jean Claude, E-mail: Jean-claude.vannier@supelec.f [Departement Energie, Ecole Superieure d' Electricite-SUPELEC, 3 Rue Joliot Curie, 91192 Gif-sur-Yvette (France)

    2010-01-15

    A nonlinear adaptive excitation controller is proposed to enhance the transient stability and voltage regulation of synchronous generators with unknown power angle and mechanical power input. The proposed method is based on a standard third-order model of a synchronous generator which requires only information about the physical available measurements of relative angular speed, active electric power, infinite bus and generator terminal voltages. The operating conditions are computed online using the above physical available measurements, the terminal voltage reference value and the estimate of the mechanical power input. The proposed design is therefore capable of providing satisfactory voltage in the presence of unknown variations of the power system operating conditions. Using the concept of sliding mode equivalent control techniques, a robust decentralized adaptive controller which insures the exponential convergence of the outputs to the desired ones, is obtained. Real-time experimental results are reported, comparing the performance of the proposed adaptive nonlinear control scheme to one of the conventional AVR/PSS controller. The high simplicity of the overall adaptive control scheme and its robustness with respect to line impedance variation including critical unbalanced operating condition and temporary turbine fault, constitute the main positive features of the proposed approach.

  20. Cigarette smoke induced autophagy-impairment regulates AMD pathogenesis mechanisms in ARPE-19 cells.

    Directory of Open Access Journals (Sweden)

    Viren Kumar Govindaraju

    Full Text Available Age related macular degeneration (AMD is one of the leading causes of blindness. Genetics, environmental insult, and age-related factors all play a key role in altering proteostasis, the homeostatic process regulating protein synthesis, degradation and processing. These factors also play a role in the pathogenesis of AMD and it has been well established that cigarette smoking (CS initiates AMD pathogenic mechanisms. The primary goal of this study is to elucidate whether CS can induce proteostasis/autophagy-impairment in retinal pigment epithelial (RPE cells. In our preliminary analysis, it was found that cigarette smoke extract (CSE induces accumulation of ubiquitinated proteins in the insoluble protein fraction (p < 0.01, which was subsequently mitigated through cysteamine (p < 0.01 or fisetin (p < 0.05 treatment. Further, it was verified that these CSE induced ubiquitinated proteins accumulated in the peri-nuclear spaces (p<0.05 that were cleared- off with cysteamine (p < 0.05 or fisetin (p < 0.05. Moreover, CSE-induced aggresome-formation (LC3B-GFP and Ub-RFP co-localization and autophagy-flux impairment was significantly (p<0.01 mitigated by cysteamine (p<0.05 or fisetin (p<0.05 treatment, indicating the restoration of CSE-mediated autophagy-impairment. CSE treatment was also found to induce intracellular reactive oxygen species (ROS, p < 0.001 while impacting cell viability (p < 0.001, which was quantified using CMH2DCFDA-dye (ROS and MTS (proliferation or propodium iodide staining (cell viability assays, respectively. Moreover, cysteamine and fisetin treatment ameliorated CS-mediated ROS production (p < 0.05 and diminished cell viability (p < 0.05. Lastly, CSE was found to induce cellular senescence (p < 0.001, which was significantly ameliorated by cysteamine (p < 0.001 or fisetin (p < 0.001. In conclusion, our study indicates that CS induced proteostasis/autophagy-impairment regulates mechanisms associated with AMD pathogenesis. Moreover

  1. Sexual conflict explains the extraordinary diversity of mechanisms regulating mitochondrial inheritance.

    Science.gov (United States)

    Radzvilavicius, Arunas L; Lane, Nick; Pomiankowski, Andrew

    2017-10-26

    Mitochondria are predominantly inherited from the maternal gamete, even in unicellular organisms. Yet an extraordinary array of mechanisms enforce uniparental inheritance, which implies shifting selection pressures and multiple origins. We consider how this high turnover in mechanisms controlling uniparental inheritance arises using a novel evolutionary model in which control of mitochondrial transmission occurs either during spermatogenesis (by paternal nuclear genes) or at/after fertilization (by maternal nuclear genes). The model treats paternal leakage as an evolvable trait. Our evolutionary analysis shows that maternal control consistently favours strict uniparental inheritance with complete exclusion of sperm mitochondria, whereas some degree of paternal leakage of mitochondria is an expected outcome under paternal control. This difference arises because mito-nuclear linkage builds up with maternal control, allowing the greater variance created by asymmetric inheritance to boost the efficiency of purifying selection and bring benefits in the long term. In contrast, under paternal control, mito-nuclear linkage tends to be much weaker, giving greater advantage to the mixing of cytotypes, which improves mean fitness in the short term, even though it imposes a fitness cost to both mating types in the long term. Sexual conflict is an inevitable outcome when there is competition between maternal and paternal control of mitochondrial inheritance. If evolution has led to complete uniparental inheritance through maternal control, it creates selective pressure on the paternal nucleus in favour of subversion through paternal leakage, and vice versa. This selective divergence provides a reason for the repeated evolution of novel mechanisms that regulate the transmission of paternal mitochondria, both in the fertilized egg and spermatogenesis. Our analysis suggests that the widespread occurrence of paternal leakage and prevalence of heteroplasmy are natural outcomes of

  2. Expression of DACT1 in children with asthma and its regulation mechanism

    Science.gov (United States)

    Zhang, Cunxue; Yang, Peili; Chen, Yan; Liu, Jing; Yuan, Xiutai

    2018-01-01

    The aim of the present study was to detect DACT1 expression levels in the lungs of children with asthma, and to investigate its role and molecular mechanisms in regulating the expression of inflammatory factors in RAW264.7 cells. DACT1, DACT2 and DACT3 expression was analyzed in biopsy specimens from 10 cases of newly diagnosed children with asthma and 10 healthy controls by reverse transcription-quantitative polymerase chain reaction, and their expression was confirmed in RAW264.7 cells. DACT1 expression was silenced by small interfering RNA or enhanced by transfection of pcDNA-3.1-DACT1 in RAW264.7 cells, and expression of β-catenin and inflammatory factors, interleukin (IL) 5, IL6 and IL13, was analyzed. Nuclear translocation of β-catenin was detected by western blot analysis, and the effect of DACT1 on β-catenin was investigated with rescue experiments. Regulation of the Wnt signaling pathway by DACT1 and β-catenin was analyzed in RAW264.7 cells after recombinant Wnt5A stimulation. DACT1, DACT2 and DACT3 were significantly upregulated in specimens from children with asthma compared with controls (Pasthma, which could induce higher pro-inflammatory factor expression. DACT1 may act via inhibiting the expression and nuclear translocation of β-catenin, a factor in the Wnt signaling pathway. The present results suggested that DACT1 may be a potential target for the treatment of asthma. PMID:29456669

  3. Design of an Adaptive Power Regulation Mechanism and a Nozzle for a Hydroelectric Power Plant Turbine Test Rig

    Science.gov (United States)

    Mert, Burak; Aytac, Zeynep; Tascioglu, Yigit; Celebioglu, Kutay; Aradag, Selin; ETU Hydro Research Center Team

    2014-11-01

    This study deals with the design of a power regulation mechanism for a Hydroelectric Power Plant (HEPP) model turbine test system which is designed to test Francis type hydroturbines up to 2 MW power with varying head and flow(discharge) values. Unlike the tailor made regulation mechanisms of full-sized, functional HEPPs; the design for the test system must be easily adapted to various turbines that are to be tested. In order to achieve this adaptability, a dynamic simulation model is constructed in MATLAB/Simulink SimMechanics. This model acquires geometric data and hydraulic loading data of the regulation system from Autodesk Inventor CAD models and Computational Fluid Dynamics (CFD) analysis respectively. The dynamic model is explained and case studies of two different HEPPs are performed for validation. CFD aided design of the turbine guide vanes, which is used as input for the dynamic model, is also presented. This research is financially supported by Turkish Ministry of Development.

  4. Regulation of p73 by Hck through kinase-dependent and independent mechanisms

    Directory of Open Access Journals (Sweden)

    Radha Vegesna

    2007-05-01

    Full Text Available Abstract Background p73, a p53 family member is a transcription factor that plays a role in cell cycle, differentiation and apoptosis. p73 is regulated through post translational modifications and protein interactions. c-Abl is the only known tyrosine kinase that phosphorylates and activates p73. Here we have analyzed the role of Src family kinases, which are involved in diverse signaling pathways, in regulating p73. Results Exogenously expressed as well as cellular Hck and p73 interact in vivo. In vitro binding assays show that SH3 domain of Hck interacts with p73. Co-expression of p73 with Hck or c-Src in mammalian cells resulted in tyrosine phosphorylation of p73. Using site directed mutational analysis, we determined that Tyr-28 was the major site of phosphorylation by Hck and c-Src, unlike c-Abl which phosphorylates Tyr-99. In a kinase dependent manner, Hck co-expression resulted in stabilization of p73 protein in the cytoplasm. Activation of Hck in HL-60 cells resulted in tyrosine phosphorylation of endogenous p73. Both exogenous and endogenous Hck localize to the nuclear as well as cytoplasmic compartment, just as does p73. Ectopically expressed Hck repressed the transcriptional activity of p73 as determined by promoter assays and semi-quantitative RT-PCR analysis of the p73 target, Ipaf and MDM2. SH3 domain- dependent function of Hck was required for its effect on p73 activity, which was also reflected in its ability to inhibit p73-mediated apoptosis. We also show that Hck interacts with Yes associated protein (YAP, a transcriptional co-activator of p73, and shRNA mediated knockdown of YAP protein reduces p73 induced Ipaf promoter activation. Conclusion We have identified p73 as a novel substrate and interacting partner of Hck and show that it regulates p73 through mechanisms that are dependent on either catalytic activity or protein interaction domains. Hck-SH3 domain-mediated interactions play an important role in the inhibition of p73

  5. Mechanisms of Heshouwuyin in regulating apoptosis of testicular cells in aging rats through mitochondrial pathway.

    Science.gov (United States)

    Chen, Jingbo; Wang, Yujuan; Hui, Chenhong; Xi, Yao; Liu, Xiang; Qi, Feng; Liu, Haokun; Wang, Zhenshan; Niu, Siyun

    2016-09-01

    Polygonum multiflorum has important effects on anti-aging and immunity enhancement. Many traditional Chinese medicine preparations based on Polygonum multiflorum are widely used for the clinical prevention and treatment of aging. However the mechanisms of these herb mixtures are often unknown. This study investigates the effect of Heshouwuyin, a Chinese herbal compound for invigorating the kidney, on the regulation of testicular cells apoptosis in aging rats. In this study, 18-month-old Wistar rats served as a model of natural aging and 12-month-old rats served as a young control group. Heshouwuyin group 1 and group 2 were comprised 18-month-old rats given Heshouwuyin intragastrically for 60 days and 30 days respectively. Then testes of the young control group were isolated in the age of 12 months, the other three groups were in the age of 18 months. TUNEL assay showed that the rate of testicular cell apoptosis was obviously higher and Flow cytometry analysis showed that the rate of cell proliferation was significantly lower in the natural aging group than in the young control group and that intervention with Heshouwuyin could reverse this phenomenon. Therefore, we further applied microarray analysis to screen out differentially expressed genes regulated by Heshouwuyin and related to cell apoptosis. The expression of these genes was observed by quantitative fluorescence PCR, immunofluorescence staining, and western blot. The results showed that the expression of 14-3-3σ was significantly lower and that the expression of DR6, BAX, caspase-3 and Cytc were significantly higher in the natural aging group than in the young control group, but intervention with Heshouwuyin significantly reversed this phenomenon. Moreover, the curative efficacy of Heshouwuyin after 60 days was better than that of Heshouwuyin after 30 days. Our study suggests that Heshouwuyin has anti-aging effects on the testis by means of inhibiting the occurrence of apoptosis in spermatogenic

  6. Microorganism-regulated mechanisms of temperature effects on the performance of anaerobic digestion.

    Science.gov (United States)

    Lin, Qiang; He, Guihua; Rui, Junpeng; Fang, Xiaoyu; Tao, Yong; Li, Jiabao; Li, Xiangzhen

    2016-06-03

    Temperature is an important factor determining the performance and stability of the anaerobic digestion process. However, the microorganism-regulated mechanisms of temperature effects on the performance of anaerobic digestion systems remain further elusive. To address this issue, we investigated the changes in composition, diversity and activities of microbial communities under temperature gradient from 25 to 55 °C using 16S rRNA gene amplicon sequencing approach based on genomic DNA (refer to as "16S rDNA") and total RNA (refer to as "16S rRNA"). Microbial community structure and activities changed dramatically along the temperature gradient, which corresponded to the variations in digestion performance (e.g., daily CH4 production, total biogas production and volatile fatty acids concentration). The ratios of 16S rRNA to 16S rDNA of microbial taxa, as an indicator of the potentially relative activities in situ, and whole activities of microbial community assessed by the similarity between microbial community based on 16S rDNA and rRNA, varied strongly along the temperature gradient, reflecting different metabolic activities. The daily CH4 production increased with temperature from 25 to 50 °C and declined at 55 °C. Among all the examined microbial properties, the whole activities of microbial community and alpha-diversity indices of both microbial communities and potentially relative activities showed highest correlations to the performance. The whole activities of microbial community and alpha-diversity indices of both microbial communities and potentially relative activities were sensitive indicators for the performance of anaerobic digestion systems under temperature gradient, while beta-diversity could predict functional differences. Microorganism-regulated mechanisms of temperature effects on anaerobic digestion performance were likely realized through increasing alpha-diversity of both microbial communities and potentially relative activities to supply

  7. The critical chemical and mechanical regulation of folic acid on neural engineering.

    Science.gov (United States)

    Kim, Gloria B; Chen, Yongjie; Kang, Weibo; Guo, Jinshan; Payne, Russell; Li, Hui; Wei, Qiong; Baker, Julianne; Dong, Cheng; Zhang, Sulin; Wong, Pak Kin; Rizk, Elias B; Yan, Jiazhi; Yang, Jian

    2018-04-03

    The mandate of folic acid supplementation in grained products has reduced the occurrence of neural tube defects by one third in the U.S since its introduction by the Food and Drug Administration in 1998. However, the advantages and possible mechanisms of action of using folic acid for peripheral nerve engineering and neurological diseases still remain largely elusive. Herein, folic acid is described as an inexpensive and multifunctional niche component that modulates behaviors in different cells in the nervous system. The multiple benefits of modulation include: 1) generating chemotactic responses on glial cells, 2) inducing neurotrophin release, and 3) stimulating neuronal differentiation of a PC-12 cell system. For the first time, folic acid is also shown to enhance cellular force generation and global methylation in the PC-12 cells, thereby enabling both biomechanical and biochemical pathways to regulate neuron differentiation. These findings are evaluated in vivo for clinical translation. Our results suggest that folic acid-nerve guidance conduits may offer significant benefits as a low-cost, off-the-shelf product for reaching the functional recovery seen with autografts in large sciatic nerve defects. Consequently, folic acid holds great potential as a critical and convenient therapeutic intervention for neural engineering, regenerative medicine, medical prosthetics, and drug delivery. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. Structural basis for the regulation mechanism of the tyrosine kinase CapB from Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Vanesa Olivares-Illana

    2008-06-01

    Full Text Available Bacteria were thought to be devoid of tyrosine-phosphorylating enzymes. However, several tyrosine kinases without similarity to their eukaryotic counterparts have recently been identified in bacteria. They are involved in many physiological processes, but their accurate functions remain poorly understood due to slow progress in their structural characterization. They have been best characterized as copolymerases involved in the synthesis and export of extracellular polysaccharides. These compounds play critical roles in the virulence of pathogenic bacteria, and bacterial tyrosine kinases can thus be considered as potential therapeutic targets. Here, we present the crystal structures of the phosphorylated and unphosphorylated states of the tyrosine kinase CapB from the human pathogen Staphylococcus aureus together with the activator domain of its cognate transmembrane modulator CapA. This first high-resolution structure of a bacterial tyrosine kinase reveals a 230-kDa ring-shaped octamer that dissociates upon intermolecular autophosphorylation. These observations provide a molecular basis for the regulation mechanism of the bacterial tyrosine kinases and give insights into their copolymerase function.

  9. Effects of the Ordering of Natural Selection and Population Regulation Mechanisms on Wright-Fisher Models.

    Science.gov (United States)

    He, Zhangyi; Beaumont, Mark; Yu, Feng

    2017-07-05

    We explore the effect of different mechanisms of natural selection on the evolution of populations for one- and two-locus systems. We compare the effect of viability and fecundity selection in the context of the Wright-Fisher model with selection under the assumption of multiplicative fitness. We show that these two modes of natural selection correspond to different orderings of the processes of population regulation and natural selection in the Wright-Fisher model. We find that under the Wright-Fisher model these two different orderings can affect the distribution of trajectories of haplotype frequencies evolving with genetic recombination. However, the difference in the distribution of trajectories is only appreciable when the population is in significant linkage disequilibrium. We find that as linkage disequilibrium decays the trajectories for the two different models rapidly become indistinguishable. We discuss the significance of these findings in terms of biological examples of viability and fecundity selection, and speculate that the effect may be significant when factors such as gene migration maintain a degree of linkage disequilibrium. Copyright © 2017 He et al.

  10. Decreased glucose uptake by hyperglycemia is regulated by different mechanisms in human cancer cells and monocytes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chae Kyun; Chung, June Key; Lee, Yong Jin; Hong, Mee Kyoung; Jeong, Jae Min; Lee, Dong Soo; Lee, Myung Chul [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

    2002-04-01

    To clarify the difference in glucose uptake between human cancer cells and monocytes, we studied ({sup 18}F) fluorodeoxyglucose (FDG) uptake in three human colon cancer cell lines (SNU-C2A, SNU-C4, SNU-C5), one human lung cancer cell line (NCI-H522), and human peripheral blood monocytes. The FDG uptake of both cancer cells and monocytes was increased in glucose-free medium, but decreased in the medium containing 16.7 mM glucose (hyperglycemic). The level of Glut1 mRNA decreased in human colon cancer cells and NCI-H522 under hyperglycemic condition. Glut1 protein expression was also decreased in the four human cancer cell lines under hyperglycemic condition, whereas it was consistently undetectable in monocytes. SNU-C2A, SNU-C4 and NCI-H522 showed a similar level of hexokinase activity (7.5-10.8 mU/mg), while SNU-C5 and moncytes showed lower range of hexokinase activity (4.3-6.5 mU/mg). These data suggest that glucose uptake is regulated by different mechanisms in human cancer cells and monocytes.

  11. Mechanisms of regulation of SNF1/AMPK/SnRK1 protein kinases

    Science.gov (United States)

    Crozet, Pierre; Margalha, Leonor; Confraria, Ana; Rodrigues, Américo; Martinho, Cláudia; Adamo, Mattia; Elias, Carlos A.; Baena-González, Elena

    2014-01-01

    The SNF1 (sucrose non-fermenting 1)-related protein kinases 1 (SnRKs1) are the plant orthologs of the budding yeast SNF1 and mammalian AMPK (AMP-activated protein kinase). These evolutionarily conserved kinases are metabolic sensors that undergo activation in response to declining energy levels. Upon activation, SNF1/AMPK/SnRK1 kinases trigger a vast transcriptional and metabolic reprograming that restores energy homeostasis and promotes tolerance to adverse conditions, partly through an induction of catabolic processes and a general repression of anabolism. These kinases typically function as a heterotrimeric complex composed of two regulatory subunits, β and γ, and an α-catalytic subunit, which requires phosphorylation of a conserved activation loop residue for activity. Additionally, SNF1/AMPK/SnRK1 kinases are controlled by multiple mechanisms that have an impact on kinase activity, stability, and/or subcellular localization. Here we will review current knowledge on the regulation of SNF1/AMPK/SnRK1 by upstream components, post-translational modifications, various metabolites, hormones, and others, in an attempt to highlight both the commonalities of these essential eukaryotic kinases and the divergences that have evolved to cope with the particularities of each one of these systems. PMID:24904600

  12. Regulation of human hepatocellular carcinoma cells by Spred2 and correlative studies on its mechanism

    International Nuclear Information System (INIS)

    Ma, Xiao-Ni; Liu, Xiao-Yun; Yang, Yue-Feng; Xiao, Feng-Jun; Li, Qing-Fang; Yan, Jun; Zhang, Qun-Wei; Wang, Li-Sheng; Li, Xue-Yan; Wang, Hua

    2011-01-01

    Highlights: → Hepatocellular carcinoma is inhibited by Spred2 through as yet unclear mechanisms. → We studied the overexpression of Spred2 in cell line and murine tumor models of HCC. → Spred2 inhibited cell proliferation and migration via attenuating ERK signaling. → Spred2 overexpression induced apoptosis via caspase-3 and downregulated Mcl-1. → A Spred2 knockdown markedly induced tumor growth in vivo. -- Abstract: Members of the Spred gene family are negative regulators of the Ras/Raf-1/ERK pathway, which has been associated with several features of the tumor malignancy. However, the effect of Spred genes on hepatocellular carcinoma (HCC) remains uninvestigated. In the present work, we analyzed the in vitro and in vivo effects of Spred2 expression on the hepatic carcinoma cell line, SMMC-7721. In addition to attenuated ERK activation, which inhibited the proliferation and migration of unstimulated and HGF-stimulated SMMC-7721 cells. Adenovirus-mediated Spred2 overexpression induced the activation of caspase-3 and apoptosis, as well as reduced the expression level of Mcl-1. Most importantly, the knockdown of Spred2 markedly enhanced tumor growth in vivo. In conclusion, these results suggest that Spred2 could qualify as a potential therapeutic target in HCC.

  13. The regulation and catalytic mechanism of the NADP-malic enzyme from tobacco leaves

    Directory of Open Access Journals (Sweden)

    VERONIKA DOUBNEROVÁ

    2009-08-01

    Full Text Available The non-photosynthetic NADP-malic enzyme EC 1.1.1.40 (NADP-ME, which catalyzes the oxidative decarboxylation of L-malate and NADP+ to produce pyruvate and NADPH, respectively, and which could be involved in plant defense responses, was isolated from Nicotiana tabacum L. leaves. The mechanism of the enzyme reaction was studied by the initial rate method and was found to be an ordered sequential one. Regulation possibilities of purified cytosolic NADP-ME by cell metabolites were tested. Intermediates of the citric acid cycle (a-ketoglutarate, succinate, fumarate, metabolites of glycolysis (pyruvate, phosphoenolpyruvate, glucose-6-phosphate, compounds connected with lipogenesis (coenzyme A, acetyl-CoA, palmitoyl-CoA and some amino acids (glutamate, glutamine, aspartate did not significantly affect the NADP-ME activity from tobacco leaves. In contrast, macroergic compounds (GTP, ATP and ADP were strong inhibitors of NADP-ME; the type of inhibition and the inhibition constants were determined in the presence of the most effective cofactors (Mn2+ or Mg2+, required by NADP-ME. Predominantly non-competitive type of inhibitions of NADP-ME with respect to NADP+ and mixed type to L-malate were found.

  14. Decreased glucose uptake by hyperglycemia is regulated by different mechanisms in human cancer cells and monocytes

    International Nuclear Information System (INIS)

    Kim, Chae Kyun; Chung, June Key; Lee, Yong Jin; Hong, Mee Kyoung; Jeong, Jae Min; Lee, Dong Soo; Lee, Myung Chul

    2002-01-01

    To clarify the difference in glucose uptake between human cancer cells and monocytes, we studied ( 18 F) fluorodeoxyglucose (FDG) uptake in three human colon cancer cell lines (SNU-C2A, SNU-C4, SNU-C5), one human lung cancer cell line (NCI-H522), and human peripheral blood monocytes. The FDG uptake of both cancer cells and monocytes was increased in glucose-free medium, but decreased in the medium containing 16.7 mM glucose (hyperglycemic). The level of Glut1 mRNA decreased in human colon cancer cells and NCI-H522 under hyperglycemic condition. Glut1 protein expression was also decreased in the four human cancer cell lines under hyperglycemic condition, whereas it was consistently undetectable in monocytes. SNU-C2A, SNU-C4 and NCI-H522 showed a similar level of hexokinase activity (7.5-10.8 mU/mg), while SNU-C5 and moncytes showed lower range of hexokinase activity (4.3-6.5 mU/mg). These data suggest that glucose uptake is regulated by different mechanisms in human cancer cells and monocytes

  15. Carbon storage regulator A contributes to the virulence of Haemophilus ducreyi in humans by multiple mechanisms.

    Science.gov (United States)

    Gangaiah, Dharanesh; Li, Wei; Fortney, Kate R; Janowicz, Diane M; Ellinger, Sheila; Zwickl, Beth; Katz, Barry P; Spinola, Stanley M

    2013-02-01

    The carbon storage regulator A (CsrA) controls a wide variety of bacterial processes, including metabolism, adherence, stress responses, and virulence. Haemophilus ducreyi, the causative agent of chancroid, harbors a homolog of csrA. Here, we generated an unmarked, in-frame deletion mutant of csrA to assess its contribution to H. ducreyi pathogenesis. In human inoculation experiments, the csrA mutant was partially attenuated for pustule formation compared to its parent. Deletion of csrA resulted in decreased adherence of H. ducreyi to human foreskin fibroblasts (HFF); Flp1 and Flp2, the determinants of H. ducreyi adherence to HFF cells, were downregulated in the csrA mutant. Compared to its parent, the csrA mutant had a significantly reduced ability to tolerate oxidative stress and heat shock. The enhanced sensitivity of the mutant to oxidative stress was more pronounced in bacteria grown to stationary phase compared to that in bacteria grown to mid-log phase. The csrA mutant also had a significant survival defect within human macrophages when the bacteria were grown to stationary phase but not to mid-log phase. Complementation in trans partially or fully restored the mutant phenotypes. These data suggest that CsrA contributes to virulence by multiple mechanisms and that these contributions may be more profound in bacterial cell populations that are not rapidly dividing in the human host.

  16. Incision and stress regulation in borderline personality disorder: neurobiological mechanisms of self-injurious behaviour.

    Science.gov (United States)

    Reitz, Sarah; Kluetsch, Rosemarie; Niedtfeld, Inga; Knorz, Teresa; Lis, Stefanie; Paret, Christian; Kirsch, Peter; Meyer-Lindenberg, Andreas; Treede, Rolf-Detlef; Baumgärtner, Ulf; Bohus, Martin; Schmahl, Christian

    2015-08-01

    Patients with borderline personality disorder frequently show non-suicidal self-injury (NSSI). In these patients, NSSI often serves to reduce high levels of stress. Investigation of neurobiological mechanisms of NSSI in borderline personality disorder. In total, 21 women with borderline personality disorder and 17 healthy controls underwent a stress induction, followed by either an incision into the forearm or a sham treatment. Afterwards participants underwent resting-state functional magnetic resonance imaging while aversive tension, heart rate and heart rate variability were assessed. We found a significant influence of incision on subjective and objective stress levels with a stronger decrease of aversive tension in the borderline personality disorder group following incision than sham. Amygdala activity decreased more and functional connectivity with superior frontal gyrus normalised after incision in the borderline personality disorder group. Decreased stress levels and amygdala activity after incision support the assumption of an influence of NSSI on emotion regulation in individuals with borderline personality disorder and aids in understanding why these patients use self-inflicted pain to reduce inner tension. © The Royal College of Psychiatrists 2015.

  17. Effects of endurance training on blood pressure, blood pressure-regulating mechanisms, and cardiovascular risk factors.

    Science.gov (United States)

    Cornelissen, Véronique A; Fagard, Robert H

    2005-10-01

    Previous meta-analyses of randomized controlled trials on the effects of chronic dynamic aerobic endurance training on blood pressure reported on resting blood pressure only. Our aim was to perform a comprehensive meta-analysis including resting and ambulatory blood pressure, blood pressure-regulating mechanisms, and concomitant cardiovascular risk factors. Inclusion criteria of studies were: random allocation to intervention and control; endurance training as the sole intervention; inclusion of healthy sedentary normotensive or hypertensive adults; intervention duration of > or =4 weeks; availability of systolic or diastolic blood pressure; and publication in a peer-reviewed journal up to December 2003. The meta-analysis involved 72 trials, 105 study groups, and 3936 participants. After weighting for the number of trained participants and using a random-effects model, training induced significant net reductions of resting and daytime ambulatory blood pressure of, respectively, 3.0/2.4 mm Hg (Phypertensive study groups (-6.9/-4.9) than in the others (-1.9/-1.6; Pendurance training decreases blood pressure through a reduction of vascular resistance, in which the sympathetic nervous system and the renin-angiotensin system appear to be involved, and favorably affects concomitant cardiovascular risk factors.

  18. PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer: Factors, Mechanism and Regulation.

    Science.gov (United States)

    Sharma, Var Ruchi; Gupta, Girish Kumar; Sharma, A K; Batra, Navneet; Sharma, Daljit K; Joshi, Amit; Sharma, Anil K

    2017-01-01

    The most recurrent and considered second most frequent cause of cancer-related deaths worldwide in women is the breast cancer. The key to diagnosis is early prediction and a curable stage but still treatment remains a great clinical challenge. Origin of the Problem: A number of studies have been carried out for the treatment of breast cancer which includes the targeted therapies and increased survival rates in women. Essential PI3K/mTOR signaling pathway activation has been observed in most breast cancers. The cell growth and tumor development in such cases involve phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) complex intracellular pathway. Through preclinical and clinical trials, it has been observed that there are a number of other inhibitors of PI3K/Akt/mTOR pathway, which either alone or in combination with cytotoxic agents can be used for endocrine therapies. Structure and regulation/deregulation of mTOR provides a greater insight into the action mechanism. Also, through this review, one could easily scan first and second generation inhibitors for PI3K/Akt/mTOR pathway besides targeted therapies for breast cancer and the precise role of mTOR. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. A Molecular Mechanism to Regulate Lysosome Motility for Lysosome Positioning and Tubulation

    Science.gov (United States)

    Li, Xinran; Rydzewski, Nicholas; Hider, Ahmad; Zhang, Xiaoli; Yang, Junsheng; Wang, Wuyang; Gao, Qiong; Cheng, Xiping; Xu, Haoxing

    2016-01-01

    To mediate the degradation of bio-macromolecules, lysosomes must traffic towards cargo-carrying vesicles for subsequent membrane fusion or fission. Mutations of the lysosomal Ca2+ channel TRPML1 cause lysosome storage disease (LSD) characterized by disordered lysosomal membrane trafficking in cells. Here we show that TRPML1 activity is required to promote Ca2+-dependent centripetal movement of lysosomes towards the perinuclear region, where autophagosomes accumulate, upon autophagy induction. ALG-2, an EF-hand-containing protein, serves as a lysosomal Ca2+ sensor that associates physically with the minus-end directed dynactin-dynein motor, while PI(3,5)P2, a lysosome-localized phosphoinositide, acts upstream of TRPML1. Furthermore, the PI(3,5)P2-TRPML1-ALG-2-dynein signaling is necessary for lysosome tubulation and reformation. In contrast, the TRPML1 pathway is not required for the perinuclear accumulation of lysosomes observed in many LSDs, which is instead likely caused by secondary cholesterol accumulation that constitutively activates Rab7-RILP-dependent retrograde transport. Collectively, Ca2+ release from lysosomes provides an on-demand mechanism regulating lysosome motility, positioning, and tubulation. PMID:26950892

  20. A Heme-Sensing Mechanism in the Translational Regulation of Mitochondrial Cytochrome c Oxidase Biogenesis

    Science.gov (United States)

    Soto, Iliana C.; Fontanesi, Flavia; Myers, Richard S.; Hamel, Patrice; Barrientos, Antoni

    2012-01-01

    Heme plays fundamental roles as cofactor and signaling molecule in multiple pathways devoted to oxygen sensing and utilization in aerobic organisms. For cellular respiration, heme serves as a prosthetic group in electron transfer proteins and redox enzymes. Here we report that in the yeast Saccharomyces cerevisiae a heme-sensing mechanism translationally controls the biogenesis of cytochrome c oxidase (COX), the terminal mitochondrial respiratory chain enzyme. We show that Mss51, a COX1 mRNA-specific translational activator and Cox1 chaperone, which coordinates Cox1 synthesis in mitoribosomes with its assembly in COX, is a heme-binding protein. Mss51 contains two heme regulatory motifs or Cys-Pro-X domains located in its N-terminus. Using a combination of in vitro and in vivo approaches, we have demonstrated that these motifs are important for heme binding and efficient performance of Mss51 functions. We conclude that heme sensing by Mss51 regulates COX biogenesis and aerobic energy production. PMID:23217259

  1. Chronic central administration of Ghrelin increases bone mass through a mechanism independent of appetite regulation.

    Directory of Open Access Journals (Sweden)

    Hyung Jin Choi

    Full Text Available Leptin plays a critical role in the central regulation of bone mass. Ghrelin counteracts leptin. In this study, we investigated the effect of chronic intracerebroventricular administration of ghrelin on bone mass in Sprague-Dawley rats (1.5 μg/day for 21 days. Rats were divided into control, ghrelin ad libitum-fed (ghrelin ad lib-fed, and ghrelin pair-fed groups. Ghrelin intracerebroventricular infusion significantly increased body weight in ghrelin ad lib-fed rats but not in ghrelin pair-fed rats, as compared with control rats. Chronic intracerebroventricular ghrelin infusion significantly increased bone mass in the ghrelin pair-fed group compared with control as indicated by increased bone volume percentage, trabecular thickness, trabecular number and volumetric bone mineral density in tibia trabecular bone. There was no significant difference in trabecular bone mass between the control group and the ghrelin ad-lib fed group. Chronic intracerebroventricular ghrelin infusion significantly increased the mineral apposition rate in the ghrelin pair-fed group as compared with control. In conclusion, chronic central administration of ghrelin increases bone mass through a mechanism that is independent of body weight, suggesting that ghrelin may have a bone anabolic effect through the central nervous system.

  2. Insight into the mechanisms regulating immune homeostasis in health and disease.

    Science.gov (United States)

    Sirisinha, Stitaya

    2011-03-01

    Innate and adaptive immune systems consist of cells and molecules that work together in concert to fight against microbial infection and maintain homeostasis. Hosts encounter microbes / exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) all the time and they must have proper mechanisms to counteract the danger such that appropriate responses (e.g., degree of inflammation and types of mediators induced) can be mounted in different scenarios. Increasing numbers of endogenous danger signals of host origin are being identified including, for example, uric acid and cholesterol crystals, high mobility group box1 (HMGB1) protein, oxidized LDL, vesicans, heat shock proteins (HSPs) and self DNA. Many of these endogenous ligands have been shown to be associated with inflammation-related diseases like atherosclerosis, gout and type 2 diabetes. Several DAMPs appear to have the ability to interact with more than one receptor. We are now beginning to understand how the immune system can distinguish infection from endogenous ligands elaborated following cellular insults and tissue damage. Appropriate responses to maintain the homeostatic state in health and disease depend largely on the recognition and response to these stimuli by germline encoded pattern-recognition receptors (PRRs) present on both immune and non-immune cells. These receptors are, for example, Toll-like receptors (TLRs), C-type lectin receptors (CLRs) and cytosolic receptors (e.g., RLRs, NLRs and some intracellular DNA sensors). Atypical PRR "danger" receptors, like the receptor for advanced glycation end products (RAGE) and their ligands have been identified. A proper response to maintain homeostasis relies on specific negative regulators and regulatory pathways to dampen its response to tissue injury while maintaining the capacity to eliminate infection and induce proper tissue repair. Moreover, some PRRs (e.g., TLR2,TLR4 and NLRP3) and atypical

  3. Regulatory Holidays and Optimal Network Expansion

    NARCIS (Netherlands)

    Willems, Bert; Zwart, Gijsbert

    2016-01-01

    We model the optimal regulation of continuous, irreversible, capacity expansion, in a model in which the regulated network firm has private information about its capacity costs, investments need to be financed out of the firm’s cash flows from selling network access and demand is stochastic. If

  4. Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms

    DEFF Research Database (Denmark)

    Srinivasan, Supriya; Sadegh, Leila; Elle, Ida C

    2008-01-01

    We investigated serotonin signaling in C. elegans as a paradigm for neural regulation of energy balance and found that serotonergic regulation of fat is molecularly distinct from feeding regulation. Serotonergic feeding regulation is mediated by receptors whose functions are not required for fat...... feeding behavior. These findings suggest that, as in mammals, C. elegans feeding behavior is regulated by extrinsic and intrinsic cues. Moreover, obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses...

  5. Brucella BioR Regulator Defines a Complex Regulatory Mechanism for Bacterial Biotin Metabolism

    Science.gov (United States)

    Xu, Jie; Zhang, Huimin; Srinivas, Swaminath

    2013-01-01

    The enzyme cofactor biotin (vitamin H or B7) is an energetically expensive molecule whose de novo biosynthesis requires 20 ATP equivalents. It seems quite likely that diverse mechanisms have evolved to tightly regulate its biosynthesis. Unlike the model regulator BirA, a bifunctional biotin protein ligase with the capability of repressing the biotin biosynthetic pathway, BioR has been recently reported by us as an alternative machinery and a new type of GntR family transcriptional factor that can repress the expression of the bioBFDAZ operon in the plant pathogen Agrobacterium tumefaciens. However, quite unusually, a closely related human pathogen, Brucella melitensis, has four putative BioR-binding sites (both bioR and bioY possess one site in the promoter region, whereas the bioBFDAZ [bio] operon contains two tandem BioR boxes). This raised the question of whether BioR mediates the complex regulatory network of biotin metabolism. Here, we report that this is the case. The B. melitensis BioR ortholog was overexpressed and purified to homogeneity, and its solution structure was found to be dimeric. Functional complementation in a bioR isogenic mutant of A. tumefaciens elucidated that Brucella BioR is a functional repressor. Electrophoretic mobility shift assays demonstrated that the four predicted BioR sites of Brucella plus the BioR site of A. tumefaciens can all interact with the Brucella BioR protein. In a reporter strain that we developed on the basis of a double mutant of A. tumefaciens (the ΔbioR ΔbioBFDA mutant), the β-galactosidase (β-Gal) activity of three plasmid-borne transcriptional fusions (bioBbme-lacZ, bioYbme-lacZ, and bioRbme-lacZ) was dramatically decreased upon overexpression of Brucella bioR. Real-time quantitative PCR analyses showed that the expression of bioBFDA and bioY is significantly elevated upon removal of bioR from B. melitensis. Together, we conclude that Brucella BioR is not only a negative autoregulator but also a repressor of

  6. Regulation Mechanism of the ald Gene Encoding Alanine Dehydrogenase in Mycobacterium smegmatis and Mycobacterium tuberculosis by the Lrp/AsnC Family Regulator AldR.

    Science.gov (United States)

    Jeong, Ji-A; Hyun, Jaekyung; Oh, Jeong-Il

    2015-10-01

    In the presence of alanine, AldR, which belongs to the Lrp/AsnC family of transcriptional regulators and regulates ald encoding alanine dehydrogenase in Mycobacterium smegmatis, changes its quaternary structure from a homodimer to an octamer with an open-ring conformation. Four AldR-binding sites (O2, O1, O4, and O3) with a consensus sequence of GA/T-N2-NWW/WWN-N2-A/TC were identified upstream of the M. smegmatis ald gene by means of DNase I footprinting analysis. O2, O1, and O4 are required for the induction of ald expression by alanine, while O3 is directly involved in the repression of ald expression. In addition to O3, both O1 and O4 are also necessary for full repression of ald expression in the absence of alanine, due to cooperative binding of AldR dimers to O1, O4, and O3. Binding of a molecule of the AldR octamer to the ald control region was demonstrated to require two AldR-binding sites separated by three helical turns between their centers and one additional binding site that is in phase with the two AldR-binding sites. The cooperative binding of AldR dimers to DNA requires three AldR-binding sites that are aligned with a periodicity of three helical turns. The aldR gene is negatively autoregulated independently of alanine. Comparative analysis of ald expression of M. smegmatis and Mycobacterium tuberculosis in conjunction with sequence analysis of both ald control regions led us to suggest that the expression of the ald genes in both mycobacterial species is regulated by the same mechanism. In mycobacteria, alanine dehydrogenase (Ald) is the enzyme required both to utilize alanine as a nitrogen source and to grow under hypoxic conditions by maintaining the redox state of the NADH/NAD(+) pool. Expression of the ald gene was reported to be regulated by the AldR regulator that belongs to the Lrp/AsnC (feast/famine) family, but the underlying mechanism was unknown. This study revealed the regulation mechanism of ald in Mycobacterium smegmatis and

  7. Pou1f1, the key transcription factor related to somatic growth in tilapia (Orechromis niloticus), is regulated by two independent post-transcriptional regulation mechanisms.

    Science.gov (United States)

    Wang, Dongfang; Qin, Jingkai; Jia, Jirong; Yan, Peipei; Li, Wensheng

    2017-01-29

    This study aims to determine the post-transcriptional regulation mechanism of the transcription factor pou1f1 (pou class 1 homeobox 1), which is the key gene for pituitary development, somatic growth in vertebrates, and transcription of several hormone genes in teleost fish. MicroRNA miR-223-3p was identified as a bona fide target of pou1f; overexpression of miR-223-3p in primary pituitary cells led to the down-regulation of pou1f1 and downstream genes, and inhibition of miR-223-3p led to the up-regulation of pou1f1 in Nile tilapia dispersed primary pituitary cells. An adenylate-uridylate-rich element (AU-Rich element) was found in the 3'UTR of pou1f1 mRNA, and deletion of the AU-Rich element led to slower mRNA decay and therefore more protein output. A potential mutual relationship between miR-223-3p and the AU-rich element was also investigated, and the results demonstrated that with or without the AU-Rich element, miR-223-3p induced the up-regulation of a reporter system under serum starvation conditions, indicating that miR-223-3p and the AU-Rich element function independent of each other. This study is the first to investigate the post-transcriptional mechanism of pou1f1, which revealed that miR-223-3p down-regulated pou1f1 and downstream gene expressions, and the AU-Rich element led to rapid decay of pou1f1 mRNA. MicroRNA miR-223-3p and the AU-Rich element co-regulated the post-transcriptional expression of pou1f1 independently in Nile tilapia, demonstrating that pou1f1 is under the control of a dual post-transcription regulation mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Mechanisms of Change in the Relationship between Self-Compassion, Emotion Regulation, and Mental Health: A Systematic Review.

    Science.gov (United States)

    Inwood, Elisa; Ferrari, Madeleine

    2018-04-19

    Research suggests that self-compassion may improve mental health by promoting emotion regulation (Berking & Whitley, ). This review aimed to identify studies which investigated the relationship between self-compassion, emotion regulation, and mental health in order to examine the role of emotional regulation as a mechanism of change. Searches were conducted in PsycINFO, CINAHL, Medline complete, Web of Science and Scopus databases. Inclusion criteria required publications to be: peer reviewed, published in English, contain validated measures of self-compassion and emotion regulation, and report a direct analysis on the relationship between these constructs. The search yielded five studies which met inclusion criteria. Emotion regulation significantly mediated the relationship between self-compassion and mental health. This pattern was consistent across community and clinical samples, for a range of mental health symptoms including stress, depression, and post-traumatic stress disorder. A critical limitation of the review was that all included studies used cross-sectional data, limiting interpretations regarding causation. Results provide preliminary evidence that emotion regulation may be a mechanism of change in the relationship between self-compassion and mental health. Self-compassion may be a pertinent preliminary treatment target for individuals who avoid experiences of emotions. © 2018 The International Association of Applied Psychology.

  9. Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism*

    Science.gov (United States)

    Dyachok, Julia; Earnest, Svetlana; Iturraran, Erica N.; Cobb, Melanie H.

    2016-01-01

    The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cell growth with its nutritional, hormonal, energy, and stress status. Amino acids are critical regulators of mTORC1 that permit other inputs to mTORC1 activity. However, the roles of individual amino acids and their interactions in mTORC1 activation are not well understood. Here we demonstrate that activation of mTORC1 by amino acids includes two discrete and separable steps: priming and activation. Sensitizing mTORC1 activation by priming amino acids is a prerequisite for subsequent stimulation of mTORC1 by activating amino acids. Priming is achieved by a group of amino acids that includes l-asparagine, l-glutamine, l-threonine, l-arginine, l-glycine, l-proline, l-serine, l-alanine, and l-glutamic acid. The group of activating amino acids is dominated by l-leucine but also includes l-methionine, l-isoleucine, and l-valine. l-Cysteine predominantly inhibits priming but not the activating step. Priming and activating steps differ in their requirements for amino acid concentration and duration of treatment. Priming and activating amino acids use mechanisms that are distinct both from each other and from growth factor signaling. Neither step requires intact tuberous sclerosis complex of proteins to activate mTORC1. Concerted action of priming and activating amino acids is required to localize mTORC1 to lysosomes and achieve its activation. PMID:27587390

  10. Regulation of the ITGA2 gene by epigenetic mechanisms in prostate cancer.

    Science.gov (United States)

    Chin, Suyin Paulynn; Marthick, James R; West, Alison C; Short, Annabel K; Chuckowree, Jyoti; Polanowski, Andrea M; Thomson, Russell J; Holloway, Adele F; Dickinson, Joanne L

    2015-05-01

    Integrin alpha2 beta1 (α2 β1 ) plays an integral role in tumour cell invasion, metastasis and angiogenesis, and altered expression of the receptor has been linked to tumour prognosis in several solid tumours. However, the relationship is complex, with both increased and decreased expression associated with different stages of tumour metastases in several tumour types. The ITGA2 gene, which codes for the α2 subunit, was examined to investigate whether a large CpG island associated with its promoter region is involved in the differential expression of ITGA2 observed in prostate cancer. Bisulphite sequencing of the ITGA2 promoter was used to assess methylation in formalin-fixed paraffin-embedded (FFPE) prostate tumour specimens and prostate cancer cell lines, PC3, 22Rv1 and LNCaP. Changes in ITGA2 mRNA expression were measured using quantitative PCR. ITGA2 functionality was interrogated using cell migration scratch assays and siRNA knockdown experiments. Bisulphite sequencing revealed strikingly decreased methylation at key CpG sites within the promoter of tumour samples, when compared with normal prostate tissue. Altered methylation of this CpG island is also associated with differences in expression in the non-invasive LNCaP, and the highly metastatic PC3 and 22Rv1 prostate cancer cell lines. Further bisulphite sequencing confirmed that selected CpGs were highly methylated in LNCaP cells, whilst only low levels of methylation were observed in PC3 and 22Rv1 cells, correlating with ITGA2 transcript levels. Examination of the increased expression of ITGA2 was shown to influence migratory potential via scratch assay in PC3, 22Rv1 and LNCaP cells, and was confirmed by siRNA knockdown experiments. Taken together, our data supports the assertion that epigenetic modification of the ITGA2 promoter is a mechanism by which ITGA2 expression is regulated. © 2015 Wiley Periodicals, Inc.

  11. Slingshot mechanism for clusters: Gas density regulates star density in the Orion Nebula Cluster (M42)

    Science.gov (United States)

    Stutz, Amelia M.

    2018-02-01

    We characterize the stellar and gas volume density, potential, and gravitational field profiles in the central ∼0.5 pc of the Orion Nebula Cluster (ONC), the nearest embedded star cluster (or rather, protocluster) hosting massive star formation available for detailed observational scrutiny. We find that the stellar volume density is well characterized by a Plummer profile ρstars(r) = 5755 M⊙ pc- 3 (1 + (r/a)2)- 5/2, where a = 0.36 pc. The gas density follows a cylindrical power law ρgas(R) = 25.9 M⊙ pc- 3 (R/pc)- 1.775. The stellar density profile dominates over the gas density profile inside r ∼ 1 pc. The gravitational field is gas-dominated at all radii, but the contribution to the total field by the stars is nearly equal to that of the gas at r ∼ a. This fact alone demonstrates that the protocluster cannot be considered a gas-free system or a virialized system dominated by its own gravity. The stellar protocluster core is dynamically young, with an age of ∼2-3 Myr, a 1D velocity dispersion of σobs = 2.6 km s-1, and a crossing time of ∼0.55 Myr. This time-scale is almost identical to the gas filament oscillation time-scale estimated recently by Stutz & Gould. This provides strong evidence that the protocluster structure is regulated by the gas filament. The protocluster structure may be set by tidal forces due to the oscillating filamentary gas potential. Such forces could naturally suppress low density stellar structures on scales ≳ a. The analysis presented here leads to a new suggestion that clusters form by an analogue of the 'slingshot mechanism' previously proposed for stars.

  12. Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB–mediated mechanism

    Science.gov (United States)

    Qiu, Jia; Thapaliya, Samjhana; Runkana, Ashok; Yang, Yu; Tsien, Cynthia; Mohan, Maradumane L.; Narayanan, Arvind; Eghtesad, Bijan; Mozdziak, Paul E.; McDonald, Christine; Stark, George R.; Welle, Stephen; Naga Prasad, Sathyamangla V.; Dasarathy, Srinivasan

    2013-01-01

    Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea. We observed elevated levels of ammonia in both plasma samples and skeletal muscle biopsies from cirrhotic patients compared with healthy controls. Furthermore, skeletal muscle from cirrhotics had increased expression of myostatin, a known inhibitor of skeletal muscle accretion and growth. In vivo studies in mice showed that hyperammonemia reduced muscle mass and strength and increased myostatin expression in wild-type compared with postdevelopmental myostatin knockout mice. We postulated that hyperammonemia is an underlying link between hepatic dysfunction in cirrhosis and skeletal muscle loss. Therefore, murine C2C12 myotubes were treated with ammonium acetate resulting in intracellular concentrations similar to those in cirrhotic muscle. In this system, we demonstrate that hyperammonemia stimulated myostatin expression in a NF-κB–dependent manner. This finding was also observed in primary murine muscle cell cultures. Hyperammonemia triggered activation of IκB kinase, NF-κB nuclear translocation, binding of the NF-κB p65 subunit to specific sites within the myostatin promoter, and stimulation of myostatin gene transcription. Pharmacologic inhibition or gene silencing of NF-κB abolished myostatin up-regulation under conditions of hyperammonemia. Our work provides unique insights into hyperammonemia-induced myostatin expression and suggests a mechanism by which sarcopenia develops in cirrhotic patients. PMID:24145431

  13. Isotope Exchange: a Potential Mechanism Regulating the Natural and Anthropogenic Pb Isotope Budget in Coastal Waters

    Science.gov (United States)

    Chen, M.; Boyle, E. A.; Zurbrick, C.; Carrasco, G. G.; Switzer, A.; Zhao, N.

    2016-02-01

    Two independent studies on anthropogenic Pb and Pb isotopes in coastal corals from the northern Arabian Gulf and the Singapore Straits have shown an isotopic excursion where the main Pb sources discharging to the water move to more crustal-like values, indicating that the Pb in coastal waters might exchange isotopically with crustal particulates without propotional change in concentration. To investigate this issue, Pb isotope exchange is assessed through a closed-system exchange experiment using estuarine waters collected at the Johor River mouth (discharging to the Singapore Straits). During the experiment, a known amount of NBS-981 (206Pb/207Pb=1.093) was spiked into the unfiltered Johor water (dissolved 206Pb/207Pb = 1.199) and the changing isotopic composition of the dissolved Pb was monitored. Shortly after the spike addition, dissolved Pb exhibited 206Pb/207Pb=1.178, reflecting the influence of the spike. Within the following few days, the 206Pb/207Pb in the water increased to >1.190 with limited changes of the dissolved Pb concentration. The observations in closed-system experiment agree with the isotope difference between Singapore aerosol and seawater in our 2-year-long field observations. The kinetics of isotope exchange were assessed using a simple model, which reproduced >70% of the observed Pb isotope variance. Both the close-system experiment and field measurements imply that isotope exchange can be an important mechanism for regulating the Pb and Pb isotopes in coastal waters. Investigations on the distribution of Pb and Pb isotope in estuaries and coastal waters should further assess the role of isotope exchange in ocean Pb chemistry.

  14. Mechanisms of hyposmotic volume regulation in isolated nematocytes of the anthozoan Aiptasia diaphana.

    Science.gov (United States)

    Marino, Angela; Morabito, Rossana; La Spada, Giuseppina; Adragna, Norma C; Lauf, Peter K

    2010-01-01

    The nature and role of potassium (K) and water transport mediating hyposmotically-induced regulatory volume decrease (RVD) were studied in nematocytes dissociated with 605 mM thiocyanate from acontia of the Anthozoan Aiptasia diaphana. Cell volume and hence RVD were calculated from the inverse ratios of the cross sectional areas of nematocytes (A/A(o)) measured before (A(o)) and after (A) challenge with 65% artificial sea water (ASW). To distinguish between K channels and K-Cl cotransport (KCC), external sodium (Na) and chloride (Cl) were replaced by K and nitrate (NO(3)), respectively. Inhibitors were added to identify K channels (barium, Ba), and putative kinase (N-ethylmaleimide, NEM) and phosphatase (okadaic acid, OA) regulation of KCC. In 65% NaCl ASW, nematocytes displayed a biphasic change in A/A(o), peaking within 4 min due to osmotic water entry and thereafter declining within 6 min due to RVD. Changing NaCl to KCl or NaNO(3) ASW did not affect the osmotic phase but attenuated RVD, consistent with K channel and KCC mechanisms. Ba (3 mM) inhibited RVD. NEM and OA, applied separately, inhibited the osmotic phase and muted RVD suggesting primary action on water transport (aquaporins). NEM and OA together reduced the peak A/A(o) ratio during the osmotic phase whereas RVD was inhibited when OA preceded NEM. Thus, both K channels and KCC partake in the nematocyte RVD, the extent of which is determined by functional thiols and dephosphorylation of putative aquaporins facilitating the preceding osmotic water shifts. Copyright 2010 S. Karger AG, Basel.

  15. Expansion joints for LMFBR

    Energy Technology Data Exchange (ETDEWEB)

    Dzenus, M.; Hundhausen, W.; Jansing, W.

    1979-10-15

    This discourse recounts efforts put into the SNR-2 project; specifically the development of compensation devices. The various prototypes of these compensation devices are described and the state of development reviewed. The expansion joints were developed on the basis of specific design criteria whereby differentiation is made between expansion joints of small and large nominal diameter. Expansion joints for installation in the sodium-filled primary piping are equipped with safety bellows in addition to the actual working bellows.

  16. Discovery of a resting stage in the harmful, brown-tide-causing pelagophyte, Aureoumbra lagunensis: a mechanism potentially facilitating recurrent blooms and geographic expansion.

    Science.gov (United States)

    Kang, Yoonja; Tang, Ying-Zhong; Taylor, Gordon T; Gobler, Christopher J

    2017-02-01

    To date, the life stages of pelagophytes have been poorly described. This study describes the ability of Aureoumbra lagunensis to enter a resting stage in response to environmental stressors including high temperature, nutrient depletion, and darkness as well as their ability to revert from resting cells back to vegetative cells after exposure to optimal light, temperature, and nutrient conditions. Resting cells became round in shape and larger in size, filled with red accumulation bodies, had smaller and fewer plastids, more vacuolar space, contained lower concentrations of chl a and RNA, displayed reduced photosynthetic efficiency, and lower respiration rates relative to vegetative cells. Analysis of vegetative and resting cells using Raman microspectrometry indicated resting cells were enriched in sterols within red accumulation bodies and were depleted in pigments relative to vegetative cells. Upon reverting to vegetative cells, cells increased their chl a content, photosynthetic efficiency, respiration rate, and growth rate and lost accumulation bodies as they became smaller. The time required for resting cells to resume vegetative growth was proportional to both the duration and temperature of dark storage, possibly due to higher metabolic demands on stored energy (sterols) reserves during longer period of storage and/or storage at higher temperature (20°C vs. 10°C). Resting cells kept in the dark at 10°C for 7 months readily reverted back to vegetative cells when transferred to optimal conditions. Thus, the ability of Aureoumbra to form a resting stage likely enables them to form annual blooms within subtropic ecosystems, resist temperature extremes, and may facilitate geographic expansion via anthropogenic transport. © 2016 Phycological Society of America.

  17. Accounting regulation and enforcement mechanisms: the auditor's role in the portuguese listed groups

    Directory of Open Access Journals (Sweden)

    Ana Fialho Silva

    2003-10-01

    Full Text Available The purpose of this article is to examine the extent to which the clauses for the exclusion of subsidiaries from consolidation are used, in order to assess the degree of compliance with accounting regulation and the effectiveness of the statutory auditor as an enforcement mechanism in case of observed non-compliance. The presentation of consolidated financial statements by Portuguese companies was not regulated in detail before the implementation of the EU's Seventh Directive and the general obligation to prepare consolidated accounts had not applied to Portuguese companies until 1991. Regulators have been responsible for the endorsement of accounting rules and managers are responsible for the information disclosed by Portuguese companies regarding the scope of group accounting. In practice, the scope of consolidation depends on the judgment of makers and managers of the parent company. Auditors may play a key role in the process of guaranteeing the correct application of prevailing standards and thus encompassing the enforcement of accounting regulations and contributing to the quality of disclosed information. Our sample includes the consolidated financial statements of all the Portuguese companies listed in the Lisbon Stock Exchange on December 31st for the year 1999, to which the Official Accounting Plan is applicable. Our conclusion is that diversity exists among accounting practices regarding the adopted group concept and the use of the clauses for excluding subsidiaries from consolidation. The role of the auditors as enforcement actors seems to be minor, as we did find few qualifications in their audit reports in the cases of observed non-compliance with the accounting regulation.Em Portugal não existiu regulamentação sobre informação consolidada até 1991, quando foi publicado o Decreto-Lei nº 238/91, de 2 de Julho, que transpôs para o ordenamento jurídico-contábil português as normas de consolidação de contas estabelecidas

  18. Topical thermal therapy with hot packs suppresses physical inactivity-induced mechanical hyperalgesia and up-regulation of NGF.

    Science.gov (United States)

    Nakagawa, Tatsuki; Hiraga, Shin-Ichiro; Mizumura, Kazue; Hori, Kiyomi; Ozaki, Noriyuki; Koeda, Tomoko

    2017-10-12

    We focused on the analgesic effect of hot packs for mechanical hyperalgesia in physically inactive rats. Male Wistar rats were randomly divided into four groups: control, physical inactivity (PI), PI + sham treatment (PI + sham), and PI + hot pack treatment (PI + hot pack) groups. Physical inactivity rats wore casts on both hind limbs in full plantar flexed position for 4 weeks. Hot pack treatment was performed for 20 min a day, 5 days a week. Although mechanical hyperalgesia and the up-regulation of NGF in the plantar skin and gastrocnemius muscle were observed in the PI and the PI + sham groups, these changes were significantly suppressed in the PI + hot pack group. The present results clearly demonstrated that hot pack treatment was effective in reducing physical inactivity-induced mechanical hyperalgesia and up-regulation of NGF in plantar skin and gastrocnemius muscle.

  19. VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis?

    International Nuclear Information System (INIS)

    Yao, Y.-G; Duh, Elia J.

    2004-01-01

    The Down syndrome critical region 1 (DSCR1) gene (also known as MCIP1, Adapt78) encodes a regulatory protein that binds to calcineurin catalytic A subunit and acts as a regulator of the calcineurin-mediated signaling pathway. We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-α, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca 2+ chelator. We hypothesized that the up-regulation of DSCR1 gene expression in endothelial cells could act as an endogenous feedback inhibitor for angiogenesis by regulating the calcineurin-NFAT signaling pathway. Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators. Our results indicate that DSCR1 up-regulation may represent a potential molecular mechanism underlying the regulation of angiogenic genes activated by the calcineurin-NFAT signaling pathway in endothelial cells

  20. Guidelines for meeting emission regulations for rotating machinery with mechanical seals

    Science.gov (United States)

    Mechanical seals have played a major role during many years in minimizing emissions to atmosphere in rotating machinery. A review is presented of the continuing innovations and new technologies to improve mechanical seal performance in terms of emissions.

  1. Use of expansion joints in power stations

    International Nuclear Information System (INIS)

    Birker; Rommerswinkel.

    1976-01-01

    The paper discusses the mode of action of different systems of expansion joints. Special regard is given to the problems of expansion of pipelines of high rated diameter as employed in today's large power plant turbines. Due to the limited space available, the important role of the spring rate of the bellows for the reaction forces and moments acting on the connection points is pointed out. Apart from this details are given on the fabrication and materials selection of expansion joint bellows, and problems are discussed which arise in connection with the mechanical or hydraulic deformation of bellows with one or more walls. The non-destructive methods now in use for the testing of expansion pipe joints are mentioned along with experiments to test their behaviour under changing loads. The paper concludes on some remarks concerning proper transport, storage and installation of expansion pipe joints. (orig./AK) [de

  2. Convergence of mayer expansions

    International Nuclear Information System (INIS)

    Brydges, D.C.

    1986-01-01

    The tree graph bound of Battle and Federbush is extended and used to provide a simple criterion for the convergence of (iterated) Mayer expansions. As an application estimates on the radius of convergence of the Mayer expansion for the two-dimensional Yukawa gas (nonstable interaction) are obtained

  3. Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms

    Directory of Open Access Journals (Sweden)

    Rodrigo eEspaña

    2012-08-01

    Full Text Available The hypocretins/orexins are comprised of two neuroexcitatory peptides that are synthesized exclusively within a circumscribed region of the lateral hypothalamus. These peptides project widely throughout the brain and interact with a variety of regions involved in the regulation of arousal-related processes including those associated with motivated behavior. The current review focuses on emerging evidence indicating that the hypocretins influence reward and reinforcement processing via actions on the mesolimbic dopamine system. We discuss contemporary perspectives of hypocretin regulation of mesolimbic dopamine signaling in both drug free and drug states, as well as hypocretin regulation of behavioral responses to drugs of abuse, particularly as it relates to cocaine.

  4. Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms

    Science.gov (United States)

    Calipari, Erin S.; España, Rodrigo A.

    2012-01-01

    The hypocretins/orexins are comprised of two neuroexcitatory peptides that are synthesized exclusively within a circumscribed region of the lateral hypothalamus. These peptides project widely throughout the brain and interact with a variety of regions involved in the regulation of arousal-related processes including those associated with motivated behavior. The current review focuses on emerging evidence indicating that the hypocretins influence reward and reinforcement processing via actions on the mesolimbic dopamine system. We discuss contemporary perspectives of hypocretin regulation of mesolimbic dopamine signaling in both drug free and drug states, as well as hypocretin regulation of behavioral responses to drugs of abuse, particularly as it relates to cocaine. PMID:22933994

  5. Negative thermal expansion materials: technological key for control of thermal expansion.

    Science.gov (United States)

    Takenaka, Koshi

    2012-02-01

    Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE) materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over -30 ppm K -1 . Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade.

  6. Negative thermal expansion materials: technological key for control of thermal expansion

    Directory of Open Access Journals (Sweden)

    Koshi Takenaka

    2012-01-01

    Full Text Available Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over −30 ppm K−1. Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade.

  7. Negative thermal expansion materials: technological key for control of thermal expansion

    International Nuclear Information System (INIS)

    Takenaka, Koshi

    2012-01-01

    Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE) materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over −30 ppm K −1 . Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade. (topical review)

  8. Mechanisms and pathways of innate immune activation and regulation in health and cancer.

    Science.gov (United States)

    Cui, Jun; Chen, Yongjun; Wang, Helen Y; Wang, Rong-Fu

    2014-01-01

    Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer.

  9. Application of a Multi-Scale form of Terzaghi’s Effective Stress Principle for Unsaturated Expansive Clays to Simulate Hydro-Mechanical Behavior During Hydration

    Directory of Open Access Journals (Sweden)

    Mainka Julia

    2016-01-01

    Full Text Available Our recently developed multi-scale form of Terzaghi’s effective stress principle for unsaturated swelling clays that was rigorously derived by periodic homogenization starting from micro- and nano-mechanical analyses is applied to numerically simulate one-dimensional swelling pressure tests of compacted bentonites during hydration. The total macroscopic stress captures the coupling between disjoining forces at the nanoscopic scale of clay platelets and capillary effects at the microscopic scale of clay aggregates over the entire water content range. The numerical results allow to draw conclusions on the water transfer mechanism between inter- and intra-aggregate pores during hydration and consequently on the evolution of the external swelling pressure resulting from the competition between capillary and disjoining forces. In addition, such application highlights the abilities and the limits of the electrical double-layer theory to compute the disjoining pressure in the nano-pores. For large platelet distances, in the range of osmotic swelling, the nature of the disjoining pressure is electro-chemical and can be computed from Poisson-Boltzmann theory. Conversely, at small distances, in the crystalline swelling, a solvation component has to be added to account for the molecular nature of the solvent. As a first improvement of the nano-scale description the solvent is treated as a hard sphere fluid using Density Functional Theory.

  10. Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms.

    Science.gov (United States)

    Enculescu, Mihaela; Metzendorf, Christoph; Sparla, Richard; Hahnel, Maximilian; Bode, Johannes; Muckenthaler, Martina U; Legewie, Stefan

    2017-01-01

    Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to ferroportin and triggers its degradation. The relative importance of individual ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular ferroportin transcription, and not by hepcidin-dependent ferroportin protein destabilization. In contrast, ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional

  11. Analysis and synthesis of a system for optimal automatic regulation of the process of mechanical cutting by a combine

    Energy Technology Data Exchange (ETDEWEB)

    Pop, E.; Coroescu, T.; Poanta, A.; Pop, M.

    1978-01-01

    Uncontrollable dynamic operating regime of a combine has a negative effect. A consequence of the uncontrolled change in productivity and rate during cutting is total decrease in productivity. The cutters of the cutting mechanism are prematurely worn out. The quality of the coal decreases. Complications with combine control reduce productivity. The motor is exposed to the maximum loads, its service life decreases, and there is an inefficient consumption of electricity. Studies of the optimal automatic regulation of the cutting process were made by the method of modeled analysis on digital and analog machines. The method uses an electronic-automatic device with integrating circuit of domestic production (A-741, A-723). This device controls and regulates the current parameters of the acting motor. The device includes primarily an element of information type of the Hall TH traductor type, the regulating element is an electronic relay, electronic power distributor, etc.

  12. Circuits regulating pleasure and happiness:the evolution of reward-seeking and misery-fleeing behavioral mechanisms in vertebrates

    Directory of Open Access Journals (Sweden)

    Anton J.M. Loonen

    2015-10-01

    Full Text Available The very first free-moving animals in the oceans over 540 million years ago must have been able to obtain food, territory and shelter, as well as reproduce. Therefore, they would have needed regulatory mechanisms to induce movements enabling achievement of these prerequisites for survival. It can be useful to consider these mechanisms in primitive chordates, which represent our earliest ancestors, to develop hypotheses addressing how these essential parts of human behavior are regulated and relate to more sophisticated behavioral manifestations such as mood. An animal comparable to lampreys was the earliest known vertebrate with a modern forebrain consisting of old and new cortical parts. Lampreys have a separate dorsal pallium, the forerunner of the most recently developed part of the cerebral cortex. In addition, the lamprey extrapyramidal system, which regulates movement, is modern. However, in lampreys and their putative forerunners, the hagfishes, the striatum, which is the input part of this extrapyramidal system, probably corresponds to the human centromedial amygdala, which in higher vertebrates is part of a system mediating fear and anxiety. Both animals have well-developed nuclear habenulae, which are involved in several critical behaviors; in lampreys this system regulates the reward system that reinforces appetitive-seeking behavior or the avoidance system that reinforces flight behavior resulting from negative inputs. Lampreys also have a distinct glutamatergic nucleus, the so-called habenula-projection globus pallidus, which receives input from glutamatergic and GABAergic signals and gives output to the lateral habenula. Via this route, this nucleus influences midbrain monoaminergic nuclei and regulates the food acquisition system. These various structures involved in motor regulation in the lampreys may be conserved in humans and include two complementary mechanisms for reward reinforcement and avoidance behaviors. The first

  13. Circuits regulating pleasure and happiness: the evolution of reward-seeking and misery-fleeing behavioral mechanisms in vertebrates.

    Science.gov (United States)

    Loonen, Anton J M; Ivanova, Svetlana A

    2015-01-01

    The very first free-moving animals in the oceans over 540 million years ago must have been able to obtain food, territory, and shelter, as well as reproduce. Therefore, they would have needed regulatory mechanisms to induce movements enabling achievement of these prerequisites for survival. It can be useful to consider these mechanisms in primitive chordates, which represent our earliest ancestors, to develop hypotheses addressing how these essential parts of human behavior are regulated and relate to more sophisticated behavioral manifestations such as mood. An animal comparable to lampreys was the earliest known vertebrate with a modern forebrain consisting of old and new cortical parts. Lampreys have a separate dorsal pallium, the forerunner of the most recently developed part of the cerebral cortex. In addition, the lamprey extrapyramidal system (EPS), which regulates movement, is modern. However, in lampreys and their putative forerunners, the hagfishes, the striatum, which is the input part of this EPS, probably corresponds to the human centromedial amygdala, which in higher vertebrates is part of a system mediating fear and anxiety. Both animals have well-developed nuclear habenulae, which are involved in several critical behaviors; in lampreys this system regulates the reward system that reinforces appetitive-seeking behavior or the avoidance system that reinforces flight behavior resulting from negative inputs. Lampreys also have a distinct glutamatergic nucleus, the so-called habenula-projection globus pallidus, which receives input from glutamatergic and GABAergic signals and gives output to the lateral habenula. Via this route, this nucleus influences midbrain monoaminergic nuclei and regulates the food acquisition system. These various structures involved in motor regulation in the lampreys may be conserved in humans and include two complementary mechanisms for reward reinforcement and avoidance behaviors. The first system is associated with

  14. Constant pH Accelerated Molecular Dynamics Investigation of the pH Regulation Mechanism of Dinoflagellate Luciferase.

    Science.gov (United States)

    Donnan, Patrick H; Ngo, Phong D; Mansoorabadi, Steven O

    2018-01-23

    The bioluminescence reaction in dinoflagellates involves the oxidation of an open-chain tetrapyrrole by the enzyme dinoflagellate luciferase (LCF). The activity of LCF is tightly regulated by pH, where the enzyme is essentially inactive at pH ∼8 and optimally active at pH ∼6. Little is known about the mechanism of LCF or the structure of the active form of the enzyme, although it has been proposed that several intramolecularly conserved histidine residues in the N-terminal region are important for the pH regulation mechanism. Here, constant pH accelerated molecular dynamics was employed to gain insight into the conformational activation of LCF induced by acidification.

  15. Regulation

    International Nuclear Information System (INIS)

    Ballereau, P.

    1999-01-01

    The different regulations relative to nuclear energy since the first of January 1999 are given here. Two points deserve to be noticed: the decree of the third august 1999 authorizing the national Agency for the radioactive waste management to install and exploit on the commune of Bures (Meuse) an underground laboratory destined to study the deep geological formations where could be stored the radioactive waste. The second point is about the uranium residues and the waste notion. The judgment of the administrative tribunal of Limoges ( 9. july 1998) forbidding the exploitation of a storage installation of depleted uranium considered as final waste and qualifying it as an industrial waste storage facility has been annulled bu the Court of Appeal. It stipulated that, according to the law number 75663 of the 15. july 1965, no criteria below can be applied to depleted uranium: production residue (possibility of an ulterior enrichment), abandonment of a personal property or simple intention to do it ( future use aimed in the authorization request made in the Prefecture). This judgment has devoted the primacy of the waste notion on this one of final waste. (N.C.)

  16. Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis

    OpenAIRE

    LaRusch, Jessica; Jung, Jinsei; General, Ignacio J.; Lewis, Michele D.; Park, Hyun Woo; Brand, Randall E.; Gelrud, Andres; Anderson, Michelle A.; Banks, Peter A.; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory

    2014-01-01

    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev ) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize tha...

  17. Vinclozolin Exposure in Utero Induces Postpubertal Prostatitis and Reduces Sperm Production via a Reversible Hormone-Regulated Mechanism

    OpenAIRE

    Cowin, Prue A.; Gold, Elspeth; Aleksova, Jasna; O'Bryan, Moira K.; Foster, Paul M. D.; Scott, Hamish S.; Risbridger, Gail P.

    2010-01-01

    Vinclozolin is an endocrine-disrupting chemical (EDC) that binds with high affinity to the androgen receptor (AR) and blocks the action of gonadal hormones on male reproductive organs. An alternative mechanism of action of Vinclozolin involves transgenerational effects on the male reproductive tract. We previously reported in utero Vinclozolin exposure-induced prostatitis (prostate inflammation) in postpubertal rats concurrent with down-regulation of AR and increased nuclear factor-κB activat...

  18. The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin.

    Science.gov (United States)

    Williamson, Danielle M; Elferich, Johannes; Ramakrishnan, Parvathy; Thomas, Gary; Shinde, Ujwal

    2013-06-28

    The proprotein convertase furin requires the pH gradient of the secretory pathway to regulate its multistep, compartment-specific autocatalytic activation. Although His-69 within the furin prodomain serves as the pH sensor that detects transport of the propeptide-enzyme complex to the trans-Golgi network, where it promotes cleavage and release of the inhibitory propeptide, a mechanistic understanding of how His-69 protonation mediates furin activation remains unclear. Here we employ biophysical, biochemical, and computational approaches to elucidate the mechanism underlying the pH-dependent activation of furin. Structural analyses and binding experiments comparing the wild-type furin propeptide with a nonprotonatable His-69 → Leu mutant that blocks furin activation in vivo revealed protonation of His-69 reduces both the thermodynamic stability of the propeptide as well as its affinity for furin at pH 6.0. Structural modeling combined with mathematical modeling and molecular dynamic simulations suggested that His-69 does not directly contribute to the propeptide-enzyme interface but, rather, triggers movement of a loop region in the propeptide that modulates access to the cleavage site and, thus, allows for the tight pH regulation of furin activation. Our work establishes a mechanism by which His-69 functions as a pH sensor that regulates compartment-specific furin activation and provides insights into how other convertases and proteases may regulate their precise spatiotemporal activation.

  19. The Mechanism by Which a Propeptide-encoded pH Sensor Regulates Spatiotemporal Activation of Furin*

    Science.gov (United States)

    Williamson, Danielle M.; Elferich, Johannes; Ramakrishnan, Parvathy; Thomas, Gary; Shinde, Ujwal

    2013-01-01

    The proprotein convertase furin requires the pH gradient of the secretory pathway to regulate its multistep, compartment-specific autocatalytic activation. Although His-69 within the furin prodomain serves as the pH sensor that detects transport of the propeptide-enzyme complex to the trans-Golgi network, where it promotes cleavage and release of the inhibitory propeptide, a mechanistic understanding of how His-69 protonation mediates furin activation remains unclear. Here we employ biophysical, biochemical, and computational approaches to elucidate the mechanism underlying the pH-dependent activation of furin. Structural analyses and binding experiments comparing the wild-type furin propeptide with a nonprotonatable His-69 → Leu mutant that blocks furin activation in vivo revealed protonation of His-69 reduces both the thermodynamic stability of the propeptide as well as its affinity for furin at pH 6.0. Structural modeling combined with mathematical modeling and molecular dynamic simulations suggested that His-69 does not directly contribute to the propeptide-enzyme interface but, rather, triggers movement of a loop region in the propeptide that modulates access to the cleavage site and, thus, allows for the tight pH regulation of furin activation. Our work establishes a mechanism by which His-69 functions as a pH sensor that regulates compartment-specific furin activation and provides insights into how other convertases and proteases may regulate their precise spatiotemporal activation. PMID:23653353

  20. Dynamic simulation of road vehicle door window regulator mechanism of cross arm type

    Science.gov (United States)

    Miklos, I. Zs; Miklos, C.; Alic, C.

    2017-01-01

    The paper presents issues related to the dynamic simulation of a motor-drive operating mechanism of cross arm type, for the manipulation of road vehicle door windows, using Autodesk Inventor Professional software. The dynamic simulation of the mechanism involves a 3D modelling, kinematic coupling, drive motion parameters and external loads, as well as the graphically view of the kinematic and kinetostatic results for the various elements and kinematic couplings of the mechanism, under real operating conditions. Also, based on the results, the analysis of the mechanism components has been carried out using the finite element method.

  1. Non-classical mechanisms of transcriptional regulation by the vitamin D receptor: insights into calcium homeostasis, immune system regulation and cancer chemoprevention.

    Science.gov (United States)

    Dimitrov, Vassil; Salehi-Tabar, Reyhaneh; An, Beum-Soo; White, John H

    2014-10-01

    Hormonal 1,25-dihydroxyvitamin D [1,25(OH)2D] signals through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor. Gene expression profiling studies have revealed that 1,25(OH)2D signaling through the VDR can lead to activation or repression of target gene transcription in roughly equal proportions. Classically, transcriptional regulation by the VDR, similar to other nuclear receptors, has been characterized by its capacity to recognize high affinity cognate vitamin D response elements (VDREs), located in the regulatory regions of target genes. Several biochemical studies revealed that the VDRE-bound receptor recruits a series of coregulatory proteins, leading to transactivation of adjacent target genes. However, genome-wide and other analyses of VDR binding have revealed that a subset of VDR binding sites does not contain VDREs, and that VDREs are not associated with transcriptionally repressed VDR target genes. Work over the last ∼20 years and in particular recent findings have revealed a diverse array of mechanisms by which VDR can form complexes with several other classes of transcriptional activators, leading to repression of gene transcription. Moreover, these efforts have led to several insights into the molecular basis for the physiological regulation of calcium homeostasis, immune system function and cancer chemoprevention by 1,25(OH)2D/VDR signaling. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Hard Work in Soft Regulation: A Discussion of the Social Mechanisms in OHS Management Standards and Possible Dilemmas in the Regulation of Psychosocial Work Environment

    Directory of Open Access Journals (Sweden)

    Pernille Hohnen

    2014-09-01

    Full Text Available Certified occupational health and safety (OHS management systems have become a global instrument in regulation of the work environment. However, their actual impact on OHS—in particular on softer psychosocial issues in the work environment—has been questioned. The most important standard of OHS management is OHSAS 18001, which has recently been supplemented with a British publically available guideline (PAS 1010 focusing specifically on psychosocial risk management. On the basis of the international literature on management standards, the present paper analyses OHSAS 18001 and PAS 1010 in order to understand the mechanism by which they work. The paper takes a social constructionist approach conceptualizing standards and their expected mechanisms as socially constructed—based on a particular kind of knowledge and logic—although they are presented as objective. Such a constructionist approach also emphasizes how standards transform specific work environment problems into generic procedures that can be audited. In the case of OHS standards, both the work environment in general and the psychosocial risks in particular are transformed into simple monocausal auditable relations whereby the complexity of psychosocial work environment issues seems to disappear. The new PAS 1010 guideline, which is particularly focusing on regulation of the psychosocial work environment, only partly succeeds in solving these shortcomings of OHSAS 18001.

  3. An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics.

    Science.gov (United States)

    Sheldon, Claire A; Kwon, Young Joon; Liu, Grant T; McCormack, Shana E

    2015-02-01

    Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.

  4. Raf kinase inhibitory protein function is regulated via a flexible pocket and novel phosphorylation-dependent mechanism.

    Science.gov (United States)

    Granovsky, Alexey E; Clark, Matthew C; McElheny, Dan; Heil, Gary; Hong, Jia; Liu, Xuedong; Kim, Youngchang; Joachimiak, Grazyna; Joachimiak, Andrzej; Koide, Shohei; Rosner, Marsha Rich

    2009-03-01

    Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics.

  5. Spatial Linkage and Urban Expansion: AN Urban Agglomeration View

    Science.gov (United States)

    Jiao, L. M.; Tang, X.; Liu, X. P.

    2017-09-01

    Urban expansion displays different characteristics in each period. From the perspective of the urban agglomeration, studying the spatial and temporal characteristics of urban expansion plays an important role in understanding the complex relationship between urban expansion and network structure of urban agglomeration. We analyze urban expansion in the Yangtze River Delta Urban Agglomeration (YRD) through accessibility to and spatial interaction intensity from core cities as well as accessibility of road network. Results show that: (1) Correlation between urban expansion intensity and spatial indicators such as location and space syntax variables is remarkable and positive, while it decreases after rapid expansion. (2) Urban expansion velocity displays a positive correlation with spatial indicators mentioned above in the first (1980-1990) and second (1990-2000) period. However, it exhibits a negative relationship in the third period (2000-2010), i.e., cities located in the periphery of urban agglomeration developing more quickly. Consequently, the hypothesis of convergence of urban expansion in rapid expansion stage is put forward. (3) Results of Zipf's law and Gibrat's law show urban expansion in YRD displays a convergent trend in rapid expansion stage, small and medium-sized cities growing faster. This study shows that spatial linkage plays an important but evolving role in urban expansion within the urban agglomeration. In addition, it serves as a reference to the planning of Yangtze River Delta Urban Agglomeration and regulation of urban expansion of other urban agglomerations.

  6. A pedagogical approach to the Magnus expansion

    International Nuclear Information System (INIS)

    Blanes, S; Casas, F; Oteo, J A; Ros, J

    2010-01-01

    Time-dependent perturbation theory as a tool to compute approximate solutions of the Schroedinger equation does not preserve unitarity. Here we present, in a simple way, how the Magnus expansion (also known as exponential perturbation theory) provides such unitary approximate solutions. The purpose is to illustrate the importance and consequences of such a property. We suggest that the Magnus expansion may be introduced to students in advanced courses of quantum mechanics.

  7. Cyclic Mechanical Stretch Up-regulates Hepatoma-Derived Growth Factor Expression in Cultured Rat Aortic Smooth Muscle Cells.

    Science.gov (United States)

    Kao, Ying-Hsien; Chen, Po-Han; Sun, Cheuk-Kwan; Chang, Yo-Chen; Lin, Yu-Chun; Tsai, Ming-Shian; Lee, Po-Huang; Cheng, Cheng-I

    2018-02-21

    Hepatoma-derived growth factor (HDGF) is a potent mitogen for vascular smooth muscle cells (SMCs) during embryogenesis and injury repair of vessel walls. Whether mechanical stimuli modulate HDGF expression remains unknown. This study aimed at investigating whether cyclic mechanical stretch plays a regulatory role in HDGF expression and regenerative cytokine production in aortic SMCs. A SMC cell line was grown on a silicone-based elastomer chamber with extracellular matrix coatings (either type I collagen or fibronectin) and received cyclic and uni-axial mechanical stretches with 10% deformation at frequency 1 Hz. Morphological observation showed that fibronectin coating provided better cell adhesion and spreading and that consecutive 6 hours of cyclic mechanical stretch remarkably induced reorientation and realignment of SMCs. Western blotting detection demonstrated that continuous mechanical stimuli elicited up-regulation of HDGF and PCNA, a cell proliferative marker. Signal kinetic profiling study indicated that cyclic mechanical stretch induced signaling activity in RhoA/ROCK and PI3K/Akt cascades. Kinase inhibition study further showed that blockade of PI3K activity suppressed the stretch-induced TNF-a, whereas RhoA/ROCK inhibition significantly blunted the IL-6 production and HDGF over-expression. Moreover, siRNA-mediated HDGF gene silencing significantly suppressed constitutive expression of IL-6, but not TNF-α, in SMCs. These findings support the role of HDGF in maintaining vascular expression of IL-6, which has been regarded a crucial regenerative factor for acute vascular injury. In conclusion, cyclic mechanical stretch may maintain constitutive expression of HDGF in vascular walls and be regarded an important biophysical regulator in vascular regeneration. ©2018 The Author(s).

  8. Regulation of electricity distribution in Spain. Principles and mechanisms for distribution

    International Nuclear Information System (INIS)

    Gomez San Roman, T.

    2007-01-01

    First, a conceptual framework for electricity network regulation is presented. In the second part, this paper reviews the current situation of electricity distribution regulation in Spain highlighting its main shortcomings. Finally, some guidelines for the design of a new remuneration model for each distribution company are proposed. This new regulatory model will increase efficiency, promoting the required investment for improving quality of supply and reducing energy losses. This model is based on two new regulatory tools: regulatory accounting and network reference models. (Author) 15 refs

  9. Controlled Thermal Expansion Alloys

    Data.gov (United States)

    National Aeronautics and Space Administration — There has always been a need for controlled thermal expansion alloys suitable for mounting optics and detectors in spacecraft applications.  These alloys help...

  10. Cell signaling mechanisms and metabolic regulation of germination and dormancy in barley seeds

    Directory of Open Access Journals (Sweden)

    Zhenguo Ma

    2017-12-01

    Full Text Available During germination of barley (Hordeum vulgare L. seeds, important morphological and physiological changes take place, including development of organs and tissues and activation of metabolic pathways. Germination and dormancy of seeds are regulated by abscisic acid, gibberellins, reactive oxygen species (ROS, reactive nitrogen species (RNS and several other factors. Activities of ascorbate–glutathione cycle enzymes, responsible for scavenging ROS, strongly increase. Catalase and superoxide dismutase activities, also scavenging ROS, decrease at the onset of seed germination and then increase. With the increase in aerobic metabolism after radicle protrusion, the activities of the fermentation enzymes lactate and alcohol dehydrogenase decline rapidly. The RNS-scavenging activity of S-nitrosoglutathione reductase decreases in the course of seed germination, in concert with elevation of nitric oxide production and protein nitrosylation. This activity supports the role of RNS in regulating seed germination. Transcription of various genes at different phases of seed germination exhibits phase-specific changes. During imbibition, genes involved in cell wall metabolism are highly expressed; in the middle phase of seed germination before radicle protrusion, genes involved in amino acid synthesis, protein synthesis, and transport and nucleic acid synthesis are upregulated significantly, and after radicle protrusion, genes involved in photosynthetic metabolism are induced. In summary, signal transduction and metabolic regulation of seed germination involve diverse reactions and complex regulation at different levels of metabolic organization. Keywords: Seed germination, Reactive oxygen species, Reactive nitrogen species, Signal transduction, Gene expression

  11. TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms

    DEFF Research Database (Denmark)

    Rosengren, Thomas; Larsen, Lasse Jonsgaard; Pedersen, Lotte Bang

    2018-01-01

    Primary cilia are sensory organelles that coordinate multiple cellular signaling pathways, including Hedgehog (HH), Wingless/Int (WNT) and Transforming Growth Factor-β (TGF-β) signaling. Similarly, primary cilia have been implicated in regulation of mTOR signaling, in which Tuberous Sclerosis Com...

  12. Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.

    Science.gov (United States)

    Foster, Paul S; Maltby, Steven; Rosenberg, Helene F; Tay, Hock L; Hogan, Simon P; Collison, Adam M; Yang, Ming; Kaiko, Gerard E; Hansbro, Philip M; Kumar, Rakesh K; Mattes, Joerg

    2017-07-01

    In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4 + T-helper type-2 lymphocytes (T H 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T H 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T H 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T H 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T H 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Mechanisms of iron sensing and regulation in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Martínez-Pastor, María Teresa; Perea-García, Ana; Puig, Sergi

    2017-04-01

    Iron is a redox active element that functions as an essential cofactor in multiple metabolic pathways, including respiration, DNA synthesis and translation. While indispensable for eukaryotic life, excess iron can lead to oxidative damage of macromolecules. Therefore, living organisms have developed sophisticated strategies to optimally regulate iron acquisition, storage and utilization in response to fluctuations in environmental iron bioavailability. In the yeast Saccharomyces cerevisiae, transcription factors Aft1/Aft2 and Yap5 regulate iron metabolism in response to low and high iron levels, respectively. In addition to producing and assembling iron cofactors, mitochondrial iron-sulfur (Fe/S) cluster biogenesis has emerged as a central player in iron sensing. A mitochondrial signal derived from Fe/S synthesis is exported and converted into an Fe/S cluster that interacts directly with Aft1/Aft2 and Yap5 proteins to regulate their transcriptional function. Various conserved proteins, such as ABC mitochondrial transporter Atm1 and, for Aft1/Aft2, monothiol glutaredoxins Grx3 and Grx4 are implicated in this iron-signaling pathway. The analysis of a wide range of S. cerevisiae strains of different geographical origins and sources has shown that yeast strains adapted to high iron display growth defects under iron-deficient conditions, and highlighted connections that exist in the response to both opposite conditions. Changes in iron accumulation and gene expression profiles suggest differences in the regulation of iron homeostasis genes.

  14. IDENTIFICATOIN AS A SOCIO-ECONOMIC MECHANISM OF REGULATION OF CONSUMER BEHAVIOR IN THE REGION

    Directory of Open Access Journals (Sweden)

    Nona Gubnelova

    2015-12-01

    Full Text Available This article discusses the concepts of basic types and factors of identification as a result of socialization and social relations. Identified criteria and specific identification of consumer behavior as regulator of material well-being and socio-economic development of the region.

  15. Control mechanisms for battery energy storage system performing primary frequency regulation and self-consumption optimization

    NARCIS (Netherlands)

    Pliatskas Stylianidis, A.

    2016-01-01

    This report contains the design of a model for the integration of a battery energy system in a household level and its use for primary frequency regulation and self-consumption optimization. The main goal of this project was to investigate what are the possible applications and the most suitable for

  16. Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism

    NARCIS (Netherlands)

    Kroes, M.C.W.; Wingen, G.A. van; Wittwer, J.; Mohajeri, M.H.; Kloek, J.; Fernandez, G.S.E.

    2014-01-01

    It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, tryptophan competes with other long-neutral-amino-acids (LNAA) for transport

  17. Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism

    NARCIS (Netherlands)

    Kroes, Marijn C. W.; van Wingen, Guido A.; Wittwer, Jonas; Mohajeri, M. Hasan; Kloek, Joris; Fernández, Guillén

    2014-01-01

    It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, hyptophan competes with other long-neutral-amino-acids (LNAA) for transport across

  18. Fuel Thermal Expansion (FTHEXP)

    International Nuclear Information System (INIS)

    Reymann, G.A.

    1978-07-01

    A model is presented which deals with dimensional changes in LWR fuel pellets caused by changes in temperature. It is capable of dealing with any combination of UO 2 and PuO 2 in solid, liquid or mixed phase states, and includes expansion due to the solid-liquid phase change. The function FTHEXP models fuel thermal expansion as a function of temperature, fraction of PuO 2 , and the fraction of fuel which is molten

  19. Role of Sodium Bicarbonate Cotransporters in Intracellular pH Regulation and Their Regulatory Mechanisms in Human Submandibular Glands.

    Science.gov (United States)

    Namkoong, Eun; Shin, Yong-Hwan; Bae, Jun-Seok; Choi, Seulki; Kim, Minkyoung; Kim, Nahyun; Hwang, Sung-Min; Park, Kyungpyo

    2015-01-01

    Sodium bicarbonate cotransporters (NBCs) are involved in the pH regulation of salivary glands. However, the roles and regulatory mechanisms among different NBC isotypes have not been rigorously evaluated. We investigated the roles of two different types of NBCs, electroneutral (NBCn1) and electrogenic NBC (NBCe1), with respect to pH regulation and regulatory mechanisms using human submandibular glands (hSMGs) and HSG cells. Intracellular pH (pHi) was measured and the pHi recovery rate from cell acidification induced by an NH4Cl pulse was recorded. Subcellular localization and protein phosphorylation were determined using immunohistochemistry and co-immunoprecipitation techniques. We determined that NBCn1 is expressed on the basolateral side of acinar cells and the apical side of duct cells, while NBCe1 is exclusively expressed on the apical membrane of duct cells. The pHi recovery rate in hSMG acinar cells, which only express NBCn1, was not affected by pre-incubation with 5 μM PP2, an Src tyrosine kinase inhibitor. However, in HSG cells, which express both NBCe1 and NBCn1, the pHi recovery rate was inhibited by PP2. The apparent difference in regulatory mechanisms for NBCn1 and NBCe1 was evaluated by artificial overexpression of NBCn1 or NBCe1 in HSG cells, which revealed that the pHi recovery rate was only inhibited by PP2 in cells overexpressing NBCe1. Furthermore, only NBCe1 was significantly phosphorylated and translocated by NH4Cl, which was inhibited by PP2. Our results suggest that both NBCn1 and NBCe1 play a role in pHi regulation in hSMG acinar cells, and also that Src kinase does not regulate the activity of NBCn1.

  20. Role of Sodium Bicarbonate Cotransporters in Intracellular pH Regulation and Their Regulatory Mechanisms in Human Submandibular Glands.

    Directory of Open Access Journals (Sweden)

    Eun Namkoong

    Full Text Available Sodium bicarbonate cotransporters (NBCs are involved in the pH regulation of salivary glands. However, the roles and regulatory mechanisms among different NBC isotypes have not been rigorously evaluated. We investigated the roles of two different types of NBCs, electroneutral (NBCn1 and electrogenic NBC (NBCe1, with respect to pH regulation and regulatory mechanisms using human submandibular glands (hSMGs and HSG cells. Intracellular pH (pHi was measured and the pHi recovery rate from cell acidification induced by an NH4Cl pulse was recorded. Subcellular localization and protein phosphorylation were determined using immunohistochemistry and co-immunoprecipitation techniques. We determined that NBCn1 is expressed on the basolateral side of acinar cells and the apical side of duct cells, while NBCe1 is exclusively expressed on the apical membrane of duct cells. The pHi recovery rate in hSMG acinar cells, which only express NBCn1, was not affected by pre-incubation with 5 μM PP2, an Src tyrosine kinase inhibitor. However, in HSG cells, which express both NBCe1 and NBCn1, the pHi recovery rate was inhibited by PP2. The apparent difference in regulatory mechanisms for NBCn1 and NBCe1 was evaluated by artificial overexpression of NBCn1 or NBCe1 in HSG cells, which revealed that the pHi recovery rate was only inhibited by PP2 in cells overexpressing NBCe1. Furthermore, only NBCe1 was significantly phosphorylated and translocated by NH4Cl, which was inhibited by PP2. Our results suggest that both NBCn1 and NBCe1 play a role in pHi regulation in hSMG acinar cells, and also that Src kinase does not regulate the activity of NBCn1.

  1. Epigenetic Mechanisms of Genomic Imprinting: Common Themes in the Regulation of Imprinted Regions in Mammals, Plants, and Insects

    Directory of Open Access Journals (Sweden)

    William A. MacDonald

    2012-01-01

    Full Text Available Genomic imprinting is a form of epigenetic inheritance whereby the regulation of a gene or chromosomal region is dependent on the sex of the transmitting parent. During gametogenesis, imprinted regions of DNA are differentially marked in accordance to the sex of the parent, resulting in parent-specific expression. While mice are the primary research model used to study genomic imprinting, imprinted regions have been described in a broad variety of organisms, including other mammals, plants, and insects. Each of these organisms employs multiple, interrelated, epigenetic mechanisms to maintain parent-specific expression. While imprinted genes and imprint control regions are often species and locus-specific, the same suites of epigenetic mechanisms are often used to achieve imprinted expression. This review examines some examples of the epigenetic mechanisms responsible for genomic imprinting in mammals, plants, and insects.

  2. [Mechanism and implication of regulation of the pricing of essential medicines in the private pharmaceutical sector in Mali].

    Science.gov (United States)

    Maïga, D; Maïga, S; Maïga, M D

    2010-04-01

    The healthcare and pharmaceutical professions in Mali were privatized in 1985. Privatization led to swift expansion of the private sector and upset the balance that had existed between the public and private sectors. A national pharmaceutical policy did not emerge until a decade later. Its purpose was to promote a system ensuring fair access to essential generic medicines for all. It was hoped that synergy between the two sectors would promote that objective. However, the policy calling for distribution of essential generic medicine through the private sector was not accompanied by an adequate system for pricing. This problem led the government to adopt a price regulation policy to realign market dynamics with public health goals. This experience shows that a sustained effort from public policy makers is necessary to prevail against the professional and business interests that can conflict with the public interest. Analysis of this experience also demonstrates the need to improve, restructure, and control the pharmaceutical industry. The government must continue to play its crucial role in the context of limited resources and inequality between consumers and pharmaceutical companies.

  3. Hyaluronan supplementation as a mechanical regulator of cartilage tissue development under joint-kinematic-mimicking loading.

    Science.gov (United States)

    Wu, Yabin; Stoddart, Martin J; Wuertz-Kozak, Karin; Grad, Sibylle; Alini, Mauro; Ferguson, Stephen J

    2017-08-01

    Articular cartilage plays an essential role in joint lubrication and impact absorption. Through this, the mechanical signals are coupled to the tissue's physiological response. Healthy synovial fluid has been shown to reduce and homogenize the shear stress acting on the cartilage surfaces due to its unique shear-thinning viscosity. As cartilage tissues are sensitive to mechanical changes in articulation, it was hypothesized that replacing the traditional culture medium with a healthy non-Newtonian lubricant could enhance tissue development in a cartilage engineering model, where joint-kinematic-mimicking mechanical loading is applied. Different amounts of hyaluronic acid were added to the culture medium to replicate the viscosities of synovial fluid at different health states. Hyaluronic acid supplementation, especially at a physiologically healthy concentration (2.0 mg ml -1 ), promoted a better preservation of chondrocyte phenotype. The ratio of collagen II to collagen I mRNA was 4.5 times that of the control group, implying better tissue development (however, with no significant difference of measured collagen II content), with a good retention of collagen II and proteoglycan in the mechanically active region. Simulating synovial fluid properties by hyaluronic acid supplementation created a favourable mechanical environment for mechanically loaded constructs. These findings may help in understanding the influence of joint articulation on tissue homeostasis, and moreover, improve methods for functional cartilage tissue engineering. © 2017 The Author(s).

  4. Antidiabetic phospholipid-nuclear receptor complex reveals the mechanism for phospholipid-driven gene regulation

    Energy Technology Data Exchange (ETDEWEB)

    Musille, Paul M; Pathak, Manish C; Lauer, Janelle L; Hudson, William H; Griffin, Patrick R; Ortlund, Eric A [Emory-MED; (Scripps)

    2013-01-31

    The human nuclear receptor liver receptor homolog-1 (LRH-1) has an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of diabetes and hepatic diseases. LRH-1 is known to bind phospholipids, but the role of phospholipids in controlling LRH-1 activation remains highly debated. Here we describe the structure of both apo LRH-1 and LRH-1 in complex with the antidiabetic phospholipid dilauroylphosphatidylcholine (DLPC). Together with hydrogen-deuterium exchange MS and functional data, our studies show that DLPC binding is a dynamic process that alters co-regulator selectivity. We show that the lipid-free receptor undergoes previously unrecognized structural fluctuations, allowing it to interact with widely expressed co-repressors. These observations enhance our understanding of LRH-1 regulation and highlight its importance as a new therapeutic target for controlling diabetes.

  5. Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior.

    Science.gov (United States)

    Ross, Heather E; Young, Larry J

    2009-10-01

    Oxytocin is produced in the hypothalamus and released into the circulation through the neurohypophyseal system. Peripherally released oxytocin facilitates parturition and milk ejection during nursing. Centrally released oxytocin coordinates the onset of maternal nurturing behavior at parturition and plays a role in mother-infant bonding. More recent studies have revealed a more general role for oxytocin in modulating affiliative behavior in both sexes. Oxytocin regulates alloparental care and pair bonding in female monogamous prairie voles. Social recognition in male and female mice is also modulated by oxytocin. In humans, oxytocin increases gaze to the eye region of human faces and enhances interpersonal trust and the ability to infer the emotions of others from facial cues. While the neurohypopheseal oxytocin system has been well characterized, less is known regarding the nature of oxytocin release within the brain. Here we review the role of oxytocin in the regulation of prosocial interactions, and discuss the neuroanatomy of the central oxytocin system.

  6. [Dry immersion effects on the mechanisms of metabolic-reflex regulation of hemodynamics during muscular work].

    Science.gov (United States)

    Bravyĭ, Ia R; Bersenev, E Iu; Missina, S S; Borovik, A S; Sharova, A P; Vinogradova, O L

    2008-01-01

    Effects of 4-d dry immersion on metabolic-reflex regulation of hemodynamics were evaluated during local static work (30% of maximum voluntary effort) of the talocrural extensors. One group of immersed test-subjects received low-frequency electrostimulation of leg muscles to offset the immersion effect on EMG of working muscles. Metabolic-reflex regulation was evaluated through comparison of cardiovascular responses to physical tests with and w/o post-exercise vascular occlusion. Immersion vaguely increased heart rate and reduced systolic arterial pressure in resting subjects; however, it did not have a distinct effect on arterial pressure and HR during muscular work or metabolic-reflex potentiation of hemodynamic shifts.

  7. The Haematopoietic Stem Cell Niche: New Insights into the Mechanisms Regulating Haematopoietic Stem Cell Behaviour

    Directory of Open Access Journals (Sweden)

    Andrew J. Lilly

    2011-01-01

    Full Text Available The concept of the haematopoietic stem cell (HSC niche was formulated by Schofield in the 1970s, as a region within the bone marrow containing functional cell types that can maintain HSC potency throughout life. Since then, ongoing research has identified numerous cell types and a plethora of signals that not only maintain HSCs, but also dictate their behaviour with respect to homeostatic requirements and exogenous stresses. It has been proposed that there are endosteal and vascular niches within the bone marrow, which are thought to regulate different HSC populations. However, recent data depicts a more complicated picture, with functional crosstalk between cells in these two regions. In this review, recent research into the endosteal/vascular cell types and signals regulating HSC behaviour are considered, together with the possibility of a single subcompartmentalised niche.

  8. The structure of arabidopsis thaliana OST1 provides insights into the kinase regulation mechanism in response to osmotic stress

    KAUST Repository

    Yunta, Cristina

    2011-11-01

    SnRK [SNF1 (sucrose non-fermenting-1)-related protein kinase] 2.6 [open stomata 1 (OST1)] is well characterized at molecular and physiological levels to control stomata closure in response to water-deficit stress. OST1 is a member of a family of 10 protein kinases from Arabidopsis thaliana (SnRK2) that integrates abscisic acid (ABA)-dependent and ABA-independent signals to coordinate the cell response to osmotic stress. A subgroup of protein phosphatases type 2C binds OST1 and keeps the kinase dephosphorylated and inactive. Activation of OST1 relies on the ABA-dependent inhibition of the protein phosphatases type 2C and the subsequent self-phosphorylation of the kinase. The OST1 ABA-independent activation depends on a short sequence motif that is conserved among all the members of the SnRK2 family. However, little is known about the molecular mechanism underlying this regulation. The crystallographic structure of OST1 shows that ABA-independent regulation motif stabilizes the conformation of the kinase catalytically essential α C helix, and it provides the basis of the ABA-independent regulation mechanism for the SnRK2 family of protein kinases. © 2011 Elsevier Ltd. All rights reserved.

  9. A conserved inter-domain communication mechanism regulates the ATPase activity of the AAA-protein Drg1.

    Science.gov (United States)

    Prattes, Michael; Loibl, Mathias; Zisser, Gertrude; Luschnig, Daniel; Kappel, Lisa; Rössler, Ingrid; Grassegger, Manuela; Hromic, Altijana; Krieger, Elmar; Gruber, Karl; Pertschy, Brigitte; Bergler, Helmut

    2017-03-17

    AAA-ATPases fulfil essential roles in different cellular pathways and often act in form of hexameric complexes. Interaction with pathway-specific substrate and adaptor proteins recruits them to their targets and modulates their catalytic activity. This substrate dependent regulation of ATP hydrolysis in the AAA-domains is mediated by a non-catalytic N-terminal domain. The exact mechanisms that transmit the signal from the N-domain and coordinate the individual AAA-domains in the hexameric complex are still the topic of intensive research. Here, we present the characterization of a novel mutant variant of the eukaryotic AAA-ATPase Drg1 that shows dysregulation of ATPase activity and altered interaction with Rlp24, its substrate in ribosome biogenesis. This defective regulation is the consequence of amino acid exchanges at the interface between the regulatory N-domain and the adjacent D1 AAA-domain. The effects caused by these mutations strongly resemble those of pathological mutations of the AAA-ATPase p97 which cause the hereditary proteinopathy IBMPFD (inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia). Our results therefore suggest well conserved mechanisms of regulation between structurally, but not functionally related members of the AAA-family.

  10. The structure of arabidopsis thaliana OST1 provides insights into the kinase regulation mechanism in response to osmotic stress

    KAUST Repository

    Yunta, Cristina; Martí nez-Ripoll, Martí n; Zhu, Jian-Kang; Albert, Armando

    2011-01-01

    SnRK [SNF1 (sucrose non-fermenting-1)-related protein kinase] 2.6 [open stomata 1 (OST1)] is well characterized at molecular and physiological levels to control stomata closure in response to water-deficit stress. OST1 is a member of a family of 10 protein kinases from Arabidopsis thaliana (SnRK2) that integrates abscisic acid (ABA)-dependent and ABA-independent signals to coordinate the cell response to osmotic stress. A subgroup of protein phosphatases type 2C binds OST1 and keeps the kinase dephosphorylated and inactive. Activation of OST1 relies on the ABA-dependent inhibition of the protein phosphatases type 2C and the subsequent self-phosphorylation of the kinase. The OST1 ABA-independent activation depends on a short sequence motif that is conserved among all the members of the SnRK2 family. However, little is known about the molecular mechanism underlying this regulation. The crystallographic structure of OST1 shows that ABA-independent regulation motif stabilizes the conformation of the kinase catalytically essential α C helix, and it provides the basis of the ABA-independent regulation mechanism for the SnRK2 family of protein kinases. © 2011 Elsevier Ltd. All rights reserved.

  11. Fetal liver stromal cells promote hematopoietic cell expansion

    International Nuclear Information System (INIS)

    Zhou, Kun; Hu, Caihong; Zhou, Zhigang; Huang, Lifang; Liu, Wenli; Sun, Hanying

    2009-01-01

    Future application of hematopoietic stem and progenitor cells (HSPCs) in clinical therapies largely depends on their successful expansion in vitro. Fetal liver (FL) is a unique hematopoietic organ in which hematopoietic cells markedly expand in number, but the mechanisms involved remain unclear. Stromal cells (StroCs) have been suggested to provide a suitable cellular environment for in vitro expansion of HSPCs. In this study, murine StroCs derived from FL at E14.5, with a high level of Sonic hedgehog (Shh) and Wnt expression, were found to have an increased ability to support the proliferation of HSPCs. This effect was inhibited by blocking Shh signaling. Supplementation with soluble Shh-N promoted the proliferation of hematopoietic cells by activating Wnt signaling. Our findings suggest that FL-derived StroCs support proliferation of HSPCs via Shh inducing an autocrine Wnt signaling loop. The use of FL-derived StroCs and regulation of the Shh pathway might further enhance HPSC expansion.

  12. Hunger and Satiety Mechanisms and Their Potential Exploitation in the Regulation of Food Intake

    OpenAIRE

    Amin, Tehmina; Mercer, Julian G.

    2016-01-01

    Effective strategies to combat recent rises in obesity levels are limited. The accumulation of excess body fat results when energy intake exceeds that expended. Energy balance is controlled by hypothalamic responses, but these can be overridden by hedonic/reward brain systems. This override, combined with unprecedented availability of cheap, energy-dense, palatable foods, may partly explain the increase in overweight and obesity. The complexity of the processes that regulate feeding behaviour...

  13. FGF signalling regulates chromatin organisation during neural differentiation via mechanisms that can be uncoupled from transcription.

    Directory of Open Access Journals (Sweden)

    Nishal S Patel

    Full Text Available Changes in higher order chromatin organisation have been linked to transcriptional regulation; however, little is known about how such organisation alters during embryonic development or how it is regulated by extrinsic signals. Here we analyse changes in chromatin organisation as neural differentiation progresses, exploiting the clear spatial separation of the temporal events of differentiation along the elongating body axis of the mouse embryo. Combining fluorescence in situ hybridisation with super-resolution structured illumination microscopy, we show that chromatin around key differentiation gene loci Pax6 and Irx3 undergoes both decompaction and displacement towards the nuclear centre coincident with transcriptional onset. Conversely, down-regulation of Fgf8 as neural differentiation commences correlates with a more peripheral nuclear position of this locus. During normal neural differentiation, fibroblast growth factor (FGF signalling is repressed by retinoic acid, and this vitamin A derivative is further required for transcription of neural genes. We show here that exposure to retinoic acid or inhibition of FGF signalling promotes precocious decompaction and central nuclear positioning of differentiation gene loci. Using the Raldh2 mutant as a model for retinoid deficiency, we further find that such changes in higher order chromatin organisation are dependent on retinoid signalling. In this retinoid deficient condition, FGF signalling persists ectopically in the elongating body, and importantly, we find that inhibiting FGF receptor (FGFR signalling in Raldh2-/- embryos does not rescue differentiation gene transcription, but does elicit both chromatin decompaction and nuclear position change. These findings demonstrate that regulation of higher order chromatin organisation during differentiation in the embryo can be uncoupled from the machinery that promotes transcription and, for the first time, identify FGF as an extrinsic signal that

  14. Molecular mechanisms regulating flowering time in sweet cherry (Prunus avium L.)

    DEFF Research Database (Denmark)

    Ionescu, Irina Alexandra

    The timing of flowering is a well-researched but at the same time incredibly complex process in angiosperms. Although we are in possession of detailed knowledge on the genetic level of flowering time regulation in the model plant Arabidopsis thaliana, it is often difficult to transfer this knowle......The timing of flowering is a well-researched but at the same time incredibly complex process in angiosperms. Although we are in possession of detailed knowledge on the genetic level of flowering time regulation in the model plant Arabidopsis thaliana, it is often difficult to transfer...... as a result of hydrogen cyanamide treatment: the jasmonate pathway, the hydrogen cyanide pathway and the cytokinin pathway. We further analyzed the levels of cyanogenic glucosides and their derivatives during endodormancy and its release in sweet cherry and almond (Prunus dulcis (Mill.) D. A. Webb). Prunasin...... and its amide coincided with flowering time in both species. Taken together, these results contribute to elucidating parts of the complex network regulating flowering time in perennial plants....

  15. TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.

    Directory of Open Access Journals (Sweden)

    Pavan Kumar P

    2014-03-01

    Full Text Available TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

  16. TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.

    Science.gov (United States)

    Kumar P, Pavan; Franklin, Sarah; Emechebe, Uchenna; Hu, Hao; Moore, Barry; Lehman, Chris; Yandell, Mark; Moon, Anne M

    2014-03-01

    TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

  17. A DNA Origami Mechanical Device for the Regulation of Microcosmic Structural Rigidity.

    Science.gov (United States)

    Wan, Neng; Hong, Zhouping; Wang, Huading; Fu, Xin; Zhang, Ziyue; Li, Chao; Xia, Han; Fang, Yan; Li, Maoteng; Zhan, Yi; Yang, Xiangliang

    2017-11-01

    DNA origami makes it feasible to fabricate a tremendous number of DNA nanostructures with various geometries, dimensions, and functionalities. Moreover, an increasing amount of research on DNA nanostructures is focused on biological and biomedical applications. Here, the reversible regulation of microcosmic structural rigidity is accomplished using a DNA origami device in vitro. The designed DNA origami monomer is composed of an internal central axis and an external sliding tube. Due to the external tube sliding, the device transforms between flexible and rigid states. By transporting the device into the liposome, the conformational change of the origami device induces a structural change in the liposome. The results obtained demonstrate that the programmed DNA origami device can be applied to regulate the microcosmic structural rigidity of liposomes. Because microcosmic structural rigidity is important to cell proliferation and function, the results obtained potentially provide a foundation for the regulation of cell microcosmic structural rigidity using DNA nanostructures. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Molecular and biophysical mechanisms regulating hypertrophic differentiation in chondrocytes and mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    D Studer

    2012-07-01

    Full Text Available Chondrocyte hypertrophy is one of the key physiological processes involved in the longitudinal growth of long bones, yet the regulation of hypertrophy is also becoming increasingly relevant for clinical application of mesenchymal stem cells (MSCs and screening for drugs to treat hypertrophic osteoarthritis. The extraordinary cell volume increase during hypertrophy is accompanied by an up-regulation of collagen X, matrix metalloproteinases (MMPs, and vascular endothelial growth factor (VEGF, all which are targets of the runt-related transcription factor 2 (Runx2. Many pathways, including parathyroid hormone-related protein (PTHrP/Indian Hedgehog, Wingless/Int (Wnt/β-catenin, and transforming growth factor beta (TGF-β/Sma and Mad Related Family (Smad pathways, can regulate hypertrophy, but factors as diverse as hypoxia, co-culture, epigenetics and biomaterial composition can also potently affect Runx2 expression. Control of hypertrophic differentiation can be exploited both for cartilage repair, where a stable phenotype is desired, but also in bone regeneration, where hypertrophic cartilage could act as a template for endochondral bone formation. We hope this review will motivate the design of novel engineered microenvironments for skeletal regeneration applications.

  19. A novel mechanism of myostatin regulation by its alternative splicing variant during myogenesis in avian species.

    Science.gov (United States)

    Shin, Sangsu; Song, Yan; Ahn, Jinsoo; Kim, Eunsoo; Chen, Paula; Yang, Shujin; Suh, Yeunsu; Lee, Kichoon

    2015-11-15

    Myostatin (MSTN) is a key negative regulator of muscle growth and development, and an increase of muscle mass is achieved by inhibiting MSTN signaling. In the current study, five alternative splicing isoforms of MSTN mRNAs in avian species were identified in various tissues. Among these five, three truncated forms of myostatin, MSTN-B, -C, and -E created premature stop codons and produced partial MSTN prodomains encoded from exon 1. MSTN-B is the second dominant isoform following full-length MSTN-A, and their expression was dynamically regulated during muscle development of chicken, turkey, and quail in vivo and in vitro. To clarify the function of MSTN-B, two stable cell lines of quail myoblasts (QM7) were generated to overexpress MSTN-A or MSTN-B. Interestingly, MSTN-B promoted both cell proliferation and differentiation similar to the function of the MSTN prodomain to counteract the negative role of MSTN on myogenesis. The coimmunoprecipitation assay revealed that MSTN-B binds to MSTN-A and reduces the generation of mature MSTN. Furthermore, the current study demonstrated that the partial prodomain encoded from exon 1 is critical for binding of MSTN-B to MSTN-A. Altogether, these data imply that alternative splicing isoforms of MSTN could negatively regulate pro-myostatin processing in muscle cells and prevent MSTN-mediated inhibition of myogenesis in avian species. Copyright © 2015 the American Physiological Society.

  20. Transport systems of Ventricaria ventricosa: asymmetry of the hyper- and hypotonic regulation mechanisms.

    Science.gov (United States)

    Bisson, M A; Beilby, M J

    2008-01-01

    Hyper- and hypotonic stresses elicit apparently symmetrical responses in the alga Ventricaria. With hypertonic stress, membrane potential difference (PD) between the vacuole and the external medium becomes more positive, conductance at positive PDs (Gmpos) increases and KCl is actively taken up to increase turgor. With hypotonic stress, the membrane PD becomes more negative, conductance at negative PDs (Gmneg) increases and KCl is lost to decrease turgor. We used inhibitors that affect active transport to determine whether agents that inhibit the K(+) pump and hypertonic regulation also inhibit hypotonic regulatory responses. Cells whose turgor pressure was held low by the pressure probe (turgor-clamped) exhibited the same response as cells challenged by hyperosmotic medium, although the response was maintained longer than in osmotically challenged cells, which regulate turgor. The role of active K(+) transport was confirmed by the effects of decreased light, dichlorophenyldimethyl urea and diethylstilbestrol, which induced a uniformly low conductance (quiet state). Cells clamped to high turgor exhibited the same response as cells challenged by hypo-osmotic medium, but the response was similarly transient, making effects of inhibitors hard to determine. Unlike clamped cells, cells challenged by hypo-osmotic medium responded to inhibitors with rapid, transient, negative-going PDs, with decreased Gmneg and increased Gmpos (linearized I-V), achieving the quiet state as PD recovered. These changes are different from those exerted on the pump state, indicating that different transport systems are responsible for turgor regulation in the two cases.

  1. The structure of brain glycogen phosphorylase-from allosteric regulation mechanisms to clinical perspectives.

    Science.gov (United States)

    Mathieu, Cécile; Dupret, Jean-Marie; Rodrigues Lima, Fernando

    2017-02-01

    Glycogen phosphorylase (GP) is the key enzyme that regulates glycogen mobilization in cells. GP is a complex allosteric enzyme that comprises a family of three isozymes: muscle GP (mGP), liver GP (lGP), and brain GP (bGP). Although the three isozymes display high similarity and catalyze the same reaction, they differ in their sensitivity to the allosteric activator adenosine monophosphate (AMP). Moreover, inactivating mutations in mGP and lGP have been known to be associated with glycogen storage diseases (McArdle and Hers disease, respectively). The determination, decades ago, of the structure of mGP and lGP have allowed to better understand the allosteric regulation of these two isoforms and the development of specific inhibitors. Despite its important role in brain glycogen metabolism, the structure of the brain GP had remained elusive. Here, we provide an overview of the human brain GP structure and its relationship with the two other members of this key family of the metabolic enzymes. We also summarize how this structure provides valuable information to understand the regulation of bGP and to design specific ligands of potential pharmacological interest. © 2016 Federation of European Biochemical Societies.

  2. Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism.

    Science.gov (United States)

    Kroes, Marijn C W; van Wingen, Guido A; Wittwer, Jonas; Mohajeri, M Hasan; Kloek, Joris; Fernández, Guillén

    2014-01-01

    It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, tryptophan competes with other long-neutral-amino-acids (LNAA) for transport across the blood-brain-barrier, a limitation that can be mitigated by increasing the tryptophan/LNAA ratio. We therefore tested in a double-blind, placebo-controlled crossover study (N=32) whether a drink with a favourable tryptophan/LNAA ratio improves mood and modulates specific brain processes as assessed by functional magnetic resonance imaging (fMRI). We show that one serving of this drink increases the tryptophan/LNAA ratio in blood plasma, lifts mood in healthy young women and alters task-specific and resting-state processing in brain regions implicated in mood regulation. Specifically, Test-drink consumption reduced neural responses of the dorsal caudate nucleus during reward anticipation, increased neural responses in the dorsal cingulate cortex during fear processing, and increased ventromedial prefrontal-lateral prefrontal connectivity under resting-state conditions. Our results suggest that increasing tryptophan/LNAA ratios can lift mood by affecting mood-regulating neurocircuits. © 2013 Elsevier Inc. All rights reserved.

  3. Resonant state expansions

    International Nuclear Information System (INIS)

    Lind, P.

    1993-02-01

    The completeness properties of the discrete set of bound state, virtual states and resonances characterizing the system of a single nonrelativistic particle moving in a central cutoff potential is investigated. From a completeness relation in terms of these discrete states and complex scattering states one can derive several Resonant State Expansions (RSE). It is interesting to obtain purely discrete expansion which, if valid, would significantly simplify the treatment of the continuum. Such expansions can be derived using Mittag-Leffler (ML) theory for a cutoff potential and it would be nice to see if one can obtain the same expansions starting from an eigenfunction theory that is not restricted to a finite sphere. The RSE of Greens functions is especially important, e.g. in the continuum RPA (CRPA) method of treating giant resonances in nuclear physics. The convergence of RSE is studied in simple cases using square well wavefunctions in order to achieve high numerical accuracy. Several expansions can be derived from each other by using the theory of analytic functions and one can the see how to obtain a natural discretization of the continuum. Since the resonance wavefunctions are oscillating with an exponentially increasing amplitude, and therefore have to be interpreted through some regularization procedure, every statement made about quantities involving such states is checked by numerical calculations.Realistic nuclear wavefunctions, generated by a Wood-Saxon potential, are used to test also the usefulness of RSE in a realistic nuclear calculation. There are some fundamental differences between different symmetries of the integral contour that defines the continuum in RSE. One kind of symmetry is necessary to have an expansion of the unity operator that is idempotent. Another symmetry must be used if we want purely discrete expansions. These are found to be of the same form as given by ML. (29 refs.)

  4. Generic concept to program the time domain of self-assemblies with a self-regulation mechanism.

    Science.gov (United States)

    Heuser, Thomas; Steppert, Ann-Kathrin; Lopez, Catalina Molano; Zhu, Baolei; Walther, Andreas

    2015-04-08

    Nature regulates complex structures in space and time via feedback loops, kinetically controlled transformations, and under energy dissipation to allow non-equilibrium processes. Although man-made static self-assemblies realize excellent control over hierarchical structures via molecular programming, managing their temporal destiny by self-regulation is a largely unsolved challenge. Herein, we introduce a generic concept to control the time domain by programming the lifetimes of switchable self-assemblies in closed systems. We conceive dormant deactivators that, in combination with fast promoters, enable a unique kinetic balance to establish an autonomously self-regulating, transient pH-state, whose duration can be programmed over orders of magnitude-from minutes to days. Coupling this non-equilibrium state to pH-switchable self-assemblies allows predicting their assembly/disassembly fate in time, similar to a precise self-destruction mechanism. We demonstrate a platform approach by programming self-assembly lifetimes of block copolymers, nanoparticles, and peptides, enabling dynamic materials with a self-regulation functionality.

  5. Constitutive, Institutive and Up-Regulation of Carotenogenesis Regulatory Mechanism via In Vitro Culture Model System and Elicitors

    International Nuclear Information System (INIS)

    Rashidi Othman; Fatimah Azzahra Mohd Zaifuddin; Norazian Mohd Hassan

    2015-01-01

    Phyto hormone abscisic acid (ABA) plays a regulatory role in many physiological processes in plants and is regulated and controlled by specific key factors or genes. Different environmental stress conditions such as water, drought, cold, light, and temperature result in increased amounts of ABA. The action of ABA involves modification of gene expression and analysis of in vitro callus model system cultures revealed several potential of constitutive, institutive and up-regulation acting regulatory mechanisms. Therefore, this study was aimed at establishing in vitro cultures as potential research tools to study the regulatory mechanisms of the carotenoid biosynthesis in selected plant species through a controlled environment. The presence and absence of zeaxanthin and neoxanthin in callus cultures and intact plants could be explained by changes in gene expression in response to stress. Abiotic stress can alter gene expression and trigger cellular metabolism in plants. This study suggested that the key factors which involved in regulatory mechanisms of individual carotenoid biosynthesis in a particular biology system of plants can be either be silenced or activated. Therefore, based on the results in this study environmental stress is made possible for enhancement or enrichment of certain carotenoid of interest in food crops without altering the genes. (author)

  6. Expansion joints for LMFBR

    International Nuclear Information System (INIS)

    Dzenus, M.; Hundhausen, W.; Jansing, W.

    1980-01-01

    This discourse recounts efforts put into the SNR-2 project; specifically the development of compensation devices. The various prototypes of these compensation devices are described and the state of the development reviewed. Large Na (sodium)-heat transfer systems require a lot of valuable space if the component lay-out does not include compensation devices. So, in order to condense the spatial requirement as much as possible, expansion joints must be integrated into the pipe system. There are two basic types to suit the purpose: axial expansion joints and angular expansion joints. The expansion joints were developed on the basis of specific design criteria whereby differentiation is made between expansion joints of small and large nominal diameter. Expansion joints for installation in the sodium-filled primary piping are equipped with safety bellows in addition to the actual working bellows. Expansion joints must be designed and mounted in a manner to completely withstand seismic forces. The design must exclude any damage to the bellows during intermittent operations, that is, when sodium is drained the bellows' folds must be completely empty; otherwise residual solidified sodium could destroy the bellows when restarting. The expansion joints must be engineered on the basis of the following design data for the secondary system of the SNR project: working pressure: 16 bar; failure mode pressure: 5 events; failure mode: 5 sec., 28.5 bar, 520 deg. C; working temperature: 520 deg. C; temperature transients: 30 deg. C/sec.; service life: 200,000 h; number of load cycles: 10 4 ; material: 1.4948 or 1.4919; layer thickness of folds: 0.5 mm; angular deflection (DN 800): +3 deg. C or; axial expansion absorption (DN 600): ±80 mm; calculation: ASME class. The bellows' development work is not handled within this scope. The bellows are supplied by leading manufacturers, and warrant highest quality. Multiple bellows were selected on the basis of maximum elasticity - a property

  7. Immune regulation of systemic hypertension, pulmonary arterial hypertension, and preeclampsia: shared disease mechanisms and translational opportunities.

    Science.gov (United States)

    Jafri, Salema; Ormiston, Mark L

    2017-12-01

    Systemic hypertension, preeclampsia, and pulmonary arterial hypertension (PAH) are diseases of high blood pressure in the systemic or pulmonary circulation. Beyond the well-defined contribution of more traditional pathophysiological mechanisms, such as changes in the renin-angiotensin-aldosterone system, to the development of these hypertensive disorders, there is substantial clinical evidence supporting an important role for inflammation and immunity in the pathogenesis of each of these three conditions. Over the last decade, work in small animal models, bearing targeted deficiencies in specific cytokines or immune cell subsets, has begun to clarify the immune-mediated mechanisms that drive changes in vascular structure and tone in hypertensive disease. By summarizing the clinical and experimental evidence supporting a contribution of the immune system to systemic hypertension, preeclampsia, and PAH, the current review highlights the cellular and molecular pathways that are common to all three hypertensive disorders. These mechanisms are centered on an imbalance in CD4 + helper T cell populations, defined by excessive Th17 responses and impaired T reg activity, as well as the excessive activation or impairment of additional immune cell types, including macrophages, dendritic cells, CD8 + T cells, B cells, and natural killer cells. The identification of common immune mechanisms in systemic hypertension, preeclampsia, and PAH raises the possibility of new therapeutic strategies that target the immune component of hypertension across multiple disorders. Copyright © 2017 the American Physiological Society.

  8. Charge regulation as a stabilization mechanism for shell-like assemblies of polyoxometalates

    NARCIS (Netherlands)

    Verhoeff, A.A.; Kistler, M.L.; Bhatt, A.; Pigga, J.; Groenewold, J.; Klokkenburg, M.; Veen, S.J.; Roy, S.; Liu, T.; Kegel, W.K.

    2007-01-01

    We show that the equilibrium size of single-layer shells composed of polyoxometalate macroions is inversely proportional to the dielectric constant of the medium in which they are dispersed. This behavior is consistent with a stabilization mechanism based on Coulomb repulsion combined with charge

  9. Ace inhibitors and cardiovascular regulation : the importance of autocrine and paracrine mechanisms

    NARCIS (Netherlands)

    Wijngaarden, Jan van

    1992-01-01

    As demonstrated in a large number of clinical studies, angiotensin converting enzyme (ACE) inhibitors are of great value for the treatment of cardiovascular disorders. Although the clinical merits of these drugs are now well recognized, their mechanism of action is not yet completely understood. The

  10. Mechanisms underlying the volume regulation of interstitial fluid by capillaries: a simulation study

    Directory of Open Access Journals (Sweden)

    Yukiko Himeno

    2016-03-01

    Conclusion: Mathematical analyses revealed that the system of the capillary is stable near the equilibrium point at steady state and normal physiological capillary pressure. The time course of the tissue-volume change was determined by two kinetic mechanisms: rapid fluid exchange and slow protein fluxes.

  11. Nitric oxide is involved in the down-regulation of sost expression induced by mechanical loading

    NARCIS (Netherlands)

    Delgado-Calle, J.; Riancho, J.A.; Klein-Nulend, J.

    2014-01-01

    Mechanical stimulation reduces sclerostin expression in rodents. However, few data are available about the effect of physical stimuli in human systems. Recently we observed that the demethylating agent AzadC induces SOST expression in bone cells. This allowed us in this study to explore the effect

  12. Accelerating the loop expansion

    International Nuclear Information System (INIS)

    Ingermanson, R.

    1986-01-01

    This thesis introduces a new non-perturbative technique into quantum field theory. To illustrate the method, I analyze the much-studied phi 4 theory in two dimensions. As a prelude, I first show that the Hartree approximation is easy to obtain from the calculation of the one-loop effective potential by a simple modification of the propagator that does not affect the perturbative renormalization procedure. A further modification then susggests itself, which has the same nice property, and which automatically yields a convex effective potential. I then show that both of these modifications extend naturally to higher orders in the derivative expansion of the effective action and to higher orders in the loop-expansion. The net effect is to re-sum the perturbation series for the effective action as a systematic ''accelerated'' non-perturbative expansion. Each term in the accelerated expansion corresponds to an infinite number of terms in the original series. Each term can be computed explicitly, albeit numerically. Many numerical graphs of the various approximations to the first two terms in the derivative expansion are given. I discuss the reliability of the results and the problem of spontaneous symmetry-breaking, as well as some potential applications to more interesting field theories. 40 refs

  13. Conformal expansions and renormalons

    Energy Technology Data Exchange (ETDEWEB)

    Rathsman, J.

    2000-02-07

    The coefficients in perturbative expansions in gauge theories are factorially increasing, predominantly due to renormalons. This type of factorial increase is not expected in conformal theories. In QCD conformal relations between observables can be defined in the presence of a perturbative infrared fixed-point. Using the Banks-Zaks expansion the authors study the effect of the large-order behavior of the perturbative series on the conformal coefficients. The authors find that in general these coefficients become factorially increasing. However, when the factorial behavior genuinely originates in a renormalon integral, as implied by a postulated skeleton expansion, it does not affect the conformal coefficients. As a consequence, the conformal coefficients will indeed be free of renormalon divergence, in accordance with previous observations concerning the smallness of these coefficients for specific observables. The authors further show that the correspondence of the BLM method with the skeleton expansion implies a unique scale-setting procedure. The BLM coefficients can be interpreted as the conformal coefficients in the series relating the fixed-point value of the observable with that of the skeleton effective charge. Through the skeleton expansion the relevance of renormalon-free conformal coefficients extends to real-world QCD.

  14. Proteolytic fragmentation of inositol 1,4,5-trisphosphate receptors: a novel mechanism regulating channel activity?

    Science.gov (United States)

    Wang, Liwei; Alzayady, Kamil J; Yule, David I

    2016-06-01

    Inositol 1,4,5-trisphosphate receptors (IP3 Rs) are a family of ubiquitously expressed intracellular Ca(2+) release channels. Regulation of channel activity by Ca(2+) , nucleotides, phosphorylation, protein binding partners and other cellular factors is thought to play a major role in defining the specific spatiotemporal characteristics of intracellular Ca(2+) signals. These properties are, in turn, believed pivotal for the selective and specific physiological activation of Ca(2+) -dependent effectors. IP3 Rs are also substrates for the intracellular cysteine proteases, calpain and caspase. Cleavage of the IP3 R has been proposed to play a role in apoptotic cell death by uncoupling regions important for IP3 binding from the channel domain, leaving an unregulated leaky Ca(2+) pore. Contrary to this hypothesis, we demonstrate following proteolysis that N- and C-termini of IP3 R1 remain associated, presumably through non-covalent interactions. Further, we show that complementary fragments of IP3 R1 assemble into tetrameric structures and retain their ability to be regulated robustly by IP3 . While peptide continuity is clearly not necessary for IP3 -gating of the channel, we propose that cleavage of the IP3 R peptide chain may alter other important regulatory events to modulate channel activity. In this scenario, stimulation of the cleaved IP3 R may support distinct spatiotemporal Ca(2+) signals and activation of specific effectors. Notably, in many adaptive physiological events, the non-apoptotic activities of caspase and calpain are demonstrated to be important, but the substrates of the proteases are poorly defined. We speculate that proteolytic fragmentation may represent a novel form of IP3 R regulation, which plays a role in varied adaptive physiological processes. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  15. Glycogen synthase kinase 3α regulates urine concentrating mechanism in mice

    OpenAIRE

    Nørregaard, Rikke; Tao, Shixin; Nilsson, Line; Woodgett, James R.; Kakade, Vijayakumar; Yu, Alan S. L.; Howard, Christiana; Rao, Reena

    2015-01-01

    In mammals, glycogen synthase kinase (GSK)3 comprises GSK3α and GSK3β isoforms. GSK3β has been shown to play a role in the ability of kidneys to concentrate urine by regulating vasopressin-mediated water permeability of collecting ducts, whereas the role of GSK3α has yet to be discerned. To investigate the role of GSK3α in urine concentration, we compared GSK3α knockout (GSK3αKO) mice with wild-type (WT) littermates. Under normal conditions, GSK3αKO mice had higher water intake and urine outp...

  16. Mechanisms Down-Regulating Sprouty1, a Growth Inhibitor in Prostate Cancer

    Science.gov (United States)

    2008-10-01

    fibroblast growth factor signaling is down-regulated in prostate cancer. Kwabi-Addo B (2004) Orlando, FL (Oral; mini symposium). • AACR/NCI/EORTC...contains a classic signal peptide PP FRS2 Sos Grb2 Cbl Ras FGFR1-DN MEK ERK STAT3 STAT3 Sprouty PLC - Extracellular stimulus Nucleus P Raf PI3K Receptor... thesis system for reverse transcription-PCR and according to the manufactur- er’s protocol. Real-time PCR was carried out in a Bio-Rad iCycler real

  17. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

    International Nuclear Information System (INIS)

    Latham, Antony M.; Odell, Adam F.; Mughal, Nadeem A.; Issitt, Theo; Ulyatt, Clare; Walker, John H.; Homer-Vanniasinkam, Shervanthi; Ponnambalam, Sreenivasan

    2012-01-01

    Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: ► Endothelial cells mount a stress response under conditions of low serum. ► Endothelial VEGFR levels are

  18. Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome.

    Science.gov (United States)

    Clarke, S D

    2001-04-01

    This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the (n-3) family, play pivotal roles as "fuel partitioners" in that they direct fatty acids away from triglyceride storage and toward oxidation, and that they enhance glucose flux to glycogen. In doing this, PUFA may protect against the adverse symptoms of the metabolic syndrome and reduce the risk of heart disease. PUFA exert their beneficial effects by up-regulating the expression of genes encoding proteins involved in fatty acid oxidation while simultaneously down-regulating genes encoding proteins of lipid synthesis. PUFA govern oxidative gene expression by activating the transcription factor peroxisome proliferator-activated receptor alpha. PUFA suppress lipogenic gene expression by reducing the nuclear abundance and DNA-binding affinity of transcription factors responsible for imparting insulin and carbohydrate control to lipogenic and glycolytic genes. In particular, PUFA suppress the nuclear abundance and expression of sterol regulatory element binding protein-1 and reduce the DNA-binding activities of nuclear factor Y, Sp1 and possibly hepatic nuclear factor-4. Collectively, the studies discussed suggest that the fuel "repartitioning" and gene expression actions of PUFA should be considered among criteria used in defining the dietary needs of (n-6) and (n-3) and in establishing the dietary ratio of (n-6) to (n-3) needed for optimum health benefit.

  19. Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis.

    Science.gov (United States)

    Glover, Louise E; Bowers, Brittelle E; Saeedi, Bejan; Ehrentraut, Stefan F; Campbell, Eric L; Bayless, Amanda J; Dobrinskikh, Evgenia; Kendrick, Agnieszka A; Kelly, Caleb J; Burgess, Adrianne; Miller, Lauren; Kominsky, Douglas J; Jedlicka, Paul; Colgan, Sean P

    2013-12-03

    Mucosal surfaces of the lower gastrointestinal tract are subject to frequent, pronounced fluctuations in oxygen tension, particularly during inflammation. Adaptive responses to hypoxia are orchestrated largely by the hypoxia-inducible transcription factors (HIFs). As HIF-1α and HIF-2α are coexpressed in mucosal epithelia that constitute the barrier between the lumen and the underlying immune milieu, we sought to define the discrete contribution of HIF-1 and HIF-2 transactivation pathways to intestinal epithelial cell homeostasis. The present study identifies creatine kinases (CKs), key metabolic enzymes for rapid ATP generation via the phosphocreatine-creatine kinase (PCr/CK) system, as a unique gene family that is coordinately regulated by HIF. Cytosolic CKs are expressed in a HIF-2-dependent manner in vitro and localize to apical intestinal epithelial cell adherens junctions, where they are critical for junction assembly and epithelial integrity. Supplementation with dietary creatine markedly ameliorated both disease severity and inflammatory responses in colitis models. Further, enzymes of the PCr/CK metabolic shuttle demonstrate dysregulated mucosal expression in a subset of ulcerative colitis and Crohn disease patients. These findings establish a role for HIF-regulated CK in epithelial homeostasis and reveal a fundamental link between cellular bioenergetics and mucosal barrier.

  20. Regulation of plant cells, cell walls and development by mechanical signals

    Energy Technology Data Exchange (ETDEWEB)

    Meyerowitz, Elliot M. [California Inst. of Technology (CalTech), Pasadena, CA (United States)

    2016-06-14

    The overall goal of the revised scope of work for the final year of funding was to characterize cell wall biosynthesis in developing cotyledons and in the shoot apical meristem of Arabidopsis thaliana, as a way of learning about developmental control of cell wall biosynthesis in plants, and interactions between cell wall biosynthesis and the microtubule cytoskeleton. The proposed work had two parts – to look at the effect of mutation in the SPIRAL2 gene on microtubule organization and reorganization, and to thoroughly characterize the glycosyltransferase genes expressed in shoot apical meristems by RNA-seq experiments, by in situ hybridization of the RNAs expressed in the meristem, and by antibody staining of the products of the glycosyltransferases in meristems. Both parts were completed; the spiral2 mutant was found to speed microtubule reorientation after ablation of adjacent cells, supporting our hypothesis that reorganization correlates with microtubule severing, the rate of which is increased by the mutation. The glycosyltransferase characterization was completed and published as Yang et al. (2016). Among the new things learned was that primary cell wall biosynthesis is strongly controlled both by cell type, and by stage of cell cycle, implying not only that different, even adjacent, cells can have different sugar linkages in their (nonshared) walls, but also that a surprisingly large proportion of glycosyltransferases is regulated in the cell cycle, and therefore that the cell cycle regulates wall maturation to a degree previously unrecognized.

  1. Thermal expansion data

    International Nuclear Information System (INIS)

    Taylor, D.

    1984-01-01

    This paper gives regression data for a modified second order polynomial fitted to the expansion data of, and percentage expansions for dioxides with (a) the fluorite and antifluorite structure: AmO 2 , BkO 2 , CeO 2 , CmO 2 , HfO 2 , Li 2 O, NpO 2 , PrO 2 , PuO 2 , ThO 2 , UO 2 , ZrO 2 , and (b) the rutile structure: CrO 2 , GeO 2 , IrO 2 , MnO 2 , NbO 2 , PbO 2 , SiO 2 , SnO 2 , TeO 2 , TiO 2 and VO 2 . Reduced expansion curves for the dioxides showed only partial grouping into iso-electronic series for the fluorite structures and showed that the 'law of corresponding states' did not apply to the rutile structures. (author)

  2. Expansion of protein domain repeats.

    Directory of Open Access Journals (Sweden)

    Asa K Björklund

    2006-08-01

    Full Text Available Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e.g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

  3. Critical analysis of mechanisms of incentive regulation operators of electricity and natural gas networks and infrastructures. Final report. Public version, 23 November 2015

    International Nuclear Information System (INIS)

    2015-01-01

    As the first mechanisms of incentive regulation of electricity and gas network operators have been introduced by the French Commission for Energy Regulation (CRE) since 2008 (the report recalls the main objectives of these mechanisms and their consequences), this report proposes a critical analysis of such mechanisms related to investments and to exploitation expenses of operators and which have been implemented in Germany, Spain, Ireland and in the United Kingdom. For each country, the report proposes a detailed description of these mechanisms for the electric power sector and the gas sector (general overview of the regulation framework, objectives, determination of the authorised income, shift processing, specific incentive mechanisms, modalities of management by the regulator), and a feedback of the different concerned actors (operators and regulators). The last part proposes a description of the status of the French regulation, and an analysis of transposition of the four foreign regulations, and states some propositions for evolutions (objectives, overview of recommended evolutions, focus on three types of regulation evolution: processing of arbitral charges, processing of other incited capital charges, processing of arbitral charges)

  4. Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators

    Science.gov (United States)

    Hubbard, Basil P.; Gomes, Ana P.; Dai, Han; Li, Jun; Case, April W.; Considine, Thomas; Riera, Thomas V.; Lee, Jessica E.; Sook Yen, E; Lamming, Dudley W.; Pentelute, Bradley L.; Schuman, Eli R.; Stevens, Linda A.; Ling, Alvin J. Y.; Armour, Sean M.; Michan, Shaday; Zhao, Huizhen; Jiang, Yong; Sweitzer, Sharon M.; Blum, Charles A.; Disch, Jeremy S.; Ng, Pui Yee; Howitz, Konrad T.; Rolo, Anabela P.; Hamuro, Yoshitomo; Moss, Joel; Perni, Robert B.; Ellis, James L.; Vlasuk, George P.; Sinclair, David A.

    2013-01-01

    A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs. PMID:23471411

  5. Molecular Mechanisms Regulating Ocular Apoptosis in Zebrafish gdf6a Mutants

    DEFF Research Database (Denmark)

    Pant, Sameer D.; March, Lindsey D.; Famulski, Jakub K.

    2013-01-01

    intrinsic or extrinsic apoptotic mechanisms were involved, morpholino antisense oligonucleotides targeting baxa, baxb, and p53 were employed. Caspase-3 immunohistochemistry (IHC) was performed to assay apoptosis. Pharmacologic inhibition (using SB203580) and IHC were used to investigate the role of p38...... occurs 28 hours post fertilization (hpf) in gdf6a(-/-) mutants that is mediated independently of p53 by intrinsic mechanisms involving Bax proteins. Also, gdf6a(-/-) mutants exhibit markedly increased p38 MAP kinase activation that can be inhibited to significantly reduce retinal apoptosis. A reduction...... in retinal smad1 expression was also noted in gdf6a(-/-) mutants. CONCLUSIONS. gdf6a(-/-)-induced apoptosis is characterized by the involvement of intrinsic apoptotic pathways, p38 MAP kinases, and dysregulated smad expression. Modulation of key mediators can inhibit retinal apoptosis offering potential...

  6. Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis.

    Science.gov (United States)

    Bozec, Aline; Hannemann, Nicole

    2016-06-03

    Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1α protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes.

  7. Evidence for a common mechanism of SIRT1 regulation by allosteric activators.

    Science.gov (United States)

    Hubbard, Basil P; Gomes, Ana P; Dai, Han; Li, Jun; Case, April W; Considine, Thomas; Riera, Thomas V; Lee, Jessica E; E, Sook Yen; Lamming, Dudley W; Pentelute, Bradley L; Schuman, Eli R; Stevens, Linda A; Ling, Alvin J Y; Armour, Sean M; Michan, Shaday; Zhao, Huizhen; Jiang, Yong; Sweitzer, Sharon M; Blum, Charles A; Disch, Jeremy S; Ng, Pui Yee; Howitz, Konrad T; Rolo, Anabela P; Hamuro, Yoshitomo; Moss, Joel; Perni, Robert B; Ellis, James L; Vlasuk, George P; Sinclair, David A

    2013-03-08

    A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.

  8. Curcumin-mediated regulation of intestinal barrier function: The mechanism underlying its beneficial effects.

    Science.gov (United States)

    Ghosh, Siddhartha S; He, Hongliang; Wang, Jing; Gehr, Todd W; Ghosh, Shobha

    2018-01-02

    Curcumin has anti-inflammatory, anti-oxidant and anti-proliferative properties established largely by in vitro studies. Accordingly, oral administration of curcumin beneficially modulates many diseases including diabetes, fatty-liver disease, atherosclerosis, arthritis, cancer and neurological disorders such as depression, Alzheimer's or Parkinson's disease. However, limited bioavailability and inability to detect curcumin in circulation or target tissues has hindered the validation of a causal role. We established curcumin-mediated decrease in the release of gut bacteria-derived lipopolysaccharide (LPS) into circulation by maintaining the integrity of the intestinal barrier function as the mechanism underlying the attenuation of metabolic diseases (diabetes, atherosclerosis, kidney disease) by curcumin supplementation precluding the need for curcumin absorption. In view of the causative role of circulating LPS and resulting chronic inflammation in the development of diseases listed above, this review summarizes the mechanism by which curcumin affects the several layers of the intestinal barrier and, despite negligible absorption, can beneficially modulate these diseases.

  9. Chondrogenesis on sulfonate-coated hydrogels is regulated by their mechanical properties.

    Science.gov (United States)

    Kwon, Hyuck Joon; Yasuda, Kazunori

    2013-01-01

    Many studies have demonstrated that sulfur-containing acidic groups induce chondrogenesis in vitro and in vivo. Recently, it is increasingly clear that mechanical properties of cell substrates largely influence cell differentiation. Thus, the present study investigated how mechanical properties of sulfonate-coated hydrogels influences chondrogenesis of mesenchymal stem cells (MSCs). Sulfonate-coated polyacrylamide gels (S-PAAm gels) which have the elastic modulus, E, of about 1, 15 and 150 kPa, were used in this study. MSCs cultured on the high stiffness S-PAAm gels (E=∼150 kPa) spread out with strong expression of stress fibers, while MSCs cultured on the low stiffness S-PAAm gels (E=∼1 kPa) had round shapes with less stress fibers but more cortical actins. Importantly, even in the absence of differentiation supplements, the lower stiffness S-PAAm gels led to the higher mRNA levels of chondrogenic markers such as Col2a1, Agc and Sox9 and the lower mRNA levels of an undifferentiation marker Sca1, indicating that the mechanical properties of S-PAAm gels strongly influence chondrogenesis. Blebbistatin which blocks myosin II-mediated mechanical sensing suppressed chondrogenesis induced by the low stiffness S-PAAm gels. The present study demonstrates that the soft S-PAAm gels effectively drive MSC chondrogenesis even in the absence of soluble differentiation factors and thus suggests that sulfonate-containing hydrogels with low stiffness could be a powerful tool for cartilage regeneration. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer.

    Science.gov (United States)

    Angus, Steven P; Zawistowski, Jon S; Johnson, Gary L

    2018-01-06

    Although targeted inhibition of oncogenic kinase drivers has achieved remarkable patient responses in many cancers, the development of resistance has remained a significant challenge. Numerous mechanisms have been identified, including the acquisition of gatekeeper mutations, activating pathway mutations, and copy number loss or gain of the driver or alternate nodes. These changes have prompted the development of kinase inhibitors with increased selectivity, use of second-line therapeutics to overcome primary resistance, and combination treatment to forestall resistance. In addition to genomic resistance mechanisms, adaptive transcriptional and signaling responses seen in tumors are gaining appreciation as alterations that lead to a phenotypic state change-often observed as an epithelial-to-mesenchymal shift or reversion to a cancer stem cell-like phenotype underpinned by remodeling of the epigenetic landscape. This epigenomic modulation driving cell state change is multifaceted and includes modulation of repressive and activating histone modifications, DNA methylation, enhancer remodeling, and noncoding RNA species. Consequently, the combination of kinase inhibitors with drugs targeting components of the transcriptional machinery and histone-modifying enzymes has shown promise in preclinical and clinical studies. Here, we review mechanisms of resistance to kinase inhibition in cancer, with special emphasis on the rewired kinome and transcriptional signaling networks and the potential vulnerabilities that may be exploited to overcome these adaptive signaling changes.

  11. Mechanical stretching stimulates collagen synthesis via down-regulating SO2/AAT1 pathway

    Science.gov (United States)

    Liu, Jia; Yu, Wen; Liu, Yan; Chen, Selena; Huang, Yaqian; Li, Xiaohui; Liu, Cuiping; Zhang, Yanqiu; Li, Zhenzhen; Du, Jie; Tang, Chaoshu; Du, Junbao; Jin, Hongfang

    2016-01-01

    The aim of the study was to investigate the role of endogenous sulfur dioxide (SO2)/ aspartate aminotransferase 1 (AAT1) pathway in stretch-induced excessive collagen expression and its mechanism. The mechanical stretch downregulated SO2/AAT1 pathway and increased collagen I and III protein expression. Importantly, AAT1 overexpression blocked the increase in collagen I and III expression, transforming growth factor-β1 (TGF- β1) expression and phosphorylation of Smad2/3 induced by stretch, but AAT1 knockdown mimicked the increase in collagen I and III expression, TGF- β1 expression and phosphorylation of Smad2/3 induced by stretch. Mechanistically, SB431542, a TGF-β1/Smad2/3 inhibitor, eliminated excessive collagen I and III accumulation induced by AAT1 knockdown, stretch or stretch plus AAT1 knockdown. In a rat model of high pulmonary blood flow-induced pulmonary vascular collagen accumulation, AAT1 expression and SO2 content in lung tissues of rat were reduced in shunt rats with high pulmonary blood flow. Supplement of SO2 derivatives inhibited activation of TGF- β1/Smad2/3 pathway and alleviated the excessive collagen accumulation in lung tissues of shunt rats. The results suggested that deficiency of endogenous SO2/AAT1 pathway mediated mechanical stretch-stimulated abnormal collagen accumulation via TGF-β1/Smad2/3 pathway. PMID:26880260

  12. Uniform gradient expansions

    CERN Document Server

    Giovannini, Massimo

    2015-01-01

    Cosmological singularities are often discussed by means of a gradient expansion that can also describe, during a quasi-de Sitter phase, the progressive suppression of curvature inhomogeneities. While the inflationary event horizon is being formed the two mentioned regimes coexist and a uniform expansion can be conceived and applied to the evolution of spatial gradients across the protoinflationary boundary. It is argued that conventional arguments addressing the preinflationary initial conditions are necessary but generally not sufficient to guarantee a homogeneous onset of the conventional inflationary stage.

  13. Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

    Science.gov (United States)

    Majed, Batoule H.

    2012-01-01

    Prostacyclin (PGI2) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A2, cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI2 is produced by endothelial cells and influences many cardiovascular processes. PGI2 acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI2 analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI2/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca2+]i, and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI2 intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI2 counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A2 (TXA2), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI2/TXA2 balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI2/TXA2 ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI2 activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI2 analogs in the management of pregnancy-associated and neonatal

  14. Model for the mechanism and regulation of chitosan synthesis in Mucor rouxii

    International Nuclear Information System (INIS)

    Davis, L.L.; Bartnicki-Garcia, S.

    1984-01-01

    The cell walls of mucoraceous fungi are characterized by the joint occurrence of chitosan and chitin, the β-1,4-linked polysaccharides of G1cN and G1cNAc, respectively. It has been proposed that chitosan is made from chitin by enzymatic deacetylation, but the evidence is inconclusive since the deacetylase isolated from Mucor rouxii is effective against glycol chitin, but not against genuine chitin; consequently, chitosan synthesis in vitro was not achieved. The authors discovered that the same deacetylase can deacetylate chitin efficiently if it is allowed to act on chitin chains as they are being formed; i.e. the simultaneous presence and operation of chitin synthetase and chitin deacetylase is required for chitosan synthesis. Subsequent studies on the effect of digitonin on chitosan synthesis were the basis for a model the authors have developed for the regulation of chitosan and chitin syntheses in vivo

  15. Nitrogen assimilation system in maize is regulated by developmental and tissue-specific mechanisms

    KAUST Repository

    Plett, Darren

    2016-08-10

    Key message: We found metabolites, enzyme activities and enzyme transcript abundances vary significantly across the maize lifecycle, but weak correlation exists between the three groups. We identified putative genes regulating nitrate assimilation. Abstract: Progress in improving nitrogen (N) use efficiency (NUE) of crop plants has been hampered by the complexity of the N uptake and utilisation systems. To understand this complexity we measured the activities of seven enzymes and ten metabolites related to N metabolism in the leaf and root tissues of Gaspe Flint maize plants grown in 0.5 or 2.5 mM NO3 − throughout the lifecycle. The amino acids had remarkably similar profiles across the lifecycle except for transient responses, which only appeared in the leaves for aspartate or in the roots for asparagine, serine and glycine. The activities of the enzymes for N assimilation were also coordinated to a certain degree, most noticeably with a peak in root activity late in the lifecycle, but with wide variation in the activity levels over the course of development. We analysed the transcriptional data for gene sets encoding the measured enzymes and found that, unlike the enzyme activities, transcript levels of the corresponding genes did not exhibit the same coordination across the lifecycle and were only weakly correlated with the levels of various amino acids or individual enzyme activities. We identified gene sets which were correlated with the enzyme activity profiles, including seven genes located within previously known quantitative trait loci for enzyme activities and hypothesise that these genes are important for the regulation of enzyme activities. This work provides insights into the complexity of the N assimilation system throughout development and identifies candidate regulatory genes, which warrant further investigation in efforts to improve NUE in crop plants. © 2016, Springer Science+Business Media Dordrecht.

  16. Mechanism of phytohormone involvement in feedback regulation of cotton leaf senescence induced by potassium deficiency.

    Science.gov (United States)

    Wang, Ye; Li, Bo; Du, Mingwei; Eneji, A Egrinya; Wang, Baomin; Duan, Liusheng; Li, Zhaohu; Tian, Xiaoli

    2012-10-01

    To elucidate the phytohormonal basis of the feedback regulation of leaf senescence induced by potassium (K) deficiency in cotton (Gossypium hirsutum L.), two cultivars contrasting in sensitivity to K deficiency were self- and reciprocally grafted hypocotyl-to-hypocotyl, using standard grafting (one scion grafted onto one rootstock), Y grafting (two scions grafted onto one rootstock), and inverted Y grafting (one scion grafted onto two rootstocks) at the seedling stage. K deficiency (0.03mM for standard and Y grafting, and 0.01mM for inverted Y grafting) increased the root abscisic acid (ABA) concentration by 1.6- to 3.1-fold and xylem ABA delivery rates by 1.8- to 4.6-fold. The K deficiency also decreased the delivery rates of xylem cytokinins [CKs; including the zeatin riboside (ZR) and isopentenyl adenosine (iPA) type] by 29-65% and leaf CK concentration by 16-57%. The leaf ABA concentration and xylem ABA deliveries were consistently greater in CCRI41 (more sensitive to K deficiency) than in SCRC22 (less sensitive to K deficiency) scions under K deficiency, and ZR- and iPA-type levels were consistently lower in the former than in the latter, irrespective of rootstock cultivar or grafting type, indicating that cotton shoot influences the levels of ABA and CKs in leaves and xylem sap. Because the scions had little influence on phytohormone levels in the roots (rootstocks) of all three types of grafts and rootstock xylem sap (collected below the graft union) of Y and inverted Y grafts, it appears that the site for basipetal feedback signal(s) involved in the regulation of xylem phytohormones is the hypocotyl of cotton seedlings. Also, the target of this feedback signal(s) is more likely to be the changes in xylem phytohormones within tissues of the hypocotyl rather than the export of phytohormones from the roots.

  17. Nitrogen assimilation system in maize is regulated by developmental and tissue-specific mechanisms

    KAUST Repository

    Plett, Darren; Holtham, Luke; Baumann, Ute; Kalashyan, Elena; Francis, Karen; Enju, Akiko; Toubia, John; Roessner, Ute; Bacic, Antony; Rafalski, Antoni; Dhugga, Kanwarpal S.; Tester, Mark A.; Garnett, Trevor; Kaiser, Brent N.

    2016-01-01

    Key message: We found metabolites, enzyme activities and enzyme transcript abundances vary significantly across the maize lifecycle, but weak correlation exists between the three groups. We identified putative genes regulating nitrate assimilation. Abstract: Progress in improving nitrogen (N) use efficiency (NUE) of crop plants has been hampered by the complexity of the N uptake and utilisation systems. To understand this complexity we measured the activities of seven enzymes and ten metabolites related to N metabolism in the leaf and root tissues of Gaspe Flint maize plants grown in 0.5 or 2.5 mM NO3 − throughout the lifecycle. The amino acids had remarkably similar profiles across the lifecycle except for transient responses, which only appeared in the leaves for aspartate or in the roots for asparagine, serine and glycine. The activities of the enzymes for N assimilation were also coordinated to a certain degree, most noticeably with a peak in root activity late in the lifecycle, but with wide variation in the activity levels over the course of development. We analysed the transcriptional data for gene sets encoding the measured enzymes and found that, unlike the enzyme activities, transcript levels of the corresponding genes did not exhibit the same coordination across the lifecycle and were only weakly correlated with the levels of various amino acids or individual enzyme activities. We identified gene sets which were correlated with the enzyme activity profiles, including seven genes located within previously known quantitative trait loci for enzyme activities and hypothesise that these genes are important for the regulation of enzyme activities. This work provides insights into the complexity of the N assimilation system throughout development and identifies candidate regulatory genes, which warrant further investigation in efforts to improve NUE in crop plants. © 2016, Springer Science+Business Media Dordrecht.

  18. Common state mechanisms regulating tribal tobacco taxation and sales, the USA, 2015.

    Science.gov (United States)

    DeLong, Hillary; Chriqui, Jamie; Leider, Julien; Chaloupka, Frank J

    2016-10-01

    Native American tribes, as sovereign nations, are exempt from state tobacco excise taxation, and self-govern on-reservation activity in the USA. Under Federal law, state excise taxes are owed by non-members purchasing tobacco on tribal land, but states are limited in how they enforce or collect these taxes. This study highlights the various policy approaches that states have taken to regulate tobacco sales on tribal lands given jurisdictional challenges. State laws (statutes, regulations and case law), Attorney General opinions, and revenue notices and rulings effective as of 1 January 2015 for all 50 states and the District of Columbia were compiled using Boolean searches in Lexis-Nexis and Westlaw. Laws were limited to those addressing taxation compacts or tobacco sales involving tribal entities. Master Settlement Agreement laws and non-codified tribal codes/compacts were excluded. Twenty of the 34 states with tribal lands address tribal tobacco sales. Fourteen states address intergovernmental compacts: 11 are tobacco specific, and suggest or require specific provisions. Fifteen states address tribal tax stamps: 2 explicitly prohibit stamping tribally sold products, 9 stamp all products, and 4 stamp some. Prepayment of excise tax is required in 12 states: 6 on all products, 4 on products in excess of quota, and 2 on products sold by non-tribal retailers. 6 states use quotas to limit tax-free tobacco available to tribes. Many states with a tribal presence have no formal strategies for non-members purchasing tobacco on tribal lands. Formalising policies and harmonising tax rates may assist states in collecting tax revenue from non-tribal consumers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  19. Low-temperature thermal expansion

    International Nuclear Information System (INIS)

    Collings, E.W.

    1986-01-01

    This chapter discusses the thermal expansion of insulators and metals. Harmonicity and anharmonicity in thermal expansion are examined. The electronic, magnetic, an other contributions to low temperature thermal expansion are analyzed. The thermodynamics of the Debye isotropic continuum, the lattice-dynamical approach, and the thermal expansion of metals are discussed. Relative linear expansion at low temperatures is reviewed and further calculations of the electronic thermal expansion coefficient are given. Thermal expansions are given for Cu, Al and Ti. Phenomenologic thermodynamic relationships are also discussed

  20. Are mechanically sensitive regulators involved in the function and (patho)physiology of cerebral palsy-related contractures?

    Science.gov (United States)

    Pingel, Jessica; Suhr, Frank

    2017-08-01

    Skeletal muscle tissue is mechanosensitive, as it is able to sense mechanical impacts and to translate these into biochemical signals making the tissue adapt. Among its mechanosensitive nature, skeletal muscle tissue is the largest metabolic organ of the human body. Disturbances in skeletal muscle mechanosensing and metabolism cause and contribute to many diseases, i.e. muscular dystrophies/myopathies, cardiovascular diseases, COPD or diabetes mellitus type 2. A less commonly focused muscle-related disorder is clinically known as muscle contractures that derive from cerebral palsy (CP) conditions in young and adults. Muscle contractures are characterized by gradually increasing passive muscle stiffness resulting in complete fixation of joints. Different mechanisms have been identified in CP-related contractures, i.e. altered calcium handling, altered metabolism or altered titin regulation. The muscle-related extracellular matrix (ECM), specifically collagens, plays a role in CP-related contractures. Herein, we focus on mechanically sensitive complexes, known as costameres (Cstms), and discuss their potential role in CP-related contractures. We extend our discussion to the ECM due to the limited knowledge of its role in CP-related contractures. The aims of this review are (1) to summarize CP-related contracture mechanisms, (2) to raise novel hypotheses on the genesis of contractures with a focus on Cstms, and (3) to stimulate novel approaches to study CP-related contractures.

  1. [New theory of holistic integrative physiology and medicine. III: New insight of neurohumoral mechanism and pattern of control and regulation for core axe of respiration, circulation and metabolism].

    Science.gov (United States)

    Sun, Xing-guo

    2015-07-01

    Systemic mechanism of neurohumoral control and regulation for human is limited. We used the new theory of holistic integrative physiology and medicine to approach the mechanism and pattern of neurohumoral control and regulation for life. As the core of human life, there are two core axes of functions. The first one is the common goal of respiration and circulation to transport oxygen and carbon dioxide for cells, and the second one is the goal of gastrointestinal tract and circulation to transport energy material and metabolic product for cells. These two core axes maintain the metabolism. The neurohumoral regulation is holistically integrated and unified for all functions in human body. We simplified explain the mechanism of neurohumoral control and regulation life (respiration and circulation) as the example pattern of sound system. Based upon integrated regulation of life, we described the neurohumoral pattern to control respiration and circulation.

  2. Biophysical modeling of in vitro and in vivo processes underlying regulated photoprotective mechanism in cyanobacteria.

    Science.gov (United States)

    Shirshin, Evgeny A; Nikonova, Elena E; Kuzminov, Fedor I; Sluchanko, Nikolai N; Elanskaya, Irina V; Gorbunov, Maxim Y; Fadeev, Victor V; Friedrich, Thomas; Maksimov, Eugene G

    2017-09-01

    Non-photochemical quenching (NPQ) is a mechanism responsible for high light tolerance in photosynthetic organisms. In cyanobacteria, NPQ is realized by the interplay between light-harvesting complexes, phycobilisomes (PBs), a light sensor and effector of NPQ, the photoactive orange carotenoid protein (OCP), and the fluorescence recovery protein (FRP). Here, we introduced a biophysical model, which takes into account the whole spectrum of interactions between PBs, OCP, and FRP and describes the experimental PBs fluorescence kinetics, unraveling interaction rate constants between the components involved and their relative concentrations in the cell. We took benefit from the possibility to reconstruct the photoprotection mechanism and its parts in vitro, where most of the parameters could be varied, to develop the model and then applied it to describe the NPQ kinetics in the Synechocystis sp. PCC 6803 mutant lacking photosystems. Our analyses revealed  that while an excess of the OCP over PBs is required to obtain substantial PBs fluorescence quenching in vitro, in vivo the OCP/PBs ratio is less than unity, due to higher local concentration of PBs, which was estimated as ~10 -5 M, compared to in vitro experiments. The analysis of PBs fluorescence recovery on the basis of the generalized model of enzymatic catalysis resulted in determination of the FRP concentration in vivo close to 10% of the OCP concentration. Finally, the possible role of the FRP oligomeric state alteration in the kinetics of PBs fluorescence was shown. This paper provides the most comprehensive model of the OCP-induced PBs fluorescence quenching to date and the results are important for better understanding of the regulatory molecular mechanisms underlying NPQ in cyanobacteria.

  3. Mechanisms Regulating Acid-Base Transporter Expression in Breast- and Pancreatic Cancer

    DEFF Research Database (Denmark)

    Gorbatenko, Andrej

    , characteristics of which are a shift towards glycolytic metabolism and increased acid production. HER2 receptor overexpression in breast cancer leads to further increased glycolysis, invasion and metastasis, drug resistance and poor prognosis. Increased tumor glycolysis requires acquisition of mechanisms...... for dealing with excess acid production. In this light, evidence accumulates on the importance of pH regulatory proteins to cancer cell survival and motility. Our group previously demonstrated upregulation of the Na+/HCO3 - co-transporter NBCn1 (SLC4A7) by a constitutively active form of HER2 receptor (p95HER...

  4. Diacylglycerol kinase ζ regulates RhoA activation via a kinase-independent scaffolding mechanism

    DEFF Research Database (Denmark)

    Ard, Ryan; Mulatz, Kirk; Abramovici, Hanan

    2012-01-01

    , but the underlying mechanisms are unclear. Diacylglycerol kinase ζ (DGKζ), which phosphorylates diacylglycerol to yield phosphatidic acid, selectively dissociates Rac1 by stimulating PAK1-mediated phosphorylation of RhoGDI on Ser-101/174. Similarly, phosphorylation of RhoGDI on Ser-34 by protein kinase Cα (PKCα......GDI and was required for efficient interaction of PKCα and RhoA. DGKζ-null fibroblasts had condensed F-actin bundles and altered focal adhesion distribution, indicative of aberrant RhoA signaling. Two targets of the RhoA effector ROCK showed reduced phosphorylation in DGKζ-null cells. Collectively our findings suggest...

  5. Molecular mechanisms regulating oxygen transport and consumption in high altitude and hibernating mammals

    DEFF Research Database (Denmark)

    Revsbech, Inge Grønvall

    2016-01-01

    The aim of this thesis is to broaden the knowledge of molecular mechanisms of adjustment in oxygen (O2) uptake, conduction, delivery and consumption in mammals adapted to extreme conditions. For this end, I have worked with animals living at high altitude as an example of environmental hypoxia...... of the repeatedly found adaptive traits in animals living at high altitude and in hibernating mammals during hibernation compared with the active state. Factors that affect O2 affinity of Hb include temperature, H+/CO2 via the Bohr effect as well as Cl- and organic phosphates, in mammals mainly 2...

  6. BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional mechanism.

    Science.gov (United States)

    Rodríguez, Andrea E; López-Crisosto, Camila; Peña-Oyarzún, Daniel; Salas, Daniela; Parra, Valentina; Quiroga, Clara; Morawe, Tobias; Chiong, Mario; Behl, Christian; Lavandero, Sergio

    2016-01-01

    Autophagy is mainly regulated by post-translational and lipid modifications of ATG proteins. In some scenarios, the induction of autophagy is accompanied by increased levels of certain ATG mRNAs such as MAP1LC3B/LC3B, ATG5 or ATG12. However, little is known about the regulation of ATG protein synthesis at the translational level. The cochaperone of the HSP70 system BAG3 (BCL2-associated athanogene 3) has been associated to LC3B lipidation through an unknown mechanism. In the present work, we studied how BAG3 controls autophagy in HeLa and HEK293 cells. Our results showed that BAG3 regulates the basal amount of total cellular LC3B protein by controlling its mRNA translation. This effect was apparently specific to LC3B because other ATG protein levels were not affected. BAG3 knockdown did not affect LC3B lipidation induced by nutrient deprivation or proteasome inhibition. We concluded that BAG3 maintains the basal amount of LC3B protein by controlling the translation of its mRNA in HeLa and HEK293 cells.

  7. Epigenetic Mechanisms Regulate Innate Immunity against Uropathogenic and Commensal-Like Escherichia coli in the Surrogate Insect Model Galleria mellonella.

    Science.gov (United States)

    Heitmueller, Miriam; Billion, André; Dobrindt, Ulrich; Vilcinskas, Andreas; Mukherjee, Krishnendu

    2017-10-01

    Innate-immunity-related genes in humans are activated during urinary tract infections (UTIs) caused by pathogenic strains of Escherichia coli but are suppressed by commensals. Epigenetic mechanisms play a pivotal role in the regulation of gene expression in response to environmental stimuli. To determine whether epigenetic mechanisms can explain the different behaviors of pathogenic and commensal bacteria, we infected larvae of the greater wax moth, Galleria mellonella , a widely used model insect host, with a uropathogenic E. coli (UPEC) strain that causes symptomatic UTIs in humans or a commensal-like strain that causes asymptomatic bacteriuria (ABU). Infection with the UPEC strain (CFT073) was more lethal to larvae than infection with the attenuated ABU strain (83972) due to the recognition of each strain by different Toll-like receptors, ultimately leading to differential DNA/RNA methylation and histone acetylation. We used next-generation sequencing and reverse transcription (RT)-PCR to correlate epigenetic changes with the induction of innate-immunity-related genes. Transcriptomic analysis of G. mellonella larvae infected with E. coli strains CFT073 and 83972 revealed strain-specific variations in the class and expression levels of genes encoding antimicrobial peptides, cytokines, and enzymes controlling DNA methylation and histone acetylation. Our results provide evidence for the differential epigenetic regulation of transcriptional reprogramming by UPEC and ABU strains of E. coli in G. mellonella larvae, which may be relevant to understanding the different behaviors of these bacterial strains in the human urinary tract. Copyright © 2017 American Society for Microbiology.

  8. Empirical Validation of a Hypothesis of the Hormetic Selective Forces Driving the Evolution of Longevity Regulation Mechanisms

    Directory of Open Access Journals (Sweden)

    Alejandra Gomez-Perez

    2016-12-01

    Full Text Available Exogenously added lithocholic bile acid and some other bile acids slow down yeast chronological aging by eliciting a hormetic stress response and altering mitochondrial functionality. Unlike animals, yeast cells do not synthesize bile acids. We therefore hypothesized that bile acids released into an ecosystem by animals may act as interspecies chemical signals that generate selective pressure for the evolution of longevity regulation mechanisms in yeast within this ecosystem. To empirically verify our hypothesis, in this study we carried out a 3-step process for the selection of long-lived yeast species by a long-term exposure to exogenous lithocholic bile acid. Such experimental evolution yielded 20 long-lived mutants, 3 of which were capable of sustaining their considerably prolonged chronological lifespans after numerous passages in medium without lithocholic acid. The extended longevity of each of the 3 long-lived yeast species was a dominant polygenic trait caused by mutations in more than two nuclear genes. Each of the 3 mutants displayed considerable alterations to the age-related chronology of mitochondrial respiration and showed enhanced resistance to chronic oxidative, thermal and osmotic stresses. Our findings empirically validate the hypothesis suggesting that hormetic selective forces can drive the evolution of longevity regulation mechanisms within an ecosystem.

  9. The fidelity of synaptonemal complex assembly is regulated by a signaling mechanism that controls early meiotic progression.

    Science.gov (United States)

    Silva, Nicola; Ferrandiz, Nuria; Barroso, Consuelo; Tognetti, Silvia; Lightfoot, James; Telecan, Oana; Encheva, Vesela; Faull, Peter; Hanni, Simon; Furger, Andre; Snijders, Ambrosius P; Speck, Christian; Martinez-Perez, Enrique

    2014-11-24

    Proper chromosome segregation during meiosis requires the assembly of the synaptonemal complex (SC) between homologous chromosomes. However, the SC structure itself is indifferent to homology, and poorly understood mechanisms that depend on conserved HORMA-domain proteins prevent ectopic SC assembly. Although HORMA-domain proteins are thought to regulate SC assembly as intrinsic components of meiotic chromosomes, here we uncover a key role for nuclear soluble HORMA-domain protein HTP-1 in the quality control of SC assembly. We show that a mutant form of HTP-1 impaired in chromosome loading provides functionality of an HTP-1-dependent checkpoint that delays exit from homology search-competent stages until all homolog pairs are linked by the SC. Bypassing of this regulatory mechanism results in premature meiotic progression and licensing of homology-independent SC assembly. These findings identify nuclear soluble HTP-1 as a regulator of early meiotic progression, suggesting parallels with the mode of action of Mad2 in the spindle assembly checkpoint. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Lace expansion for dummies

    NARCIS (Netherlands)

    Bolthausen, Erwin; Van Der Hofstad, Remco; Kozma, Gady

    2018-01-01

    We show Green's function asymptotic upper bound for the two-point function of weakly self-Avoiding walk in d >4, revisiting a classic problem. Our proof relies on Banach algebras to analyse the lace-expansion fixed point equation and is simpler than previous approaches in that it avoids Fourier

  11. OPEC future capacity expansions

    International Nuclear Information System (INIS)

    Sandrea, I.

    2005-01-01

    This conference presentation examined OPEC future capacity expansions including highlights from 2000-2004 from the supply perspective and actions by OPEC; OPEC spare capacity in 2005/2006; medium-term capacity expansion and investments; long-term scenarios, challenges and opportunities; and upstream policies in member countries. Highlights from the supply perspective included worst than expected non-OPEC supply response; non-OPEC supply affected by a number of accidents and strikes; geopolitical tensions; and higher than expected demand for OPEC crude. OPEC's actions included closer relationship with other producers and consumers; capacity expansions in 2004 and 2005/2006; and OPEC kept the market well supplied with crude in 2004. The presentation also provided data using graphical charts on OPEC net capacity additions until 2005/2006; OPEC production versus spare capacity from 2003 to 2005; OPEC production and capacity to 2010; and change in required OPEC production from 2005-2020. Medium term expansion to 2010 includes over 60 projects. Medium-term risks such as project execution, financing, costs, demand, reserves, depletion, integration of Iraq, and geopolitical tensions were also discussed. The presentation concluded that in the long term, large uncertainties remain; the peak of world supply is not imminent; and continued and enhanced cooperation is essential to market stability. tabs., figs

  12. AUTO-EXPANSIVE FLOW

    Science.gov (United States)

    Physics suggests that the interplay of momentum, continuity, and geometry in outward radial flow must produce density and concomitant pressure reductions. In other words, this flow is intrinsically auto-expansive. It has been proposed that this process is the key to understanding...

  13. Regulation mechanisms of pituitary-thyroid axis in normal subjects and patients with Graves' disease

    International Nuclear Information System (INIS)

    Takagi, Shinko; Yamauchi, Kazuyuki; Mori, Yuichi

    1986-01-01

    The regulatory mechanism of the pituitary-thyroid axis in normal subjects and patients with Graves' disease was investigated using a highly sensitive TSH assay based on the immunoradiometric assay. All of the normal subjects had detectable TSH values within the range 0.35 to 6.0 μU/ml. No negative correlations between TSH and free thyroid hormones existed in normal subjects. Patients with thyroid carcinoma who seemed to have normal pituitary-thyroid function showed a rapid increase of TSH after total thyroidectomy. On the other hand, while untreated patients with Graves' disease all had undetectable TSH values, these patients took 1 to 3.5 months longer to normalize their TSH values than to normalize free thyroid hormones on antithyroid drug therapy. During the recovery phase by the treatment with decrease of antithyroid drug or supplement of T 4 from iatrogenic hypothyroid state after treatment for Graves' disease and thyroid carcinoma, normalization of TSH levels was delayed than that of free thyroid hormones. Patients with Graves' disease in remission showed an extremely positive correlation between basal and peak TSH levels in TRH test, and a negative correlation between basal TSH and FT 4 . In conclusion, an individual patient may have a different set point concerning the regulatory mechanism of the pituitary-thyroid axis, and the persistence of the hyperthyroid state would seem to have caused some reversible dysfunction of the pituitary gland. (author)

  14. Mechanisms regulating the reduction of selenite by aerobic gram (+) and (-) bacteria

    International Nuclear Information System (INIS)

    Garbisu, C.; Ishii, Takahisa; Yee, B.C.; Carlson, D.E.; Buchanan, B.B.; Leighton, T.; Smith, N.R.; Yee, A.

    1995-01-01

    Toxic species of selenium are pollutants found in agricultural and oil refinery wastestreams. Selenium contamination is particularly problematic in areas that have seleniferous subsurface geology, such as the central valley of California. The authors are developed a bacterial treatment system to mitigate selenium-contaminated wastestreams using Bacillus subtilis and Pseudomonas fluorescens, respectively, as model gram (+) and (-) soil bacteria. They have found that, during growth, both organisms reduce selenite, a major soluble toxic species, to red elemental selenium--an insoluble product generally regarded as nontoxic. In both cases, reduction depended on growth substrate and was effected by an inducible system that effectively removed selenite at concentrations typical of polluted sites--i.e., 50 to 300 microg/L. The bacteria studied differed in one respect: when grown in medium supplemented with nitrate or sulfate, the ability of P. fluorescens to remediate selenite was enhanced, whereas that of B. subtilis was unchanged. Current efforts are being directed toward understanding the biochemical mechanism(s) of detoxification and determining whether bacteria occurring in polluted environments such as soils and sludge systems are capable of selenite remediation

  15. On a generalized oscillator system: interbasis expansions

    Energy Technology Data Exchange (ETDEWEB)

    Kibler, M [Lyon-1 Univ., 69 - Villeurbanne (France). Inst. de Physique Nucleaire; Mardoyan, L G; Pogosyan, G S [Joint Inst. for Nuclear Research, Dubna (Russian Federation). Lab. of Theoretical Physics

    1997-12-31

    This article deals with a nonrelativistic quantum mechanical study of a dynamical system which generalizes the isotropic harmonic oscillator system in three dimensions. The Schroedinger equation for this generalized oscillator system is separable in spherical, cylindrical, and spheroidal (prolate and oblate) coordinates. The quantum mechanical spectrum of this system is worked out in some details. The problem of interbasis expansions of the wave functions is completely solved. The coefficients for the expansion of the cylindrical basis in terms of the spherical basis, and vice-versa, are found to be analytic continuations (to real values of their arguments) of Clebsch-Gordan coefficients for the group SU(2). The interbasis expansion coefficients for the prolate and oblate spheroidal bases in terms of the spherical or the cylindrical bases are shown to satisfy three-term recursion relations. Finally, a connection between the generalized oscillator system (projected on the z-line) and the Morse system (in one dimension) are discussed. 41 refs.,.

  16. On a generalized oscillator system: interbasis expansions

    International Nuclear Information System (INIS)

    Kibler, M.; Mardoyan, L.G.; Pogosyan, G.S.

    1996-01-01

    This article deals with a nonrelativistic quantum mechanical study of a dynamical system which generalizes the isotropic harmonic oscillator system in three dimensions. The Schroedinger equation for this generalized oscillator system is separable in spherical, cylindrical, and spheroidal (prolate and oblate) coordinates. The quantum mechanical spectrum of this system is worked out in some details. The problem of interbasis expansions of the wave functions is completely solved. The coefficients for the expansion of the cylindrical basis in terms of the spherical basis, and vice-versa, are found to be analytic continuations (to real values of their arguments) of Clebsch-Gordan coefficients for the group SU(2). The interbasis expansion coefficients for the prolate and oblate spheroidal bases in terms of the spherical or the cylindrical bases are shown to satisfy three-term recursion relations. Finally, a connection between the generalized oscillator system (projected on the z-line) and the Morse system (in one dimension) are discussed. 41 refs.,

  17. Transport mechanisms and their pathology-induced regulation govern tyrosine kinase inhibitor delivery in rheumatoid arthritis.

    Directory of Open Access Journals (Sweden)

    Christian Schmidt-Lauber

    Full Text Available BACKGROUND: Tyrosine kinase inhibitors (TKIs are effective in treating malignant disorders and were lately suggested to have an impact on non-malignant diseases. However, in some inflammatory conditions like rheumatoid arthritis (RA the in vivo effect seemed to be moderate. As most TKIs are taken up actively into cells by cell membrane transporters, this study aimed to evaluate the role of such transporters for the accumulation of the TKI Imatinib mesylates in RA synovial fibroblasts as well as their regulation under inflammatory conditions. METHODOLOGY/PRINCIPAL FINDINGS: The transport and accumulation of Imatinib was investigated in transporter-transfected HEK293 cells and human RA synovial fibroblasts (hRASF. Transporter expression was quantified by qRT-PCR. In transfection experiments, hMATE1 showed the highest apparent affinity for Imatinib among all known Imatinib transporters. Experiments quantifying the Imatinib uptake in the presence of specific transporter inhibitors and after siRNA knockdown of hMATE1 indeed identified hMATE1 to mediate Imatinib transport in hRASF. The anti-proliferative effect of Imatinib on PDGF stimulated hRASF was quantified by cell counting and directly correlated with the uptake activity of hMATE1. Expression of hMATE1 was investigated by Western blot and immuno-fluorescence. Imatinib transport under disease-relevant conditions, such as an altered pH and following stimulation with different cytokines, was also investigated by HPLC. The uptake was significantly reduced by an acidic extracellular pH as well as by the cytokines TNFα, IL-1β and IL-6, which all decreased the expression of hMATE1-mRNA and protein. CONCLUSION/SIGNIFICANCE: The regulation of Imatinib uptake via hMATE1 in hRASF and resulting effects on their proliferation may explain moderate in vivo effects on RA. Moreover, our results suggest that investigating transporter mediated drug processing under normal and pathological conditions is important

  18. Phosphoproteomic Analysis Reveals a Novel Mechanism of CaMKIIα Regulation Inversely Induced by Cocaine Memory Extinction versus Reconsolidation

    Science.gov (United States)

    Rich, Matthew T.; Abbott, Thomas B.; Chung, Lisa; Gulcicek, Erol E.; Stone, Kathryn L.; Colangelo, Christopher M.; Lam, TuKiet T.; Nairn, Angus C.; Taylor, Jane R.

    2016-01-01

    Successful addiction treatment depends on maintaining long-term abstinence, making relapse prevention an essential therapeutic goal. However, exposure to environmental cues associated with drug use often thwarts abstinence efforts by triggering drug using memories that drive craving and relapse. We sought to develop a dual approach for weakening cocaine memories through phosphoproteomic identification of targets regulated in opposite directions by memory extinction compared with reconsolidation in male Sprague-Dawley rats that had been trained to self-administer cocaine paired with an audiovisual cue. We discovered a novel, inversely regulated, memory-dependent phosphorylation event on calcium-calmodulin-dependent kinase II α (CaMKIIα) at serine (S)331. Correspondingly, extinction-associated S331 phosphorylation inhibited CaMKIIα activity. Intra-basolateral amygdala inhibition of CaMKII promoted memory extinction and disrupted reconsolidation, leading to a reduction in subsequent cue-induced reinstatement. CaMKII inhibition had no effect if the memory was neither retrieved nor extinguished. Therefore, inhibition of CaMKII represents a novel mechanism for memory-based addiction treatment that leverages both extinction enhancement and reconsolidation disruption to reduce relapse-like behavior. SIGNIFICANCE STATEMENT Preventing relapse to drug use is an important goal for the successful treatment of addictive disorders. Relapse-prevention therapies attempt to interfere with drug-associated memories, but are often hindered by unintentional memory strengthening. In this study, we identify phosphorylation events that are bidirectionally regulated by the reconsolidation versus extinction of a cocaine-associated memory, including a novel site on CaMKIIα. Additionally, using a rodent model of addiction, we show that CaMKII inhibition in the amygdala can reduce relapse-like behavior. Together, our data supports the existence of mechanisms that can be used to enhance

  19. Dna2 nuclease-helicase structure, mechanism and regulation by Rpa.

    Science.gov (United States)

    Zhou, Chun; Pourmal, Sergei; Pavletich, Nikola P

    2015-11-02

    The Dna2 nuclease-helicase maintains genomic integrity by processing DNA double-strand breaks, Okazaki fragments and stalled replication forks. Dna2 requires ssDNA ends, and is dependent on the ssDNA-binding protein Rpa, which controls cleavage polarity. Here we present the 2.3 Å structure of intact mouse Dna2 bound to a 15-nucleotide ssDNA. The nuclease active site is embedded in a long, narrow tunnel through which the DNA has to thread. The helicase domain is required for DNA binding but not threading. We also present the structure of a flexibly-tethered Dna2-Rpa interaction that recruits Dna2 to Rpa-coated DNA. We establish that a second Dna2-Rpa interaction is mutually exclusive with Rpa-DNA interactions and mediates the displacement of Rpa from ssDNA. This interaction occurs at the nuclease tunnel entrance and the 5' end of the Rpa-DNA complex. Hence, it only displaces Rpa from the 5' but not 3' end, explaining how Rpa regulates cleavage polarity.

  20. Testing optimal punishment mechanisms under price regulation : the case of the retail market for gasoline

    International Nuclear Information System (INIS)

    Gagne, R.; Versaevel, B.

    2003-01-01

    The effects of a price floor on price wars in the retail market for gasoline were analyzed. The authors selected a theoretical model which assumed a Bertrand oligopoly supergame, where firms initially collude by charging the monopolistic price. Once a deviation from this strategy is detected by the firms, a switch to a lower price is made in what can be called a punishment phase (price war), before returning to collusive prices. A natural experiment for the testing of the model was provided by the introduction of a price floor regulation in the Quebec retail market for gasoline in 1996. A Markov Switching Model with two latent states was used to simultaneously identify the periods of price-collusion/price war, and also to estimate the parameters which characterized each state. The results indicated that the intensity of price wars was reduced by the introduction of the price floor, but the expected duration of those wars was raised. 14 refs., 5 tabs., 1 fig

  1. Role of orexins in the central and peripheral regulation of glucose homeostasis: Evidences & mechanisms.

    Science.gov (United States)

    Rani, Monika; Kumar, Raghuvansh; Krishan, Pawan

    2018-04-01

    Orexins (A & B), neuropeptides of hypothalamic origin, act through G-protein coupled receptors, orexin 1 receptor (OX 1 R) and orexin 2 receptor (OX 2 R). The wide projection of orexin neurons in the hypothalamic region allows them to interact with the other neurons and regulate food intake, emotional status, sleep wake cycle and energy metabolism. The autonomic nervous system plays an important regulatory role in the energy metabolism as well as glucose homeostasis. Orexin neurons are also under the control of GABAergic neurons. Emerging preclinical as well as clinical research has reported the role of orexins in the glucose homeostasis since orexins are involved in hypothalamic metabolism circuitry and also rely on sensing peripheral metabolic signals such as gut, adipose derived and pancreatic peptides. Apart from the hypothalamic origin, integration and control in various physiological functions, peripheral origin in wide organs, raises the possibility of use of orexins as a therapeutic biomarker in the management of metabolic disorders. The present review focuses the central as well as peripheral roles of orexins in the glucose homeostasis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models.

    Science.gov (United States)

    Orsini, Caitlin A; Moorman, David E; Young, Jared W; Setlow, Barry; Floresco, Stan B

    2015-11-01

    Over the past 20 years there has been a growing interest in the neural underpinnings of cost/benefit decision-making. Recent studies with animal models have made considerable advances in our understanding of how different prefrontal, striatal, limbic and monoaminergic circuits interact to promote efficient risk/reward decision-making, and how dysfunction in these circuits underlies aberrant decision-making observed in numerous psychiatric disorders. This review will highlight recent findings from studies exploring these questions using a variety of behavioral assays, as well as molecular, pharmacological, neurophysiological, and translational approaches. We begin with a discussion of how neural systems related to decision subcomponents may interact to generate more complex decisions involving risk and uncertainty. This is followed by an overview of interactions between prefrontal-amygdala-dopamine and habenular circuits in regulating choice between certain and uncertain rewards and how different modes of dopamine transmission may contribute to these processes. These data will be compared with results from other studies investigating the contribution of some of these systems to guiding decision-making related to rewards vs. punishment. Lastly, we provide a brief summary of impairments in risk-related decision-making associated with psychiatric disorders, highlighting recent translational studies in laboratory animals. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. G protein-coupled receptor 56 regulates mechanical overload-induced muscle hypertrophy.

    Science.gov (United States)

    White, James P; Wrann, Christiane D; Rao, Rajesh R; Nair, Sreekumaran K; Jedrychowski, Mark P; You, Jae-Sung; Martínez-Redondo, Vicente; Gygi, Steven P; Ruas, Jorge L; Hornberger, Troy A; Wu, Zhidan; Glass, David J; Piao, Xianhua; Spiegelman, Bruce M

    2014-11-04

    Peroxisome proliferator-activated receptor gamma coactivator 1-alpha 4 (PGC-1α4) is a protein isoform derived by alternative splicing of the PGC1α mRNA and has been shown to promote muscle hypertrophy. We show here that G protein-coupled receptor 56 (GPR56) is a transcriptional target of PGC-1α4 and is induced in humans by resistance exercise. Furthermore, the anabolic effects of PGC-1α4 in cultured murine muscle cells are dependent on GPR56 signaling, because knockdown of GPR56 attenuates PGC-1α4-induced muscle hypertrophy in vitro. Forced expression of GPR56 results in myotube hypertrophy through the expression of insulin-like growth factor 1, which is dependent on Gα12/13 signaling. A murine model of overload-induced muscle hypertrophy is associated with increased expression of both GPR56 and its ligand collagen type III, whereas genetic ablation of GPR56 expression attenuates overload-induced muscle hypertrophy and associated anabolic signaling. These data illustrate a signaling pathway through GPR56 which regulates muscle hypertrophy associated with resistance/loading-type exercise.

  4. Mitotic Spindle Asymmetry: A Wnt/PCP-Regulated Mechanism Generating Asymmetrical Division in Cortical Precursors

    Directory of Open Access Journals (Sweden)

    Delphine Delaunay

    2014-01-01

    Full Text Available The regulation of asymmetric cell division (ACD during corticogenesis is incompletely understood. We document that spindle-size asymmetry (SSA between the two poles occurs during corticogenesis and parallels ACD. SSA appears at metaphase and is maintained throughout division, and we show it is necessary for proper neurogenesis. Imaging of spindle behavior and division outcome reveals that neurons preferentially arise from the larger-spindle pole. Mechanistically, SSA magnitude is controlled by Wnt7a and Vangl2, both members of the Wnt/planar cell polarity (PCP-signaling pathway, and relayed to the cell cortex by P-ERM proteins. In vivo, Vangl2 and P-ERM downregulation promotes early cell-cycle exit and prevents the proper generation of late-born neurons. Thus, SSA is a core component of ACD that is conserved in invertebrates and vertebrates and plays a key role in the tight spatiotemporal control of self-renewal and differentiation during mammalian corticogenesis.

  5. Testing optimal punishment mechanisms under price regulation : the case of the retail market for gasoline

    Energy Technology Data Exchange (ETDEWEB)

    Gagne, R. [Montreal Univ., Quebec, PQ (Canada). Ecole des Hautes Etudes Commerciales; Van Norden, S. [Montreal Univ., Quebec, PQ (Canada). Ecole des Hautes Etudes Commerciales]|[Centre for Interuniversity Research and Analysis on Organizations, Montreal, PQ (Canada); Versaevel, B.

    2003-09-01

    The effects of a price floor on price wars in the retail market for gasoline were analyzed. The authors selected a theoretical model which assumed a Bertrand oligopoly supergame, where firms initially collude by charging the monopolistic price. Once a deviation from this strategy is detected by the firms, a switch to a lower price is made in what can be called a punishment phase (price war), before returning to collusive prices. A natural experiment for the testing of the model was provided by the introduction of a price floor regulation in the Quebec retail market for gasoline in 1996. A Markov Switching Model with two latent states was used to simultaneously identify the periods of price-collusion/price war, and also to estimate the parameters which characterized each state. The results indicated that the intensity of price wars was reduced by the introduction of the price floor, but the expected duration of those wars was raised. 14 refs., 5 tabs., 1 fig.

  6. Mechanism of H₂O₂-induced oxidative stress regulating viability and biocontrol ability of Rhodotorula glutinis.

    Science.gov (United States)

    Chen, Jian; Li, Boqiang; Qin, Guozheng; Tian, Shiping

    2015-01-16

    The use of antagonistic yeasts to control postharvest pathogens is a promising alternative to fungicides. The effectiveness of the antagonists against fungal pathogens is greatly dependent on their viability, which is usually mediated by reactive oxygen species (ROS). Here, we investigated the effects of H₂O₂-induced oxidative stress on the viability and biocontrol efficacy of Rhodotorula glutinis and, using flow cytometric analysis, observed the changes of ROS accumulation and apoptosis in the yeast cells with or without H₂O₂ treatment. We found that the viability of R. glutinis decreased in a time- and dose-dependent manner under H₂O₂-induced oxidative stress. Compared to the control, yeast cells exposed to oxidative stress exhibited more accumulation of ROS and higher levels of protein oxidative damage, but showed lower efficacy for biocontrol of Penicillium expansum causing blue mold rot on peach fruit. The results indicate that apoptosis is a main cause of the cell viability loss in R. glutinis, which is attributed to ROS accumulation under oxidative stress. These findings offer a plausible explanation that oxidative stress affects biocontrol efficacy of R. glutinis via regulating its viability and cell apoptosis. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Deciphering the combinatorial roles of geometric, mechanical, and adhesion cues in regulation of cell spreading.

    Directory of Open Access Journals (Sweden)

    Greg M Harris

    Full Text Available Significant effort has gone towards parsing out the effects of surrounding microenvironment on macroscopic behavior of stem cells. Many of the microenvironmental cues, however, are intertwined, and thus, further studies are warranted to identify the intricate interplay among the conflicting downstream signaling pathways that ultimately guide a cell response. In this contribution, by patterning adhesive PEG (polyethylene glycol hydrogels using Dip Pen Nanolithography (DPN, we demonstrate that substrate elasticity, subcellular elasticity, ligand density, and topography ultimately define mesenchymal stem cells (MSCs spreading and shape. Physical characteristics are parsed individually with 7 kilopascal (kPa hydrogel islands leading to smaller, spindle shaped cells and 105 kPa hydrogel islands leading to larger, polygonal cell shapes. In a parallel effort, a finite element model was constructed to characterize and confirm experimental findings and aid as a predictive tool in modeling cell microenvironments. Signaling pathway inhibition studies suggested that RhoA is a key regulator of cell response to the cooperative effect of the tunable substrate variables. These results are significant for the engineering of cell-extra cellular matrix interfaces and ultimately decoupling matrix bound cues presented to cells in a tissue microenvironment for regenerative medicine.

  8. Immune mechanisms regulating pharmacokinetics and pharmacodynamics of PEGylated liposomal anticancer agents

    Science.gov (United States)

    Song, Gina

    Nanotechnology has made significant advances in drug delivery system for the treatment of cancer. Among various nanoparticle (NP) platforms, liposomes have been most widely used as a NP drug carrier for cancer therapy. High variation in pharmacokinetics (PK) and pharmacodynamics (PD) of liposome-based therapeutics has been reported. However, the interaction of liposome-based therapeutics with the immune system, specifically the mononuclear phagocyte system (MPS), and underlying molecular mechanisms for variable responses to liposomal drugs remain poorly understood. The objective of this dissertation was to elucidate immune mechanisms for the variable responses to PEGylated liposomal doxorubicin (PLD; DoxilRTM), a clinically relevant NP, in animal models and in patients. In vitro, in vivo and clinical systems were investigated to evaluate the effects of chemokines (CCL2 and CCL5), heterogeneity of the tumor microenvironment, and genetic variations on PK and PD of PLD. Results showed that there was a significantly positive linear relationship between PLD exposure (AUC) and total amount of CCL2 and CCL5, most prevalent chemokines in plasma, in patients with recurrent ovarian cancer. Consistent with these findings, preclinical studies using mice bearing SKOV3 orthotopic ovarian cancer xenografts demonstrated that PLD induced the production and secretion of chemokines into plasma. In addition, in vitro studies using human monocytic THP-1 cells demonstrated that PLD altered monocyte migration towards CCL2 and CCL5. The PK and efficacy studies of PLD in murine models of breast cancer showed that heterogeneous tumor microenvironment was associated with significantly different tumor delivery and efficacy of PLD, but not small molecule doxorubicin between two breast tumor models. A candidate genetic locus that was associated with clearance of PLD in 23 inbred mouse strains contains a gene that encodes for engulfment adapter PTB domain containing 1 (Gulp1). By using

  9. Subordinate Mechanism of Legal Regulation of Relations in the Framework of the Contract Procurement System to Meet the Needs of the Public

    Directory of Open Access Journals (Sweden)

    Evgeny V. Solomonov

    2016-01-01

    Full Text Available The article discusses the theoretical issues of legal regulation mechanism features of separate stages of public procurement. Conclusions about the legal nature of the type of legal regulation, its relationship with the peculiarities of the legal facts and legal relations are given.

  10. Effects of sex steroids on expression of genes regulating growth-related mechanisms in rainbow trout (Oncorhynchus mykiss).

    Science.gov (United States)

    Cleveland, Beth M; Weber, Gregory M

    2015-05-15

    Effects of a single injection of 17β-estradiol (E2), testosterone (T), or 5β-dihydrotestosterone (DHT) on expression of genes central to the growth hormone (GH)/insulin-like growth factor (IGF) axis, muscle-regulatory factors, transforming growth factor-beta (TGFβ) superfamily signaling cascade, and estrogen receptors were determined in rainbow trout (Oncorhynchus mykiss) liver and white muscle tissue. In liver in addition to regulating GH sensitivity and IGF production, sex steroids also affected expression of IGF binding proteins, as E2, T, and DHT increased expression of igfbp2b and E2 also increased expression of igfbp2 and igfbp4. Regulation of this system also occurred in white muscle in which E2 increased expression of igf1, igf2, and igfbp5b1, suggesting anabolic capacity may be maintained in white muscle in the presence of E2. In contrast, DHT decreased expression of igfbp5b1. DHT and T decreased expression of myogenin, while other muscle regulatory factors were either not affected or responded similarly for all steroid treatments. Genes within the TGFβ superfamily signaling cascade responded to steroid treatment in both liver and muscle, suggesting a regulatory role for sex steroids in the ability to transmit signals initiated by TGFβ superfamily ligands, with a greater number of genes responding in liver than in muscle. Estrogen receptors were also regulated by sex steroids, with era1 expression increasing for all treatments in muscle, but only E2- and T-treatment in liver. E2 reduced expression of erb2 in liver. Collectively, these data identify how physiological mechanisms are regulated by sex steroids in a manner that promotes the disparate effects of androgens and estrogens on growth in salmonids. Published by Elsevier Inc.

  11. A self-regulating braking mechanism in black-hole X-ray binaries

    International Nuclear Information System (INIS)

    Meyer, F.; Meyer-Hofmeister, E.

    2001-01-01

    The outbursts of black hole X-ray transients can be understood as caused by a limit cycle instability in the accretion disk, similar to dwarf nova outbursts. For adequately low mass overflow rates from the companion star long outburst recurrence times are expected. Buth the fact that we find predominantly long recurrence times or that only one X-ray nova outburst was detected at all poses a problem. The question arises whether any braking mechanism could act in a way that long recurrence times are favoured. We suggest that a circumbinary disk exists and brakes the orbital motion of the binary stars by tidal interaction. The irradiation during an outburst leads to mass loss by winds from the circumbinary disk, relieving the braking force until the removed matter is refilled by diffusion from outer parts. We show that this reduction of braking will self-adjust the mass transfer to the marginal rate that gives long recurrence times. (orig.)

  12. A complementary switching mechanism for organic memory devices to regulate the conductance of binary states

    Science.gov (United States)

    Vyas, Giriraj; Dagar, Parveen; Sahu, Satyajit

    2016-06-01

    We have fabricated an organic non-volatile memory device wherein the ON/OFF current ratio has been controlled by varying the concentration of a small organic molecule, 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ), in an insulating matrix of a polymer Poly(4-vinylphenol) (PVP). A maximum ON-OFF ratio of 106 is obtained when the concentration of DDQ is half or 10 wt. % of PVP. In this process, the switching direction for the devices has also been altered, indicating the disparity in conduction mechanism. Conduction due to metal filament formation through the active material and the voltage dependent conformational change of the organic molecule seem to be the motivation behind the gradual change in the switching direction.

  13. Angiotensin II regulation of neuromodulation: downstream signaling mechanism from activation of mitogen-activated protein kinase.

    Science.gov (United States)

    Lu, D; Yang, H; Raizada, M K

    1996-12-01

    Angiotensin II (Ang II) stimulates expression of tyrosine hydroxylase and norepinephrine transporter genes in brain neurons; however, the signal-transduction mechanism is not clearly defined. This study was conducted to determine the involvement of the mitogen-activated protein (MAP) kinase signaling pathway in Ang II stimulation of these genes. MAP kinase was localized in the perinuclear region of the neuronal soma. Ang II caused activation of MAP kinase and its subsequent translocation from the cytoplasmic to nuclear compartment, both effects being mediated by AT1 receptor subtype. Ang II also stimulated SRE- and AP1-binding activities and fos gene expression and its translocation in a MAP kinase-dependent process. These observations are the first demonstration of a downstream signaling pathway involving MAP kinase in Ang II-mediated neuromodulation in noradrenergic neurons.

  14. Calcium oscillations in wounded fibroblast monolayers are spatially regulated through substrate mechanics

    Science.gov (United States)

    Lembong, Josephine; Sabass, Benedikt; Stone, Howard A.

    2017-08-01

    The maintenance of tissue integrity is essential for the life of multicellular organisms. Healing of a skin wound is a paradigm for how various cell types localize and repair tissue perturbations in an orchestrated fashion. To investigate biophysical mechanisms associated with wound localization, we focus on a model system consisting of a fibroblast monolayer on an elastic substrate. We find that the creation of an edge in the monolayer causes cytosolic calcium oscillations throughout the monolayer. The oscillation frequency increases with cell density, which shows that wound-induced calcium oscillations occur collectively. Inhibition of myosin II reduces the number of oscillating cells, demonstrating a coupling between actomyosin activity and calcium response. The spatial distribution of oscillating cells depends on the stiffness of the substrate. For soft substrates with a Young’s modulus E ~ 360 Pa, oscillations occur on average within 0.2 mm distance from the wound edge. Increasing substrate stiffness leads to an average localization of oscillations away from the edge (up to ~0.6 mm). In addition, we use traction force microscopy to determine stresses between cells and substrate. We find that an increase of substrate rigidity leads to a higher traction magnitude. For E    ~8 kPa, traction magnitude is on average almost uniform beneath the monolayer. Thus, the spatial occurrence of calcium oscillations correlates with the cell-substrate traction. Overall, the experiments with fibroblasts demonstrate a collective, chemomechanical localization mechanism at the edge of a wound with a potential physiological role.

  15. Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support.

    Science.gov (United States)

    Yang, Kai-Chien; Yamada, Kathryn A; Patel, Akshar Y; Topkara, Veli K; George, Isaac; Cheema, Faisal H; Ewald, Gregory A; Mann, Douglas L; Nerbonne, Jeanne M

    2014-03-04

    Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) expression in failing human heart before and after mechanical support with a left ventricular (LV) assist device (LVAD). Deep sequencing of RNA isolated from paired nonischemic (NICM; n=8) and ischemic (ICM; n=8) human failing LV samples collected before and after LVAD and from nonfailing human LV (n=8) was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with nonfailing LV. Among these, only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18 480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ≈10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes ICM from NICM. Further analysis suggests that cis-gene regulation represents a major mechanism of action of human cardiac lncRNAs. The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

  16. Reversible oxidative modification: a key mechanism of Na+-K+ pump regulation.

    Science.gov (United States)

    Figtree, Gemma A; Liu, Chia-Chi; Bibert, Stephanie; Hamilton, Elisha J; Garcia, Alvaro; White, Caroline N; Chia, Karin K M; Cornelius, Flemming; Geering, Kaethi; Rasmussen, Helge H

    2009-07-17

    Angiotensin II (Ang II) inhibits the cardiac sarcolemmal Na(+)-K(+) pump via protein kinase (PK)C-dependent activation of NADPH oxidase. We examined whether this is mediated by oxidative modification of the pump subunits. We detected glutathionylation of beta(1), but not alpha(1), subunits in rabbit ventricular myocytes at baseline. beta(1) Subunit glutathionylation was increased by peroxynitrite (ONOO(-)), paraquat, or activation of NADPH oxidase by Ang II. Increased glutathionylation was associated with decreased alpha(1)/beta(1) subunit coimmunoprecipitation. Glutathionylation was reversed after addition of superoxide dismutase. Glutaredoxin 1, which catalyzes deglutathionylation, coimmunoprecipitated with beta(1) subunit and, when included in patch pipette solutions, abolished paraquat-induced inhibition of myocyte Na(+)-K(+) pump current (I(p)). Cysteine (Cys46) of the beta(1) subunit was the likely candidate for glutathionylation. We expressed Na(+)-K(+) pump alpha(1) subunits with wild-type or Cys46-mutated beta(1) subunits in Xenopus oocytes. ONOO(-) induced glutathionylation of beta(1) subunit and a decrease in Na(+)-K(+) pump turnover number. This was eliminated by mutation of Cys46. ONOO(-) also induced glutathionylation of the Na(+)-K(+) ATPase beta(1) subunit from pig kidney. This was associated with a approximately 2-fold decrease in the rate-limiting E(2)-->E(1) conformational change of the pump, as determined by RH421 fluorescence. We propose that kinase-dependent regulation of the Na(+)-K(+) pump occurs via glutathionylation of its beta(1) subunit at Cys46. These findings have implications for pathophysiological conditions characterized by neurohormonal dysregulation, myocardial oxidative stress and raised myocyte Na(+) levels.

  17. Acetylcholinesterase Regulates Skeletal In Ovo Development of Chicken Limbs by ACh-Dependent and -Independent Mechanisms.

    Directory of Open Access Journals (Sweden)

    Janine Spieker

    Full Text Available Formation of the vertebrate limb presents an excellent model to analyze a non-neuronal cholinergic system (NNCS. Here, we first analyzed the expression of acetylcholinesterase (AChE by IHC and of choline acetyltransferase (ChAT by ISH in developing embryonic chicken limbs (stages HH17-37. AChE outlined formation of bones, being strongest at their distal tips, and later also marked areas of cell death. At onset, AChE and ChAT were elevated in two organizing centers of the limb anlage, the apical ectodermal ridge (AER and zone of polarizing activity (ZPA, respectively. Thereby ChAT was expressed shortly after AChE, thus strongly supporting a leading role of AChE in limb formation. Then, we conducted loss-of-function studies via unilateral implantation of beads into chicken limb anlagen, which were soaked in cholinergic components. After varying periods, the formation of cartilage matrix and of mineralizing bones was followed by Alcian blue (AB and Alizarin red (AR stainings, respectively. Both acetylcholine (ACh- and ChAT-soaked beads accelerated bone formation in ovo. Notably, inhibition of AChE by BW284c51, or by the monoclonal antibody MAB304 delayed cartilage formation. Since bead inhibition of BChE was mostly ineffective, an ACh-independent action during BW284c51 and MAB304 inhibition was indicated, which possibly could be due to an enzymatic side activity of AChE. In conclusion, skeletogenesis in chick is regulated by an ACh-dependent cholinergic system, but to some extent also by an ACh-independent aspect of the AChE protein.

  18. Necrosis, a regulated mechanism of cell death La necrosis, un mecanismo regulado de muerte celular

    Directory of Open Access Journals (Sweden)

    Mauricio Rojas López

    2010-05-01

    Full Text Available

    Three types of cellular death have been defined by morphological and biochemical criteria: apoptosis, necrosis and autophagy. Apoptosis is a regulated cell death, mainly mediated by caspases; autophagy induces degradation of intracellular damaged organelles through the formation of vesicles that fuse with hydrolytic vacuoles.

     

    Necrosis has been traditionally defined by the rupture the cytoplasmic membrane with subsequent release of intracellular material, triggering localized inflammatory Intrinsic cellular activities and the events preceding cellular collapse are critical to determine the type of tissue damage.

     

    The fact that all three types of cellular death can coexist in any organ and tissue with different availabilities of ATP, suggests that necrosis can be conceived as an active event and that to some extent it may be regulated. Alterations in the structure of proteins and in the

  19. Imaging the Antistaphylococcal Activity of CATH-2: Mechanism of Attack and Regulation of Inflammatory Response

    Science.gov (United States)

    Schneider, Viktoria A. F.; Coorens, Maarten; Tjeerdsma-van Bokhoven, Johanna L. M.; Posthuma, George; van Dijk, Albert; Veldhuizen, Edwin J. A.

    2017-01-01

    ABSTRACT Chicken cathelicidin-2 (CATH-2) is a broad-spectrum antimicrobial host defense peptide (HDP) that may serve as a paradigm for the development of new antimicrobial agents. While previous studies have elucidated the mechanism by which CATH-2 kills Escherichia coli, its mode of action against Gram-positive bacteria remains to be determined. In this study, we explored the underlying antibacterial mechanism of CATH-2 against a methicillin-resistant strain of Staphylococcus aureus and the effect of CATH-2-mediated S. aureus killing on immune activation. Visualization of the antimicrobial activity of CATH-2 against S. aureus with live-imaging confocal microscopy demonstrated that CATH-2 directly binds the bacteria, which is followed by membrane permeabilization and cell shrinkage. Transmission electron microscopy (TEM) studies further showed that CATH-2 initiated pronounced morphological changes of the membrane (mesosome formation) and ribosomal structures (clustering) in a dose-dependent manner. Immunolabeling of these sections demonstrated that CATH-2 binds and passes the bacterial membrane at subminimal bactericidal concentrations (sub-MBCs). Furthermore, competition assays and isothermal titration calorimetry (ITC) analysis provided evidence that CATH-2 directly interacts with lipoteichoic acid and cardiolipin. Finally, stimulation of macrophages with S. aureus and CATH-2 showed that CATH-2 not only kills S. aureus but also has the potential to limit S. aureus-induced inflammation at or above the MBC. Taken together, it is concluded that at sub-MBCs, CATH-2 perturbs the bacterial membrane and subsequently enters the cell and binds intracellular S. aureus components, while at or above the MBC, CATH-2 causes disruption of membrane integrity and inhibits S. aureus-induced macrophage activation. IMPORTANCE Due to the high use of antibiotics in both human and veterinary settings, many bacteria have become resistant to those antibiotics that we so heavily

  20. On the Convergence of the Virial Expansion

    NARCIS (Netherlands)

    Ramawadh, S.D.

    2015-01-01

    The virial expansion appears in statistical mechanics, an area where physics and mathematics intersect. Throughout this thesis we will mostly ignore the physics and mainly focus on the mathematical aspects. This is a deliberate choice, made for two reasons. Firstly, there are several books that

  1. Epigenetic mechanisms and associated brain circuits in the regulation of positive emotions: A role for transposable elements.

    Science.gov (United States)

    Gaudi, Simona; Guffanti, Guia; Fallon, James; Macciardi, Fabio

    2016-10-15

    Epigenetic programming and reprogramming are at the heart of cellular differentiation and represent developmental and evolutionary mechanisms in both germline and somatic cell lines. Only about 2% of our genome is composed of protein-coding genes, while the remaining 98%, once considered "junk" DNA, codes for regulatory/epigenetic elements that control how genes are expressed in different tissues and across time from conception to death. While we already know that epigenetic mechanisms are at play in cancer development and in regulating metabolism (cellular and whole body), the role of epigenetics in the developing prenatal and postnatal brain, and in maintaining a proper brain activity throughout the various stages of life, in addition to having played a critical role in human evolution, is a relatively new domain of knowledge. Here we present the current state-of-the-art techniques and results of these studies within the domain of emotions, and then speculate on how genomic and epigenetic mechanisms can modify and potentially alter our emotional (limbic) brain and affect our social interactions. J. Comp. Neurol. 524:2944-2954, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. Physiological Mechanisms Only Tell Half Story: Multiple Biological Processes are involved in Regulating Freezing Tolerance of Imbibed Lactuca sativa Seeds.

    Science.gov (United States)

    Jaganathan, Ganesh K; Han, Yingying; Li, Weijie; Song, Danping; Song, Xiaoyan; Shen, Mengqi; Zhou, Qiang; Zhang, Chenxue; Liu, Baolin

    2017-03-13

    The physiological mechanisms by which imbibed seeds survive freezing temperatures in their natural environment have been categorized as freezing avoidance by supercooling and freezing tolerance by extracellular freeze-desiccation, but the biochemical and molecular mechanisms conferring seed freezing tolerance is unexplored. In this study, using imbibed Lactuca sativa seeds we show that fast cooled seeds (60 °C h -1 ) suffered significantly higher membrane damage at temperature between -20 °C and -10 °C than slow cooled (3 °Ch -1 ) seeds (P  0.05). However, both SOD activity and accumulation of free proline were induced significantly after slow cooling to -20 °C compared with fast cooling. RNA-seq demonstrated that multiple pathways were differentially regulated between slow and fast cooling. Real-time verification of some differentially expressed genes (DEGs) revealed that fast cooling caused mRNA level changes of plant hormone and ubiquitionation pathways at higher sub-zero temperature, whilst slow cooling caused mRNA level change of those pathways at lower sub-zero ttemperatures. Thus, we conclude that imbibed seed tolerate low temperature not only by physiological mechanisms but also by biochemical and molecular changes.

  3. Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding.

    Directory of Open Access Journals (Sweden)

    Janet Chamberlain

    Full Text Available Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1 signaling in the vessel wall would raise arterial blood pressure and promote atheroma.Apoe(-/- and Apoe(-/-/IL-1R1(-/- mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. Apoe(-/-/IL-R1(-/- mice had a reduced blood pressure and significantly less atheroma than Apoe(-/- mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p < 0.05. This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress.The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man.

  4. Load speed regulation in compliant mechanical transmission systems using feedback and feedforward control actions.

    Science.gov (United States)

    Raul, P R; Dwivedula, R V; Pagilla, P R

    2016-07-01

    The problem of controlling the load speed of a mechanical transmission system consisting of a belt-pulley and gear-pair is considered. The system is modeled as two inertia (motor and load) connected by a compliant transmission. If the transmission is assumed to be rigid, then using either the motor or load speed feedback provides the same result. However, with transmission compliance, due to belts or long shafts, the stability characteristics and performance of the closed-loop system are quite different when either motor or load speed feedback is employed. We investigate motor and load speed feedback schemes by utilizing the singular perturbation method. We propose and discuss a control scheme that utilizes both motor and load speed feedback, and design an adaptive feedforward action to reject load torque disturbances. The control algorithms are implemented on an experimental platform that is typically used in roll-to-roll manufacturing and results are shown and discussed. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

  5. Sequence-dependent response of DNA to torsional stress: a potential biological regulation mechanism.

    Science.gov (United States)

    Reymer, Anna; Zakrzewska, Krystyna; Lavery, Richard

    2018-02-28

    Torsional restraints on DNA change in time and space during the life of the cell and are an integral part of processes such as gene expression, DNA repair and packaging. The mechanical behavior of DNA under torsional stress has been studied on a mesoscopic scale, but little is known concerning its response at the level of individual base pairs and the effects of base pair composition. To answer this question, we have developed a geometrical restraint that can accurately control the total twist of a DNA segment during all-atom molecular dynamics simulations. By applying this restraint to four different DNA oligomers, we are able to show that DNA responds to both under- and overtwisting in a very heterogeneous manner. Certain base pair steps, in specific sequence environments, are able to absorb most of the torsional stress, leaving other steps close to their relaxed conformation. This heterogeneity also affects the local torsional modulus of DNA. These findings suggest that modifying torsional stress on DNA could act as a modulator for protein binding via the heterogeneous changes in local DNA structure.

  6. Modeling and simulating the neuromuscular mechanisms regulating ankle and knee joint stiffness during human locomotion.

    Science.gov (United States)

    Sartori, Massimo; Maculan, Marco; Pizzolato, Claudio; Reggiani, Monica; Farina, Dario

    2015-10-01

    This work presents an electrophysiologically and dynamically consistent musculoskeletal model to predict stiffness in the human ankle and knee joints as derived from the joints constituent biological tissues (i.e., the spanning musculotendon units). The modeling method we propose uses electromyography (EMG) recordings from 13 muscle groups to drive forward dynamic simulations of the human leg in five healthy subjects during overground walking and running. The EMG-driven musculoskeletal model estimates musculotendon and resulting joint stiffness that is consistent with experimental EMG data as well as with the experimental joint moments. This provides a framework that allows for the first time observing 1) the elastic interplay between the knee and ankle joints, 2) the individual muscle contribution to joint stiffness, and 3) the underlying co-contraction strategies. It provides a theoretical description of how stiffness modulates as a function of muscle activation, fiber contraction, and interacting tendon dynamics. Furthermore, it describes how this differs from currently available stiffness definitions, including quasi-stiffness and short-range stiffness. This work offers a theoretical and computational basis for describing and investigating the neuromuscular mechanisms underlying human locomotion. Copyright © 2015 the American Physiological Society.

  7. Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions

    International Nuclear Information System (INIS)

    Eibl, Clarissa; Hessenberger, Manuel; Wenger, Julia; Brandstetter, Hans

    2014-01-01

    Pyrin domains (PYDs) recruit downstream effector molecules in NLR signalling. A specific charge-relay system suggests a the formation of a signalling complex involving a PYD dimer. The cytosolic tripartite NLR receptors serve as important signalling platforms in innate immunity. While the C-terminal domains act as sensor and activation modules, the N-terminal death-like domain, e.g. the CARD or pyrin domain, is thought to recruit downstream effector molecules by homotypic interactions. Such homotypic complexes have been determined for all members of the death-domain superfamily except for pyrin domains. Here, crystal structures of human NLRP14 pyrin-domain variants are reported. The wild-type protein as well as the clinical D86V mutant reveal an unexpected rearrangement of the C-terminal helix α6, resulting in an extended α5/6 stem-helix. This reordering mediates a novel symmetric pyrin-domain dimerization mode. The conformational switching is controlled by a charge-relay system with a drastic impact on protein stability. How the identified charge relay allows classification of NLRP receptors with respect to distinct recruitment mechanisms is discussed

  8. Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection

    Energy Technology Data Exchange (ETDEWEB)

    Kohio, Hinissan P.; Adamson, Amy L., E-mail: aladamso@uncg.edu

    2013-09-15

    As new influenza virus strains emerge, finding new mechanisms to control infection is imperative. In this study, we found that we could control influenza infection of mammalian cells by altering the level of glucose given to cells. Higher glucose concentrations induced a dose-specific increase in influenza infection. Linking influenza virus infection with glycolysis, we found that viral replication was significantly reduced after cells were treated with glycolytic inhibitors. Addition of extracellular ATP after glycolytic inhibition restored influenza infection. We also determined that higher levels of glucose promoted the assembly of the vacuolar-type ATPase within cells, and increased vacuolar-type ATPase proton-transport activity. The increase of viral infection via high glucose levels could be reversed by inhibition of the proton pump, linking glucose metabolism, vacuolar-type ATPase activity, and influenza viral infection. Taken together, we propose that altering glucose metabolism may be a potential new approach to inhibit influenza viral infection. - Highlights: • Increased glucose levels increase Influenza A viral infection of MDCK cells. • Inhibition of the glycolytic enzyme hexokinase inhibited Influenza A viral infection. • Inhibition of hexokinase induced disassembly the V-ATPase. • Disassembly of the V-ATPase and Influenza A infection was bypassed with ATP. • The state of V-ATPase assembly correlated with Influenza A infection of cells.

  9. Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection

    International Nuclear Information System (INIS)

    Kohio, Hinissan P.; Adamson, Amy L.

    2013-01-01

    As new influenza virus strains emerge, finding new mechanisms to control infection is imperative. In this study, we found that we could control influenza infection of mammalian cells by altering the level of glucose given to cells. Higher glucose concentrations induced a dose-specific increase in influenza infection. Linking influenza virus infection with glycolysis, we found that viral replication was significantly reduced after cells were treated with glycolytic inhibitors. Addition of extracellular ATP after glycolytic inhibition restored influenza infection. We also determined that higher levels of glucose promoted the assembly of the vacuolar-type ATPase within cells, and increased vacuolar-type ATPase proton-transport activity. The increase of viral infection via high glucose levels could be reversed by inhibition of the proton pump, linking glucose metabolism, vacuolar-type ATPase activity, and influenza viral infection. Taken together, we propose that altering glucose metabolism may be a potential new approach to inhibit influenza viral infection. - Highlights: • Increased glucose levels increase Influenza A viral infection of MDCK cells. • Inhibition of the glycolytic enzyme hexokinase inhibited Influenza A viral infection. • Inhibition of hexokinase induced disassembly the V-ATPase. • Disassembly of the V-ATPase and Influenza A infection was bypassed with ATP. • The state of V-ATPase assembly correlated with Influenza A infection of cells

  10. A rainfall-based mechanism to regulate the release of water from Ranger uranium mine

    International Nuclear Information System (INIS)

    Carter, M.W.

    1989-01-01

    The far north of Australia (the Top End) has a monsoon-like climate. This wet-dry climate presents problems in water management for mining operations. These problems are exacerbated for the Ranger uranium mine at Jabiru due to the need to protect the environment of the surrounding Kakadu National Park, particularly the major wetland system downstream of the Ranger mine. An analysis of rainfall records for the wet-dry tropics of the far north of Australia is presented. A probability curve of the ratio between rainfall at a given date and rainfall at the year end, has been produced from actual data and can be used with a normalized curve to set levels of confidence of predicted rainfall being exceeded. The results of this analysis are used to develop a regulatory mechanism to limit release of waste water from a uranium mine to particularly wet years in accordance with the Australian Government's environmental protection policy. 19 refs., 11 tabs., 17 figs

  11. Immune and Metabolic Regulation Mechanism of Dangguiliuhuang Decoction against Insulin Resistance and Hepatic Steatosis

    Directory of Open Access Journals (Sweden)

    Hui Cao

    2017-07-01

    Full Text Available Dangguiliuhuang decoction (DGLHD is a traditional Chinese medicine (TCM formula, which mainly consists of angelica, radix rehmanniae, radix rehmanniae praeparata, scutellaria baicalensis, coptis chinensis, astragalus membranaceus, and golden cypress, and used for the treatment of diabetes and some autoimmune diseases. In this study, we explored the potential mechanism of DGLHD against insulin resistance and fatty liver in vivo and in vitro. Our data revealed that DGLHD normalized glucose and insulin level, increased the expression of adiponectin, diminished fat accumulation and lipogenesis, and promoted glucose uptake. Metabolomic analysis also demonstrated that DGLHD decreased isoleucine, adenosine, and cholesterol, increased glutamine levels in liver and visceral adipose tissue (VAT of ob/ob mice. Importantly, DGLHD promoted the shift of pro-inflammatory to anti-inflammatory cytokines, suppressed T lymphocytes proliferation, and enhanced regulatory T cells (Tregs differentiation. DGLHD also inhibited dendritic cells (DCs maturation, attenuated DCs-stimulated T cells proliferation and secretion of IL-12p70 cytokine from DCs, and promoted the interaction of DCs with Tregs. Further studies indicated that the changed PI3K/Akt signaling pathway and elevated PPAR-γ expression were not only observed with the ameliorated glucose and lipid metabolism in adipocytes and hepatocytes, but also exhibited in DCs and T cells by DGLHD. Collectively, our results suggest that DGLHD exerts anti-insulin resistant and antisteatotic effects by improving abnormal immune and metabolic homeostasis. And DGLHD may be a novel approach to the treatment of obesity-related insulin resistance and hepatic steatosis.

  12. Statistical state dynamics-based analysis of the physical mechanisms sustaining and regulating turbulence in Couette flow

    Science.gov (United States)

    Farrell, Brian F.; Ioannou, Petros J.

    2017-08-01

    This paper describes a study of the self-sustaining process in wall turbulence. The study is based on a second order statistical state dynamics model of Couette flow in which the state variables are the streamwise mean flow (first cumulant) and perturbation covariance (second cumulant). This statistical state dynamics model is closed by either setting the third cumulant to zero or by replacing it with a stochastic parametrization. Statistical state dynamics models with this form are referred to as S3T models. S3T models have been shown to self-sustain turbulence with a mean flow and second order perturbation structure similar to that obtained by direct numerical simulation of the equations of motion. The use of a statistical state dynamics model to study the physical mechanisms underlying turbulence has important advantages over the traditional approach of studying the dynamics of individual realizations of turbulence. One advantage is that the analytical structure of S3T statistical state dynamics models isolates the interaction between the mean flow and the perturbation components of the turbulence. Isolation of the interaction between these components reveals how this interaction underlies both the maintenance of the turbulence variance by transfer of energy from the externally driven flow to the perturbation components as well as the enforcement of the observed statistical mean turbulent state by feedback regulation between the mean and perturbation fields. Another advantage of studying turbulence using statistical state dynamics models of S3T form is that the analytical structure of S3T turbulence can be completely characterized. For example, the perturbation component of turbulence in the S3T system is demonstrably maintained by a parametric perturbation growth mechanism in which fluctuation of the mean flow maintains the perturbation field which in turn maintains the mean flow fluctuations in a synergistic interaction. Furthermore, the equilibrium

  13. Epigenetic mechanisms of peptidergic regulation of gene expression during aging of human cells.

    Science.gov (United States)

    Ashapkin, V V; Linkova, N S; Khavinson, V Kh; Vanyushin, B F

    2015-03-01

    Expression levels of genes encoding specific transcription factors and other functionally important proteins vary upon aging of pancreatic and bronchial epithelium cell cultures. The peptides KEDW and AEDL tissue-specifically affect gene expression in pancreatic and bronchial cell cultures, respectively. It is established in this work that the DNA methylation patterns of the PDX1, PAX6, NGN3, NKX2-1, and SCGB1A1 gene promoter regions change upon aging in pancreatic and bronchial cell cultures in correlation with variations in their expression levels. Thus, stable changes in gene expression upon aging of cell cultures could be caused by changes in their promoter methylation patterns. The methylation patterns of the PAX4 gene in pancreatic cells as well as those of the FOXA1, SCGB3A2, and SFTPA1 genes in bronchial cells do not change upon aging and are unaffected by peptides, whereas their expression levels change in both cases. The promoter region of the FOXA2 gene in pancreatic cells contains a small number of methylated CpG sites, their methylation levels being affected by cell culture aging and KEDW, though without any correlation with gene expression levels. The promoter region of the FOXA2 gene is completely unmethylated in bronchial cells irrespective of cell culture age and AEDL action. Changes in promoter methylation might be the cause of age- and peptide-induced variations in expression levels of the PDX1, PAX6, and NGN3 genes in pancreatic cells and NKX2-1 and SCGB1A1 genes in bronchial cells. Expression levels of the PAX4 and FOXA2 genes in pancreatic cells and FOXA1, FOXA2, SCGB3A2, and SFTPA1 genes in bronchial cells seem to be controlled by some other mechanisms.

  14. Keratinocyte proliferation, differentiation, and apoptosis-Differential mechanisms of regulation by curcumin, EGCG and apigenin

    International Nuclear Information System (INIS)

    Balasubramanian, Sivaprakasam; Eckert, Richard L.

    2007-01-01

    We have proposed that it is important to examine the impact of chemopreventive agents on the function of normal human epidermal keratinocytes since these cells comprise the barrier that protects the body from a range of environmental insults. In this context, it is widely appreciated that cancer may be retarded by consumption or topical application of naturally occurring food-derived chemopreventive agents. Our studies show that (-)-epigallocatechin-3-gallate (EGCG), a green tea-derived polyphenol, acts to enhance the differentiation of normal human keratinocytes as evidenced by its ability to increase involucrin (hINV), transglutaminase type 1 (TG1) and caspase-14 gene expression. EGCG also stimulates keratinocyte morphological differentiation. These actions of EGCG are mediated via activation of a nPKC, Ras, MEKK1, MEK3, p38δ-ERK1/2 signaling cascade which leads to increased activator protein 1 (AP1) and CAATT enhancer binding protein (C/EBP) transcription factor expression, increased binding of these factors to DNA, and increased gene transcription. In contrast, apigenin, a dietary flavonoid derived from plants and vegetables, and curcumin, an agent derived from turmeric, inhibit differentiation by suppressing MAPK signal transduction and reducing API transcription factor level. Curcumin also acts to enhance apoptosis, although EGCG and apigenin do not stimulate apoptosis. In addition, all of these agents inhibit keratinocyte proliferation. These findings indicate that each of these diet-derived chemopreventive agents has a profound impact on normal human keratinocyte function and that they operate via distinct and sometimes opposing mechanisms. However, all are expected to act as chemopreventive agents

  15. TOPOISOMERASE1α Acts through Two Distinct Mechanisms to Regulate Stele and Columella Stem Cell Maintenance.

    Science.gov (United States)

    Zhang, Yonghong; Zheng, Lanlan; Hong, Jing Han; Gong, Ximing; Zhou, Chun; Pérez-Pérez, José Manuel; Xu, Jian

    2016-05-01

    TOPOISOMERASE1 (TOP1), which releases DNA torsional stress generated during replication through its DNA relaxation activity, plays vital roles in animal and plant development. In Arabidopsis (Arabidopsis thaliana), TOP1 is encoded by two paralogous genes (TOP1α and TOP1β), of which TOP1α displays specific developmental functions that are critical for the maintenance of shoot and floral stem cells. Here, we show that maintenance of two different populations of root stem cells is also dependent on TOP1α-specific developmental functions, which are exerted through two distinct novel mechanisms. In the proximal root meristem, the DNA relaxation activity of TOP1α is critical to ensure genome integrity and survival of stele stem cells (SSCs). Loss of TOP1α function triggers DNA double-strand breaks in S-phase SSCs and results in their death, which can be partially reversed by the replenishment of SSCs mediated by ETHYLENE RESPONSE FACTOR115 In the quiescent center and root cap meristem, TOP1α is epistatic to RETINOBLASTOMA-RELATED (RBR) in the maintenance of undifferentiated state and the number of columella stem cells (CSCs). Loss of TOP1α function in either wild-type or RBR RNAi plants leads to differentiation of CSCs, whereas overexpression of TOP1α mimics and further enhances the effect of RBR reduction that increases the number of CSCs Taken together, these findings provide important mechanistic insights into understanding stem cell maintenance in plants. © 2016 American Society of Plant Biologists. All Rights Reserved.

  16. Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms

    Science.gov (United States)

    Bishayee, Anupam; Bhatia, Deepak; Thoppil, Roslin J.; Darvesh, Altaf S.; Nevo, Eviatar; Lansky, Ephraim P.

    2011-01-01

    Hepatocellular carcinoma (HCC), one of the most prevalent and lethal cancers, has shown an alarming rise in the USA. Without effective therapy for HCC, novel chemopreventive strategies may effectively circumvent the current morbidity and mortality. Oxidative stress predisposes to hepatocarcinogenesis and is the major driving force of HCC. Pomegranate, an ancient fruit, is gaining tremendous attention due to its powerful antioxidant properties. Here, we examined mechanism-based chemopreventive potential of a pomegranate emulsion (PE) against dietary carcinogen diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis that mimics human HCC. PE treatment (1 or 10 g/kg), started 4 weeks prior to the DENA challenge and continued for 18 weeks thereafter, showed striking chemopreventive activity demonstrated by reduced incidence, number, multiplicity, size and volume of hepatic nodules, precursors of HCC. Both doses of PE significantly attenuated the number and area of γ-glutamyl transpeptidase-positive hepatic foci compared with the DENA control. PE also attenuated DENA-induced hepatic lipid peroxidation and protein oxidation. Mechanistic studies revealed that PE elevated gene expression of an array of hepatic antioxidant and carcinogen detoxifying enzymes in DENA-exposed animals. PE elevated protein and messenger RNA expression of the hepatic nuclear factor E2-related factor 2 (Nrf2). Our results provide substantial evidence, for the first time, that pomegranate constituents afford chemoprevention of hepatocarcinogenesis possibly through potent antioxidant activity achieved by upregulation of several housekeeping genes under the control of Nrf2 without toxicity. The outcome of this study strongly supports the development of pomegranate-derived products in the prevention and treatment of human HCC, which remains a devastating disease. PMID:21389260

  17. Expansion at Olympic Dam

    International Nuclear Information System (INIS)

    Lewis, C.

    1997-01-01

    The Olympic Dam orebody is the 6th largest copper and the single largest uranium orebody in the world. Mine production commenced in June 1988, at an annual production rate of around 45,000 tonnes of copper and 1,000 tonnes of uranium. Western Mining Corporation announced in 1996 a proposed $1.25 billion expansion of the Olympic Dam operation to raise the annual production capacity of the mine to 200,000 tonnes of copper, approximately 3,700 tonnes of uranium, 75,000 ounces of gold and 950,000 ounces of silver by 2001. Further optimisation work has identified a faster track expansion route, with an increase in the capital cost to $1.487 billion but improved investment outcome, a new target completion date of end 1999, and a new uranium output of 4,600 tonnes per annum from that date

  18. Financing electricity expansion

    International Nuclear Information System (INIS)

    Hyman, L.S.

    1994-01-01

    Expansion of electricity supply is associated with economic development. The installation and enlargement of power systems in developing countries entails a huge financial burden, however. Energy consumers in such countries must pay not only for supplies but for the cost of raising the capital for expansion on the international markets. Estimates are presented for the capital expenditure for electricity supply over the period 1990 to 2020 for the major world regions, using approximations for the cost of plant and capital and for the returns earned. These data lead to the conclusion that the five regions with the lowest per capita incomes are those which will need the major part of the capital expenditure and the highest percentage of external finance. (6 tables) (UK)

  19. Bigravity from gradient expansion

    International Nuclear Information System (INIS)

    Yamashita, Yasuho; Tanaka, Takahiro

    2016-01-01

    We discuss how the ghost-free bigravity coupled with a single scalar field can be derived from a braneworld setup. We consider DGP two-brane model without radion stabilization. The bulk configuration is solved for given boundary metrics, and it is substituted back into the action to obtain the effective four-dimensional action. In order to obtain the ghost-free bigravity, we consider the gradient expansion in which the brane separation is supposed to be sufficiently small so that two boundary metrics are almost identical. The obtained effective theory is shown to be ghost free as expected, however, the interaction between two gravitons takes the Fierz-Pauli form at the leading order of the gradient expansion, even though we do not use the approximation of linear perturbation. We also find that the radion remains as a scalar field in the four-dimensional effective theory, but its coupling to the metrics is non-trivial.

  20. Expansion of magnetic clouds

    International Nuclear Information System (INIS)

    Suess, S.T.

    1987-01-01

    Magnetic clouds are a carefully defined subclass of all interplanetary signatures of coronal mass ejections whose geometry is thought to be that of a cylinder embedded in a plane. It has been found that the total magnetic pressure inside the clouds is higher than the ion pressure outside, and that the clouds are expanding at 1 AU at about half the local Alfven speed. The geometry of the clouds is such that even though the magnetic pressure inside is larger than the total pressure outside, expansion will not occur because the pressure is balanced by magnetic tension - the pinch effect. The evidence for expansion of clouds at 1 AU is nevertheless quite strong so another reason for its existence must be found. It is demonstrated that the observations can be reproduced by taking into account the effects of geometrical distortion of the low plasma beta clouds as they move away from the Sun

  1. CodY Regulates Thiol Peroxidase Expression as Part of the Pneumococcal Defense Mechanism against H2O2 Stress.

    Science.gov (United States)

    Hajaj, Barak; Yesilkaya, Hasan; Shafeeq, Sulman; Zhi, Xiangyun; Benisty, Rachel; Tchalah, Shiran; Kuipers, Oscar P; Porat, Nurith

    2017-01-01

    Streptococcus pneumoniae is a facultative anaerobic pathogen. Although it maintains fermentative metabolism, during aerobic growth pneumococci produce high levels of H 2 O 2 , which can have adverse effects on cell viability and DNA, and influence pneumococcal interaction with its host. The pneumococcus is unusual in its dealing with toxic reactive oxygen species (ROS) in that it neither has catalase nor the global regulators of peroxide stress resistance. Previously, we identified pneumococcal thiol peroxidase (TpxD) as the key enzyme for enzymatic removal of H 2 O 2 , and showed that TpxD synthesis is up-regulated upon exposure to H 2 O 2 . This study aimed to reveal the mechanism controlling TpxD expression under H 2 O 2 stress. We hypothesize that H 2 O 2 activates a transcription factor which in turn up-regulates tpxD expression. Microarray analysis revealed a pneumococcal global transcriptional response to H 2 O 2 . Mutation of tpxD abolished H 2 O 2 -mediated response to high H 2 O 2 levels, signifying the need for an active TpxD under oxidative stress conditions. Bioinformatic tools, applied to search for a transcription factor modulating tpxD expression, pointed toward CodY as a potential candidate. Indeed, a putative 15-bp consensus CodY binding site was found in the proximal region of tpxD- coding sequence. Binding of CodY to this site was confirmed by EMSA, and genetic engineering techniques demonstrated that this site is essential for TpxD up-regulation under H 2 O 2 stress. Furthermore, tpxD expression was reduced in a Δ codY mutant. These data indicate that CodY is an activator of tpxD expression, triggering its up-regulation under H 2 O 2 stress. In addition we show that H 2 O 2 specifically oxidizes the 2 CodY cysteines. This oxidation may trigger a conformational change in CodY, resulting in enhanced binding to DNA. A schematic model illustrating the contribution of TpxD and CodY to pneumococcal global transcriptional response to H 2 O 2 is

  2. Domoic acid toxicokinetics in Dungeness crabs: New insights into mechanisms that regulate bioaccumulation

    Energy Technology Data Exchange (ETDEWEB)

    Schultz, Irvin R., E-mail: ir_schultz@pnl.gov; Skillman, Ann; Sloan-Evans, Siobhan; Woodruff, Dana

    2013-09-15

    uptake and distribution is regulated by crustacean orthologs of ATP-binding cassette (ABC) type transporters. We tested this hypothesis by co-exposing crabs to DA and known inhibitors of ABC transporters (verapamil, cyclosporine A and MK-571) and through in vitro studies using isolated hepatopancreas tissue and mixed cell suspensions prepared from hepatopancreas tissue. The in vivo results were inconclusive in that the toxicokinetics of DA was not consistently altered by co-administration of the inhibitors. Two exceptions were MK-571, which significantly increased the total body clearance of DA and co-administration of verapamil, which significantly increased the hepatopancreas tissue content of DA 24 h after IV injection. Isolated pieces of hepatopancreas tissue were able to readily absorb DA from incubation media, but mixed cell suspensions did not. The absorption of DA or lack thereof was largely unaffected by co-incubation with verapamil although cell suspensions appeared to accumulate small quantities of DA in the presence of verapamil. Collectively, the results of this study suggest DA accumulates in the extracellular spaces of the hepatopancreas, such as the tubular lumen. Under natural circumstances, crabs feeding on contaminated shellfish would be expected to readily absorb DA, which is then stored and slowly eliminated in urine. If the DA exposure level exceeds the storage capacity of the tissue (as occurred with the 20 mg/kg dose), breakthrough occurs resulting in much higher systemic exposure and potential for DA toxicity.

  3. IKEA's International Expansion

    OpenAIRE

    Harapiak, Clayton

    2013-01-01

    This case concerns a global retailing firm that is dealing with strategic management and marketing issues. Applying a scenario of international expansion, this case provides a thorough analysis of the current business environment for IKEA. Utilizing a variety of methods (e.g. SWOT, PESTLE, McKinsey Matrix) the overall objective is to provide students with the opportunity to apply their research skills and knowledge regarding a highly competitive industry to develop strategic marketing strateg...

  4. Symmetric eikonal expansion

    International Nuclear Information System (INIS)

    Matsuki, Takayuki

    1976-01-01

    Symmetric eikonal expansion for the scattering amplitude is formulated for nonrelativistic and relativistic potential scatterings and also for the quantum field theory. The first approximations coincide with those of Levy and Sucher. The obtained scattering amplitudes are time reversal invariant for all cases and are crossing symmetric for the quantum field theory in each order of approximation. The improved eikonal phase introduced by Levy and Sucher is also derived from the different approximation scheme from the above. (auth.)

  5. Series expansions without diagrams

    International Nuclear Information System (INIS)

    Bhanot, G.; Creutz, M.; Horvath, I.; Lacki, J.; Weckel, J.

    1994-01-01

    We discuss the use of recursive enumeration schemes to obtain low- and high-temperature series expansions for discrete statistical systems. Using linear combinations of generalized helical lattices, the method is competitive with diagrammatic approaches and is easily generalizable. We illustrate the approach using Ising and Potts models. We present low-temperature series results in up to five dimensions and high-temperature series in three dimensions. The method is general and can be applied to any discrete model

  6. Closed-form solutions for linear regulator-design of mechanical systems including optimal weighting matrix selection

    Science.gov (United States)

    Hanks, Brantley R.; Skelton, Robert E.

    1991-01-01

    This paper addresses the re