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Sample records for cellular mechanisms involved

  1. Mechanisms involved in cellular ceramide homeostasis

    Directory of Open Access Journals (Sweden)

    Hussain M

    2012-07-01

    Full Text Available Abstract Sphingolipids are ubiquitous and critical components of biological membranes. Their biosynthesis starts with soluble precursors in the endoplasmic reticulum and culminates in the Golgi complex and plasma membrane. Ceramides are important intermediates in the biosynthesis of sphingolipids, such as sphingomyelin, and their overload in the membranes is injurious to cells. The major product of ceramide metabolism is sphingomyelin. We observed that sphingomyelin synthase (SMS 1 or SMS2 deficiencies significantly decreased plasma and liver sphingomyelin levels. However, SMS2 but not SMS1 deficiency increased plasma ceramides. Surprisingly, SMS1 deficiency significantly increased glucosylceramide and ganglioside GM3, but SMS2 deficiency did not. To explain these unexpected findings about modest to no significant changes in ceramides and increases in other sphingolipids after the ablation of SMS1, we hypothesize that cells have evolved several organelle specific mechanisms to maintain ceramide homeostasis. First, ceramides in the endoplasmic reticulum membranes are controlled by its export to Golgi by protein mediated transfer. Second, in the Golgi, ceramide levels are modulated by their enzymatic conversion to different sphingolipids such as sphingomyelin, and glucosylceramides. Additionally, these sphingolipids can become part of triglyceride-rich apolipoprotein B-containing lipoproteins and be secreted. Third, in the plasma membrane ceramide levels are maintained by ceramide/sphingomyelin cycle, delivery to lysosomes, and efflux to extracellular plasma acceptors. All these pathways might have evolved to ensure steady cellular ceramide levels.

  2. Cellular and Humoral Mechanisms Involved in the Control of Tuberculosis

    Directory of Open Access Journals (Sweden)

    Joaquin Zuñiga

    2012-01-01

    Full Text Available Mycobacterium tuberculosis (Mtb infection is a major international public health problem. One-third of the world's population is thought to have latent tuberculosis, a condition where individuals are infected by the intracellular bacteria without active disease but are at risk for reactivation, if their immune system fails. Here, we discuss the role of nonspecific inflammatory responses mediated by cytokines and chemokines induced by interaction of innate receptors expressed in macrophages and dendritic cells (DCs. We also review current information regarding the importance of several cytokines including IL-17/IL-23 in the development of protective cellular and antibody-mediated protective responses against Mtb and their influence in containment of the infection. Finally, in this paper, emphasis is placed on the mechanisms of failure of Mtb control, including the immune dysregulation induced by the treatment with biological drugs in different autoimmune diseases. Further functional studies, focused on the mechanisms involved in the early host-Mtb interactions and the interplay between host innate and acquired immunity against Mtb, may be helpful to improve the understanding of protective responses in the lung and in the development of novel therapeutic and prophylactic tools in TB.

  3. Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs.

    Science.gov (United States)

    Cunha-Oliveira, Teresa; Rego, Ana Cristina; Oliveira, Catarina R

    2008-06-01

    Substance abuse and addiction are the most costly of all the neuropsychiatric disorders. In the last decades, much progress has been achieved in understanding the effects of the drugs of abuse in the brain. However, efficient treatments that prevent relapse have not been developed. Drug addiction is now considered a brain disease, because the abuse of drugs affects several brain functions. Neurological impairments observed in drug addicts may reflect drug-induced neuronal dysfunction and neurotoxicity. The drugs of abuse directly or indirectly affect neurotransmitter systems, particularly dopaminergic and glutamatergic neurons. This review explores the literature reporting cellular and molecular alterations reflecting the cytotoxicity induced by amphetamines, cocaine and opiates in neuronal systems. The neurotoxic effects of drugs of abuse are often associated with oxidative stress, mitochondrial dysfunction, apoptosis and inhibition of neurogenesis, among other mechanisms. Understanding the mechanisms that underlie brain dysfunction observed in drug-addicted individuals may contribute to improve the treatment of drug addiction, which may have social and economic consequences. PMID:18440072

  4. Involvement of the Wnt/β-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis.

    Directory of Open Access Journals (Sweden)

    Sachiko Matsuzaki

    Full Text Available BACKGROUND: During the development and progression of endometriotic lesions, excess fibrosis may lead to scarring, chronic pain, and altered tissue function. However, the cellular and molecular mechanisms of fibrosis in endometriosis remain to be clarified. OBJECTIVES: The objective of the present study was to investigate whether the Wnt/β-catenin signaling pathway was involved in regulating the cellular and molecular mechanisms of fibrosis in endometriosis in vitro and to evaluate whether fibrosis could be prevented by targeting the Wnt/β-catenin pathway in a xenograft model of endometriosis in immunodeficient nude mice. METHODS: Seventy patients (40 with and 30 without endometriosis with normal menstrual cycles were recruited. In vitro effects of small-molecule antagonists of the Tcf/β-catenin complex (PKF 115-584 and CGP049090 on fibrotic markers (alpha smooth muscle actin, type I collagen, connective tissue growth factor, fibronectin and collagen gel contraction were evaluated in endometrial and endometriotic stromal cells from patients with endometriosis. In vitro effects of activation of the Wnt/β-catenin signaling pathway by treatment with recombinant Wnt3a on profibrotic responses were evaluated in endometrial stromal cells of patients without endometriosis. The effects of CGP049090 treatment on the fibrosis of endometriotic implants were evaluated in a xenograft model of endometriosis in immunodeficient nude mice. RESULTS: Treatment with PKF 115-584 and CGP049090 significantly decreased the expression of alpha smooth muscle actin, type I collagen, connective tissue growth factor and fibronectin mRNAs in both endometriotic and endometrial stromal cells with or without transforming growth factor-β1 stimulation. Both endometriotic and endometrial stromal cell-mediated contraction of collagen gels was significantly decreased by treatment with PKF 115-584 and CGP049090 as compared to that of untreated cells. The animal experiments

  5. Cellular mechanics and motility

    Science.gov (United States)

    Hénon, Sylvie; Sykes, Cécile

    2015-10-01

    The term motility defines the movement of a living organism. One widely known example is the motility of sperm cells, or the one of flagellar bacteria. The propulsive element of such organisms is a cilium(or flagellum) that beats. Although cells in our tissues do not have a flagellum in general, they are still able to move, as we will discover in this chapter. In fact, in both cases of movement, with or without a flagellum, cell motility is due to a dynamic re-arrangement of polymers inside the cell. Let us first have a closer look at the propulsion mechanism in the case of a flagellum or a cilium, which is the best known, but also the simplest, and which will help us to define the hydrodynamic general conditions of cell movement. A flagellum is sustained by cellular polymers arranged in semi-flexible bundles and flagellar beating generates cell displacement. These polymers or filaments are part of the cellular skeleton, or "cytoskeleton", which is, in this case, external to the cellular main body of the organism. In fact, bacteria move in a hydrodynamic regime in which viscosity dominates over inertia. The system is thus in a hydrodynamic regime of low Reynolds number (Box 5.1), which is nearly exclusively the case in all cell movements. Bacteria and their propulsion mode by flagella beating are our unicellular ancestors 3.5 billion years ago. Since then, we have evolved to form pluricellular organisms. However, to keep the ability of displacement, to heal our wounds for example, our cells lost their flagellum, since it was not optimal in a dense cell environment: cells are too close to each other to leave enough space for the flagella to accomplish propulsion. The cytoskeleton thus developed inside the cell body to ensure cell shape changes and movement, and also mechanical strength within a tissue. The cytoskeleton of our cells, like the polymers or filaments that sustain the flagellum, is also composed of semi-flexible filaments arranged in bundles, and also in

  6. The involvement of selected membrane transport mechanisms in the cellular uptake of 177Lu-labeled bombesin, somatostatin and gastrin analogues

    International Nuclear Information System (INIS)

    Introduction: Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides. Methods: In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin (177Lu-DOTA-[Tyr3]octreotate, 177Lu-DOTA-[1-Nal3]octreotide), gastrin (177Lu-DOTA-sargastrin) and bombesin (177Lu-DOTA-[Pro1,Tyr4]bombesin, 177Lu-DOTA-[Lys3]bombesin, 177Lu-PCTA-[Lys3]bombesin) analogues were involved in the study. Results: RAP, albumin and low temperature decreased the accumulation of all the studied peptides significantly. With one exception, rottlerin caused the concentration dependent inhibition of the cellular accumulation of the radiopeptides. No significant differences in the uptake of the peptides between the control cells and those transfected with hOAT1 or hOCT2 were observed. Conclusion: The study showed that active transport mechanisms are decisive for the cellular accumulation in all tested 177Lu-labeled somatostatin, gastrin and bombesin analogues. Besides receptor-mediated endocytosis by megalin, FPE participates significantly in the uptake. The tested types of renal SLC transporters are not involved in this process

  7. Cellular mechanisms during vascular development

    OpenAIRE

    Blum, Yannick

    2012-01-01

    The vascular system is an essential organ in vertebrate animals and provides the organism with enough oxygen and nutrients. It is composed of an interconnected network of blood vessels, which form using a number of different morphogenetic mechanisms. Angiogenesis describes the formation of new blood vessels from preexisting vessels. A number of molecular pathways have been shown to be essential during angiogenesis. However, cellular architecture of blood vessels as well as cellular mechanisms...

  8. Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes.

    Directory of Open Access Journals (Sweden)

    Mohammad F Saeed

    Full Text Available Zaire ebolavirus (ZEBOV, a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. Currently no specific therapy or vaccine is available. Virus entry is an attractive target for therapeutic intervention. However, current knowledge of the ZEBOV entry mechanism is limited. While it is known that ZEBOV enters cells through endocytosis, which of the cellular endocytic mechanisms used remains unclear. Previous studies have produced differing outcomes, indicating potential involvement of multiple routes but many of these studies were performed using noninfectious surrogate systems such as pseudotyped retroviral particles, which may not accurately recapitulate the entry characteristics of the morphologically distinct wild type virus. Here we used replication-competent infectious ZEBOV as well as morphologically similar virus-like particles in specific infection and entry assays to demonstrate that in HEK293T and Vero cells internalization of ZEBOV is independent of clathrin, caveolae, and dynamin. Instead the uptake mechanism has features of macropinocytosis. The binding of virus to cells appears to directly stimulate fluid phase uptake as well as localized actin polymerization. Inhibition of key regulators of macropinocytosis including Pak1 and CtBP/BARS as well as treatment with the drug EIPA, which affects macropinosome formation, resulted in significant reduction in ZEBOV entry and infection. It is also shown that following internalization, the virus enters the endolysosomal pathway and is trafficked through early and late endosomes, but the exact site of membrane fusion and nucleocapsid penetration in the cytoplasm remains unclear. This study identifies the route for ZEBOV entry and identifies the key cellular factors required for the uptake of this filamentous virus. The findings greatly expand our understanding of the ZEBOV entry mechanism that can be applied to development of new

  9. Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes.

    Science.gov (United States)

    Saeed, Mohammad F; Kolokoltsov, Andrey A; Albrecht, Thomas; Davey, Robert A

    2010-01-01

    Zaire ebolavirus (ZEBOV), a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. Currently no specific therapy or vaccine is available. Virus entry is an attractive target for therapeutic intervention. However, current knowledge of the ZEBOV entry mechanism is limited. While it is known that ZEBOV enters cells through endocytosis, which of the cellular endocytic mechanisms used remains unclear. Previous studies have produced differing outcomes, indicating potential involvement of multiple routes but many of these studies were performed using noninfectious surrogate systems such as pseudotyped retroviral particles, which may not accurately recapitulate the entry characteristics of the morphologically distinct wild type virus. Here we used replication-competent infectious ZEBOV as well as morphologically similar virus-like particles in specific infection and entry assays to demonstrate that in HEK293T and Vero cells internalization of ZEBOV is independent of clathrin, caveolae, and dynamin. Instead the uptake mechanism has features of macropinocytosis. The binding of virus to cells appears to directly stimulate fluid phase uptake as well as localized actin polymerization. Inhibition of key regulators of macropinocytosis including Pak1 and CtBP/BARS as well as treatment with the drug EIPA, which affects macropinosome formation, resulted in significant reduction in ZEBOV entry and infection. It is also shown that following internalization, the virus enters the endolysosomal pathway and is trafficked through early and late endosomes, but the exact site of membrane fusion and nucleocapsid penetration in the cytoplasm remains unclear. This study identifies the route for ZEBOV entry and identifies the key cellular factors required for the uptake of this filamentous virus. The findings greatly expand our understanding of the ZEBOV entry mechanism that can be applied to development of new therapeutics as well as

  10. Cellular Entry of Ebola Virus Involves Uptake by a Macropinocytosis-Like Mechanism and Subsequent Trafficking through Early and Late Endosomes

    OpenAIRE

    Saeed, Mohammad F.; Kolokoltsov, Andrey A.; Albrecht, Thomas; Davey, Robert A.

    2010-01-01

    Zaire ebolavirus (ZEBOV), a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. Currently no specific therapy or vaccine is available. Virus entry is an attractive target for therapeutic intervention. However, current knowledge of the ZEBOV entry mechanism is limited. While it is known that ZEBOV enters cells through endocytosis, which of the cellular endocytic mechanisms used remains unclear. Previous studies have produced differing o...

  11. A novel antibody-dependent cellular cytotoxicity mechanism involved in defense against malaria requires costimulation of monocytes FcgammaRII and FcgammaRIII

    DEFF Research Database (Denmark)

    Jafarshad, Ali; Dziegiel, Morten Hanefeld; Lundquist, Rasmus; Nielsen, Leif K; Singh, Subhash; Druilhe, Pierre L

    2007-01-01

    Clinical experiments have shown that the Ab-dependent cell-mediated inhibition of Plasmodium falciparum is a major mechanism controlling malaria parasitemia and thereby symptoms. In this study, we demonstrate that a single merozoite per monocyte (MN) is sufficient to trigger optimal antiparasitic......-dependent cellular cytotoxicity and implies that all MN are not equally effective. These findings have both fundamental and practical implications, particularly for vaccine discovery....

  12. Cellular mechanisms involved during oxytocin-induced prostaglandin F2alpha production in endometrial epithelial cells in vitro: role of cyclooxygenase-2.

    Science.gov (United States)

    Asselin, E; Drolet, P; Fortier, M A

    1997-11-01

    PGs are important regulators of reproductive processes. At the time ofluteolysis in vivo, PGF2alpha is produced by endometrial cells, in response to oxytocin (OT). The mechanism by which OT induces the release of PGF2alpha remains to be defined. We have used 13 different cultures of bovine epithelial endometrial cells to study the effect of OT on the regulation of PGF2alpha and to identify the possible involvement of cyclooxygenases (COXs). OT induced a dose-dependent increase of both inositol phosphates (IPs) and [Ca2+]i concentration in epithelial cells labeled with [3H]-myoinositol or loaded with fura-2 (using a fluorescent microscope imaging system), respectively. OT induced a dose-dependent increase of both PGF2alpha production and COX-2 gene expression (as demonstrated by RT-PCR and Northern blots). PGF2alpha production was increased from 13.3 +/- 2.0 to 166.8 +/- 22.5 ng/ml (P gene expression (as determined by densitometric analysis) was increased 5.1 +/- 0.7-fold (P sheep, for COX-1, respectively. COX-2 was found to bear 84%, 86%, and 87% of homology in relation to rat, guinea pig, and human, respectively. Collectively, these results demonstrate, for the first time, that COX-2 is involved in the mechanism by which OT regulates PGF2alpha production in the endometrium. PMID:9348208

  13. Cytotoxicity and cellular mechanisms involved in the toxicity of CdS quantum dots in hemocytes and gill cells of the mussel Mytilus galloprovincialis

    International Nuclear Information System (INIS)

    Highlights: • CdS QDs were cytotoxic for mussel hemocytes and gill cells in vitro. • Ionic Cd was the most toxic form, followed by CdS QDs and bulk CdS. • CdS QDs altered oxidative balance and caused DNA damage in mussel cells. • CdS QDs caused a particle-specific immunostimulation on phagocytosis of hemocytes. • Conceptual models for cellular handling and toxicity of CdS QDs are proposed. - Abstract: CdS quantum dots (QDs) show a great promise for treatment and diagnosis of cancer and for targeted drug delivery, due to their size-tunable fluorescence and ease of functionalization for tissue targeting. In spite of their advantages it is important to determine if CdS QDs can exert toxicity on biological systems. In the present work, cytotoxicity of CdS QDs (5 nm) at a wide range of concentrations (0.001–100 mg Cd/L) was screened using neutral red (NR) and thiazolyl blue tetrazolium bromide (MTT) assays in isolated hemocytes and gill cells of mussels (Mytilus galloprovincialis). The mechanisms of action of CdS QDs were assessed at sublethal concentrations (0.31–5 mg Cd/L) in the same cell types through a series of functional in vitro assays: production of reactive oxygen species (ROS), catalase (CAT) activity, DNA damage, lysosomal acid phosphatase (AcP) activity, multixenobiotic resistance (MXR) transport activity, Na-K-ATPase activity (only in gill cells) and phagocytic activity and damage to actin cytoskeleton (only in hemocytes). Exposures to CdS QDs lasted for 24 h and were performed in parallel with exposures to bulk CdS and ionic Cd. Ionic Cd was the most toxic form to both cell types, followed by CdS QDs and bulk CdS. ROS production, DNA damage, AcP activity and MXR transport were significantly increased in both cell types exposed to the 3 forms of Cd. CAT activity increased in hemocytes exposed to the three forms of Cd while in gill cells only in those exposed to ionic Cd. No effects were found on hemocytes cytoskeleton integrity. Effects on

  14. Cytotoxicity and cellular mechanisms involved in the toxicity of CdS quantum dots in hemocytes and gill cells of the mussel Mytilus galloprovincialis

    Energy Technology Data Exchange (ETDEWEB)

    Katsumiti, A. [CBET Research Group, Dept. Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country (Spain); Gilliland, D. [EU Commission–Joint Research Centre, Institute of Health and Consumer Protection, NSB Unit, Ispra (Italy); Arostegui, I. [Department of Applied Mathematics, Statistics and Operations Research, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa (Spain); Cajaraville, M.P., E-mail: mirenp.cajaraville@ehu.es [CBET Research Group, Dept. Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country (Spain)

    2014-08-15

    Highlights: • CdS QDs were cytotoxic for mussel hemocytes and gill cells in vitro. • Ionic Cd was the most toxic form, followed by CdS QDs and bulk CdS. • CdS QDs altered oxidative balance and caused DNA damage in mussel cells. • CdS QDs caused a particle-specific immunostimulation on phagocytosis of hemocytes. • Conceptual models for cellular handling and toxicity of CdS QDs are proposed. - Abstract: CdS quantum dots (QDs) show a great promise for treatment and diagnosis of cancer and for targeted drug delivery, due to their size-tunable fluorescence and ease of functionalization for tissue targeting. In spite of their advantages it is important to determine if CdS QDs can exert toxicity on biological systems. In the present work, cytotoxicity of CdS QDs (5 nm) at a wide range of concentrations (0.001–100 mg Cd/L) was screened using neutral red (NR) and thiazolyl blue tetrazolium bromide (MTT) assays in isolated hemocytes and gill cells of mussels (Mytilus galloprovincialis). The mechanisms of action of CdS QDs were assessed at sublethal concentrations (0.31–5 mg Cd/L) in the same cell types through a series of functional in vitro assays: production of reactive oxygen species (ROS), catalase (CAT) activity, DNA damage, lysosomal acid phosphatase (AcP) activity, multixenobiotic resistance (MXR) transport activity, Na-K-ATPase activity (only in gill cells) and phagocytic activity and damage to actin cytoskeleton (only in hemocytes). Exposures to CdS QDs lasted for 24 h and were performed in parallel with exposures to bulk CdS and ionic Cd. Ionic Cd was the most toxic form to both cell types, followed by CdS QDs and bulk CdS. ROS production, DNA damage, AcP activity and MXR transport were significantly increased in both cell types exposed to the 3 forms of Cd. CAT activity increased in hemocytes exposed to the three forms of Cd while in gill cells only in those exposed to ionic Cd. No effects were found on hemocytes cytoskeleton integrity. Effects on

  15. Mechanisms of cellular transformation by carcinogenic agents

    International Nuclear Information System (INIS)

    This book contains 14 chapters. Some of the chapter titles are: DNA Modification by Chemical Carcinogens; Role of DNA Lesions and Repair in the Transformation of Human Cells; The Induction and Regulation of Radiogenic Transformation In Vitro: Cellular and Molecular Mechanisms; Cellular Transformation by Adenoviruses; and The fos Gene

  16. Mechanisms of cellular transformation by carcinogenic agents

    Energy Technology Data Exchange (ETDEWEB)

    Grunberger, D.; Goff, S.P.

    1987-01-01

    This book contains 14 chapters. Some of the chapter titles are: DNA Modification by Chemical Carcinogens; Role of DNA Lesions and Repair in the Transformation of Human Cells; The Induction and Regulation of Radiogenic Transformation In Vitro: Cellular and Molecular Mechanisms; Cellular Transformation by Adenoviruses; and The fos Gene.

  17. Cellular and molecular mechanisms in kidney fibrosis

    Science.gov (United States)

    Duffield, Jeremy S.

    2014-01-01

    Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progression. This review focuses on new findings that enhance understanding of cellular and molecular mechanisms of fibrosis, the characteristics of myofibroblasts, their progenitors, and molecular pathways regulating both fibrogenesis and its resolution. PMID:24892703

  18. Cellular mechanisms that control mistranslation

    DEFF Research Database (Denmark)

    Reynolds, Noah M; Lazazzera, Beth A; Ibba, Michael

    2010-01-01

    Mistranslation broadly encompasses the introduction of errors during any step of protein synthesis, leading to the incorporation of an amino acid that is different from the one encoded by the gene. Recent research has vastly enhanced our understanding of the mechanisms that control mistranslation...

  19. Mechanism of cellular phospholipid efflux.

    Science.gov (United States)

    Kozar, R A; McKeone, B J; Pownall, H J

    1993-11-01

    Plasma phospholipid binding to cell-derived cholesterol is important in reverse cholesterol transport, a key step in the regression of atherosclerosis. However, the mechanism by which phospholipids are transferred from cells to plasma remains unclear. [3H]Choline-labeled phospholipid efflux from fibroblasts has been studied using plasma and its components as acceptors. The kinetics were resolved into a fast component (k1 = 0.119 +/- 0.23 min-1) that corresponded to high-affinity binding of high-density lipoproteins (HDL) to the cell surface and a slow component (k2 = 0.0047 +/- 0.0009 min-1) due to protein-mediated desorption (n = 3). Altering the donor charge with heparinase or the acceptor charge by acetylation abolished the fast component, while the slow phase was unchanged. Only HDL displayed biexponential kinetics, comparable to whole plasma. Half-lives for low-density lipoprotein and very-low-density lipoprotein were t1/2 = 278 +/- 22 min and t1/2 = 1003 +/- 147 min, respectively. In the absence of transfer factor, HDL alone significantly reduced phospholipid efflux (t1/2 = 663 min). Phospholipid transfer protein restored biexponential kinetics. We conclude that cell membranes are a potentially important source of plasma phospholipids and that protein-mediated transfer to HDL is the major route for cell-to-plasma transfer. This step represents a locus for anti-atherosclerotic intervention. PMID:8231174

  20. Cellular and molecular mechanisms in kidney fibrosis

    OpenAIRE

    Duffield, Jeremy S.

    2014-01-01

    Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progressi...

  1. Investigating the specific core genetic-and-epigenetic networks of cellular mechanisms involved in human aging in peripheral blood mononuclear cells.

    Science.gov (United States)

    Li, Cheng-Wei; Wang, Wen-Hsin; Chen, Bor-Sen

    2016-02-23

    Aging is an inevitable part of life for humans, and slowing down the aging process has become a main focus of human endeavor. Here, we applied a systems biology approach to construct protein-protein interaction networks, gene regulatory networks, and epigenetic networks, i.e. genetic and epigenetic networks (GENs), of elderly individuals and young controls. We then compared these GENs to extract aging mechanisms using microarray data in peripheral blood mononuclear cells, microRNA (miRNA) data, and database mining.The core GENs of elderly individuals and young controls were obtained by applying principal network projection to GENs based on Principal Component Analysis. By comparing the core networks, we identified that to overcome the accumulated mutation of genes in the aging process the transcription factor JUN can be activated by stress signals, including the MAPK signaling, T-cell receptor signaling, and neurotrophin signaling pathways through DNA methylation of BTG3, G0S2, and AP2B1 and the regulations of mir-223 let-7d, and mir-130a. We also address the aging mechanisms in old men and women. Furthermore, we proposed that drugs designed to target these DNA methylated genes or miRNAs may delay aging. A multiple drug combination comprising phenylalanine, cholesterol, and palbociclib was finally designed for delaying the aging process. PMID:26895224

  2. Cellular and molecular mechanisms in liver fibrogenesis.

    Science.gov (United States)

    Novo, Erica; Cannito, Stefania; Paternostro, Claudia; Bocca, Claudia; Miglietta, Antonella; Parola, Maurizio

    2014-04-15

    Liver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process, potentially reversible, that drives the progression of chronic liver diseases (CLD) towards liver cirrhosis and hepatic failure. Hepatic myofibroblasts (MFs), the pro-fibrogenic effector cells, originate mainly from activation of hepatic stellate cells and portal fibroblasts being characterized by a proliferative and survival attitude. MFs also contract in response to vasoactive agents, sustain angiogenesis and recruit and modulate activity of cells of innate or adaptive immunity. Chronic activation of wound healing and oxidative stress as well as derangement of epithelial-mesenchymal interactions are "major" pro-fibrogenic mechanisms, whatever the etiology. However, literature has outlined a complex network of pro-fibrogenic factors and mediators proposed to modulate CLD progression, with some of them being at present highly debated in the field, including the role of epithelial to mesenchymal transition and Hedgehog signaling pathways. Hypoxia and angiogenesis as well as inflammasomes are recently emerged as ubiquitous pro-inflammatory and pro-fibrogenic determinants whereas adipokines are mostly involved in CLD related to metabolic disturbances (metabolic syndrome and/or obesity and type 2 diabetes). Finally, autophagy as well as natural killer and natural killer-T cells have been recently proposed to significantly affect fibrogenic CLD progression. PMID:24631571

  3. Cellular mechanisms of nociception in the frog

    Czech Academy of Sciences Publication Activity Database

    Kuffler, D. P.; Lyfenko, Alla; Vyklický st., Ladislav; Vlachová, Viktorie

    2002-01-01

    Roč. 88, č. 4 (2002), s. 1843-1850. ISSN 0022-3077 R&D Projects: GA ČR GA305/00/1639; GA MŠk LN00B122 Grant ostatní: NATO(XX) Grant 977062 Institutional research plan: CEZ:AV0Z5011922 Keywords : cellular mechanisms of nociception * frog Subject RIV: FH - Neurology Impact factor: 3.743, year: 2002

  4. Molecular and cellular mechanisms of cadmium carcinogenesis

    International Nuclear Information System (INIS)

    Cadmium is a heavy metal, which is widely used in industry, affecting human health through occupational and environmental exposure. In mammals, it exerts multiple toxic effects and has been classified as a human carcinogen by the International Agency for Research on Cancer. Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Cd2+ does not catalyze Fenton-type reactions because it does not accept or donate electrons under physiological conditions, and it is only weakly genotoxic. Hence, indirect mechanisms are implicated in the carcinogenicity of cadmium. In this review multiple mechanisms are discussed, such as modulation of gene expression and signal transduction, interference with enzymes of the cellular antioxidant system and generation of reactive oxygen species (ROS), inhibition of DNA repair and DNA methylation, role in apoptosis and disruption of E-cadherin-mediated cell-cell adhesion. Cadmium affects both gene transcription and translation. The major mechanisms of gene induction by cadmium known so far are modulation of cellular signal transduction pathways by enhancement of protein phosphorylation and activation of transcription and translation factors. Cadmium interferes with antioxidant defense mechanisms and stimulates the production of reactive oxygen species, which may act as signaling molecules in the induction of gene expression and apoptosis. The inhibition of DNA repair processes by cadmium represents a mechanism by which cadmium enhances the genotoxicity of other agents and may contribute to the tumor initiation by this metal. The disruption of E-cadherin-mediated cell-cell adhesion by cadmium probably further stimulates the development of tumors. It becomes clear that there exist multiple mechanisms which contribute to the carcinogenicity of cadmium, although the relative weights of these contributions are difficult to estimate

  5. Cellular and molecular mechanisms underlying radiation carcinogenesis

    International Nuclear Information System (INIS)

    When considering and analyzing experimental material concerning cellular aspects of the problem of radiation carcinogenesis, the following conclusions can be made: neoplastic transformation of cells in a culture is caused already by small radiation doses, under the effect of which the level of DNA injury is quite insignificant; the frequency of cell transformation depends on the type of radiation, it is particularly pronounced under the effect of radiations with a high linear energy transfer; a correlation between the processes of postradiation recovery and radiogenic transformation of cells is detected, nonrepairable injures of DNA playing the most important role in radiation carcinogenesis; tumour promoters and anticarcinogenic agens produce a modifying effect on the transformation of irradiated cells. Molecular mechanisms of oncogene activation are thoroughly studied using the model of virus carcinogenesis, the problem of the nature of chemical and, in particular, radiation cell transformation remains scantily investigated

  6. Multiple Pathways Involved in Porcine Parvovirus Cellular Entry and Trafficking toward the Nucleus▿

    OpenAIRE

    Boisvert, Maude; Fernandes, Sandra; Tijssen, Peter

    2010-01-01

    Porcine parvovirus (PPV) is a major cause of reproductive failure in swine. The mechanisms implicated in the first steps of infection that lead to the delivery of the PPV genome to the nucleus are poorly understood. In the present work, a panel of chemical inhibitors was used to dissect the cellular mechanisms involved in establishing a PPV infection. The results demonstrated that following binding to sialic acids on cell surface glycoproteins, the virus used both clathrin-mediated endocytosi...

  7. Cellular functions of vaults and their involvement in multidrug resistance.

    Science.gov (United States)

    Steiner, E; Holzmann, K; Elbling, L; Micksche, M; Berger, W

    2006-08-01

    Vaults are evolutionary highly conserved ribonucleoprotein (RNP) particles with a hollow barrel-like structure. They are 41 x 73 nm in size and are composed of multiple copies of three proteins and small untranslated RNA (vRNA). The main component of vaults represents the 110 kDa major vault protein (MVP), whereas the two minor vault proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (VPARP) and the 240 kDa telomerase-associated protein-1 (TEP1). Vaults are abundantly present in the cytoplasm of eukaryotic cells and they were found to be associated with cytoskeletal elements as well as occasionally with the nuclear envelope. Vaults and MVP have been associated with several cellular processes which are also involved in cancer development like cell motility and differentiation. Due to the over-expression of MVP (also termed lung resistance-related protein or LRP) in several P-glycoprotein (P-gp)-negative chemoresistant cancer cell lines, vaults have been linked to multidrug resistance (MDR). Accordingly, high levels of MVP were found in tissues chronically exposed to xenobiotics. In addition, the expression of MVP correlated with the degree of malignancy in certain cancer types, suggesting a direct involvement in tumor development and/or progression. Based on the finding that MVP binds several phosphatases and kinases including PTEN, SHP-2 as well as Erk, evidence is accumulating that MVP might be involved in the regulation of important cell signalling pathways including the PI3K/Akt and the MAPK pathways. In this review we summarize the current knowledge concerning the vault particle and discuss its possible cellular functions, focusing on the role of vaults in chemotherapy resistance. PMID:16918321

  8. Mechanical oscillations at the cellular scale

    CERN Document Server

    Jülicher, F

    2001-01-01

    Active phenomena which involve force generation and motion play a key role in a number of phenomena in living cells such as cell motility, muscle contraction and the active transport of material and organelles. Here we discuss mechanical oscillations generated by active systems in cells. Examples are oscillatory regimes in muscles, the periodic beating of axonemal cilia and flagella and spontaneous oscillations of auditory hair cells which play a role in active amplification of weak sounds in hearing. As a prototype system for oscillation generation by proteins, we discuss a general mechanism by which many coupled active elements such as motor molecules can generate oscillations.

  9. Involvement of oxygen reactive species in the cellular response of carcinoma cells to irradiation

    International Nuclear Information System (INIS)

    After a presentation of oxygen reactive species and their sources, the author describes the enzymatic and non-enzymatic anti-oxidative defenses, the physiological roles of oxygen reactive species, the oxidative stress, the water radiolysis, the anti-oxidative enzymes and the effects of ionizing radiations. The author then reports an investigation on the contribution of oxygen reactive species in the cellular response to irradiation, and an investigation on the influence of the breathing chain on the persistence of a radio-induced oxidative stress. He also reports a research on molecular mechanisms involved in the cellular radio-sensitivity

  10. Plant regeneration: cellular origins and molecular mechanisms.

    Science.gov (United States)

    Ikeuchi, Momoko; Ogawa, Yoichi; Iwase, Akira; Sugimoto, Keiko

    2016-05-01

    Compared with animals, plants generally possess a high degree of developmental plasticity and display various types of tissue or organ regeneration. This regenerative capacity can be enhanced by exogenously supplied plant hormones in vitro, wherein the balance between auxin and cytokinin determines the developmental fate of regenerating organs. Accumulating evidence suggests that some forms of plant regeneration involve reprogramming of differentiated somatic cells, whereas others are induced through the activation of relatively undifferentiated cells in somatic tissues. We summarize the current understanding of how plants control various types of regeneration and discuss how developmental and environmental constraints influence these regulatory mechanisms. PMID:27143753

  11. Molecular and cellular mechanisms of adipogenesis

    Directory of Open Access Journals (Sweden)

    Aleksander Dmitrievich Egorov

    2015-03-01

    Full Text Available The main components of metabolic syndrome include insulin resistance, hypertriglyceridemia and arterial hypertension. Obesity is the cause of metabolic syndrome, mainly as a consequence of the endocrine function of adipose tissue. The volume of adipose tissue depends on the size of individual adipocytes and on their number. The number of adipocytes increases as a result of enhanced adipocyte differentiation. The transcriptional cascade that regulates this differentiation has been well studied. The major adipogenic transcription factor peroxisome proliferator-activated receptor gamma is a ligand-activated nuclear receptor with essential roles in adipogenesis. Its ligands are used to treat metabolic syndrome and type 2 diabetes mellitus. The present article describes the basic molecular and cellular mechanisms of adipogenesis and discusses the impact of insulin, glucocorticoids, cyclic adenosine monophosphate-activating agents, nuclear receptors and transcription factors on the process of adipogenesis. New regulatory regions of the genome that are capable of binding multiple transcription factors are described, and the most promising drug targets for the treatment of metabolic syndrome and obesity, including the homeodomain proteins Pbx1 and Prep1, are discussed.

  12. Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin

    Directory of Open Access Journals (Sweden)

    Sarah Spreckelmeyer

    2014-09-01

    Full Text Available The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir. Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.

  13. Cellular Mechanisms of Ciliary Length Control

    Directory of Open Access Journals (Sweden)

    Jacob Keeling

    2016-01-01

    Full Text Available Cilia and flagella are evolutionarily conserved, membrane-bound, microtubule-based organelles on the surface of most eukaryotic cells. They play important roles in coordinating a variety of signaling pathways during growth, development, cell mobility, and tissue homeostasis. Defects in ciliary structure or function are associated with multiple human disorders called ciliopathies. These diseases affect diverse tissues, including, but not limited to the eyes, kidneys, brain, and lungs. Many processes must be coordinated simultaneously in order to initiate ciliogenesis. These include cell cycle, vesicular trafficking, and axonemal extension. Centrioles play a central role in both cell cycle progression and ciliogenesis, making the transition between basal bodies and mitotic spindle organizers integral to both processes. The maturation of centrioles involves a functional shift from cell division toward cilium nucleation which takes place concurrently with its migration and fusion to the plasma membrane. Several proteinaceous structures of the distal appendages in mother centrioles are required for this docking process. Ciliary assembly and maintenance requires a precise balance between two indispensable processes; so called assembly and disassembly. The interplay between them determines the length of the resulting cilia. These processes require a highly conserved transport system to provide the necessary substances at the tips of the cilia and to recycle ciliary turnover products to the base using a based microtubule intraflagellar transport (IFT system. In this review; we discuss the stages of ciliogenesis as well as mechanisms controlling the lengths of assembled cilia.

  14. Propagation Mechanism of Cylindrical Cellular Detonation

    Science.gov (United States)

    Han, Wen-Hu; Wang, Cheng; Ning, Jian-Guo

    2012-10-01

    We investigate the evolution of cylindrical cellular detonation with different instabilities. The numerical results show that with decreasing initial temperature, detonation becomes more unstable and the cells of the cylindrical detonation tend to be irregular. For stable detonation, a divergence of cylindrical detonation cells is formed eventually due to detonation instability resulting from a curved detonation front. For mildly unstable detonation, local overdriven detonation occurs. The detonation cell diverges and its size decreases. For highly unstable detonation, locally driven detonation is more obvious and the front is highly wrinkled. As a result, the diverging cylindrical detonation cell becomes highly irregular.

  15. Computer Studies on the Mechanisms Controlling Cellular Proliferation

    International Nuclear Information System (INIS)

    A model of the autoregulation of mitotic and functional activity of the cells is used (R. Tsanev and B. Sendov, J. theoret. Biol. 12 (1966) 327) to study by means of a digital computer the reaction of different cellular systems (a synchronous cellular population, liver and epidermis) to injuring agents disturbing the steady state of the system. The reaction of the cellular models to different kinds of injury was found to imitate adequately some particular features of the real regenerative processes. The model may also be useful to check different hypotheses concerning the mechanisms by which irradiation affects cellular proliferation. (author)

  16. Symposium on molecular and cellular mechanisms of mutagenesis

    International Nuclear Information System (INIS)

    These proceedings contain abstracts only of the 21 papers presented at the Sympsoium. The papers dealt with molecular mechanisms of mutagenesis and cellular responses to chemical and physical mutagenic agents

  17. Cellular and molecular mechanisms underlying muscular dystrophy

    OpenAIRE

    Rahimov, Fedik; Kunkel, Louis M

    2013-01-01

    The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying ...

  18. Material and mechanical factors:new strategy in cellular neurogenesis

    Institute of Scientific and Technical Information of China (English)

    Hillary Stoll; Il Keun Kwon; Jung Yul Lim

    2014-01-01

    Since damaged neural circuits are not generally self-recovered, developing methods to stimulate neurogenesis is critically required. Most studies have examined the effects of soluble pharma-cological factors on the cellular neurogenesis. On the other hand, it is now recognized that the other extracellular factors, including material and mechanical cues, also have a strong potential to induce cellular neurogenesis. This article will review recent data on the material (chemical patterning, micro/nano-topography, carbon nanotube, graphene) and mechanical (static cue from substrate stiffness, dynamic cue from stretch and lfow shear) stimulations of cellular neuro-genesis. These approaches may provide new neural regenerative medicine protocols. Scaffolding material templates capable of triggering cellular neurogenesis can be explored in the presence of neurogenesis-stimulatory mechanical environments, and also with conventional soluble factors, to enhance axonal growth and neural network formation in neural tissue engineering.

  19. Cellular and molecular mechanisms of muscle atrophy

    Directory of Open Access Journals (Sweden)

    Paolo Bonaldo

    2013-01-01

    Full Text Available Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

  20. Cellular and molecular mechanisms of chemical synaptic transmission.

    Science.gov (United States)

    Millhorn, D E; Bayliss, D A; Erickson, J T; Gallman, E A; Szymeczek, C L; Czyzyk-Krzeska, M; Dean, J B

    1989-12-01

    During the last decade much progress has been made in understanding the cellular and molecular mechanisms by which nerve cells communicate with each other and nonneural (e.g., muscle) target tissue. This review is intended to provide the reader with an account of this work. We begin with an historical overview of research on cell-to-cell communication and then discuss recent developments that, in some instances, have led to dramatic changes in the concept of synaptic transmission. For instance, the finding that single neurons often contain multiple messengers (i.e., neurotransmitters) invalidated the long-held theory (i.e., Dale's Law) that individual neurons contain and release one and only one type of neurotransmitter. Moreover, the last decade witnessed the inclusion of an entire group of compounds, the neuropeptides, as messenger molecules. Enormous progress has also been made in elucidating postsynaptic receptor complexes and biochemical intermediaries involved in synaptic transmission. Here the development of recombinant DNA technology has made it possible to clone and determine the molecular structure for a number of receptors. This information has been used to gain insight into how these receptors function either as a ligand-gated channel or as a G protein-linked ligand recognition molecule. Perhaps the most progress made during this era was in understanding the molecular linkage of G protein-linked receptors to intramembranous and cytoplasmic macromolecules involved in signal amplification and transduction. We conclude with a brief discussion of how synaptic transmission leads to immediate alterations in the electrical activity and, in some cases, to a change in phenotype by altering gene expression. These alterations in cellular behavior are believed to be mediated by phosphoproteins, the final biochemical product of signal transduction. PMID:2575357

  1. Cellular pressure and volume regulation and implications for cell mechanics.

    Science.gov (United States)

    Jiang, Hongyuan; Sun, Sean X

    2013-08-01

    In eukaryotic cells, small changes in cell volume can serve as important signals for cell proliferation, death, and migration. Volume and shape regulation also directly impacts the mechanics of cells and tissues. Here, we develop a mathematical model of cellular volume and pressure regulation, incorporating essential elements such as water permeation, mechanosensitive channels, active ion pumps, and active stresses in the cortex. The model can fully explain recent experimental data, and it predicts cellular volume and pressure for several models of cell cortical mechanics. Moreover, we show that when cells are subjected to an externally applied load, such as in an atomic force microscopy indentation experiment, active regulation of volume and pressure leads to a complex cellular response. Instead of the passive mechanics of the cortex, the observed cell stiffness depends on several factors working together. This provides a mathematical explanation of rate-dependent response of cells under force. PMID:23931309

  2. The involvement of XPC protein in the cisplatin DNA damaging treatment-mediated cellular response

    Institute of Scientific and Technical Information of China (English)

    Gan WANG; Alan DOMBKOWSKI; Lynn CHUANG; Xiao Xin S XU

    2004-01-01

    Recognition of DNA damage is a critical step for DNA damage-mediated cellular response. XPC is an important DNA damage recognition protein involved in nucleotide excision repair (NER). We have studied the XPC protein in cisplatin DNA damaging treatment-mediated cellular response. Comparison of the microarray data from both normal and XPCdefective human fibroblasts identified 861 XPC-responsive genes in the cisplatin treatment (with minimum fold change≥1.5).The cell cycle and cell proliferation-related genes are the most affected genes by the XPC defect in the treatment. Many other cellular function genes, especially the DNA repair and signal transduction-related genes, were also affected by the XPC defect in the treatment. To validate the microarray data, the transcription levels of some microarray-identified genes were also determined by an RT-PCR based real time PCR assay. The real time PCR results are consistent with the microarray data for most of the tested genes, indicating the reliability of the microarray data. To further validate the microarray data, the cisplatin treatment-mediated caspase-3 activation was also determined. The Western blot hybridization results indicate that the XPC defect greatly attenuates the cisplatin treatment-mediated Caspase-3 activation. We elucidated the role of p53 protein in the XPC protein DNA damage recognition-mediated signaling process. The XPC defect reduces the cisplatin treatment-mediated p53 response. These results suggest that the XPC protein plays an important role in the cisplatin treatment-mediated cellular response. It may also suggest a possible mechanism of cancer cell drug resistance.

  3. Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell-based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies.

    Science.gov (United States)

    Babizhayev, Mark A; Yegorov, Yegor E

    2015-12-01

    Accumulated data indicate that wound-care products should have a composition equivalent to that of the skin: a combination of particular growth factors and extracellular matrix (ECM) proteins endogenous to the skin, together with viable epithelial cells, fibroblasts, and mesenchymal stem cells (MSCs). Strategies consisting of bioengineered dressings and cell-based products have emerged for widespread clinical use; however, their performance is not optimal because chronic wounds persist as a serious unmet medical need. Telomerase, the ribonucleoprotein complex that adds telomeric repeats to the ends of chromosomes, is responsible for telomere maintenance, and its expression is associated with cell immortalization and, in certain cases, cancerogenesis. Telomerase contains a catalytic subunit, the telomerase reverse transcriptase (hTERT). Introduction of TERT into human cells extends both their lifespan and their telomeres to lengths typical of young cells. The regulation of TERT involves transcriptional and posttranscriptional molecular biology mechanisms. The manipulation, regulation of telomerase is multifactorial in mammalian cells, involving overall telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Reactive oxygen species (ROS) have been implicated in aging, apoptosis, and necrosis of cells in numerous diseases. Upon production of high levels of ROS from exogenous or endogenous generators, the redox balance is perturbed and cells are shifted into a state of oxidative stress, which subsequently leads to modifications of intracellular proteins and membrane lipid peroxidation and to direct DNA damage. When the oxidative stress is severe, survival of the cell is dependent on the repair or replacement of damaged molecules, which can result in induction of apoptosis in the injured with ROS cells. ROS-mediated oxidative stress induces the depletion of hTERT from the nucleus via export through the nuclear pores

  4. Cellular mechanisms underlying the interaction between cannabinoid and opioid system.

    Science.gov (United States)

    Parolaro, D; Rubino, T; Viganò, D; Massi, P; Guidali, C; Realini, N

    2010-04-01

    Recently, the presence of functional interaction between the opioid and cannabinoid system has been shown in various pharmacological responses. Although there is an increasing interest for the feasible therapeutic application of a co-administration of cannabinoids and opioids in some disorders (i.e. to manage pain, to modulate immune system and emotions) and the combined use of the two drugs by drug abusers is becoming largely diffuse, only few papers focused on cellular and molecular mechanisms underlying this interaction. This review updates the biochemical and molecular underpinnings of opioid and cannabinoid interaction, both within the central nervous system and periphery. The most convincing theory for the explanation of this reciprocal interaction involves (i) the release of opioid peptides by cannabinoids or endocannabinoids by opioids, (ii) the existence of a direct receptor-receptor interaction when the receptors are co-expressed in the same cells, and (iii) the interaction of their intracellular pathways. Finally, the cannabinoid/opioid interaction might be different in the brain rewarding networks and in those accounting for other pharmacological effects (antinociception, modulation of emotionality and cognitive behavior), as well as between the central nervous system and periphery. Further insights about the cannabinoid/opioid interaction could pave the way for new and promising therapeutic approaches. PMID:20017730

  5. Cellular Mechanisms of L-arginine Induced Experimental Acute Pancreatitis

    OpenAIRE

    Masood, Omar

    2013-01-01

    AbstractThe University Of ManchesterOmar MasoodMD Thesis 2013Cellular Mechanisms of L-arginine Induced Experimental Acute Pancreatitis. IntroductionImpairment of cytosolic calcium ([Ca2+]i) signaling and in particular calcium overload has emerged as a possible unifying mechanism for precipitating acute pancreatitis (AP.)In the L-arginine (L-arg) experimental model of AP, nitric oxide (NO) has been implicated however the disease progression is largely unaffected by nitric oxide synthase (NOS) ...

  6. Disruption of a cystine transporter downregulates expression of genes involved in sulfur regulation and cellular respiration.

    Science.gov (United States)

    Simpkins, Jessica A; Rickel, Kirby E; Madeo, Marianna; Ahlers, Bethany A; Carlisle, Gabriel B; Nelson, Heidi J; Cardillo, Andrew L; Weber, Emily A; Vitiello, Peter F; Pearce, David A; Vitiello, Seasson P

    2016-01-01

    Cystine and cysteine are important molecules for pathways such as redox signaling and regulation, and thus identifying cellular deficits upon deletion of the Saccharomyces cerevisiae cystine transporter Ers1p allows for a further understanding of cystine homeostasis. Previous complementation studies using the human ortholog suggest yeast Ers1p is a cystine transporter. Human CTNS encodes the protein Cystinosin, a cystine transporter that is embedded in the lysosomal membrane and facilitates the export of cystine from the lysosome. When CTNS is mutated, cystine transport is disrupted, leading to cystine accumulation, the diagnostic hallmark of the lysosomal storage disorder cystinosis. Here, we provide biochemical evidence for Ers1p-dependent cystine transport. However, the accumulation of intracellular cystine is not observed when the ERS1 gene is deleted from ers1-Δ yeast, supporting the existence of modifier genes that provide a mechanism in ers1-Δ yeast that prevents or corrects cystine accumulation. Upon comparison of the transcriptomes of isogenic ERS1+ and ers1-Δ strains of S. cerevisiae by DNA microarray followed by targeted qPCR, sixteen genes were identified as being differentially expressed between the two genotypes. Genes that encode proteins functioning in sulfur regulation, cellular respiration, and general transport were enriched in our screen, demonstrating pleiotropic effects of ers1-Δ. These results give insight into yeast cystine regulation and the multiple, seemingly distal, pathways that involve proper cystine recycling. PMID:27142334

  7. Porosity and Mechanical Strength of an Autoclaved Clayey Cellular Concrete

    Directory of Open Access Journals (Sweden)

    P. O. Guglielmi

    2010-01-01

    Full Text Available This paper investigates the porosity and the mechanical strength of an Autoclaved Clayey Cellular Concrete (ACCC with the binder produced with 75 wt% kaolinite clay and 25 wt% Portland cement. Aluminum powder was used as foaming agent, from 0.2 wt% to 0.8 wt%, producing specimens with different porosities. The results show that the specimens with higher content of aluminum presented pore coalescence, which can explain the lower porosity of these samples. The porosities obtained with the aluminum contents used in the study were high (approximately 80%, what accounts for the low mechanical strength of the investigated cellular concretes (maximum of 0.62 MPa. Nevertheless, comparing the results obtained in this study to the ones for low temperature clayey aerated concrete with similar compositions, it can be observed that autoclaving is effective for increasing the material mechanical strength.

  8. Composite alginate gels for tunable cellular microenvironment mechanics

    Science.gov (United States)

    Khavari, Adele; Nydén, Magnus; Weitz, David A.; Ehrlicher, Allen J.

    2016-01-01

    The mechanics of the cellular microenvironment can be as critical as biochemistry in directing cell behavior. Many commonly utilized materials derived from extra-cellular-matrix create excellent scaffolds for cell growth, however, evaluating the relative mechanical and biochemical effects independently in 3D environments has been difficult in frequently used biopolymer matrices. Here we present 3D sodium alginate hydrogel microenvironments over a physiological range of stiffness (E = 1.85 to 5.29 kPa), with and without RGD binding sites or collagen fibers. We use confocal microscopy to measure the growth of multi-cellular aggregates (MCAs), of increasing metastatic potential in different elastic moduli of hydrogels, with and without binding factors. We find that the hydrogel stiffness regulates the growth and morphology of these cell clusters; MCAs grow larger and faster in the more rigid environments similar to cancerous breast tissue (E = 4–12 kPa) as compared to healthy tissue (E = 0.4–2 kpa). Adding binding factors from collagen and RGD peptides increases growth rates, and change maximum MCA sizes. These findings demonstrate the utility of these independently tunable mechanical/biochemistry gels, and that mechanical confinement in stiffer microenvironments may increase cell proliferation. PMID:27484403

  9. Composite alginate gels for tunable cellular microenvironment mechanics

    Science.gov (United States)

    Khavari, Adele; Nydén, Magnus; Weitz, David A.; Ehrlicher, Allen J.

    2016-08-01

    The mechanics of the cellular microenvironment can be as critical as biochemistry in directing cell behavior. Many commonly utilized materials derived from extra-cellular-matrix create excellent scaffolds for cell growth, however, evaluating the relative mechanical and biochemical effects independently in 3D environments has been difficult in frequently used biopolymer matrices. Here we present 3D sodium alginate hydrogel microenvironments over a physiological range of stiffness (E = 1.85 to 5.29 kPa), with and without RGD binding sites or collagen fibers. We use confocal microscopy to measure the growth of multi-cellular aggregates (MCAs), of increasing metastatic potential in different elastic moduli of hydrogels, with and without binding factors. We find that the hydrogel stiffness regulates the growth and morphology of these cell clusters; MCAs grow larger and faster in the more rigid environments similar to cancerous breast tissue (E = 4–12 kPa) as compared to healthy tissue (E = 0.4–2 kpa). Adding binding factors from collagen and RGD peptides increases growth rates, and change maximum MCA sizes. These findings demonstrate the utility of these independently tunable mechanical/biochemistry gels, and that mechanical confinement in stiffer microenvironments may increase cell proliferation.

  10. Cellular Pressure and Volume Regulation and Implications for Cell Mechanics

    OpenAIRE

    Jiang, Hongyuan; Sun, Sean X.

    2013-01-01

    In eukaryotic cells, small changes in cell volume can serve as important signals for cell proliferation, death, and migration. Volume and shape regulation also directly impacts the mechanics of cells and tissues. Here, we develop a mathematical model of cellular volume and pressure regulation, incorporating essential elements such as water permeation, mechanosensitive channels, active ion pumps, and active stresses in the cortex. The model can fully explain recent experimental data, and it pr...

  11. Underlying molecular and cellular mechanisms in childhood irritable bowel syndrome.

    Science.gov (United States)

    Chumpitazi, Bruno P; Shulman, Robert J

    2016-12-01

    Irritable bowel syndrome (IBS) affects a large number of children throughout the world. The symptom expression of IBS is heterogeneous, and several factors which may be interrelated within the IBS biopsychosocial model play a role. These factors include visceral hyperalgesia, intestinal permeability, gut microbiota, psychosocial distress, gut inflammation, bile acids, food intolerance, colonic bacterial fermentation, and genetics. The molecular and cellular mechanisms of these factors are being actively investigated. In this mini-review, we present updates of these mechanisms and, where possible, relate the findings to childhood IBS. Mechanistic elucidation may lead to the identification of biomarkers as well as personalized childhood IBS therapies. PMID:26883355

  12. Composition, structure and mechanical properties of several natural cellular materials

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The stem piths of sunflower, kaoliang and corn are natural cellular materials. In this paper, the contents of the compositions of these piths are determined and their cell shapes and structures are examined through scanning electron microscope (SEM) and optical microscope. Further research is conducted in the effects of the compositions and structures of the piths on the mechanical properties after testing the partial mechanical properties. The results show that the total cellulose, hemicelluloses and lignin content of each sample approaches 75% of the dry mass of its primary cell walls. With the fall of R value, a parameter relative to the contents of the main compositions, the flexibilities of the cellular piths descend while their stresses and rigidities increase. The basic cell shape making up the sunflower pith is approximately a tetrakaidehedron. The stem piths of kaoliang and corn are made up of cells close to hexangular prisms and a few tubular ones which can observably reinforce their mechanical properties in the axial directions.

  13. Investigation of the Cellular and Molecular Mechanisms of Radiation-induced Bystander Effects

    OpenAIRE

    Furlong, Hayley

    2014-01-01

    The overall aim of this study was to investigate the cellular and molecular mechanisms involved in radiation-induced bystander effects in HaCaT cells, predominantly at low-doses of irradiation. They do not follow the original dose-response theory and exhibit a unique cascade of signalling events, which are under intense investigation for radiation risk purposes. An in vitro system was first used to observe the bystander effect, comparing two cell viability assays while measuring apoptotic cel...

  14. Identification of the cellular mechanisms undelying the contribution of stress and glucocorticoids to Alzheimer's disease pathology

    OpenAIRE

    Sotiropoulos, Ioannis

    2006-01-01

    Clinical evidence suggests the involvement of stress and glucocorticoids (GC) in the etiopathogenesis of Alzheimer’s disease (AD), a disease marked by severe memory impairments as well as alterations in mood and emotional state. The experiments described in this dissertation represent an attempt to establish the cellular mechanisms through which stress and GC may impact on the development of AD. These studies focused on the hippocampus and prefrontal cortex (PFC), brain areas that are severel...

  15. Cellular mechanisms of cadmium-induced toxicity: a review.

    Science.gov (United States)

    Rani, Anju; Kumar, Anuj; Lal, Ankita; Pant, Manu

    2014-08-01

    Cadmium is a widespread toxic pollutant of occupational and environmental concern because of its diverse toxic effects: extremely protracted biological half-life (approximately 20-30 years in humans), low rate of excretion from the body and storage predominantly in soft tissues (primarily, liver and kidneys). It is an extremely toxic element of continuing concern because environmental levels have risen steadily due to continued worldwide anthropogenic mobilization. Cadmium is absorbed in significant quantities from cigarette smoke, food, water and air contamination and is known to have numerous undesirable effects in both humans and animals. Cadmium has a diversity of toxic effects including nephrotoxicity, carcinogenicity, teratogenicity and endocrine and reproductive toxicities. At the cellular level, cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Current evidence suggests that exposure to cadmium induces genomic instability through complex and multifactorial mechanisms. Most important seems to be cadmium interaction with DNA repair mechanism, generation of reactive oxygen species and induction of apoptosis. In this article, we have reviewed recent developments and findings on cadmium toxicology. PMID:24117228

  16. Mechanism of cellular uptake of genotoxic silica nanoparticles

    Directory of Open Access Journals (Sweden)

    Mu Qingshan

    2012-07-01

    Full Text Available Abstract Mechanisms for cellular uptake of nanoparticles have important implications for nanoparticulate drug delivery and toxicity. We have explored the mechanism of uptake of amorphous silica nanoparticles of 14 nm diameter, which agglomerate in culture medium to hydrodynamic diameters around 500 nm. In HT29, HaCat and A549 cells, cytotoxicity was observed at nanoparticle concentrations ≥ 1 μg/ml, but DNA damage was evident at 0.1 μg/ml and above. Transmission electron microscopy (TEM combined with energy-dispersive X-ray spectroscopy confirmed entry of the silica particles into A549 cells exposed to 10 μg/ml of nanoparticles. The particles were observed in the cytoplasm but not within membrane bound vesicles or in the nucleus. TEM of cells exposed to nanoparticles at 4°C for 30 minutes showed particles enter cells when activity is low, suggesting a passive mode of entry. Plasma lipid membrane models identified physical interactions between the membrane and the silica NPs. Quartz crystal microbalance experiments on tethered bilayer lipid membrane systems show that the nanoparticles strongly bind to lipid membranes, forming an adherent monolayer on the membrane. Leakage assays on large unilamellar vesicles (400 nm diameter indicate that binding of the silica NPs transiently disrupts the vesicles which rapidly self-seal. We suggest that an adhesive interaction between silica nanoparticles and lipid membranes could cause passive cellular uptake of the particles.

  17. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma.

    Science.gov (United States)

    Pelaia, Girolamo; Vatrella, Alessandro; Busceti, Maria Teresa; Gallelli, Luca; Calabrese, Cecilia; Terracciano, Rosa; Maselli, Rosario

    2015-01-01

    Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments. PMID:25878402

  18. Cellular Mechanisms Underlying Eosinophilic and Neutrophilic Airway Inflammation in Asthma

    Directory of Open Access Journals (Sweden)

    Girolamo Pelaia

    2015-01-01

    Full Text Available Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments.

  19. Neural and cellular mechanisms of fear and extinction memory formation.

    Science.gov (United States)

    Orsini, Caitlin A; Maren, Stephen

    2012-08-01

    Over the course of natural history, countless animal species have evolved adaptive behavioral systems to cope with dangerous situations and promote survival. Emotional memories are central to these defense systems because they are rapidly acquired and prepare organisms for future threat. Unfortunately, the persistence and intrusion of memories of fearful experiences are quite common and can lead to pathogenic conditions, such as anxiety and phobias. Over the course of the last 30 years, neuroscientists and psychologists alike have attempted to understand the mechanisms by which the brain encodes and maintains these aversive memories. Of equal interest, though, is the neurobiology of extinction memory formation as this may shape current therapeutic techniques. Here we review the extant literature on the neurobiology of fear and extinction memory formation, with a strong focus on the cellular and molecular mechanisms underlying these processes. PMID:22230704

  20. Relationship between cellular response models and biochemical mechanisms

    International Nuclear Information System (INIS)

    In most cellular response experiments, survival reflects the kinetics of a variety of damage and repair processes. Unfortunately, biochemical studies of molecular repair deal with mechanisms which cannot be readily correlated with these kinetic observations. The difference in these approaches sometimes leads to confusion over terms such as potentially-lethal and sublethal damage. These terms were introduced with operation definitions, derived from kinetic studies of cell survival, but some researchers have since attempted to associate them with specific biochemical mechanisms. Consequently, the terms are often used in totally different ways be different investigators. The use of carefully constructed models originating either out of assumptions based on mechanisms, or on kinetics, can be used to design experiments to eliminate some alternative kinetic schemes. In turn, some mechanisms may also be eliminated, resulting in a reduction in the number of mechanisms which must be investigated biochemically. One must take advantage of a wide range of specialized radiation procedures in order to accomplish this. Examples of the use of such specialized experimental designs, which have led to a more detailed understanding of the kinetics of both algal and mammalian cell responses, are discussed

  1. Cardiovascular effects of cocaine: cellular, ionic and molecular mechanisms.

    Science.gov (United States)

    Turillazzi, E; Bello, S; Neri, M; Pomara, C; Riezzo, I; Fineschi, V

    2012-01-01

    Cocaine is a widely abused drug responsible for the majority of deaths ascribed to drug overdose. Many mechanisms have been proposed in order to explain the various cocaine associated cardiovascular complications. Conventionally, cocaine cardiotoxicity has been thought to be mediated indirectly through its sympathomimetic effect, i.e., by inhibiting the reuptake and thus increasing the levels of neuronal catecholamines at work on adrenoceptors. Increased oxidative stress, reactive oxygen species, and cocaine-induced apoptosis in the heart muscle have suggested a new way to understand the cardiotoxic effects of cocaine. More recent studies have led the attention to the interaction of cocaine and some metabolites with cardiac sodium, calcium and potassium channels. The current paper is aimed to investigate the molecular mechanisms of cocaine cardiotoxicity which have a specific clinical and forensic interest. From a clinical point of view the full knowledge of the exact mechanisms by which cocaine exerts cardio - vascular damage is essential to identify potential therapeutic targets and improve novel strategies for cocaine related cardiovascular diseases. From a forensic point of view, it is to be underlined that cocaine use is often associated to sudden death in young, otherwise healthy individuals. While such events are widely reported, the relationship between cardiac morphological alterations and molecular/cellular mechanisms is still controversial. In conclusion, the study of cocaine cardiovascular toxicity needs a strict collaboration between clinicians and pathologists which may be very effective in further dissecting the mechanisms underlying cocaine cardiotoxicity and understanding the cardiac cocaine connection. PMID:22856657

  2. Physiopathologic mechanisms involved in mare endometrosis.

    Science.gov (United States)

    Rebordão, M R; Galvão, A; Szóstek, A; Amaral, A; Mateus, L; Skarzynski, D J; Ferreira-Dias, G

    2014-10-01

    Endometrosis is a degenerative chronic process, characterized by paramount fibrosis development in mare endometrium. This condition is one of the major causes of subfertility/infertility in mares. As in other organs, fibrosis might be a pathologic sequel of many chronic inflammatory diseases. However, aetiology and physiopathologic mechanisms involved in endometrial fibrosis are still controversial. This review presents new hypotheses based on our newest data. As the first line of innate immune defence, systemic neutrophils arrive in the uterus at mating or in the presence of pathogens. A novel paradigm is that neutrophils cast out their DNA in response to infectious stimuli and form neutrophil extracellular traps (NETs). We have shown that bacterial strains of Streptococcus zooepidemicus, Escherichia coli or Staphylococcus capitis, known to cause endometritis in mares were able to induce NETs release in vitro by equine PMN to different extents. An intriguing dilemma is the dual action of NETs. While NETs play a desirable role fighting micro-organisms in mare uterus, they may also contribute to endometrial fibrosis. A long-term in vitro exposure of mare endometrium explants to NETs components (myeloperoxidase, elastase and cathepsin G) up-regulated fibrosis markers TGFβ and Tissue inhibitor of metalloproteinase (TIMP-1). Also, pro-fibrotic cytokines regulated collagen deposition and fibrosis. Changes in expression of connective tissue growth factor (CTGF), interleukins (IL)1-α, IL-1β, IL-6 and receptors in endometrium with different degrees of fibrosis and/or inflammation were observed. A putative role of CTGF, IL and NETs components in endometrosis development should be considered. Additionally, we speculate that in sustained endometritis in mares, prostaglandins may not only cause early luteolysis or early pregnancy loss, but may also be related to endometrial fibrosis pathogenesis by stimulating collagen deposition. PMID:25277436

  3. Tensegrity, cellular biophysics, and the mechanics of living systems

    Science.gov (United States)

    Ingber, Donald E.; Wang, Ning; Stamenović, Dimitrije

    2014-01-01

    The recent convergence between physics and biology has led many physicists to enter the fields of cell and developmental biology. One of the most exciting areas of interest has been the emerging field of mechanobiology that centers on how cells control their mechanical properties, and how physical forces regulate cellular biochemical responses, a process that is known as mechanotransduction. In this article, we review the central role that tensegrity (tensional integrity) architecture, which depends on tensile prestress for its mechanical stability, plays in biology. We describe how tensional prestress is a critical governor of cell mechanics and function, and how use of tensegrity by cells contributes to mechanotransduction. Theoretical tensegrity models are also described that predict both quantitative and qualitative behaviors of living cells, and these theoretical descriptions are placed in context of other physical models of the cell. In addition, we describe how tensegrity is used at multiple size scales in the hierarchy of life — from individual molecules to whole living organisms — to both stabilize three-dimensional form and to channel forces from the macroscale to the nanoscale, thereby facilitating mechanochemical conversion at the molecular level. PMID:24695087

  4. Tensegrity, cellular biophysics, and the mechanics of living systems

    Science.gov (United States)

    Ingber, Donald E.; Wang, Ning; Stamenović, Dimitrije

    2014-04-01

    The recent convergence between physics and biology has led many physicists to enter the fields of cell and developmental biology. One of the most exciting areas of interest has been the emerging field of mechanobiology that centers on how cells control their mechanical properties, and how physical forces regulate cellular biochemical responses, a process that is known as mechanotransduction. In this article, we review the central role that tensegrity (tensional integrity) architecture, which depends on tensile prestress for its mechanical stability, plays in biology. We describe how tensional prestress is a critical governor of cell mechanics and function, and how use of tensegrity by cells contributes to mechanotransduction. Theoretical tensegrity models are also described that predict both quantitative and qualitative behaviors of living cells, and these theoretical descriptions are placed in context of other physical models of the cell. In addition, we describe how tensegrity is used at multiple size scales in the hierarchy of life—from individual molecules to whole living organisms—to both stabilize three-dimensional form and to channel forces from the macroscale to the nanoscale, thereby facilitating mechanochemical conversion at the molecular level.

  5. Tensegrity, cellular biophysics, and the mechanics of living systems

    International Nuclear Information System (INIS)

    The recent convergence between physics and biology has led many physicists to enter the fields of cell and developmental biology. One of the most exciting areas of interest has been the emerging field of mechanobiology that centers on how cells control their mechanical properties, and how physical forces regulate cellular biochemical responses, a process that is known as mechanotransduction. In this article, we review the central role that tensegrity (tensional integrity) architecture, which depends on tensile prestress for its mechanical stability, plays in biology. We describe how tensional prestress is a critical governor of cell mechanics and function, and how use of tensegrity by cells contributes to mechanotransduction. Theoretical tensegrity models are also described that predict both quantitative and qualitative behaviors of living cells, and these theoretical descriptions are placed in context of other physical models of the cell. In addition, we describe how tensegrity is used at multiple size scales in the hierarchy of life—from individual molecules to whole living organisms—to both stabilize three-dimensional form and to channel forces from the macroscale to the nanoscale, thereby facilitating mechanochemical conversion at the molecular level. (review article)

  6. Mitochondrial and cellular mechanisms for managing lipid excess

    Directory of Open Access Journals (Sweden)

    Miguel A Aon

    2014-07-01

    Full Text Available Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete.Cells store fatty acids (FAs as triacylglycerol and package them into cytoplasmic lipid droplets (LDs. New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates.Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g. exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain ROS within levels compatible with signaling while ensuring robust and reliable energy supply.

  7. Molecular and cellular mechanisms of aldosterone producing adenoma development

    Directory of Open Access Journals (Sweden)

    Sheerazed eBoulkroun

    2015-06-01

    Full Text Available Primary aldosteronism (PA is the most common form of secondary hypertension with an estimated prevalence of ~10% in referred patients. PA occurs as a result of a dysregulation of the normal mechanisms controlling adrenal aldosterone production. It is characterized by hypertension with low plasma renin and elevated aldosterone and often associated with hypokalemia. The two major causes of PA are unilateral aldosterone producing adenoma (APA and bilateral adrenal hyperplasia, accounting together for ~95% of cases. In addition to the well-characterized effect of excess mineralocorticoids on blood pressure, high levels of aldosterone also have cardiovascular, renal and metabolic consequences. Hence, long-term consequences of PA include increased risk of coronary artery disease, myocardial infarction, heart failure and atrial fibrillation. Despite recent progress in the management of patients with PA, critical issues related to diagnosis, subtype differentiation and treatment of non-surgically correctable forms still persist. A better understanding of the pathogenic mechanisms of the disease should lead to the identification of more reliable diagnostic and prognostic biomarkers for a more sensitive and specific screening and new therapeutic options. In this review we will summarize our current knowledge on the molecular and cellular mechanisms of APA development. On one hand, we will discuss how various animal models have improved our understanding of the pathophysiology of excess aldosterone production. On the other hand, we will summarize the major advances made during the last few years in the genetics of APA due to transcriptomic studies and whole exome sequencing. The identification of recurrent and somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D and ATPases (ATP1A1 and ATP2B3 allowed highlighting the central role of calcium signaling in autonomous aldosterone production by the adrenal.

  8. Mechanisms of cocarcinogenesis involving endogenous retroviruses

    International Nuclear Information System (INIS)

    This review article with 118 references summarizes recent in vivo and in vitro experimental results related to cocarcenogenesis and some potential mechanisms of virus - radiation/chemical carcinogen interactions. The RNA tumor viruses (retroviruses) may disrupt repair synthesis of DNA, thereby serving to indirectly increase the probability that exposure to a carcinogen could result in transformation. Several alternative mechanisms are proposed to explain these interactions

  9. Cortisol involvement in mechanisms of behavioral inhibition

    NARCIS (Netherlands)

    Tops, Mattie; Boksem, Maarten A. S.

    2011-01-01

    We studied whether baseline cortisol is associated with post-error slowing, a measure that depends upon brain areas involved in behavioral inhibition. Moreover, we studied whether this association holds after controlling for positive associations with behavioral inhibition scores and error-related n

  10. Antidiarrheal efficacy and cellular mechanisms of a Thai herbal remedy.

    Science.gov (United States)

    Tradtrantip, Lukmanee; Ko, Eun-A; Verkman, Alan S

    2014-02-01

    Screening of herbal remedies for Cl(-) channel inhibition identified Krisanaklan, a herbal extract used in Thailand for treatment of diarrhea, as an effective antidiarrheal in mouse models of secretory diarrheas with inhibition activity against three Cl(-) channel targets. Krisanaklan fully inhibited cholera toxin-induced intestinal fluid secretion in a closed-loop mouse model with ∼50% inhibition at a 1 ∶ 50 dilution of the extract. Orally administered Krisanaklan (5 µL/g) prevented rotavirus-induced diarrhea in neonatal mice. Short-circuit current measurements showed full inhibition of cAMP and Ca(2+) agonist-induced Cl(-) conductance in human colonic epithelial T84 cells, with ∼ 50% inhibition at a 1 ∶ 5,000 dilution of the extract. Krisanaklan also strongly inhibited intestinal smooth muscle contraction in an ex vivo preparation. Together with measurements using specific inhibitors, we conclude that the antidiarrheal actions of Krisanaklan include inhibition of luminal CFTR and Ca(2+)-activated Cl(-) channels in enterocytes. HPLC fractionation indicated that the three Cl(-) inhibition actions of Krisanaklan are produced by different components in the herbal extract. Testing of individual herbs comprising Krisanaklan indicated that agarwood and clove extracts as primarily responsible for Cl(-) channel inhibition. The low cost, broad antidiarrheal efficacy, and defined cellular mechanisms of Krisanaklan suggests its potential application for antisecretory therapy of cholera and other enterotoxin-mediated secretory diarrheas in developing countries. PMID:24551253

  11. Antidiarrheal efficacy and cellular mechanisms of a Thai herbal remedy.

    Directory of Open Access Journals (Sweden)

    Lukmanee Tradtrantip

    2014-02-01

    Full Text Available Screening of herbal remedies for Cl(- channel inhibition identified Krisanaklan, a herbal extract used in Thailand for treatment of diarrhea, as an effective antidiarrheal in mouse models of secretory diarrheas with inhibition activity against three Cl(- channel targets. Krisanaklan fully inhibited cholera toxin-induced intestinal fluid secretion in a closed-loop mouse model with ∼50% inhibition at a 1 ∶ 50 dilution of the extract. Orally administered Krisanaklan (5 µL/g prevented rotavirus-induced diarrhea in neonatal mice. Short-circuit current measurements showed full inhibition of cAMP and Ca(2+ agonist-induced Cl(- conductance in human colonic epithelial T84 cells, with ∼ 50% inhibition at a 1 ∶ 5,000 dilution of the extract. Krisanaklan also strongly inhibited intestinal smooth muscle contraction in an ex vivo preparation. Together with measurements using specific inhibitors, we conclude that the antidiarrheal actions of Krisanaklan include inhibition of luminal CFTR and Ca(2+-activated Cl(- channels in enterocytes. HPLC fractionation indicated that the three Cl(- inhibition actions of Krisanaklan are produced by different components in the herbal extract. Testing of individual herbs comprising Krisanaklan indicated that agarwood and clove extracts as primarily responsible for Cl(- channel inhibition. The low cost, broad antidiarrheal efficacy, and defined cellular mechanisms of Krisanaklan suggests its potential application for antisecretory therapy of cholera and other enterotoxin-mediated secretory diarrheas in developing countries.

  12. Unraveling the cellular and molecular mechanisms of repetitive magnetic stimulation

    Directory of Open Access Journals (Sweden)

    Florian Müller-Dahlhaus

    2013-12-01

    Full Text Available Despite numerous clinical studies, which have investigated the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS in various brain diseases, our knowledge of the cellular and molecular mechanisms underlying rTMS-based therapies remains limited. Thus, a deeper understanding of rTMS-induced neural plasticity is required to optimize current treatment protocols. Studies in small animals or appropriate in vitro preparations (including models of brain diseases provide highly useful experimental approaches in this context. State-of-the-art electrophysiological and live-cell imaging techniques that are well established in basic neuroscience can help answering some of the major questions in the field, such as (i which neural structures are activated during TMS, (ii how does rTMS induce Hebbian plasticity, and (iii are other forms of plasticity (e.g., metaplasticity, structural plasticity induced by rTMS? We argue that data gained from these studies will support the development of more effective and specific applications of rTMS in clinical practice.

  13. Cellular mechanisms of skin repair in humans and other mammals.

    Science.gov (United States)

    Rittié, Laure

    2016-06-01

    The increased incidence of non-healing skin wounds in developed societies has prompted tremendous research efforts on the complex process known as "wound healing". Unfortunately, the weak relevance of modern wound healing research to human health continues to be a matter of concern. This review summarizes the current knowledge of the cellular mechanisms that mediate wound closure in the skin of humans and laboratory animals. The author highlights the anatomical singularities of human skin vs. the skin of other mammals commonly used for wound healing research (i.e. as mice, rats, rabbits, and pigs), and discusses the roles of stem cells, myofibroblasts, and the matrix environment in the repair process. The majority of this review focuses on reepithelialization and wound closure. Other aspects of wound healing (e.g. inflammation, fibrous healing) are referred to when relevant to the main topic. This review aims at providing the reader with a clear understanding of the similarities and differences that have been reported over the past 100 years between the healing of human wounds and that of other mammals. PMID:27170326

  14. Involvement of Mechanical Stress in Androgenetic Alopecia

    OpenAIRE

    Tellez-Segura, Rafael

    2015-01-01

    Context: Androgenetic alopecia (AGA) is a frequent disorder characterized by progressive hair miniaturization in a very similar pattern among all affected men. The pathogenesis is related to androgen-inducible overexpression of transforming growth factor β-1 from balding dermal papilla cells, which is involved in epithelial inhibition and perifollicular fibrosis. Recent research shows that hair follicle androgen sensitivity is regulated by Hic-5, an androgen receptor co-activator which may be...

  15. Molecular and Cellular Mechanisms Elucidating Neurocognitive Basis of Functional Impairments Associated with Intellectual Disability in Down Syndrome

    Science.gov (United States)

    Rachidi, Mohammed; Lopes, Carmela

    2010-01-01

    Down syndrome, the most common genetic cause of intellectual disability, is associated with brain disorders due to chromosome 21 gene overdosage. Molecular and cellular mechanisms involved in the neuromorphological alterations and cognitive impairments are reported herein in a global model. Recent advances in Down syndrome research have lead to…

  16. Simultaneous occurrence of follicular lymphoma and mixed-cellularity Hodgkin's lymphoma: lymph node and extranodal involvement

    Directory of Open Access Journals (Sweden)

    Grangeiro Maria do Patrocínio F.

    2004-01-01

    Full Text Available An unusual and well-characterised case of composite lymphoma in the spleen and lymph node is presented. The simultaneous occurrence of mixed-cellularity Hodgkin's lymphoma (HL and follicular non-Hodgkin's lymphoma (NHL was demonstrated in a 66-year-old man admitted in our Service with anaemia, hepatosplenomegaly and multiple abdominal lymph nodes. The morphological study of the spleen and lymph node of the splenic hilum showed an infiltrate composed of two distinct neoplasias. The liver was involved by NHL infiltrate and the peripancreatic lymph node exhibited HL. The Reed-Sternberg (RS cells expressed CD 15 and CD 30, whereas the NHL cells presented standard immunohistochemical features of follicular lymphoma. To our knowledge, this is the fifth case report of concurrent spleen involvement by composite lymphoma. The incidence, clinicopathological and immunohistochemical features of this rare association are discussed.

  17. Molecular mechanisms involved in intestinal iron absorption

    Institute of Scientific and Technical Information of China (English)

    Paul Sharp; Surjit Kaila Srai

    2007-01-01

    Iron is an essential trace metal in the human diet due to its obligate role in a number of metabolic processes.In the diet, iron is present in a number of different forms, generally described as haem (from haemoglobin and myoglobin in animal tissue) and non-haem iron (including ferric oxides and salts, ferritin and lactoferrin).This review describes the molecular mechanisms that co-ordinate the absorption of iron from the diet and its release into the circulation. While many components of the iron transport pathway have been elucidated, a number of key issues still remain to be resolved. Future work in this area will provide a clearer picture regarding the transcellular flux of iron and its regulation by dietary and humoral factors.

  18. Molecular mechanisms involved in chemoresistance in paediatric acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Stanković Tatjana

    2008-01-01

    Full Text Available Acute lymphoblastic leukaemia (ALL is the most common paediatric cancer. Despite cure rates approaching 80%, resistance to treatment and disease relapse remain a significant clinical problem. Identification of the genes and biological pathways responsible for chemoresistance is therefore crucial for the design of novel therapeutic approaches aiming to improve patient survival. Mutations in the membrane transporter P-glycoprotein genes, genetic variations in drug-metabolising enzymes and defects in apoptotic pathways are mechanisms of chemoresistance common to a wide spectrum of cancers and also play a role in paediatric ALL. In addition, several recent microarray studies have identified transcriptional profiles specifically associated with chemoresistance and pointed to a number of potentially novel therapeutic targets. These microarray studies have shown that genes discriminating between clinically responsive and resistant leukaemias tend to be involved in cellular processes such as regulation of cell cycle, proliferation, and DNA repair. Here we review the outcomes of these microarray studies and also present our own investigations into apoptotic resistance to DNA double strand breaks (DSBs in paediatric ALL. We present stratification of paediatric ALL by the profile of DNA damage response following ionising radiation (IR in vitro. This approach allows classification of ALL tumours at presentation into IR-apoptotic sensitive and IR-apoptotic resistant. Furthermore, apoptotic resistant leukaemias exhibit abnormal response of NFkB pathway following irradiation and inhibition of this pathway can sensitise leukaemic cells to IR-induced DSBs.

  19. Glucan: mechanisms involved in its radioprotective effect

    International Nuclear Information System (INIS)

    It has generally been accepted that most biologically derived agents that are radioprotective in the hemopoietic-syndrome dose range (eg, endotoxin, Bacillus Calmette Guerin, Corynebacterium parvum, etc) exert their beneficial properties by enhancing hemopoietic recovery and hence, by regenerating the host's ability to resist life-threatening opportunistic infections. However, using glucan as a hemopoietic stimulant/radioprotectant, we have demonstrated that host resistance to opportunistic infection is enhanced in these mice even prior to the detection of significant hemopoietic regeneration. This early enhanced resistance to microbial invasion in glucan-treated irradiated mice could be correlated with enhanced and/or prolonged macrophage (but not granulocyte) function. These results suggest that early after irradiation glucan may mediate its radioprotection by enhancing resistance to microbial invasion via mechanisms not necessarily predicated on hemopoietic recovery. In addition, preliminary evidence suggests that glucan can also function as an effective free-radical scavenger. Because macrophages have been shown to selectively phagocytize and sequester glucan, the possibility that these specific cells may be protected by virtue of glucan's scavenging ability is also suggested

  20. Antibody-dependent cellular inhibition is associated with reduced risk against febrile malaria in a longitudinal cohort study involving Ghanaian children

    DEFF Research Database (Denmark)

    Tiendrebeogo, Regis W; Adu, Bright; Singh, Susheel K; Dziegiel, Morten H; Nébié, Issa; Sirima, Sodiomon B; Christiansen, Michael; Dodoo, Daniel; Theisen, Michael

    2015-01-01

    The antibody-dependent respiratory burst and opsonic phagocytosis assays have been associated with protection against malaria; however, other mechanisms may also be involved. The antibody-dependent cellular inhibition (ADCI) assay is yet to be correlated with protection in longitudinal cohort stu...... ADCI assay as a correlate of protection to guide malaria vaccine studies.......The antibody-dependent respiratory burst and opsonic phagocytosis assays have been associated with protection against malaria; however, other mechanisms may also be involved. The antibody-dependent cellular inhibition (ADCI) assay is yet to be correlated with protection in longitudinal cohort...... studies (LCS). We investigated the relationship between ADCI activity of immunoglobulin G before malaria season and risk of malaria in a LCS involving Ghanaian children. High ADCI activity was significantly associated with reduced risk against malaria. Findings here suggest a potential usefulness of the...

  1. Signaling pathways involved in PDGF-evoked cellular responses in human RPE cells

    International Nuclear Information System (INIS)

    We examined whether PDGF may directly stimulate the expression of VEGF by retinal pigment epithelial (RPE) cells in vitro, and the involvement of three signal transduction pathways in the regulation of PDGF-evoked cell proliferation, migration, and production of VEGF-A was investigated. PDGF stimulated the gene and protein expression of VEGF-A by RPE cells, and increased cell proliferation and chemotaxis. PDGF activated all signaling pathways investigated, as determined by increased phosphorylation levels of ERK1/2, p38, and Akt proteins. The three signaling pathways were involved in the mediation of PDGF-evoked cell proliferation, while p38 and PI3K mediated cell migration, and PI3K mediated secretion of VEGF-A. In addition to VEGF-A, the cells expressed mRNAs for various members of the VEGF family and for their receptors, including VEGF-B, -C, -D, flt-1, and KDR. The data indicate that PDGF selectively stimulates the expression of VEGF-A in RPE cells. PDGF evokes at least three signal transduction pathways which are differentially involved in various cellular responses

  2. Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness

    International Nuclear Information System (INIS)

    The evolutionary-conserved interactions between KASH and SUN domain-containing proteins within the perinuclear space establish physical connections, called LINC complexes, between the nucleus and the cytoskeleton. Here, we show that the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. These constructs disrupt endogenous LINC complexes as indicated by the displacement of endogenous Nesprins from the nuclear envelope. We also provide evidence that KASH domains most probably fit a pocket provided by SUN domains and that post-translational modifications are dispensable for that interaction. We demonstrate that the disruption of endogenous LINC complexes affect cellular mechanical stiffness to an extent that compares to the loss of mechanical stiffness previously reported in embryonic fibroblasts derived from mouse lacking A-type lamins, a mouse model of muscular dystrophies and cardiomyopathies. These findings support a model whereby physical connections between the nucleus and the cytoskeleton are mediated by interactions between diverse combinations of Sun proteins and Nesprins through their respective evolutionary-conserved domains. Furthermore, they emphasize, for the first time, the relevance of LINC complexes in cellular mechanical stiffness suggesting a possible involvement of their disruption in various laminopathies, a group of human diseases linked to mutations of A-type lamins

  3. Mood disorders in Huntington’s disease: from behavior to cellular and molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Patrick Pla

    2014-04-01

    Full Text Available Huntington’s disease (HD is a neurodegenerative disorder that is best known for its effect on motor control. Mood disturbances such as depression, anxiety, and irritability also have a high prevalence in patients with HD, and often start before the onset of motor symptoms. Various rodent models of HD recapitulate the anxiety/depressive behavior seen in patients. HD is caused by an expanded polyglutamine stretch in the N-terminal part of a 350 kDa protein called huntingtin (HTT. HTT is ubiquitously expressed and is implicated in several cellular functions including control of transcription, vesicular trafficking, ciliogenesis, and mitosis. This review summarizes progress in efforts to understand the cellular and molecular mechanisms underlying behavioral disorders in patients with HD. Dysfunctional HTT affects cellular pathways that are involved in mood disorders or in the response to antidepressants, including BDNF/TrkB and serotonergic signaling. Moreover, HTT affects adult hippocampal neurogenesis, a physiological phenomenon that is implicated in some of the behavioral effects of antidepressants and is linked to the control of anxiety. These findings are consistent with the emerging role of wild-type HTT as a crucial component of neuronal development and physiology. Thus, the pathogenic polyQ expansion in HTT could lead to mood disorders not only by the gain of a new toxic function but also by the perturbation of its normal function.

  4. Genomic interrogation of mechanism(s) underlying cellular responses to toxicants

    International Nuclear Information System (INIS)

    Assessment of the impact of xenobiotic exposure on human health and disease progression is complex. Knowledge of mode(s) of action, including mechanism(s) contributing to toxicity and disease progression, is valuable for evaluating compounds. Toxicogenomics, the subdiscipline which merges genomics with toxicology, holds the promise to contributing significantly toward the goal of elucidating mechanism(s) by studying genome-wide effects of xenobiotics. Global gene expression profiling, revolutionized by microarray technology and a crucial aspect of a toxicogenomic study, allows measuring transcriptional modulation of thousands of genes following exposure to a xenobiotic. We use our results from previous studies on compounds representing two different classes of xenobiotics (barbiturate and peroxisome proliferator) to discuss the application of computational approaches for analyzing microarray data to elucidate mechanism(s) underlying cellular responses to toxicants. In particular, our laboratory demonstrated that chemical-specific patterns of gene expression can be revealed using cDNA microarrays. Transcript profiling provides discrimination between classes of toxicants, as well as, genome-wide insight into mechanism(s) of toxicity and disease progression. Ultimately, the expectation is that novel approaches for predicting xenobiotic toxicity in humans will emerge from such information

  5. Identification of human genes involved in cellular responses to ionizing radiation: molecular and cellular studies of gene encoding the p68 helicase in mammalian cells

    International Nuclear Information System (INIS)

    Cells submitted to genotoxic factors -like IR- activate several and important mechanisms such as repair, cell cycle arrest or 'apoptosis' to maintain genetic integrity. So, the damaged cells will induce many and different genes. The human transcriptome analysis by 'SSH' method in a human breast carcinoma cell line MCF7 γ-irradiated versus not irradiated, allowed to identify about one hundred genes. Among of these genes, we have focused our study on a radio-induced gene encoding the p68 helicase. In the conditions of irradiation used, our results show that the kinetic and the regulation of this gene expression differs between the nature of radiations used. Indeed, in γ-irradiated mammalian cells, ATM, a protein kinase activated by DSB and IR, is required to induce quickly P68 gene via the important transcription factor p53 stabilized by IR. In the case of UVC-irradiated cells, the P68 gene induction is late and the intracellular signalling pathway that lead to this induction is independent from the p53 protein. Finally, we show that the p68 protein under-expression is responsible for an increased radiosensitivity of MCF7 cells. Consequently, we can postulate that the p68 protein is involved in cellular responses to radiations to reduce the increased radiosensitivity of cells exposed to γ-rays. (author)

  6. A sub-cellular viscoelastic model for cell population mechanics.

    Directory of Open Access Journals (Sweden)

    Yousef Jamali

    Full Text Available Understanding the biomechanical properties and the effect of biomechanical force on epithelial cells is key to understanding how epithelial cells form uniquely shaped structures in two or three-dimensional space. Nevertheless, with the limitations and challenges posed by biological experiments at this scale, it becomes advantageous to use mathematical and 'in silico' (computational models as an alternate solution. This paper introduces a single-cell-based model representing the cross section of a typical tissue. Each cell in this model is an individual unit containing several sub-cellular elements, such as the elastic plasma membrane, enclosed viscoelastic elements that play the role of cytoskeleton, and the viscoelastic elements of the cell nucleus. The cell membrane is divided into segments where each segment (or point incorporates the cell's interaction and communication with other cells and its environment. The model is capable of simulating how cells cooperate and contribute to the overall structure and function of a particular tissue; it mimics many aspects of cellular behavior such as cell growth, division, apoptosis and polarization. The model allows for investigation of the biomechanical properties of cells, cell-cell interactions, effect of environment on cellular clusters, and how individual cells work together and contribute to the structure and function of a particular tissue. To evaluate the current approach in modeling different topologies of growing tissues in distinct biochemical conditions of the surrounding media, we model several key cellular phenomena, namely monolayer cell culture, effects of adhesion intensity, growth of epithelial cell through interaction with extra-cellular matrix (ECM, effects of a gap in the ECM, tensegrity and tissue morphogenesis and formation of hollow epithelial acini. The proposed computational model enables one to isolate the effects of biomechanical properties of individual cells and the

  7. Mediated coalescence: a possible mechanism for tumor cellular heterogeneity

    Science.gov (United States)

    Ambrose, Joseph; Livitz, Michelle; Wessels, Deborah; Kuhl, Spencer; Lusche, Daniel F; Scherer, Amanda; Voss, Edward; Soll, David R

    2015-01-01

    Recently, we demonstrated that tumorigenic cell lines and fresh tumor cells seeded in a 3D Matrigel model, first grow as clonal islands (primary aggregates), then coalesce through the formation and contraction of cellular cables. Non-tumorigenic cell lines and cells from normal tissue form clonal islands, but do not form cables or coalesce. Here we show that as little as 5% tumorigenic cells will actively mediate coalescence between primary aggregates of majority non-tumorigenic or non-cancerous cells, by forming cellular cables between them. We suggest that this newly discovered, specialized characteristic of tumorigenic cells may explain, at least in part, why tumors contain primarily non-tumorigenic cells. PMID:26807328

  8. Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

    OpenAIRE

    Adams, Drew J.; Dai, Mingji; Pellegrino, Giovanni; Wagner, Bridget K.; Stern, Andrew M.; Shamji, Alykhan F.; Schreiber, Stuart L.

    2012-01-01

    Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells ...

  9. Cellular solid behaviour of liquid crystal colloids. 2. Mechanical properties

    OpenAIRE

    Anderson, V.J.; Terentjev, E. M.

    2000-01-01

    This paper presents the results of a rheological study of thermotropic nematic colloids aggregated into cellular structures. Small sterically stabilised PMMA particles dispersed in a liquid crystal matrix densely pack on cell interfaces, but reversibly mix with the matrix when the system is heated above Tni. We obtain a remarkably high elastic modulus, G'~10^5 Pa, which is a nearly linear function of particle concentration. A characteristic yield stress is required to disrupt the continuity o...

  10. Molecular and Cellular Evidence for the Alternative Lengthening of Telomeres (ALT) Mechanism in Chicken

    OpenAIRE

    O'Hare, T.H.; Delany, M. E.

    2011-01-01

    Telomere maintenance is an important genetic mechanism controlling cellular proliferation. Normally, telomeres are maintained by telomerase which is downregulated upon cellular differentiation in most somatic cell lineages. Telomerase activity is upregulated in immortalized cells and cancers to support an infinite lifespan and uncontrolled cell growth; however, some immortalized and transformed cells lack telomerase activity. Telomerase-negative tumors and immortalized cells utilize an altern...

  11. Regulation of hTERT transcription: a target of cellular and viral mechanisms for immortalization and carcinogenesis

    OpenAIRE

    Horikawa, Izumi; Michishita, Eriko; Barrett, J. Carl

    2004-01-01

    A hallmark of human cancer cells is immortal cell growth, which is associated with telomere maintenance by telomerase. The transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is a major mechanism that negatively and positively controls telomerase activity in normal and cancer cells, respectively. A growing body of data suggests that various cellular and viral factors and pathways involved in cell senescence, immortalization and carcinogenesis act on the hTERT...

  12. Robust mechanisms of ventral furrow invagination require the combination of cellular shape changes

    International Nuclear Information System (INIS)

    Ventral furrow formation in Drosophila is the first large-scale morphogenetic movement during the life of the embryo, and is driven by co-ordinated changes in the shape of individual epithelial cells within the cellular blastoderm. Although many of the genes involved have been identified, the details of the mechanical processes that convert local changes in gene expression into whole-scale changes in embryonic form remain to be fully understood. Biologists have identified two main cell deformation modes responsible for ventral furrow invagination: constriction of the apical ends of the cells (apical wedging) and deformation along their apical–basal axes (radial lengthening/shortening). In this work, we used a computer 2D finite element model of ventral furrow formation to investigate the ability of different combinations of three plausible elementary active cell shape changes to bring about epithelial invagination: ectodermal apical–basal shortening, mesodermal apical–basal lengthening/shortening and mesodermal apical constriction. We undertook a systems analysis of the biomechanical system, which revealed many different combinations of active forces (invagination mechanisms) were able to generate a ventral furrow. Two important general features were revealed. First that combinations of shape changes are the most robust to environmental and mutational perturbation, in particular those combining ectodermal pushing and mesodermal wedging. Second, that ectodermal pushing plays a big part in all of the robust mechanisms (mesodermal forces alone do not close the furrow), and this provides evidence that it may be an important element in the mechanics of invagination in Drosophila

  13. Effects of Mechanical Properties on Tumor Invasion: Insights from a Cellular Model

    KAUST Repository

    Li, YZ

    2014-08-01

    Understanding the regulating mechanism of tumor invasion is of crucial importance for both fundamental cancer research and clinical applications. Previous in vivo experiments have shown that invasive cancer cells dissociate from the primary tumor and invade into the stroma, forming an irregular invasive morphology. Although cell movements involved in tumor invasion are ultimately driven by mechanical forces of cell-cell interactions and tumor-host interactions, how these mechanical properties affect tumor invasion is still poorly understood. In this study, we use a recently developed two-dimensional cellular model to study the effects of mechanical properties on tumor invasion. We study the effects of cell-cell adhesions as well as the degree of degradation and stiffness of extracellular matrix (ECM). Our simulation results show that cell-cell adhesion relationship must be satisfied for tumor invasion. Increased adhesion to ECM and decreased adhesion among tumor cells result in invasive tumor behaviors. When this invasive behavior occurs, ECM plays an important role for both tumor morphology and the shape of invasive cancer cells. Increased stiffness and stronger degree of degradation of ECM promote tumor invasion, generating more aggressive tumor invasive morphologies. It can also generate irregular shape of invasive cancer cells, protruding towards ECM. The capability of our model suggests it a useful tool to study tumor invasion and might be used to propose optimal treatment in clinical applications.

  14. Mechanobiology and the microcirculation: cellular, nuclear and fluid mechanics

    OpenAIRE

    Dahl, Kris Noel; Kalinowski, Agnieszka; Pekkan, Kerem

    2010-01-01

    Endothelial cells are stimulated by shear stress throughout the vasculature and respond with changes in gene expression and by morphological reorganization. Mechanical sensors of the cell are varied and include cell surface sensors that activate intracellular chemical signaling pathways. Here, possible mechanical sensors of the cell including reorganization of the cytoskeleton and the nucleus are discussed in relation to shear flow. A mutation in the nuclear structural protein lamin A, relate...

  15. Molecular and cellular mechanisms of vomeronasal signaling in mammals

    OpenAIRE

    Cichy, Annika

    2013-01-01

    The mouse vomeronasal organ plays a critical role in chemosensory communication and regulates diverse social and sexual behaviors. However, many physiological mechanisms underlying vomeronasal chemosensory signaling remain elusive. Therefore, the overall aim of my thesis was to gain a deeper understanding of the basic mechanisms that control VNO physiology. Specifically, my research focused on HCN channel-mediated vomeronasal proton-sensing and its potential role in sensory gain control of so...

  16. Predicting bulk mechanical properties of cellularized collagen gels using multiphoton microscopy

    OpenAIRE

    Raub, CB; Putnam, AJ; Tromberg, BJ; George, SC

    2010-01-01

    Cellularized collagen gels are a common model in tissue engineering, but the relationship between the microstructure and bulk mechanical properties is only partially understood. Multiphoton microscopy (MPM) is an ideal non-invasive tool to examine collagen microstructure, cellularity and crosslink content in these gels. In order to identify robust image parameters that characterize microstructural determinants of the bulk elastic modulus, we performed serial MPM and mechanical tests on acellu...

  17. Linking Cellular and Mechanical Processes in Articular Cartilage Lesion Formation: A Mathematical Model

    OpenAIRE

    Kapitanov, Georgi I.; Wang, Xiayi; Ayati, Bruce P; Brouillette, Marc J.; Martin, James A.

    2016-01-01

    A severe application of stress on articular cartilage can initiate a cascade of biochemical reactions that can lead to the development of osteoarthritis. We constructed a multiscale mathematical model of the process with three components: cellular, chemical, and mechanical. The cellular component describes the different chondrocyte states according to the chemicals these cells release. The chemical component models the change in concentrations of those chemicals. The mechanical component cont...

  18. Cellular mechanisms for presynaptic inhibition of sensory afferents

    DEFF Research Database (Denmark)

    Perrier, Jean-Francois Marie; delgado-lezama, rodolfo; Christensen, Rasmus Kordt;

    It is well established that presynaptic inhibition of primary afferents involves the activation of GABAA receptors located on presynaptic terminals. However, the source of GABA remains unknown. In an integrated preparation of the spinal cord of the adult turtle, we evoked dorsal root potentials (...

  19. Involvement of the iron regulatory protein from Eisenia andrei earthworms in the regulation of cellular iron homeostasis.

    Directory of Open Access Journals (Sweden)

    Petra Procházková

    Full Text Available Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs of the 5'- or 3'-untranslated regions (UTR of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP. The earthworm IRE site in 5'-UTR of ferritin mRNA most likely folds into a secondary structure that differs from the conventional IRE structures of ferritin due to the absence of a typically unpaired cytosine that participates in protein binding. Prepared recombinant EaIRP and proteins from mammalian liver extracts are able to bind both mammalian and Eisenia IRE structures of ferritin mRNA, although the affinity of the rEaIRP/Eisenia IRE structure is rather low. This result suggests the possible contribution of a conventional IRE structure. When IRP is supplemented with a Fe-S cluster, it can function as a cytosolic aconitase. Cellular cytosolic and mitochondrial fractions, as well as recombinant EaIRP, exhibit aconitase activity that can be abolished by the action of oxygen radicals. The highest expression of EaIRP was detected in parts of the digestive tract. We can assume that earthworms may possess an IRE/IRP regulatory network as a potential mechanism for maintaining cellular iron homeostasis, although the aconitase function of EaIRP is most likely more relevant.

  20. Involvement of the iron regulatory protein from Eisenia andrei earthworms in the regulation of cellular iron homeostasis.

    Science.gov (United States)

    Procházková, Petra; Škanta, František; Roubalová, Radka; Šilerová, Marcela; Dvořák, Jiří; Bilej, Martin

    2014-01-01

    Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs) that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs) of the 5'- or 3'-untranslated regions (UTR) of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP). The earthworm IRE site in 5'-UTR of ferritin mRNA most likely folds into a secondary structure that differs from the conventional IRE structures of ferritin due to the absence of a typically unpaired cytosine that participates in protein binding. Prepared recombinant EaIRP and proteins from mammalian liver extracts are able to bind both mammalian and Eisenia IRE structures of ferritin mRNA, although the affinity of the rEaIRP/Eisenia IRE structure is rather low. This result suggests the possible contribution of a conventional IRE structure. When IRP is supplemented with a Fe-S cluster, it can function as a cytosolic aconitase. Cellular cytosolic and mitochondrial fractions, as well as recombinant EaIRP, exhibit aconitase activity that can be abolished by the action of oxygen radicals. The highest expression of EaIRP was detected in parts of the digestive tract. We can assume that earthworms may possess an IRE/IRP regulatory network as a potential mechanism for maintaining cellular iron homeostasis, although the aconitase function of EaIRP is most likely more relevant. PMID:25279857

  1. Antibody-dependent cellular inhibition is associated with reduced risk against febrile malaria in a longitudinal cohort study involving Ghanaian children

    DEFF Research Database (Denmark)

    Tiendrebeogo, Regis W; Adu, Bright; Singh, Susheel K; Dziegiel, Morten H; Nébié, Issa; Sirima, Sodiomon B; Christiansen, Michael; Dodoo, Daniel; Theisen, Michael

    2015-01-01

    studies (LCS). We investigated the relationship between ADCI activity of immunoglobulin G before malaria season and risk of malaria in a LCS involving Ghanaian children. High ADCI activity was significantly associated with reduced risk against malaria. Findings here suggest a potential usefulness of the...... ADCI assay as a correlate of protection to guide malaria vaccine studies.......The antibody-dependent respiratory burst and opsonic phagocytosis assays have been associated with protection against malaria; however, other mechanisms may also be involved. The antibody-dependent cellular inhibition (ADCI) assay is yet to be correlated with protection in longitudinal cohort...

  2. Cellular electron transfer and radical mechanisms for drug metabolism

    International Nuclear Information System (INIS)

    Aerobic and anaerobic reductions of various nitroaromatic compounds by mammalian cells result in the production of reactive intermediates. Drug reduction is dependent upon glucose, nonprotein thiols, endogenous enzyme levels, and drug electron affinity. Drugs with electron affinities approaching that of oxygen are reduced, in the presence of oxygen, beyond a one-electron radical anion. Nitroaromatic radical anion inactivation occurs by reaction with cellular ferricytochrome c, endogenous thiols, and with oxygen. In the latter case the reaction results in the production of peroxide. Drugs that are substrates for the enzyme glutathione-S-transferase remove endogeneous thiols and demonstrate peroxide production without prior thiol removal. Less electron affinic drugs such as misonidazole require thiol removal as well as the presence of cyanide or azide for maximal peroxide production. Under anaerobic conditions radical anion and nitroso intermediates are reactive with glutathione. Removal of endogenous thiols by hypoxic preincubation with misonidazole may be related to the enhanced radiation response and cytotoxicity of this drug. Reduction of nitro compounds in the presence of DNA and chemicals such as dithionite, zinc dust, or polarographic techniques causes binding to macromolecules and DNA breaks. Chemical-reduction of nitro compounds by ascorbate in the presence of cells enhances drug cytotoxic effects

  3. Cellular Magnesium Matrix Foam Composites for Mechanical Damping Applications

    Science.gov (United States)

    Shunmugasamy, Vasanth Chakravarthy; Mansoor, Bilal; Gupta, Nikhil

    2016-01-01

    The damping characteristics of metal alloys and metal matrix composites are relevant to the automotive, aerospace, and marine structures. Use of lightweight materials can help in increasing payload capacity and in decreasing fuel consumption. Lightweight composite materials possessing high damping capabilities that can be designed as structural members can greatly benefit in addressing these needs. In this context, the damping properties of lightweight metals such as aluminum and magnesium and their respective composites have been studied in the existing literature. This review focuses on analyzing the damping properties of aluminum and magnesium alloys and their cellular composites. The damping properties of various lightweight alloys and composites are compared on the basis of their density to understand the potential for weight saving in structural applications. Magnesium alloys are observed to possess better damping properties in comparison to aluminum. However, aluminum matrix syntactic foams reinforced with silicon carbide hollow particles possess a damping capacity and density comparable to magnesium alloy. By using the data presented in the study, composites with specific compositions and properties can be selected for a given application. In addition, the comparison of the results helps in identifying the areas where attention needs to be focused to address the future needs.

  4. Lipoprotein(a: Cellular Effects and Molecular Mechanisms

    Directory of Open Access Journals (Sweden)

    Kirsten Riches

    2012-01-01

    Full Text Available Lipoprotein(a (Lp(a is an independent risk factor for the development of cardiovascular disease (CVD. Indeed, individuals with plasma concentrations >20 mg/dL carry a 2-fold increased risk of developing CVD, accounting for ~25% of the population. Circulating levels of Lp(a are remarkably resistant to common lipid lowering therapies, and there are currently no robust treatments available for reduction of Lp(a apart from plasma apheresis, which is costly and labour intensive. The Lp(a molecule is composed of two parts, an LDL/apoB-100 core and a unique glycoprotein, apolipoprotein(a (apo(a, both of which can interact with components of the coagulation cascade, inflammatory pathways, and cells of the blood vessel wall (smooth muscle cells (SMC and endothelial cells (EC. Therefore, it is of key importance to determine the molecular pathways by which Lp(a exerts its influence on the vascular system in order to design therapeutics to target its cellular effects. This paper will summarise the role of Lp(a in modulating cell behaviour in all aspects of the vascular system including platelets, monocytes, SMC, and EC.

  5. Potential cellular receptors involved in hepatitis C virus entry into cells

    Directory of Open Access Journals (Sweden)

    Muellhaupt Beat

    2005-04-01

    Full Text Available Abstract Hepatitis C virus (HCV infects hepatocytes and leads to permanent, severe liver damage. Since the genomic sequence of HCV was determined, progress has been made towards understanding the functions of the HCV-encoded proteins and identifying the cellular receptor(s responsible for adsorption and penetration of the virus particle into the target cells. Several cellular receptors for HCV have been proposed, all of which are associated with lipid and lipoprotein metabolism. This article reviews the cellular receptors for HCV and suggests a general model for HCV entry into cells, in which lipoproteins play a crucial role.

  6. Molecular and Cellular Mechanisms of Memory Allocation in Neuronetworks

    OpenAIRE

    Won, Jaejoon; Silva, Alcino J.

    2007-01-01

    Determining how neuronal networks encode memories is a key goal of neuroscience. Although neuronal circuit processes involved in encoding, storing and retrieving memory have attracted a great deal of attention, the processes that allocate individual memories to specific neurons within a network have remained elusive. Recent findings unraveled the first insights into the processes that modulate memory allocation in neuronetworks. They showed that neurons in the lateral amygdala compete to take...

  7. Axial level-dependent molecular and cellular mechanisms underlying the genesis of the embryonic neural plate.

    Science.gov (United States)

    Kondoh, Hisato; Takada, Shinji; Takemoto, Tatsuya

    2016-06-01

    The transcription factor gene Sox2, centrally involved in neural primordial regulation, is activated by many enhancers. During the early stages of embryonic development, Sox2 is regulated by the enhancers N2 and N1 in the anterior neural plate (ANP) and posterior neural plate (PNP), respectively. This differential use of the enhancers reflects distinct regulatory mechanisms underlying the genesis of ANP and PNP. The ANP develops directly from the epiblast, triggered by nodal signal inhibition, and via the combined action of TFs SOX2, OTX2, POU3F1, and ZIC2, which promotes the the ANP development and inhibits other cell lineages. In contrast, the PNP is derived from neuromesodermal bipotential axial stem cells that develop into the neural plate when Sox2 is activated by the N1 enhancer, whereas they develop into the paraxial mesoderm when the N1 enhancer is repressed by the action of TBX6. The axial stem cells are maintained by the activity of WNT3a and T (Brachyury). However, at axial levels more anterior to the 8th somites (cervical levels), the development of both the neural plate and somite proceeds in the absence of WNT3a, T, or TBX6. These observations indicate that distinct molecular and cellular mechanisms determine neural plate genesis based on the axial level, and contradict the classical concept of the term "neural induction," which assumes a pan-neural plate mechanism. PMID:27279156

  8. Mechanics of Cellular Adhesion to Artificial Artery Templates

    OpenAIRE

    Knöner, Gregor; Rolfe, Barbara E.; Campbell, Julie H.; Parkin, Simon J.; Heckenberg, Norman R.; Rubinsztein-Dunlop, Halina

    2006-01-01

    We are using polymer templates to grow artificial artery grafts in vivo for the replacement of diseased blood vessels. We have previously shown that adhesion of macrophages to the template starts the graft formation. We present a study of the mechanics of macrophage adhesion to these templates on a single cell and single bond level with optical tweezers. For whole cells, in vitro cell adhesion densities decreased significantly from polymer templates polyethylene to silicone to Tygon (167, 135...

  9. Antidiabetic properties of dietary flavonoids: a cellular mechanism review

    OpenAIRE

    Vinayagam, Ramachandran; Xu, Baojun

    2015-01-01

    Background Natural food products have been used for combating human diseases for thousands of years. Naturally occurring flavonoids including flavones, flavonols, flavanones, flavonols, isoflavones and anthocyanidins have been proposed as effective supplements for management and prevention of diabetes and its long-term complications based on in vitro and animal models. Aim To summarize the roles of dietary flavonoids in diabetes management and their molecular mechanisms. Findings Tremendous s...

  10. Active Cellular Mechanics and Information Processing in the Living Cell

    Science.gov (United States)

    Rao, M.

    2014-07-01

    I will present our recent work on the organization of signaling molecules on the surface of living cells. Using novel experimental and theoretical approaches we have found that many cell surface receptors are organized as dynamic clusters driven by active currents and stresses generated by the cortical cytoskeleton adjoining the cell surface. We have shown that this organization is optimal for both information processing and computation. In connecting active mechanics in the cell with information processing and computation, we bring together two of the seminal works of Alan Turing.

  11. Ochratoxin A carcinogenicity involves a complex network of epigenetic mechanisms.

    Science.gov (United States)

    Marin-Kuan, Maricel; Cavin, Christophe; Delatour, Thierry; Schilter, Benoît

    2008-08-01

    Ochratoxin A (OTA) is a mycotoxin occurring in a wide range of food products. Because of the limitation of human epidemiological data, the safety significance of OTA in food has to rely on animal data, with renal toxicity and carcinogenicity being considered the pivotal effects. The elucidation of the mechanism of action would improve the use of experimental animal data for risk assessment. Direct genotoxicity versus epigenetic mechanisms appears to be a key question. In the present review, the increasingly documented epigenetic cellular effects of OTA and their potential toxicological relevance are discussed. The information available suggests that OTA is unlikely to act through a single, well-defined mechanism of action. Instead, it is proposed that a network of interacting epigenetic mechanisms, including protein synthesis inhibition, oxidative stress and the activation of specific cell signalling pathways, is responsible for OTA carcinogenicity. From a risk assessment perspective, it has to be noted that the mechanisms proposed above depend mainly upon gene expression and enzyme activation, and are, therefore, likely to be thresholded. PMID:18649906

  12. The Molecular Genetics and Cellular Mechanisms Underlying Pulmonary Arterial Hypertension

    Directory of Open Access Journals (Sweden)

    Rajiv D. Machado

    2012-01-01

    Full Text Available Pulmonary arterial hypertension (PAH is an incurable disorder clinically characterised by a sustained elevation of mean arterial pressure in the absence of systemic involvement. As the adult circulation is a low pressure, low resistance system, PAH represents a reversal to a foetal state. The small pulmonary arteries of patients exhibit luminal occlusion resultant from the uncontrolled growth of endothelial and smooth muscle cells. This vascular remodelling is comprised of hallmark defects, most notably the plexiform lesion. PAH may be familial in nature but the majority of patients present with spontaneous disease or PAH associated with other complications. In this paper, the molecular genetic basis of the disorder is discussed in detail ranging from the original identification of the major genetic contributant to PAH and moving on to current next-generation technologies that have led to the rapid identification of additional genetic risk factors. The impact of identified mutations on the cell is examined, particularly, the determination of pathways disrupted in disease and critical to pulmonary vascular maintenance. Finally, the application of research in this area to the design and development of novel treatment options for patients is addressed along with the future directions PAH research is progressing towards.

  13. MECANISMOS CELULARES EN RESPUESTA AL ESTRÉS:: SIRTUINAS Cellular mechanisms in response to stress: sirtuin

    Directory of Open Access Journals (Sweden)

    Nancy Paola Echeverri-Ruíz

    2010-07-01

    Full Text Available Desde hace algún tiempo se conoce el papel de la restricción calórica sobre la longevidad y la prevención de enfermedades crónicas, pero hasta hace poco los mecanismos celulares involucrados comienzan a ser elucidados. El estrés celular se podría definir como el estado en el que la célula no presenta las condiciones óptimas de supervivencia, siendo el oxidativo un tipo de estrés en el que se generan radicales libres nocivos para las estructuras celulares. La restricción calórica podría incrementar la resistencia celular a diferentes formas de estrés. Las sirtuinas, proteínas deacetilasas de histonas tipo III, están involucradas en la relación entre balance energético y transcripción génica, permitiendo que la célula responda a la restricción calórica y sobreviva a situaciones de estrés oxidativo. En esta relación las sirtuinas regulan genes de la familia FOXO, cMYC, hTERT, p53, entre otros. La activación o silenciamiento de estos genes es importante en los procesos de apoptosis, reparación y muerte celular.The role of caloric restriction on longevity and prevention of chronic diseases has been known for some time; recently, cellular mechanisms involved are beginning to be elucidated. Cellular stress could be defined as the state in which the cell does not present optimal survival conditions; oxidative stress is a type of stress in which free radicals harmful cell structures. Caloric restriction might increase cellular resistance to various forms of stress. Sirtuins, histone deacetylases type III proteins are involved in the relationship between energy balance and gene transcription, allowing cell to respond to caloric restriction and to survive to oxidative stress. In this relationship, sirtuins regulate FOXO family genes, cMYC, hTERT, p53, among others. Activation or silencing of those genes is important in the process of apoptosis, repair and cell death

  14. Nonlinear dose-response relationships and inducible cellular defence mechanisms

    International Nuclear Information System (INIS)

    With the inclusion of inducible radioprotective mechanisms in a radiobiological state-vector model it was possible to explain plateaus in dose-response relationships for neoplastic transformation produced by in vitro irradiation of different cell lines with low-LET irradiation at high dose rates. The current study repeated the simulation of one data set that contains a plateau at mid doses. In contrast to earlier studies, the new one did not model the repair of double-strand breaks (DSBs) located in bulk DNA (likely via non-homologous end joining) as being inducible. Repair of specific DSBs located in actively transcribed genes was assumed to occur via homologous recombination and was considered to be inducible. This reduced the number of parameters that have to be determined by fitting the model to data. In addition, all types of radical scavengers were formerly considered to be inducible by radiation. This was redefined in the current work and the effectiveness of scavengers was implemented in a refined way. The current work investigated whether these and other model adjustments lead to an improved fit of the data set. (author)

  15. Action principle for cellular automata and the linearity of quantum mechanics

    CERN Document Server

    Elze, Hans-Thomas

    2014-01-01

    We introduce an action principle for a class of integer valued cellular automata and obtain Hamiltonian equations of motion. Employing sampling theory, these discrete deterministic equations are invertibly mapped on continuum equations for a set of bandwidth limited harmonic oscillators, which encode the Schr\\"odinger equation. Thus, the linearity of quantum mechanics is related to the action principle of such cellular automata and its conservation laws to discrete ones.

  16. Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes.

    Science.gov (United States)

    Shah, Manasi S; Brownlee, Michael

    2016-05-27

    The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca

  17. Use of Computational Modeling to Evaluate Hypotheses About the Molecular and Cellular Mechanisms of Bystander Effects

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yuchao; Conolly, Rory B; Andersen, Melvin E.

    2006-11-21

    This report describes the development of a computational systems biology approach to evaluate the hypotheses of molecular and cellular mechanisms of adaptive response to low dose ionizing radiation. Our concept is that computational models of signaling pathways can be developed and linked to biologically based dose response models to evaluate the underlying molecular mechanisms which lead to adaptive response. For development of quantitatively accurate, predictive models, it will be necessary to describe tissues consisting of multiple cell types where the different types each contribute in their own way to the overall function of the tissue. Such a model will probably need to incorporate not only cell type-specific data but also spatial information on the architecture of the tissue and on intercellular signaling. The scope of the current model was more limited. Data obtained in a number of different biological systems were synthesized to describe a chimeric, “average” population cell. Biochemical signaling pathways involved in sensing of DNA damage and in the activation of cell cycle checkpoint controls and the apoptotic path were also included. As with any computational modeling effort, it was necessary to develop these simplified initial descriptions (models) that can be iteratively refined. This preliminary model is a starting point which, with time, can evolve to a level of refinement where large amounts of detailed biological information are synthesized and a capability for robust predictions of dose- and time-response behaviors is obtained.

  18. Cellular Mechanisms of Calcium-Mediated Triggered Activity

    Science.gov (United States)

    Song, Zhen

    Life-threatening cardiac arrhythmias continue to pose a major health problem. Ventricular fibrillation, which is a complex form of electrical wave turbulence in the lower chambers of the heart, stops the heart from pumping and is the largest cause of natural death in the United States. Atrial fibrillation, a related form of wave turbulence in the upper heart chambers, is in turn the most common arrhythmia diagnosed in clinical practice. Despite extensive research to date, mechanisms of cardiac arrhythmias remain poorly understood. It is well established that both spatial disorder of the refractory period of heart cells and triggered activity (TA) jointly contribute to the initiation and maintenance of arrhythmias. TA broadly refers to the abnormal generation of a single or a sequence of abnormal excitation waves from a small submillimeter region of the heart in the interval of time between two normal waves generated by the heart's natural pacemaker (the sinoatrial node). TA has been widely investigated experimentally and occurs in several pathological conditions where the intracellular concentration of free Ca2+ ions in heart cells becomes elevated. Under such conditions, Ca2+ can be spontaneously released from intracellular stores, thereby driving an electrogenic current that exchanges 3Na+ ions for one Ca2+ ion across the cell membrane. This current in turn depolarizes the membrane of heart cells after a normal excitation. If this calcium-mediated "delayed after depolarization'' (DAD) is sufficiently large, it can generate an action potential. While the arrhythmogenic importance of spontaneous Ca2+ release and DADs is well appreciated, the conditions under which they occur in heart pathologies remain poorly understood. Calcium overload is only one factor among several other factors that can promote DADs, including sympathetic nerve stimulation, different expression levels of membrane ion channels and calcium handling proteins, and different mutations of those

  19. Boolean Modeling of Cellular and Molecular Pathways Involved in Influenza Infection

    Directory of Open Access Journals (Sweden)

    Christopher S. Anderson

    2016-01-01

    Full Text Available Systems virology integrates host-directed approaches with molecular profiling to understand viral pathogenesis. Self-contained statistical approaches that combine expression profiles of genes with the available databases defining the genes involved in the pathways (gene-sets have allowed characterization of predictive gene-signatures associated with outcome of the influenza virus (IV infection. However, such enrichment techniques do not take into account interactions among pathways that are responsible for the IV infection pathogenesis. We investigate dendritic cell response to seasonal H1N1 influenza A/New Caledonia/20/1999 (NC infection and infer the Boolean logic rules underlying the interaction network of ligand induced signaling pathways and transcription factors. The model reveals several novel regulatory modes and provides insights into mechanism of cross talk between NFκB and IRF mediated signaling. Additionally, the logic rule underlying the regulation of IL2 pathway that was predicted by the Boolean model was experimentally validated. Thus, the model developed in this paper integrates pathway analysis tools with the dynamic modeling approaches to reveal the regulation between signaling pathways and transcription factors using genome-wide transcriptional profiles measured upon influenza infection.

  20. Tuning of the electro-mechanical behavior of the cellular carbon nanotube structures with nanoparticle dispersions

    International Nuclear Information System (INIS)

    The mechanical and electrical characteristics of cellular network of the carbon nanotubes (CNT) impregnated with metallic and nonmetallic nanoparticles were examined simultaneously by employing the nanoindentation technique. Experimental results show that the nanoparticle dispersion not only enhances the mechanical strength of the cellular CNT by two orders of magnitude but also imparts variable nonlinear electrical characteristics; the latter depends on the contact resistance between nanoparticles and CNT, which is shown to depend on the applied load while indentation. Impregnation with silver nanoparticles enhances the electrical conductance, the dispersion with copper oxide and zinc oxide nanoparticles reduces the conductance of CNT network. In all cases, a power law behavior with suppression in the differential conductivity at zero bias was noted, indicating electron tunneling through the channels formed at the CNT-nanoparticle interfaces. These results open avenues for designing cellular CNT foams with desired electro-mechanical properties and coupling

  1. PTH1 receptor is involved in mediating cellular response to long-chain polyunsaturated fatty acids.

    Directory of Open Access Journals (Sweden)

    Jose Candelario

    Full Text Available The molecular pathways by which long chain polyunsaturated fatty acids (LCPUFA influence skeletal health remain elusive. Both LCPUFA and parathyroid hormone type 1 receptor (PTH1R are known to be involved in bone metabolism while any direct link between the two is yet to be established. Here we report that LCPUFA are capable of direct, PTH1R dependent activation of extracellular ligand-regulated kinases (ERK. From a wide range of fatty acids studied, varying in chain length, saturation, and position of double bonds, eicosapentaenoic (EPA and docosahexaenoic fatty acids (DHA caused the highest ERK phosphorylation. Moreover, EPA potentiated the effect of parathyroid hormone (PTH(1-34 in a superagonistic manner. EPA or DHA dependent ERK phosphorylation was inhibited by the PTH1R antagonist and by knockdown of PTH1R. Inhibition of PTH1R downstream signaling molecules, protein kinases A (PKA and C (PKC, reduced EPA and DHA dependent ERK phosphorylation indicating that fatty acids predominantly activate G-protein pathway and not the β-arrestin pathway. Using picosecond time-resolved fluorescence microscopy and a genetically engineered PTH1R sensor (PTH-CC, we detected conformational responses to EPA similar to those caused by PTH(1-34. PTH1R antagonist blocked the EPA induced conformational response of the PTH-CC. Competitive binding studies using fluorescence anisotropy technique showed that EPA and DHA competitively bind to and alter the affinity of PTH1 receptor to PTH(1-34 leading to a superagonistic response. Finally, we showed that EPA stimulates protein kinase B (Akt phosphorylation in a PTH1R-dependent manner and affects the osteoblast survival pathway, by inhibiting glucocorticoid-induced cell death. Our findings demonstrate for the first time that LCPUFAs, EPA and DHA, can activate PTH1R receptor at nanomolar concentrations and consequently provide a putative molecular mechanism for the action of fatty acids in bone.

  2. Pathogenic Mechanisms Involved in the Hematological Alterations of Arenavirus-induced Hemorrhagic Fevers

    Directory of Open Access Journals (Sweden)

    Roberto G. Pozner

    2013-01-01

    Full Text Available Viral hemorrhagic fevers (VHFs caused by arenaviruses are acute diseases characterized by fever, headache, general malaise, impaired cellular immunity, eventual neurologic involvement, and hemostatic alterations that may ultimately lead to shock and death. The causes of the bleeding are still poorly understood. However, it is generally accepted that these causes are associated to some degree with impaired hemostasis, endothelial cell dysfunction and low platelet counts or function. In this article, we present the current knowledge about the hematological alterations present in VHF induced by arenaviruses, including new aspects on the underlying pathogenic mechanisms.

  3. Cellular mechanisms of arrhythmias: from rate-dependent APD variations to heterocellular coupling

    OpenAIRE

    Salvarani, Nicolò

    2008-01-01

    It is well established that a variety of pathological conditions induces structural and electrical remodeling of the heart which can lead to heart failure and cardiac arrhythmias. Clinically, structural remodeling is characterized by changes in the shape, size and function of the heart. These changes are based on diverse and complex cellular reactions to injury and involve both cardiomyocytes and non-cardiomyocytes. Histopathologically, remodeling typically involves cardiomyocyte hypertrophy,...

  4. Neurophysiological mechanisms involved in language learning in adults

    OpenAIRE

    Rodríguez-Fornells, Antoni; Cunillera, Toni; Mestres-Missé, Anna; de Diego-Balaguer, Ruth

    2009-01-01

    Little is known about the brain mechanisms involved in word learning during infancy and in second language acquisition and about the way these new words become stable representations that sustain language processing. In several studies we have adopted the human simulation perspective, studying the effects of brain-lesions and combining different neuroimaging techniques such as event-related potentials and functional magnetic resonance imaging in order to examine the language learning (LL) pro...

  5. Computational up-scaling of anisotropic swelling and mechanical behavior of hierarchical cellular material

    CERN Document Server

    Rafsanjani, Ahmad; Wittel, Falk K; Carmeliet, Jan

    2015-01-01

    The hygro-mechanical behavior of a hierarchical cellular material, i.e. growth rings of softwood is investigated using a two-scale micro-mechanics model based on a computational homogenization technique. The lower scale considers the individual wood cells of varying geometry and dimensions. Honeycomb unit cells with periodic boundary conditions are utilized to calculate the mechanical properties and swelling coefficients of wood cells. Using the cellular scale results, the anisotropy in mechanical and swelling behavior of a growth ring in transverse directions is investigated. Predicted results are found to be comparable to experimental data. It is found that the orthotropic swelling properties of the cell wall in thin-walled earlywood cells produce anisotropic swelling behavior while, in thick latewood cells, this anisotropy vanishes. The proposed approach provides the ability to consider the complex microstructure when predicting the effective mechanical and swelling properties of softwood.

  6. The linearity of quantum mechanics from the perspective of Hamiltonian cellular automata

    CERN Document Server

    Elze, Hans-Thomas

    2014-01-01

    We discuss the action principle and resulting Hamiltonian equations of motion for a class of integer-valued cellular automata introduced recently [1]. Employing sampling theory, these deterministic finite-difference equations are mapped reversibly on continuum equations describing a set of bandwidth limited harmonic oscillators. They represent the Schroedinger equation. However, modifications reflecting the bandwidth limit are incorporated, i.e., the presence of a time (or length) scale. When this discreteness scale is taken to zero, the usual results are obtained. Thus, the linearity of quantum mechanics can be traced to the postulated action principle of such cellular automata and its conservation laws to discrete ones. The cellular automaton conservation laws are in one-to-one correspondence with those of the related quantum mechanical model, while admissible symmetries are not.

  7. The linearity of quantum mechanics from the perspective of Hamiltonian cellular automata

    International Nuclear Information System (INIS)

    We discuss the action principle and resulting Hamiltonian equations of motion for a class of integer-valued cellular automata introduced recently [1]. Employing sampling theory, these deterministic finite-difference equations are mapped reversibly on continuum equations describing a set of bandwidth limited harmonic oscillators. They represent the Schrödinger equation. However, modifications reflecting the bandwidth limit are incorporated, i.e., the presence of a time (or length) scale. When this discreteness scale is taken to zero, the usual results are obtained. Thus, the linearity of quantum mechanics can be traced to the postulated action principle of such cellular automata and its conservation laws to discrete ones. The cellular automaton conservation laws are in one-to-one correspondence with those of the related quantum mechanical model, while admissible symmetries are not.

  8. p120 Catenin Translocation is Involved in Enhancement of Hepatoma Cellular Malignant Features

    Institute of Scientific and Technical Information of China (English)

    Huayi Huang; Chaozan Nong; Weisheng He; Lingxiao Guo; Shaoyun Nong; Lili Pan; Xiliang Zha

    2005-01-01

    OBJECTIVE To investigate the relationship between p120ctn translocation and hepatocellular carcinoma cell malignant features and the relationship between p120ctn and β-catenin translocation in cell signaling.METHODS Human hepatocellular carcinoma cells were over expressed with p120ctn isoform 3A using a DNA transfection method. The effects of transfection and expression of p120ctn and its binding capacity to E-cadherin were examined using immunoprecipitation and immunoblotting methods. P120ctn subcellular localization and its relation with β-catenin were detected using immunofluorescent microscopy. P120ctn phosphorylation was produced by EGF treatment. Cell adhesion, cell migration and cell proliferation were also examined in this study.RESULTS We found that p120ctnexpression was increased after transfection and the binding capacity of p120ctn to E-cadherin was enhanced. Tyrosine phosphorylation of p120ctn increased after transfection and EGF treatment.p120ctn and β-catenin cellular localization displayd a membrane and cytoplasmic expression pattern, but they translocated into the nucleus for relocalization after p120ctn overexpression plus EGF stimulation. Cell adhesion ability was increased and migration ability reduced after transfection without EGF. Following transfection without EGF cellular proliferation was reduced,but increased after EGF treatment.CONCLUSION Our results suggest that p120ctn plays an important role in hepatocellular carcinoma cell adhesion, migration and proliferation. In addition there is a relationship between p120ctn and β-catenin subcellular localization and signaling.

  9. Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Juliana Pereira Borges

    2015-01-01

    Full Text Available Background: Acute myocardial infarction is the leading cause of morbidity and mortality worldwide. Furthermore, research has shown that exercise, in addition to reducing cardiovascular risk factors, can also protect the heart against injury due to ischemia and reperfusion through a direct effect on the myocardium. However, the specific mechanism involved in exerciseinduced cardiac preconditioning is still under debate. Objective: To perform a systematic review of the studies that have addressed the mechanisms by which aerobic exercise promotes direct cardioprotection against ischemia and reperfusion injury. Methods: A search was conducted using MEDLINE, Literatura Latino-Americana e do Caribe de Informação em Ciências da Saúde, and Scientific Electronic Library Online databases. Data were extracted in a standardized manner by two independent researchers, who were responsible for assessing the methodological quality of the studies. Results: The search retrieved 78 studies; after evaluating the abstracts, 30 studies were excluded. The manuscripts of the remaining 48 studies were completely read and, of these, 20 were excluded. Finally, 28 studies were included in this systematic review. Conclusion: On the basis of the selected studies, the following are potentially involved in the cardioprotective response to exercise: increased heat shock protein production, nitric oxide pathway involvement, increased cardiac antioxidant capacity, improvement in ATP-dependent potassium channel function, and opioid system activation. Despite all the previous investigations, further research is still necessary to obtain more consistent conclusions.

  10. Cellular and molecular mechanisms of repair in acute and chronic wound healing

    OpenAIRE

    Martin, P.; Nunan, R

    2015-01-01

    Summary A considerable understanding of the fundamental cellular and molecular mechanisms underpinning healthy acute wound healing has been gleaned from studying various animal models, and we are now unravelling the mechanisms that lead to chronic wounds and pathological healing including fibrosis. A small cut will normally heal in days through tight orchestration of cell migration and appropriate levels of inflammation, innervation and angiogenesis. Major surgeries may take several weeks to ...

  11. Cellular and molecular mechanisms of osteoporosis: current concepts and future direction treatment

    OpenAIRE

    A. T. Dolzhenko; S. Sagalovsky

    2016-01-01

    The article presents review of literature dedicated to the contemporary view on the cellular-molecular mechanisms of the bone remodeling and pathogenesis of the osteoporosis. The discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in process bone remodeling has made progress in understanding the mechanisms development disease and possible to development drugs of the new generation – denosumab, a fully human RANKL monoclonal antibody and inhibitor cathepsin ...

  12. Cellular immunity and pathogen strategies in combative interactions involving Drosophila hosts and their endoparasitic wasps

    Directory of Open Access Journals (Sweden)

    AJ Nappi

    2010-09-01

    Full Text Available Various cellular innate immune responses protect invertebrates from attack by eukaryotic pathogens. In insects, assessments of the factor(s causing, or contributing to, pathogen mortality have long considered as toxic components certain molecules associated with enzyme-mediated melanogenesis. In Drosophila hosts, observations that have prompted additional or alternative considerations are those that document either the survival of certain endoparasitic wasps despite melanotic encapsulation, or the destruction of the parasite with no evidence of this type of host response. Investigations of the production of some reactive intermediates of oxygen and nitrogen during infection provide a basis for proposing that these molecules constitute important elements of the immune arsenal of Drosophila. Studies of the target specificity of virulence factors injected by female wasps during infection that suppress the host immune response will likely facilitate identification of the toxic host molecules, and contribute to a more detailed understanding of the cell-signaling pathways that regulate their synthesis.

  13. 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.

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

    International Nuclear Information System (INIS)

    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)

  15. Mechanism resulting in chemical imbalance due to cellular damage associated with mechanoporation: A molecular dynamics study

    Science.gov (United States)

    Sliozberg, Yelena R.; Chantawansri, Tanya L.

    2016-05-01

    To elucidate the mechanism of ion transport through a transmembrane pore, all-atom molecular dynamics simulations were employed. A model membrane where a pore connects the intra- and extra-cellular compartment was considered. Pores with radii of 1.5 nm or less exhibited resealing over the course of 135 ns simulations, and ionic disturbance is minimal. Ion transport through a larger pore (2 nm radius) leads to a substantial change in the intra- and extra-cellular ionic concentrations. The influx of Na+ and Cl- ions down their concentration gradients is greater than the efflux of K+ leading to an osmotic influx of water.

  16. Determination of the mechanical properties of solid and cellular polymeric dosage forms by diametral compression.

    Science.gov (United States)

    Blaesi, Aron H; Saka, Nannaji

    2016-07-25

    At present, the immediate-release solid dosage forms, such as the oral tablets and capsules, are granular solids. They release drug rapidly and have adequate mechanical properties, but their manufacture is fraught with difficulties inherent in processing particulate matter. Such difficulties, however, could be overcome by liquid-based processing. Therefore, we have recently introduced polymeric cellular (i.e., highly porous) dosage forms prepared from a melt process. Experiments have shown that upon immersion in a dissolution medium, the cellular dosage forms with polyethylene glycol (PEG) as excipient and with predominantly open-cell topology disintegrate by exfoliation, thus enabling rapid drug release. If the volume fraction of voids of the open-cell structures is too large, however, their mechanical strength is adversely affected. At present, the common method for determining the tensile strength of brittle, solid dosage forms (such as select granular forms) is the diametral compression test. In this study, the theory of diametral compression is first refined to demonstrate that the relevant mechanical properties of ductile and cellular solids (i.e., the elastic modulus and the yield strength) can also be extracted from this test. Diametral compression experiments are then conducted on PEG-based solid and cellular dosage forms. It is found that the elastic modulus and yield strength of the open-cell structures are about an order of magnitude smaller than those of the non-porous solids, but still are substantially greater than the stiffness and strength requirements for handling the dosage forms manually. This work thus demonstrates that melt-processed polymeric cellular dosage forms that release drug rapidly can be designed and manufactured to have adequate mechanical properties. PMID:27178343

  17. A versatile transreplication-based system to identify cellular proteins involved in geminivirus replication.

    Science.gov (United States)

    Morilla, Gabriel; Castillo, Araceli G; Preiss, Werner; Jeske, Holger; Bejarano, Eduardo R

    2006-04-01

    A versatile green fluorescent protein (GFP) expression cassette containing the replication origins of the monopartite begomovirus Tomato yellow leaf curl Sardinia virus (TYLCSV) is described. Transgenic Nicotiana benthamiana plants containing one copy of the cassette stably integrated into their genome were superinfected with TYLCSV, which mobilized and replicated the cassette as an episomal replicon. The expression of the reporter gene (the GFP gene) was thereby modified. Whereas GFP fluorescence was dimmed in the intercostal areas, an increase of green fluorescence in veins of all leaves placed above the inoculation site, as well as in transport tissues of roots and stems, was observed. The release of episomal trans replicons from the transgene and the increase in GFP expression were dependent on the cognate geminiviral replication-associated protein (Rep) and required interaction between Rep and the intergenic region of TYLCSV. This expression system is able to monitor the replication status of TYLCSV in plants, as induction of GFP expression is only produced in those tissues where Rep is present. To further confirm this notion, the expression of a host factor required for geminivirus replication, the proliferating cellular nuclear antigen (PCNA) was transiently silenced. Inhibition of PCNA prevented GFP induction in veins and reduced viral DNA. We propose that these plants could be widely used to easily identify host factors required for geminivirus replication by virus-induced gene silencing. PMID:16537630

  18. Neurophysiological mechanisms involved in language learning in adults.

    Science.gov (United States)

    Rodríguez-Fornells, Antoni; Cunillera, Toni; Mestres-Missé, Anna; de Diego-Balaguer, Ruth

    2009-12-27

    Little is known about the brain mechanisms involved in word learning during infancy and in second language acquisition and about the way these new words become stable representations that sustain language processing. In several studies we have adopted the human simulation perspective, studying the effects of brain-lesions and combining different neuroimaging techniques such as event-related potentials and functional magnetic resonance imaging in order to examine the language learning (LL) process. In the present article, we review this evidence focusing on how different brain signatures relate to (i) the extraction of words from speech, (ii) the discovery of their embedded grammatical structure, and (iii) how meaning derived from verbal contexts can inform us about the cognitive mechanisms underlying the learning process. We compile these findings and frame them into an integrative neurophysiological model that tries to delineate the major neural networks that might be involved in the initial stages of LL. Finally, we propose that LL simulations can help us to understand natural language processing and how the recovery from language disorders in infants and adults can be accomplished. PMID:19933142

  19. Molecular, Cellular, and Structural Mechanisms of Cocaine Addiction: A Key Role for MicroRNAs

    Science.gov (United States)

    Jonkman, Sietse; Kenny, Paul J

    2013-01-01

    The rewarding properties of cocaine play a key role in establishing and maintaining the drug-taking habit. However, as exposure to cocaine increases, drug use can transition from controlled to compulsive. Importantly, very little is known about the neurobiological mechanisms that control this switch in drug use that defines addiction. MicroRNAs (miRNAs) are small non-protein coding RNA transcripts that can regulate the expression of messenger RNAs that code for proteins. Because of their highly pleiotropic nature, each miRNA has the potential to regulate hundreds or even thousands of protein-coding RNA transcripts. This property of miRNAs has generated considerable interest in their potential involvement in complex psychiatric disorders such as addiction, as each miRNA could potentially influence the many different molecular and cellular adaptations that arise in response to drug use that are hypothesized to drive the emergence of addiction. Here, we review recent evidence supporting a key role for miRNAs in the ventral striatum in regulating the rewarding and reinforcing properties of cocaine in animals with limited exposure to the drug. Moreover, we discuss evidence suggesting that miRNAs in the dorsal striatum control the escalation of drug intake in rats with extended cocaine access. These findings highlight the central role for miRNAs in drug-induced neuroplasticity in brain reward systems that drive the emergence of compulsive-like drug use in animals, and suggest that a better understanding of how miRNAs control drug intake will provide new insights into the neurobiology of drug addiction. PMID:22968819

  20. Identification of Circular RNAs From the Parental Genes Involved in Multiple Aspects of Cellular Metabolism in Barley

    Directory of Open Access Journals (Sweden)

    Behrooz eDarbani

    2016-06-01

    Full Text Available RNA circularization made by head-to-tail back-splicing events is involved in the regulation of gene expression from transcriptional to post-translational levels. By exploiting RNA-Seq data and down-stream analysis, we shed light on the importance of circular RNAs in plants. The results introduce circular RNAs as novel interactors in the regulation of gene expression in plants and imply the comprehensiveness of this regulatory pathway by identifying circular RNAs for a diverse set of genes. These genes are involved in several aspects of cellular metabolism as hormonal signaling, intracellular protein sorting, carbohydrate metabolism and cell-wall biogenesis, respiration, amino acid biosynthesis, transcription and translation, and protein ubiquitination. Additionally, these parental loci of circular RNAs, from both nuclear and mitochondrial genomes, encode for different transcript classes including protein coding transcripts, microRNA, rRNA, and long non-coding/microprotein coding RNAs. The results shed light on the mitochondrial exonic circular RNAs and imply the importance of circular RNAs for regulation of mitochondrial genes. Importantly, we introduce circular RNAs in barley and elucidate their cellular-level alterations across tissues and in response to micronutrients iron and zinc. In further support of circular RNAs' functional roles in plants, we report several cases where fluctuations of circRNAs do not correlate with the levels of their parental-loci encoded linear transcripts.Keywords: circular RNAs, coding and non-coding transcripts, leaves, seeds, transfer cells, micronutrients, mitochondria

  1. Identification of Circular RNAs from the Parental Genes Involved in Multiple Aspects of Cellular Metabolism in Barley

    Science.gov (United States)

    Darbani, Behrooz; Noeparvar, Shahin; Borg, Søren

    2016-01-01

    RNA circularization made by head-to-tail back-splicing events is involved in the regulation of gene expression from transcriptional to post-translational levels. By exploiting RNA-Seq data and down-stream analysis, we shed light on the importance of circular RNAs in plants. The results introduce circular RNAs as novel interactors in the regulation of gene expression in plants and imply the comprehensiveness of this regulatory pathway by identifying circular RNAs for a diverse set of genes. These genes are involved in several aspects of cellular metabolism as hormonal signaling, intracellular protein sorting, carbohydrate metabolism and cell-wall biogenesis, respiration, amino acid biosynthesis, transcription and translation, and protein ubiquitination. Additionally, these parental loci of circular RNAs, from both nuclear and mitochondrial genomes, encode for different transcript classes including protein coding transcripts, microRNA, rRNA, and long non-coding/microprotein coding RNAs. The results shed light on the mitochondrial exonic circular RNAs and imply the importance of circular RNAs for regulation of mitochondrial genes. Importantly, we introduce circular RNAs in barley and elucidate their cellular-level alterations across tissues and in response to micronutrients iron and zinc. In further support of circular RNAs' functional roles in plants, we report several cases where fluctuations of circRNAs do not correlate with the levels of their parental-loci encoded linear transcripts. PMID:27375638

  2. Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system.

    Science.gov (United States)

    Forger, Nancy G; Strahan, J Alex; Castillo-Ruiz, Alexandra

    2016-01-01

    Neuroscientists are likely to discover new sex differences in the coming years, spurred by the National Institutes of Health initiative to include both sexes in preclinical studies. This review summarizes the current state of knowledge of the cellular and molecular mechanisms underlying sex differences in the mammalian nervous system, based primarily on work in rodents. Cellular mechanisms examined include neurogenesis, migration, the differentiation of neurochemical and morphological cell phenotype, and cell death. At the molecular level we discuss evolving roles for epigenetics, sex chromosome complement, the immune system, and newly identified cell signaling pathways. We review recent findings on the role of the environment, as well as genome-wide studies with some surprising results, causing us to re-think often-used models of sexual differentiation. We end by pointing to future directions, including an increased awareness of the important contributions of tissues outside of the nervous system to sexual differentiation of the brain. PMID:26790970

  3. Quantum-Mechanical Calculations on Molecular Substructures Involved in Nanosystems

    Directory of Open Access Journals (Sweden)

    Beata Szefler

    2014-09-01

    Full Text Available In this review article, four ideas are discussed: (a aromaticity of fullerenes patched with flowers of 6-and 8-membered rings, optimized at the HF and DFT levels of theory, in terms of HOMA and NICS criteria; (b polybenzene networks, from construction to energetic and vibrational spectra computations; (c quantum-mechanical calculations on the repeat units of various P-type crystal networks and (d construction and stability evaluation, at DFTB level of theory, of some exotic allotropes of diamond D5, involved in hyper-graphenes. The overall conclusion was that several of the yet hypothetical molecular nanostructures herein described are serious candidates to the status of real molecules.

  4. Cellular Mechanisms of High Mobility Group 1 (HMGB-1) Protein Action in the Diabetic Retinopathy

    OpenAIRE

    Santos, Andrea Rachelle C.; Dvoriantchikova, Galina; Li, Yiwen; Mohammad, Ghulam; Abu El-Asrar, Ahmed M.; Wen, Rong; Ivanov, Dmitry

    2014-01-01

    Diabetic retinopathy is one of the main microvascular complications of diabetes and remains one of the leading causes of blindness worldwide. Recent studies have revealed an important role of inflammatory and proangiogenic high mobility group 1 (HMGB-1) cytokine in diabetic retinopathy. To elucidate cellular mechanisms of HMGB-1 activity in the retina, we performed this study. The histological features of diabetic retinopathy include loss of blood-vessel pericytes and endothelial cells, as we...

  5. Optimization of the diabetic nephropathy treatment with attention to the special features of cellular inflammation mechanisms

    OpenAIRE

    Щербань, Тетяна Дмитрівна

    2016-01-01

    Aim. Optimization of the diabetic nephropathy (DN) treatment in association with hypertonic disease (HD) based on the study of neutrophil chain of pathogenic cellular mechanisms of these diseases development and the special features of its clinical course.Materials and methods. There were complexly examined 86 patients with HD associated with DN and 30 patients with isolated HD. The control group was formed by 30 practically healthy persons. The activity of NO-synthases in neutrophils was det...

  6. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding

    OpenAIRE

    Tchoukalova, Yourka D.; Votruba, Susanne B; Tchkonia, Tamara; Giorgadze, Nino; Kirkland, James L.; Jensen, Michael D.

    2010-01-01

    Body fat distribution is an important predictor of the metabolic consequences of obesity, but the cellular mechanisms regulating regional fat accumulation are unknown. We assessed the changes in adipocyte size (photomicrographs) and number in response to overfeeding in upper- and lower-body s.c. fat depots of 28 healthy, normal weight adults (15 men) age 29 ± 2 y. We analyzed how these changes relate to regional fat gain (dual energy X-ray absorptiometry and computed tomography) and baseline ...

  7. Cellular and Molecular Mechanisms of Novel Therapies to Ameliorate Liver Sinusoidal Dysfunction in Cirrhotic Portal Hypertension

    OpenAIRE

    Marrone, Giusi

    2014-01-01

    Increased intrahepatic vascular resistance (IHVR), mainly due to elevated vascular tone together with the maturation of hepatic fibrosis and the drop of the hepatic endothelial function, is the main factor in the development of portal hypertension (PH) in cirrhosis. This PhD thesis investigates the cellular and molecular mechanisms necessary for the identification of new therapeutic targets and evaluates the possible cross- talk between the hepatic cells in static and physiological conditions...

  8. Diesel exhaust: current knowledge of adverse effects and underlying cellular mechanisms

    OpenAIRE

    Steiner, Sandro; Bisig, Christoph; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

    2016-01-01

    Diesel engine emissions are among the most prevalent anthropogenic pollutants worldwide, and with the growing popularity of diesel-fueled engines in the private transportation sector, they are becoming increasingly widespread in densely populated urban regions. However, a large number of toxicological studies clearly show that diesel engine emissions profoundly affect human health. Thus the interest in the molecular and cellular mechanisms underlying these effects is large, especially c...

  9. Immune cellular response to HPV: current concepts

    Directory of Open Access Journals (Sweden)

    Maria Alice Guimarães Gonçalves

    2004-02-01

    Full Text Available Although cellular immunity is essential for the elimination of human papillomavirus (HPV, the mechanisms involved are still poorly understood. We summarize the main mechanisms involved in cellular immune response to infections caused by HPV. Immunotherapies for HPV-related cancers require the disruption of T-cell response control mechanisms, associated with the stimulation of the Th1 cytokine response.

  10. Mechanisms involved in vibratory destabilization of NAPL ganglia in sands

    International Nuclear Information System (INIS)

    Immiscible liquids when spilled into the ground or leaked from underground storage tanks tend to remain trapped in the form of discrete ganglia due to strong capillary forces. These ganglia often have low solubility in water and may remain in the subsurface over long periods of time creating a continuous source of pollution. Previous studies, which were exploratory in nature, showed that creation of localized vibrations could recover high percentages of trapped ganglia. In this paper, the mechanisms involved in the vibratory destabilization of ganglia are analyzed using results from two sets of experimental studies. It is postulated that, when vibrations result in compaction of sands, viscous pressures tend to destabilize the ganglia by splitting them whereas buoyancy pressures increase the maximum sustainable lengths. The roles of viscous and buoyancy pressures are reversed when vibrations result in increased porosities due to expansion (dilation) of soil. The volumes of trapped ganglia recovered during the experiments are consistent with these postulates. Experimental results also indicate significant recoveries in the cases where the ganglia are supposed to remain stable. These recoveries are attributed to the transient particle rearrangement during vibrations, which is concluded to be an important mechanism

  11. Cellular and molecular mechanisms of osteoporosis: current concepts and future direction treatment

    Directory of Open Access Journals (Sweden)

    A. T. Dolzhenko

    2016-01-01

    Full Text Available The article presents review of literature dedicated to the contemporary view on the cellular-molecular mechanisms of the bone remodeling and pathogenesis of the osteoporosis. The discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in process bone remodeling has made progress in understanding the mechanisms development disease and possible to development drugs of the new generation – denosumab, a fully human RANKL monoclonal antibody and inhibitor cathepsin K odanacatib that inhibits of the bone resorption.

  12. Mechanical models of the cellular cytoskeletal network for the analysis of intracellular mechanical properties and force distributions: a review.

    Science.gov (United States)

    Chen, Ting-Jung; Wu, Chia-Ching; Su, Fong-Chin

    2012-12-01

    The cytoskeleton, which is the major mechanical component of cells, supports the cell body and regulates the cellular motility to assist the cell in performing its biological functions. Several cytoskeletal network models have been proposed to investigate the mechanical properties of cells. This review paper summarizes these models with a focus on the prestressed cable network, the semi-flexible chain network, the open-cell foam, the tensegrity, and the granular models. The components, material parameters, types of connection joints, tension conditions, and the advantages and disadvantages of each model are evaluated from a structural and biological point of view. The underlying mechanisms that are associated with the morphological changes of spreading cells are expected to be simulated using a cytoskeletal model; however, it is still paid less attention most likely due to the lack of a suitable cytoskeletal model that can accurately model the spreading process. In this review article, the established cytoskeletal models are hoped to provide useful information for the development of future cytoskeletal models with different degrees of cell attachment for the study of the mechanical mechanisms underlying the cellular behaviors in response to external stimulations. PMID:23062682

  13. Relative Contributions of Various Cellular Mechanisms to Loss of Algae during Cnidarian Bleaching

    Science.gov (United States)

    Bieri, Tamaki; Onishi, Masayuki; Xiang, Tingting; Grossman, Arthur R.; Pringle, John R

    2016-01-01

    When exposed to stress such as high seawater temperature, corals and other cnidarians can bleach due to loss of symbiotic algae from the host tissue and/or loss of pigments from the algae. Although the environmental conditions that trigger bleaching are reasonably well known, its cellular and molecular mechanisms are not well understood. Previous studies have reported the occurrence of at least four different cellular mechanisms for the loss of symbiotic algae from the host tissue: in situ degradation of algae, exocytic release of algae from the host, detachment of host cells containing algae, and death of host cells containing algae. The relative contributions of these several mechanisms to bleaching remain unclear, and it is also not known whether these relative contributions change in animals subjected to different types and/or durations of stresses. In this study, we used a clonal population of the small sea anemone Aiptasia, exposed individuals to various precisely controlled stress conditions, and quantitatively assessed the several possible bleaching mechanisms in parallel. Under all stress conditions tested, except for acute cold shock at 4°C, expulsion of intact algae from the host cells appeared to be by far the predominant mechanism of bleaching. During acute cold shock, in situ degradation of algae and host-cell detachment also became quantitatively significant, and the algae released under these conditions appeared to be severely damaged. PMID:27119147

  14. Roles for glycosylation of cell surface receptors involved in cellular immune recognition.

    Science.gov (United States)

    Rudd, P M; Wormald, M R; Stanfield, R L; Huang, M; Mattsson, N; Speir, J A; DiGennaro, J A; Fetrow, J S; Dwek, R A; Wilson, I A

    1999-10-22

    The majority of cell surface receptors involved in antigen recognition by T cells and in the orchestration of the subsequent cell signalling events are glycoproteins. The length of a typical N-linked sugar is comparable with that of an immunoglobulin domain (30 A). Thus, by virtue of their size alone, oligosaccharides may be expected to play a significant role in the functions and properties of the cell surface proteins to which they are attached. A databank of oligosaccharide structures has been constructed from NMR and crystallographic data to aid in the interpretation of crystal structures of glycoproteins. As unambiguous electron density can usually only be assigned to the glycan cores, the remainder of the sugar is then modelled into the crystal lattice by superimposing the appropriate oligosaccharide from the database. This approach provides insights into the roles that glycosylation might play in cell surface receptors, by providing models that delineate potential close packing interactions on the cell surface. It has been proposed that the specific recognition of antigen by T cells results in the formation of an immunological synapse between the T cell and the antigen-presenting cell. The cell adhesion glycoproteins, such as CD2 and CD48, help to form a cell junction, providing a molecular spacer between opposing cells. The oligosaccharides located on the membrane proximal domains of CD2 and CD48 provide a scaffold to orient the binding faces, which leads to increased affinity. In the next step, recruitment of the peptide major histocompatibility complex (pMHC) by the T-cell receptors (TCRs) requires mobility on the membrane surface. The TCR sugars are located such that they could prevent non-specific aggregation. Importantly, the sugars limit the possible geometry and spacing of TCR/MHC clusters which precede cell signalling. We postulate that, in the final stage, the sugars could play a general role in controlling the assembly and stabilisation of the

  15. [Glycotoxins and cellular dysfunction. A new mechanism for understanding the preventive effects of lifestyle modifications].

    Science.gov (United States)

    Michalsen, A; Bierhaus, A; Nawroth, P P; Dobos, G J

    2006-08-01

    Recently the AGE-RAGE interaction was identified as a potential mechanism underlying chronic and inflammatory diseases like atherosclerosis, diabetes mellitus and kidney disease. Advanced glycation end products (AGEs) are the derivatives of glucose-protein or glucose-lipid reactions and are mainly generated from the diet (depending on intensity of heating, cooking time and oxygenation). Binding of AGEs or other ligands to the AGE receptor (RAGE) results in cellular activation, i.e. increased expression of inflammatory mediators and oxidative stress. Diet-derived AGEs thus induce deleterious effects on tissues and the cardiovascular system. Recent research also found that other lifestyle factors are associated with pronounced inflammatory activation, e.g. psychosocial stress and smoking. In addition, each intake of meals is associated with proinflammatory cellular changes. The AGE-RAGE model and investigations of the underlying cellular mechanisms thus may lead to a better understanding of the health benefits of diets (Mediterranean diet, uncooked vegetarian diets), caloric restriction and intermittent fasting. The clinical impact of low-AGE diets and fasting and the interaction between stress and food intake should be further investigated in controlled trials. PMID:16897151

  16. Diesel exhaust: current knowledge of adverse effects and underlying cellular mechanisms.

    Science.gov (United States)

    Steiner, Sandro; Bisig, Christoph; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

    2016-07-01

    Diesel engine emissions are among the most prevalent anthropogenic pollutants worldwide, and with the growing popularity of diesel-fueled engines in the private transportation sector, they are becoming increasingly widespread in densely populated urban regions. However, a large number of toxicological studies clearly show that diesel engine emissions profoundly affect human health. Thus the interest in the molecular and cellular mechanisms underlying these effects is large, especially concerning the nature of the components of diesel exhaust responsible for the effects and how they could be eliminated from the exhaust. This review describes the fundamental properties of diesel exhaust as well as the human respiratory tract and concludes that adverse health effects of diesel exhaust not only emerge from its chemical composition, but also from the interplay between its physical properties, the physiological and cellular properties, and function of the human respiratory tract. Furthermore, the primary molecular and cellular mechanisms triggered by diesel exhaust exposure, as well as the fundamentals of the methods for toxicological testing of diesel exhaust toxicity, are described. The key aspects of adverse effects induced by diesel exhaust exposure described herein will be important for regulators to support or ban certain technologies or to legitimate incentives for the development of promising new technologies such as catalytic diesel particle filters. PMID:27165416

  17. Patterns and Cellular Mechanisms of Arm Regeneration in Adult Starfish Asterias rollestoni Bell

    Institute of Scientific and Technical Information of China (English)

    FAN Tingjun; FAN Xianyuan; DU Yutang; SUN Wenjie; ZHANG Shaofeng; LI Jiaxin

    2011-01-01

    To understand the mechanisms of starfish regeneration,the arms of adult starfish Asterias rollestoni Bell were amputated and their regeneration pattems and cellular mechanisms were studied.It was found that cells in the outer epidermis and inner parietal peritoneum near the end of the stump began to dedifferentiate 4d after amputation.The dedifferentiated cells in the outer epidermis proliferated,migrated to the wound site and formed a thickened pre-epidermis which would then re-differentiate gradually into mature epidermis.The new parietal peritoneum formed on the coelomic side of wound might be from the curvely elongated parietal peritoneum,resulting from the dedifferentiated and proliferated cells by extension.Afterwards,the proliferated cells made the outer epidermis and inner parietal peritoneum invaginate into the interior dermis and formed blastema-like structures together with induced dedifferentiated dermal cells.Most interestingly,the arm regeneration in A.rollestoni was achieved synchronously by de novo arm-bud formation and growth,and arm-stump elongation.The crucial aspects of arm-bud formation included cell dedifferentiation,proliferation and migration,while those of arm-stump elongation included cell dedifferentiation,proliferation,invagination,and arm-wall-across blastema-like structure formation.The unique pattern and cellular mechanisms of amputated arm regeneration make it easier to understand the rapid regeneration process of adult starfish.This study may lay solid foundations for the research into molecular mechanisms of echinoderm regeneration.

  18. Inter-cellular nanovesicle mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth

    Science.gov (United States)

    Kogure, Takayuki; Lin, Wen-Lang; Yan, Irene K.; Braconi, Chiara; Patel, Tushar

    2011-01-01

    Hepatocellular carcinoma (HCC) is characterized by a propensity for multifocality, growth by local spread, and dysregulation of multiple signaling pathways. These features may be determined by the tumoral microenvironment. The potential of tumor cells to modulate HCC growth and behavior by secreted proteins has been extensively studied. In contrast the potential for genetic modulation is poorly understood. We investigated the role and involvement of tumor derived nanovesicles capable of altering gene expression, and characterized their ability to modulate cell signaling and biological effects in other cells. We show that HCC cells can produce nanovesicles, exosomes, that differ in both RNA and protein content from their cells of origin. These can be taken up and internalized by other cells, and can transmit a functional transgene. The microRNA content of these exosomes was examined, and a subset that is highly enriched within exosomes was identified. A combinatorial approach to identify potential targets identified transforming growth factor β activated kinase-1 (TAK1) as the most likely candidate pathway that could be modulated by these miRNA. Loss of TAK1 has been implicated in hepatocarcinogenesis and is a biologically plausible target for inter-cellular modulation. We showed that HCC cell derived exosomes can modulate TAK1 expression and associated signaling and enhance transformed cell growth in recipient cells. Conclusion: Exosome mediated miRNA transfer is an important mechanism of inter-cellular communication in HCC cells. These observations identify a unique inter-cellular mechanism that could potentially contribute to local spread, intrahepatic metastases or multifocal growth in HCC. PMID:21721029

  19. DMPD: Anti-inflammatory actions of PPAR ligands: new insights on cellular andmolecular mechanisms. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17981503 Anti-inflammatory actions of PPAR ligands: new insights on cellular andmol...) (.html) (.csml) Show Anti-inflammatory actions of PPAR ligands: new insights on cellular andmolecular mech...anisms. PubmedID 17981503 Title Anti-inflammatory actions of PPAR ligands: new in

  20. Cellular and molecular investigations of the adhesion and mechanics of Listeria monocytogenes

    Science.gov (United States)

    Eskhan, Asma Omar

    Atomic force microscopy has been used to quantify the adherence and mechanical properties of an array of L. monocytogenes strains and their surface biopolymers. First, eight L. monocytogenes strains that represented the two major lineages of the species were compared for their adherence and mechanics at cellular and molecular levels. Our results indicated that strains of lineage' II were characterized by higher adhesion and Young's moduli, longer and more rigid surface biopolymers and lower specific and nonspecific forces when compared to lineage' I strains. Additionally, adherence and mechanical properties of eight L. monocytogenes epidemic and environmental strains were probed. Our results pointed to that environmental and epidemic strains representative of a given lineage were similar in their adherence and mechanical properties when investigated at a cellular level. However, when the molecular properties of the strains were considered, epidemic strains were characterized by higher specific and nonspecific forces, shorter, denser and more flexible biopolymers compared to environmental strains. Second, the role of environmental pH conditions of growth on the adhesion and mechanics of a pathogenic L. monocytogenes EGDe was investigated. Our results pointed to a transition in the adhesion energies for cells cultured at pH 7. In addition, when the types of molecular forces that govern the adhesion were quantified using Poisson statistical approach and using a new proposed method, specific hydrogen-bond energies dominated the bacterial adhesion process. Such a finding is instrumental to researchers designing methods to control bacterial adhesion. Similarly, bacterial cells underwent a transition in their mechanical properties. We have shown that cells cultured at pH 7 were the most rigid compared to those cultured in lower or higher pH conditions of growth. Due to transitions observed in adherence and mechanics when cells were cultured at pH 7, we hypothesized that

  1. In vitro kinetic studies on the mechanism of oxygen-dependent cellular uptake of copper radiopharmaceuticals

    International Nuclear Information System (INIS)

    The development of hypoxia-selective radiopharmaceuticals for use as therapeutic and/or imaging agents is of vital importance for both early identification and treatment of cancer and in the design of new drugs. Radiotracers based on copper for use in positron emission tomography have received great attention due to the successful application of copper(II) bis(thiosemicarbazonato) complexes, such as [60/62/64Cu(II)ATSM] and [60/62/64Cu(II)PTSM], as markers for tumour hypoxia and blood perfusion, respectively. Recent work has led to the proposal of a revised mechanism of hypoxia-selective cellular uptake and retention of [Cu(II)ATSM]. The work presented here describes non-steady-state kinetic simulations in which the reported pO2-dependent in vitro cellular uptake and retention of [64Cu(II)ATSM] in EMT6 murine carcinoma cells has been modelled by using the revised mechanistic scheme. Non-steady-state (NSS) kinetic analysis reveals that the model is in very good agreement with the reported experimental data with a root-mean-squared error of less than 6% between the simulated and experimental cellular uptake profiles. Estimated rate constants are derived for the cellular uptake and washout (k1 = 9.8 ± 0.59 x 10-4 s-1 and k2 = 2.9 ± 0.17 x 10-3 s-1), intracellular reduction (k3 = 5.2 ± 0.31 x 10-2 s-1), reoxidation (k4 = 2.2 ± 0.13 mol-1 dm3 s-1) and proton-mediated ligand dissociation (k5 = 9.0 ± 0.54 x 10-5 s-1). Previous mechanisms focused on the reduction and reoxidation steps. However, the data suggest that the origins of hypoxia-selective retention may reside with the stability of the copper(I) anion with respect to protonation and ligand dissociation. In vitro kinetic studies using the nicotimamide adenine dinucleotide (NADH)-dependent ferredoxin reductase enzyme PuR isolated from the bacterium Rhodopseudomonas palustris have also been conducted. NADH turnover frequencies are found to be dependent on the structure of the ligand and the results confirm that

  2. The yeast mitogen-activated protein kinase Slt2 is involved in the cellular response to genotoxic stress

    Directory of Open Access Journals (Sweden)

    Soriano-Carot María

    2012-02-01

    Full Text Available Abstract Background The maintenance of genomic integrity is essential for cell viability. Complex signalling pathways (DNA integrity checkpoints mediate the response to genotoxic stresses. Identifying new functions involved in the cellular response to DNA-damage is crucial. The Saccharomyces cerevisiae SLT2 gene encodes a member of the mitogen-activated protein kinase (MAPK cascade whose main function is the maintenance of the cell wall integrity. However, different observations suggest that SLT2 may also have a role related to DNA metabolism. Results This work consisted in a comprehensive study to connect the Slt2 protein to genome integrity maintenance in response to genotoxic stresses. The slt2 mutant strain was hypersensitive to a variety of genotoxic treatments, including incubation with hydroxyurea (HU, methylmetanosulfonate (MMS, phleomycin or UV irradiation. Furthermore, Slt2 was activated by all these treatments, which suggests that Slt2 plays a central role in the cellular response to genotoxic stresses. Activation of Slt2 was not dependent on the DNA integrity checkpoint. For MMS and UV, Slt2 activation required progression through the cell cycle. In contrast, HU also activated Slt2 in nocodazol-arrested cells, which suggests that Slt2 may respond to dNTP pools alterations. However, neither the protein level of the distinct ribonucleotide reductase subunits nor the dNTP pools were affected in a slt2 mutant strain. An analysis of the checkpoint function revealed that Slt2 was not required for either cell cycle arrest or the activation of the Rad53 checkpoint kinase in response to DNA damage. However, slt2 mutant cells showed an elongated bud and partially impaired Swe1 degradation after replicative stress, indicating that Slt2 could contribute, in parallel with Rad53, to bud morphogenesis control after genotoxic stresses. Conclusions Slt2 is activated by several genotoxic treatments and is required to properly cope with DNA damage. Slt

  3. Two-step mechanism involving active-site conformational changes regulates human telomerase DNA binding.

    Science.gov (United States)

    Tomlinson, Christopher G; Moye, Aaron L; Holien, Jessica K; Parker, Michael W; Cohen, Scott B; Bryan, Tracy M

    2015-01-15

    The ribonucleoprotein enzyme telomerase maintains telomeres and is essential for cellular immortality in most cancers. Insight into the telomerase mechanism can be gained from syndromes such as dyskeratosis congenita, in which mutation of telomerase components manifests in telomere dysfunction. We carried out detailed kinetic and thermodynamic analyses of wild-type telomerase and two disease-associated mutations in the reverse transcriptase domain. Differences in dissociation rates between primers with different 3' ends were independent of DNA affinities, revealing that initial binding of telomerase to telomeric DNA occurs through a previously undescribed two-step mechanism involving enzyme conformational changes. Both mutations affected DNA binding, but through different mechanisms: P704S specifically affected protein conformational changes during DNA binding, whereas R865H showed defects in binding to the 3' region of the DNA. To gain further insight at the structural level, we generated the first homology model of the human telomerase reverse transcriptase domain; the positions of P704S and R865H corroborate their observed mechanistic defects, providing validation for the structural model. Our data reveal the importance of protein interactions with the 3' end of telomeric DNA and the role of protein conformational change in telomerase DNA binding, and highlight naturally occurring disease mutations as a rich source of mechanistic insight. PMID:25365545

  4. Distinct cellular mechanisms of blood vessel fusion in the zebrafish embryo.

    Science.gov (United States)

    Herwig, Lukas; Blum, Yannick; Krudewig, Alice; Ellertsdottir, Elin; Lenard, Anna; Belting, Heinz-Georg; Affolter, Markus

    2011-11-22

    Although many of the cellular and molecular mechanisms of angiogenesis have been intensely studied [1], little is known about the processes that underlie vascular anastomosis. We have generated transgenic fish lines expressing an EGFP-tagged version of the junctional protein zona occludens 1 (ZO1) to visualize individual cell behaviors that occur during vessel fusion and lumen formation in vivo. These life observations show that endothelial cells (ECs) use two distinct morphogenetic mechanisms, cell membrane invagination and cord hollowing to generate different types of vascular tubes. During initial steps of anastomosis, cell junctions that have formed at the initial site of cell contacts expand into rings, generating a cellular interface of apical membrane compartments, as defined by the localization of the apical marker podocalyxin-2 (Pdxl2). During the cord hollowing process, these apical membrane compartments are brought together via cell rearrangements and extensive junctional remodeling, resulting in lumen coalescence and formation of a multicellular tube. Vessel fusion by membrane invagination occurs adjacent to a preexisting lumen in a proximal to distal direction and is blood-flow dependent. Here, the invaginating inner cell membrane undergoes concomitant apicobasal polarization and the vascular lumen is formed by the extension of a transcellular lumen through the EC, which forms a unicellular or seamless tube. PMID:22079115

  5. The biocompatibility of fluorescent nanodiamonds and their mechanism of cellular uptake

    Science.gov (United States)

    Vaijayanthimala, Vairakkannu; Tzeng, Yan-Kai; Chang, Huan-Cheng; Li, Chung-Leung

    2009-10-01

    The labeling of cells with fluorescent nanoparticles is promising for various biomedical applications. The objective of this study is to evaluate the biocompatibility and the mechanism of the cellular uptake of fluorescent nanodiamonds (FNDs) in cancer cells (HeLa) and pre-adipocytes (3T3-L1). With flow cytometry and the use of a battery of metabolic and cytoskeletal inhibitors, we found that the mechanism of the FND uptake in both cells is by energy-dependent clathrin-mediated endocytosis. In addition, the surface charge of FND influences its cellular uptake, as the uptake of poly-L-lysine-coated FNDs is better than that of oxidative-acid-purified FNDs at the same concentration in regular medium with or without serum. We also confirm that the proliferative potential of FND-treated and untreated cells does not exhibit any significant differences when measured at bulk cultures, and more stringently at clonal cell density. Further biocompatibility studies indicate that the in vitro differentiation of 3T3-L1 pre-adipocytes and 489-2 osteoprogenitors is not affected by the FND treatment. Our results show that FNDs are biocompatible and ideal candidates for potential applications in human stem cell research.

  6. The mechanics of cellular compartmentalization as a model for tumor spreading

    Science.gov (United States)

    Fritsch, Anatol; Pawlizak, Steve; Zink, Mareike; Kaes, Josef A.

    2012-02-01

    Based on a recently developed surgical method of Michael H"ockel, which makes use of cellular confinement to compartments in the human body, we study the mechanics of the process of cell segregation. Compartmentalization is a fundamental process of cellular organization and occurs during embryonic development. A simple model system can demonstrate the process of compartmentalization: When two populations of suspended cells are mixed, this mixture will eventually segregate into two phases, whereas mixtures of the same cell type will not. In the 1960s, Malcolm S. Steinberg formulated the so-called differential adhesion hypothesis which explains the segregation in the model system and the process of compartmentalization by differences in surface tension and adhesiveness of the interacting cells. We are interested in to which extend the same physical principles affect tumor growth and spreading between compartments. For our studies, we use healthy and cancerous breast cell lines of different malignancy as well as primary cells from human cervix carcinoma. We apply a set of techniques to study their mechanical properties and interactions. The Optical Stretcher is used for whole cell rheology, while Cell-cell-adhesion forces are directly measured with a modified AFM. In combination with 3D segregation experiments in droplet cultures we try to clarify the role of surface tension in tumor spreading.

  7. Cellular intrinsic mechanism affecting the outcome of AML treated with Ara-C in a syngeneic mouse model.

    Directory of Open Access Journals (Sweden)

    Wenjun Zhao

    Full Text Available The mechanisms underlying acute myeloid leukemia (AML treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.

  8. On the effects of geometry, defects, and material asymmetry on the mechanical response of shape memory alloy cellular lattice structures

    Science.gov (United States)

    Karamooz Ravari, M. R.; Nasr Esfahani, S.; Taheri Andani, M.; Kadkhodaei, M.; Ghaei, A.; Karaca, H.; Elahinia, M.

    2016-02-01

    Shape memory alloy (such as NiTi) cellular lattice structures are a new class of advanced materials with many potential applications. The cost of fabrication of these structures however is high. It is therefore necessary to develop modeling methods to predict the functional behavior of these alloys before fabrication. The main aim of the present study is to assess the effects of geometry, microstructural imperfections and material asymmetric response of dense shape memory alloys on the mechanical response of cellular structures. To this end, several cellular and dense NiTi samples are fabricated using a selective laser melting process. Both cellular and dense specimens were tested in compression in order to obtain their stress-strain response. For modeling purposes, a three -dimensional (3D) constitutive model based on microplane theory which is able to describe the material asymmetry was employed. Five finite element models based on unit cell and multi-cell methods were generated to predict the mechanical response of cellular lattices. The results show the considerable effects of the microstructural imperfections on the mechanical response of the cellular lattice structures. The asymmetric material response of the bulk material also affects the mechanical response of the corresponding cellular structure.

  9. Early Passage Dependence of Mesenchymal Stem Cell Mechanics Influences Cellular Invasion and Migration.

    Science.gov (United States)

    Spagnol, Stephen T; Lin, Wei-Chun; Booth, Elizabeth A; Ladoux, Benoit; Lazarus, Hillard M; Dahl, Kris Noel

    2016-07-01

    The cellular structures and mechanical properties of human mesenchymal stem cells (hMSCs) vary significantly during culture and with differentiation. Previously, studies to measure mechanics have provided divergent results using different quantitative parameters and mechanical models of deformation. Here, we examine hMSCs prepared for clinical use and subject them to mechanical testing conducive to the relevant deformability associated with clinical injection procedures. Micropipette aspiration of hMSCs shows deformation as a viscoelastic fluid, with little variation from cell to cell within a population. After two passages, hMSCs deform as viscoelastic solids. Further, for clinical applicability during stem cell migration in vivo, we investigated the ability of hMSCs to invade into micropillar arrays of increasing confinement from 12 to 8 μm spacing between adjacent micropillars. We find that hMSC samples with reduced deformability and cells that are more solid-like with passage are more easily able to enter the micropillar arrays. Increased cell fluidity is an advantage for injection procedures and optimization of cell selection based on mechanical properties may enhance efficacy of injected hMSC populations. However, the ability to invade and migrate within tight interstitial spaces appears to be increased with a more solidified cytoskeleton, likely from increased force generation and contractility. Thus, there may be a balance between optimal injection survival and in situ tissue invasion. PMID:26581348

  10. Finite element analysis of the mechanical properties of cellular aluminium based on micro-computed tomography

    International Nuclear Information System (INIS)

    Research highlights: → Elastic and plastic anisotropy is observed for both materials → Both show qualitatively similar characteristics with quantitative differences → Distinctly higher mechanical properties for closed-cell foam → The 'big' and 'small' models show good agreement for the closed-cell foam. - Abstract: In the present paper, the macroscopic mechanical properties of open-cell M-Pore sponge (porosity of 91-93%) and closed-cell Alporas foam (porosity of 80-86%) are investigated. The complex geometry of these cellular materials is scanned by micro-computed tomography and used in finite element (FE) analysis. The mechanical properties are determined by uni-axial compression simulations in three perpendicular directions (x-, y- and z-direction). M-Pore and Alporas exhibit the same qualitative mechanical characteristics but with quantitative differences. In both cases, strong anisotropy is observed for Young's modulus and the 0.002 offset yield stress. Furthermore, for the investigated relative density range a linear dependence between relative density and mechanical properties is found. Finally, a distinctly higher Young's modulus and 0.002 offset yield stress is observed for Alporas.

  11. Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

    Science.gov (United States)

    Narayanan, Kannan Badri; Ali, Manaf; Barclay, Barry J; Cheng, Qiang Shawn; D'Abronzo, Leandro; Dornetshuber-Fleiss, Rita; Ghosh, Paramita M; Gonzalez Guzman, Michael J; Lee, Tae-Jin; Leung, Po Sing; Li, Lin; Luanpitpong, Suidjit; Ratovitski, Edward; Rojanasakul, Yon; Romano, Maria Fiammetta; Romano, Simona; Sinha, Ranjeet K; Yedjou, Clement; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G; Ryan, Elizabeth P; Colacci, Annamaria; Hamid, Roslida A; Mondello, Chiara; Raju, Jayadev; Salem, Hosni K; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Kim, Seo Yun; Bisson, William H; Lowe, Leroy; Park, Hyun Ho

    2015-06-01

    Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis. PMID:26106145

  12. Mechanism of cellular uptake and impact of ferucarbotran on macrophage physiology.

    Directory of Open Access Journals (Sweden)

    Chung-Yi Yang

    Full Text Available Superparamagnetic iron oxide (SPIO nanoparticles are contrast agents used for magnetic resonance imaging. Ferucarbotran is a clinically approved SPIO-coated carboxydextran with a diameter of about 45-60 nm. We investigated the mechanism of cellular uptake of Ferucarbotran with a cell model using the murine macrophage cell line Raw 264.7. We observed a dose-dependent uptake of these SPIO particles by spectrophotometer analysis and also a dose-dependent increase in the granularity of the macrophages as determined by flow cytometry. There was a linear correlation between the side scattering mean value and iron content (P<0.001, R(2 = 0. 8048. For evaluation of the endocytotic pathway of these ingested SPIO particles, different inhibitors of the endocytotic pathways were employed. There was a significant decrease of side scattering counts in the cells and a less significant change in signal intensity based on magnetic resonance in the phenylarsine oxide-treated macrophages. After labeling with SPIO particles, the macrophages showed an increase in the production of reactive oxygen species at 2, 24, and 48 h; a decrease in mitochondrial membrane potential at 24 h; and an increase in cell proliferation at 24 h. We concluded that Ferucarbotran was internalized into macrophages via the clathrin-mediated pathway and can change the cellular behavior of these cells after labeling.

  13. Molecular Dissection of The Cellular Mechanisms Involved In Nickel Hyperaccumulation in Plants

    Energy Technology Data Exchange (ETDEWEB)

    David E. Salt

    2002-04-08

    Hyperaccumulator plant species are able to accumulate between 1-5% of their biomass as metal. However, these plants are often small, slow growing, and do not produce a high biomass. Phytoextraction, a cost-effective, in situ, plant based approach to soil remediation takes advantage of the remarkable ability of hyperaccumulating plants to concentrate metals from the soil and accumulate them in their harvestable, above-ground tissues. However, to make use of the valuable genetic resources identified in metal hyperaccumulating species, it will be necessary to transfer this material to high biomass rapidly growing crop plants. These plants would then be ideally suited to the phytoremediation process, having the ability to produce large amount of metal-rich plant biomass for rapid harvest and soil cleanup. Although progress is being made in understanding the genetic basis of metal hyperaccumulation a more complete understanding will be necessary before we can take full advantage of the genetic potential of these plants.

  14. Molecular dissection of the cellular mechanisms involved in nickel hyperaccumulation in plants. 1998 annual progress report

    Energy Technology Data Exchange (ETDEWEB)

    Salt, D.

    1998-06-01

    'Phytoremediation, the use of plants for environmental cleanup of pollutants, including toxic metals, holds the potential to allow the economic restoration of heavy metal and radionuclide contaminated sites. A number of terrestrial plants are known to naturally accumulate high levels of metals in their shoots (1--2% dry weight), and these plants have been termed metal-hyperaccumulators. Clearly, the genetic traits that determine metal-hyperaccumulation offers the potential for the development of practical phytoremediation processes. The long-term objective is to rationally design and generate plants ideally suited for phytoremediation using this unique genetic material. Initially, the strategy will focus on isolating and characterizing the key genetic information needed for expression of the metal-hyperaccumulation phenotype. Recently, histidine has been shown to play a major role in Ni hyperaccumulation. Based on this information the authors propose to investigate, at the molecular level, the role of histidine biosynthesis in Ni hyperaccumulation in Thlaspi goesingense, a Ni hyperaccumulator species.'

  15. A mathematical model of cortical bone remodeling at cellular level under mechanical stimulus

    Institute of Scientific and Technical Information of China (English)

    Qing-Hua Qin; Ya-Nan Wang

    2012-01-01

    A bone cell population dynamics model for cortical bone remodeling under mechanical stimulus is developed in this paper.The external experiments extracted from the literature which have not been used in the creation of the model are used to test the validity of the model.Not only can the model compare reasonably well with these experimental results such as the increase percentage of final values of bone mineral content (BMC) and bone fracture energy (BFE) among different loading schemes (which proves the validity of the model),but also predict the realtime development pattern of BMC and BFE,as well as the dynamics of osteoblasts (OBA),osteoclasts (OCA),nitric oxide (NO) and prostaglandin E2 (PGE2) for each loading scheme,which can hardly be monitored through experiment.In conclusion,the model is the first of its kind that is able to provide an insight into the quantitative mechanism of bone remodeling at cellular level by which bone cells are activated by mechanical stimulus in order to start resorption/formation of bone mass.More importantly,this model has laid a solid foundation based on which future work such as systemic control theory analysis of bone remodeling under mechanical stimulus can be investigated.The to-be identified control mechanism will help to develop effective drugs and combined nonpharmacological therapies to combat bone loss pathologies.Also this deeper understanding of how mechanical forces quantitatively interact with skeletal tissue is essential for the generation of bone tissue for tissue replacement purposes in tissue engineering.

  16. Cellular origin and developmental mechanisms during the formation of skin melanocytes

    Energy Technology Data Exchange (ETDEWEB)

    Ernfors, Patrik, E-mail: patrik.ernfors@ki.se [Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm (Sweden)

    2010-05-01

    Melanocytes are derived from the neural crest (NC), which are transient multipotent cells arising by delamination from the developing dorsal neural tube. During recent years, signaling systems and molecular mechanisms of melanocyte development have been studied in detail, but the exact diversification of the NC into melanocytes and how they migrate, expand and disperse in the skin have not been fully understood. The recent finding that Schwann cell precursors (SCPs) of the growing nerve represents a stem cell niche from which various cell types, including Schwann cells, endoneural fibroblasts and melanocytes arise has exposed new knowledge on the cellular basis for melanocyte development. This opens for the identification of new factors and reinterpretation of old data on cell fate instructive, proliferative, survival and cell homing factors participating in melanocyte development.

  17. Understanding the mechanisms of ATPase beta family genes for cellular thermotolerance in crossbred bulls

    Science.gov (United States)

    Deb, Rajib; Sajjanar, Basavaraj; Singh, Umesh; Alex, Rani; Raja, T. V.; Alyethodi, Rafeeque R.; Kumar, Sushil; Sengar, Gyanendra; Sharma, Sheetal; Singh, Rani; Prakash, B.

    2015-12-01

    Na+/K+-ATPase is an integral membrane protein composed of a large catalytic subunit (alpha), a smaller glycoprotein subunit (beta), and gamma subunit. The beta subunit is essential for ion recognition as well as maintenance of the membrane integrity. Present study was aimed to analyze the expression pattern of ATPase beta subunit genes (ATPase B1, ATPase B2, and ATPase B3) among the crossbred bulls under different ambient temperatures (20-44 °C). The present study was also aimed to look into the relationship of HSP70 with the ATPase beta family genes. Our results demonstrated that among beta family genes, transcript abundance of ATPase B1 and ATPase B2 is significantly ( P P mechanisms of ATPase beta family genes for cellular thermotolerance in cattle.

  18. Cellular and molecular mechanisms of HGF/Met in the cardiovascular system.

    Science.gov (United States)

    Gallo, Simona; Sala, Valentina; Gatti, Stefano; Crepaldi, Tiziana

    2015-12-01

    Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the

  19. Cellular and deafness mechanisms underlying connexin mutation induced hearing loss – A common hereditary deafness

    Directory of Open Access Journals (Sweden)

    Hong-Bo Zhao

    2015-05-01

    Full Text Available Hearing loss due to mutations in the connexin gene family which encodes gap junctional proteins is a common form of hereditary deafness. In particular, connexin 26 (Cx26, GJB2 mutations are responsible for ~50% of nonsyndromic hearing loss, which is the highest incidence of genetic disease. In the clinic, Cx26 mutations cause various auditory phenotypes ranging from profound congenital deafness at birth to mild, progressive hearing loss in late childhood. Recent experiments demonstrate that congenital deafness mainly results from cochlear developmental disorders rather than hair cell degeneration and endocochlear potential (EP reduction, while late-onset hearing loss results from reduction of active cochlear amplification, even though cochlear hair cells have no connexin expression. Moreover, new experiments further demonstrate that the hypothesized K+-recycling disruption is not a principal deafness mechanism for connexin deficiency induced hearing loss. Additionally, there is no clear relationship between specific changes in connexin (channel functions and the phenotypes of mutation-induced hearing loss. Cx30, Cx29, Cx31, and Cx43 mutations can also cause hearing loss with distinct pathological changes in the cochlea. These new studies provide invaluable information about deafness mechanisms underlying connexin mutation induced hearing loss and also provide important information for developing new protective and therapeutic strategies for this common deafness. However, the detailed cellular mechanisms underlying these pathological changes and pathogeneses of specific-mutation induced hearing loss remain unclear. Finally, little information is available for humans. Further studies to address these deficiencies are urgently required.

  20. Electrospun PCL/Gelatin composite fibrous scaffolds: mechanical properties and cellular responses.

    Science.gov (United States)

    Yao, Ruijuan; He, Jing; Meng, Guolong; Jiang, Bo; Wu, Fang

    2016-06-01

    Electrospinning of hybrid polymer has gained widespread interest by taking advantages of the biological property of the natural polymer and the mechanical property of the synthetic polymer. However, the effect of the blend ratio on the above two properties has been less reported despite the importance to balance these two properties in various tissue engineering applications. To this aim, we investigated the electrospun PCL/Gelatin composite fibrous scaffolds with different blend ratios of 4:1, 2:1, 1:1, 1:2, 1:4, respectively. The morphology of the electrospun samples was observed by SEM and the result showed that the fiber diameter distribution became more uniform with the increase of the gelatin content. The mechanical testing results indicated that the 2:1 PCL/Gelatin sample had both the highest tensile strength of 3.7 MPa and the highest elongation rate of about 90%. Surprisingly, the 2:1 PCL/Gelatin sample also showed the best mesenchymal stem cell responses in terms of attachment, spreading, and cytoskeleton organization. Such correlation might be partly due to the fact that the enhanced mechanical property, an integral part of the physical microenvironment, likely played an important role in regulating the cellular functions. Overall, our results indicated that the PCL/Gelatin sample with the blend ratio of 2:1 was a superior candidate for scaffolds for tissue engineering applications. PMID:27044505

  1. Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species

    International Nuclear Information System (INIS)

    Developmental pathologies may result from endogenous or xenobiotic-enhanced formation of reactive oxygen species (ROS), which oxidatively damage cellular macromolecules and/or alter signal transduction. This minireview focuses upon several model drugs (phenytoin, thalidomide, methamphetamine), environmental chemicals (benzo[a]pyrene) and gamma irradiation to examine this hypothesis in vivo and in embryo culture using mouse, rat and rabbit models. Embryonic prostaglandin H synthases (PHSs) and lipoxygenases bioactivate xenobiotics to free radical intermediates that initiate ROS formation, resulting in oxidation of proteins, lipids and DNA. Oxidative DNA damage and embryopathies are reduced in PHS knockout mice, and in mice treated with PHS inhibitors, antioxidative enzymes, antioxidants and free radical trapping agents. Thalidomide causes embryonic DNA oxidation in susceptible (rabbit) but not resistant (mouse) species. Embryopathies are increased in mutant mice deficient in the antioxidative enzyme glucose-6-phosphate dehydrogenase (G6PD), or by glutathione (GSH) depletion, or inhibition of GSH peroxidase or GSH reductase. Inducible nitric oxide synthase knockout mice are partially protected. Inhibition of Ras or NF-kB pathways reduces embryopathies, implicating ROS-mediated signal transduction. Atm and p53 knockout mice deficient in DNA damage response/repair are more susceptible to xenobiotic or radiation embryopathies, suggesting a teratological role for DNA damage, consistent with enhanced susceptibility to methamphetamine in ogg1 knockout mice with deficient repair of oxidative DNA damage. Even endogenous embryonic oxidative stress carries a risk, since untreated G6PD- or ATM-deficient mice have increased embryopathies. Thus, embryonic processes regulating the balance of ROS formation, oxidative DNA damage and repair, and ROS-mediated signal transduction may be important determinants of teratological risk

  2. Cellular Mechanism of Inner Ear Genetic Disease, roles of Kv7.1 (KCNQ1) Channel

    Science.gov (United States)

    Mousavi Nik, Atefeh

    Potassium channels are the most diverse and widely distributed membrane protein in all living organisms. They have various roles in the body such as controlling membrane potential, cell volume, and cell migration. Many studies have shown that mutation in these channels is associated with different diseases for example: Hearing Defect, Cardiac Arrhythmia, Episodic Ataxia, Seizure and Neuromyotonia. One of the most important diseases associated with K+ channel mutations is called Jervell and Lange-Nielsen syndrome (JLNS). This disease causes bilateral congenital deafness and the patients also suffer from Long QT and they usually experience syncopal episodes in their life and eventually die as a result of cardiac arrest. The gene KCNQ1 encodes the Kv7.1 voltage gated potassium channel. This channel expresses in apical membrane of marginal cell in stria vasularis of cochlea and secret K+ ion to endolymp to keep the endocochlear potential stable, which is necessary for the inner ear to function properly. Kv7.1 channel also expresses in cardiac myocytes and mutation in this gene is associated with another syndrome called Romano-Ward syndrome (RWS). Although Romano-Ward patients have mutation in KCNQ1, similar to Jervell and Lange-Nielsen patients, they only suffer from cardiac defect, and their hearing is completely normal. Several studies identified that mutations in Kv7.1 gene is associated with JLNS and RWS, but the biophysical and cellular mechanisms of these mutations are still unknown. To determine the cellular mechanisms of JLNS and RWS, and to provide mechanistic insight on the functional outputs of JLNS versus RWS mutations, we generated several mutant forms of the human Kv7.1 ( KCNQ1) clone, using site-directed mutagenesis to define their sub-cellular localization and examined their electrophysiological properties. We identified JLNS and RWS mutations at the S4-S5-linker, the pore loop (P-loop) and the C-terminus of hKv7.1 which have been found to control

  3. Structural-mechanical model of wax crystal networks—a mesoscale cellular solid approach

    International Nuclear Information System (INIS)

    Mineral waxes are widely used materials in industrial applications; however, the relationship between structure and mechanical properties is poorly understood. In this work, mineral wax-oil networks were characterized as closed-cell cellular solids, and differences in their mechanical response predicted from structural data. The systems studied included straight-chain paraffin wax (SW)-oil mixtures and polyethylene wax (PW)-oil mixtures. Analysis of cryogenic-SEM images of wax-oil networks allowed for the determination of the length (l) and thickness (t) of the wax cell walls as a function of wax mass fraction (Φ). A linear relationship between t/l and Φ (t/l ∼ Φ 0.89) suggested that wax-oil networks were cellular solids of the closed-cell type. However, the scaling behavior of the elastic modulus with the volume fraction of solids did not agree with theoretical predictions, yielding the same scaling exponent, μ = 0.84, for both waxes. This scaling exponent obtained from mechanical measurements could be predicted from the scaling behavior of the effective wax cell size as a function of wax mass fraction in oil obtained by cryogenic scanning electron microscopy. Microscopy studies allowed us to propose that wax-oil networks are structured as an ensemble of close-packed spherical cells filled with oil, and that it is the links between cells that yield under simple uniaxial compression. Thus, the Young’s moduli for the links between cells in SW and PW wax systems could be estimated as E L(SW) = 2.76 × 109 Pa and E L(PW) = 1.64 × 109 Pa, respectively. The structural parameter responsible for the observed differences in the mechanical strength between the two wax-oil systems is the size of the cells. Polyethylene wax has much smaller cell sizes than the straight chain wax and thus displays a higher Young’s modulus and yield stress. (papers)

  4. Orosensory self-stimulation by sucrose involves brain dopaminergic mechanisms.

    Science.gov (United States)

    Schneider, L H

    1989-01-01

    The most convincing body of evidence supporting a role for brain dopaminergic mechanisms in sweet taste reward has been obtained using the sham-feeding rat. In rats prepared with a chronic gastric fistula and tested with the cannula open, intake is a direct function of the palatability of the solution offered as well as of the state of food deprivation. Because essentially none of the ingested fluid passes on to the intestine, negative postingestive feedback is eliminated. Thus, the relative orosensory/hedonic potency of the food determines and sustains the rate of sham intake; long periods of food deprivation are not required. In this way, the sham feeding of sweet solutions may be considered a form of oral self-stimulation behavior and afford a preparation through which the neurochemical and neuranatomical substrates of sweet taste reward may be identified. The results obtained in the series of experiments summarized in this paper clearly indicate that central D-1 and D-2 receptor mechanisms are critical for the orosensory self-stimulation by sucrose in the rat. In conclusion, I suggest that such investigations of the roles of brain dopaminergic mechanisms in the sucrose sham-feeding rat preparation may further our understanding of normal and aberrant attractions to sweet fluids in humans (see Cabanac, Drewnowski, and Halmi, this volume), as an innate, positive affective response of human neonates to sucrose and the sustained positive hedonic ratings for glucose when tasted but not when consumed have demonstrated. PMID:2699194

  5. Cellular mechanisms of alpha herpesvirus egress: live cell fluorescence microscopy of pseudorabies virus exocytosis.

    OpenAIRE

    Hogue, Ian B.; Jens B Bosse; Jiun-Ruey Hu; Thiberge, Stephan Y.; Enquist, Lynn W.

    2014-01-01

    Egress of newly assembled herpesvirus particles from infected cells is a highly dynamic process involving the host secretory pathway working in concert with viral components. To elucidate the location, dynamics, and molecular mechanisms of alpha herpesvirus egress, we developed a live-cell fluorescence microscopy method to visualize the final transport and exocytosis of pseudorabies virus (PRV) particles in non-polarized epithelial cells. This method is based on total internal reflection fluo...

  6. Mechanisms involved in quinolone resistance in Mycoplasma mycoides subsp. capri.

    Science.gov (United States)

    Antunes, Nuno T; Assunção, Patrícia; Poveda, José B; Tavío, María M

    2015-06-01

    Mycoplasma mycoides subsp. capri is a causative agent of contagious agalactia in goats. In this study, M. mycoides subsp. capri mutants were selected for resistance to fluoroquinolones (norfloxacin, enrofloxacin and ciprofloxacin) by serial passes in broth with increasing concentrations of antibiotic. Mutations conferring cross-resistance to the three fluoroquinolones were found in the quinolone resistance determining regions of the four genes encoding DNA gyrase and topoisomerase IV. Different mutations in the DNA gyrase GyrA subunit suggest a different mechanism of inhibition between norfloxacin and the other tested fluoroquinolones. The presence of an adenosine triphosphate-dependent efflux system was suggested through the use of the inhibitor orthovanadate. PMID:25951987

  7. Cellular mechanisms of tissue fibrosis. 6. Purinergic signaling and response in fibroblasts and tissue fibrosis.

    Science.gov (United States)

    Lu, David; Insel, Paul A

    2014-05-01

    Tissue fibrosis occurs as a result of the dysregulation of extracellular matrix (ECM) synthesis. Tissue fibroblasts, resident cells responsible for the synthesis and turnover of ECM, are regulated via numerous hormonal and mechanical signals. The release of intracellular nucleotides and their resultant autocrine/paracrine signaling have been shown to play key roles in the homeostatic maintenance of tissue remodeling and in fibrotic response post-injury. Extracellular nucleotides signal through P2 nucleotide and P1 adenosine receptors to activate signaling networks that regulate the proliferation and activity of fibroblasts, which, in turn, influence tissue structure and pathologic remodeling. An important component in the signaling and functional responses of fibroblasts to extracellular ATP and adenosine is the expression and activity of ectonucleotideases that attenuate nucleotide-mediated signaling, and thereby integrate P2 receptor- and subsequent adenosine receptor-initiated responses. Results of studies of the mechanisms of cellular nucleotide release and the effects of this autocrine/paracrine signaling axis on fibroblast-to-myofibroblast conversion and the fibrotic phenotype have advanced understanding of tissue remodeling and fibrosis. This review summarizes recent findings related to purinergic signaling in the regulation of fibroblasts and the development of tissue fibrosis in the heart, lungs, liver, and kidney. PMID:24352335

  8. Mechanism of acute cadmium toxicity in the testis of the rat: a cellular and molecular inquiry

    International Nuclear Information System (INIS)

    The more sensitive Sertoli cells were chosen as a model to investigate a molecular mechanism of toxicity. Primary rat Sertoli cells were exposed to sublethal concentrations of cadmium and the changes in [32P]-orthophosphate-labelled phosphoproteins using two-dimensional polyacrylamide gel electrophoresis were examined. Resultant autoradiograms showed a delayed dose- and time-dependent increase in intensity of two acidic proteins having identical molecular weights. These changes were most probably a result of increased synthesis of the proteins. Pretreatment of the cells with zinc, a cadmium antagonist, partially reduced the effect of cadmium. This research concludes that Sertoli cells are relatively more sensitive to the effects of cadmium than interstitial cells. A time- and dose dependent increase in [32P]-associated activity to two small Sertoli cell phosphoproteins was consistently seen after cadmium exposure, whereas no effect could be seen using essential, non-toxic metals. This response may be an early indicator in the disruption of cellular homeostasis by cadmium, and will hopefully contribute positive evidence in the search for a molecular mechanism of cadmium toxicity

  9. Modeling mechanical behaviors of composites with various ratios of matrixeinclusion properties using movable cellular automaton method

    Institute of Scientific and Technical Information of China (English)

    A.Yu. SMOLIN; E.V. SHILKO; S.V. ASTAFUROV; I.S. KONOVALENKO; S.P. BUYAKOVA; S.G. PSAKHIE

    2015-01-01

    Two classes of composite materials are considered: classical metaleceramic composites with reinforcing hard inclusions as well as hard ceramics matrix with soft gel inclusions. Movable cellular automaton method is used for modeling the mechanical behaviors of such different heterogeneous materials. The method is based on particle approach and may be considered as a kind of discrete element method. The main feature of the method is the use of many-body forces of inter-element interaction within the formalism of simply deformable element approximation. It was shown that the strength of reinforcing particles and the width of particle-binder interphase boundaries had determining influence on the service characteristics of metaleceramic composite. In particular, the increasing of strength of carbide inclusions may lead to significant increase in the strength and ultimate strain of composite material. On the example of porous zirconia ceramics it was shown that the change in the mechanical properties of pore surface leads to the corresponding change in effective elastic modulus and strength limit of the ceramic sample. The less is the pore size, the more is this effect. The increase in the elastic properties of pore surface of ceramics may reduce its fracture energy.

  10. Kinetics and mechanisms of reactions involving small aromatic reactive intermediates

    Energy Technology Data Exchange (ETDEWEB)

    Lin, M.C. [Emory Univ., Atlanta, GA (United States)

    1993-12-01

    Small aromatic radicals such as C{sub 6}H{sub 5}, C{sub 6}H{sub 5}O and C{sub 6}H{sub 4} are key prototype species of their homologs. C{sub 6}H{sub 5} and its oxidation product, C{sub 6}H{sub 5}O are believed to be important intermediates which play a pivotal role in hydrocarbon combustion, particularly with regard to soot formation. Despite their fundamental importance, experimental data on the reaction mechanisms and reactivities of these species are very limited. For C{sub 6}H{sub 5}, most kinetic data except its reactions with NO and NO{sub 2}, were obtained by relative rate measurements. For C{sub 6}H{sub 5}O, the authors have earlier measured its fragmentation reaction producing C{sub 5}H{sub 5} + CO in shock waves. For C{sub 6}H{sub 4}, the only rate constant measured in the gas phase is its recombination rate at room temperature. The authors have proposed to investigate systematically the kinetics and mechanisms of this important class of molecules using two parallel laser diagnostic techniques--laser resonance absorption (LRA) and resonance enhanced multiphoton ionization mass spectrometry (REMPI/MS). In the past two years, study has been focused on the development of a new multipass adsorption technique--the {open_quotes}cavity-ring-down{close_quotes} technique for kinetic applications. The preliminary results of this study appear to be quite good and the sensitivity of the technique is at least comparable to that of the laser-induced fluorescence method.

  11. Coral bleaching under thermal stress: putative involvement of host/symbiont recognition mechanisms

    Directory of Open Access Journals (Sweden)

    Tambutte Sylvie

    2009-08-01

    Full Text Available Abstract Background Coral bleaching can be defined as the loss of symbiotic zooxanthellae and/or their photosynthetic pigments from their cnidarian host. This major disturbance of reef ecosystems is principally induced by increases in water temperature. Since the beginning of the 1980s and the onset of global climate change, this phenomenon has been occurring at increasing rates and scales, and with increasing severity. Several studies have been undertaken in the last few years to better understand the cellular and molecular mechanisms of coral bleaching but the jigsaw puzzle is far from being complete, especially concerning the early events leading to symbiosis breakdown. The aim of the present study was to find molecular actors involved early in the mechanism leading to symbiosis collapse. Results In our experimental procedure, one set of Pocillopora damicornis nubbins was subjected to a gradual increase of water temperature from 28°C to 32°C over 15 days. A second control set kept at constant temperature (28°C. The differentially expressed mRNA between the stressed states (sampled just before the onset of bleaching and the non stressed states (control were isolated by Suppression Subtractive Hybridization. Transcription rates of the most interesting genes (considering their putative function were quantified by Q-RT-PCR, which revealed a significant decrease in transcription of two candidates six days before bleaching. RACE-PCR experiments showed that one of them (PdC-Lectin contained a C-Type-Lectin domain specific for mannose. Immunolocalisation demonstrated that this host gene mediates molecular interactions between the host and the symbionts suggesting a putative role in zooxanthellae acquisition and/or sequestration. The second gene corresponds to a gene putatively involved in calcification processes (Pdcyst-rich. Its down-regulation could reflect a trade-off mechanism leading to the arrest of the mineralization process under stress

  12. Mechanisms and secondary factors involved in the induction of radiation transformation in vitro

    International Nuclear Information System (INIS)

    The long term of this research program was to gain information concerning the mechanisms that determine the carcinogenic effects of ionizing radiation, particularly high LET radiation exposure. The experimental approach involves parallel studies of the induction of malignant transformation in BALB/3T3 cells and of specific gene mutations in human lymphoblastoid cells. Emphasis was on the biologic effects of internally incorporated Auger electron emitting radionuclides and the initiation of studies to determine the effects of low dose-rate neutron exposure. Auger electron irradiation sever as a model for high LET-type radiation effects and as an experimental tool for studying the effects of radiation at specific sites within the cell. Auger-emitting radiosotopes are commonly used in clinical nuclear medicine, rendering them a potential hazard to human populations. We examined the influence of cellular localization of Auger-emitting radionuclides and the spectrum of energy distribution in DNA on their mutagenic, cytogenetic, and transformational effects. The effects of 125I (an energetic beta emitter) were compared. We studied the induction of cytogenetic changes by 125I exposure of the cell membrane, as well as its potential to promote (enhance) transformation initiated by low dose external x-ray exposure. We will investigate the Relative Biological Effectiveness for mutagenesis and transformation of low doses of fast neutrons delivered continuously at variable low dose-rates. 34 refs., 1 tab

  13. The use of global transcriptional analysis to reveal the biological and cellular events involved in distinct development phases of Trichophyton rubrum conidial germination

    Directory of Open Access Journals (Sweden)

    Ding Guohui

    2007-04-01

    Full Text Available Abstract Background Conidia are considered to be the primary cause of infections by Trichophyton rubrum. Results We have developed a cDNA microarray containing 10250 ESTs to monitor the transcriptional strategy of conidial germination. A total of 1561 genes that had their expression levels specially altered in the process were obtained and hierarchically clustered with respect to their expression profiles. By functional analysis, we provided a global view of an important biological system related to conidial germination, including characterization of the pattern of gene expression at sequential developmental phases, and changes of gene expression profiles corresponding to morphological transitions. We matched the EST sequences to GO terms in the Saccharomyces Genome Database (SGD. A number of homologues of Saccharomyces cerevisiae genes related to signalling pathways and some important cellular processes were found to be involved in T. rubrum germination. These genes and signalling pathways may play roles in distinct steps, such as activating conidial germination, maintenance of isotropic growth, establishment of cell polarity and morphological transitions. Conclusion Our results may provide insights into molecular mechanisms of conidial germination at the cell level, and may enhance our understanding of regulation of gene expression related to the morphological construction of T. rubrum.

  14. A DNA-dependent stress response involving DNA-PK occurs in hypoxic cells and contributes to cellular adaptation to hypoxia.

    Science.gov (United States)

    Bouquet, Fanny; Ousset, Marielle; Biard, Denis; Fallone, Frédérique; Dauvillier, Stéphanie; Frit, Philippe; Salles, Bernard; Muller, Catherine

    2011-06-01

    DNA-dependent protein kinase (DNA-PK) is involved in DNA double-strand break (DSB) signalling and repair. We report that DNA-PK is activated by mild hypoxia conditions (0.1-1% O₂) as shown by (1) its autophosphorylation on Ser2056, and (2) its mobilisation from a soluble nucleoplasmic compartment to a less extractable nuclear fraction. The recruitment of DNA-PK was not followed by activation and recruitment of the XRCC4-DNA-ligase-IV complex, suggesting that DSBs are not responsible for activation of DNA-PK. To unravel the mechanism of DNA-PK activation, we show that exposure of cells to trichostatin A, a histone deacetylase inhibitor, leads to DNA-PK autophosphorylation and relocalisation to DNA. Histone acetylation (mainly H3K14) is increased in hypoxic cells and treatment with anacardic acid, an inhibitor of histone acetyl transferase, prevented both histone modifications and DNA-PK activation in hypoxic conditions. Importantly, in using either silenced DNA-PK cells or cells exposed to a specific DNA-PK inhibitor (NU7026), we demonstrated that hypoxic DNA-PK activation positively regulates the key transcription factor HIF-1 and one subsequent target gene, GLUT1. Our results show that hypoxia initiates chromatin modification and consequently DNA-PK activation, which positively regulate cellular oxygen-sensing and oxygen-signalling pathways. PMID:21576354

  15. Mechanisms involved in alternariol-induced cell cycle arrest

    International Nuclear Information System (INIS)

    Alternariol (AOH), a mycotoxin produced by Alternaria sp, is often found as a contaminant in fruit and cereal products. Here we employed the murine macrophage cell line RAW 264.7 to test the hypothesis that AOH causes toxicity as a response to DNA damage. AOH at concentrations of 15–30 μM almost completely blocked cell proliferation. Within 30 min treatment, AOH (30 μM) significantly increased the level of reactive oxygen species (ROS). Furthermore, DNA base oxidations as well as DNA strand breaks and/or alkaline labile sites were detected by the comet assay after 2 h exposure of AOH. Cell death (mostly necrosis) was observed after prolonged exposure to the highest concentration of AOH (60 μM for 24 and 48 h) in our study. The DNA damage response involved phosphorylation (activation) of histone H2AX and check point kinase-1- and 2 (Chk-1/2). Moreover, AOH activated p53 and increased the expression of p21, Cyclin B, MDM2, and Sestrin 2; likewise the level of several miRNA was affected. AOH-induced Sestrin 2 expression was regulated by p53 and could at least partly be inhibited by antioxidants, suggesting a role of ROS in the response. Interestingly, the addition of antioxidants did not inhibit cell cycle arrest. Although the formation of ROS by itself was not directly linked cell proliferation, AOH-induced DNA damage and resulting transcriptional changes in p21, MDM2, and Cyclin B likely contribute to the reduced cell proliferation; while Sestrin 2 would contribute to the oxidant defense.

  16. Mechanisms involved in alternariol-induced cell cycle arrest

    Energy Technology Data Exchange (ETDEWEB)

    Solhaug, A., E-mail: Anita.Solhaug@vetinst.no [Norwegian Veterinary Institute, Oslo (Norway); Vines, L.L. [Michigan State University, Department of Food Science and Human Nutrition, East Lansing, MI (United States); Ivanova, L.; Spilsberg, B. [Norwegian Veterinary Institute, Oslo (Norway); Holme, J.A. [Norwegian Institute of Public Health, Division of Environmental Medicine, Oslo (Norway); Pestka, J. [Michigan State University, Department of Food Science and Human Nutrition, East Lansing, MI (United States); Collins, A. [University of Oslo, Department of Nutrition, Faculty of Medicine, Oslo (Norway); Eriksen, G.S. [Norwegian Veterinary Institute, Oslo (Norway)

    2012-10-15

    Alternariol (AOH), a mycotoxin produced by Alternaria sp, is often found as a contaminant in fruit and cereal products. Here we employed the murine macrophage cell line RAW 264.7 to test the hypothesis that AOH causes toxicity as a response to DNA damage. AOH at concentrations of 15-30 {mu}M almost completely blocked cell proliferation. Within 30 min treatment, AOH (30 {mu}M) significantly increased the level of reactive oxygen species (ROS). Furthermore, DNA base oxidations as well as DNA strand breaks and/or alkaline labile sites were detected by the comet assay after 2 h exposure of AOH. Cell death (mostly necrosis) was observed after prolonged exposure to the highest concentration of AOH (60 {mu}M for 24 and 48 h) in our study. The DNA damage response involved phosphorylation (activation) of histone H2AX and check point kinase-1- and 2 (Chk-1/2). Moreover, AOH activated p53 and increased the expression of p21, Cyclin B, MDM2, and Sestrin 2; likewise the level of several miRNA was affected. AOH-induced Sestrin 2 expression was regulated by p53 and could at least partly be inhibited by antioxidants, suggesting a role of ROS in the response. Interestingly, the addition of antioxidants did not inhibit cell cycle arrest. Although the formation of ROS by itself was not directly linked cell proliferation, AOH-induced DNA damage and resulting transcriptional changes in p21, MDM2, and Cyclin B likely contribute to the reduced cell proliferation; while Sestrin 2 would contribute to the oxidant defense.

  17. Cellular mechanisms of activity-dependent BDNF expression in primary sensory neurons.

    Science.gov (United States)

    Vermehren-Schmaedick, A; Khanjian, R A; Balkowiec, A

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) is abundantly expressed by both developing and adult rat visceral sensory neurons from the nodose ganglion (NG) in vivo and in vitro. We have previously shown that BDNF is released from neonatal NG neurons by activity and regulates dendritic development in their postsynaptic targets in the brainstem. The current study was carried out to examine the cellular and molecular mechanisms of activity-dependent BDNF expression in neonatal rat NG neurons, using our established in vitro model of neuronal activation by electrical field stimulation with patterns that mimic neuronal activity in vivo. We show that BDNF mRNA (transcript 4) increases over threefold in response to a 4-h tonic or bursting pattern delivered at the frequency of 6 Hz, which corresponds to the normal heart rate of a newborn rat. No significant increase in BDNF expression was observed following stimulation at 1 Hz. The latter effect suggests a frequency-dependent mechanism of regulated BDNF expression. In addition to BDNF transcript 4, which is known to be regulated by activity, transcript 1 also showed significant upregulation. The increases in BDNF mRNA were followed by BDNF protein upregulation of a similar magnitude after 24h of stimulation at 6 Hz. Electrical stimulation-evoked BDNF expression was inhibited by pretreating neurons with the blocker of voltage-gated sodium channels tetrodotoxin and by removing extracellular calcium. Moreover, our data show that repetitive stimulation-evoked BDNF expression requires calcium influx through N-, but not L-type, channels. Together, our study reveals novel mechanisms through which electrical activity stimulates de novo synthesis of BDNF in sensory neurons, and points to the role of N-type calcium channels in regulating BDNF expression in sensory neurons in response to repetitive stimulation. PMID:26459016

  18. [Changes of the neuronal membrane excitability as cellular mechanisms of learning and memory].

    Science.gov (United States)

    Gaĭnutdinov, Kh L; Andrianov, V V; Gaĭnutdinova, T Kh

    2011-01-01

    In the presented review given literature and results of own studies of dynamics of electrical characteristics of neurons, which change are included in processes both an elaboration of learning, and retention of the long-term memory. Literary datas and our results allow to conclusion, that long-term retention of behavioural reactions during learning is accompanied not only by changing efficiency of synaptic transmission, as well as increasing of excitability of command neurons of the defensive reflex. This means, that in the process of learning are involved long-term changes of the characteristics a membrane of certain elements of neuronal network, dependent from the metabolism of the cells. see text). Thou phenomena possible mark as cellular (electrophysiological) correlates of long-term plastic modifications of the behaviour. The analyses of having results demonstrates an important role of membrane characteristics of neurons (their excitability) and parameters an synaptic transmission not only in initial stage of learning, as well as in long-term modifications of the behaviour (long-term memory). PMID:21442956

  19. Mechanisms involved in calcium oxalate endocytosis by Madin-Darby canine kidney cells

    Directory of Open Access Journals (Sweden)

    A.H. Campos

    2000-01-01

    Full Text Available Calcium oxalate (CaOx crystals adhere to and are internalized by tubular renal cells and it seems that this interaction is related (positively or negatively to the appearance of urinary calculi. The present study analyzes a series of mechanisms possibly involved in CaOx uptake by Madin-Darby canine kidney (MDCK cells. CaOx crystals were added to MDCK cell cultures and endocytosis was evaluated by polarized light microscopy. This process was inhibited by an increase in intracellular calcium by means of ionomycin (100 nM; N = 6; 43.9% inhibition; P<0.001 or thapsigargin (1 µM; N = 6; 33.3% inhibition; P<0.005 administration, and via blockade of cytoskeleton assembly by the addition of colchicine (10 µM; N = 8; 46.1% inhibition; P<0.001 or cytochalasin B (10 µM; N = 8; 34.2% inhibition; P<0.001. Furthermore, CaOx uptake was reduced when the activity of protein kinase C was inhibited by staurosporine (10 nM; N = 6; 44% inhibition; P<0.01, or that of cyclo-oxygenase by indomethacin (3 µM; N = 12; 17.2% inhibition; P<0.05; however, the uptake was unaffected by modulation of potassium channel activity with glibenclamide (3 µM; N = 6, tetraethylammonium (1 mM; N = 6 or cromakalim (1 µM; N = 6. Taken together, these data indicate that the process of CaOx internalization by renal tubular cells is similar to the endocytosis reported for other systems. These findings may be relevant to cellular phenomena involved in early stages of the formation of renal stones.

  20. Mechanism involved in enhancement of osteoblast differentiation by hyaluronic acid

    Energy Technology Data Exchange (ETDEWEB)

    Kawano, Michinao [Division of Maxillofacial Diagnostic and Surgical Science, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, Kitakyushu 803-8580 (Japan); Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, Kitakyushu 803-8580 (Japan); Ariyoshi, Wataru [Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, Kitakyushu 803-8580 (Japan); Iwanaga, Kenjiro [Division of Maxillofacial Diagnostic and Surgical Science, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, Kitakyushu 803-8580 (Japan); Okinaga, Toshinori [Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, Kitakyushu 803-8580 (Japan); Habu, Manabu [Division of Maxillofacial Diagnostic and Surgical Science, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, Kitakyushu 803-8580 (Japan); Yoshioka, Izumi [Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan); Tominaga, Kazuhiro [Division of Maxillofacial Diagnostic and Surgical Science, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, Kitakyushu 803-8580 (Japan); Oral Bioresearch Center, Kyushu Dental College, 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, Kitakyushu 803-8580 (Japan); Oral Bioresearch Center, Kyushu Dental College, Kitakyushu 803-8580 (Japan)

    2011-02-25

    Research highlights: {yields} In this study was to investigate the effects of HA on osteoblast differentiation induced by BMP-2. {yields} MG63 cells were incubated with BMP-2 and HA for various time periods. {yields} Phosphorylation of Smad 1/5/8, p38, and ERK proteins was determined by western blot analysis. To elucidate the nuclear translocation of phosphorylated Smad 1/5/8, stimulated cells were subjected to immunofluorescence microscopy. {yields} HA enhanced BMP-2 induces osteoblastic differentiation in MG63 cells via down-regulation of BMP-2 antagonists and ERK phosphorylation. -- Abstract: Objectives: Bone morphogenetic protein-2 (BMP-2) is expected to be utilized to fill bone defects and promote healing of fractures. However, it is unable to generate an adequate clinical response for use in bone regeneration. Recently, it was reported that glycosaminoglycans, including heparin, heparan sulfate, keratan sulfate, dermatan sulfate, chondroitin-4-sulfate, chondroitin-6-sulfate, and hyaluronic acid (HA), regulate BMP-2 activity, though the mechanism by which HA regulates osteogenic activities has not been fully elucidated. The aim of this study was to investigate the effects of HA on osteoblast differentiation induced by BMP-2. Materials and methods: Monolayer cultures of osteoblastic lineage MG63 cells were incubated with BMP-2 and HA for various time periods. To determine osteoblastic differentiation, alkaline phosphatase (ALP) activity in the cell lysates was quantified. Phosphorylation of Smad 1/5/8, p38, and ERK proteins was determined by Western blot analysis. To elucidate the nuclear translocation of phosphorylated Smad 1/5/8, stimulated cells were subjected to immunofluorescence microscopy. To further elucidate the role of HA in enhancement of BMP-2-induced Smad signaling, mRNA expressions of the BMP-2 receptor antagonists noggin and follistatin were detected using real-time RT-PCR. Results: BMP-2-induced ALP activation, Smad 1/5/8 phosphorylation, and

  1. Mechanism involved in enhancement of osteoblast differentiation by hyaluronic acid

    International Nuclear Information System (INIS)

    Research highlights: → In this study was to investigate the effects of HA on osteoblast differentiation induced by BMP-2. → MG63 cells were incubated with BMP-2 and HA for various time periods. → Phosphorylation of Smad 1/5/8, p38, and ERK proteins was determined by western blot analysis. To elucidate the nuclear translocation of phosphorylated Smad 1/5/8, stimulated cells were subjected to immunofluorescence microscopy. → HA enhanced BMP-2 induces osteoblastic differentiation in MG63 cells via down-regulation of BMP-2 antagonists and ERK phosphorylation. -- Abstract: Objectives: Bone morphogenetic protein-2 (BMP-2) is expected to be utilized to fill bone defects and promote healing of fractures. However, it is unable to generate an adequate clinical response for use in bone regeneration. Recently, it was reported that glycosaminoglycans, including heparin, heparan sulfate, keratan sulfate, dermatan sulfate, chondroitin-4-sulfate, chondroitin-6-sulfate, and hyaluronic acid (HA), regulate BMP-2 activity, though the mechanism by which HA regulates osteogenic activities has not been fully elucidated. The aim of this study was to investigate the effects of HA on osteoblast differentiation induced by BMP-2. Materials and methods: Monolayer cultures of osteoblastic lineage MG63 cells were incubated with BMP-2 and HA for various time periods. To determine osteoblastic differentiation, alkaline phosphatase (ALP) activity in the cell lysates was quantified. Phosphorylation of Smad 1/5/8, p38, and ERK proteins was determined by Western blot analysis. To elucidate the nuclear translocation of phosphorylated Smad 1/5/8, stimulated cells were subjected to immunofluorescence microscopy. To further elucidate the role of HA in enhancement of BMP-2-induced Smad signaling, mRNA expressions of the BMP-2 receptor antagonists noggin and follistatin were detected using real-time RT-PCR. Results: BMP-2-induced ALP activation, Smad 1/5/8 phosphorylation, and nuclear translocation

  2. Characterization of Wave Dispersion in Viscoelastic Cellular Assemblies by Doublet Mechanics

    Institute of Scientific and Technical Information of China (English)

    JIN Yan-Fang; XIONG Chun-Yang; FANG Jing; FERRARI Mauro

    2009-01-01

    Using the Voigt model, we analyze wave propagation in viscoelastic granular media with a monatomic lattice, planar simple cubic package and cubical-tetrahedral assembly within the context of doublet mechanics. Microstrains of elongation between the doublet particles are considered in the models. Wave dispersive relations are derived from dynamic equations of the particles involved in the media, and phase velocities and attenuations of the dispersive waves are obtained for the different assemblies. Variations in these dispersion characteristics are analyzed with the changes of cell interval, modulus, and wave frequency. The relations between micro-constants and macro-parameters are presented under the condition of non-scale continuity of the media.

  3. The Physical Mechanism for Retinal Discrete Dark Noise: Thermal Activation or Cellular Ultraweak Photon Emission?

    Science.gov (United States)

    Salari, Vahid; Scholkmann, Felix; Bokkon, Istvan; Shahbazi, Farhad; Tuszynski, Jack

    2016-01-01

    For several decades the physical mechanism underlying discrete dark noise of photoreceptors in the eye has remained highly controversial and poorly understood. It is known that the Arrhenius equation, which is based on the Boltzmann distribution for thermal activation, can model only a part (e.g. half of the activation energy) of the retinal dark noise experimentally observed for vertebrate rod and cone pigments. Using the Hinshelwood distribution instead of the Boltzmann distribution in the Arrhenius equation has been proposed as a solution to the problem. Here, we show that the using the Hinshelwood distribution does not solve the problem completely. As the discrete components of noise are indistinguishable in shape and duration from those produced by real photon induced photo-isomerization, the retinal discrete dark noise is most likely due to ‘internal photons’ inside cells and not due to thermal activation of visual pigments. Indeed, all living cells exhibit spontaneous ultraweak photon emission (UPE), mainly in the optical wavelength range, i.e., 350–700 nm. We show here that the retinal discrete dark noise has a similar rate as UPE and therefore dark noise is most likely due to spontaneous cellular UPE and not due to thermal activation. PMID:26950936

  4. Multiple Molecular and Cellular Mechanisms of Action of Lycopene in Cancer Inhibition

    Directory of Open Access Journals (Sweden)

    Cristina Trejo-Solís

    2013-01-01

    Full Text Available Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.

  5. Mechanism(S) Involved in the Colon-Specific Expression of the Thiamine Pyrophosphate (Tpp) Transporter

    Science.gov (United States)

    Nabokina, Svetlana M.; Ramos, Mel Brendan; Said, Hamid M.

    2016-01-01

    Microbiota of the large intestine synthesizes considerable amount of vitamin B1 (thiamine) in the form of thiamine pyrophosphate (TPP). We have recently demonstrated the existence of an efficient and specific carrier-mediated uptake process for TPP in human colonocytes, identified the TPP transporter (TPPT) involved (product of the SLC44A4 gene), and shown that expression of TPPT along the gastrointestinal (GI) tract is restricted to the colon. Our aim in this study was to determine the molecular basis of the colon-specific expression of TPPT focusing on a possible epigenetic mechanism. Our results showed that the CpG island predicted in the SLC44A4 promoter is non-methylated in the human colonic epithelial NCM460 cells, but is hyper-methylated in the human duodenal epithelial HuTu80 cells (as well as in the human retinal pigment epithelial ARPE19 cells). In the mouse (where TPPT expression in the GI tract is also restricted to the colon), the CpG island predicted in the Slc44a4 promoter is non-methylated in both the jejunum and colon, thus arguing against possible contribution of DNA methylation in the colon-specific expression of TPPT. A role for histone modifications in the tissue-specific pattern of Slc44a4 expression, however, was suggested by the findings that in mouse colon, histone H3 in the 5’-regulatory region of Slc44a4 is tri-methylated at lysine 4 and acetylated at lysine 9, whereas the tri-methylation at lysine 27 modification was negligible. In contrast, in the mouse jejunum, histone H3 is hyper-trimethylated at lysine 27 (repressor mark). Similarly, possible involvement of miRNA(s) in the tissue-specific expression of TPPT was also suggested by the findings that the 3’-UTR of SLC44A4 is targeted by specific miRNAs/RNA binding proteins in non-colonic, but not in colonic, epithelial cells. These studies show, for the first time, epigenetic mechanisms (histone modifications) play a role in determining the tissue-specific pattern of expression of

  6. Cellular polarization: Interaction between extrinsic bounded noises and the wave-pinning mechanism

    Science.gov (United States)

    de Franciscis, Sebastiano; d'Onofrio, Alberto

    2013-09-01

    Cell polarization (cued or uncued) is a fundamental mechanism in cell biology. As an alternative to the classical Turing bifurcation, it has been proposed that the onset of cell polarity might arise by means of the well-known phenomenon of wave-pinning [Gamba , Proc. Natl. Acad. Sci. USAPNASA60027-842410.1073/pnas.0503974102 102, 16927 (2005)]. A particularly simple and elegant deterministic model of cell polarization based on the wave-pinning mechanism has been proposed by Edelstein-Keshet and coworkers [Biophys. J.BIOJAU0006-349510.1529/biophysj.107.120824 94, 3684 (2008)]. This model consists of a small biomolecular network where an active membrane-bound factor interconverts into its inactive form that freely diffuses in the cell cytosol. However, biomolecular networks do communicate with other networks as well as with the external world. Thus, their dynamics must be considered as perturbed by extrinsic noises. These noises may have both a spatial and a temporal correlation, and in any case they must be bounded to preserve the biological meaningfulness of the perturbed parameters. Here we numerically show that the inclusion of external spatiotemporal bounded parametric perturbations in the above wave-pinning-based model of cellular polarization may sometimes destroy the polarized state. The polarization loss depends on both the extent of temporal and spatial correlations and on the kind of noise employed. For example, an increase of the spatial correlation of the noise induces an increase of the probability of cell polarization. However, if the noise is spatially homogeneous then the polarization is lost in the majority of cases. These phenomena are independent of the type of noise. Conversely, an increase of the temporal autocorrelation of the noise induces an effect that depends on the model of noise.

  7. Phytoplankton calcification as an effective mechanism to alleviate cellular calcium poisoning

    Science.gov (United States)

    Müller, M. N.; Ramos, J. Barcelos e.; Schulz, K. G.; Riebesell, U.; Kaźmierczak, J.; Gallo, F.; Mackinder, L.; Li, Y.; Nesterenko, P. N.; Trull, T. W.; Hallegraeff, G. M.

    2015-11-01

    Marine phytoplankton have developed the remarkable ability to tightly regulate the concentration of free calcium ions in the intracellular cytosol at a level of ~ 0.1 μmol L-1 in the presence of seawater Ca2+ concentrations of 10 mmol L-1. The low cytosolic calcium ion concentration is of utmost importance for proper cell signalling function. While the regulatory mechanisms responsible for the tight control of intracellular Ca2+ concentration are not completely understood, phytoplankton taxonomic groups appear to have evolved different strategies, which may affect their ability to cope with changes in seawater Ca2+ concentrations in their environment on geological timescales. For example, the Cretaceous (145 to 66 Ma), an era known for the high abundance of coccolithophores and the production of enormous calcium carbonate deposits, exhibited seawater calcium concentrations up to 4 times present-day levels. We show that calcifying coccolithophore species (Emiliania huxleyi, Gephyrocapsa oceanica and Coccolithus braarudii) are able to maintain their relative fitness (in terms of growth rate and photosynthesis) at simulated Cretaceous seawater calcium concentrations, whereas these rates are severely reduced under these conditions in some non-calcareous phytoplankton species (Chaetoceros sp., Ceratoneis closterium and Heterosigma akashiwo). Most notably, this also applies to a non-calcifying strain of E. huxleyi which displays a calcium sensitivity similar to the non-calcareous species. We hypothesize that the process of calcification in coccolithophores provides an efficient mechanism to alleviate cellular calcium poisoning and thereby offered a potential key evolutionary advantage, responsible for the proliferation of coccolithophores during times of high seawater calcium concentrations. The exact function of calcification and the reason behind the highly ornate physical structures of coccoliths remain elusive.

  8. Crystal structure of a murine α-class glutathione S-transferase involved in cellular defense against oxidative stress

    NARCIS (Netherlands)

    Krengel, Ute; Schröter, Klaus-Hasso; Hoier, Helga; Arkema, Anita; Kalk, Kor H.; Zimniak, Piotr; Dijkstra, Bauke W.

    1998-01-01

    Glutathione S-transferases (GSTs) are ubiquitous multifunctional enzymes which play a key role in cellular detoxification. The enzymes protect the cells against toxicants by conjugating them to glutathione. Recently, a novel subgroup of α-class GSTs has been identified with altered substrate specifi

  9. PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Cellular and molecular mechanisms of heat stress related to bovine ovarian function.

    Science.gov (United States)

    Roth, Z

    2015-05-01

    In light of the intensive genetic selection for high milk production and the onset of global warming, it seems that the reduced fertility of lactating cows during the summer will worsen in coming years. Although not entirely clear, the mechanism appears to be multifactorial in nature. It includes alterations in follicular development, depression of follicular dominance, and impairment of steroidogenesis and gonadotropin secretion. Heat-induced perturbations in the physiology of the follicle-enclosed oocyte have also been documented, expressed by impaired cleavage rate and reduced developmental competence. With respect to the oocyte, alterations include an increase in PUFA in the membrane, reactive oxygen species, ceramide formation and caspase activity, and induction of apoptosis via the sphingomyelin and/or mitochondrial pathways. New insight into cellular and molecular alterations has revealed that heat induces perturbations in both nuclear and cytoplasmic maturation events, such as resumption of meiosis, metaphase II plate formation, cytoskeleton rearrangement, and translocation of cortical granules. Alterations in mitochondrial distribution (i.e., low proportion of category I mitochondria) and function (i.e., low membrane potential) have recently been reported for oocytes collected during the summer. These were associated with impaired expression of both nuclear (succinate dehydrogenase subunit [SDHD], adenosine triphosphate [ATP] synthase subunit beta [ATP5B]), mitochondrially NADH dehydrogenase subunit 2 (ND2), and mitochondiral (cytochrome c oxidase subunit II [MT-CO2] and cytochrome b [MT-CYB]) genes that are crucial in the mitochondrial respiratory chain. In addition, season-induced alteration in the stored maternal mRNA has been documented, expressed by reduced transcript levels (oocyte maturation factor MOS [C-MOS], growth differentiation factor 9 [GDF9], POU domain class 5 transcription factor 1 [POU5F1], and glyceraldehyde-3-phosphate dehydrogenase

  10. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans

    Science.gov (United States)

    Abegglen, Lisa M.; Caulin, Aleah F.; Chan, Ashley; Lee, Kristy; Robinson, Rosann; Campbell, Michael S.; Kiso, Wendy K.; Schmitt, Dennis L.; Waddell, Peter J; Bhaskara, Srividya; Jensen, Shane T.; Maley, Carlo C.; Schiffman, Joshua D.

    2016-01-01

    IMPORTANCE Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. OBJECTIVE To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). DESIGN, SETTING, AND PARTICIPANTS A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. EXPOSURES Ionizing radiation and doxorubicin. MAIN OUTCOMES AND MEASURES Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. RESULTS Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95%CI, 0%–5%]; African wild dog, 8%[95%CI, 0%–16%]; lion, 2%[95%CI, 0% –7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95%CI, 3.14%–6.49%), compared with humans, who have 11% to 25%cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain

  11. Microstructures, mechanical behavior, cellular response, and hemocompatibility of bulk ultrafine-grained pure tantalum.

    Science.gov (United States)

    Nie, F L; Zheng, Y F; Wang, Y; Wang, J T

    2014-02-01

    Bulk ultrafine-grained (UFG) pure Ta had been successfully prepared by equal channel angular pressing (ECAP) technique till eight passes. The 1st, 2nd, 4th, and 8th ECAPed Ta samples were investigated in the current study, with the 0th ECAPed Ta sample as the microcrystalline counterpart control. The microstructure and grain size distribution were characterized by X-ray diffractometer patterns, scanning electron microscopy, and transmission electron microscopy analysis by means of histogram. Although the mechanical behavior of all the experimental samples were analyzed through uniaxial tensile measurement and microhardness test, in vitro biological interactions onto the substrates such as protein adsorption, cellular responses derived from different types of cell lines, and the activity of erythrocyte and platelets were further evaluated and specifically assessed by bicinchoninic acid assay, enzyme-linked immunosorbent assay, and the method of colorimetric reading. A superior percentage of protein adsorption can be observed on the substrate of the UFG 8th ECAPed Ta (around 90%), even above those on the tissue culture plate (control) and the other ECAPed Ta samples. Furthermore, the UFG 8th ECAPed Ta shows no cytotoxic within 4 days culture when incubated with the murine fibroblast cell lines (L929). In addition, a priority order in the growth of endothelial cells (ECV304) other than vascular smooth muscle cells was observed in the case of the UFG 8th ECAPed Ta. In terms of hemolysis rate and adhered platelets (both the amount and the individual morphology), an evolutionary outcome of preferentially enhanced hemocompatibility can be concluded for the case of the UFG 8th ECAPed Ta. PMID:23908098

  12. Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment

    Directory of Open Access Journals (Sweden)

    Gaurav eSinghal

    2014-04-01

    Full Text Available Recent studies on environmental enrichment (EE have shown cytokines, cellular immune components (e.g. T lymphocytes, NK cells and glial cells in causal relationship to EE in bringing out changes to neurobiology and behavior. The purpose of this review is to evaluate these neuroimmune mechanisms associated with neurobiological and behavioral changes in response to different EE methods. We systematically reviewed common research databases. After applying all inclusion and exclusion criteria, 328 articles remained for this review. Physical exercise, a form of EE, elicits anti-inflammatory and neuromodulatory effects through interaction with several immune pathways including IL-6 secretion from muscle fibers, reduced expression of TLR’s on monocytes and macrophages, reduced secretion of adipokines, modulation of hippocampal T cells, priming of microglia and upregulation of MKP-1 in CNS. In contrast, immunomodulatory roles of other enrichment methods are not studied extensively. Nonetheless, studies showing reduction in the expression of IL-1β and TNF-α in response to enrichment with novel objects and accessories suggest anti-inflammatory effects of novel environment. Likewise, social enrichment, though considered a necessity for healthy behavior, results in immunosuppression in socially defeated animals. This has been attributed to reduction in T lymphocytes, NK cells and IL-10 in subordinate animals. EE through sensory stimuli has been investigated to a lesser extent and the effect on immune factors has not been evaluated yet. Discovery of this multidimensional relationship between immune system, brain functioning and EE has paved a way towards formulating environ-immuno therapies for treating psychiatric illnesses with minimal use of pharmacotherapy. While the immuno-modulatory role of physical exercise has been evaluated extensively, more research is required to investigate neuroimmune changes associated with other enrichment methods.

  13. Adaptation of the black yeast Wangiella dermatitidis to ionizing radiation: molecular and cellular mechanisms.

    Directory of Open Access Journals (Sweden)

    Kelly L Robertson

    Full Text Available Observations of enhanced growth of melanized fungi under low-dose ionizing radiation in the laboratory and in the damaged Chernobyl nuclear reactor suggest they have adapted the ability to survive or even benefit from exposure to ionizing radiation. However, the cellular and molecular mechanism of fungal responses to such radiation remains poorly understood. Using the black yeast Wangiella dermatitidis as a model, we confirmed that ionizing radiation enhanced cell growth by increasing cell division and cell size. Using RNA-seq technology, we compared the transcriptomic profiles of the wild type and the melanin-deficient wdpks1 mutant under irradiation and non-irradiation conditions. It was found that more than 3000 genes were differentially expressed when these two strains were constantly exposed to a low dose of ionizing radiation and that half were regulated at least two fold in either direction. Functional analysis indicated that many genes for amino acid and carbohydrate metabolism and cell cycle progression were down-regulated and that a number of antioxidant genes and genes affecting membrane fluidity were up-regulated in both irradiated strains. However, the expression of ribosomal biogenesis genes was significantly up-regulated in the irradiated wild-type strain but not in the irradiated wdpks1 mutant, implying that melanin might help to contribute radiation energy for protein translation. Furthermore, we demonstrated that long-term exposure to low doses of radiation significantly increased survivability of both the wild-type and the wdpks1 mutant, which was correlated with reduced levels of reactive oxygen species (ROS, increased production of carotenoid and induced expression of genes encoding translesion DNA synthesis. Our results represent the first functional genomic study of how melanized fungal cells respond to low dose ionizing radiation and provide clues for the identification of biological processes, molecular pathways and

  14. A computational model of cellular mechanisms of temporal coding in the medial geniculate body (MGB.

    Directory of Open Access Journals (Sweden)

    Cal F Rabang

    Full Text Available Acoustic stimuli are often represented in the early auditory pathway as patterns of neural activity synchronized to time-varying features. This phase-locking predominates until the level of the medial geniculate body (MGB, where previous studies have identified two main, largely segregated response types: Stimulus-synchronized responses faithfully preserve the temporal coding from its afferent inputs, and Non-synchronized responses, which are not phase locked to the inputs, represent changes in temporal modulation by a rate code. The cellular mechanisms underlying this transformation from phase-locked to rate code are not well understood. We use a computational model of a MGB thalamocortical neuron to test the hypothesis that these response classes arise from inferior colliculus (IC excitatory afferents with divergent properties similar to those observed in brain slice studies. Large-conductance inputs exhibiting synaptic depression preserved input synchrony as short as 12.5 ms interclick intervals, while maintaining low firing rates and low-pass filtering responses. By contrast, small-conductance inputs with Mixed plasticity (depression of AMPA-receptor component and facilitation of NMDA-receptor component desynchronized afferent inputs, generated a click-rate dependent increase in firing rate, and high-pass filtered the inputs. Synaptic inputs with facilitation often permitted band-pass synchrony along with band-pass rate tuning. These responses could be tuned by changes in membrane potential, strength of the NMDA component, and characteristics of synaptic plasticity. These results demonstrate how the same synchronized input spike trains from the inferior colliculus can be transformed into different representations of temporal modulation by divergent synaptic properties.

  15. Study of the mechanisms involved in the laser superficial hardening process of metallic alloys

    International Nuclear Information System (INIS)

    The laser superficial hardening process of a ferrous alloy (gray cast iron) and of an aluminum-silicon alloy was investigated in this work. These metallic alloys are used in the automobile industry for manufacturing cylinders and pistons, respectively. By application of individual pulses and single tracks, the involved mechanisms during the processing were studied. Variables such as energy density, power density, temporal width, beam diameter on the sample surface, atmosphere of the processing region, overlapping and scanning velocity. The hardened surface was characterized by optical and scanning electronic microscopy, dispersive energy microanalysis, X-ray mapping, X-ray diffraction, and measurements of roughness and Vickers microhardness. Depending on the processing parameters, it is possible to obtain different microstructures. The affected area of gray cast iron, can be hardened by remelting or transformation hardening (total or partial) if the reached temperature is higher or not that of melting temperature. Laser treatment originated new structures such as retained austenite, martensite and, occasionally, eutectic of cellular dendritic structure. Aluminum-silicon alloy does not have phase transformation in solid state, it can be hardened only by remelting. The increase of hardness is a function of the precipitation hardening process, which makes the silicon particles smaller and more disperse in the matrix. Maximal values of microhardness (700-1000 HV) were reached with the laser treatment in gray cast iron samples. The initial microhardness is of 242 HV. For aluminum-silicon alloy, the laser remelting increases the initial microhardness of 128 HV to the range of 160-320 HV. The found results give a new perspective for using the CLA/IPEN's laser in the heat treatment area. Besides providing a higher absorptivity to the materials, compared with the CO2 laser, and optical fiber access, the superficial hardening with Nd:YAG laser, depending on the level of

  16. Endoplasmic reticulum quality control is involved in the mechanism of endoglin-mediated hereditary haemorrhagic telangiectasia.

    Directory of Open Access Journals (Sweden)

    Bassam R Ali

    Full Text Available Hereditary haemorrhagic telangiectasia (HHT is an autosomal dominant genetic condition affecting the vascular system and is characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. This disorder affects approximately 1 in 8,000 people worldwide. Significant morbidity is associated with this condition in affected individuals, and anaemia can be a consequence of repeated haemorrhages from telangiectasia in the gut and nose. In the majority of the cases reported, the condition is caused by mutations in either ACVRL1 or endoglin genes, which encode components of the TGF-beta signalling pathway. Numerous missense mutations in endoglin have been reported as causative defects for HHT but the exact underlying cellular mechanisms caused by these mutations have not been fully established despite data supporting a role for the endoplasmic reticulum (ER quality control machinery. For this reason, we examined the subcellular trafficking of twenty-five endoglin disease-causing missense mutations. The mutant proteins were expressed in HeLa and HEK293 cell lines, and their subcellular localizations were established by confocal fluorescence microscopy alongside the analysis of their N-glycosylation profiles. ER quality control was found to be responsible in eight (L32R, V49F, C53R, V125D, A160D, P165L, I271N and A308D out of eleven mutants located on the orphan extracellular domain in addition to two (C363Y and C382W out of thirteen mutants in the Zona Pellucida (ZP domain. In addition, a single intracellular domain missense mutant was examined and found to traffic predominantly to the plasma membrane. These findings support the notion of the involvement of the ER's quality control in the mechanism of a significant number, but not all, missense endoglin mutants found in HHT type 1 patients. Other mechanisms including loss of interactions with signalling partners as well as adverse effects on functional

  17. Bone marrow involvement in diffuse large B-cell lymphoma: correlation between FDG-PET uptake and type of cellular infiltrate

    International Nuclear Information System (INIS)

    To assess, in patients with diffuse large B-cell lymphoma (DLBCL), whether the low sensitivity of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for bone marrow assessment may be explained by histological characteristics of the cellular infiltrate. From a prospective cohort of 110 patients with newly diagnosed aggressive lymphoma, 21 patients with DLBCL had bone marrow involvement. Pretherapeutic FDG-PET images were interpreted visually and semiquantitatively, then correlated with the type of cellular infiltrate and known prognostic factors. Of these 21 patients, 7 (33%) had lymphoid infiltrates with a prominent component of large transformed lymphoid cells (concordant bone marrow involvement, CBMI) and 14 (67%) had lymphoid infiltrates composed of small cells (discordant bone marrow involvement, DBMI). Only 10 patients (48%) had abnormal bone marrow FDG uptake, 6 of the 7 with CBMI and 4 of the 14 with DBMI. Therefore, FDG-PET positivity in the bone marrow was significantly associated with CBMI, while FDG-PET negativity was associated with DBMI (Fisher's exact test, p=0.024). There were no significant differences in gender, age and overall survival between patients with CBMI and DBMI, while the international prognostic index was significantly higher in patients with CBMI. Our study suggests that in patients with DLBCL with bone marrow involvement bone marrow FDG uptake depends on two types of infiltrate, comprising small (DBMI) or large (CBMI) cells. This may explain the apparent low sensitivity of FDG-PET previously reported for detecting bone marrow involvement. (orig.)

  18. A computational framework for 3D mechanical modeling of plant morphogenesis with cellular resolution.

    Directory of Open Access Journals (Sweden)

    Frédéric Boudon

    2015-01-01

    Full Text Available The link between genetic regulation and the definition of form and size during morphogenesis remains largely an open question in both plant and animal biology. This is partially due to the complexity of the process, involving extensive molecular networks, multiple feedbacks between different scales of organization and physical forces operating at multiple levels. Here we present a conceptual and modeling framework aimed at generating an integrated understanding of morphogenesis in plants. This framework is based on the biophysical properties of plant cells, which are under high internal turgor pressure, and are prevented from bursting because of the presence of a rigid cell wall. To control cell growth, the underlying molecular networks must interfere locally with the elastic and/or plastic extensibility of this cell wall. We present a model in the form of a three dimensional (3D virtual tissue, where growth depends on the local modulation of wall mechanical properties and turgor pressure. The model shows how forces generated by turgor-pressure can act both cell autonomously and non-cell autonomously to drive growth in different directions. We use simulations to explore lateral organ formation at the shoot apical meristem. Although different scenarios lead to similar shape changes, they are not equivalent and lead to different, testable predictions regarding the mechanical and geometrical properties of the growing lateral organs. Using flower development as an example, we further show how a limited number of gene activities can explain the complex shape changes that accompany organ outgrowth.

  19. gC1q-R/p33, a member of a new class of multifunctional and multicompartmental cellular proteins, is involved in inflammation and infection.

    Science.gov (United States)

    Ghebrehiwet, B; Lim, B L; Kumar, R; Feng, X; Peerschke, E I

    2001-04-01

    Human gC1q-R (p33, p32, C1qBP, TAP) is a ubiquitously expressed, multiligand-binding, multicompartmental cellular protein involved in various ligand-mediated cellular responses. Although expressed on the surface of cells, an intriguing feature of the membrane-associated form of gC1q-R is that its translated amino acid sequence does not predict the presence of either a sequence motif compatible with a transmembrane segment or a consensus site for a glycosylphosphatidylinositol anchor. Moreover, the N-terminal sequence of the pre-pro-protein gC1q-R contains a motif that targets the molecule to the mitochondria and as such was deemed unlikely to be expressed on the surface. However, several lines of experimental evidence clearly show that gC1q-R is present in all compartments of the cell, including the extracellular cell surface. First, surface labeling of B lymphocytes with the membrane-impermeable reagent sulfosuccinimidyl 6-(biotinamido)hexanoate shows specific biotin incorporation into the surface-expressed but not the intracellular form of gC1q-R. Second, FACS and confocal laser scanning microscopic analyses using anti-gC1q-R IgG mAb 60.11 or 74.5.2, and the fluorophore Alexa 488-conjugated F(ab')2 goat anti-mouse IgG as a probe, demonstrated specific staining of Raji cells (>95% viable). Three-dimensional analyses of the same cells by confocal microscopy showed staining distribution that was consistent with surface expression. Third, endothelial gC1q-R, which is associated with the urokinase plasminogen activator receptor, and cytokeratin 1 bind 125I-high molecular weight kininogen in a specific manner, and the binding is inhibited dose-dependently by mAb 74.5.2 recognizing gC1q-R residues 204-218. Fourth, native gC1q-R purified from Raji cell membranes but not intracellular gC1q-R is glycosylated, as evidenced by a positive periodic acid Schiff stain as well as sensitivity to digestion with endoglycosidase H and F. Finally, cross-linking experiments using C1q

  20. Olfactory stem cells, a new cellular model for studying molecular mechanisms underlying familial dysautonomia.

    Directory of Open Access Journals (Sweden)

    Nathalie Boone

    Full Text Available BACKGROUND: Familial dysautonomia (FD is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells. METHODOLOGY/PRINCIPAL FINDINGS: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion:MU (exon 20 skipping ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation. CONCLUSIONS/SIGNIFICANCE: hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better

  1. Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast

    Directory of Open Access Journals (Sweden)

    Lanthaler Karin

    2011-10-01

    Full Text Available Abstract Background The uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane. The recent recognition that drug uptake is mostly carrier-mediated raises the question of which drugs use which carriers. Results To answer this, we have constructed a chemical genomics platform built upon the yeast gene deletion collection, using competition experiments in batch fermenters and robotic automation of cytotoxicity screens, including protection by 'natural' substrates. Using these, we tested 26 different drugs and identified the carriers required for 18 of the drugs to gain entry into yeast cells. Conclusions As well as providing a useful platform technology, these results further substantiate the notion that the cellular uptake of pharmaceutical drugs normally occurs via carrier-mediated transport and indicates that establishing the identity and tissue distribution of such carriers should be a major consideration in the design of safe and effective drugs.

  2. The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence

    Science.gov (United States)

    Burla, Romina; Carcuro, Mariateresa; Torre, Mattia La; Fratini, Federica; Crescenzi, Marco; D'Apice, Maria Rosaria; Spitalieri, Paola; Raffa, Grazia Daniela; Astrologo, Letizia; Lattanzi, Giovanna; Cundari, Enrico; Raimondo, Domenico; Biroccio, Annamaria; Gatti, Maurizio

    2016-01-01

    AKTIP is a shelterin-interacting protein required for replication of telomeric DNA. Here, we show that AKTIP biochemically interacts with A- and B-type lamins and affects lamin A, but not lamin C or B, expression. In interphase cells, AKTIP localizes at the nuclear rim and in discrete regions of the nucleoplasm just like lamins. Double immunostaining revealed that AKTIP partially co-localizes with lamin B1 and lamin A/C in interphase cells, and that proper AKTIP localization requires functional lamin A. In mitotic cells, AKTIP is enriched at the spindle poles and at the midbody of late telophase cells similar to lamin B1. AKTIP-depleted cells show senescence-associated markers and recapitulate several aspects of the progeroid phenotype. Collectively, our results indicate that AKTIP is a new player in lamin-related processes, including those that govern nuclear architecture, telomere homeostasis and cellular senescence. PMID:27512140

  3. Elucidating the cellular uptake mechanism of aptamer-functionalized graphene-isolated-Au-nanocrystals with dual-modal imaging.

    Science.gov (United States)

    Wang, Shanshan; Liu, Zhangkun; Zou, Yuxiu; Lai, Xiaofang; Ding, Ding; Chen, Long; Zhang, Liqin; Wu, Yuan; Chen, Zhuo; Tan, Weihong

    2016-05-23

    Elucidating the endocytosis and metabolism of nanoparticles in cells could improve the diagnostic sensitivity and therapeutic efficiency. In this work, we explore the cellular uptake mechanism of a biocompatible nanocrystal nanostructure, graphene-isolated-Au-nanocrystals (GIANs), by monitoring the intrinsic Raman and two-photon luminescence signals of GIANs in live cells. Aptamers functionalized on the GIAN nanostructure through simple, but strong, π-π interactions entered the cells through a clathrin-dependent pathway, while unmodified GIANs mainly entered the cells through a caveolae-mediated endocytosis pathway. Thus, it can be concluded that the mechanism of cellular uptake in these graphene-isolated-Au-nanocrystal nanostructures is determined by the presence or absence of aptamer modification. PMID:27111129

  4. RNase-L control of cellular mRNAs: roles in biologic functions and mechanisms of substrate targeting.

    Science.gov (United States)

    Brennan-Laun, Sarah E; Ezelle, Heather J; Li, Xiao-Ling; Hassel, Bret A

    2014-04-01

    RNase-L is a mediator of type 1 interferon-induced antiviral activity that has diverse and critical cellular roles, including the regulation of cell proliferation, differentiation, senescence and apoptosis, tumorigenesis, and the control of the innate immune response. Although RNase-L was originally shown to mediate the endonucleolytic cleavage of both viral and ribosomal RNAs in response to infection, more recent evidence indicates that RNase-L also functions in the regulation of cellular mRNAs as an important mechanism by which it exerts its diverse biological functions. Despite this growing body of work, many questions remain regarding the roles of mRNAs as RNase-L substrates. This review will survey known and putative mRNA substrates of RNase-L, propose mechanisms by which it may selectively cleave these transcripts, and postulate future clinical applications. PMID:24697205

  5. Protein tyrosine phosphatase is possibly involved in cellular signal transduction and the regulation of ABA accumulation in response to water deficit in Maize L. coleoptile

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Water deficit-induced ABA accumulation is an ideal model or "stimulus-response" system to investigate cellular stress signaling in plant cells, using such a model the cellular stress signaling triggered by water deficit was investigated in Maize L. coleoptile. Water deficit-induced ABA accumulation was sensitively blocked by NaVO3, a potent inhibitor both to plasma membrane H+-ATPase (PM-H+- ATPase) and protein tyrosine phosphatase (PTPase). However, while PM- H+-ATPase activity was unaffected under water deficit and PM- H+-ATPase activator did not induce an ABA accumulation instead of water deficit, water deficit induced an increase in the protein phosphatase activity, and furthermore, ABA accumulation was inhibited by PAO, a specific inhibitor of PTPase. These results indicate that protein phosphtases may be involved in the cellular signaling in response to water deficit. Further studies identified at least four species of protein phosphtase as assayed by using pNPP as substrate, among which one component was especially sensitive to NaVO3. The NaVO3-sensitive enzyme was purified and finally showed a protein band about 66 kD on SDS/PAGE. The purified enzyme showed a great activity to some specific PTPase substrates at pH 6.0. In addition to NaVO3, the enzyme was also sensitive to some other PTPase inhibitors such as Zn2+ and MO33+, but not to Ca2+ and Mg2+, indicating that it might be a protein tyrosine phosphatase. Interestingly, the purified enzyme could be deactivated by some reducing agent DTT, which was previously proved to be an inhibitor of water deficit-induced ABA accumulation. This result further proved that PTPase might be involved in the cellular signaling of ABA accumulation in response to water deficit.

  6. Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

    OpenAIRE

    Yu, Tao; Tao, Yonghui; Yang, Meiqiang; Chen, Peng; Gao, XiaoBo; Zhang, Yanbo; Zhang,Tao; Chen, Zi; Hou, Jian; Zhang, Yan; Ruan, Kangcheng; Wang, Hongyan; Hu, Ronggui

    2014-01-01

    Global change in protein turnover (protein degradome) constitutes a central part of cellular responses to intrinsic or extrinsic stimuli. However, profiling protein degradome remains technically challenging. Recently, inhibition of the proteasome, e.g., by using bortezomib (BTZ), has emerged as a major chemotherapeutic strategy for treating multiple myeloma and other human malignancies, but systematic understanding of the mechanisms for BTZ drug action and tumor drug resistance is yet to be a...

  7. Complex I Disorders: Causes, Mechanisms, and Development of Treatment Strategies at the Cellular Level

    Science.gov (United States)

    Valsecchi, Federica; Koopman, Werner J. H.; Manjeri, Ganesh R.; Rodenburg, Richard J.; Smeitink, Jan A. M.; Willems, Peter H. G. M.

    2010-01-01

    Mitochondrial oxidative phosphorylation (OXPHOS) represents the final step in the conversion of nutrients into cellular energy. Genetic defects in the OXPHOS system have an incidence between 1:5,000 and 1:10,000 live births. Inherited isolated deficiency of the first complex (CI) of this system, a multisubunit assembly of 45 different proteins,…

  8. Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy.

    Science.gov (United States)

    Gill, Harinder; Leung, Anskar Y H; Kwong, Yok-Lam

    2016-01-01

    Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown that genetic aberrations also have critical impacts on treatment outcome. Moreover, these genetic alterations may themselves be a target for treatment. The mutation landscape in MDS is shaped by gene aberrations involved in DNA methylation (TET2, DNMT3A, IDH1/2), histone modification (ASXL1, EZH2), the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1/2), transcription (RUNX1, TP53, BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2, MPL, FLT3, GNAS, KIT), RAS pathways (KRAS, NRAS, CBL, NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21). A detailed understanding of the pathogenetic mechanisms leading to transformation is critical for designing single-agent or combinatorial approaches in target therapy of MDS. PMID:27023522

  9. Molecular and cellular mechanisms for the regulation of ovarian follicular function in cows.

    Science.gov (United States)

    Shimizu, Takashi

    2016-08-25

    Ovary is an important organ that houses the oocytes (reproductive cell). Oocyte growth depends on the function of follicular cells such as the granulosa and theca cells. Two-cell two gonadotropin systems are associated with oocyte growth and follicular cell functions. In addition to these systems, it is also known that several growth factors regulate oocyte growth and follicular cell functions. Vascular endothelial growth factor (VEGF) is involved in thecal vasculature during follicular development and the suppression of granulosa cell apoptosis. Metabolic factors such as insulin, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) also play critical roles in the process of follicular development and growth. These factors are associated not only with follicular development, but also with follicular cell function. Steroid hormones (estrogens, androgens, and progestins) that are secreted from follicular cells influence the function of the female genital tract and its affect the susceptibility to bacterial infection. This review covers our current understanding of the mechanisms by which gonadotrophins and/or steroid hormones regulate the growth factors in the follicular cells of the bovine ovary. In addition, this review describes the effect of endotoxin on the function of follicular cells. PMID:27097851

  10. Numerical study of mechanical behavior of ceramic composites under compression loading in the framework of movable cellular automaton method

    Energy Technology Data Exchange (ETDEWEB)

    Konovalenko, Igor S., E-mail: igkon@ispms.tsc.ru; Smolin, Alexey Yu., E-mail: igkon@ispms.tsc.ru; Konovalenko, Ivan S., E-mail: igkon@ispms.tsc.ru [Institute of Strength Physics and Materials Science SB RAS, Tomsk, 634055 (Russian Federation); Promakhov, Vladimir V. [Institute of Strength Physics and Materials Science SB RAS, Tomsk, 634055, Russia and National Research Tomsk State University, Tomsk, 634050 (Russian Federation); Psakhie, Sergey G. [Institute of Strength Physics and Materials Science SB RAS, Tomsk, 634055 (Russian Federation); National Research Tomsk State University, Tomsk, 634050 (Russian Federation); National Research Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation)

    2014-11-14

    Movable cellular automaton method was used for investigating the mechanical behavior of ceramic composites under uniaxial compression. A 2D numerical model of ceramic composites based on oxides of zirconium and aluminum with different structural parameters was developed using the SEM images of micro-sections of a real composite. The influence of such structural parameters as the geometrical dimensions of layers, inclusions, and their spatial distribution in the sample, the volume content of the composite components and their mechanical properties (as well as the amount of zirconium dioxide that underwent the phase transformation) on the fracture, strength, deformation and dissipative properties was investigated.

  11. An evaluation of the mechanism of ABCA7 on cellular lipid release in ABCA7-HEC293 cell

    Institute of Scientific and Technical Information of China (English)

    WU Cheng-ai; WANG Na; ZHAO Dan-hui

    2013-01-01

    Background ABCA7 is a member of the ABCA subfamily that shows a high degree of homology to ABCA1 and,like ABCA1,mediates cellular cholesterol and phospholipid release by apolipoproteins when transfected in vitro.However,expression of ABCA7 has been shown to be downregulated by increased cellular cholesterol while ABCA1 was upregulated.Methods The underlying mechanism for this effect was examined in ABCA1 or ABCA7-transfected HEC293.Lipid content in the medium and cells was determined by enzymatic assays.Gene expression was quantitated by real time PCR,and protein content was determined by Western blotting.Results While ABCA7 mRNA was decreased by 25-hydroxycholesterol treatment,ABCA1 was apparently increased.Treatment with the synthetic LXR agonist T0901317 (T09) upregulated ABCA1 expression and apoAI-mediated cellular lipid release in ABCA1-transfected HEC293 cells,but ABCA7 expression and cellular lipid release in ABCA7-transfected HEC293 cells showed no obvious changes.Conclusion The ABCA7 gene is regulated by sterol in a direction opposite to that of ABCA1.

  12. Phyto-mediated nanostructured carriers based on dual vegetable actives involved in the prevention of cellular damage.

    Science.gov (United States)

    Istrati, D; Lacatusu, I; Bordei, N; Badea, G; Oprea, O; Stefan, L M; Stan, R; Badea, N; Meghea, A

    2016-07-01

    The growing scientific interest in exploitation of vegetable bioactives has raised a number of questions regarding their imminent presence in pharmaceutical formulations. This study intends to demonstrate that a dual combination between vegetable oil (e.g. thistle oil, safflower oil, sea buckthorn oil) and a carrot extract represents an optimal approach to formulate safe carrier systems that manifest cell regeneration effect and promising antioxidant and anti-inflammatory activity. Inclusion of both natural actives into lipid carriers imparted a strong negative charge on the nanocarrier surface (up to -45mV) and displayed average sizes of 70nm to 140nm. The entrapment efficiency of carrot extract into nanostructured carriers ranged between 78.3 and 88.3%. The in vitro release study has demonstrated that the entrapment of the extract represents a viable way for an equilibrated release of carotenoids. Besides the excellent antioxidant properties (e.g. scavenging up to 98% of the free oxygen radicals), the results of cellular integrity (e.g. cell viability of 133%) recommend these nanocarriers based on dual carrot extract-bioactive oil as a promising trend for the treatment of certain disorders in which oxidative stress plays a prominent role. In addition, the lipid nanocarriers based on safflower oil and sea buckthorn oil demonstrated an anti-inflammatory effect on LPS induced THP-1 macrophages, by inhibiting the secretion of two pro-inflammatory cytokines, IL-6 and TNF-α. PMID:27127051

  13. PUMILIO-2 Is Involved in the Positive Regulation of Cellular Proliferation in Human Adipose-Derived Stem Cells

    OpenAIRE

    Shigunov, Patrícia; Sotelo-Silveira, Jose; Kuligovski, Crisciele; de Aguiar, Alessandra Melo; Rebelatto, Carmen K.; Moutinho, José A.; Brofman, Paulo S.; Krieger, Marco A; Goldenberg, Samuel; Munroe, David; Correa, Alejandro; Dallagiovanna, Bruno

    2011-01-01

    Stem cells can either differentiate into more specialized cells or undergo self-renewal. Several lines of evidence from different organisms suggest that these processes depend on the post-transcriptional regulation of gene expression. The presence of the PUF [Pumilio/FBF (fem-3 binding factor)] domain defines a conserved family of RNA binding proteins involved in repressing gene expression. It has been suggested that a conserved function of PUF proteins is to repress differentiation and susta...

  14. The UL24 protein of herpes simplex virus 1 affects the sub-cellular distribution of viral glycoproteins involved in fusion

    International Nuclear Information System (INIS)

    Mutations in UL24 of herpes simplex virus type 1 can lead to a syncytial phenotype. We hypothesized that UL24 affects the sub-cellular distribution of viral glycoproteins involved in fusion. In non-immortalized human foreskin fibroblasts (HFFs) we detected viral glycoproteins B (gB), gD, gH and gL present in extended blotches throughout the cytoplasm with limited nuclear membrane staining; however, in HFFs infected with a UL24-deficient virus (UL24X), staining for the viral glycoproteins appeared as long, thin streaks running across the cell. Interestingly, there was a decrease in co-localized staining of gB and gD with F-actin at late times in UL24X-infected HFFs. Treatment with chemical agents that perturbed the actin cytoskeleton hindered the formation of UL24X-induced syncytia in these cells. These data support a model whereby the UL24 syncytial phenotype results from a mislocalization of viral glycoproteins late in infection. - Highlights: • UL24 affects the sub-cellular distribution of viral glycoproteins required for fusion. • Sub-cellular distribution of viral glycoproteins varies in cell-type dependent manner. • Drugs targeting actin microfilaments affect formation of UL24-related syncytia in HFFs

  15. Cellular origins and differentiation control mechanisms during periodontal development and wound healing.

    Science.gov (United States)

    Pitaru, S; McCulloch, C A; Narayanan, S A

    1994-03-01

    In the context of cellular origins, odontogenic epithelium and oral epithelium are the sources for junctional epithelium during development and during wound healing respectively. In contrast, both odontogenic and non-odontogenic mesenchyme contain the progenitors for gingival fibroblasts in developing tissues while in wounded tissues, gingival fibroblasts are derived from gingival connective tissues and comprise a heterogeneous population of cells with diverse properties and functions. Periodontal ligament, bone and cementum cell populations apparently originate from dental follicle progenitor cells during development, but during wound healing derive from ancestral cells in periodontal ligament and bone. Cellular differentiation in developing periodontium is governed in part by epithelial-mesenchymal interactions that generate specific signals which regulate selective cell populations in time and space. On the other hand, differentiation during wound healing and regeneration is regulated by a vast array of extracellular matrix informational molecules and by cytokines that induce both selective and non-selective responses in the different cell lineages and their precursors. Further, several important signalling systems are irretrievably lost after development is complete. Thus, in the context of cellular origins and differentiation, developing and wounded periodontal tissues exhibit fundamental differences. Future prospects for improved healing and regeneration of periodontal tissues may derive from identification and isolation of informational molecules that are stored in connective tissue matrices. These molecules and elucidation of their functions may open new perspectives in our understanding of the biology of periodontal wound healing and may provide novel approaches to periodontal regeneration. PMID:8158503

  16. Investigation of mechanical properties for open cellular structure CoCrMo alloy fabricated by selective laser melting process

    Science.gov (United States)

    Azidin, A.; Taib, Z. A. M.; Harun, W. S. W.; Che Ghani, S. A.; Faisae, M. F.; Omar, M. A.; Ramli, H.

    2015-12-01

    Orthodontic implants have been a major focus through mechanical and biological performance in advance to fabricate shape of complex anatomical. Designing the part with a complex mechanism is one of the challenging process and addition to achieve the balance and desired mechanical performance brought to the right manufacture technique to fabricate. Metal additive manufacturing (MAM) is brought forward to the newest fabrication technology in this field. In this study, selective laser melting (SLM) process was utilized on a medical grade cobalt-chrome molybdenum (CoCrMo) alloy. The work has focused on mechanical properties of the CoCrMo open cellular structures samples with 60%, 70%, and 80% designed volume porosity that could potentially emulate the properties of human bone. It was observed that hardness values decreased as the soaking time increases except for bottom face. For compression test, 60% designed volume porosity demonstrated highest ultimate compressive strength compared to 70% and 80%.

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

    International Nuclear Information System (INIS)

    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/cm2) 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/Ca2+ 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/Ca2+ pathway.

  18. PUMILIO-2 is involved in the positive regulation of cellular proliferation in human adipose-derived stem cells.

    Science.gov (United States)

    Shigunov, Patrícia; Sotelo-Silveira, Jose; Kuligovski, Crisciele; de Aguiar, Alessandra Melo; Rebelatto, Carmen K; Moutinho, José A; Brofman, Paulo S; Krieger, Marco A; Goldenberg, Samuel; Munroe, David; Correa, Alejandro; Dallagiovanna, Bruno

    2012-01-20

    Stem cells can either differentiate into more specialized cells or undergo self-renewal. Several lines of evidence from different organisms suggest that these processes depend on the post-transcriptional regulation of gene expression. The presence of the PUF [Pumilio/FBF (fem-3 binding factor)] domain defines a conserved family of RNA binding proteins involved in repressing gene expression. It has been suggested that a conserved function of PUF proteins is to repress differentiation and sustain the mitotic proliferation of stem cells. In humans, Pumilio-2 (PUM2) is expressed in embryonic stem cells and adult germ cells. Here we show that PUM2 is expressed in a subpopulation of adipose-derived stem cell (ASC) cultures, with a granular pattern of staining in the cytoplasm. Protein levels of PUM2 showed no changes during the differentiation of ASCs into adipocytes. Moreover, RNAi knockdown of pum2 did not alter the rate of adipogenic differentiation compared with wild-type control cells. A ribonomic approach was used to identify PUM2-associated mRNAs. Microarray analysis showed that PUM2-bound mRNAs are part of gene networks involved in cell proliferation and gene expression control. We studied pum2 expression in cell cultures with low or very high levels of proliferation and found that changes in pum2 production were dependent on the proliferation status of the cell. Transient knockdown of pum2 expression by RNAi impaired proliferation of ASCs in vitro. Our results suggest that PUM2 does not repress differentiation of ASCs but rather is involved in the positive control of ASCs division and proliferation. PMID:21649561

  19. Involvement of the Iron Regulatory Protein from Eisenia andrei Earthworms in the Regulation of Cellular Iron Homeostasis

    OpenAIRE

    Petra Procházková; František Škanta; Radka Roubalová; Marcela Šilerová; Jiří Dvořák; Martin Bilej

    2014-01-01

    Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs) that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs) of the 5'- or 3'-untranslated regions (UTR) of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP). The earthworm IRE site in 5'-UTR of ferritin mRNA most likely f...

  20. A novel mechanism involved in the coupling of mitochondrial biogenesis to oxidative phosphorylation

    Directory of Open Access Journals (Sweden)

    Jelena Ostojić

    2014-01-01

    Full Text Available Mitochondria are essential organelles that are central to a multitude of cellular processes, including oxidative phosphorylation (OXPHOS, which produces most of the ATP in animal cells. Thus it is important to understand not only the mechanisms and biogenesis of this energy production machinery but also how it is regulated in both physiological and pathological contexts. A recent study by Ostojić et al. [Cell Metabolism (2013 18, 567-577] has uncovered a regulatory loop by which the biogenesis of a major enzyme of the OXPHOS pathway, the respiratory complex III, is coupled to the energy producing activity of the mitochondria.

  1. Identification of PM10 characteristics involved in cellular responses in human bronchial epithelial cells (Beas-2B).

    Science.gov (United States)

    Van Den Heuvel, Rosette; Den Hond, Elly; Govarts, Eva; Colles, Ann; Koppen, Gudrun; Staelens, Jeroen; Mampaey, Maja; Janssen, Nicole; Schoeters, Greet

    2016-08-01

    reduction in cell viability was significantly correlated with BC, Cd and Pb. The induction of IL-8 in Beas-2B cells was significantly associated with Cu, Ni and Zn and endotoxin. Endotoxin levels explained 33% of the variance in IL-8 induction. A significant interaction between ambient temperature and endotoxin on the pro-inflammatory activity was seen. No association was found between OP and the cellular responses. This study supports the hypothesis that, on an equal mass basis, PM10 induced biological effects differ due to differences in PM10 characteristics. Metals (Cd, Cu, Ni and Zn), BC, and endotoxin were among the main determinants for the observed biological responses. PMID:27177354

  2. Cellular and circuit mechanisms maintain low spike co-variability and enhance population coding in somatosensory cortex

    Directory of Open Access Journals (Sweden)

    Cheng eLy

    2012-03-01

    Full Text Available The responses of cortical neurons are highly variable across repeated presentations of a stimulus. Understanding this variability is critical for theories of both sensory and motor processing, since response variance affects the accuracy of neural codes. Despite this influence, the cellular and circuit mechanisms that shape the trial-to-trial variability of population responses remain poorly understood. We used a combination of experimental and computational techniques to uncover the mechanisms underlying response variability of populations of pyramidal (E cells in layer 2/3 of rat whisker barrel cortex. Spike trains recorded from pairs of E-cells during either spontaneous activity or whisker deflected responses show similarly low levels of spiking co-variability, despite large differences in network activation between the two states. We developed network models that show how spike threshold nonlinearities dilutes E-cell spiking co-variability during spontaneous activity and low velocity whisker deflections. In contrast, during high velocity whisker deflections, cancelation mechanisms mediated by feedforward inhibition maintain low E-cell pairwise co-variability. Thus, the combination of these two mechanisms ensure low E-cell population variability over a wide range of whisker deflection velocities. Finally, we show how this active decorrelation of population variability leads to a drastic increase in the population information about whisker velocity. The canonical cellular and circuit components of our study suggest that low network variability over a broad range of neural states may generalize across the nervous system.

  3. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

    Energy Technology Data Exchange (ETDEWEB)

    Munira A Kadhim

    2010-03-05

    To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim

  4. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.

    Science.gov (United States)

    Lindqvist, Daniel; Epel, Elissa S; Mellon, Synthia H; Penninx, Brenda W; Révész, Dóra; Verhoeven, Josine E; Reus, Victor I; Lin, Jue; Mahan, Laura; Hough, Christina M; Rosser, Rebecca; Bersani, F Saverio; Blackburn, Elizabeth H; Wolkowitz, Owen M

    2015-08-01

    Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell's mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets. PMID:25999120

  5. Helicobacter pylori eradication to prevent gastric cancer:underlying molecular and cellular mechanisms

    Institute of Scientific and Technical Information of China (English)

    Shingo Tsuji; Norio Hayashi; Masahiko Tsujii; Hiroaki Murata; Tsutomu Nishida; Masato Komori; Masakazu Yasumaru; Shuji Ishii; Yoshiaki Sasayama; Sunao Kawano

    2006-01-01

    Numerous cellular and molecular events have been described in development of gastric cancer. In this article,we overviewed roles of Helicobacter pylori(H pylori) infection on some of the important events in gastric carcinogenesis and discussed whether these cellular and molecular events are reversible after cure of the infection. There are several bacterial components affecting gastric epithelial kinetics and promotion of gastric carcinogenesis. The bacterium also increases risks of genetic instability and mutations due to NO and other reactive oxygen species. Epigenetic silencing of tumor suppressor genes such as RUNX3 may alter the frequency of phenotype change of gastric glands to those with intestinal metaplasia. Host factors such as increased expression of growth factors, cytokines and COX-2 have been also reported in non-cancerous tissue in H pylori-positive subjects. It is noteworthy that most of the above phenomena are reversed after the cure of the infection. However,some of them including overexpression of COX-2 continue to exist and may increase risks for carcinogenesis in metaplastic or dysplastic mucosa even after successful H pylori eradication. Thus, H pylori eradication may not completely abolish the risk for gastric carcinogenesis. Efficiency of the cure of the infection in suppressing gastric cancer depends on the timing and the target population,and warrant further investigation.

  6. Cellular graphene aerogel combines ultralow weight and high mechanical strength: A highly efficient reactor for catalytic hydrogenation

    Science.gov (United States)

    Zhang, Bingxing; Zhang, Jianling; Sang, Xinxin; Liu, Chengcheng; Luo, Tian; Peng, Li; Han, Buxing; Tan, Xiuniang; Ma, Xue; Wang, Dong; Zhao, Ning

    2016-01-01

    The construction of three-dimensional graphene aerogels (GAs) is of great importance owing to their outstanding properties for various applications. Up to now, the combination of ultralow weight and super mechanical strength for GA remains a great challenge. Here we demonstrate the fabrication of cellular GAs by a facile, easily controlled and versatile route, i.e. the chemical reduction of graphene oxide assemblies at oil-water interface under a mild condition (70 °C). The GA is ultralight (with density <3 mg cm−3) yet mechanically resilient because the walls of the cell closely pack in a highly ordered manner to maximize mechanical strength. The GA has been utilized as an appealing reactor for catalytic hydrogenation, which exhibited great advantages such as large oil absorption capability, exceptional catalytic activity, ease of product separation and high stability. PMID:27174450

  7. Cellular graphene aerogel combines ultralow weight and high mechanical strength: A highly efficient reactor for catalytic hydrogenation.

    Science.gov (United States)

    Zhang, Bingxing; Zhang, Jianling; Sang, Xinxin; Liu, Chengcheng; Luo, Tian; Peng, Li; Han, Buxing; Tan, Xiuniang; Ma, Xue; Wang, Dong; Zhao, Ning

    2016-01-01

    The construction of three-dimensional graphene aerogels (GAs) is of great importance owing to their outstanding properties for various applications. Up to now, the combination of ultralow weight and super mechanical strength for GA remains a great challenge. Here we demonstrate the fabrication of cellular GAs by a facile, easily controlled and versatile route, i.e. the chemical reduction of graphene oxide assemblies at oil-water interface under a mild condition (70 °C). The GA is ultralight (with density <3 mg cm(-3)) yet mechanically resilient because the walls of the cell closely pack in a highly ordered manner to maximize mechanical strength. The GA has been utilized as an appealing reactor for catalytic hydrogenation, which exhibited great advantages such as large oil absorption capability, exceptional catalytic activity, ease of product separation and high stability. PMID:27174450

  8. Use of static lung mechanics to identify early pulmonary involvement in patients with ankylosing spondylitis.

    OpenAIRE

    Aggarwal A; Gupta D; Wanchu A; Jindal S

    2001-01-01

    AIM: To assess if a detailed analysis of lung mechanics could help in early recognition of pulmonary abnormalities in patients with ankylosing spondylitis. METHODS: Static pulmonary mechanics were studied in 17 patients (16 men and one woman) of ankylosing spondylitis with no obvious clinical or radiological evidence of pulmonary involvement. Lung pressure-volume relationship was generated using a whole body plethysmograph, and a monoexponential equation fitted to this data. RESULTS: Total lu...

  9. Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae. V. Anamnestic cellular and humoral responses following challenge infection

    Energy Technology Data Exchange (ETDEWEB)

    Correa-Oliveira, R.; Sher, A.; James, S.L.

    1984-03-01

    Mice vaccinated with radiation-attenuated cercariae display low levels of cellular and humoral immune responses toward schistosomulum antigens, as measured in vitro by lymphocyte blastogenesis and quantitation of anti-larval antibodies by indirect immunofluorescence. Both responses wane with time after vaccination. However subsequent challenge infection provokes immune responses of classical anamnestic character, being both more rapid in appearance and of greater magnitude. Antigen responsive cells appear in lymph nodes draining the challenge site within 24 hours after infection. Both circulating anti-schistosomulum surface antibodies as well as cytophilic IgE anti-worm antigen antibodies increase substantially by 1 week after challenge. All of the anamnestic circulating antibodies belong to the IgG class. Those findings support the concept that vaccine-induced resistance to Schistosoma mansoni infection involves sensitized T and B lymphocytes, and point to the possible role of post-challenge anamnestic responses in the effector mechanism of parasite killing in this model.

  10. Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae. V. Anamnestic cellular and humoral responses following challenge infection

    International Nuclear Information System (INIS)

    Mice vaccinated with radiation-attenuated cercariae display low levels of cellular and humoral immune responses toward schistosomulum antigens, as measured in vitro by lymphocyte blastogenesis and quantitation of anti-larval antibodies by indirect immunofluorescence. Both responses wane with time after vaccination. However subsequent challenge infection provokes immune responses of classical anamnestic character, being both more rapid in appearance and of greater magnitude. Antigen responsive cells appear in lymph nodes draining the challenge site within 24 hours after infection. Both circulating anti-schistosomulum surface antibodies as well as cytophilic IgE anti-worm antigen antibodies increase substantially by 1 week after challenge. All of the anamnestic circulating antibodies belong to the IgG class. Those findings support the concept that vaccine-induced resistance to Schistosoma mansoni infection involves sensitized T and B lymphocytes, and point to the possible role of post-challenge anamnestic responses in the effector mechanism of parasite killing in this model

  11. Cellular and molecular mechanism study of declined intestinal transit function in the cholesterol gallstone formation process of the guinea pig

    OpenAIRE

    Fan, Ying; Wu, Shuodong; YIN, ZHENHUA; Fu, Bei-Bei

    2014-01-01

    The aim of this study was to investigate the cellular and molecular mechanisms of declined intestinal transit (IT) function in the cholesterol gallstone (CG) formation process. Forty guinea pigs were divided into an experimental group (EG) and a control group (CoG), and the reverse transcription-polymerase chain reaction (RT-PCR) was performed for the analysis of c-kit and stem cell factor (scf) mRNA expression in the small bowel. In addition, immunofluorescence staining and confocal laser mi...

  12. MECHANISMS OF DAMAGING EFFECT OF MANGENESE IN TOXIC CONCENTRATIONS ON CELLULAR AND SUBCELLULAR LEVELS

    Directory of Open Access Journals (Sweden)

    Goncharenko A. V.

    2012-11-01

    Full Text Available Influence of subtoxic concentration of manganese chloride in dose equal to LD 50 on condition of plasmatic membranes (model: erythrocytes and functional activity of cell power (model: the isolated liver mitochondrion of rats was studied. It was established that manganese chloride in fixed concentration caused authentic augmentation of sorption capacity of erythrocytes towards alcian blue, influenced increasing of their spontaneous haemolysis and activation of peroxide oxidation of lipids. In experiment on the isolated mitochondrion it was proved that manganese chloride caused dissociation of an oxidizing phosphorusling and complete inhibition of respiration in concentrations of 3 and 4,5mM. These dependences testify that subtoxic concentration of manganese can damage the cell energy. Thus, this pilot research indicated damaging effect of manganese on cellular (erythrocytes and subcellular (mitochondrion levels which are realized through external functioning of membrane structures and deprived them from restoration.

  13. Mechanisms and Regulation of Intestinal Absorption of Water-soluble Vitamins: Cellular and Molecular Aspects

    DEFF Research Database (Denmark)

    Nexø, Ebba; Said, Hamid M

    2012-01-01

    The water-soluble vitamins represent a group of structurally and functionally unrelated compounds that share the common feature of being essential for normal cellular functions, growth, and development. With the exception of some endogenous production of niacin, human cells cannot synthesize thes...... deficiency. An impaired absorptive function occurs in a variety of conditions including congenital defects in the digestive or absorptive processes, intestinal diseases, drug interaction, and chronic alcohol use....... micronutrients, and thus, must obtain them from exogenous sources via intestinal absorption. The intestine, therefore, plays a critical role in maintaining and regulating normal body homeostasis of these essential nutrients, and interference with its normal absorptive function could lead to suboptimal states or...

  14. Cellular and Molecular Mechanisms of 3,3′-Diindolylmethane in Gastrointestinal Cancer

    Directory of Open Access Journals (Sweden)

    Soo Mi Kim

    2016-07-01

    Full Text Available Studies in humans have shown that 3,3′-diindolylmethane (DIM, which is found in cruciferous vegetables, such as cabbage and broccoli, is effective in the attenuation of gastrointestinal cancers. This review presents the latest findings on the use, targets, and modes of action of DIM for the treatment of human gastrointestinal cancers. DIM acts upon several cellular and molecular processes in gastrointestinal cancer cells, including apoptosis, autophagy, invasion, cell cycle regulation, metastasis, angiogenesis, and endoplasmic reticulum (ER stress. In addition, DIM increases the efficacy of other drugs or therapeutic chemicals when used in combinatorial treatment for gastrointestinal cancer. The studies to date offer strong evidence to support the use of DIM as an anticancer and therapeutic agent for gastrointestinal cancer. Therefore, this review provides a comprehensive understanding of the preventive and therapeutic properties of DIM in addition to its different perspective on the safety of DIM in clinical applications for the treatment of gastrointestinal cancers.

  15. Cellular Interrogation: Exploiting Cell-to-Cell Variability to Discriminate Regulatory Mechanisms in Oscillatory Signalling

    Science.gov (United States)

    Gibson, Daniel; Chang, Frederick; Gnad, Florian; Gunawardena, Jeremy

    2016-01-01

    The molecular complexity within a cell may be seen as an evolutionary response to the external complexity of the cell’s environment. This suggests that the external environment may be harnessed to interrogate the cell’s internal molecular architecture. Cells, however, are not only nonlinear and non-stationary, but also exhibit heterogeneous responses within a clonal, isogenic population. In effect, each cell undertakes its own experiment. Here, we develop a method of cellular interrogation using programmable microfluidic devices which exploits the additional information present in cell-to-cell variation, without requiring model parameters to be fitted to data. We focussed on Ca2+ signalling in response to hormone stimulation, which exhibits oscillatory spiking in many cell types and chose eight models of Ca2+ signalling networks which exhibit similar behaviour in simulation. We developed a nonlinear frequency analysis for non-stationary responses, which could classify models into groups under parameter variation, but found that this question alone was unable to distinguish critical feedback loops. We further developed a nonlinear amplitude analysis and found that the combination of both questions ruled out six of the models as inconsistent with the experimentally-observed dynamics and heterogeneity. The two models that survived the double interrogation were mathematically different but schematically identical and yielded the same unexpected predictions that we confirmed experimentally. Further analysis showed that subtle mathematical details can markedly influence non-stationary responses under parameter variation, emphasising the difficulty of finding a “correct” model. By developing questions for the pathway being studied, and designing more versatile microfluidics, cellular interrogation holds promise as a systematic strategy that can complement direct intervention by genetics or pharmacology. PMID:27367445

  16. On reaction mechanisms involved in the deuteron–induced surrogate reactions

    International Nuclear Information System (INIS)

    An extended analysis of the nuclear reaction mechanisms involved within deuteron interaction with nuclei, namely the breakup, stripping, pick-up, pre-equilibrium emission, and evaporation from fully equilibrated compound nucleus, is presented in order to highlight the importance of the direct mechanisms still neglected in the analysis of deuteron-induced surrogate reactions. Particularly, the dominance of the breakup mechanism at low energies around the Coulomb barrier should be considered in the case of (d,x) surrogate reactions on actinide target nuclei

  17. On reaction mechanisms involved in the deuteron–induced surrogate reactions

    Energy Technology Data Exchange (ETDEWEB)

    Avrigeanu, M.; Avrigeanu, V.; Mănăilescu, C. [Horia Hulubei National Institute for Physics and Nuclear Engineering, P.O. Box MG-6, 077125 Bucharest-Magurele (Romania)

    2015-02-24

    An extended analysis of the nuclear reaction mechanisms involved within deuteron interaction with nuclei, namely the breakup, stripping, pick-up, pre-equilibrium emission, and evaporation from fully equilibrated compound nucleus, is presented in order to highlight the importance of the direct mechanisms still neglected in the analysis of deuteron-induced surrogate reactions. Particularly, the dominance of the breakup mechanism at low energies around the Coulomb barrier should be considered in the case of (d,x) surrogate reactions on actinide target nuclei.

  18. A theoretical study of the molecular mechanism of the GAPDH Trypanosoma cruzi enzyme involving iodoacetate inhibitor

    Science.gov (United States)

    Carneiro, Agnaldo Silva; Lameira, Jerônimo; Alves, Cláudio Nahum

    2011-10-01

    The glyceraldehyde-3-phosphate dehydrogenase enzyme (GAPDH) is an important biological target for the development of new chemotherapeutic agents against Chagas disease. In this Letter, the inhibition mechanism of GAPDH involving iodoacetate (IAA) inhibitor was studied using the hybrid quantum mechanical/molecular mechanical (QM/MM) approach and molecular dynamic simulations. Analysis of the potential energy surface and potential of mean force show that the covalent attachment of IAA inhibitor to the active site of the enzyme occurs as a concerted process. In addition, the energy terms decomposition shows that NAD+ plays an important role in stabilization of the reagents and transition state.

  19. Tetracapsuloides bryosalmonae infection affects the expression of genes involved in cellular signal transduction and iron metabolism in the kidney of the brown trout Salmo trutta.

    Science.gov (United States)

    Kumar, Gokhlesh; Sarker, Subhodeep; Menanteau-Ledouble, Simon; El-Matbouli, Mansour

    2015-06-01

    Tetracapsuloides bryosalmonae is an enigmatic endoparasite which causes proliferative kidney disease in various species of salmonids in Europe and North America. The life cycle of the European strain of T. bryosalmonae generally completes in an invertebrate host freshwater bryozoan and vertebrate host brown trout (Salmo trutta) Linnaeus, 1758. Little is known about the gene expression in the kidney of brown trout during the developmental stages of T. bryosalmonae. In the present study, quantitative real-time PCR was applied to quantify the target genes of interest in the kidney of brown trout at different time points of T. bryosalmonae development. PCR primers specific for target genes were designed and optimized, and their gene expression levels were quantified in the cDNA kidney samples using SYBR Green Supermix. Expression of Rab GDP dissociation inhibitor beta, integral membrane protein 2B, NADH dehydrogenase 1 beta subcomplex subunit 6, and 26S protease regulatory subunit S10B were upregulated significantly in infected brown trout, while the expression of the ferritin M middle subunit was downregulated significantly. These results suggest that host genes involved in cellular signal transduction, proteasomal activities, including membrane transporters and cellular iron storage, are differentially upregulated or downregulated in the kidney of brown trout during parasite development. The gene expression pattern of infected renal tissue may support the development of intraluminal sporogonic stages of T. bryosalmonae in the renal tubular lumen of brown trout which may facilitate the release of viable parasite spores to transmit to the invertebrate host bryozoan. PMID:25786607

  20. Mechanism of Laser/light beam interaction at cellular and tissue level and study of the influential factors for the application of low level laser therapy

    OpenAIRE

    Khalid, Muhammad Zeeshan

    2016-01-01

    After the discovery of laser therapy it was realized it has useful application of wound healing and reduce pain, but due to the poor understanding of the mechanism and dose response this technique remained to be controversial for therapeutic applications. In order to understand the working and effectiveness different experiments were performed to determine the laser beam effect at the cellular and tissue level. This article discusses the mechanism of beam interaction at tissues and cellular l...

  1. Cellular graphene aerogel combines ultralow weight and high mechanical strength: A highly efficient reactor for catalytic hydrogenation

    Science.gov (United States)

    Zhang, Bingxing; Zhang, Jianling; Sang, Xinxin; Liu, Chengcheng; Luo, Tian; Peng, Li; Han, Buxing; Tan, Xiuniang; Ma, Xue; Wang, Dong; Zhao, Ning

    2016-05-01

    The construction of three-dimensional graphene aerogels (GAs) is of great importance owing to their outstanding properties for various applications. Up to now, the combination of ultralow weight and super mechanical strength for GA remains a great challenge. Here we demonstrate the fabrication of cellular GAs by a facile, easily controlled and versatile route, i.e. the chemical reduction of graphene oxide assemblies at oil-water interface under a mild condition (70 °C). The GA is ultralight (with density resilient because the walls of the cell closely pack in a highly ordered manner to maximize mechanical strength. The GA has been utilized as an appealing reactor for catalytic hydrogenation, which exhibited great advantages such as large oil absorption capability, exceptional catalytic activity, ease of product separation and high stability.

  2. Factors influencing the transfection efficiency and cellular uptake mechanisms of Pluronic P123-modified polypropyleneimine/pDNA polyplexes in multidrug resistant breast cancer cells.

    Science.gov (United States)

    Gu, Jijin; Hao, Junguo; Fang, Xiaoling; Sha, Xianyi

    2016-04-01

    Generally, the major obstacles for efficient gene delivery are cellular internalization and endosomal escape of nucleic acid such as plasmid DNA (pDNA) or small interfering RNA (siRNA). We previously developed Pluronic P123 modified polypropyleneimine (PPI)/pDNA (P123-PPI/pDNA) polyplexes as a gene delivery system. The results showed that P123-PPI/pDNA polyplexes revealed higher transfection efficiency than PPI/pDNA polyplexes in multidrug resistant breast cancer cells. As a continued effort, the present investigation on the factors influencing the transfection efficiency, cellular uptake mechanisms, and intracellular fate of P123-PPI/pDNA polyplexes is reported. The presence of P123 was the main factor influencing the transfection efficiency of P123-PPI/pDNA polyplexes in MCF-7/ADR cells, but other parameters, such as N/P ratio, FBS concentration, incubation time and temperature were important as well. The endocytic inhibitors against clathrin-mediated endocytosis (CME), caveolae-mediated endocytosis (CvME), and macropinocytosis were involved in the internalization to investigate their effects on the cellular uptake and transfection efficiency of P123-PPI/pDNA polyplexes in vitro. The data showed that the internalization of P123-PPI/pDNA polyplexes was obtained from both CME and CvME. Colocalization experiments with TRITC-transferrin (CME indicator), Alexa Fluor 555-CTB (CvME indicator), monoclonal anti-α-tubulin (microtubule indicator), and LysoTracker Green (Endosome/lysosome indicator) were carried out to confirm the internalization routes. The results showed that both CME and CvME played vital roles in the effective transfection of P123-PPI/pDNA polyplexes. Endosome/lysosome system and skeleton, including actin filament and microtubule, were necessary for the transportation after internalization. PMID:26741268

  3. The cellular prion protein PrP(c is involved in the proliferation of epithelial cells and in the distribution of junction-associated proteins.

    Directory of Open Access Journals (Sweden)

    Etienne Morel

    Full Text Available BACKGROUND: The physiological function of the ubiquitous cellular prion protein, PrP(c, is still under debate. It was essentially studied in nervous system, but poorly investigated in epithelial cells. We previously reported that PrP(c is targeted to cell-cell junctions of polarized epithelial cells, where it interacts with c-Src. METHODOLOGY/FINDINGS: We show here that, in cultured human enterocytes and in intestine in vivo, the mature PrP(c is differentially targeted either to the nucleus in dividing cells or to cell-cell contacts in polarized/differentiated cells. By proteomic analysis, we demonstrate that the junctional PrP(c interacts with cytoskeleton-associated proteins, such as gamma- and beta-actin, alpha-spectrin, annexin A2, and with the desmosome-associated proteins desmoglein, plakoglobin and desmoplakin. In addition, co-immunoprecipitation experiments revealed complexes associating PrP(c, desmoglein and c-Src in raft domains. Through siRNA strategy, we show that PrP(c is necessary to complete the process of epithelial cell proliferation and for the sub-cellular distribution of proteins involved in cell architecture and junctions. Moreover, analysis of the architecture of the intestinal epithelium of PrP(c knock-out mice revealed a net decrease in the size of desmosomal junctions and, without change in the amount of BrdU incorporation, a shortening of the length of intestinal villi. CONCLUSIONS/SIGNIFICANCE: From these results, PrP(c could be considered as a new partner involved in the balance between proliferation and polarization/differentiation in epithelial cells.

  4. 3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response.

    Science.gov (United States)

    Maiti, A; Small, W; Lewicki, J P; Weisgraber, T H; Duoss, E B; Chinn, S C; Pearson, M A; Spadaccini, C M; Maxwell, R S; Wilson, T S

    2016-01-01

    3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long-term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature-superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter's improved long-term stability and mechanical performance. PMID:27117858

  5. 3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response

    Science.gov (United States)

    Maiti, A.; Small, W.; Lewicki, J. P.; Weisgraber, T. H.; Duoss, E. B.; Chinn, S. C.; Pearson, M. A.; Spadaccini, C. M.; Maxwell, R. S.; Wilson, T. S.

    2016-04-01

    3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long-term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature-superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter’s improved long-term stability and mechanical performance.

  6. 3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response

    Science.gov (United States)

    Maiti, A.; Small, W.; Lewicki, J. P.; Weisgraber, T. H.; Duoss, E. B.; Chinn, S. C.; Pearson, M. A.; Spadaccini, C. M.; Maxwell, R. S.; Wilson, T. S.

    2016-01-01

    3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long-term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature-superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter’s improved long-term stability and mechanical performance. PMID:27117858

  7. Life under Climate Change Scenarios: Sea Urchins’ Cellular Mechanisms for Reproductive Success

    Directory of Open Access Journals (Sweden)

    Desislava Bögner

    2016-03-01

    Full Text Available Ocean Acidification (OA represents a major field of research and increased efforts are being made to elucidate its repercussions on biota. Species survival is ensured by successful reproduction, which may be threatened under detrimental environmental conditions, such as OA acting in synergy with other climate change related stressors. Achieving successful gametogenesis, fertilization, and the development of larvae into healthy juveniles and adults is crucial for the perpetuation of species and, thus, ecosystems’ functionality. The considerable vulnerability of the abovementioned developmental stages to the adverse conditions that future OA may impose has been shown in many species, including sea urchins which are commonly used due to the feasibility of their maintenance in captivity and the great amount of gametes that a mature adult is able to produce. In the present review, the latest knowledge about the impact of OA on various stages of the life cycle of sea urchins is summarized with remarks on the possible impact of other stressors. The cellular physiology of the gametes before, at fertilization and, at early development, is extensively described with a focus on the complex enzymatic machinery and the intracellular pH (pHi and Ca2+ homeostasis for their vulnerability when facing adverse conditions such as acidification, temperature variations, or hypoxia.

  8. The asymmetric self-assembly mechanism of adherens junctions: a cellular push–pull unit

    International Nuclear Information System (INIS)

    To form adherens junctions (AJ), cells first establish contact by sending out lamellipodia onto neighboring cells. We investigated the role of contacting cells in AJ assembly by studying an asymmetric AJ motif: finger-like AJ extending across the cell–cell interface. Using a cytoskeleton replica and immunofluorescence, we observed that actin bundles embedded in the lamellipodia are co-localized with stress fibers in the neighboring cell at the AJ. This suggests that donor lamellipodia present actin fingers, which are stabilized by acceptor lamellae via acto-myosin contractility. Indeed, we show that changes in actin network geometry promoted by Rac overexpression lead to corresponding changes in AJ morphology. Moreover, contractility inhibition and enhancement (via drugs or local traction) lead respectively to the disappearance and further growth of AJ fingers. Thus, we propose that receiving lamellae exert a local pull on AJ, promoting further polymerization of the donor actin bundles. In spite of different compositions, AJ and focal contacts both act as cellular mechanosensors

  9. Fundamental molecular mechanism for the cellular uptake of guanidinium-rich molecules.

    Science.gov (United States)

    Herce, Henry D; Garcia, Angel E; Cardoso, M Cristina

    2014-12-17

    Guanidinium-rich molecules, such as cell-penetrating peptides, efficiently enter living cells in a non-endocytic energy-independent manner and transport a wide range of cargos, including drugs and biomarkers. The mechanism by which these highly cationic molecules efficiently cross the hydrophobic barrier imposed by the plasma membrane remains a fundamental open question. Here, a combination of computational results and in vitro and live-cell experimental evidence reveals an efficient energy-independent translocation mechanism for arginine-rich molecules. This mechanism unveils the essential role of guanidinium groups and two universal cell components: fatty acids and the cell membrane pH gradient. Deprotonated fatty acids in contact with the cell exterior interact with guanidinium groups, leading to a transient membrane channel that facilitates the transport of arginine-rich peptides toward the cell interior. On the cytosolic side, the fatty acids become protonated, releasing the peptides and resealing the channel. This fundamental mechanism appears to be universal across cells from different species and kingdoms. PMID:25405895

  10. Cellular mechanisms underlying the laxative effect of flavonol naringenin on rat constipation model.

    Directory of Open Access Journals (Sweden)

    Zi-Huan Yang

    Full Text Available BACKGROUND & AIMS: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively. METHODS/PRINCIPAL FINDINGS: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC, which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid, but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid. Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl azacyclotridecan-2-imine-hydrochloride pretreatment reduced the naringenin-induced I(SC. In addition, significant inhibition of the naringenin-induced I(SC by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group. CONCLUSIONS: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation.

  11. 'Effective inefficiency': cellular control of protein trafficking as a mechanism of post-translational regulation.

    Science.gov (United States)

    Conn, P Michael; Janovick, Jo Ann; Brothers, Shaun P; Knollman, Paul E

    2006-07-01

    The great writer and polyglot, W Somerset Maugham said, 'I'll give you my opinion of the human race in a nutshell...their heart's in the right place, but their head is a thoroughly inefficient organ.' If his words are applied to trafficking of the human pituitary gonadotropin-releasing hormone receptor, it turns out that he was more right than he knew. Paradoxically, the inefficiency of receptor trafficking to the plasma membrane can bring regulatory advantages to cells. Understanding the mechanism by which cells recognize correctly folded proteins in health and disease opens doors to new therapeutic approaches and provides a more accurate view of mechanisms of normal cell function than is presently available. PMID:16837606

  12. Cellular Mechanisms of Tissue Fibrosis. 6. Purinergic signaling and response in fibroblasts and tissue fibrosis

    OpenAIRE

    Lu, David; Insel, Paul A.

    2013-01-01

    Tissue fibrosis occurs as a result of the dysregulation of extracellular matrix (ECM) synthesis. Tissue fibroblasts, resident cells responsible for the synthesis and turnover of ECM, are regulated via numerous hormonal and mechanical signals. The release of intracellular nucleotides and their resultant autocrine/paracrine signaling have been shown to play key roles in the homeostatic maintenance of tissue remodeling and in fibrotic response post-injury. Extracellular nucleotides signal throug...

  13. Chinese Medicines Induce Cell Death: The Molecular and Cellular Mechanisms for Cancer Therapy

    OpenAIRE

    Xuanbin Wang; Yibin Feng; Ning Wang; Fan Cheung; Hor Yue Tan; Sen Zhong; Charlie Li; Seiichi Kobayashi

    2014-01-01

    Chinese medicines have long history in treating cancer. With the growing scientific evidence of biomedical researches and clinical trials in cancer therapy, they are increasingly accepted as a complementary and alternative treatment. One of the mechanisms is to induce cancer cell death. Aim. To comprehensively review the publications concerning cancer cell death induced by Chinese medicines in recent years and provide insights on anticancer drug discovery from Chinese medicines. Materials and...

  14. Molecular, Cellular, and Structural Mechanisms of Cocaine Addiction: A Key Role for MicroRNAs

    OpenAIRE

    Jonkman, Sietse; Kenny, Paul J.

    2012-01-01

    The rewarding properties of cocaine play a key role in establishing and maintaining the drug-taking habit. However, as exposure to cocaine increases, drug use can transition from controlled to compulsive. Importantly, very little is known about the neurobiological mechanisms that control this switch in drug use that defines addiction. MicroRNAs (miRNAs) are small non-protein coding RNA transcripts that can regulate the expression of messenger RNAs that code for proteins. Because of their high...

  15. Fundamental Molecular Mechanism for the Cellular Uptake of Guanidinium-Rich Molecules

    OpenAIRE

    Herce, Henry D.; Garcia, Angel E.; Cardoso, M. Cristina

    2014-01-01

    Guanidinium-rich molecules, such as cell-penetrating peptides, efficiently enter living cells in a non-endocytic energy-independent manner and transport a wide range of cargos, including drugs and biomarkers. The mechanism by which these highly cationic molecules efficiently cross the hydrophobic barrier imposed by the plasma membrane remains a fundamental open question. Here, a combination of computational results and in vitro and live-cell experimental evidence reveals an efficient energy-i...

  16. Phytoplankton calcification as an effective mechanism to alleviate cellular calcium poisoning

    OpenAIRE

    Müller, M. N.; Barcelos e Ramos, J.; Schulz, K. G.; U. Riebesell; J. Kaźmierczak; Gallo, F.; Mackinder, L.; Li, Y; P. N. Nesterenko; T. W. Trull; Hallegraeff, G.M.

    2015-01-01

    Marine phytoplankton have developed the remarkable ability to tightly regulate the concentration of free calcium ions in the intracellular cytosol at a level of ~ 0.1 μmol L−1 in the presence of seawater Ca2+ concentrations of 10 mmol L−1. The low cytosolic calcium ion concentration is of utmost importance for proper cell signalling function. While the regulatory mechanisms responsible for the tight control of intracellular Ca2+ concentration are not completely understood, ...

  17. Phytoplankton calcification as an effective mechanism to prevent cellular calcium poisoning

    OpenAIRE

    Müller, M. N.; J. Barcelos e Ramos; Schulz, K. G.; U. Riebesell; J. Kaźmierczak; Gallo, F.; Mackinder, L.; Y. Li; P. N. Nesterenko; T. W. Trull; Hallegraeff, G.M.

    2015-01-01

    Marine phytoplankton has developed the remarkable ability to tightly regulate the concentration of free calcium ions in the intracellular cytosol at a level of ~ 0.1 μmol L−1 in the presence of seawater Ca2+ concentrations of 10 mmol L−1. The low cytosolic calcium ion concentration is of utmost importance for proper cell signalling function. While the regulatory mechanisms responsible for the tight control of intracellular Ca2+ concentration are not completely understood, ...

  18. 1. Morphological Implication on Cellular Response to Mechanical Stress in Bone.

    Science.gov (United States)

    Amizuka, Norio

    2016-08-01

    In bone, there are 3 distinct cell types: an osteoblast, a bone forming cell; an osteocyte embedded in bone matrix as a consequence of being differentiated from an osteoblast; and an osteoclast, a multinucleated giant cell responsible for bone resorption. Bone is always remodeled by replacing old bone with new bone (bone remodeling), by which bone can maintain its stiffness and flexibility. However, in an osteoporotic state, the disrupted balance between bone resorption and formation results in not only markedly reduced bone mass, but also in disorganized geometry of trabecules, which can often give rise to a bone fracture. Osteocytes located in their lacunae insert their fine cytoplasmic processes into narrow passageways referred to as osteocytic canaliculi. Neighboring osteocytes connect to each other by means of a gap junction in their cytoplasmic processes. Therefore, osteocytes and their lacunae/canaliculi appear to form functional syncytium called osteocytic lacunar canalicular system (OLCS). The geometrical distribution of OLCS is poorly arranged in immature bone, while it appears well-arranged distribution in mature bone (cortical bone), in which molecular transports and sensing mechanical stress seems to be efficient, and therefore, may be able to respond to mechanical stress. In this seminar, I will introduce our recent findings on the morphology and function of OLCS which may respond to mechanical stress. PMID:27441762

  19. (Some cellular mechanisms influencing the transcription of human endogenous retrovirus, HERV-Fc1.

    Directory of Open Access Journals (Sweden)

    Magdalena Janina Laska

    Full Text Available DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. DNA methylation is considered an important mechanism for silencing of retroelements in the mammalian genome. However, the methylation of human endogenous retroviruses (HERVs is not well investigated. The aim of this study was to investigate the transcriptional potential of HERV-Fc1 proviral 5'LTR in more detail, and examined the specific influence of CpG methylation on this LTR in number of cell lines. Specifically, the role of demethylating chemicals e.g. 5-aza-2' deoxycytidine and Trichostatin-A, in inducing or reactivating expression of HERV-Fc1 specific sequences and the mechanisms were investigated. In our present study, 5-aza-dC is shown to be a powerful inducer of HERV-Fc1, and at the same time it strongly inhibits methylation of DNA. Treatment with this demethylating agent 5-aza-dC, results in significantly increased levels of HERV-Fc1 expression in cells previously not expressing HERV-Fc1, or with a very low expression level. The extent of expression of HERV-Fc1 RNAs precisely correlates with the apparent extent of demethylation of the related DNA sequences. In conclusion, the results suggest that inhibition of DNA methylation/histone deacetylase can interfere with gene silencing mechanisms affecting HERV-Fc1 expression in human cells.

  20. Energy cost and putative benefits of cellular mechanisms modulating buoyancy in aflagellate marine phytoplankton.

    Science.gov (United States)

    Lavoie, Michel; Raven, John A; Levasseur, Maurice

    2016-04-01

    Little information is available on the energetics of buoyancy modulation in aflagellate phytoplankton, which comprises the majority of autotrophic cells found in the ocean. Here, we computed for three aflagellate species of marine phytoplankton (Emiliania huxleyi, Thalassiosira pseudonana, and Ethmodiscus rex) the theoretical minimum energy cost as photons absorbed and nitrogen resource required of the key physiological mechanisms (i.e., replacement of quaternary ammonium by dimethyl-sulfoniopropionate, storage of polysaccharides, and cell wall biosynthesis) affecting the cell's vertical movement as a function of nitrogen (N) availability. These energy costs were also normalized to the capacity of each buoyancy mechanism to modulate sinking or rising rates based on Stokes' law. The three physiological mechanisms could act as ballast in the three species tested in conditions of low N availability at a low fraction (<12%) of the total photon energy cost for growth. Cell wall formation in E. huxleyi was the least costly ballast strategy, whereas in T. pseudonana, the photon energy cost of the three ballast strategies was similar. In E. rex, carbohydrate storage and mobilization appear to be energetically cheaper than modulations in organic solute synthesis to achieve vertical migration. This supports the carbohydrate-ballast strategy for vertical migration for this species, but argues against the theory of replacement of low- or high-density organic solutes. This study brings new insights into the energy cost and potential selective advantages of several strategies modulating the buoyancy of aflagellate marine phytoplankton. PMID:27037589

  1. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Directory of Open Access Journals (Sweden)

    Ana-Maria Florea

    2011-03-01

    Full Text Available Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs and might provide new therapeutic strategies and reduce side effects.

  2. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Energy Technology Data Exchange (ETDEWEB)

    Florea, Ana-Maria [Department of Neuropathology, Heinrich-Heine University, Düsseldorf (Germany); Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha (Qatar)

    2011-03-15

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

  3. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

    International Nuclear Information System (INIS)

    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

  4. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

    Energy Technology Data Exchange (ETDEWEB)

    Latham, Antony M.; Odell, Adam F. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Mughal, Nadeem A. [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Issitt, Theo; Ulyatt, Clare; Walker, John H. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Homer-Vanniasinkam, Shervanthi [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Ponnambalam, Sreenivasan, E-mail: s.ponnambalam@leeds.ac.uk [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom)

    2012-11-01

    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: Black-Right-Pointing-Pointer Endothelial cells mount a stress response under conditions of low serum. Black

  5. Cellular Mechanism of Newly Synthesized Indoledione Derivative-induced Immunological Death of Tumor Cell

    OpenAIRE

    Oh, Su-Jin; Ryu, Chung-Kyu; Baek, So-Young; Lee, Hyunah

    2011-01-01

    Background EY-6 is one of the newly synthesized indoledione derivatives to induce tumor cell-specific cell death. In this study, we investigated the mechanism of immunological death induced by EY-6 at mouse colon cancer cell as well as at the normal immune cell represented by dendritic cell. Methods C57BL/6 mouse syngeneic colon cancer cell MC38 was treated with EY-6, and analyzed by MTT for viability test, flow cytometry for confirming surface expressing molecules and ELISA for detection of ...

  6. Physical mechanisms involved in grooved flat heat pipes: experimental and numerical analyses

    OpenAIRE

    Lips, S.; Lefevre, F.; Bonjour, J.

    2011-01-01

    An experimental database, obtained with flat plate heat pipes (FPHP) with longitudinal grooves is presented. The capillary pressure measured by confocal microscopy and the temperature field in the wall are presented in various experimental conditions (vapour space thickness, filing ratio, heat transfer rate, tilt angle, fluid). Coupled hydrodynamic and thermal models are developed. Experimental results are compared to results of numerical models. Physical mechanisms involved in grooved heat p...

  7. Mechanisms of Cellular Membrane Reorganization to Support Hepatitis C Virus Replication.

    Science.gov (United States)

    Wang, Hongliang; Tai, Andrew W

    2016-01-01

    Like all positive-sense RNA viruses, hepatitis C virus (HCV) induces host membrane alterations for its replication termed the membranous web (MW). Assembling replication factors at a membranous structure might facilitate the processes necessary for genome replication and packaging and shield viral components from host innate immune defenses. The biogenesis of the HCV MW is a complex process involving a concerted effort of HCV nonstructural proteins with a growing list of host factors. Although a comprehensive understanding of MW formation is still missing, a number of important viral and host determinants have been identified. This review will summarize the recent studies that have led to our current knowledge of the role of viral and host factors in the biogenesis of the MWs and discuss how HCV uses this specialized membrane structure for its replication. PMID:27213428

  8. Mechanisms of Cellular Membrane Reorganization to Support Hepatitis C Virus Replication

    Science.gov (United States)

    Wang, Hongliang; Tai, Andrew W.

    2016-01-01

    Like all positive-sense RNA viruses, hepatitis C virus (HCV) induces host membrane alterations for its replication termed the membranous web (MW). Assembling replication factors at a membranous structure might facilitate the processes necessary for genome replication and packaging and shield viral components from host innate immune defenses. The biogenesis of the HCV MW is a complex process involving a concerted effort of HCV nonstructural proteins with a growing list of host factors. Although a comprehensive understanding of MW formation is still missing, a number of important viral and host determinants have been identified. This review will summarize the recent studies that have led to our current knowledge of the role of viral and host factors in the biogenesis of the MWs and discuss how HCV uses this specialized membrane structure for its replication. PMID:27213428

  9. Chinese Medicines Induce Cell Death: The Molecular and Cellular Mechanisms for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Xuanbin Wang

    2014-01-01

    Full Text Available Chinese medicines have long history in treating cancer. With the growing scientific evidence of biomedical researches and clinical trials in cancer therapy, they are increasingly accepted as a complementary and alternative treatment. One of the mechanisms is to induce cancer cell death. Aim. To comprehensively review the publications concerning cancer cell death induced by Chinese medicines in recent years and provide insights on anticancer drug discovery from Chinese medicines. Materials and Methods. Chinese medicines (including Chinese medicinal herbs, animal parts, and minerals were used in the study. The key words including “cancer”, “cell death”, “apoptosis”, “autophagy,” “necrosis,” and “Chinese medicine” were used in retrieval of related information from PubMed and other databases. Results. The cell death induced by Chinese medicines is described as apoptotic, autophagic, or necrotic cell death and other types with an emphasis on their mechanisms of anticancer action. The relationship among different types of cell death induced by Chinese medicines is critically reviewed and discussed. Conclusions. This review summarizes that CMs treatment could induce multiple pathways leading to cancer cell death, in which apoptosis is the dominant type. To apply these preclinical researches to clinic application will be a key issue in the future.

  10. The Effect of Structural Design on Mechanical Properties and Cellular Response of Additive Manufactured Titanium Scaffolds

    Directory of Open Access Journals (Sweden)

    Jan Wieding

    2012-08-01

    Full Text Available Restoration of segmental defects in long bones remains a challenging task in orthopedic surgery. Although autologous bone is still the ‘Gold Standard’ because of its high biocompatibility, it has nevertheless been associated with several disadvantages. Consequently, artificial materials, such as calcium phosphate and titanium, have been considered for the treatment of bone defects. In the present study, the mechanical properties of three different scaffold designs were investigated. The scaffolds were made of titanium alloy (Ti6Al4V, fabricated by means of an additive manufacturing process with defined pore geometry and porosities of approximately 70%. Two scaffolds exhibited rectangular struts, orientated in the direction of loading. The struts for the third scaffold were orientated diagonal to the load direction, and featured a circular cross-section. Material properties were calculated from stress-strain relationships under axial compression testing. In vitro cell testing was undertaken with human osteoblasts on scaffolds fabricated using the same manufacturing process. Although the scaffolds exhibited different strut geometry, the mechanical properties of ultimate compressive strength were similar (145–164 MPa and in the range of human cortical bone. Test results for elastic modulus revealed values between 3.7 and 6.7 GPa. In vitro testing demonstrated proliferation and spreading of bone cells on the scaffold surface.

  11. The cytotoxicity of polycationic iron oxide nanoparticles: Common endpoint assays and alternative approaches for improved understanding of cellular response mechanism

    Directory of Open Access Journals (Sweden)

    Hoskins Clare

    2012-04-01

    Our findings indicate that common in vitro cell endpoint assays do not give detailed and complete information on cellular state and it is essential to explore novel approaches and carry out more in-depth studies to elucidate cellular response mechanism to magnetic nanoparticles.

  12. Use of static lung mechanics to identify early pulmonary involvement in patients with ankylosing spondylitis.

    Directory of Open Access Journals (Sweden)

    Aggarwal A

    2001-04-01

    Full Text Available AIM: To assess if a detailed analysis of lung mechanics could help in early recognition of pulmonary abnormalities in patients with ankylosing spondylitis. METHODS: Static pulmonary mechanics were studied in 17 patients (16 men and one woman of ankylosing spondylitis with no obvious clinical or radiological evidence of pulmonary involvement. Lung pressure-volume relationship was generated using a whole body plethysmograph, and a monoexponential equation fitted to this data. RESULTS: Total lung capacity (TLC was reduced in one (5.9% and static lung compliance (Cst in nine (52.9% patients. Four (23.5% patients had normal TLC, yet Cst and shape constant (K were reduced. Five (29.4% patients had reduced TLC and Cst; four of them had low K. One (5.9% patient had normal TLC but elevated Cst and K. CONCLUSIONS: Pulmonary involvement in patients with ankylosing spondylitis is probably diffuse and begins much earlier than generally presumed. Evaluation of static lung mechanics can identify pulmonary involvement early in the course of disease in several of these patients.

  13. Effects and mechanisms of 3α,5α,-THP on emotion, motivation, and reward functions involving pregnane xenobiotic receptor

    Directory of Open Access Journals (Sweden)

    Cheryl A Frye

    2012-01-01

    Full Text Available Progestogens [progesterone (P4 and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mechanisms, and sources of neurosteroids have challenged traditional dogma about steroid action. How the P4 metabolite and neurosteroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP, influences cellular functions and behavioral processes involved in emotion/affect, motivation, and reward, is the focus of the present review. To further understand these processes, we have utilized an animal model assessing the effects, mechanisms, and sources of 3α,5α-THP. In the ventral tegmental area (VTA, 3α,5α-THP has actions to facilitate affective, and motivated, social behaviors through non-traditional targets, such as GABA, glutamate, and dopamine receptors. 3α,5α-THP levels in the midbrain VTA both facilitate, and/or are enhanced by, affective and social behavior. The pregnane xenobiotic receptor (PXR mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. The role of PXR to influence 3α,5α-THP production from central biosynthesis, and/or metabolism of peripheral P4, in the VTA, as well as its role to facilitate, or be increased by, affective/social behaviors is under investigation. Investigating novel behavioral functions of 3α,5α-THP extends our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate affect and motivated processes, such as those important for stress regulation and neuropsychiatric disorders (anxiety, depression, schizophrenia, drug dependence. Thus, further understanding of 3α,5α-THP’s role and mechanisms to enhance affective and motivated

  14. Morphogenesis of the lymphatic vasculature: A focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels.

    Science.gov (United States)

    Kazenwadel, Jan; Harvey, Natasha L

    2016-03-01

    Lymphatic vessels serve crucial roles in the regulation of tissue fluid homeostasis, dietary lipid absorption and immune cell trafficking. Defects in lymphatic vessel morphogenesis and function have been associated with lymphedema, obesity, hypertension and tumour metastasis. Morphogenetic events important for construction of the lymphatic vasculature during development include the specification and emergence of lymphatic endothelial progenitor cells, their differentiation and assembly into interconnected vessels and vascular remodeling, ultimately giving rise to a functional vascular network. Despite the embryonic origins of lymphatic endothelial progenitor cells being long debated, work performed over the last decade had overwhelmingly supported at least a great majority of progenitor cells arising from the venous vasculature. Here, we review the most recent advances in the field of lymphatic vessel morphogenesis, with a focus on studies that have identified novel sources of embryonic lymphatic endothelial progenitor cells, together with the cellular mechanisms by which lymphatic vessels are initially assembled. PMID:26228815

  15. Mechanical Properties of 3-D Printed Cellular Foams with triangular cells

    Science.gov (United States)

    Bunga, Pratap Kumar

    In the present work, poly lactic acid (PLA) is used as a model system to investigate the mechanical behavior of 3-D printed foams with triangular cells. Solid PLA tension and compression specimens and foams made of PLA were fabricated using fused deposition 3-D printing technique. The solid PLA tension specimens were characterized for their densities and found to be about 10% lower in density as compared to their bulk counter parts. The triangular foams had a relative density of about 64%. The relationships between the structure of the foams and its deformation behavior under compression along two in-plane directions were characterized. Furthermore, simple finite element models were developed to understand the observed deformation behavior of triangular foams.

  16. Auxin apical control of the auxin polar transport and its oscillation - a suggested cellular transduction mechanism

    Directory of Open Access Journals (Sweden)

    Tomasz J. Wodzicki

    2014-02-01

    Full Text Available The proposed hypothesis concerns the transduction of auxin molecular signals arriving from the apoplast at the plasma membrane or recognized by the proteineous receptors of the responding cell, to the concentration gradients oscillating in the supracellular space, associated usually with the specific plant growth and differentiation. Acting as an agonist from outside the target cell auxin stimulates in this cell: (1 the liberation of auxin from the cytosolic pool of its conjugates directly into the basipetal efflux; (2 the synthesis of new auxin which restores the cytosolic reserve of auxin conjugates. The functioning of such a system may be effective in a series of processes initiated by the changing concentration of cytosolic calcium. The hypothesis suggests a molecular mechanism for the development and effective operation of the morphogenetic field in the supracellular space of the plant body, such as the field resulting from auxin waves discovered in cambium.

  17. Cellular Microcultures: Programming Mechanical and Physicochemical Properties of 3D Hydrogel Cellular Microcultures via Direct Ink Writing (Adv. Healthcare Mater. 9/2016).

    Science.gov (United States)

    McCracken, Joselle M; Badea, Adina; Kandel, Mikhail E; Gladman, A Sydney; Wetzel, David J; Popescu, Gabriel; Lewis, Jennifer A; Nuzzo, Ralph G

    2016-05-01

    R. Nuzzo and co-workers show on page 1025 how compositional differences in hydrogels are used to tune their cellular compliance by controlling their polymer mesh properties and subsequent uptake of the protein poly-l-lysine (green spheres in circled inset). The cover image shows pyramid micro-scaffolds prepared using direct ink writing (DIW) that differentially direct fibroblast and preosteoblast growth in 3D, depending on cell motility and surface treatment. PMID:27166616

  18. Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu.

    Science.gov (United States)

    Cooley, S; Burns, L J; Repka, T; Miller, J S

    1999-10-01

    Treatment of advanced breast cancer with autologous stem cell transplantation is limited by a high probability of disease relapse. In clinical trials, interleukin 2 (IL-2) alone can expand natural killer (NK) cells in vivo and increase their cytotoxic activity against breast cancer cell lines, but this increase is modest. Understanding the mechanisms that mediate NK cell lysis of breast cancer targets may lead to improvements of current immunotherapy strategies. NK cells from normal donors or patients receiving subcutaneous IL-2 were tested in cytotoxicity assays against five breast cancer cell lines. The role of adhesion molecules and antibodies that interact through Fc receptors on NK cells was explored. NK cell lysis of breast cancer targets is variable and is partially dependent on recognition through ICAM-1 and CD18. While blocking CD2 slightly decreased cytotoxicity, contrary to expectations, an antibody against CD58 (the ligand for CD2), failed to block killing and instead mediated an increased cytotoxicity that correlated with target density of CD58. The CD58 antibody-enhanced killing was dependent not only on FcRgammaIII but also on CD2 and ICAM-1/CD18. To further elucidate the mechanism of this CD58 antibody-dependent cellular cytotoxicity (ADCC), another antibody was tested. Trastuzumab (Herceptin), a humanized antibody against HER2/neu, mediated potent ADCC against all the HER2/neu positive breast cancer targets. Unlike CD58 antibody-mediated ADCC, Herceptin ADCC was minimally affected by blocking antibodies to CD2 or ICAM-1/CD18, which suggests a different mechanism of action. This study shows that multiple mechanisms are involved in NK cell lysis of breast cancer targets, that none of the targets are inherently resistant to killing, and that two distinct mechanisms of ADCC can target immunotherapy to breast cancer cells. PMID:10517495

  19. Cellular uptake of the antitumor agent Dp44mT occurs via a carrier/receptor-mediated mechanism.

    Science.gov (United States)

    Merlot, Angelica M; Pantarat, Namfon; Menezes, Sharleen V; Sahni, Sumit; Richardson, Des R; Kalinowski, Danuta S

    2013-12-01

    The chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) shows potent and selective anticancer and antimetastatic activity. However, the mechanism by which it is initially transported into cells to induce cytotoxicity is unknown. Hence, the current investigation examined the cellular uptake of ¹⁴C-Dp44mT relative to two structurally related ligands, namely the aroylhydrazone ¹⁴C-pyridoxal isonicotinoyl hydrazone (¹⁴C-PIH) and the thiosemicarbazone (¹⁴C-2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (¹⁴C-Bp4eT). In marked contrast to the cellular uptake of ¹⁴C-PIH and ¹⁴C-Bp4eT, which were linear as a function of concentration, ¹⁴C-Dp44mT uptake was saturable using SK-N-MC neuroepithelioma cells (Bmax, 4.28 × 10⁷ molecules of chelator/cell; and Kd, 2.45 μM). Together with the fact that ¹⁴C-Dp44mT uptake was temperature-dependent and significantly (P complex [Fe(¹⁴C-Dp44mT)₂] was not saturable as a function of concentration and was much greater than the ligand alone, indicating an alternate mode of transport. Studies examining the tissue distribution of ¹⁴C-Dp44mT injected intravenously into a mouse tumor model demonstrated the ¹⁴C label was primarily identified in the excretory system. Collectively, these findings examining the mechanism of Dp44mT uptake and its distribution and excretion have clinical implications for its bioavailability and uptake in vivo. PMID:24085840

  20. Sesquiterpene lactones: Mechanism of antineoplastic activity; relationship of cellular glutathione to cytotoxicity; and disposition

    International Nuclear Information System (INIS)

    Helenalin, a sesquiterpene lactone, inhibited the growth of P388 lymphocytic and L1210 lymphoid leukemia, and Ehrlich ascites and KB carcinoma cells. The L1210 leukemia cells were most sensitive to the cytotoxic effects of helenalin. Helenalin's antineoplastic effects were due to inhibition of DNA synthesis by suppressing the activities of enzymes involved in this biosynthetic pathway; i.e., IMP dehydrogenase, ribonucleoside diphosphate reductase, thioredoxin complex, GSH disulfide oxidoreductase and DNA polymerase α activities. The relationship of reduced glutathione (GSH) to the cytotoxic effects of helanalin was evaluated. L1210 cells, which were more sensitive to helenalin's toxicity, contained lower basal concentrations of GSH. Helenalin decreased the concentration of reduced glutathione in both L1210 and P388 leukemia cells. Concurrent administration of helanalin with agents reported to raise GSH concentrations did not substantially effect GSH levels, nor were survival times of tumor-bearing mice enhanced. Following intraperitoneal administration of 3H-plenolin, no radioactive drug and/or metabolite was sequestered in the organs of BDF1 mice. Approximately 50% of 3H-plenolin and/or its metabolites were eliminated via urine while lesser amounts of radioactive drug and/or metabolites were eliminated in the feces

  1. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low

    Energy Technology Data Exchange (ETDEWEB)

    Kadhim, Munira A

    2012-08-22

    The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program. To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e. less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these "non-targeted responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate non-targeted effects of ionizing radiation with a focus on the induction of genomic instability (GI) in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/CaH and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition in these models on genomic instability. We will specifically focus on the effects of low doses of low LET radiation, down to the dose of 10mGy (0.01Gy) X-rays. Using conventional X-ray and we will be able to assess the role of genetic variation under various conditions at a range of doses down to the very low dose of 0.01Gy. Irradiations will be carried out using facilities in routine operation for such studies. Mechanistic studies of instability in different cell

  2. Linking Cellular Mechanisms to Behavior: Entorhinal Persistent Spiking and Membrane Potential Oscillations May Underlie Path Integration, Grid Cell Firing, and Episodic Memory

    Directory of Open Access Journals (Sweden)

    Michael E. Hasselmo

    2008-01-01

    Full Text Available The entorhinal cortex plays an important role in spatial memory and episodic memory functions. These functions may result from cellular mechanisms for integration of the afferent input to entorhinal cortex. This article reviews physiological data on persistent spiking and membrane potential oscillations in entorhinal cortex then presents models showing how both these cellular mechanisms could contribute to properties observed during unit recording, including grid cell firing, and how they could underlie behavioural functions including path integration. The interaction of oscillations and persistent firing could contribute to encoding and retrieval of trajectories through space and time as a mechanism relevant to episodic memory.

  3. Application of cellular mechanisms to growth and development of food producing animals.

    Science.gov (United States)

    Chung, K Y; Johnson, B J

    2008-04-01

    Postnatal skeletal muscle growth is a result of hypertrophy of existing skeletal muscle fibers in food producing animals. Accumulation of additional nuclei, as a source of DNA, to the multinucleated skeletal muscle fiber aids in fiber hypertrophy during periods of rapid skeletal muscle growth. Muscle satellite cells are recognized as the source of nuclei to support muscle hypertrophy. Exogenous growth-enhancing compounds have been used to modulate growth rate and efficiency in meat animals for over a half century. In cattle, these compounds enhance efficiency of growth by preferentially stimulating skeletal muscle growth compared with adipose tissue. There are 2 main classes of compounds approved for use in cattle in the United States, anabolic steroids and beta-adrenergic agonists (beta-AA). Administration of both trenbolone acetate and estradiol-17beta, as implants, increased carcass protein accumulation 8 to 10% in yearling steers. Muscle satellite cells isolated from steers implanted with trenbolone acetate/ estradiol-17beta had a shorter lag phase in culture compared with satellite cells isolated from control steers. Collectively, these data indicate that activation, increased proliferation, and subsequent fusion of satellite cells in muscles of implanted cattle may be an important mechanism by which anabolic steroids enhance muscle hypertrophy. Oral administration of beta-AA to ruminants does not alter DNA accumulation in skeletal muscle over a typical feeding period (28 to 42 d). Enhanced muscle hypertrophy observed due to beta-AA feeding occurs by direct, receptor-mediated changes in protein synthesis and degradation rates of skeletal muscle tissue. Proper timing of anabolic steroid administration when coupled with beta-AA feeding could result in a synergistic response in skeletal muscle growth due to the effects of anabolic steroids at increasing satellite cell activity, which then can support the rapid hypertrophic changes of the muscle fiber when exposed

  4. Cellular mechanism underlying formaldehyde-stimulated Cl- secretion in rat airway epithelium.

    Directory of Open Access Journals (Sweden)

    Yu-Li Luo

    Full Text Available BACKGROUND: Recent studies suggest that formaldehyde (FA could be synthesized endogeneously and transient receptor potential (TRP channel might be the sensor of FA. However, the physiological significance is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: The present study investigated the FA induced epithelial Cl(- secretion by activation of TRPV-1 channel located in the nerve ending fiber. Exogenously applied FA induced an increase of I(SC in intact rat trachea tissue but not in the primary cultured epithelial cells. Western blot and immunofluorescence analysis identified TRPV-1 expression in rat tracheal nerve ending. Capsazepine (CAZ, a TRPV-1 specific antagonist significantly blocked the I(SC induced by FA. The TRPV-1 agonist capsaicin (Cap induced an increase of I(SC, which was similar to the I(SC induced by FA. L-703606, an NK-1 specific inhibitor and propranolol, an adrenalin β receptor inhibitor significantly abolished the I(SC induced by FA or Cap. In the ion substitute analysis, FA could not induce I(SC in the absence of extracelluar Cl(-. The I(SC induced by FA could be blocked by the non-specific Cl(- channel inhibitor DPC and the CFTR specific inhibitor CFTR(i-172, but not by the Ca(2+-activated Cl(- channel inhibitor DIDS. Furthermore, both forskolin, an agonist of adenylate cyclase (AC and MDL-12330A, an antagonist of AC could block FA-induced I(SC. CONCLUSION: Our results suggest that FA-induced epithelial I(SC response is mediated by nerve, involving the activation of TRPV-1 and release of adrenalin as well as substance P.

  5. Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

    Energy Technology Data Exchange (ETDEWEB)

    Brenes, J.C. [Experimental and Physiological Psychology, Philipps-University of Marburg, Marburg (Germany); Broiz, A.C.; Bassi, G.S. [Instituto de Neurociências e Comportamento, Campus USP, Ribeirão Preto, SP (Brazil); Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Schwarting, R.K.W. [Experimental and Physiological Psychology, Philipps-University of Marburg, Marburg (Germany); Brandão, M.L. [Instituto de Neurociências e Comportamento, Campus USP, Ribeirão Preto, SP (Brazil); Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2012-03-09

    Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by {sub Y}-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

  6. Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

    International Nuclear Information System (INIS)

    Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by Y-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG

  7. Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

    Directory of Open Access Journals (Sweden)

    J.C. Brenes

    2012-04-01

    Full Text Available Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG and inferior colliculus (IC, produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing. These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 μL, a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

  8. Uncoupling of oxidative phosphorylation by curcumin: Implication of its cellular mechanism of action

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Han Wern; Lim, Hwee Ying [Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260 (Singapore); Wong, Kim Ping, E-mail: bchsitkp@nus.edu.sg [Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260 (Singapore)

    2009-11-06

    Curcumin is a phytochemical isolated from the rhizome of turmeric. Recent reports have shown curcumin to have antioxidant, anti-inflammatory and anti-tumor properties as well as affecting the 5'-AMP activated protein kinase (AMPK), mTOR and STAT-3 signaling pathways. We provide evidence that curcumin acts as an uncoupler. Well-established biochemical techniques were performed on isolated rat liver mitochondria in measuring oxygen consumption, F{sub 0}F{sub 1}-ATPase activity and ATP biosynthesis. Curcumin displays all the characteristics typical of classical uncouplers like fccP and 2,4-dinitrophenol. In addition, at concentrations higher than 50 {mu}M, curcumin was found to inhibit mitochondrial respiration which is a characteristic feature of inhibitory uncouplers. As a protonophoric uncoupler and as an activator of F{sub 0}F{sub 1}-ATPase, curcumin causes a decrease in ATP biosynthesis in rat liver mitochondria. The resulting change in ATP:AMP could disrupt the phosphorylation status of the cell; this provides a possible mechanism for its activation of AMPK and its downstream mTOR and STAT-3 signaling.

  9. Uncoupling of oxidative phosphorylation by curcumin: Implication of its cellular mechanism of action

    International Nuclear Information System (INIS)

    Curcumin is a phytochemical isolated from the rhizome of turmeric. Recent reports have shown curcumin to have antioxidant, anti-inflammatory and anti-tumor properties as well as affecting the 5'-AMP activated protein kinase (AMPK), mTOR and STAT-3 signaling pathways. We provide evidence that curcumin acts as an uncoupler. Well-established biochemical techniques were performed on isolated rat liver mitochondria in measuring oxygen consumption, F0F1-ATPase activity and ATP biosynthesis. Curcumin displays all the characteristics typical of classical uncouplers like fccP and 2,4-dinitrophenol. In addition, at concentrations higher than 50 μM, curcumin was found to inhibit mitochondrial respiration which is a characteristic feature of inhibitory uncouplers. As a protonophoric uncoupler and as an activator of F0F1-ATPase, curcumin causes a decrease in ATP biosynthesis in rat liver mitochondria. The resulting change in ATP:AMP could disrupt the phosphorylation status of the cell; this provides a possible mechanism for its activation of AMPK and its downstream mTOR and STAT-3 signaling.

  10. Peripheral and Central Mechanisms Involved in the Hormonal Control of Male and Female Reproduction.

    Science.gov (United States)

    Rudolph, L M; Bentley, G E; Calandra, R S; Paredes, A H; Tesone, M; Wu, T J; Micevych, P E

    2016-07-01

    Reproduction involves the integration of hormonal signals acting across multiple systems to generate a synchronised physiological output. A critical component of reproduction is the luteinising hormone (LH) surge, which is mediated by oestradiol (E2 ) and neuroprogesterone interacting to stimulate kisspeptin release in the rostral periventricular nucleus of the third ventricle in rats. Recent evidence indicates the involvement of both classical and membrane E2 and progesterone signalling in this pathway. A metabolite of gonadotrophin-releasing hormone (GnRH), GnRH-(1-5), has been shown to stimulate GnRH expression and secretion, and has a role in the regulation of lordosis. Additionally, gonadotrophin release-inhibitory hormone (GnIH) projects to and influences the activity of GnRH neurones in birds. Stress-induced changes in GnIH have been shown to alter breeding behaviour in birds, demonstrating another mechanism for the molecular control of reproduction. Peripherally, paracrine and autocrine actions within the gonad have been suggested as therapeutic targets for infertility in both males and females. Dysfunction of testicular prostaglandin synthesis is a possible cause of idiopathic male infertility. Indeed, local production of melatonin and corticotrophin-releasing hormone could influence spermatogenesis via immune pathways in the gonad. In females, vascular endothelial growth factor A has been implicated in an angiogenic process that mediates development of the corpus luteum and thus fertility via the Notch signalling pathway. Age-induced decreases in fertility involve ovarian kisspeptin and its regulation of ovarian sympathetic innervation. Finally, morphological changes in the arcuate nucleus of the hypothalamus influence female sexual receptivity in rats. The processes mediating these morphological changes have been shown to involve the rapid effects of E2 controlling synaptogenesis in this hypothalamic nucleus. In summary, this review highlights new

  11. Involvement of three mechanisms in the alteration of cytokine responses by sodium methyldithiocarbamate

    International Nuclear Information System (INIS)

    Sodium methyldithiocarbamate (SMD) is the third most abundantly used conventional pesticide in the U.S. We recently reported that it alters the induction of cytokine production mediated though Toll-like receptor (TLR) 4 at relevant dosages in mice. Its chemical properties and evidence from the literature suggest thee potential mechanisms of action for this compound. It could either act as a free radical scavenger (by means of its free S-group) or promote oxidation by breaking down to form methylisothiocyanate, which can deplete glutathione. It is a potent copper chelator and may affect the availability of copper to a number of copper-dependent enzymes (including some signaling molecules). SMD induces a classical neuroendocrine stress response characterized by elevated serum corticosterone concentrations, which could affect cytokine production. Although each of these mechanisms could potentially contribute to altered cytokine responses, direct evidence is lacking. The present study was conducted to obtain such evidence. The role of redox balance was investigated by pretreating mice with N-acetyl cysteine (NAC), which increases cellular glutathione concentrations, before administration of SMD. NAC exacerbated the SMD-induced suppression of IL-12 and the SMD-induced enhancement of IL-10 in the serum. The role of copper chelation was investigated by comparing the effects of SMD with an equimolar dose to SMD that was administered in the form of a copper chelation complex. Addition of copper significantly decreased the action of SMD on IL-12 production but not on IL-10 production. The role of the stress response was investigated by pretreating mice with antagonists of corticosterone and catecholamines. This treatment partially prevented the action of SMD on IL-10 and IL-12 in the peritoneal fluid. The results suggest that all of the proposed mechanisms have some role in the alteration of cytokine production by SMD

  12. Phytoremediation potential of the novel atrazine tolerant Lolium multiflorum and studies on the mechanisms involved

    International Nuclear Information System (INIS)

    Atrazine impact on human health and the environment have been extensively studied. Phytoremediation emerged as a low cost, environmental friendly biotechnological solution for atrazine pollution in soil and water. In vitro atrazine tolerance assays were performed and Lolium multiflorum was found as a novel tolerant species, able to germinate and grow in the presence of 1 mg kg-1 of the herbicide. L. multiflorum presented 20% higher atrazine removal capacity than the natural attenuation, with high initial degradation rate in microcosms. The mechanisms involved in atrazine tolerance such as mutation in psbA gene, enzymatic detoxification via P450 or chemical hydrolysis through benzoxazinones were evaluated. It was demonstrated that atrazine tolerance is conferred by enhanced enzymatic detoxification via P450. Due to its atrazine degradation capacity in soil and its agronomical properties, L. multiflorum is a candidate for designing phytoremediation strategies for atrazine contaminated agricultural soils, especially those involving run-off avoiding. - Finding of a novel atrazine-tolerant species, as a potential candidate for phytoremediating herbicide-contaminated agriculture soils and elucidation of the mechanisms involved in tolerance.

  13. Phytoremediation potential of the novel atrazine tolerant Lolium multiflorum and studies on the mechanisms involved

    Energy Technology Data Exchange (ETDEWEB)

    Merini, Luciano J. [Catedra de Microbiologia Industrial y Biotecnologia, Universidad de Buenos Aires (Argentina); Bobillo, Cecilia [Servicio de Huellas Digitales Geneticas, Facultad de Farmacia y Bioquimica, Microbiologia Industrial y Biotecnologia, Universidad de Buenos Aires, Junin 956, BS As (Argentina); Cuadrado, Virginia [Catedra de Microbiologia Industrial y Biotecnologia, Universidad de Buenos Aires (Argentina); Corach, Daniel [Servicio de Huellas Digitales Geneticas, Facultad de Farmacia y Bioquimica, Microbiologia Industrial y Biotecnologia, Universidad de Buenos Aires, Junin 956, BS As (Argentina); Giulietti, Ana M., E-mail: agiule@ffyb.uba.a [Catedra de Microbiologia Industrial y Biotecnologia, Universidad de Buenos Aires (Argentina)

    2009-11-15

    Atrazine impact on human health and the environment have been extensively studied. Phytoremediation emerged as a low cost, environmental friendly biotechnological solution for atrazine pollution in soil and water. In vitro atrazine tolerance assays were performed and Lolium multiflorum was found as a novel tolerant species, able to germinate and grow in the presence of 1 mg kg{sup -1} of the herbicide. L. multiflorum presented 20% higher atrazine removal capacity than the natural attenuation, with high initial degradation rate in microcosms. The mechanisms involved in atrazine tolerance such as mutation in psbA gene, enzymatic detoxification via P{sub 450} or chemical hydrolysis through benzoxazinones were evaluated. It was demonstrated that atrazine tolerance is conferred by enhanced enzymatic detoxification via P{sub 450}. Due to its atrazine degradation capacity in soil and its agronomical properties, L. multiflorum is a candidate for designing phytoremediation strategies for atrazine contaminated agricultural soils, especially those involving run-off avoiding. - Finding of a novel atrazine-tolerant species, as a potential candidate for phytoremediating herbicide-contaminated agriculture soils and elucidation of the mechanisms involved in tolerance.

  14. Study on the Cellular Molecular Mechanism of Intrauterine Transmission of Hepatitis B Virus

    Institute of Scientific and Technical Information of China (English)

    王健; 孙琳

    2003-01-01

    Objective: To study intrauterine transmission of HBV and its celbular molecular mechanism and influence on the fetus. Methods: A total of 46 cases of Fegnant uxnnen who suffered from HBV were divided into HBeAg (+) and HBeAg (-) groups. HBV-DNA in serum and peripheral blood mononuclear cells ( PBMC ) of 46 cases of pregnant women before delivery urns detected by polymerase chain reaction ( PCR). After placenta being delivery, HBV-DNA in serum and cord blood mononuclear cells ( CBMC) was also detected by PCR. Results: The total of positive rates of HBV-DNA in serum and PBMC of pregnant women with hepatitis B were 69.57% (32/46) and 41.30% (19/46). The positive rates of HBV-DNA in serum of cord blood and CBMC were 56.52%(26/46) and 21.74% (10/46) respectively. Among them, the positive rates of HBV-DNA inserum and PBMC of pregnant women with HBeAg (+) were 100. 00% (25/25) and 60.00% (15/25) respectively. The positive rates of HBV-DNA in serum of cord blood and CBMC were 88.00% (22/25) and 32. 00% (8/25) respectively. The positive rates of HBV-DNA in serum and PBMC of pregnant women with HBeAg (-) were 33.33%(7/21) and 19.05%(4/21) respectively. The positive rates of HBV-DNA in serum of card blood and CBMC were 19.05%(4/21) and 9.52%(2/21) resspectively. The positive rates of HBV-DNA in serum of card blood and CBMC of newborns were higher in the group of pregnant women with HBeAg (+) than those in the group of pregnant women with HBeAg (--) (P<0. O1 and P<0. 05). There was no HBV-DNA in serum, PBMC and CBMC of normal pregnant women and normal neorwles. Conclusion : The intrauterine transmission of HBV can be existent and its transmission way not only can be induced by serum but also can be induced by PBMC. The way of intrauterine transmission of HBV in-duced by PBMC was concealed. The dangerous possibility of intrauterine transmission is higher in thepregnant women with HBeAg (+) than that in the group of pregnant women with HBeAg (-).

  15. Differential gene expression in seasonal sympatry: mechanisms involved in diverging life histories.

    Science.gov (United States)

    Fudickar, Adam M; Peterson, Mark P; Greives, Timothy J; Atwell, Jonathan W; Bridge, Eli S; Ketterson, Ellen D

    2016-03-01

    In an era of climate change, understanding the genetic and physiological mechanisms underlying flexibility in phenology and life history has gained greater importance. These mechanisms can be elucidated by comparing closely related populations that differ in key behavioural and physiological traits such as migration and timing of reproduction. We compared gene expression in two recently diverged dark-eyed Junco ( Junco hyemalis) subspecies that live in seasonal sympatry during winter and early spring, but that differ in behaviour and physiology, despite exposure to identical environmental cues. We identified 547 genes differentially expressed in blood and pectoral muscle. Genes involved in lipid transport and metabolism were highly expressed in migrant juncos, while genes involved in reproductive processes were highly expressed in resident breeders. Seasonal differences in gene expression in closely related populations residing in the same environment provide significant insights into mechanisms underlying variation in phenology and life history, and have potential implications for the role of seasonal timing differences in gene flow and reproductive isolation. PMID:26979563

  16. Assessment of Mechanisms Involved in Antinociception Produced by the Alkaloid Caulerpine

    Directory of Open Access Journals (Sweden)

    Luiz Henrique Agra Cavalcante-Silva

    2014-09-01

    Full Text Available In previous works we showed that oral administration of caulerpine, a bisindole alkaloid isolated from algae of the genus Caulerpa, produced antinociception when assessed in chemical and thermal models of nociception. In this study, we evaluated the possible mechanism of action of this alkaloid in mice, using the writhing test. The antinociceptive effect of caulerpine was not affected by intraperitoneal (i.p. pretreatment of mice with naloxone, flumazenil, l-arginine or atropine, thus discounting the involvement of the opioid, GABAergic, l-arginine-nitric oxide and (muscarinic cholinergic pathways, respectively. In contrast, i.p. pretreatment with yohimbine, an α2-adrenoceptor antagonist, or tropisetron, a 5-HT3 antagonist, significantly blocked caulerpine-induced antinociception. These results suggest that caulerpine exerts its antinociceptive effect in the writhing test via pathways involving α2-adrenoceptors and 5-HT3 receptors. In summary, this alkaloid could be of interest in the development of new dual-action analgesic drugs.

  17. Absorption of Carotenoids and Mechanisms Involved in Their Health-Related Properties.

    Science.gov (United States)

    Cervantes-Paz, Braulio; Victoria-Campos, Claudia I; Ornelas-Paz, José de Jesús

    2016-01-01

    Carotenoids participate in the normal metabolism and function of the human body. They are involved in the prevention of several diseases, especially those related to the inflammation syndrome. Their main mechanisms of action are associated to their potent antioxidant activity and capacity to regulate the expression of specific genes and proteins. Recent findings suggest that carotenoid metabolites may explain several processes where the participation of their parent carotenoids was unclear. The health benefits of carotenoids strongly depend on their absorption and transformation during gastrointestinal digestion. The estimation of the 'bioaccessibility' of carotenoids through in vitro models have made possible the evaluation of the effect of a large number of factors on key stages of carotenoid digestion and intestinal absorption. The bioaccessibility of these compounds allows us to have a clear idea of their potential bioavailability, a term that implicitly involves the biological activity of these compounds. PMID:27485232

  18. Multiple mechanisms involved in oxytocin-induced modulation of myometrial contractility

    Institute of Scientific and Technical Information of China (English)

    Anatoly SHMYGOL; Joanna GULLAM; Andrew BLANKS; Steven THORNTON

    2006-01-01

    Oxytocin is a small peptide hormone with multiple sites of action in human body.It regulates a large number of reproduction-related processes in all species.Particularly important is its ability to stimulate uterine contractility.This is achieved by multiple mechanisms involving sarcoplasmic reticulum Ca2+ release and sensitization of the contractile apparatus to Ca2+.In this paper,we review the data published by US and other groups on oxytocin-induced modulation of uterine contractility.We conclude that sensitization of contractile apparatus to Ca2+ is the most relevant physiological effect of oxytocin on human myometrium.

  19. Prostaglandin A2 enhances cellular insulin sensitivity via a mechanism that involves the orphan nuclear receptor NR4A3.

    Science.gov (United States)

    Zhu, X; Walton, R G; Tian, L; Luo, N; Ho, S-R; Fu, Y; Garvey, W T

    2013-03-01

    We have previously reported that members of the NR4A family of orphan nuclear receptors can augment insulin's ability to stimulate glucose transport in adipocytes. In the current study, we endeavored to test for an insulin-sensitizing effect in muscle cells and to identify a potential transactivator. Lentiviral constructs were used to engineer both hyperexpression and shRNA silencing of NR4A3 in C2C12 myocytes. The NR4A3 hyper-expression construct led to a significant increase in glucose transport rates in the presence of maximal insulin while the NR4A3 knock-down exhibited a significant reduction in insulin-stimulated glucose transport rates. Consistently, insulin-mediated AKT phosphorylation was increased by NR4A3 hyperexpression and decreased following shRNA NR4A3 suppression. Then, we examined effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation. PGA2 augmented insulin-stimulated glucose uptake in C2C12 myocytes and AKT phosphorylation after 12-h treatment, without significant effects on basal transport or basal AKT phosphorylation. More importantly, we demonstrated that PGA2 led to a greater improvement in insulin-stimulated glucose rates in NR4A3 overexpressing C2C12 myocytes, when compared with Lac-Z controls stimulated with insulin and PGA2. Moreover, the sensitizing effect of PGA2 was significantly diminished in NR4A3 knockdown myocytes compared to scramble controls. These results show for the first time that: (i) PGA2 augments insulin action in myocytes as manifested by enhanced stimulation of glucose transport and AKT phosphorylation; and (ii) the insulin sensitizing effect is dependent upon the orphan nuclear receptor NR4A3. PMID:23104421

  20. A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity.

    Directory of Open Access Journals (Sweden)

    Mónica Bañez-Coronel

    Full Text Available Huntington's disease (HD is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater induced cell death and increased levels of small CAG-repeated RNAs (sCAGs, of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches.

  1. The mechanism of sperm-egg interaction and the involvement of IZUM01 in fusion

    Institute of Scientific and Technical Information of China (English)

    Naokazu Inoue; Masahito Ikawa; Masaru Okabe

    2011-01-01

    An average human ejaculate contains over 100 million sperm,but only a few succeed in accomplishing the journey to an egg by migration through the female reproductive tract.Among these few sperm,only one participates in fertilization.There might be an ingenious molecular mechanism to ensure that the very best sperm fertilize an egg.However,recent gene disruption experiments in mice have revealed that many factors previously described as important for fertilization are largely dispensable.One could argue that the fertilization mechanism is made robust against gene disruptions.However,this is not likely,as there are already six different gene-disrupted mouse lines (Calmegin,Adam1a,Adam2,Adam3,Aceand Pgap1),all of which result in male sterility.The sperm from these animals are known to have defective zona-binding ability and at the same time lose oviduct-migrating ability.Concerning spermzona binding,the widely accepted involvement of sugar moiety on zona pellucida 3 (ZP3) is indicated to be dispensable by gene disruption experiments.Thus,the landscape of the mechanism of fertilization is revolving considerably.In the sperm-egg fusion process,CD9 on egg and IZUM01 on sperm have emerged as essential factors.This review focuses on the mechanism of fertilization elucidated by gene-manipulated animals.

  2. Mechanism of electron transfer reaction of ternary dipicolinatochromium(III) complex involving oxalate as secondary ligand

    Indian Academy of Sciences (India)

    Hassan Amroun Ewais; Iqbal Mohamed Ibrhium Ismail

    2013-09-01

    Mechanism of electron transfer reaction of ternary Mechanism of the oxidation of [CrIII(DPA)(OX)(H2O)]− (DPA = dipicolinate and OX = oxalate) by periodate in aqueous acidic medium has been studied spectrophotometrically over the pH range of 4.45-5.57 at different temperatures. The reaction is first order with respect to both [IO$^{−}_{4}$] and the complex concentration, and it obeys the following rate law: $$d[{\\text Cr}^{\\text{VI}}]/dt = k_6K_4K_6[{\\text IO}^−_4][{\\text{Cr}}^{\\text{III}}]_{\\text{T}}/\\{([H^+] + K_4) + (K_5[H+] + K_6K_4)[{\\text{IO}}^{−}_{4}]\\}.$$ The rate of the reaction increases with increasing pH due to the deprotonation equilibria of the complex. The experimental rate law is consistent with a mechanism in which the deprotonated form [CrIII(DPA)(OX)(OH)]2− is more reactive than the conjugated acid. It is proposed that electron transfer proceeds through an inner-sphere mechanism via coordination of IO$^{−}_{4}$ to chromium(III). Thermodynamic activation parameters were calculated using the transition state theory equation.dipicolinatochromium(III) complex involving oxalate as secondary ligand

  3. Mechanism of Laser/light beam interaction at cellular and tissue level and study of the influential factors for the application of low level laser therapy

    CERN Document Server

    Khalid, Muhammad Zeeshan

    2016-01-01

    After the discovery of laser therapy it was realized it has useful application of wound healing and reduce pain, but due to the poor understanding of the mechanism and dose response this technique remained to be controversial for therapeutic applications. In order to understand the working and effectiveness different experiments were performed to determine the laser beam effect at the cellular and tissue level. This article discusses the mechanism of beam interaction at tissues and cellular level with different light sources and dosimetry principles for clinical application of low level laser therapy. Different application techniques and methods currently in use for clinical treatment has also been reviewed.

  4. Soil biochar amendment as a climate change mitigation tool: Key parameters and mechanisms involved.

    Science.gov (United States)

    Brassard, Patrick; Godbout, Stéphane; Raghavan, Vijaya

    2016-10-01

    Biochar, a solid porous material obtained from the carbonization of biomass under low or no oxygen conditions, has been proposed as a climate change mitigation tool because it is expected to sequester carbon (C) for centuries and to reduce greenhouse gas (GHG) emissions from soils. This review aimed to identify key biochar properties and production parameters that have an effect on these specific applications of the biochar. Moreover, mechanisms involved in interactions between biochar and soils were highlighted. Following a compilation and comparison of the characteristics of 76 biochars from 40 research studies, biochars with a lower N content, and consequently a higher C/N ratio (>30), were found to be more suitable for mitigation of N2O emissions from soils. Moreover, biochars produced at a higher pyrolysis temperature, and with O/C ratio <0.2, H/Corg ratio <0.4 and volatile matter below 80% may have high C sequestration potential. Based on these observations, biochar production and application to the field can be used as a tool to mitigate climate change. However, it is important to determine the pyrolysis conditions and feedstock needed to produce a biochar with the desired properties for a specific application. More research studies are needed to identify the exact mechanisms involved following biochar amendment to soil. PMID:27420171

  5. Antinociceptive Activity of Methanol Extract of Muntingia calabura Leaves and the Mechanisms of Action Involved

    Directory of Open Access Journals (Sweden)

    M. H. Mohd. Sani

    2012-01-01

    Full Text Available Muntingia calabura L. (family Elaeocarpaceae has been traditionally used to relieve various pain-related ailments. The present study aimed to determine the antinociceptive activity of methanol extract of M. calabura leaves (MEMC and to elucidate the possible mechanism of antinociception involved. The in vivo chemicals (acetic acid-induced abdominal constriction and formalin-, capsaicin-, glutamate-, serotonin-induced paw licking test and thermal (hot plate test models of nociception were used to evaluate the extract antinociceptive activity. The extract (100, 250, and 500 mg/kg was administered orally 60 min prior to subjection to the respective test. The results obtained demonstrated that MEMC produced significant (P<0.05 antinociceptive response in all the chemical- and thermal-induced nociception models, which was reversed after pretreatment with 5 mg/kg naloxone, a non-selective opioid antagonist. Furthermore, pretreatment with L-arginine (a nitric oxide (NO donor, NG-nitro-L-arginine methyl esters (L-NAME; an inhibitor of NO synthase (NOS, methylene blue (MB; an inhibitor of cyclic-guanosine monophosphate (cGMP pathway, or their combination also caused significant (P<0.05 change in the intensity of the MEMC antinociception. In conclusion, the MEMC antinociceptive activity involves activation of the peripheral and central mechanisms, and modulation via, partly, the opioid receptors and NO/cGMP pathway.

  6. Metabolomics Reveals New Mechanisms for Pathogenesis in Barth Syndrome and Introduces Novel Roles for Cardiolipin in Cellular Function.

    Science.gov (United States)

    Sandlers, Yana; Mercier, Kelly; Pathmasiri, Wimal; Carlson, Jim; McRitchie, Susan; Sumner, Susan; Vernon, Hilary J

    2016-01-01

    Barth Syndrome is the only known Mendelian disorder of cardiolipin remodeling, with characteristic clinical features of cardiomyopathy, skeletal myopathy, and neutropenia. While the primary biochemical defects of reduced mature cardiolipin and increased monolysocardiolipin are well-described, much of the downstream biochemical dysregulation has not been uncovered, and biomarkers are limited. In order to further expand upon the knowledge of the biochemical abnormalities in Barth Syndrome, we analyzed metabolite profiles in plasma from a cohort of individuals with Barth Syndrome compared to age-matched controls via 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. A clear distinction between metabolite profiles of individuals with Barth Syndrome and controls was observed, and was defined by an array of metabolite classes including amino acids and lipids. Pathway analysis of these discriminating metabolites revealed involvement of mitochondrial and extra-mitochondrial biochemical pathways including: insulin regulation of fatty acid metabolism, lipid metabolism, biogenic amine metabolism, amino acid metabolism, endothelial nitric oxide synthase signaling, and tRNA biosynthesis. Taken together, this data indicates broad metabolic dysregulation in Barth Syndrome with wide cellular effects. PMID:27015085

  7. Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor.

    Science.gov (United States)

    Bariani, María Victoria; Domínguez Rubio, Ana Paula; Cella, Maximiliano; Burdet, Juliana; Franchi, Ana María; Aisemberg, Julieta

    2015-12-01

    Prematurity is the leading cause of perinatal morbidity and mortality worldwide. There is a strong causal relationship between infection and preterm births. Intrauterine infection elicits an immune response involving the release of inflammatory mediators like cytokines and prostaglandins (PG) that trigger uterine contractions and parturition events. Anandamide (AEA) is an endogenous ligand for the cannabinoid receptors CB1 and CB2. Similarly to PG, endocannabinoids are implicated in different aspects of reproduction, such as maintenance of pregnancy and parturition. Little is known about the involvement of endocannabinoids on the onset of labor in an infectious milieu. Here, using a mouse model of preterm labor induced by lipopolysaccharide (LPS), we explored changes on the expression of components of endocannabinoid system (ECS). We have also determined whether AEA and CB antagonists alter PG production that induces labor. We observed an increase in uterine N-acylphosphatidylethanolamine-specific phospholipase D expression (NAPE-PLD, the enzyme that synthesizes AEA) upon LPS treatment. Activity of catabolic enzyme fatty acid amide hydrolase (FAAH) did not change significantly. In addition, we also found that LPS modulated uterine cannabinoid receptors expression by downregulating Cb2 mRNA levels and upregulating CB1 protein expression. Furthermore, LPS and AEA induced PGF2a augmentation, and this was reversed by antagonizing CB1 receptor. Collectively, our results suggest that ECS may be involved in the mechanism by which infection causes preterm birth. PMID:26347521

  8. Minocycline mechanism of neuroprotection involves the Bcl-2 gene family in optic nerve transection.

    Science.gov (United States)

    Levkovitch-Verbin, Hani; Waserzoog, Yael; Vander, Shelly; Makarovsky, Daria; Ilia, Piven

    2014-10-01

    The second-generation tetracycline, minocycline, has been shown to exhibit neuroprotective therapeutic benefits in many neurodegenerative diseases including experimental glaucoma and optic nerve transection (ONT). This study investigated the mechanism underlying minocycline neuroprotection in a model of ONT. ONT was applied unilaterally in 36 Wistar rat eyes. The rats were randomly divided into a minocycline (22 mg/kg/d) treatment group and a saline treatment group (control). Treatment (minocycline or saline) was given by intraperitoneal injections initiated 3 d before ONT and continued daily until the end of the experiment. The involvement of pro-apoptotic, pro-survival and inflammatory pathways was analyzed by quantitative Real-Time Polymerase Chain Reaction at 4 h and 3 d after the transection in both treatment groups. The involvement of Bcl-2 protein was evaluated by immunohistochemistry. We found that Minocycline significantly increased the expression of the antiapoptotic gene bcl-2 4 h after transection (n = 8, p = 0.008) and decreased the expression of Bax at the same time point (n = 8, p = 0.03). Tumor Necrosis Factor α (TNFα), Inhibitor of Apoptosis Protein (IAP1) and Gadd45α were significantly upregulated in the retinas of eyes with ONTs compared to control (n = 10 for each gene, p = 0.02, p = 0.03, p = 0.04, respectively) but this effect was unaffected by minocycline. This study further support that the mechanism underlying minocycline neuroprotection involves the Bcl-2 gene family, suggesting that minocycline has antiapoptotic properties that support its value as a promising neuroprotective drug. PMID:24410139

  9. Induction of multixenobiotic defense mechanisms in resistant Daphnia magna clones as a general cellular response to stress.

    Science.gov (United States)

    Jordão, Rita; Campos, Bruno; Lemos, Marco F L; Soares, Amadeu M V M; Tauler, Romà; Barata, Carlos

    2016-06-01

    Multixenobiotic resistance mechanisms (MXR) were recently identified in Daphnia magna. Previous results characterized gene transcripts of genes encoding and efflux activities of four putative ABCB1 and ABCC transporters that were chemically induced but showed low specificity against model transporter substrates and inhibitors, thus preventing us from distinguishing between activities of different efflux transporter types. In this study we report on the specificity of induction of ABC transporters and of the stress protein hsp70 in clones selected to be genetically resistant to ABCB1 chemical substrates. Clones resistant to mitoxantrone, ivermectin and pentachlorophenol showed distinctive transcriptional responses of transporter protein coding genes and of putative transporter dye activities. Expression of hsp70 proteins also varied across resistant clones. Clones resistant to mitoxantrone and pentachlorophenol showed high constitutive levels of hsp70. Transcriptional levels of the abcb1 gene transporter and of putative dye transporter activity were also induced to a greater extent in the pentachlorophenol resistant clone. Observed higher dye transporter activities in individuals from clones resistant to mitoxantrone and ivermectin were unrelated with transcriptional levels of the studied four abcc and abcb1 transporter genes. These findings suggest that Abcb1 induction in D. magna may be a part of a general cellular stress response. PMID:27039215

  10. Differentiation of autonomic reflex control begins with cellular mechanisms at the first synapse within the nucleus tractus solitarius

    Directory of Open Access Journals (Sweden)

    M.C. Andresen

    2004-04-01

    Full Text Available Visceral afferents send information via cranial nerves to the nucleus tractus solitarius (NTS. The NTS is the initial step of information processing that culminates in homeostatic reflex responses. Recent evidence suggests that strong afferent synaptic responses in the NTS are most often modulated by depression and this forms a basic principle of central integration of these autonomic pathways. The visceral afferent synapse is uncommonly powerful at the NTS with large unitary response amplitudes and depression rather than facilitation at moderate to high frequencies of activation. Substantial signal depression occurs through multiple mechanisms at this very first brainstem synapse onto second order NTS neurons. This review highlights new approaches to the study of these basic processes featuring patch clamp recordings in NTS brain slices and optical techniques with fluorescent tracers. The vanilloid receptor agonist, capsaicin, distinguishes two classes of second order neurons (capsaicin sensitive or capsaicin resistant that appear to reflect unmyelinated and myelinated afferent pathways. The differences in cellular properties of these two classes of NTS neurons indicate clear functional differentiation at both the pre- and postsynaptic portions of these first synapses. By virtue of their position at the earliest stage of these pathways, such mechanistic differences probably impart important differentiation in the performance over the entire reflex pathways.

  11. Suppression of cellular immunity by head and neck irradiation. Precipitating factors and reparative mechanisms in an experimental model

    International Nuclear Information System (INIS)

    A model was developed in C3H mice to investigate the immunosuppressive effects of head and neck irradiation and to explore mechanisms for repair of the defects. Mice receiving 1200 rad (12 Gy) of head and neck irradiation showed significant depression of delayed-type hypersensitivity, peripheral blood lymphocyte counts, spleen cell counts, and spleen cell production of interleukin-2. Treatment with optimal dosages of thymosin alpha 1 (T alpha-1) produced significant increases in all of these values, in some instances to levels higher than in the nonirradiated controls. In identical experiments with mice irradiated to a portal limited to the pelvic region, T alpha-1 induced only partial remission of the abnormalities. The dose response of T alpha-1 with head and neck irradiation showed a relatively limited dose range for immune restoration, a finding that warrants similar determinations in clinical trials with immunomodulating agents. The results suggest a potential clinical usefulness of T alpha-1 and also interleukin-2 in restoring cellular immunity after irradiation for head and neck cancers. The model appears to be useful for investigating immunomodulating agents before they are clinically evaluated as adjuvants with head and neck irradiation regimens

  12. Cellular basis of radiation-induced fibrosis

    International Nuclear Information System (INIS)

    Fibrosis is a common sequela of both cancer treatment by radiotherapy and accidental irradiation and has been described in many tissues including skin, lung, heart and liver. The underlying mechanisms of the radiation-induced fibrosis still remain to be resolved. In the present review we tried to illustrate the basic cellular mechanisms of radiation-induced fibrosis based on the newest findings arising from molecular radiobiology and cell biology. Based on these findings the cellular mechanism of radiation-induced fibrosis can be seen as a multicellular process involving various interacting cell systems in the target organ resulting in the fibrotic phenotype of the fibroblast/fibrocyte cell system

  13. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    International Nuclear Information System (INIS)

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells

  14. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    Energy Technology Data Exchange (ETDEWEB)

    Massi, Paola [Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan (Italy); Valenti, Marta; Solinas, Marta; Parolaro, Daniela, E-mail: daniela.parolaro@uninsubria.it [Department of Structural and Functional Biology, Section of Pharmacology, Center of Neuroscience, University of Insubria, Via A. da Giussano 10, 20152 Busto Arsizio, Varese (Italy)

    2010-05-26

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.

  15. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Paola Massi

    2010-05-01

    Full Text Available Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.

  16. A case of primary spinal myoclonus: clinical presentation and possible mechanisms involved

    Directory of Open Access Journals (Sweden)

    Campos Cynthia Resende

    2003-01-01

    Full Text Available Spinal myoclonus is a rare movement disorder characterized by myoclonic involvement of a group of muscles supplied by a few contiguous segments of the spinal cord. Structural lesions are usually the cause, but in primary spinal myoclonus the etiology remains unknown. We present the case of a 26-year-old woman with cervical spinal myoclonus in which both clinical and electromyographic findings pointed to the segment C1-C3 as the origin of the myoclonus. Laboratorial examinations were normal and no structural lesion was found in magnetic resonance imaging (MRI. Botulinum toxin type A was injected in infrahyoid muscles and cervical paraspinal musculature. The patient remained free of symptoms for almost five months. The pathophysiology of spinal myoclonus remains speculative, but there is evidence that various possible mechanisms can be involved: loss of inhibitory function of local dorsal horn interneurons, abnormal hyperactivity of local anterior horn neurons, aberrant local axons re-excitations and loss of inhibition from suprasegmentar descending pathways.

  17. Effect of diet and fenfluramine on thermogenesis in the rat: possible involvement of serotonergic mechanisms.

    Science.gov (United States)

    Rothwell, N J; Stock, M J

    1987-01-01

    A single injection of 5-hydroxytryptamine (5HT, 1 mg/kg, s.c.) in rats stimulated resting oxygen consumption (Vo2) by 21 percent; this was reduced (to 8 percent) by pretreatment with hexamethonium (5 mg/kg, s.c.). DL-fenfluramine injection (20 mg/kg, s.c.) stimulated metabolic rate (Vo2) by about 40 percent, but caused only 11 and 15 per cent increases in animals pretreated with hexamethonium or metergoline (5 mg/kg, s.c.), respectively. Interscapular brown adipose tissue (BAT) activity, assessed from mitochondrial GDP-binding, was increased by 96 per cent in intact tissue 1 h after fenfluramine injection; this response was completely prevented by surgical sympathectomy of interscapular BAT. Metergoline significantly inhibited (by 46 percent) the acute thermic response (postprandial rise in Vo2) to a 40-kJ meal in normal rats, and depressed resting Vo2 in protein-deficient rats by 18 percent, but did not affect resting Vo2 in control animals. BAT activity (mitochondrial GDP-binding) was elevated by 56 per cent in rats fed the low-protein diet, but this difference was almost completely abolished by prior treatment with metergoline. These data demonstrate a potent thermogenic effect of fenfluramine which apparently involves serotonergic pathways and activation of sympathetic outflow to BAT, and indicate that acute thermic responses to food and chronic thermogenic responses to low-protein diets may also involve serotonergic mechanisms. PMID:3667065

  18. Mechanisms involved in ceramide-induced cell cycle arrest in human hepatocarcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Xiao-Wen Lv; Jie-Ping Shi; Xiao-Song Hu

    2007-01-01

    AIM:To investigate the effect of ceramide on the cell cycle in human hepatocarcinoma Bel7402 cells.Possible molecular mechanisms were explored.METHODS:[3-(4,5)-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide(MTT)assay,plasmid transfection,reporter assay,FACS and Western blotting analyses were employed to investigate the effect and the related molecular mechanisms of C2-ceramide on the cell cycle of Bel7402 cells.RESULTS:C2-ceramide was found to inhibit the growth of Bel7402 cells by inducing cell cycle arrest.During the process,the expression of p21 protein increased,while that of cyclinD1,phospho-ERK1/2 and c-myc decreased.Furthermore,the level of CDK7 was downregulated,while the transcriptional activity of PPARγ was upregulated.Addition of GW9662,which is a PPARγ specific antagonist,could reserve the modulation action on CDK7.CONCLUSION:Our results support the hypothesis that cell cycle arrest induced by C2-ceramide may be mediated via accumulation of p21 and reduction of cyclinD1 and CDK7,at least partly,through PPARγ activation.The ERK signaling pathway was involved in this process.

  19. Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothionein

    Directory of Open Access Journals (Sweden)

    Moon Sung-Pyo

    2004-10-01

    Full Text Available Abstract Background Heptaplatin is a new platinum derivative with anticancer activity against various cancer cell lines, including cisplatin-resistant cancer cell lines (Cancer Chemother Pharmacol 1995; 35: 441. Methods Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines has been investigated in connection with metallothionein (MT. Cytotoxicity was determined by an MTT assay. MT mRNA, was determined by RT-PCR assay. Transfection study was carried out to examine the function of MT. Results Of various gastric cancer cell lines, SNU-638 and SNU-601 showed the highest and lowest levels of MT mRNA, respectively, showing 80-fold difference. The IC50 values of SNU-638 to cisplatin, carboplatin and heptaplatin were 11.2-fold, 5.1-fold and 2.0-fold greater than those of SNU-601, respectively. Heptaplatin was more effective against cisplatin-resistant and MT-transfected gastric cancer sublines than cisplatin or carboplatin was. In addition, heptaplatin attenuated cadmium, but not zinc, induction of MT. Conclusion These results indicate that molecular mechanisms of heptaplatin effective against cisplatin-resistant gastric cancer sublines is at least in part due to the less involvement of MT in heptaplatin resistance as well as its attenuation of MT induction.

  20. A role of nitric oxide mechanism involved in the protective effects of venlafaxine in sleep deprivation.

    Science.gov (United States)

    Kumar, Anil; Garg, Ruchika

    2008-12-12

    The present study was designed to explore the possible nitric oxide mechanism in protective effect of venlafaxine in sleep deprivation in mice. Laca mice were sleep deprived for period of 72 h using grid suspended over water method. Venlafaxine (2.5, 5 and 10mg/kg, ip), l-arginine (50mg/kg, ip), l-NAME (10mg/kg, ip) and methylene blue (10mg/kg, ip) were administered for 5 days, starting 2 days before 72-h sleep deprivation. Various behavioral tests (plus maze, zero maze, mirror chamber tests for anxiety, and actophotometer test) followed by oxidative stress parameters (malondialdehyde level, glutathione, catalase, nitrite and protein) were assessed. The present study showed that venlafaxine (5 and 10mg/kg, ip) drug treatment significantly reversed 72-h sleep deprivation caused anxiety like behavior, impairment in locomotor activity and oxidative damage (increased lipid peroxidation and nitrite levels and depleted reduced glutathione and catalase activity) as compared to control. l-NAME (10mg/kg) and methylene blue (10mg/kg) pretreatment with lower dose of venlafaxine (5mg/kg) potentiated the protective effect of venlafaxine (5mg/kg). However, l-arginine (50mg/kg) pretreatment with venlafaxine (5mg/kg) reversed the protective effect of venlafaxine. Results of present study suggest that nitric oxide mechanism is involved in the protective effect of venlafaxine against sleep-deprivation-induced behavior alteration and oxidative damage in mice. PMID:18674568

  1. Depletion of bovine pituitary prolactin by cysteamine involves a thiol:disulfide mechanism

    International Nuclear Information System (INIS)

    Cysteamine [2-aminoethanethiol (CySH)] reduces measurable PRL concentrations in vivo and in vitro. Since secretion is also inhibited, CySH may block conversion from a poorly assayable hormone storage form(s) to readily assayable, releasable PRL. This would represent a previously unrecognized mechanism for secretory regulation. We undertook the present study to identify the sites involved in the loss of measurable PRL (depletion) induced by cysteamine. The disulfide cystamine was ineffective on secretory granules unless combined with reduced glutathione, indicating the generation of the active CySH-thiol form. Pretreatment of granules with thiol-blocking agents resulted in dose-dependent enhancement of CySH inhibition, achieving nearly complete inhibition with 5 mM iodoacetamide. In contrast, pretreatment with reduced glutathione or dithiothreitol, respectively, impaired or abolished the CySH effect. These data suggest that the mechanism by which CySH causes PRL depletion is mediated by granule disulfides and the -SH of CySH. The regulation of thiol:disulfide equilibria appears to be an important determinant of the detectability of PRL storage forms and of their secretion

  2. A host defense mechanism involving CFTR-mediated bicarbonate secretion in bacterial prostatitis.

    Directory of Open Access Journals (Sweden)

    Chen Xie

    Full Text Available BACKGROUND: Prostatitis is associated with a characteristic increase in prostatic fluid pH; however, the underlying mechanism and its physiological significance have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study a primary culture of rat prostatic epithelial cells and a rat prostatitis model were used. Here we reported the involvement of CFTR, a cAMP-activated anion channel conducting both Cl(- and HCO(3(-, in mediating prostate HCO(3(- secretion and its possible role in bacterial killing. Upon Escherichia coli (E. coli-LPS challenge, the expression of CFTR and carbonic anhydrase II (CA II, along with several pro-inflammatory cytokines was up-regulated in the primary culture of rat prostate epithelial cells. Inhibiting CFTR function in vitro or in vivo resulted in reduced bacterial killing by prostate epithelial cells or the prostate. High HCO(3(- content (>50 mM, rather than alkaline pH, was found to be responsible for bacterial killing. The direct action of HCO(3(- on bacterial killing was confirmed by its ability to increase cAMP production and suppress bacterial initiation factors in E. coli. The relevance of the CFTR-mediated HCO(3(- secretion in humans was demonstrated by the upregulated expression of CFTR and CAII in human prostatitis tissues. CONCLUSIONS/SIGNIFICANCE: The CFTR and its mediated HCO(3(- secretion may be up-regulated in prostatitis as a host defense mechanism.

  3. A non-cardiomyocyte autonomous mechanism of cardioprotection involving the SLO1 BK channel

    Directory of Open Access Journals (Sweden)

    Andrew P. Wojtovich

    2013-03-01

    Full Text Available Opening of BK-type Ca2+ activated K+ channels protects the heart against ischemia-reperfusion (IR injury. However, the location of BK channels responsible for cardioprotection is debated. Herein we confirmed that openers of the SLO1 BK channel, NS1619 and NS11021, were protective in a mouse perfused heart model of IR injury. As anticipated, deletion of the Slo1 gene blocked this protection. However, in an isolated cardiomyocyte model of IR injury, protection by NS1619 and NS11021 was insensitive to Slo1 deletion. These data suggest that protection in intact hearts occurs by a non-cardiomyocyte autonomous, SLO1-dependent, mechanism. In this regard, an in-situ assay of intrinsic cardiac neuronal function (tachycardic response to nicotine revealed that NS1619 preserved cardiac neurons following IR injury. Furthermore, blockade of synaptic transmission by hexamethonium suppressed cardioprotection by NS1619 in intact hearts. These results suggest that opening SLO1 protects the heart during IR injury, via a mechanism that involves intrinsic cardiac neurons. Cardiac neuronal ion channels may be useful therapeutic targets for eliciting cardioprotection.

  4. RNase-L Control of Cellular mRNAs: Roles in Biologic Functions and Mechanisms of Substrate Targeting

    OpenAIRE

    Brennan-Laun, Sarah E.; Ezelle, Heather J.; Li, Xiao-Ling; Hassel, Bret A.

    2014-01-01

    RNase-L is a mediator of type 1 interferon-induced antiviral activity that has diverse and critical cellular roles, including the regulation of cell proliferation, differentiation, senescence and apoptosis, tumorigenesis, and the control of the innate immune response. Although RNase-L was originally shown to mediate the endonucleolytic cleavage of both viral and ribosomal RNAs in response to infection, more recent evidence indicates that RNase-L also functions in the regulation of cellular mR...

  5. The influence of receptor-mediated interactions on reaction-diffusion mechanisms of cellular self-organisation.

    Science.gov (United States)

    Klika, Václav; Baker, Ruth E; Headon, Denis; Gaffney, Eamonn A

    2012-04-01

    Understanding the mechanisms governing and regulating self-organisation in the developing embryo is a key challenge that has puzzled and fascinated scientists for decades. Since its conception in 1952 the Turing model has been a paradigm for pattern formation, motivating numerous theoretical and experimental studies, though its verification at the molecular level in biological systems has remained elusive. In this work, we consider the influence of receptor-mediated dynamics within the framework of Turing models, showing how non-diffusing species impact the conditions for the emergence of self-organisation. We illustrate our results within the framework of hair follicle pre-patterning, showing how receptor interaction structures can be constrained by the requirement for patterning, without the need for detailed knowledge of the network dynamics. Finally, in the light of our results, we discuss the ability of such systems to pattern outside the classical limits of the Turing model, and the inherent dangers involved in model reduction. PMID:22072186

  6. Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection.

    Science.gov (United States)

    Okada-Ogawa, Akiko; Nakaya, Yuka; Imamura, Yoshiki; Kobayashi, Masayuki; Shinoda, Masamichi; Kita, Kozue; Sessle, Barry J; Iwata, Koichi

    2015-05-01

    In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at

  7. Development of neurodevelopmental disorders: a regulatory mechanism involving bromodomain-containing proteins

    Directory of Open Access Journals (Sweden)

    Li Junlin

    2013-02-01

    Full Text Available Abstract Neurodevelopmental disorders are classified as diseases that cause abnormal functions of the brain or central nervous system. Children with neurodevelopmental disorders show impaired language and speech abilities, learning and memory damage, and poor motor skills. However, we still know very little about the molecular etiology of these disorders. Recent evidence implicates the bromodomain-containing proteins (BCPs in the initiation and development of neurodevelopmental disorders. BCPs have a particular domain, the bromodomain (Brd, which was originally identified as specifically binding acetyl-lysine residues at the N-terminus of histone proteins in vitro and in vivo. Other domains of BCPs are responsible for binding partner proteins to form regulatory complexes. Once these complexes are assembled, BCPs alter chromosomal states and regulate gene expression. Some BCP complexes bind nucleosomes, are involved in basal transcription regulation, and influence the transcription of many genes. However, most BCPs are involved in targeting. For example, some BCPs function as a recruitment platform or scaffold through their Brds-binding targeting sites. Others are recruited to form a complex to bind the targeting sites of their partners. The regulation mediated by these proteins is especially critical during normal and abnormal development. Mutant BCPs or dysfunctional BCP-containing complexes are implicated in the initiation and development of neurodevelopmental disorders. However, the pathogenic molecular mechanisms are not fully understood. In this review, we focus on the roles of regulatory BCPs associated with neurodevelopmental disorders, including mental retardation, Fragile X syndrome (FRX, Williams syndrome (WS, Rett syndrome and Rubinstein-Taybi syndrome (RTS. A better understanding of the molecular pathogenesis, based upon the roles of BCPs, will lead to screening of targets for the treatment of neurodevelopmental disorders.

  8. Development of neurodevelopmental disorders: a regulatory mechanism involving bromodomain-containing proteins.

    Science.gov (United States)

    Li, Junlin; Zhao, Guifang; Gao, Xiaocai

    2013-01-01

    Neurodevelopmental disorders are classified as diseases that cause abnormal functions of the brain or central nervous system. Children with neurodevelopmental disorders show impaired language and speech abilities, learning and memory damage, and poor motor skills. However, we still know very little about the molecular etiology of these disorders. Recent evidence implicates the bromodomain-containing proteins (BCPs) in the initiation and development of neurodevelopmental disorders. BCPs have a particular domain, the bromodomain (Brd), which was originally identified as specifically binding acetyl-lysine residues at the N-terminus of histone proteins in vitro and in vivo. Other domains of BCPs are responsible for binding partner proteins to form regulatory complexes. Once these complexes are assembled, BCPs alter chromosomal states and regulate gene expression. Some BCP complexes bind nucleosomes, are involved in basal transcription regulation, and influence the transcription of many genes. However, most BCPs are involved in targeting. For example, some BCPs function as a recruitment platform or scaffold through their Brds-binding targeting sites. Others are recruited to form a complex to bind the targeting sites of their partners. The regulation mediated by these proteins is especially critical during normal and abnormal development. Mutant BCPs or dysfunctional BCP-containing complexes are implicated in the initiation and development of neurodevelopmental disorders. However, the pathogenic molecular mechanisms are not fully understood. In this review, we focus on the roles of regulatory BCPs associated with neurodevelopmental disorders, including mental retardation, Fragile X syndrome (FRX), Williams syndrome (WS), Rett syndrome and Rubinstein-Taybi syndrome (RTS). A better understanding of the molecular pathogenesis, based upon the roles of BCPs, will lead to screening of targets for the treatment of neurodevelopmental disorders. PMID:23425632

  9. Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

    International Nuclear Information System (INIS)

    Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4+CD25+Foxp3+ regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation

  10. Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jun [Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan (China); Cao, Hui [Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Wang, Hongjie [Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, FL (United States); Yin, Guoxiao; Du, Jiao; Xia, Fei; Lu, Jingli [Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Xiang, Ming, E-mail: xiangming@mails.tjmu.edu.cn [Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China)

    2015-06-15

    Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation.

  11. The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity

    DEFF Research Database (Denmark)

    Gordillo, M.; Vega, H.; Trainer, A.H.;

    2008-01-01

    Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced grow...

  12. Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty.

    Science.gov (United States)

    de Carvalho Myskiw, Jociane; Furini, Cristiane Regina Guerino; Benetti, Fernando; Izquierdo, Ivan

    2014-03-25

    Exposure to a novel environment enhances the extinction of contextual fear. This has been explained by tagging of the hippocampal synapses used in extinction, followed by capture of proteins from the synapses that process novelty. The effect is blocked by the inhibition of hippocampal protein synthesis following the novelty or the extinction. Here, we show that it can also be blocked by the postextinction or postnovelty intrahippocampal infusion of the NMDA receptor antagonist 2-amino-5-phosphono pentanoic acid; the inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII), autocamtide-2-related inhibitory peptide; or the blocker of L-voltage-dependent calcium channels (L-VDCCs), nifedipine. Inhibition of proteasomal protein degradation by β-lactacystin has no effect of its own on extinction or on the influence of novelty thereon but blocks the inhibitory effects of all the other substances except that of rapamycin on extinction, suggesting that their action depends on concomitant synaptic protein turnover. Thus, the tagging-and-capture mechanism through which novelty enhances fear extinction involves more molecular processes than hitherto thought: NMDA receptors, L-VDCCs, CaMKII, and synaptic protein turnover. PMID:24591622

  13. Mechanisms involved in alleviation of intestinal inflammation by bifidobacterium breve soluble factors.

    Directory of Open Access Journals (Sweden)

    Elise Heuvelin

    Full Text Available OBJECTIVES: Soluble factors released by Bifidobacterium breve C50 (Bb alleviate the secretion of pro-inflammatory cytokines by immune cells, but their effect on intestinal epithelium remains elusive. To decipher the mechanisms accounting for the cross-talk between bacteria/soluble factors and intestinal epithelium, we measured the capacity of the bacteria, its conditioned medium (Bb-CM and other Gram(+ commensal bacteria to dampen inflammatory chemokine secretion. METHODS: TNFalpha-induced chemokine (CXCL8 secretion and alteration of NF-kappaB and AP-1 signalling pathways by Bb were studied by EMSA, confocal microscopy and western blotting. Anti-inflammatory capacity was also tested in vivo in a model of TNBS-induced colitis in mice. RESULTS: Bb and Bb-CM, but not other commensal bacteria, induced a time and dose-dependent inhibition of CXCL8 secretion by epithelial cells driven by both AP-1 and NF-kappaB transcription pathways and implying decreased phosphorylation of p38-MAPK and IkappaB-alpha molecules. In TNBS-induced colitis in mice, Bb-CM decreased the colitis score and inflammatory cytokine expression, an effect reproduced by dendritic cell conditioning with Bb-CM. CONCLUSIONS: Bb and secreted soluble factors contribute positively to intestinal homeostasis by attenuating chemokine production. The results indicate that Bb down regulate inflammation at the epithelial level by inhibiting phosphorylations involved in inflammatory processes and by protective conditioning of dendritic cells.

  14. Hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5) communicates cellular iron and oxygen availability by distinct mechanisms.

    Science.gov (United States)

    Chollangi, Srinivas; Thompson, Joel W; Ruiz, Julio C; Gardner, Kevin H; Bruick, Richard K

    2012-07-01

    Iron regulatory proteins play a principal role in maintaining cellular iron homeostasis by post-transcriptionally regulating factors responsible for iron uptake, utilization, and storage. An E3 ubiquitin ligase complex containing FBXL5 targets IRP2 for proteasomal degradation under iron- and oxygen-replete conditions, whereas FBXL5 itself is degraded when iron and oxygen availability decreases. FBXL5 contains a hemerythrin-like (Hr) domain at its N terminus that mediates its own differential stability. Here, we investigated the iron- and oxygen-dependent conformational changes within FBXL5-Hr that underlie its role as a cellular sensor. As predicted, FBXL5-Hr undergoes substantive structural changes when iron becomes limiting, accounting for its switch-like behavior. However, these same changes are not observed in response to oxygen depletion, indicating that this domain accommodates two distinct sensing mechanisms. Moreover, FBXL5-Hr does not behave as a dynamic sensor that continuously samples the cellular environment, assuming conformations in equilibrium with ever-changing cellular iron levels. Instead, the isolated domain appears competent to incorporate iron only at or near the time of its own synthesis. These observations have important implications for mechanisms by which these metabolites are sensed within mammalian cells. PMID:22648410

  15. Cellular resilience.

    Science.gov (United States)

    Smirnova, Lena; Harris, Georgina; Leist, Marcel; Hartung, Thomas

    2015-01-01

    Cellular resilience describes the ability of a cell to cope with environmental changes such as toxicant exposure. If cellular metabolism does not collapse directly after the hit or end in programmed cell death, the ensuing stress responses promote a new homeostasis under stress. The processes of reverting "back to normal" and reversal of apoptosis ("anastasis") have been studied little at the cellular level. Cell types show astonishingly similar vulnerability to most toxicants, except for those that require a very specific target, metabolism or mechanism present only in specific cell types. The majority of chemicals triggers "general cytotoxicity" in any cell at similar concentrations. We hypothesize that cells differ less in their vulnerability to a given toxicant than in their resilience (coping with the "hit"). In many cases, cells do not return to the naive state after a toxic insult. The phenomena of "pre-conditioning", "tolerance" and "hormesis" describe this for low-dose exposures to toxicants that render the cell more resistant to subsequent hits. The defense and resilience programs include epigenetic changes that leave a "memory/scar" - an alteration as a consequence of the stress the cell has experienced. These memories might have long-term consequences, both positive (resistance) and negative, that contribute to chronic and delayed manifestations of hazard and, ultimately, disease. This article calls for more systematic analyses of how cells cope with toxic perturbations in the long-term after stressor withdrawal. A technical prerequisite for these are stable (organotypic) cultures and a characterization of stress response molecular networks. PMID:26536287

  16. Mechanism involved in trichloroethylene-induced liver cancer: Importance to environmental cleanup. 1998 annual progress report

    International Nuclear Information System (INIS)

    'The objective of this project is to develop critical data for changing risk-based clean-up standards for trichloroethylene (TCE). The project is organized around two interrelated tasks: Task 1 addresses the tumorigenic and dosimetry issues for the metabolites of TCE that produce liver cancer in mice, dichloroacetate (DCA) and trichloroacetate (TCA). Early work had suggested that TCA was primarily responsible for TCE-induced liver tumors, but several, more mechanistic observations suggest that DCA may play a prominent role. This task is aimed at determining the basis for the selection hypothesis and seeks to prove that this mode of action is responsible for TCE-induced tumors. This project will supply the basic dose-response data from which low-dose extrapolations would be made. Task 2 seeks specific evidence that TCA and DCA are capable of promoting the growth of spontaneously initiated cells from mouse liver, in vitro. The data provide the clearest evidence that both metabolites act by a mechanism of selection rather than mutation. These data are necessary to select between a linear (i.e. no threshold) and non-linear low-dose extrapolation model. As of May of 1998, this research has identified two plausible modes of action by which TCE produces liver tumors in mice. These modes of action do not require the compounds to be mutagenic. The bulk of the experimental evidence suggests that neither TCE nor the two hepatocarcinogenic metabolites of TCE are mutagenic. The results from the colony formation assay clearly establish that both of these metabolites cause colony growth from initiated cells that occur spontaneously in the liver of B 6 C 3 F 1 mice, although the phenotypes of the colonies differ in the same manner as tumors differ, in vivo. In the case of DCA, a second mechanism may occur at a lower dose involving the release of insulin. This observation is timely as it was recently reported that occupational exposures to trichloroethylene results in 2 to 4-fold

  17. Cellular prion protein is required for neuritogenesis: fine-tuning of multiple signaling pathways involved in focal adhesions and actin cytoskeleton dynamics

    Directory of Open Access Journals (Sweden)

    Alleaume-Butaux A

    2013-07-01

    Full Text Available Aurélie Alleaume-Butaux,1,2 Caroline Dakowski,1,2 Mathéa Pietri,1,2 Sophie Mouillet-Richard,1,2 Jean-Marie Launay,3,4 Odile Kellermann,1,2 Benoit Schneider1,2 1INSERM, UMR-S 747, 2Paris Descartes University, Sorbonne Paris Cité, UMR-S 747, 3Public Hospital of Paris, Department of Biochemistry, INSERM UMR-S 942, Lariboisière Hospital, Paris, France; 4Pharma Research Department, Hoffmann La Roche Ltd, Basel, Switzerland Abstract: Neuritogenesis is a dynamic phenomenon associated with neuronal differentiation that allows a rather spherical neuronal stem cell to develop dendrites and axon, a prerequisite for the integration and transmission of signals. The acquisition of neuronal polarity occurs in three steps: (1 neurite sprouting, which consists of the formation of buds emerging from the postmitotic neuronal soma; (2 neurite outgrowth, which represents the conversion of buds into neurites, their elongation and evolution into axon or dendrites; and (3 the stability and plasticity of neuronal polarity. In neuronal stem cells, remodeling and activation of focal adhesions (FAs associated with deep modifications of the actin cytoskeleton is a prerequisite for neurite sprouting and subsequent neurite outgrowth. A multiple set of growth factors and interactors located in the extracellular matrix and the plasma membrane orchestrate neuritogenesis by acting on intracellular signaling effectors, notably small G proteins such as RhoA, Rac, and Cdc42, which are involved in actin turnover and the dynamics of FAs. The cellular prion protein (PrPC, a glycosylphosphatidylinositol (GPI-anchored membrane protein mainly known for its role in a group of fatal neurodegenerative diseases, has emerged as a central player in neuritogenesis. Here, we review the contribution of PrPC to neuronal polarization and detail the current knowledge on the signaling pathways fine-tuned by PrPC to promote neurite sprouting, outgrowth, and maintenance. We emphasize that Pr

  18. Early differential cell death and survival mechanisms initiate and contribute to the development of OPIDN: A study of molecular, cellular, and anatomical parameters

    International Nuclear Information System (INIS)

    Organophosphorus-ester induced delayed neurotoxicity (OPIDN) is a neurodegenerative disorder characterized by ataxia progressing to paralysis with a concomitant central and peripheral, distal axonapathy. Diisopropylphosphorofluoridate (DFP) produces OPIDN in the chicken that results in mild ataxia in 7–14 days and severe paralysis as the disease progresses with a single dose. White leghorn layer hens were treated with DFP (1.7 mg/kg, sc) after prophylactic treatment with atropine (1 mg/kg, sc) in normal saline and eserine (1 mg/kg, sc) in dimethyl sulfoxide. Control groups were treated with vehicle propylene glycol (0.1 ml/kg, sc), atropine in normal saline and eserine in dimethyl sulfoxide. The hens were euthanized at different time points such as 1, 2, 5, 10 and 20 days, and the tissues from cerebrum, midbrain, cerebellum, brainstem and spinal cord were quickly dissected and frozen for mRNA (northern) studies. Northern blots were probed with BCL2, GADD45, beta actin, and 28S RNA to investigate their expression pattern. Another set of hens was treated for a series of time points and perfused with phosphate buffered saline and fixative for histological studies. Various staining protocols such as Hematoxylin and Eosin (H and E); Sevier-Munger; Cresyl echt Violet for Nissl substance; and Gallocynin stain for Nissl granules were used to assess various patterns of cell death and degenerative changes. Complex cell death mechanisms may be involved in the neuronal and axonal degeneration. These data indicate altered and differential mRNA expressions of BCL2 (anti apoptotic gene) and GADD45 (DNA damage inducible gene) in various tissues. Increased cell death and other degenerative changes noted in the susceptible regions (spinal cord and cerebellum) than the resistant region (cerebrum), may indicate complex molecular pathways via altered BCL2 and GADD45 gene expression, causing the homeostatic imbalance between cell survival and cell death mechanisms. Semi quantitative

  19. Early differential cell death and survival mechanisms initiate and contribute to the development of OPIDN: A study of molecular, cellular, and anatomical parameters

    Energy Technology Data Exchange (ETDEWEB)

    Damodaran, T.V., E-mail: tdamodar@nccu.edu [Dept of Medicine, Duke University Medical Center, Durham, NC (United States); Pharmacology and Cancer biology, Duke University Medical Center, Durham, NC (United States); Dept of Biology, North Carolina Central University, Durham, NC 27707 (United States); Attia, M.K. [Pharmacology and Cancer biology, Duke University Medical Center, Durham, NC (United States); Abou-Donia, M.B., E-mail: donia@mc.duke.edu [Pharmacology and Cancer biology, Duke University Medical Center, Durham, NC (United States)

    2011-11-15

    Organophosphorus-ester induced delayed neurotoxicity (OPIDN) is a neurodegenerative disorder characterized by ataxia progressing to paralysis with a concomitant central and peripheral, distal axonapathy. Diisopropylphosphorofluoridate (DFP) produces OPIDN in the chicken that results in mild ataxia in 7-14 days and severe paralysis as the disease progresses with a single dose. White leghorn layer hens were treated with DFP (1.7 mg/kg, sc) after prophylactic treatment with atropine (1 mg/kg, sc) in normal saline and eserine (1 mg/kg, sc) in dimethyl sulfoxide. Control groups were treated with vehicle propylene glycol (0.1 ml/kg, sc), atropine in normal saline and eserine in dimethyl sulfoxide. The hens were euthanized at different time points such as 1, 2, 5, 10 and 20 days, and the tissues from cerebrum, midbrain, cerebellum, brainstem and spinal cord were quickly dissected and frozen for mRNA (northern) studies. Northern blots were probed with BCL2, GADD45, beta actin, and 28S RNA to investigate their expression pattern. Another set of hens was treated for a series of time points and perfused with phosphate buffered saline and fixative for histological studies. Various staining protocols such as Hematoxylin and Eosin (H and E); Sevier-Munger; Cresyl echt Violet for Nissl substance; and Gallocynin stain for Nissl granules were used to assess various patterns of cell death and degenerative changes. Complex cell death mechanisms may be involved in the neuronal and axonal degeneration. These data indicate altered and differential mRNA expressions of BCL2 (anti apoptotic gene) and GADD45 (DNA damage inducible gene) in various tissues. Increased cell death and other degenerative changes noted in the susceptible regions (spinal cord and cerebellum) than the resistant region (cerebrum), may indicate complex molecular pathways via altered BCL2 and GADD45 gene expression, causing the homeostatic imbalance between cell survival and cell death mechanisms. Semi quantitative

  20. Physiological mechanisms involved in resistance to cotton verticillium wilt induced by AM fungi

    Institute of Scientific and Technical Information of China (English)

    LIU Bing-jiang; LIU Run-jin

    2004-01-01

    @@ It was proved that arbuscular mycorrhizal (AM) fungi played an important role in increasing plant resistance to soilborne pathogens, especially when plants were pre-inoculated with AM fungi.Mechanisms involved in this phenomenon are not yet well understood. On the basis of the former experiment results in our lab, effects of AM fungi on cotton Verticillium wilt and the mechanisms of increasing disease resisitance by the tested fungi were studied in pot culture under greenhouse conditions. Two cotton cutivars Litai 8 and 86-1 which are susceptible to Verticillium dahliae were pre-inoculated with Glomus fasiculatum, and Gigaspora margarita, then inoculated with the strain of Verticillium dahliae, namely "An-Yang" (belong to intermediate virulent type) 30 days after the former inoculation. Results showed that AM fungi could improve the growth and development of cotton plants, increase plants dry mass, decrease incidence and disease index of Verticillium wilt of cotton plants, inhibit the infection and development of V. dahliae to different extent in the rhizosphere of cotton pre-inoculated with AM fungi, while the colonization and spore numbers of AM fungi were not reduced significantly by this pathogen. The defence enzymes, such as phenylalanine ammonia-lyase (PAL), chitinase, β-1, 3-glucanase, peroxidase, polyphenoloxidase (PPO) were induced, and their activities and peak increased by AM fungi in roots and leaves, and the increasing speed and peak of the enzyme activity were higher in treatment with AM fungus preinoculation than the inoculation with only V. dahliae, which suggested that defense response was activated by AM fungi, and then made the cotton to react strongly and rapidly to the infection of V. dahliae. In addition, AM fungi decreased the content of malondiadehyde (MDA) in cotton roots and leaves,protected membrane system and alleviated the damage caused by the pathogen. The AM fungus,Glomus fasiculatum showed the superior effects of biological

  1. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

    Directory of Open Access Journals (Sweden)

    Sagai Masaru

    2011-12-01

    moderate oxidative stress. Recently these concepts have become widely accepted. The versatility of ozone in treating vascular and degenerative diseases as well as skin lesions, hernial disc and primary root carious lesions in children is emphasized. Further researches able to elucidate whether the mechanisms of action of ozone therapy involve nuclear transcription factors, such as Nrf2, NFAT, AP-1, and HIF-1α are warranted.

  2. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

    Science.gov (United States)

    2011-01-01

    oxidative stress. Recently these concepts have become widely accepted. The versatility of ozone in treating vascular and degenerative diseases as well as skin lesions, hernial disc and primary root carious lesions in children is emphasized. Further researches able to elucidate whether the mechanisms of action of ozone therapy involve nuclear transcription factors, such as Nrf2, NFAT, AP-1, and HIF-1α are warranted. PMID:22185664

  3. Inhibition of cAMP-activated intestinal chloride secretion by diclofenac: cellular mechanism and potential application in cholera.

    Directory of Open Access Journals (Sweden)

    Pawin Pongkorpsakol

    2014-09-01

    Full Text Available Cyclic AMP-activated intestinal Cl- secretion plays an important role in pathogenesis of cholera. This study aimed to investigate the effect of diclofenac on cAMP-activated Cl- secretion, its underlying mechanisms, and possible application in the treatment of cholera. Diclofenac inhibited cAMP-activated Cl- secretion in human intestinal epithelial (T84 cells with IC50 of ∼ 20 µM. The effect required no cytochrome P450 enzyme-mediated metabolic activation. Interestingly, exposures of T84 cell monolayers to diclofenac, either in apical or basolateral solutions, produced similar degree of inhibitions. Analyses of the apical Cl- current showed that diclofenac reversibly inhibited CFTR Cl- channel activity (IC50 ∼ 10 µM via mechanisms not involving either changes in intracellular cAMP levels or CFTR channel inactivation by AMP-activated protein kinase and protein phosphatase. Of interest, diclofenac had no effect on Na(+-K(+ ATPases and Na(+-K(+-Cl- cotransporters, but inhibited cAMP-activated basolateral K(+ channels with IC50 of ∼ 3 µM. In addition, diclofenac suppressed Ca(2+-activated Cl- channels, inwardly rectifying Cl- channels, and Ca(2+-activated basolateral K(+ channels. Furthermore, diclofenac (up to 200 µM; 24 h of treatment had no effect on cell viability and barrier function in T84 cells. Importantly, cholera toxin (CT-induced Cl- secretion across T84 cell monolayers was effectively suppressed by diclofenac. Intraperitoneal administration of diclofenac (30 mg/kg reduced both CT and Vibrio cholerae-induced intestinal fluid secretion by ∼ 70% without affecting intestinal fluid absorption in mice. Collectively, our results indicate that diclofenac inhibits both cAMP-activated and Ca(2+-activated Cl- secretion by inhibiting both apical Cl- channels and basolateral K+ channels in intestinal epithelial cells. Diclofenac may be useful in the treatment of cholera and other types of secretory diarrheas resulting from intestinal

  4. A knock-in model of human epilepsy in Drosophila reveals a novel cellular mechanism associated with heat-induced seizure

    OpenAIRE

    Sun, Lei; Gilligan, Jeff; Staber, Cynthia; Schutte, Ryan J; Nguyen, Vivian; O'Dowd, Diane K.; Reenan, Robert

    2012-01-01

    Over 40 missense mutations in the human SCN1A sodium channel gene are linked to an epilepsy syndrome termed genetic epilepsy with febrile seizures plus (GEFS+). Inheritance of GEFS+ is dominant but the underlying cellular mechanisms remain poorly understood. Here we report knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semi-dominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains o...

  5. Pathophysiological mechanisms involved in non-alcoholicsteatohepatitis and novel potential therapeutic targets

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major healthcare problem and represents the hepatic expression ofthe metabolic syndrome. NAFLD is classified as nonalcoholicfatty liver (NAFL) or simple steatosis, and nonalcoholicsteatohepatitis (NASH). NASH is characterizedby the presence of steatosis and inflammation withor without fibrosis. The physiopathology of NAFL andNASH and their progression to cirrhosis involve severalparallel and interrelated mechanisms, such as, insulinresistance (IR), lipotoxicity, inflammation, oxidativestress, and recently the gut-liver axis interaction has beendescribed. Incretin-based therapies could play a role inthe treatment of NAFLD. Glucagon-like peptide-1 (GLP-1)is an intestinal mucosa-derived hormone which is secretedinto the bloodstream in response to nutrient ingestion;it favors glucose-stimulated insulin secretion, inhibitionof postprandial glucagon secretion and delayed gastricemptying. It also promotes weight loss and is involvedin lipid metabolism. Once secreted, GLP-1 is quicklydegraded by dipeptidyl peptidase-4 (DPP-4). Therefore,DPP-4 inhibitors are able to extend the activity of GLP-1.Currently, GLP-1 agonists and DPP-4 inhibitors representattractive options for the treatment of NAFLD andNASH. The modulation of lipid and glucose metabolismthrough nuclear receptors, such as the farsenoid Xreceptor, also constitutes an attractive therapeutic target.Obeticholic acid is a potent activator of the farnesoidX nuclear receptor and reduces liver fat content andfibrosis in animal models. Ursodeoxycholic acid (UDCA)is a hydrophilic bile acid with immunomodulatory, antiinflammatory,antiapoptotic, antioxidant and antifibroticproperties. UDCA can improve IR and modulatelipid metabolism through its interaction with nuclearreceptors such as, TGR5, farnesoid X receptor-a, orthe small heterodimeric partner. Finally, pharmacologicmodulation of the gut microbiota could have a role in thetherapy of NAFLD and

  6. Mechanisms involved in the selective transfer of long chain polyunsaturted fatty acids to the fetus

    Directory of Open Access Journals (Sweden)

    Alfonso eGil-Sánchez

    2011-09-01

    Full Text Available The concentration of long chain polyunsaturated fatty acid (LCPUFA in the fetal brain increases dramatically from the third trimester until 18 months of life. Several studies have shown an association between the percentage of maternal plasma docosahexaenoic acid (DHA during gestation and development of the cognitive functions in the neonate. Since only very low levels of LCPUFA are synthesized in the fetus and placenta, their primary source for the fetus is that of maternal origin. Both in vitro and human in vivo studies using labelled fatty acids have shown the preferential transfer of LCPUFA from the placenta to the fetus compared with other fatty acids, although the mechanisms involved are still uncertain. The placenta takes up circulating maternal non-esterified fatty acids (NEFA and fatty acids released mainly by maternal lipoprotein lipase and endothelial lipase. These NEFA may enter the cell by passive diffusion or by means of membrane carrier proteins. Once in the cytosol, NEFA bind to cytosolic fatty acid-binding proteins for transfer to the fetal circulation or can be oxidized within the trophoblasts and even re-esterified and stored in lipid droplets (LD. Although trophoblast cells are not specialized in lipid storage, LCPUFA may up-regulate peroxisome proliferator activated receptor-γ (PPARγ and hence the gene expression of fatty acid transport carriers, fatty acid acyl-CoA synthetases and adipophilin or other enzymes related with lipolysis, modifying their rate of placental transfer and metabolization. The placental transfer of LCPUFA during pregnancy seems to be a key factor in the neurological development of the fetus. Increased knowledge on the factors that modify placental transfer of fatty acids would contribute to our understanding of this complex process.

  7. Mechanisms of antibody-dependent cellular cytotoxicity: the use of effector cells from chronic granulomatous disease patients as investigative probes.

    OpenAIRE

    Katz, P.; Simone, C B; Henkart, P A; Fauci, A S

    1980-01-01

    The present study characterized the antibody-dependent cellular cytoxicity (ADCC) of leukocyte effector cells (neutrophils, lymphocytes, and monocytes) from normal subjects and from chronic granulomatous disease (CGD) patients. CGD phagocytic cells (neutrophils and monocytes) had depressed ADCC activity against antibody-coated human erythrocyte (HRBC) targets in suspension cultures indicative of abnormal intracellular postphagocytic killing. However, when phagocytosis was prevented by using a...

  8. p16(INK4a suppression by glucose restriction contributes to human cellular lifespan extension through SIRT1-mediated epigenetic and genetic mechanisms.

    Directory of Open Access Journals (Sweden)

    Yuanyuan Li

    Full Text Available Although caloric restriction (CR has been shown to increase lifespan in various animal models, the mechanisms underlying this phenomenon have not yet been revealed. We developed an in vitro system to mimic CR by reducing glucose concentration in cell growth medium which excludes metabolic factors and allows assessment of the effects of CR at the cellular and molecular level. We monitored cellular proliferation of normal WI-38, IMR-90 and MRC-5 human lung fibroblasts and found that glucose restriction (GR can inhibit cellular senescence and significantly extend cellular lifespan compared with cells receiving normal glucose (NG in the culture medium. Moreover, GR decreased expression of p16(INK4a (p16, a well-known senescence-related gene, in all of the tested cell lines. Over-expressed p16 resulted in early replicative senescence in glucose-restricted cells suggesting a crucial role of p16 regulation in GR-induced cellular lifespan extension. The decreased expression of p16 was partly due to GR-induced chromatin remodeling through effects on histone acetylation and methylation of the p16 promoter. GR resulted in an increased expression of SIRT1, a NAD-dependent histone deacetylase, which has positive correlation with CR-induced longevity. The elevated SIRT1 was accompanied by enhanced activation of the Akt/p70S6K1 signaling pathway in response to GR. Furthermore, knockdown of SIRT1 abolished GR-induced p16 repression as well as Akt/p70S6K1 activation implying that SIRT1 may affect p16 repression through direct deacetylation effects and indirect regulation of Akt/p70S6K1 signaling. Collectively, these results provide new insights into interactions between epigenetic and genetic mechanisms on CR-induced longevity that may contribute to anti-aging approaches and also provide a general molecular model for studying CR in vitro in mammalian systems.

  9. The Influence of Receptor-Mediated Interactions on Reaction-Diffusion Mechanisms of Cellular Self-organisation

    KAUST Repository

    Klika, Václav

    2011-11-10

    Understanding the mechanisms governing and regulating self-organisation in the developing embryo is a key challenge that has puzzled and fascinated scientists for decades. Since its conception in 1952 the Turing model has been a paradigm for pattern formation, motivating numerous theoretical and experimental studies, though its verification at the molecular level in biological systems has remained elusive. In this work, we consider the influence of receptor-mediated dynamics within the framework of Turing models, showing how non-diffusing species impact the conditions for the emergence of self-organisation. We illustrate our results within the framework of hair follicle pre-patterning, showing how receptor interaction structures can be constrained by the requirement for patterning, without the need for detailed knowledge of the network dynamics. Finally, in the light of our results, we discuss the ability of such systems to pattern outside the classical limits of the Turing model, and the inherent dangers involved in model reduction. © 2011 Society for Mathematical Biology.

  10. Modulation of NADH Levels by Arabidopsis Nudix Hydrolases, AtNUDX6 and 7, and the Respective Proteins Themselves Play Distinct Roles in the Regulation of Various Cellular Responses Involved in Biotic/Abiotic Stresses.

    Science.gov (United States)

    Ogawa, Takahisa; Muramoto, Kohei; Takada, Risa; Nakagawa, Shouya; Shigeoka, Shigeru; Yoshimura, Kazuya

    2016-06-01

    Arabidopsis Nudix hydrolases, AtNUDX6 and 7, exhibit pyrophosphohydrolase activities toward NADH and contribute to the modulation of various defense responses, such as the poly(ADP-ribosyl)ation (PAR) reaction and salicylic acid (SA)-induced Nonexpresser of Pathogenesis-Related genes 1 (NPR1)-dependent defense pathway, against biotic and abiotic stresses. However, the mechanisms by which these enzymes regulate such cellular responses remain unclear. To clarify the functional role(s) of AtNUDX6 and 7 and NADH metabolism, we examined the effects of the transient expression of the active and inactive forms of AtNUDX6 and 7 under the control of an estrogen (ES)-inducible system on various stress responses. The transient expression of active AtNUDX6 and 7 proteins suppressed NADH levels and induced PAR activity, whereas that of their inactive forms did not, indicating the involvement of NADH metabolism in the regulation of the PAR reaction. A transcriptome analysis using KO-nudx6, KO-nudx7 and double KO-nudx6/7 plants, in which intracellular NADH levels increased, identified genes (NADH-responsive genes, NRGs) whose expression levels positively and negatively correlated with NADH levels. Many NRGs did not overlap with the genes whose expression was reported to be responsive to various types of oxidants and reductants, suggesting a novel role for intracellular NADH levels as a redox signaling cue. The active and inactive AtNUDX6 proteins induced the expression of thioredoxin-h5, the activator of NPR1 and SA-induced NPR1-dependent defense genes, while the active and inactive AtNUDX7 proteins suppressed the accumulation of SA and subsequent gene expression, indicating that AtNUDX6 and 7 proteins themselves play distinct roles in stress responses. PMID:27095738

  11. Comparison on cellular mechanisms of iron and cadmium accumulation in rice: prospects for cultivating Fe-rich but Cd-free rice.

    Science.gov (United States)

    Gao, Lei; Chang, Jiadong; Chen, Ruijie; Li, Hubo; Lu, Hongfei; Tao, Longxing; Xiong, Jie

    2016-12-01

    Iron (Fe) is essential for rice growth and humans consuming as their staple food but is often deficient because of insoluble Fe(III) in soil for rice growth and limited assimilation for human bodies, while cadmium (Cd) is non-essential and toxic for rice growth and humans if accumulating at high levels. Over-accumulated Cd can cause damage to human bodies. Selecting and breeding Fe-rich but Cd-free rice cultivars are ambitious, challenging and meaningful tasks for researchers. Although evidences show that the mechanisms of Fe/Cd uptake and accumulation in rice are common to some extent as a result of similar entry routes within rice, an increasing number of researchers have discovered distinct mechanisms between Fe/Cd uptake and accumulation in rice. This comprehensive review systematically elaborates and compares cellular mechanisms of Fe/Cd uptake and accumulation in rice, respectively. Mechanisms for maintaining Fe homeostasis and Cd detoxicification are also elucidated. Then, effects of different fertilizer management on Fe/Cd accumulation in rice are discussed. Finally, this review enumerates various approaches for reducing grain Cd accumulation and enhancing Fe content in rice. In summary, understanding of discrepant cellular mechanisms of Fe/Cd accumulation in rice provides guidance for cultivating Fe-fortified rice and has paved the way to develop rice that are tolerant to Cd stress, aiming at breeding Fe-rich but Cd-free rice. PMID:27502932

  12. Early-life Stress Impacts the Developing Hippocampus and Primes Seizure Occurrence: cellular, molecular, and epigenetic mechanisms

    Directory of Open Access Journals (Sweden)

    Li-Tung eHuang

    2014-02-01

    Full Text Available Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures and an increase in epileptogenesis. This article reviews the cellular and molecular changes encountered during prenatal and postnatal stress, and assesses the possible link between these changes and increases in seizure occurrence and epileptogenesis in the developing hippocampus. In addititon, the priming effect of prenatal and postnatal stress for seizures and epileptogenesis is discussed. Finally, the roles of epigenetic modifications in hippocampus and HPA axis programming, early-life stress, and epilepsy are discussed.

  13. DNA-Destabilizing Agents as an Alternative Approach for Targeting DNA: Mechanisms of Action and Cellular Consequences

    Directory of Open Access Journals (Sweden)

    Gaëlle Lenglet

    2010-01-01

    Full Text Available DNA targeting drugs represent a large proportion of the actual anticancer drug pharmacopeia, both in terms of drug brands and prescription volumes. Small DNA-interacting molecules share the ability of certain proteins to change the DNA helix's overall organization and geometrical orientation via tilt, roll, twist, slip, and flip effects. In this ocean of DNA-interacting compounds, most stabilize both DNA strands and very few display helix-destabilizing properties. These types of DNA-destabilizing effect are observed with certain mono- or bis-intercalators and DNA alkylating agents (some of which have been or are being developed as cancer drugs. The formation of locally destabilized DNA portions could interfere with protein/DNA recognition and potentially affect several crucial cellular processes, such as DNA repair, replication, and transcription. The present paper describes the molecular basis of DNA destabilization, the cellular impact on protein recognition, and DNA repair processes and the latter's relationships with antitumour efficacy.

  14. Differential Effects of Polymer-Surface Decoration on Drug Delivery, Cellular Retention, and Action Mechanisms of Functionalized Mesoporous Silica Nanoparticles.

    Science.gov (United States)

    You, Yuanyuan; Hu, Hao; He, Lizhen; Chen, Tianfeng

    2015-12-01

    Polymer-surface decoration has been found to be an effective strategy to enhance the biological activities of nanomedicine. Herein, three different types of polymers with a cancer-targeting ligand Arg-Gly-Asp peptide (RGD) have been used to decorate mesoporous silica nanoparticles (MSNs) and the functionalized nanosystems were used as drug carriers of oxaliplatin (OXA). The results showed that polymer-surface decoration of the MSNs nanosystem by poly(ethylene glycol) (PEG) and polyethyleneimine (PEI) significantly enhanced the anticancer efficacy of OXA, which was much higher than that of chitosan (CTS). This effect was closely related to the enhancement of the cellular uptake and cellular drug retention. Moreover, PEI@MSNs-OXA possessed excellent advantages in penetrating ability and inhibitory effects on SW480 spheroids that were used to simulate the in vivo tumor environments. Therefore, this study provides useful information for the rational design of a cancer-targeted MSNs nanosystem with polymer-surface decoration. PMID:26248202

  15. Mechanisms involved in the psychological distress of Black Caribbeans in the United States

    Science.gov (United States)

    Govia, Ishtar O.

    The mental health of ethnic minorities in the United States is of urgent concern. The accelerated growth of groups of ethnic minorities and immigrants in the United States and the stressors to which they are exposed, implores academic researchers to investigate more deeply health disparities and the factors that exacerbate or minimize such inequalities. This dissertation attended to that concern. It used data from the National Survey of American Life (NSAL), the first survey with a national representative sample of Black Caribbeans, to explore mechanisms that involved in the psychological distress of Black Caribbeans in the United States. In a series of three studies, the dissertation investigated the role and consequence of (1) chronic discrimination, immigration factors, and closeness to ethnic and racial groups; (2) personal control and social support; and (3) family relations and social roles in the psychological distress of Black Caribbeans. Study 1 examined how the associations between discrimination and psychological distress were buffered or exacerbated by closeness to ethnic group and closeness to racial group. It also examined how these associations differed depending on immigration factors. Results indicated that the buffering or exacerbating effect of ethnic and racial group closeness varied according to the type of discrimination (subtle or severe) and were more pronounced among those born in the United States. Using the stress process framework, Study 2 tested moderation and mediation models of the effects of social support and personal control in the association between discrimination and distress. Results from a series of analyses on 579 respondents suggested that personal control served as a mediator in this relationship and that emotional support exerted a direct distress deterring function. Study 3 investigated sex differences in the associations between social roles, intergenerational family relationship perceptions and distress. Results

  16. Early-life Stress Impacts the Developing Hippocampus and Primes Seizure Occurrence: cellular, molecular, and epigenetic mechanisms

    OpenAIRE

    Li-Tung eHuang

    2014-01-01

    Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures...

  17. Early-life stress impacts the developing hippocampus and primes seizure occurrence: cellular, molecular, and epigenetic mechanisms

    OpenAIRE

    Huang, Li-Tung

    2014-01-01

    Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures...

  18. Contributions of mass spectrometry-based proteomics to defining cellular mechanisms and diagnostic markers for systemic lupus erythematosus

    OpenAIRE

    Korte, Erik A.; Gaffney, Patrick M.; Powell, David W.

    2012-01-01

    Systematic lupus erythematosus (SLE) is a complex disease for which molecular diagnostics are limited and pathogenesis is not clearly understood. Important information is provided in this regard by identification and characterization of more specific molecular and cellular targets in SLE immune cells and target tissue and markers of early-onset and effective response to treatment of SLE complications. In recent years, advances in proteomic technologies and applications have facilitated such d...

  19. Mangiferin, a natural xanthone, accelerates gastrointestinal transit in mice involving cholinergic mechanism

    Institute of Scientific and Technical Information of China (English)

    Talita Cavalcante Morais; Synara Cavalcante Lopes; Karine Maria Martins Bezerra Carvalho; Bruno Rodrigues Arruda; Francisco Thiago Correia de Souza; Maria Teresa Salles Trevisan; Vietla Satyanarayana Rao; Flávia Almeida Santos

    2012-01-01

    AIM:To investigate the effects of mangiferin on gastrointestinal transit (GIT) in normal and constipated mice,together with the possible mechanism.METHODS:Intragastrically-administered charcoal meal was used to measure GIT in overnight starved Swiss mice.In the first experiments,mangiferin (3 mg/kg,10mg/kg,30 mg/kg,and 100 mg/kg,po) or tegaserod (1mg/kg,ip) were administered 30 min before the charcoal meal to study their effects on normal transit.In the second series,mangiferin (30 mg/kg) was tested on delayed GIT induced by several different pharmacological agonists (morphine,clonidine,capsaicin) or antagonists (ondansetron,verapamil,and atropine) whereas in the third series,mangiferin (30 mg/kg,100mg/kg and 300 mg/kg) or tegaserod (1 mg/kg) were tested on 6 h fecal pellets outputted by freely fed mice.The ratio of wet to dry weight was calculated and used as a marker of fecal water content.RESULTS:Mangiferin administered orally significantly (P < 0.05) accelerated GIT at 30 mg/kg and 100 mg/kg (89%and 93%,respectively),similarly to 5-hydroxytryptamine4 (5-HT4) agonist tegaserod (81%) when compared to vehicle-treated control (63%).Co-administered mangiferin (30 mg/kg) totally reversed the inhibitory effect of opioid agonist morphine,5-HT3-receptor antagonist ondansetron and transient receptor potential vanilloid-1 receptor agonist capsaicin on GIT,but only to a partial extent with the GIT-delay induced by α2-adrenoceptor agonist clonidine,and calcium antagonist verapamil.However,co-administered atropine completely blocked the stimulant effect of mangiferin on GIT,suggesting the involvement of muscarinic acetylcholine receptor activation.Although mangiferin significantly enhanced the 6 h fecal output at higher doses (245.5 ± 10.43 mg vs 161.9 ± 10.82 mg and 227.1 ± 20.11 mg vs 161.9 ±10.82 mg of vehicle-treated control,at 30 and 100 mg/kg,P < 0.05,respectively),the effect of tegaserod was more potent (297.4 ± 7.42 mg vs 161.9 ± 10.82 mg of

  20. Confocal imaging of whole vertebrate embryos reveals novel insights into molecular and cellular mechanisms of organ development

    Science.gov (United States)

    Hadel, Diana M.; Keller, Bradley B.; Sandell, Lisa L.

    2014-03-01

    Confocal microscopy has been an invaluable tool for studying cellular or sub-cellular biological processes. The study of vertebrate embryology is based largely on examination of whole embryos and organs. The application of confocal microscopy to immunostained whole mount embryos, combined with three dimensional (3D) image reconstruction technologies, opens new avenues for synthesizing molecular, cellular and anatomical analysis of vertebrate development. Optical cropping of the region of interest enables visualization of structures that are morphologically complex or obscured, and solid surface rendering of fluorescent signal facilitates understanding of 3D structures. We have applied these technologies to whole mount immunostained mouse embryos to visualize developmental morphogenesis of the mammalian inner ear and heart. Using molecular markers of neuron development and transgenic reporters of neural crest cell lineage we have examined development of inner ear neurons that originate from the otic vesicle, along with the supporting glial cells that derive from the neural crest. The image analysis reveals a previously unrecognized coordinated spatial organization between migratory neural crest cells and neurons of the cochleovestibular nerve. The images also enable visualization of early cochlear spiral nerve morphogenesis relative to the developing cochlea, demonstrating a heretofore unknown association of neural crest cells with extending peripheral neurite projections. We performed similar analysis of embryonic hearts in mouse and chick, documenting the distribution of adhesion molecules during septation of the outflow tract and remodeling of aortic arches. Surface rendering of lumen space defines the morphology in a manner similar to resin injection casting and micro-CT.

  1. A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-α

    Directory of Open Access Journals (Sweden)

    Dickinson Bryony A

    2009-06-01

    Full Text Available Abstract Background Long-term depression (LTD in the hippocampus can be induced by activation of different types of G-protein coupled receptors, in particular metabotropic glutamate receptors (mGluRs and muscarinic acethycholine receptors (mAChRs. Since mGluRs and mAChRs activate the same G-proteins and isoforms of phospholipase C (PLC, it would be expected that these two forms of LTD utilise the same molecular mechanisms. However, we find a distinct mechanism of LTD involving GRIP and liprin-α. Results Whilst both forms of LTD require activation of tyrosine phosphatases and involve internalisation of AMPARs, they use different molecular interactions. Specifically, mAChR-LTD, but not mGluR-LTD, is blocked by peptides that inhibit the binding of GRIP to the AMPA receptor subunit GluA2 and the binding of GRIP to liprin-α. Thus, different receptors that utilise the same G-proteins can regulate AMPAR trafficking and synaptic efficacy via distinct molecular mechanisms. Conclusion Our results suggest that mAChR-LTD selectively involves interactions between GRIP and liprin-α. These data indicate a novel mechanism of synaptic plasticity in which activation of M1 receptors results in AMPAR endocytosis, via a mechanism involving interactions between GluA2, GRIP and liprin-α.

  2. Involvement of mast cells and proteinase-activated receptor 2 in oxaliplatin-induced mechanical allodynia in mice.

    Science.gov (United States)

    Sakamoto, Ayumi; Andoh, Tsugunobu; Kuraishi, Yasushi

    2016-03-01

    The chemotherapeutic agent oxaliplatin induces neuropathic pain, a dose-limiting side effect, but the underlying mechanisms are not fully understood. Here, we show the potential involvement of cutaneous mast cells in oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin induced mechanical allodynia, which peaked on day 10 after injection. Oxaliplatin-induced mechanical allodynia was almost completely prevented by congenital mast cell deficiency. The numbers of total and degranulated mast cells was significantly increased in the skin after oxaliplatin administration. Repetitive topical application of the mast cell stabilizer azelastine hydrochloride inhibited mechanical allodynia and the degranulation of mast cells without affecting the number of mast cells in oxaliplatin-treated mice. The serine protease inhibitor camostat mesilate and the proteinase-activated receptor 2 (PAR2) antagonist FSLLRY-NH2 significantly inhibited oxaliplatin-induced mechanical allodynia. However, it was not inhibited by the H1 histamine receptor antagonist terfenadine. Single oxaliplatin administration increased the activity of cutaneous serine proteases, which was attenuated by camostat and mast cell deficiency. Depletion of the capsaicin-sensitive primary afferents by neonatal capsaicin treatment almost completely prevented oxaliplatin-induced mechanical allodynia, the increase in the number of mast cells, and the activity of cutaneous serine proteases. These results suggest that serine protease(s) released from mast cells and PAR2 are involved in oxaliplatin-induced mechanical allodynia. Therefore, oxaliplatin may indirectly affect the functions of mast cells through its action on capsaicin-sensitive primary afferents. PMID:26804251

  3. Rapid, Opioid-sensitive Mechanisms Involved in Transient Receptor Potential Vanilloid 1 Sensitization*S⃞

    OpenAIRE

    Vetter, Irina; Cheng, Wei; Peiris, Madusha; Wyse, Bruce D; Sarah J. Roberts-Thomson; Zheng, Jie; Monteith, Gregory R.; Cabot, Peter J.

    2008-01-01

    TRPV1 is a nociceptive, Ca2+-selective ion channel involved in the development of several painful conditions. Sensitization of TRPV1 responses by cAMP-dependent PKA crucially contributes to the development of inflammatory hyperalgesia. However, the pathways involved in potentiation of TRPV1 responses by cAMP-dependent PKA remain largely unknown. Using HEK cells stably expressing TRPV1 and the μ opioid receptor, we demonstrated that treatment with the adenylate cyclase ...

  4. Adult criminal involvement: A cross-sectional inquiry into correlates and mechanisms over the life course

    OpenAIRE

    DePadilla, Lara; Perkins, Molly M.; Elifson, Kirk W.; Sterk, Claire E.

    2012-01-01

    In this paper, we examine the relative contribution of four domains of predictors that have been linked to adult criminal involvement: (1) socio-demographic characteristics, (2) family-of-origin factors, (3) proximal processes developed during adolescence, and (4) current lifestyle and situational factors. Cross-sectional data were collected through face-to-face interviews with 242 community-recruited adults. Data analysis involved negative binomial regression. Being male, f...

  5. Fatty-acid metabolism is involved in stress-resistance mechanisms of Caenorhabditis elegans

    OpenAIRE

    Horikawa, Makoto; Sakamoto, Kazuichi

    2009-01-01

    Fatty acids are the major components of the phospholipid bilayer and are involved in several functions of cell membrane. We previously reported that fatty-acid metabolism is involved in the regulation of DAF-2/insulin signal in Caenorhabditis elegans. In this study, we investigate the role of fatty-acid metabolism in stress resistance with respect to daf-16 in nematode. We found that fatty-acid metabolism regulates heat, osmotic, and oxidative-stress resistance in C. elegans. RNA interference...

  6. Involvement of a glibenclamide-sensitive mechanism in the nitrergic neurotransmission of the pig intravesical ureter

    Science.gov (United States)

    Hernández, Medardo; Prieto, Dolores; Orensanz, Luis M; Barahona, María Victoria; Jiménez-Cidre, Miguel; Rivera, Luis; García-Sacristán, Albino; Simonsen, Ulf

    1997-01-01

    The present study was designed to investigate whether potassium (K+) channels are involved in the relaxations to nitric oxide (NO) of pig intravesical ureteral preparations suspended in organ baths for isometric tension recordings. In ureteral strips treated with guanethidine (10−5 M) and atropine (10−7 M) to block adrenergic neurotransmission and muscarinic receptors, respectively, NO was either released from nitrergic nerves by electrical field stimulation (EFS, 0.5–10 Hz, 1 ms duration, 20 s trains), or exogenously-applied as an acidified solution of sodium nitrite (NaNO2, 10−6–10−3 M).Incubation with an inhibitor of guanylate cyclase activation by NO, methylene blue (10−5 M) did not change the basal tension of intravesical ureteral strips but inhibited the relaxation induced by EFS or exogenous NO on ureteral preparations contracted with the thromboxane analogue U46619 (10−7 M).Incubation with charybdotoxin (3×10−8 M) and apamin (5×10−7 M), which are inhibitors of large and small conductance calcium (Ca2+)-activated K+ channels, respectively, did not modify basal tension or the relaxations induced by EFS and exogenous NO. Treatment with charybdotoxin or apamin plus methylene blue (10−5 M) significantly reduced the relaxations to EFS and exogenous NO. However, in both cases the reductions were similar to the inhibition evoked by methylene blue alone. The combined addition of charybdotoxin plus apamin did not change the relaxations to EFS or exogenously added NO of the porcine intravesical ureter.Cromakalim (10−8–3×10−6 M), an opener of ATP-sensitive K+ channels, evoked a dose-dependent relaxation with a pD2 of 7.3±0.2 and maximum relaxant effect of a 71.8±4.2% of the contraction induced by U46619 in the pig intravesical ureter. The blocker of ATP-sensitive K+ channels, glibenclamide (10−6 M), inhibited markedly the relaxations to cromakalim.Glibenclamide (10−6 M) had no effect on the basal tone of

  7. Purely Mechanical Memristors: Perfect Massless Memory Resistors, the Missing Perfect Mass-Involving Memristor, and Massive Memristive Systems

    OpenAIRE

    Vongehr, Sascha

    2015-01-01

    We define a mechanical analog to the electrical basic circuit element M = d{\\phi}/dQ, namely the ideal mechanical memristance M = dp/dx; p is momentum. We then introduce a mechanical memory resistor which has M(x) independent of velocity v, so it is a perfect (= not-just-memristive) memristor, although its memristance does not crucially involve inert mass. It is practically realizable with a 1cm radius hollow sphere in heavy fuel oil with a temperature gradient. It has a pinched hysteretic lo...

  8. Swarming mechanisms in the yellow fever mosquito: aggregation pheromones involved in the mating behavior of Aedes aegypti

    Science.gov (United States)

    Mosquitoes of various species mate in swarms comprised of tens to thousands flying males. Yet little information is known about mosquito swarming mechanism. Discovering chemical cues involved in mosquito biology leads to better adaptation of disease control interventions. In this study, we aimed ...

  9. Study of the Chemical Mechanism Involved in the Formation of Tungstite in Benzyl Alcohol by the Advanced QEXAFS Technique

    DEFF Research Database (Denmark)

    Olliges‐Stadler, Inga; Stötzel, Jan; Koziej, Dorota;

    2012-01-01

    Insight into the complex chemical mechanism for the formation of tungstite nanoparticles obtained by the reaction of tungsten hexachloride with benzyl alcohol is presented herein. The organic and inorganic species involved in the formation of the nanoparticles were studied by time‐dependent gas c...

  10. Molecular mechanism for the involvement of nuclear receptor FXR in HBV-associated hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Yong-dong Niu

    2011-08-01

    Full Text Available Farnesoid X receptor (FXR, also termed nuclear receptor NR1H4 is critically involved in the regulation of nascent bile formation and bile acid enterohepatic circulation. FXR and bile acids have been shown to play roles in liver regeneration and inflammatory responses. There is increasing evidence suggesting that FXR and the FXR signaling pathway are involved in the pathophysiology of a wide range of liver diseases, such as viral hepatitis, cirrhosis, and hepatocellular carcinoma (HCC. Here we discuss the latest discoveries of FXR functions with relevance to bile acid metabolism and HBV-associated HCC. More specifically, the goal of this review is to discuss the roles of FXR and bile acids in regulating HBV replication and how disregulation of the FXR-bile acid signaling pathway is involved in HBV-associated hepatocarcinogenesis.

  11. A Mechanism for Land-Atmosphere Feedback Involving Planetary Wave Structures

    Science.gov (United States)

    Koster, Randal D.; Chang, Yehui; Schubert, Siegfried D.

    2014-01-01

    While the ability of land surface conditions to influence the atmosphere has been demonstrated in various modeling and observational studies, the precise mechanisms by which land-atmosphere feedback occurs are still largely unknown particularly the mechanisms that allow land moisture state in one region to affect atmospheric conditions in another. Such remote impacts are examined here in the context of atmospheric general circulation model (AGCM) simulations, leading to the identification of one potential mechanism: the phase-locking and amplification of a planetary wave through the imposition of a spatial pattern of soil moisture at the land surface. This mechanism, shown here to be relevant in the AGCM, apparently also operates in nature, as suggested by supporting evidence found in reanalysis data.

  12. Positive and negative regulatory mechanisms for fine-tuning cellularity and functions of medullary thymic epithelial cells

    Directory of Open Access Journals (Sweden)

    Taishin eAkiyama

    2015-09-01

    Full Text Available Self-tolerant T cells and regulatory T cells develop in the thymus. A wide variety of cell-cell interactions in the thymus is required for the differentiation, proliferation, and repertoire selection of T cells. Various secreted and cell surface molecules expressed in thymic epithelial cells mediate these processes. Moreover, cytokines expressed by cells of hematopoietic origin regulate the cellularity of thymic epithelial cells (TECs. Tumor necrosis factor (TNF family RANK ligand, lymphotoxin, and CD40 ligand, expressed in T cells and innate lymphoid cells (ILCs, promote the differentiation and proliferation of medullary TECs (mTECs that play critical roles in the induction of immune tolerance. A recent study suggests that interleukin-22 (IL-22 produced by ILCs promotes regeneration of TECs after irradiation. Intriguingly, TGF-β and osteoprotegerin limit cellularity of mTECs, thereby attenuating regulatory T cell generation. We will review recent insights into the molecular basis for cell-cell interactions regulating differentiation and proliferation of mTECs and also discuss about a perspective on use of mathematical models for understanding this complicated system.

  13. Molecules and mechanisms involved in the generation and migration of cortical interneurons

    Directory of Open Access Journals (Sweden)

    Luis R Hernández‑Miranda

    2010-03-01

    Full Text Available The GABA (γ-aminobutyric acid-containing interneurons of the neocortex are largely derived from the ganglionic eminences in the subpallium. Numerous studies have previously defined the migratory paths travelled by these neurons from their origins to their destinations in the cortex. We review here results of studies that have identified many of the genes expressed in the subpallium that are involved in the specification of the subtypes of cortical interneurons, and the numerous transcription factors, motogenic factors and guidance molecules that are involved in their migration.

  14. Attentional Biases toward Attractive Alternatives and Rivals: Mechanisms Involved in Relationship Maintenance among Chinese Women

    OpenAIRE

    Ma, Yidan; Zhao, Guang; Tu, Shen; Zheng, Yong

    2015-01-01

    A long-term romantic relationship can offer many benefits to committed individuals. Thus, humans possess relationship maintenance mechanisms to protect against threats from those who serve as attractive alternatives or intrasexual rivals. Many studies have indicated that romantic love can act as a commitment device to activate these mechanisms. To examine the attentional bias associated with relationship maintenance among 108 college students (49 single and 59 committed females) in China, we ...

  15. A conflict monitoring account of the control mechanisms involved in dual-tasking

    OpenAIRE

    Olszanowski, Michal; Bajo, Maria Teresa; Szmalec, Arnaud

    2015-01-01

    The present study investigates the cognitive mechanism underlying the control of interference during dual-task coordination. Partially inspired by the Conflict Monitoring Hypothesis (Botvinick et al., 2001), we test the assumption that dual-task interference is resolved by a top-down adaptation mechanism that is responsible for behavioral adjustments in the prioritization of the coordinated tasks. In a series of two experiments, we measured conflict adaptation to the so-called Gratton effect—...

  16. Cellular automata

    CERN Document Server

    Codd, E F

    1968-01-01

    Cellular Automata presents the fundamental principles of homogeneous cellular systems. This book discusses the possibility of biochemical computers with self-reproducing capability.Organized into eight chapters, this book begins with an overview of some theorems dealing with conditions under which universal computation and construction can be exhibited in cellular spaces. This text then presents a design for a machine embedded in a cellular space or a machine that can compute all computable functions and construct a replica of itself in any accessible and sufficiently large region of t

  17. Sensitizing Children to the Social and Emotional Mechanisms Involved in Racism: A Program Evaluation

    Science.gov (United States)

    Triliva, Sofia; Anagnostopoulou, Tanya; Vleioras, Georgios

    2014-01-01

    This paper describes and discusses the results of an intervention aiming to sensitize children to the social and emotional processes involved in racism. The intervention was applied and evaluated in 10 Greek elementary schools. The goals and the intervention methods of the program modules are briefly outlined and the results of the program…

  18. Rapid Disruption of Cellular Integrity of Zinc-treated Astroglia Is Regulated by p38 MAPK and Ca2+-dependent Mechanisms

    OpenAIRE

    Im, Joo-Young; Joo, Hyo-Jin; Han, Pyung-Lim

    2011-01-01

    Cultured cortical primary astroglia treated with zinc died while rapidly detached from culture plates, a distinct part of zinc-treated astroglia. In the present study, we investigated the mechanism underlying the rapid change in the morphologic integrity of zinc-treated astroglia. Among the early cellular events occurring in zinc-treated astroglia, strong activation of p38 MAPK and JNK was evident. Although inhibitors of p38 (SB203580 and SB202190) or JNK (SP600125) did not protect zinc-insul...

  19. BCR-ABL negative myeloproliferative neoplasia: a review of involved molecular mechanisms.

    Science.gov (United States)

    Koopmans, Suzanne M; Schouten, Harry C; van Marion, Ariënne M W

    2015-02-01

    The clonal bone marrow stem cell disorders essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) belong to the group of Philadelphia chromosome negative myeloproliferative neoplasia (Ph- MPN). In 2005 the JAK2(V617F) mutation was discovered which has generated more insight in the pathogenetic mechanism of the MPNs. More mutations have been detected in MPN patients since. However, the underlying cause of MPN has not been discovered so far. The mechanism of increased angiogenesis in MPNs and the development of fibrosis in the bone marrow in PMF patients and in some ET and PV patients is still not known. This review will focus on the most important molecular pathogenetic mechanisms in MPN patients. PMID:25196073

  20. The Role and Mechanisms of Action of Glucocorticoid Involvement in Memory Storage

    Directory of Open Access Journals (Sweden)

    Carmen Sandi

    1998-01-01

    integral aspect of the neurobiological mechanism underlying memory formation. By reviewing the work carried out in different learning models in chicks (passive avoidance learning and rats (spatial orientation in the Morris water maze and contextual fear conditioning, a role for brain corticosterone action through the glucocorticoid receptor type on the mechanisms of memory consolidation is hypothesized. Evidence is also presented to relate post-training corticosterone levels to the strength of memory storage. Finally, the possible molecular mechanisms that might mediate the influences of glucocorticoids in synaptic plasticity subserving long-term memory formation are considered, mainly by focusing on studies implicating a steroid action through (i glutamatergic transmission and (ii cell adhesion molecules.

  1. Tibolone protects astrocytic cells from glucose deprivation through a mechanism involving estrogen receptor beta and the upregulation of neuroglobin expression.

    Science.gov (United States)

    Avila-Rodriguez, Marco; Garcia-Segura, Luis Miguel; Hidalgo-Lanussa, Oscar; Baez, Eliana; Gonzalez, Janneth; Barreto, George E

    2016-09-15

    Tibolone, a synthetic steroid used for the prevention of osteoporosis and the treatment of climacteric symptoms in post-menopausal women, may exert tissue selective estrogenic actions acting on estrogen receptors (ERs). We previously showed that tibolone protects human T98G astroglial cells against glucose deprivation (GD). In this study we have explored whether the protective effect of tibolone on these cells is mediated by ERs. Experimental studies showed that both ERα and ERβ were involved in the protection by tibolone on GD cells, being ERβ preferentially involved on these actions over ERα. Tibolone increased viability of GD cells by a mechanism fully blocked by an ERβ antagonist and partially blocked by an ERα antagonist. Furthermore, ERβ inhibition prevented the effect of tibolone on nuclear fragmentation, ROS and mitochondrial membrane potential in GD cells. The protective effect of tibolone was mediated by neuroglobin. Tibolone upregulated neuroglobin in T98G cells and primary mouse astrocytes by a mechanism involving ERβ and neuroglobin silencing prevented the protective action of tibolone on GD cells. In summary, tibolone protects T98G cells by a mechanism involving ERβ and the upregulation of neuroglobin. PMID:27250720

  2. Mechanisms involved in the evasion of the host defence by Pseudomonas aeruginosa

    DEFF Research Database (Denmark)

    Kharazmi, A

    1991-01-01

    Pseudomonas aeruginosa, an extracellular opportunistic pathogen, utilizes two major mechanisms to evade the host defence system. One of these mechanisms is the production of a large number of extracellular products, such as proteases, toxins, and lipases. The two proteases, alkaline protease and...... elastase, inhibit the function of the cells of the immune system (phagocytes, NK cells, T cells), inactivate several cytokines (IL-1, IL-2, IFN-r, TNF), cleave immunoglobulins and inactivate complement. Inhibition of the local immune response by bacterial proteases provides an environment for the...

  3. VIGS for dissecting mechanisms involved in the symbiotic interaction of microbes with plants

    DEFF Research Database (Denmark)

    Grønlund, Mette

    Virus-induced gene silencing (VIGS) is an alternative reverse genetics tool for silencing of genes in some plants which are difficult to transform. The pea early browning virus (PEBV) has been developed as a VIGS vector and used in pea for functional analysis of several genes. Here, a PEBV-VIGS p......-VIGS protocol is described which is suitable for reverse genetics studies in pea for genes involved in the symbiosis with arbuscular mycorrhizal fungi and Rhizobium....

  4. Study of the effects of dietary polyunsaturated fatty acids: Molecular mechanisms involved intestinal inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Knoch, B.; Barnett, M. P. G.; Roy, N. C.; McNabb, W. C.

    2009-07-01

    The use of omics techniques in combination with model systems and molecular tools allows to understand how foods and food components act on metabolic pathways to regulate transcriptional processes. Polyunsaturated fatty acids have distinctive nutritional and metabolic effects because they give rise to lipid mediated products and affect the expression of various genes involved in intestinal inflammation. The present review focuses on the molecular effects of dietary polyunsaturated fatty acids on intestinal inflammation. (Author) 74 refs.

  5. Understanding the molecular mechanisms involved in the interfacial self-healing of supramolecular rubbers

    NARCIS (Netherlands)

    Bose, R.K.; Garcia Espallargas, S.J.; Van der Zwaag, S.

    2013-01-01

    Supramolecular rubbers based on 2-aminoethylimidazolidone and fatty acids with epoxy crosslinks have been shown to self-heal via multiple hydrogen bonding sites. In this work, several tools are used to investigate the molecular mechanisms taking place at the interface to understand cohesive healing

  6. Different mechanisms are involved in the antibody mediated inhibition of ligand binding to the urokinase receptor

    DEFF Research Database (Denmark)

    List, K; Høyer-Hansen, G; Rønne, E;

    1999-01-01

    Certain monoclonal antibodies are capable of inhibiting the biological binding reactions of their target proteins. At the molecular level, this type of effect may be brought about by completely different mechanisms, such as competition for common binding determinants, steric hindrance or...

  7. Radiation protection following nuclear power accidents: a survey of putative mechanisms involved in the radioprotective actions of taurine during and after radiation exposure.

    Directory of Open Access Journals (Sweden)

    Olav Christophersen

    2012-02-01

    damaged tissues, especially in the intestines, and 4 by functioning as an antifibrogenic agent. A detailed discussion is given of possible mechanisms involved both in the antioxidant effects of taurine, in its anti-inflammatory effects and in its role as a growth factor for leukocytes and nerve cells, which might be closely related to its role as an osmolyte important for cellular volume regulation because of the close connection between cell volume regulation and the regulation of protein synthesis as well as cellular protein degradation. While taurine supplementation alone would be expected to exert a therapeutic effect far better than negligible in patients that have been exposed to high doses of ionizing radiation, it may on theoretical grounds be expected that much better results may be obtained by using taurine as part of a multifactorial treatment strategy, where it may interact synergistically with several other nutrients, hormones or other drugs for optimizing antioxidant protection and minimizing harmful posttraumatic inflammatory reactions, while using other nutrients to optimize DNA and tissue repair processes, and using a combination of good diet, immunostimulatory hormones and perhaps other nontoxic immunostimulants (such as beta-glucans for optimizing the recovery of antiviral and antibacterial immune functions. Similar multifactorial treatment strategies may presumably be helpful in several other disease situations (including severe infectious diseases and severe asthma as well as for treatment of acute intoxications or acute injuries (both mechanical ones and severe burns where severely enhanced oxidative and/or nitrative stress and/or too much secretion of vasodilatory neuropeptides from C-fibres are important parts of the pathogenetic mechanisms that may lead to the death of the patient. Some case histories (with discussion of some of those mechanisms that may have been responsible for the observed therapeutic outcome are given for illustration of the

  8. Hormesis and Cellular Quality Control: A Possible Explanation for the Molecular Mechanisms that Underlie the Benefits of Mild Stress

    OpenAIRE

    Wiegant, F.A.C.; de Poot, S A H; Boers-Trilles, V.E.; Schreij, A.M.A

    2012-01-01

    In contrast to the detrimental action of severe stress conditions, the beneficial effects of mild stress, known as hormesis, is increasingly discussed and studied. A variety of applications for hormesis in risk assessment processes, anti-ageing strategies and clinical therapies have been proposed. The molecular mechanisms underlying the phenomenon of hormesis, however, are not yet fully understood. A possible mechanism that has been proposed for hormesis, the homoeostasis overshoot hypothesis...

  9. Mechanisms of post-transcriptional regulation of genes involved in FTDP-17

    OpenAIRE

    Fontana, Francesca

    2015-01-01

    MicroRNAs (miRNAs) are small non coding RNAs of 18-25 nt, capable of regulating mRNA translation and gene expression at post-transcriptional level. Alteration of miRNAs expression is often associated with human diseases, such as cancers and neurodegenerative pathologies. The main objective of this study is an analysis of the post-transcriptional regulation played by miRNAs of two important genes, MAPT and GRN, involved in Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP...

  10. Understanding the molecular mechanisms involved in the interfacial self-healing of supramolecular rubbers

    OpenAIRE

    Bose, R.K.; Garcia Espallargas, S.J.; Zwaag, S. van der

    2013-01-01

    Supramolecular rubbers based on 2-aminoethylimidazolidone and fatty acids with epoxy crosslinks have been shown to self-heal via multiple hydrogen bonding sites. In this work, several tools are used to investigate the molecular mechanisms taking place at the interface to understand cohesive healing in these polymers. The quantification of self-healing was performed via a tapered double cantilever beam (TDCB) geometry. The TDCB geometry is especially amenable to studying multiple healing cycle...

  11. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

    OpenAIRE

    Sagai Masaru; Bocci Velio

    2011-01-01

    Abstract The potential mechanisms of action of ozone therapy are reviewed in this paper. The therapeutic efficacy of ozone therapy may be partly due the controlled and moderate oxidative stress produced by the reactions of ozone with several biological components. The line between effectiveness and toxicity of ozone may be dependent on the strength of the oxidative stress. As with exercise, it is well known that moderate exercise is good for health, whereas excessive exercise is not. Severe o...

  12. Optimization of the Asymptotic Property of Mutual Learning Involving an Integration Mechanism of Ensemble Learning

    OpenAIRE

    Hara, Kazuyuki; Yamada, Takahiro

    2007-01-01

    We propose an optimization method of mutual learning which converges into the identical state of optimum ensemble learning within the framework of on-line learning, and have analyzed its asymptotic property through the statistical mechanics method.The proposed model consists of two learning steps: two students independently learn from a teacher, and then the students learn from each other through the mutual learning. In mutual learning, students learn from each other and the generalization er...

  13. Recovery of Respiratory Activity after C2 hemisection (C2HS): Involvement of Adenosinergic Mechanisms

    OpenAIRE

    Nantwi, Kwaku D

    2009-01-01

    Consequences of spinal cord injury (SCI) depend on the level and extent of injury. Cervical SCI often results in a compromised respiratory system. Primary treatment of SCI patients with respiratory insufficiency continues to be with mechanical ventilatory support. In an animal model of SCI, an upper cervical spinal cord hemisection paralyzes the hemidiaphragm ipsilateral to the side of injury. However, a latent respiratory motor pathway can be activated to restore respiratory function after i...

  14. Physiological and Molecular Mechanism of Nitric Oxide (NO) Involved in Bermudagrass Response to Cold Stress

    OpenAIRE

    Fan, Jibiao; Chen, Ke; Amombo, Erick; Hu, Zhengrong; Chen, Liang; Fu, Jinmin

    2015-01-01

    Bermudagrass is widely utilized in parks, lawns, and golf courses. However, cold is a key factor limiting resource use in bermudagrass. Therefore, it is meaningful to study the mechanism of bermudagrass response to cold. Nitric oxide (NO) is a crucial signal molecule with multiple biological functions. Thus, the objective of this study was to investigate whether NO play roles in bermudagrass response to cold. Sodium nitroprusside (SNP) was used as NO donor, while 2-phenyl-4,4,5,5-tetramentyli...

  15. Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B

    OpenAIRE

    Bhatt, Siddhartha R.; Lokhandwala, Mustafa F.; Banday, Anees Ahmad

    2014-01-01

    The association of oxidative stress with hypertension is well known. However, a causal role of oxidative stress in hypertension is unclear. Vascular angiotensin II type 1 receptor (AT1R) upregulation is a prominent contributor to pathogenesis of hypertension. However, the mechanisms causing this upregulation are unknown. Oxidative stress is an important regulator of protein expression via activation of transcription factors such as nuclear factor kappa B (NFκB). The present study was carried ...

  16. Pathogenic Mechanism of an Autism-Associated Neuroligin Mutation Involves Altered AMPA-Receptor Trafficking

    OpenAIRE

    Chanda, Soham; Aoto, Jason; Lee, Sung-Jin; Wernig, Marius; Südhof, Thomas C.

    2015-01-01

    Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Although the general synaptic role of neuroligins is undisputed, their specific functions at a synapse remain unclear, even controversial. Moreover, many neuroligin gene mutations were associated with autism, but the pathophysiological relevance of these mutations is often unknown, and their mechanisms of action uninvestigated. Here, we examine the synaptic effects of an autism-associated neuroligin-4 sub...

  17. Molecular mechanisms involved in the bidirectional relationship between diabetes mellitus and periodontal disease

    Directory of Open Access Journals (Sweden)

    Harpreet Singh Grover

    2013-01-01

    Full Text Available Both diabetes and periodontitis are chronic diseases. Diabetes has many adverse effects on the periodontium, and conversely periodontitis may have deleterious effects further aggravating the condition in diabetics. The potential common pathophysiologic pathways include those associated with inflammation, altered host responses, altered tissue homeostasis, and insulin resistance. This review examines the relationship that exists between periodontal diseases and diabetes mellitus with a focus on potential common pathophysiologic mechanisms.

  18. Phenanthrene causes ocular developmental toxicity in zebrafish embryos and the possible mechanisms involved

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Lixing [State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005 (China); Wang, Chonggang [State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005 (China); State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen (China); Zhang, Youyu; Wu, Meifang [State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005 (China); Zuo, Zhenghong, E-mail: zuozhenghong@xmu.edu.cn [State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005 (China); State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen (China)

    2013-10-15

    Highlights: • Phe exposure caused obvious morphological changes in the retina. • Phe exposure caused apoptosis and reduction of cell proliferation in the retina. • Phe causes ocular toxicity might be via the AhR/Zeb1/Mitf/Pax6 signaling pathway. • AhR is a repressor of Zeb1. -- Abstract: Recent studies show that polycyclic aromatic hydrocarbons (PAHs) may be a candidate cause of developmental defects of the retina, but the mechanism is still unclear. We evaluated the mechanism(s) underlying PAH-induced retinal development defects due to exposure to environmental concentrations of Phenanthrene (Phe) in zebrafish. We found that exposure to environmental concentrations of Phe caused obvious morphological changes, developmental retardation, apoptosis, and reduction of cell proliferation in the retina. Our results indicated that Phe could cause visual system developmental defects. Phe exposure up-regulated aryl hydrocarbon receptor (AhR) and microphthalmia-associated transcription factor (Mtif) expression, and down-regulated zinc finger E-box binding homeobox 1 (Zeb1) and paired box 6 (Pax6). Moreover, we demonstrated that AhR was a repressor of Zeb1. We propose that Phe's ocular toxicity is mediated by up-regulating AhR, which then down-regulates Zeb1, in turn inducing Mitf expression while inhibiting Pax6 expression.

  19. Involvement of cellular immunity and humoral immunity in mixed allergy induced by trichloroethylene%三氯乙烯致细胞免疫和体液免疫参与的混合型变态反应研究

    Institute of Scientific and Technical Information of China (English)

    徐新云; 李学余; 刘月峰

    2014-01-01

    目的 探讨三氯乙烯(TCE)致变态反应是否存在细胞免疫和体液免疫共同参与,为研究其发病机制提供科学依据.方法 应用豚鼠和大鼠进行实验,分别设立阴性对照组、阳性对照组、TCE实验组,用皮内注射方式分别注射橄榄油、2,4-二硝基氯苯(DNCB)和TCE.实验结束后收集大鼠外周血液,用流式细胞仪检测淋巴细胞CD3+、CD4+、CD8+比例;收集豚鼠外周血液测定IgG、IgA、IgM、C3、C4水平;收集豚鼠脾淋巴细胞,用荧光定量PCR检测免疫相关基因GATA3、T-bet、CTLA4和Foxp3的mRNA表达水平.此外,选取TCE药疹样皮炎患者作为病例组,采用荧光定量PCR检测外周血Foxp3、GATA3、CTLA4、T-bet的mRNA表达水平.结果 (1)TCE对豚鼠皮肤有明显致敏作用,致敏率为83.3%;TCE实验组和阳性对照组IgG水平比阴性对照组显著升高(P<0.01);TCE实验组和阳性对照组GATA3、T-bet、CTLA4 mRNA表达水平显著高于阴性对照组,Foxp3 mRNA表达水平低于阴性对照组.(2)TCE实验组和阳性对照组大鼠外周血淋巴细胞CD3+比例高于阴性对照组,TCE实验组CD4+、CD8+、CD4+/CD8+与阴性对照组比较无统计学差异.(3)TCE病例组Foxp3、GATA3、CTLA4 mRNA表达水平比对照组分别升高115%、97%和241%(P<0.01),T-bet mRNA表达水平下降47%(P<0.01).结论 TCE可引起细胞免疫和体液免疫发生明显改变,说明TCE导致的免疫损伤属于细胞免疫和体液免疫共同参与的混合型变态反应,可能是Ⅳ型和Ⅱ型变态反应.%Objective To investigate whether cellular immunity and humoral immunity are involved in trichlorethylene (TCE)-induced mixed allergy,then provide the scientific basis for the mechanism of this disease.Methods Guinea pigs and rats were tested for this study by application of guinea pig maximization test (GPMT),the animals were randomly divided into negative control,positive control and TCE treatment groups.Animals of these groups were

  20. Mechanism(s) Involved in Carbon Monoxide-releasing Molecule-2-mediated Cardioprotection During Ischaemia-reperfusion Injury in Isolated Rat Heart

    OpenAIRE

    Soni, H. M.; Jain, M. R.; Anita A. Mehta

    2012-01-01

    The purpose of the present study was to determine the mechanism(s) involved in carbon monoxide-releasing molecule-2, carbon monoxide-releasing molecule-2-induced cardioprotection. We used the transition metal carbonyl compound carbon monoxide-releasing molecule-2 that can act as carbon monoxide donor in cardiac ischaemia-reperfusion injury model using isolated rat heart preparation. Langendorff′s perfused rat hearts when treated with carbon monoxide-releasing molecule-2 (50 μM) for 10 min bef...

  1. Uncertainties in neutrinoless $\\beta \\beta $ decay transition matrix elements within mechanisms involving light Majorana neutrinos, classical Majorons and sterile neutrinos

    CERN Document Server

    Rath, P K; Chaturvedi, K; Lohani, P; Raina, P K; Hirsch, J G

    2013-01-01

    In the PHFB model, uncertainties in the nuclear transition matrix elements for the neutrinoless double-$\\beta $ decay of $\\ ^{94,96}$Zr, $^{98,100}$Mo, $^{104}$Ru, $^{110}$Pd, $^{128,130}$Te and $^{150}$Nd isotopes within mechanisms involving light Majorana neutrinos, classical Majorons and sterile neutrinos are statistically estimated by considering sets of sixteen (twenty-four) matrix elements calculated with four different parametrization of the pairing plus multipolar type of effective two-body interaction, two sets of form factors and two (three) different parameterizations of Jastrow type of short range correlations. In the mechanisms involving the light Majorana neutrinos and classical Majorons, the maximum uncertainty is about 15% and in the scenario of sterile neutrinos, it varies in between approximately 4 (9)%--20 (36)% without(with) Jastrow short range correlations with Miller-Spencer parametrization, depending on the considered mass of the sterile neutrinos.

  2. Task Group 7B: Cellular and Molecular Mechanisms of Biological Aging: The Roles of Nature, Nurture and Chance in the Maintenance of Human Healthspan

    Energy Technology Data Exchange (ETDEWEB)

    Weier, Heinz-Ulrich; Arya, Suresh; Grant, Christine; Miller, Linda; Ono, Santa Jeremy; Patil, Chris; Shay, Jerry; Topol, Eric; Torry, Michael; Weier, Heinz-Ulrich G.; Tse, Iris; Lin, Su-Ju; Miller, Richard

    2007-11-14

    The degree to which an individual organism maintains healthspan and lifespan is a function of complex interactions between genetic inheritance ('nature'), environment, including cultural inheritance (nurture) and stochastic events ('luck' or 'chance'). This task group will focus upon the role of chance because it is so poorly understood and because it appears to be of major importance in the determination of individual variations in healthspan and lifespan within species. The major factor determining variations in healthspan and lifespan between species is genetic inheritance. Broader aspects of cellular and molecular mechanisms of biological aging will also be considered, given their importance for understanding the cellular and molecular basis of successful aging. The task force will consider the cellular and molecular basis for nature, nurture and chance in healthspan and life span determination. On the basis of comparisons between identical and non-identical twins, geneticists have estimated that genes control no more than about a quarter of the inter-individual differences in lifespan (Herskind 1996). Twin studies of very old individuals, however, show substantially greater genetic contributions to Healthspan (McClearn 2004; Reed 2003). The environment clearly plays an important role in the length and the quality of life. Tobacco smoke, for example has the potential to impact upon multiple body systems in ways that appear to accelerate the rates at which those systems age (Bernhard 2007). To document the role of chance events on aging, one must rigorously control both the genetic composition of an organism and its environment. This has been done to a remarkable degree in a species of nematodes, Caenorhabditis elegans (Vanfleteren 1998). The results confirm hundreds of previous studies with a wide range of species, especially those with inbred rodents housed under apparently identical but less well controlled environments. One

  3. Down-regulation of mechanisms involved in cell transport and maintenance of mucosal integrity in pigs infected with Lawsonia intracellularis

    OpenAIRE

    Smith, Sionagh H; Wilson, Alison D.; Van Ettinger, Imke; MacIntyre, Neil; Archibald, Alan L.; Ait-Ali, Tahar

    2014-01-01

    International audience Lawsonia intracellularis is an obligate intracellular bacterium, responsible for the disease complex known as proliferative enteropathy (PE). L. intracellularis is associated with intestinal crypt epithelial cell proliferation but the mechanisms responsible are yet to be defined. Microarray analysis was used to investigate the host-pathogen interaction in experimentally infected pigs to identify pathways that may be involved. Ileal samples originating from twenty-eig...

  4. Key stages of mammary gland development: Molecular mechanisms involved in the formation of the embryonic mammary gland

    OpenAIRE

    Hens, Julie R; Wysolmerski, John J

    2005-01-01

    The development of the embryonic mammary gland involves communication between the epidermis and mesenchyme and is coordinated temporally and spatially by various signaling pathways. Although many more genes are likely to control mammary gland development, functional roles have been identified for Wnt, fibroblast growth factor, and parathyroid hormone-related protein signaling. This review describes what is known about the molecular mechanisms that regulate embryonic mammary gland development.

  5. Mechanical properties and cellular response of novel electrospun nanofibers for ligament tissue engineering: Effects of orientation and geometry.

    Science.gov (United States)

    Pauly, Hannah M; Kelly, Daniel J; Popat, Ketul C; Trujillo, Nathan A; Dunne, Nicholas J; McCarthy, Helen O; Haut Donahue, Tammy L

    2016-08-01

    Electrospun nanofibers are a promising material for ligamentous tissue engineering, however weak mechanical properties of fibers to date have limited their clinical usage. The goal of this work was to modify electrospun nanofibers to create a robust structure that mimics the complex hierarchy of native tendons and ligaments. The scaffolds that were fabricated in this study consisted of either random or aligned nanofibers in flat sheets or rolled nanofiber bundles that mimic the size scale of fascicle units in primarily tensile load bearing soft musculoskeletal tissues. Altering nanofiber orientation and geometry significantly affected mechanical properties; most notably aligned nanofiber sheets had the greatest modulus; 125% higher than that of random nanofiber sheets; and 45% higher than aligned nanofiber bundles. Modifying aligned nanofiber sheets to form aligned nanofiber bundles also resulted in approximately 107% higher yield stresses and 140% higher yield strains. The mechanical properties of aligned nanofiber bundles were in the range of the mechanical properties of the native ACL: modulus=158±32MPa, yield stress=57±23MPa and yield strain=0.38±0.08. Adipose derived stem cells cultured on all surfaces remained viable and proliferated extensively over a 7 day culture period and cells elongated on nanofiber bundles. The results of the study suggest that aligned nanofiber bundles may be useful for ligament and tendon tissue engineering based on their mechanical properties and ability to support cell adhesion, proliferation, and elongation. PMID:27082129

  6. SMTCI: Secure Multi-Trial Trust Evaluation and Cost- Effective Incentive Mechanism for Multi-Hop Cellular Networks

    Directory of Open Access Journals (Sweden)

    B.Sumathi

    2013-04-01

    Full Text Available In multi-hop cellular networks, finding an optimum and trusted route in the network through intermediate node is a major issue. At MCN, or the next-generation wireless networks, can significantly improve network performance and deployment and help implement many novel applications and services. However, when compared to wired and single-hop wireless networks, MCNs are highly vulnerable to serious security threats because packets may be relayed through integrated networks and autonomous devices. Our Proposed work has been focusing on developing secure trust based protocols for securing MCNs. Specifically, we are interested in securing route establishment and data transmission processes, establishing stable routes, and preserving users’ anonymity and location privacy. In this paperwe propose a multi-trial trust evaluation scheme, trusted node based ad hoc routing using trials to establish security accomplishes establishment of trusted networks in MANETs. We apply the same idea todevelop our proposed algorithm TBARA to rate neighbor nodes using hash values for identifying the misbehaving nodes. After the successful transmission of packets from source to destination, thedestination will send acknowledgement for the corresponding packet, upon receiving of acknowledgement incentive will be generated. It reduces the number of public-key cryptographic operations and protectagainst collusion attack.

  7. The cellular uptake mechanism, intracellular transportation, and exocytosis of polyamidoamine dendrimers in multidrug-resistant breast cancer cells.

    Science.gov (United States)

    Zhang, Jie; Liu, Dan; Zhang, Mengjun; Sun, Yuqi; Zhang, Xiaojun; Guan, Guannan; Zhao, Xiuli; Qiao, Mingxi; Chen, Dawei; Hu, Haiyang

    2016-01-01

    Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH2 was much lower and exocytosis of PAMAM-NH2 was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH2 from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH2 aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH2 in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH2 in MCF-7/ADR cells and provided a guide of using PAMAM-NH2 as a drug and gene vector in resistant cells. PMID:27536106

  8. Neural mechanisms involved in the detection of our first name : A combined ERPs and PET study

    OpenAIRE

    Perrin, Fabien; Maquet, Pierre; Peigneux, Philippe; Ruby, P.; Degueldre, Christian; Balteau, Evelyne; Del Fiore, Guy; Moonen, Gustave; Luxen, André; Laureys, Steven

    2005-01-01

    In everyday social interactions, hearing our own first name captures our attention and gives rise to a sense of self-awareness, since it is one of the most socially self related stimulus. In the present study, we combined ERPs and PET scan methods to explore the cerebral mechanisms underlying the detection of our own name. While categorical analyses of PET data failed to reveal significant results, we found that the amplitude of the P3 component, elicited when hearing one's own name, correlat...

  9. GR-127935-sensitive mechanism mediating hypotension in anesthetized rats: are 5-HT5B receptors involved?

    Science.gov (United States)

    Sánchez-Maldonado, Carolina; López-Sánchez, Pedro; Anguiano-Robledo, Liliana; Leopoldo, Marcello; Lacivita, Enza; Terrón, José A

    2015-04-01

    The 5-HT1B/1D receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 receptor agonist, and 5-HT5A/5B receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D receptor antagonists. Also, expression of 5-HT5A and 5-HT5B receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 μg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5-HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 receptors. This mechanism, however, resembles putative 5-HT5B receptors. PMID:25502305

  10. Mechanisms involved in the swelling of erythrocytes caused by Pacific and Caribbean ciguatoxins

    OpenAIRE

    Sauviat, M. P.; Boydron Le Garrec, Raphaëlle; Masson, J.B.; Lewis, R.L.; Vernoux, J. P.; Molgo, J; Laurent, Dominique; Benoit, E.

    2006-01-01

    The mechanisms underlying the swelling of frog red blood cells (RBC), induced by Pacific (P-CTX-1) and Caribbean (C-CTX-1) ciguatoxins (CTXs), were investigated by measuring the length, width and surface of their elliptic shape. P-CTX-1 (0.5 to 5 nM) and C-CTX-1 (1 mu M) induced RBC swelling within 60 min. The CTXs-induced RBC swelling was blocked by apamin (1 mu M) and by Sr2+ (1 mu M). P-CTX-1-induced RBC swelling was prevented and inhibited by H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one(27 ...

  11. Some mechanisms involved in the radiosensitization of E.coli B/r by paracetamol

    International Nuclear Information System (INIS)

    Paracetamol, a widely-used analgesic and antipyretic drug, sensitized E.coli B/r to 60Co gamma-rays under hypoxic conditions. Part of the sensitizing effect has been shown to be due to an electron adduct of the drug. Paracetamol inhibited both post-irradiation DNA and protein syntheses. The targets involved in the inhibition of post-irradiation DNA synthesis have been shown to be different in the presence of the sensitizer. Increased DNA degradation after irradiation was also observed when E.coli B/r were irradiated in the presence of the drug. The presence of paracetamol during hypoxic irradiation of E.coli B/r resulted in the enhancement of DNA single-strand scissions with no apparent effect on their rejoining. (author)

  12. Sensitizing Children to the Social and Emotional Mechanisms involved in Racism: a program evaluation

    Directory of Open Access Journals (Sweden)

    Sofia Triliva

    2014-11-01

    Full Text Available This paper describes and discusses the results of an intervention aiming to sensitize children to the social and emotional processes involved in racism. The intervention was applied and evaluated in 10 Greek elementary schools. The goals and the intervention methods of the program modules are briefly outlined and the results of the program evaluation are elaborated and discussed. Two-hundred students participated in the program and 180 took part in the pre-and-post-testing which assessed their ability to identify emotions associated with prejudice, discrimination and stereotypical thinking; to understand similarities and differences between people; and to develop perspective taking and empathic skills in relation to diverse others. Results indicate gains in all three areas of assessment although the increased ability to identify similarities between people can also be attributed to age/grade effects. The implications of the findings are discussed with regard to antiracism intervention methods and evaluation strategies.

  13. Signaling mechanisms involved in the acute effects of estradiol on 5-HT clearance.

    Science.gov (United States)

    Benmansour, Saloua; Privratsky, Anthony A; Adeniji, Opeyemi S; Frazer, Alan

    2014-05-01

    Estradiol was found previously to have an antidepressant-like effect and to block the ability of selective serotonin reuptake inhibitors (SSRIs) to have an antidepressant-like effect. The antidepressant-like effect of estradiol was due to estrogen receptor β (ERβ) and/or GPR30 activation, whereas estradiol's blockade of the effect of an SSRI was mediated by ERα. This study focuses on investigating signaling pathways as well as interacting receptors associated with these two effects of estradiol. In vivo chronoamperometry was used to measure serotonin transporter (SERT) function. The effect of local application of estradiol or selective agonists for ERα (PPT) or ERβ (DPN) into the CA3 region of the hippocampus of ovariectomized (OVX) rats on 5-hydroxytryptamine (5-HT) clearance as well as on the ability of fluvoxamine to slow 5-HT clearance was examined after selective blockade of signaling pathways or that of interacting receptors. Estradiol- or DPN-induced slowing of 5-HT clearance mediated by ERβ was blocked after inhibition of MAPK/ERK1/2 but not of PI3K/Akt signaling pathways. This effect also involved interactions with TrkB, and IGF-1 receptors. Estradiol's or PPT's inhibition of the fluvoxamine-induced slowing of 5-HT clearance mediated by ERα, was blocked after inhibition of either MAPK/ERK1/2 or PI3K/Akt signaling pathways. This effect involved interactions with the IGF-1 receptor and with the metabotropic glutamate receptor 1, but not with TrkB. This study illustrates some of the signaling pathways required for the effects of estradiol on SERT function, and particularly shows that ER subtypes elicit different as well as common signaling pathways for their actions. PMID:24423185

  14. A possible new mechanism involved in non-uniform field breakdown in gaseous dielectrics

    International Nuclear Information System (INIS)

    The electrical breakdown of gases under uniform field conditions is fairly well understood in terms of the Townsend's breakdown theory. In most cases involving uniform fields, the breakdown voltage can be estimated via this theory using basic electron impact parameters for molecules in their ground electronic states. In contrast, a consistent model of gaseous breakdown under nonuniform fields is not available at present although substantial progress has been made recently. We point out the possibility that electron impact processes involving high-lying electronically-excited states may play a significant role under non-uniform field conditions. Thus, such processes may need to be included in order to obtain a better understanding of non-uniform field breakdown phenomena. The general, breakdown characteristics of highly non-uniform field gaps can be illustrated by that for a point-plane geometry. It has been found that the breakdown voltage for such a gap can be calculated by a simple streamer criterion if the pressure P, is above a critical value, Pc; for P c, the estimated breakdown voltage is found to coincide with the corona inception voltage, with the actual breakdown occurring at a higher voltage, corona discharges occur only for P c. In other words, the presence of corona in the pressure region below Pc seems to prevent the breakdown from occurring at the predicted value. This has led to the term ''corona stabilization'' to describe the enhancement in the breakdown voltage for pressures below Pc. Non-uniform field breakdown measurements in gases will be discussed. We will discuss the possibility that the ''corona stabilization'' is due to the prevention of avalanche progression by attachment of free electrons to molecules in their high-lying electronically-excited states. Information on electron attachment to electronically-excited states of molecules was not available up until the late 1980's

  15. A possible new mechanism involved in non-uniform field breakdown in gaseous dielectrics

    Energy Technology Data Exchange (ETDEWEB)

    Pinnaduwage, L.A.; Christophorou, L.G.

    1994-06-01

    The electrical breakdown of gases under uniform field conditions is fairly well understood in terms of the Townsend`s breakdown theory. In most cases involving uniform fields, the breakdown voltage can be estimated via this theory using basic electron impact parameters for molecules in their ground electronic states. In contrast, a consistent model of gaseous breakdown under nonuniform fields is not available at present although substantial progress has been made recently. We point out the possibility that electron impact processes involving high-lying electronically-excited states may play a significant role under non-uniform field conditions. Thus, such processes may need to be included in order to obtain a better understanding of non-uniform field breakdown phenomena. The general, breakdown characteristics of highly non-uniform field gaps can be illustrated by that for a point-plane geometry. It has been found that the breakdown voltage for such a gap can be calculated by a simple streamer criterion if the pressure P, is above a critical value, P{sub c}; for P < P{sub c}, the estimated breakdown voltage is found to coincide with the corona inception voltage, with the actual breakdown occurring at a higher voltage, corona discharges occur only for P < P{sub c}. In other words, the presence of corona in the pressure region below P{sub c} seems to prevent the breakdown from occurring at the predicted value. This has led to the term ``corona stabilization`` to describe the enhancement in the breakdown voltage for pressures below P{sub c}. Non-uniform field breakdown measurements in gases will be discussed. We will discuss the possibility that the ``corona stabilization`` is due to the prevention of avalanche progression by attachment of free electrons to molecules in their high-lying electronically-excited states. Information on electron attachment to electronically-excited states of molecules was not available up until the late 1980`s.

  16. Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536

    Directory of Open Access Journals (Sweden)

    Tomas Koltai

    2015-03-01

    Full Text Available Objective: To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs based on evidences reported in the published literature. Methods: We extensively reviewed the literature concerning nelfinavir (NFV as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed. Conclusions: The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress-unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down-regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS, decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes.

  17. A cell-regulatory mechanism involving feedback between contraction and tissue formation guides wound healing progression.

    Directory of Open Access Journals (Sweden)

    Clara Valero

    Full Text Available Wound healing is a process driven by cells. The ability of cells to sense mechanical stimuli from the extracellular matrix that surrounds them is used to regulate the forces that cells exert on the tissue. Stresses exerted by cells play a central role in wound contraction and have been broadly modelled. Traditionally, these stresses are assumed to be dependent on variables such as the extracellular matrix and cell or collagen densities. However, we postulate that cells are able to regulate the healing process through a mechanosensing mechanism regulated by the contraction that they exert. We propose that cells adjust the contraction level to determine the tissue functions regulating all main activities, such as proliferation, differentiation and matrix production. Hence, a closed-regulatory feedback loop is proposed between contraction and tissue formation. The model consists of a system of partial differential equations that simulates the evolution of fibroblasts, myofibroblasts, collagen and a generic growth factor, as well as the deformation of the extracellular matrix. This model is able to predict the wound healing outcome without requiring the addition of phenomenological laws to describe the time-dependent contraction evolution. We have reproduced two in vivo experiments to evaluate the predictive capacity of the model, and we conclude that there is feedback between the level of cell contraction and the tissue regenerated in the wound.

  18. Mechanical Properties Involved in the Micro-forming of Ultra-thin Stainless Steel Sheets

    Science.gov (United States)

    Pham, Cong-Hanh; Thuillier, Sandrine; Manach, Pierre-Yves

    2015-08-01

    The objective of this paper is to characterize the mechanical behavior of an ultra-thin stainless steel, of 0.15-mm thickness, that is commonly used in the manufacturing of miniature connectors. The main focus is the relationship between some microstructural features, like grain size and surface roughness, and the macroscopic mechanical behavior investigated in uniaxial tension and simple shear. In tension, adaptations to the very small sheet thickness, in order to hold the specimen under the grips, are presented. Yield stress, initial elastic modulus, and evolution of the loading-unloading slope with plastic deformation were evaluated. Moreover, the kinematic contribution to the hardening was characterized by monotonic and cyclic simple shear test and reproduced by a mixed hardening law implemented in Abaqus finite element code. Then, the evolution of surface roughness with plastic strain, both in tension and simple shear, was analyzed. It was shown that in the case of an ultra-thin sheet, the stress levels, calculated either from an average thickness or when considering the effect of the surface roughness, exhibit a significant difference. Finally, the influence of surface roughness on the fracture of a tensile specimen was also investigated.

  19. Modeling of glycerol-3-phosphate transporter suggests a potential 'tilt' mechanism involved in its function.

    Science.gov (United States)

    Tsigelny, Igor F; Greenberg, Jerry; Kouznetsova, Valentina; Nigam, Sanjay K

    2008-10-01

    Many major facilitator superfamily (MFS) transporters have similar 12-transmembrane alpha-helical topologies with two six-helix halves connected by a long loop. In humans, these transporters participate in key physiological processes and are also, as in the case of members of the organic anion transporter (OAT) family, of pharmaceutical interest. Recently, crystal structures of two bacterial representatives of the MFS family--the glycerol-3-phosphate transporter (GlpT) and lac-permease (LacY)--have been solved and, because of assumptions regarding the high structural conservation of this family, there is hope that the results can be applied to mammalian transporters as well. Based on crystallography, it has been suggested that a major conformational "switching" mechanism accounts for ligand transport by MFS proteins. This conformational switch would then allow periodic changes in the overall transporter configuration, resulting in its cyclic opening to the periplasm or cytoplasm. Following this lead, we have modeled a possible "switch" mechanism in GlpT, using the concept of rotation of protein domains as in the DynDom program17 and membranephilic constraints predicted by the MAPAS program.(23) We found that the minima of energies of intersubunit interactions support two alternate positions consistent with their transport properties. Thus, for GlpT, a "tilt" of 9 degrees -10 degrees rotation had the most favorable energetics of electrostatic interaction between the two halves of the transporter; moreover, this confirmation was sufficient to suggest transport of the ligand across the membrane. We conducted steered molecular dynamics simulations of the GlpT-ligand system to explore how glycerol-3-phosphate would be handled by the "tilted" structure, and obtained results generally consistent with experimental mutagenesis data. While biochemical data remain most consistent with a single-site alternating access model, our results raise the possibility that, while the

  20. Potassium channel and NKCC cotransporter involvement in ocular refractive control mechanisms.

    Directory of Open Access Journals (Sweden)

    Sheila G Crewther

    Full Text Available Myopia affects well over 30% of adult humans globally. However, the underlying physiological mechanism is little understood. This study tested the hypothesis that ocular growth and refractive compensation to optical defocus can be controlled by manipulation of potassium and chloride ion-driven transretinal fluid movements to the choroid. Chicks were raised with +/-10D or zero power optical defocus rendering the focal plane of the eye in front of, behind, or at the level of the retinal photoreceptors respectively. Intravitreal injections of barium chloride, a non-specific inhibitor of potassium channels in the retina and RPE or bumetanide, a selective inhibitor of the sodium-potassium-chloride cotransporter were made, targeting fluid control mechanisms. Comparison of refractive compensation to 5 mM Ba(2+ and 10(-5 M bumetanide compared with control saline injected eyes shows significant change for both positive and negative lens defocus for Ba(2+ but significant change only for negative lens defocus with bumetanide (Rx(SAL(-10D = -8.6 +/- .9 D; Rx(Ba2+(-10D = -2.9 +/- .9 D; Rx(Bum(-10D = -2.9 +/- .9 D; Rx(SAL(+10D = +8.2 +/- .9 D; Rx(Ba2+(+10D = +2.8 +/- 1.3 D; Rx(Bum(+10D = +8.0 +/- .7 D. Vitreous chamber depths showed a main effect for drug conditions with less depth change in response to defocus shown for Ba(2+ relative to Saline, while bumetanide injected eyes showed a trend to increased depth without a significant interaction with applied defocus. The results indicate that both K channels and the NKCC cotransporter play a role in refractive compensation with NKCC blockade showing far more specificity for negative, compared with positive, lens defocus. Probable sites of action relevant to refractive control include the apical retinal pigment epithelium membrane and the photoreceptor/ON bipolar synapse. The similarities between the biometric effects of NKCC inhibition and biometric reports of the blockade of the retinal ON response, suggest a

  1. Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells.

    Science.gov (United States)

    Han, Anna; Bennett, Natalie; MacDonald, Amber; Johnstone, Megan; Whelan, Jay; Donohoe, Dallas R

    2016-08-01

    Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc. PMID:26661480

  2. By Different Cellular Mechanisms, Lymphatic Vessels Sprout by Endothelial Cell Recruitment Whereas Blood Vessels Grow by Vascular Expansion

    Science.gov (United States)

    Parsons-Wingerter, Patricia; McKay, Terri L.; Leontiev, Dmitry; Condrich, Terence K.; DiCorleto, Paul E.

    2005-01-01

    The development of effective vascular therapies requires the understanding of all modes of vessel formation contributing to vasculogenesis, angiogenesis (here termed hemangiogenesis) and lymphangiogenesis. We show that lymphangiogenesis proceeds by blind-ended vessel sprouting via recruitment of isolated endothelial progenitor cells to the tips of growing vessels, whereas hemangiogenesis occurs by non-sprouting vessel expansion from the capillary network, during middevelopment in the quail chorioallantoic membrane (CAM). Blood vessels expanded out of capillaries that displayed transient expression of alpha smooth muscle actin (alphaSMA), accompanied by mural recruitment of migratory progenitor cells expressing SMA. Lymphatics and blood vessels were identified by confocal/fluorescence microscopy of vascular endothelial growth factor (VEGF) receptors VEGFR-1 and VEGFR-2, alphaSMA (expressed on CAM blood vessels but not on lymphatics), homeobox transcription factor Prox-1 (specific to CAM lymphatic endothelium), and the quail hematopoetic/vascular marker, QH-1. Expression of VEGFR-1 was highly restricted to blood vessels (primarily capillaries). VEGFR-2 was expressed intensely in isolated hematopoietic cells, lymphatic vessels and moderately in blood vessels. Prox-1 was absent from endothelial progenitor cells prior to lymphatic recruitment. Although vascular endothelial growth factor-165 (VEGF(sub 165)) is a key regulator of numerous cellular processes in hemangiogenesis and vasculogenesis, the role of VEGF(sub 165) in lymphangiogenesis is less clear. Exogenous VEGF(sub 165) increased blood vessel density without changing endogenous modes of vascular/lymphatic vessel formation or marker expression patterns. However, VEGF(sub 165) did increase the frequency of blood vascular anastomoses and strongly induced the antimaturational dissociation of lymphatics from blood vessels, with frequent formation of homogeneous lymphatic networks.

  3. Molecular mechanisms involved in adaptive responses to radiation, UV light, and heat

    International Nuclear Information System (INIS)

    Viable organisms recognize and respond to environmental changes or stresses. When these environmental changes and their responses by organisms are extreme, they can limit viability. However, organisms can adapt to these different stresses by utilizing different possible responses via signal transduction pathways when the stress is not lethal. In particular, prior mild stresses can provide some aid to prepare organisms for subsequent more severe stresses. These adjustments or adaptations for future stresses have been called adaptive responses. These responses are present in bacteria, plants and animals. The following review covers recent research which can help describe or postulate possible mechanisms which may be active in producing adaptive responses to radiation, ultraviolet light, and heat. (author)

  4. Attentional Biases toward Attractive Alternatives and Rivals: Mechanisms Involved in Relationship Maintenance among Chinese Women.

    Science.gov (United States)

    Ma, Yidan; Zhao, Guang; Tu, Shen; Zheng, Yong

    2015-01-01

    A long-term romantic relationship can offer many benefits to committed individuals. Thus, humans possess relationship maintenance mechanisms to protect against threats from those who serve as attractive alternatives or intrasexual rivals. Many studies have indicated that romantic love can act as a commitment device to activate these mechanisms. To examine the attentional bias associated with relationship maintenance among 108 college students (49 single and 59 committed females) in China, we used a semantic priming procedure to activate mental representations associated with romantic love and then asked participants to complete a dot-probe task for the purpose of making a distinction between the engage and disengage components of attention. No significant engaging effects toward attractive faces were observed among committed females, but the following significant disengaging effects were found: when primed with romantic love, single females showed increased attention toward and difficulty in disengaging from attractive male faces, whereas females already in a committed relationship did not alter their attention, remaining as inattentive to attractive alternatives as they were in the baseline condition. In addition, committed females responded to love priming by exhibiting difficulty in disengaging from attractive rivals. The present findings provide evidence in the Chinese cultural context for the existence of early-stage attentional processes in the domain of relationship maintenance that committed Chinese females protected an ongoing relationship by not only being inattentive to attractive males who could serve as attractive alternatives, but also being more attentive to attractive females who could be potential rivals when mental representations associated with romantic love were primed. PMID:26309232

  5. Attentional Biases toward Attractive Alternatives and Rivals: Mechanisms Involved in Relationship Maintenance among Chinese Women.

    Directory of Open Access Journals (Sweden)

    Yidan Ma

    Full Text Available A long-term romantic relationship can offer many benefits to committed individuals. Thus, humans possess relationship maintenance mechanisms to protect against threats from those who serve as attractive alternatives or intrasexual rivals. Many studies have indicated that romantic love can act as a commitment device to activate these mechanisms. To examine the attentional bias associated with relationship maintenance among 108 college students (49 single and 59 committed females in China, we used a semantic priming procedure to activate mental representations associated with romantic love and then asked participants to complete a dot-probe task for the purpose of making a distinction between the engage and disengage components of attention. No significant engaging effects toward attractive faces were observed among committed females, but the following significant disengaging effects were found: when primed with romantic love, single females showed increased attention toward and difficulty in disengaging from attractive male faces, whereas females already in a committed relationship did not alter their attention, remaining as inattentive to attractive alternatives as they were in the baseline condition. In addition, committed females responded to love priming by exhibiting difficulty in disengaging from attractive rivals. The present findings provide evidence in the Chinese cultural context for the existence of early-stage attentional processes in the domain of relationship maintenance that committed Chinese females protected an ongoing relationship by not only being inattentive to attractive males who could serve as attractive alternatives, but also being more attentive to attractive females who could be potential rivals when mental representations associated with romantic love were primed.

  6. Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin.

    Science.gov (United States)

    Zhou, Junmin; Donatelli, Sarah S; Gilvary, Danielle L; Tejera, Melba M; Eksioglu, Erika A; Chen, Xianghong; Coppola, Domenico; Wei, Sheng; Djeu, Julie Y

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) constitute a key checkpoint that impedes tumor immunity against cancer. Chemotherapeutic intervention of MDSCs has gained ground as a strategy for cancer therapy but its mechanism remains obscure.We report here a unique mechanism by which monocytic (M)-MDSCs are spared, allowing them to polarize towards M1 macrophages for reactivation of immunity against breast cancer. We first demonstrated that curcumin, like docetaxel (DTX), can selectively target CD11b(+)Ly6G(+)Ly6C(low) granulocytic (G)-MDSCs, sparing CD11b(+)Ly6G(-)Ly6C(high) M-MDSCs, with reduced tumor burden in 4T1-Neu tumor-bearing mice. Curcumin treatment polarized surviving M-MDSCs toward CCR7(+) Dectin-1(-)M1 cells, accompanied by IFN-γ production and cytolytic function in T cells. Selective M-MDSC chemoresistence to curcumin and DTX was mediated by secretory/cytoplasmic clusterin (sCLU). sCLU functions by trapping Bax from mitochondrial translocation, preventing the apoptotic cascade. Importantly, sCLU was only found in M-MDSCs but not in G-MDSCs. Knockdown of sCLU in M-MDSCs and RAW264.7 macrophages was found to reverse their natural chemoresistance. Clinically, breast cancer patients possess sCLU expression only in mature CD68(+) macrophages but not in immature CD33(+) immunosuppressive myeloid cells infiltrating the tumors. We thus made the seminal discovery that sCLU expression in M-MDSCs accounts for positive immunomodulation by chemotherapeutic agents. PMID:27405665

  7. Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin

    Science.gov (United States)

    Zhou, Junmin; Donatelli, Sarah S.; Gilvary, Danielle L.; Tejera, Melba M.; Eksioglu, Erika A.; Chen, Xianghong; Coppola, Domenico; Wei, Sheng; Djeu, Julie Y.

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) constitute a key checkpoint that impedes tumor immunity against cancer. Chemotherapeutic intervention of MDSCs has gained ground as a strategy for cancer therapy but its mechanism remains obscure.We report here a unique mechanism by which monocytic (M)-MDSCs are spared, allowing them to polarize towards M1 macrophages for reactivation of immunity against breast cancer. We first demonstrated that curcumin, like docetaxel (DTX), can selectively target CD11b+Ly6G+Ly6Clow granulocytic (G)-MDSCs, sparing CD11b+Ly6G−Ly6Chigh M-MDSCs, with reduced tumor burden in 4T1-Neu tumor-bearing mice. Curcumin treatment polarized surviving M-MDSCs toward CCR7+ Dectin-1−M1 cells, accompanied by IFN-γ production and cytolytic function in T cells. Selective M-MDSC chemoresistence to curcumin and DTX was mediated by secretory/cytoplasmic clusterin (sCLU). sCLU functions by trapping Bax from mitochondrial translocation, preventing the apoptotic cascade. Importantly, sCLU was only found in M-MDSCs but not in G-MDSCs. Knockdown of sCLU in M-MDSCs and RAW264.7 macrophages was found to reverse their natural chemoresistance. Clinically, breast cancer patients possess sCLU expression only in mature CD68+ macrophages but not in immature CD33+ immunosuppressive myeloid cells infiltrating the tumors. We thus made the seminal discovery that sCLU expression in M-MDSCs accounts for positive immunomodulation by chemotherapeutic agents. PMID:27405665

  8. Evolutionary mechanisms involved in the virulence of infectious salmon anaemia virus (ISAV), a piscine orthomyxovirus

    International Nuclear Information System (INIS)

    Infectious salmon anaemia virus (ISAV) is an orthomyxovirus causing a multisystemic, emerging disease in Atlantic salmon. Here we present, for the first time, detailed sequence analyses of the full-genome sequence of a presumed avirulent isolate displaying a full-length hemagglutinin-esterase (HE) gene (HPR0), and compare this with full-genome sequences of 11 Norwegian ISAV isolates from clinically diseased fish. These analyses revealed the presence of a virulence marker right upstream of the putative cleavage site R267 in the fusion (F) protein, suggesting a Q266 → L266 substitution to be a prerequisite for virulence. To gain virulence in isolates lacking this substitution, a sequence insertion near the cleavage site seems to be required. This strongly suggests the involvement of a protease recognition pattern at the cleavage site of the fusion protein as a determinant of virulence, as seen in highly pathogenic influenza A virus H5 or H7 and the paramyxovirus Newcastle disease virus

  9. Modelling and pathway identification involving the transport mechanism of a complex metabolic system in batch culture

    Science.gov (United States)

    Yuan, Jinlong; Zhang, Xu; Zhu, Xi; Feng, Enmin; Yin, Hongchao; Xiu, Zhilong

    2014-06-01

    The bio-dissimilation of glycerol to 1,3-propanediol (1,3-PD) by Klebsiella pneumoniae (K. pneumoniae) can be characterized by a complex metabolic system of interactions among biochemical fluxes, metabolic compounds, key enzymes and genetic regulation. In this paper, in consideration of the fact that the transport ways of 1,3-PD and glycerol with different weights across cell membrane are still unclear in batch culture, we consider 121 possible metabolic pathways and establish a novel mathematical model which is represented by a complex metabolic system. Taking into account the difficulty in accurately measuring the concentration of intracellular substances and the absence of equilibrium point for the metabolic system of batch culture, the novel approach used here is to define quantitatively biological robustness of the intracellular substance concentrations for the overall process of batch culture. To determine the most possible metabolic pathway, we take the defined biological robustness as cost function and establish an identification model, in which 1452 system parameters and 484 pathway parameters are involved. Simultaneously, the identification model is subject to the metabolic system, continuous state constraints and parameter constraints. As such, solving the identification model by a serial program is a very complicated task. We propose a parallel migration particle swarm optimization algorithm (MPSO) capable of solving the identification model in conjunction with the constraint transcription and smoothing approximation techniques. Numerical results show that the most possible metabolic pathway and the corresponding metabolic system can reasonably describe the process of batch culture.

  10. Genes and molecular mechanisms involved in the epileptogenesis of idiopathic absence epilepsies.

    Science.gov (United States)

    Yalçın, Ozlem

    2012-03-01

    Idiopathic absence epilepsies (IAE), that have high prevalence particularly among children and adolescents, are complex disorders mainly caused by genetic factors. Childhood absence epilepsy and juvenile absence epilepsy are among the most common subtypes of IAEs. While the role of ion channels has been the primary focus of epilepsy research, the analysis of mutation and association in both patients with absence epilepsies and animal models revealed the involvement of GABA receptors and calcium channels, but also of novel non-ion channel proteins in inducing spike wave discharges (SWD). Functional studies on a mutated variant of these proteins also support their role in the epileptogenesis of absence seizures. Studies in animal models point to both the thalamus and cortex as the origin of SWDs: the abnormalities in the components of these circuits leading to seizure activity. This review examines the current research on mutations and susceptibility alleles determined in the genes that code for the subunits of GABA receptors (GABRG2, GABRA1, GABRB3, GABRA5, GABA(B1) and GABA(B2)), calcium channels (CACNA1A, CACNA1G, CACNA1H, CACNA1I, CACNAB4, CACNAG2 and CACNG3), and novel non-ion channel proteins, taking into account the results of functional studies on these variants. PMID:22206818

  11. Transmission electron microscopy study of the reaction mechanisms involved in the carbothermal reduction of anatase

    International Nuclear Information System (INIS)

    The carbothermal reduction of anatase in titanium oxycarbide was studied by transmission electron microscopy (TEM). This study emphasizes that the reaction proceeds through complex solid–gas equilibria involving three main steps. During the first step, the carbon-monoxide-enriched atmosphere prevailing within the furnace provokes the direct transformation of anatase into the Magnéli phase. This transformation is accompanied by abnormal oxide grain growth showing a high number of stacking defects. The ordering tendency of such defects and their progressive increasing density lead to the final Ti3O5 compound. The second step of the reaction concerns the destabilization of Ti3O5 and carbon black in a high pCO atmosphere to form the oxycarbide. The titanium oxycarbide (TixOyCz) nucleates in the carbon black aggregates, giving rise to a first generation of defect-free faceted crystals (automorphous habit) characterized by a constant chemical composition. During the third step, Ti3O5 is missing and the primary carbide enters a maturation step characterized by carbon enrichment, attested by an increase in its cell parameter. This third step is characterized by the recrystallization phenomenon of the primary oxycarbide into the secondary one with an abrupt change in stoichiometry. The latter is characterized by rounded crystals (xenomorphous habit) bearing either a high density of dislocations or geometrical internal porosity linked to the migration of vacancies through the Kirkendall effect. Its further enrichment in carbon is assumed to be assisted by dislocation motion

  12. Cellular and molecular evidence for a role of tumor necrosis factor alpha in the ovulatory mechanism of trout

    Directory of Open Access Journals (Sweden)

    Bobe Julien

    2010-04-01

    Full Text Available Abstract Background The relevance of immune-endocrine interactions to the regulation of ovarian function in teleosts is virtually unexplored. As part of the innate immune response during infection, a number of cytokines such as tumor necrosis factor alpha (TNF alpha and other immune factors, are produced and act on the reproductive system. However, TNF alpha is also an important physiological player in the ovulatory process in mammals. In the present study, we have examined for the first time the effects of TNF alpha in vitro in preovulatory ovarian follicles of a teleost fish, the brown trout (Salmo trutta. Methods To determine the in vivo regulation of TNF alpha expression in the ovary, preovulatory brook trout (Salvelinus fontinalis were injected intraperitoneally with either saline or bacterial lipopolysaccharide (LPS. In control and recombinant trout TNF alpha (rtTNF alpha-treated brown trout granulosa cells, we examined the percentage of apoptosis by flow cytometry analysis and cell viability by propidium iodide (PI staining. Furthermore, we determined the in vitro effects of rtTNF alpha on follicle contraction and testosterone production in preovulatory brown trout ovarian follicles. In addition, we analyzed the gene expression profiles of control and rtTNF alpha-treated ovarian tissue by microarray and real-time PCR (qPCR analyses. Results LPS administration in vivo causes a significant induction of the ovarian expression of TNF alpha. Treatment with rtTNF alpha induces granulosa cell apoptosis, decreases granulosa cell viability and stimulates the expression of genes known to be involved in the normal ovulatory process in trout. In addition, rtTNF alpha causes a significant increase in follicle contraction and testosterone production. Also, using a salmonid-specific microarray platform (SFA2.0 immunochip we observed that rtTNF alpha induces the expression of genes known to be involved in inflammation, proteolysis and tissue remodeling

  13. Mechanism of cellular uptake of HIV-TAT peptide & effects of TAT-SOD against ultraviolet induced skin damage

    OpenAIRE

    Chen, Xiaochao

    2013-01-01

    TAT peptide is one of the best-characterised cell penetrating peptides (CPPs) derived from the transactivator of transcription protein from the human immunodeficiency virus 1 (HIV-1). TAT peptide is able to cross the cell membrane and deliver various biomolecules into cells with low immunogenicity and no toxicity. However, the exact mechanism of internalization still remains a subject of controversy. Lamellar neutron scattering was used to determine the location of TAT pepti...

  14. Cellular differentiation in 3D-bioprinted mesenchymal stem cell-loaded hydrogels with varying structural and mechanical properties

    OpenAIRE

    Duarte Campos, Daniela Filipa

    2016-01-01

    Hydrogels are a promising alternative to rigid biomaterials typically used in the field of bone tissue engineering for the treatment of musculoskeletal disorders. By hydrogel-based 3D-bioprinting, the native ornamentation of cells and matrix from bone tissue could be resembled. Herein, it was hypothesized the combination of polysaccharides (agarose, alginate) with biological components (collagen, fibrinogen) would increase mechanical stiffness of printed constructs as well as support the prin...

  15. Study of the physical mechanisms involved in the femtosecond laser optical breakdown of dielectric materials

    International Nuclear Information System (INIS)

    We have carried out detailed time resolved experimental studies of the mechanism of electron excitation-relaxation, when an ultrashort (60 fs-1 ps) laser (UV and IR) pulse interacts with a wide band gap dielectric material. The studies cover a range of different dielectric materials and the investigated regimes span from nondestructive ionization of the material at the low power end (∼TW/cm2) to ablative domain at a higher laser power (∼10 TW/cm2). This gives fundamental insight into the understanding of the laser damaging process taking place under our irradiation conditions. The usage of time-resolved spectral interferometry technique allows to directly measure the electron density of the irradiated material under different excitation conditions and hence leads to quantification of the process. The measurements, carried out at the optical breakdown threshold utilizing different pulse durations, raise questions regarding the usage of critical excitation density as a universal ablation criterion. A new criterion related to the exchanged energy is proposed. Additionally, the use of an experimental setup implementing a double pump pulse allows the identification of different excitation mechanisms taking place at time scales of the order of the pulse duration used. Electronic avalanche is observed in some materials (SiO2, NaCl) while this is not the case for others (Al2O3, MgO). These differences are discussed in detail. Next, we measure the energy spectrum of excited electrons with a complementary technique: the photoemission spectroscopy. These results allow us on one hand to show a crossed effect between the two 'pump' pulses and on the other hand to measure electron relaxation characteristic times, as a function of their kinetic energy. Finally, a morphological study of craters resulting from ablation in the case of a single pulse has been carried out for different irradiation parameters: number of shots, energy and pulse duration. This work has been extended

  16. Dopamine as a potent inducer of cellular glutathione and NAD(P)H:quinone oxidoreductase 1 in PC12 neuronal cells: a potential adaptive mechanism for dopaminergic neuroprotection.

    Science.gov (United States)

    Jia, Zhenquan; Zhu, Hong; Misra, Bhaba R; Li, Yunbo; Misra, Hara P

    2008-11-01

    Dopamine auto-oxidation and the consequent formation of reactive oxygen species and electrophilic quinone molecules have been implicated in dopaminergic neuronal cell death in Parkinson's disease. We reported here that in PC12 dopaminergic neuronal cells dopamine at noncytotoxic concentrations (50-150 muM) potently induced cellular glutathione (GSH) and the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), two critical cellular defenses in detoxification of ROS and electrophilic quinone molecules. Incubation of PC12 cells with dopamine also led to a marked increase in the mRNA levels for gamma-glutamylcysteine ligase catalytic subunit (GCLC) and NQO1. In addition, treatment of PC12 cells with dopamine resulted in a significant elevation of GSH content in the mitochondrial compartment. To determine whether treatment with dopamine at noncytotoxic concentrations, which upregulated the cellular defenses could protect the neuronal cells against subsequent lethal oxidative and electrophilic injury, PC12 cells were pretreated with dopamine (150 muM) for 24 h and then exposed to various cytotoxic concentrations of dopamine or 6-hydroxydopamine (6-OHDA). We found that pretreatment of PC12 cells with dopamine at a noncytotoxic concentration led to a remarkable protection against cytotoxicity caused by dopamine or 6-OHDA at lethal concentrations, as detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium reduction assay. In view of the critical roles of GSH and NQO1 in protecting against dopaminergic neuron degeneration, the above findings implicate that upregulation of both GSH and NQO1 by dopamine at noncytotoxic concentrations may serve as an important adaptive mechanism for dopaminergic neuroprotection. PMID:18368484

  17. Cellular regulation of the structure and function of aortic valves

    Directory of Open Access Journals (Sweden)

    Ismail El-Hamamsy

    2010-01-01

    Full Text Available The aortic valve was long considered a passive structure that opens and closes in response to changes in transvalvular pressure. Recent evidence suggests that the aortic valve performs highly sophisticated functions as a result of its unique microscopic structure. These functions allow it to adapt to its hemodynamic and mechanical environment. Understanding the cellular and molecular mechanisms involved in normal valve physiology is essential to elucidate the mechanisms behind valve disease. We here review the structure and developmental biology of aortic valves; we examine the role of its cellular parts in regulating its function and describe potential pathophysiological and clinical implications.

  18. Involvement of Epigenetic Mechanisms in the Regulation of Secreted Phospholipase A2 Expressions in Jurkat Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Mario Menschikowski

    2008-11-01

    Full Text Available Epigenetic changes provide a frequent mechanism for transcriptional silencing of genes in cancer cells. We previously established that epigenetic mechanisms are important for control of group IIA phospholipase A2 (PLA2G2A gene transcription in human DU-145 prostate cells. In this study, we analyzed the involvement of such mechanisms in the regulation of five sPLA2 isozymes and the M-type receptor of sPLA2 (sPLA2-R in human leukemic Jurkat cells. These cells constitutively expressed sPLA2-IB, sPLA2-III, sPLA2-X, and sPLA2-R but not sPLA2-IIA and sPLA2-V. Transcription of sPLA2-IIA and sPLA2-V was, however, detected after exposure of cells to the DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC. Expression of sPLA2-IIA was further enhanced by additional exposure to interferon-γ and blocked by inhibitors of specificity protein 1, nuclear factor κB, and Janus kinase/signal transducer and activator of transcription-dependent pathways. Sequence analysis and methylation-specific polymerase chain reaction of bisulfite-modified genomic DNA revealed two 5′-CpG sites (-111 and -82 in the sPLA2-IIA proximal promoter that were demethylated after 5-aza-dC treatment. These sites may be involved in the DNA binding of specificity protein 1 and other transcription factors. Similar findings after treatment of human U937 leukemia cells with 5-aza-dC indicate that this mechanism of PLA2G2A gene silencing is not restricted to Jurkat and DU-145 cells. These data establish that regulation of sPLA2-IIA and sPLA2-V in Jurkat and other cells involves epigenetic silencing by DNA hypermethylation.

  19. Sex differences in cerebellar mechanisms involved in pain-related safety learning.

    Science.gov (United States)

    Labrenz, Franziska; Icenhour, Adriane; Thürling, Markus; Schlamann, Marc; Forsting, Michael; Timmann, Dagmar; Elsenbruch, Sigrid

    2015-09-01

    Recent studies have suggested that the cerebellum contributes to the central processing of pain, including pain-related learning and memory processes. As a complex experience with multiple emotional and cognitive facets, the response to pain and its underlying neural correlates differ between men and women. However, it remains poorly understood whether and to what extent sex differences exist in the cerebellar contribution to pain-related associative learning processes. In the present conditioning study with experimental abdominal pain as unconditioned stimuli (US), we assessed sex-dependent differences in behavioral and neural responses to conditioned warning and safety cues in healthy volunteers. The results revealed that in response to visual stimuli signaling safety from abdominal pain (CS(-)), women showed enhanced cerebellar activation in lobules I-IV, V, VI, VIIIa, IX and X as well as Crus II and the dentate nucleus, which are mostly representative of somatomotor networks. On the other hand, men showed enhanced neural activation in lobules I-IV, VI, VIIb, VIIIb, IX as well as Crus I and II in response to CS(-), which are representative of frontoparietal and ventral attention networks. No sex differences were observed in response to pain-predictive warning signals (CS(+)). Similarly, men and women did not differ in behavioral measures of conditioning, including conditioned changes in CS valence and contingency awareness. Together, we could demonstrate that the cerebellum is involved in associative learning processes of conditioned anticipatory safety from pain and mediates sex differences in the underlying neural processes. Given the high prevalence of chronic pain conditions in women, these results may contribute to improve our understanding of the acquisition and manifestation of chronic abdominal pain syndromes. PMID:26004678

  20. Is the loss of endothelial thrombomodulin involved in the mechanism of chronicity in late radiation enteropathy?

    International Nuclear Information System (INIS)

    Background and purpose: Radiation enteropathy is characterized by locally elevated levels of inflammatory and fibrogenic c cytokines. Microvascular injury may sustain these alterations through persistent local hypercoagulopathy, platelet aggregation, leukocyte adhesion and release of biologically active mediators. This study assessed the relationship of endothelial thrombomodulin (TM), a key regulator of the protein C anticoagulant pathway and marker of endothelial function, with transforming growth factor β (TGF-β) immunoreactivity and morphologic alterations in radiation enteropathy. Materials and methods: Small bowel resection specimens from 9 patients with radiation enteropathy were analyzed by computerized quantitative immunohistochemistry using antibodies against TM, von Willebrand factor (vWF) and TGF-β. Identical measurements were performed on intestinal resection specimens from otherwise healthy penetrating trauma victims and on archived small intestines. A previously validated image analysis technique was used to assess submucosal vessels for TM and vWF immunoreactivity, and the intestinal wall for total extracellular matrix-associated TGF-β immunoreactivity. Results: Specimens from irradiated patients showed prominent submucosal and subserosal thickening and fibrosis, and obliterative vasculopathy. Control specimens were histopathologically normal. Vascular density and vWF immunoreactivity were similar in radiation enteropathy patients and controls. The image-analysis techniques were highly reproducible, with correlation coefficients for repeated measurements ranging from 0.86 to 0.93. Radiation enteropathy specimens exhibited a highly significant reduction in the number and proportion of TM-positive submucosal vessels per unit area (P < 0.0001) and increased intestinal wall TGF-β immunoreactivity (P = 0.002). Conclusions: These data support the theory that sustained endothelial dysfunction is involved in the molecular pathogenesis of radiation

  1. Mechanisms of shrub encroachment into Northern Chihuahuan Desert grasslands and impacts of climate change investigated using a cellular automata model

    Science.gov (United States)

    Caracciolo, Domenico; Istanbulluoglu, Erkan; Noto, Leonardo Valerio; Collins, Scott L.

    2016-05-01

    Arid and semiarid grasslands of southwestern North America have changed dramatically over the last 150 years as a result of woody plant encroachment. Overgrazing, reduced fire frequency, and climate change are known drivers of woody plant encroachment into grasslands. In this study, relatively simple algorithms for encroachment factors (i.e., grazing, grassland fires, and seed dispersal by grazers) are proposed and implemented in the ecohydrological Cellular-Automata Tree Grass Shrub Simulator (CATGraSS). CATGraSS is used in a 7.3 km2 rectangular domain located in central New Mexico along a zone of grassland to shrubland transition, where shrub encroachment is currently active. CATGraSS is calibrated and used to investigate the relative contributions of grazing, fire frequency, seed dispersal by herbivores and climate change on shrub abundance over a 150-year period of historical shrub encroachment. The impact of future climate change is examined using a model output that realistically represents current vegetation cover as initial condition, in a series of stochastic CATGraSS future climate simulations. Model simulations are found to be highly sensitive to the initial distribution of shrub cover. Encroachment factors more actively lead to shrub propagation within the domain when the model starts with randomly distributed individual shrubs. However, when shrubs are naturally evolved into clusters, the model response to encroachment factors is muted unless the effect of seed dispersal by herbivores is amplified. The relative contribution of different drivers on modeled shrub encroachment varied based on the initial shrub cover condition used in the model. When historical weather data is used, CATGraSS predicted loss of shrub and grass cover during the 1950 s drought. While future climate change is found to amplify shrub encroachment (∼13% more shrub cover by 2100), grazing remains the dominant factor promoting shrub encroachment. When we modeled future climate

  2. Studies of the mechanisms involved in the laser surface hardening process of aluminum base alloys

    International Nuclear Information System (INIS)

    The Al-Si alloys are widely used in industry to replace the steel and gray cast iron in high-tech sectors. The commercial importance of these alloys is mainly due to its low weight, excellent wear (abrasion) and corrosion resistance, high resistance at elevated temperatures, low coefficient of thermal expansion and lesser fuel consumption that provide considerable reduction of emission of pollutants. In this work, Al-Si alloy used in the automotive industry to manufacture pistons of internal combustion engines, was undergone to surface treatments using LASER remelting (Nd:YAG, λ = 1.06 μm, pulsed mode). The LASER enables various energy concentrations with accurate transfer to the material without physical contact. The intense energy transfer causes the occurrence of structural changes in the superficial layer of the material. Experiments with single pulses and trails were conducted under various conditions of LASER processing in order to analyze microstructural changes resulting from treatments and their effects on the hardness. For the characterization of hardened layer was utilized the following techniques: optical microscopy, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), x-ray mapping, Vickers microhardness and maximum roughness tests. The high cooling rate caused a change in the alloy structure due to the refinement of the primary eutectic silicon particles, resulting in increase of the mechanical properties (hardness) of the Al-Si alloy. (author)

  3. Involvement of a joker mutation in a polymerase-independent lethal mutagenesis escape mechanism.

    Science.gov (United States)

    Agudo, Rubén; de la Higuera, Ignacio; Arias, Armando; Grande-Pérez, Ana; Domingo, Esteban

    2016-07-01

    We previously characterized a foot-and-mouth disease virus (FMDV) with three amino acid replacements in its polymerase (3D) that conferred resistance to the mutagenic nucleoside analogue ribavirin. Here we show that passage of this mutant in the presence of high ribavirin concentrations resulted in selection of viruses with the additional replacement I248T in 2C. This 2C substitution alone (even in the absence of replacements in 3D) increased FMDV fitness mainly in the presence of ribavirin, prevented an incorporation bias in favor of A and U associated with ribavirin mutagenesis, and conferred the ATPase activity of 2C decreased sensitivity to ribavirin-triphosphate. Since in previous studies we described that 2C with I248T was selected under different selective pressures, this replacement qualifies as a joker substitution in FMDV evolution. The results have identified a role of 2C in nucleotide incorporation, and have unveiled a new polymerase-independent mechanism of virus escape to lethal mutagenesis. PMID:27136067

  4. Radiotherapy for glioblastoma: reorganization of genome maintenance mechanisms involved in the process of inhibiting cancer

    International Nuclear Information System (INIS)

    Glioblastoma is a very aggressive brain tumor, which occurs in Glial cells. The treatment consists in chemotherapy, surgery and radiotherapy. The radiotherapy is a treatment method that uses ionizing radiation to kill cancer cells. The cells have genome maintenance mechanisms (MMG) distributed in apoptosis, DNA damage response, and cell cycle pathways. These pathways are formed by sets of proteins and perform specific functions within the cell (example: induce cell death). The mutation of these proteins associated with the failure of the MMG can cause the activation of mutations and consequently induce the development of cancer. This work, objective has to identify pathways and proteins expressed in cancer treatment using free software of the statistical analysis, developed in Fortran and R platforms to show the effects caused by radiation in the proteins of cancerous tissues. The results, were fond to pathways of glioblastoma treated with radiotherapy, activation of apoptosis and response to DNA damage pathways, indicating that there is death of carcinogenic tissue caused by radiation and that some cells are triggering a process of DNA repair. (author)

  5. Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking.

    Science.gov (United States)

    Chanda, S; Aoto, J; Lee, S-J; Wernig, M; Südhof, T C

    2016-02-01

    Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Although the general synaptic role of neuroligins is undisputed, their specific functions at a synapse remain unclear, even controversial. Moreover, many neuroligin gene mutations were associated with autism, but the pathophysiological relevance of these mutations is often unknown, and their mechanisms of action uninvestigated. Here, we examine the synaptic effects of an autism-associated neuroligin-4 substitution (called R704C), which mutates a cytoplasmic arginine residue that is conserved in all neuroligins. We show that the R704C mutation, when introduced into neuroligin-3, enhances the interaction between neuroligin-3 and AMPA receptors, increases AMPA-receptor internalization and decreases postsynaptic AMPA-receptor levels. When introduced into neuroligin-4, conversely, the R704C mutation unexpectedly elevated AMPA-receptor-mediated synaptic responses. These results suggest a general functional link between neuroligins and AMPA receptors, indicate that both neuroligin-3 and -4 act at excitatory synapses but perform surprisingly distinct functions, and demonstrate that the R704C mutation significantly impairs the normal function of neuroligin-4, thereby validating its pathogenicity. PMID:25778475

  6. What Do Effective Treatments for Multiple Sclerosis Tell Us about the Molecular Mechanisms Involved in Pathogenesis?

    Directory of Open Access Journals (Sweden)

    Katherine A. Buzzard

    2012-10-01

    Full Text Available Multiple sclerosis is a potentially debilitating disease of the central nervous system. A concerted program of research by many centers around the world has consistently demonstrated the importance of the immune system in its pathogenesis. This knowledge has led to the formal testing of a number of therapeutic agents in both animal models and humans. These clinical trials have shed yet further light on the pathogenesis of MS through their sometimes unexpected effects and by their differential effects in terms of impact on relapses, progression of the disease, paraclinical parameters (MRI and the adverse events that are experienced. Here we review the currently approved medications for the commonest form of multiple sclerosis (relapsing-remitting and the emerging therapies for which preliminary results from phase II/III clinical trials are available. A detailed analysis of the molecular mechanisms responsible for the efficacy of these medications in multiple sclerosis indicates that blockade or modulation of both T- and B-cell activation and migration pathways in the periphery or CNS can lead to amelioration of the disease. It is hoped that further therapeutic trials will better delineate the pathogenesis of MS, ultimately leading to even better treatments with fewer adverse effects.

  7. Cellular and molecular basis of cerebellar development

    Science.gov (United States)

    Martinez, Salvador; Andreu, Abraham; Mecklenburg, Nora; Echevarria, Diego

    2013-01-01

    Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function. PMID:23805080

  8. Cellular and Molecular Basis of Cerebellar Development

    Directory of Open Access Journals (Sweden)

    Salvador eMartinez

    2013-06-01

    Full Text Available Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function.

  9. Aroclor 1254 causes atrophy of exocrine pancreas in mice and the mechanism involved.

    Science.gov (United States)

    Lin, Moudan; Wu, Tian; Sun, Lingbin; Lin, Jackie Jin; Zuo, Zhenghong; Wang, Chonggang

    2016-06-01

    Polychlorinated biphenyls (PCBs) are a class of organic pollutants that have been linked to pancreatic disease. However, their role in affecting the exocrine function of pancreas and the underlying mechanism remains elusive. In the present study, male C57 mice were treated with Aroclor 1254, a commercially available PCBs mixture, at a dosage of 0.5, 5, 50, or 500 μg kg(-1) every 3 days by oral gavage. Decrease in pancreas/soma index and acinar atrophy were observed in the mice after exposure for 50 days. Aroclor 1254 exposure significantly decreased the PCNA-positive cells in the pancreatic acini in a dose-dependent manner. In addition, western blot analysis showed that PCNA expression was decreased in pancreas in the presence of Aroclor 1254, which suggests that Aroclor 1254 suppresses cell proliferation. TUNEL-positive apoptotic cells as well as the expression of Bcl2, BclXL, BAX, and Bad of exocrine pancreas did not show significant changes in the treated mice, indicating that Aroclor 1254 has no effect on apoptosis. We also found that phosphorylation of ERK1/2, P90RSK1 and Bad was increased in the treated groups; this compensatory activation of phosphorylation in ERK1/2-P90RSK1-Bad signaling cascade could protect cell from apoptosis to maintain the cell numbers and function of exocrine pancreas. Moreover, we found that the expression of Kras and TNFα was increased in the pancreas, indicating that Aroclor 1254 exposure could result in increased risk of inflammation and carcinoma. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 671-678, 2016. PMID:25409620

  10. Mechanisms of Binder Removal Involved in Supercritical Debinding of Injection Moulded Ceramics

    Science.gov (United States)

    Chartier, Thierry; Delhomme, Eric; Baumard, Jean-François

    1997-02-01

    Extraction of organic additives from extrusion-moulded ceramic parts by supercritical carbon dioxide has proved to be an efficient method for debinding [1,2]. A model of binder extraction based on diffusion equations was developed. This model was found to be in fair agreement with experimental results. Experimental kinetics of extraction of low melt point paraffins, by supercritical fluids, from injection-moulded samples are now established. A redistribution of the binder in the liquid state in the porosity of the sample, during supercritical debinding, is put in evidence. The importance of this mechanism and its influence on the validity of the model are discussed. Des études précédentes [1, 2] ont montré l'intérêt de l'extraction, à l'aide de gaz carbonique dans l'état supercritique, des additifs organiques de mise en forme de pièces céramiques. Elles ont permis de développer un modèle, établi à partir des équations de diffusion, qui est en bon accord avec les résultats expérimentaux. Les cinétiques expérimentales d'extraction, par fluide supercritique, de paraffines à bas point de fusion utilisées comme liant pour des compositions d'injection sont maintenant étudiées. Une redistribution du liant à l'état liquide au sein de la porosité de l'échantillon pendant le déliantage supercritique est mise en évidence. L'importance de ce mécanisme et son influence sur la validité du modèle sont discutées.

  11. Anorexic response to rapamycin does not appear to involve a central mechanism.

    Science.gov (United States)

    Toklu, Hale Z; Bruce, Erin B; Sakarya, Yasemin; Carter, Christy S; Morgan, Drake; Matheny, Michael K; Kirichenko, Nataliya; Scarpace, Philip J; Tümer, Nihal

    2016-09-01

    The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes-like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 μg/day for 4 weeks) was infused into 23-25-month-old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain. PMID:27232670

  12. Physiological and Molecular Mechanism of Nitric Oxide (NO Involved in Bermudagrass Response to Cold Stress.

    Directory of Open Access Journals (Sweden)

    Jibiao Fan

    Full Text Available Bermudagrass is widely utilized in parks, lawns, and golf courses. However, cold is a key factor limiting resource use in bermudagrass. Therefore, it is meaningful to study the mechanism of bermudagrass response to cold. Nitric oxide (NO is a crucial signal molecule with multiple biological functions. Thus, the objective of this study was to investigate whether NO play roles in bermudagrass response to cold. Sodium nitroprusside (SNP was used as NO donor, while 2-phenyl-4,4,5,5-tetramentylimidazoline-l-oxyl-3-xide (PTIO plus NG-nitro-L-arginine methyl ester (L-NAME were applied as NO inhibitor. Wild bermudagrass was subjected to 4 °C in a growth chamber under different treatments (Control, SNP, PTIO + L-NAME. The results indicated lower levels of malondialdehyde (MDA content and electrolyte leakage (EL, higher value for chlorophyll content, superoxide dismutase (SOD and peroxidase (POD activities after SNP treatment than that of PTIO plus L-NAME treatments under cold stress. Analysis of Chlorophyll (Chl a fluorescence transient displayed that the OJIP transient curve was higher after treatment with SNP than that of treated with PTIO plus L-NAME under cold stress. The values of photosynthetic fluorescence parameters were higher after treatment with SNP than that of treated with PTIO plus L-NAME under cold stress. Expression of cold-responsive genes was altered under cold stress after treated with SNP or PTIO plus L-NAME. In summary, our findings indicated that, as an important strategy to protect bermudagrass against cold stress, NO could maintain the stability of cell membrane, up-regulate the antioxidant enzymes activities, recover process of photosystem II (PSII and induce the expression of cold-responsive genes.

  13. Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms.

    Science.gov (United States)

    Bohlooly-Y, M; Olsson, B; Gritli-Linde, A; Brusehed, O; Isaksson, O G; Ohlsson, C; Söderpalm, B; Törnell, J; Ola, B

    2001-10-01

    Clinical and experimental studies indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. Recently we showed that transgenic mice with general overexpression of bovine GH display increased spontaneous locomotor activity. In the present study, we investigated whether this behavioral change is owing to a direct action of GH in the central nervous system or to peripheral GH actions. A transgenic construct, containing the glial fibrillary acidic protein promoter directing specific expression of bovine GH to the central nervous system, was designed. The central nervous system-specific expression of bovine GH in the glial fibrillary acidic protein-bovine GH transgenic mice was confirmed, but no effect on spontaneous locomotor activity was observed. Serum bovine GH levels were increased in glial fibrillary acidic protein-bovine GH transgenic mice but clearly lower than in transgenic mice with general overexpression of bovine GH. In contrast to the transgenic mice with general overexpression of bovine GH, glial fibrillary acidic protein-bovine GH mice did not display any difference in serum IGF-I levels. The levels of free T(3) and the conversion of the free T(4) to free T(3) were only increased in transgenic mice with general overexpression of bovine GH, but serum corticosterone levels were similarly increased in both transgenic models. These results suggest that free T(3) and/or IGF-I, affecting dopamine and serotonin systems in the central nervous system, may mediate the enhanced locomotor activity observed in transgenic mice with general overexpression of bovine GH. PMID:11564723

  14. The Vulnerability of Vessels Involved in the Role of Embolism and Hypoperfusion in the Mechanisms of Ischemic Cerebrovascular Diseases

    Directory of Open Access Journals (Sweden)

    Yong Peng Yu

    2016-01-01

    Full Text Available Accurate definition and better understanding of the mechanisms of stroke are crucial as this will guide the effective care and therapy. In this paper, we review the previous basic and clinical researches on the causes or mechanisms of ischemic cerebrovascular diseases (ICVD and interpret the correlation between embolism and hypoperfusion based on vascular stenosis and arterial intimal lesions. It was suggested that if there is no embolus (dynamic or in situ emboli, there might be no cerebral infarction. Three kinds of different clinical outcomes of TIA were theoretically interpreted based on its mechanisms. We suppose that there is a correlation between embolism and hypoperfusion, and which mechanisms (hypoperfusion or hypoperfusion induced microemboli playing the dominant role in each type of ICVD depends on the unique background of arterial intimal lesions (the vulnerability of vessels. That is to say, the vulnerability of vessels is involved in the role of embolism and hypoperfusion in the mechanisms of ischemic cerebrovascular diseases. This inference might enrich and provide better understandings for the underlying etiologies of ischemic cerebrovascular events.

  15. The Vulnerability of Vessels Involved in the Role of Embolism and Hypoperfusion in the Mechanisms of Ischemic Cerebrovascular Diseases

    Science.gov (United States)

    2016-01-01

    Accurate definition and better understanding of the mechanisms of stroke are crucial as this will guide the effective care and therapy. In this paper, we review the previous basic and clinical researches on the causes or mechanisms of ischemic cerebrovascular diseases (ICVD) and interpret the correlation between embolism and hypoperfusion based on vascular stenosis and arterial intimal lesions. It was suggested that if there is no embolus (dynamic or in situ emboli), there might be no cerebral infarction. Three kinds of different clinical outcomes of TIA were theoretically interpreted based on its mechanisms. We suppose that there is a correlation between embolism and hypoperfusion, and which mechanisms (hypoperfusion or hypoperfusion induced microemboli) playing the dominant role in each type of ICVD depends on the unique background of arterial intimal lesions (the vulnerability of vessels). That is to say, the vulnerability of vessels is involved in the role of embolism and hypoperfusion in the mechanisms of ischemic cerebrovascular diseases. This inference might enrich and provide better understandings for the underlying etiologies of ischemic cerebrovascular events.

  16. Cellular basis of memory for addiction.

    Science.gov (United States)

    Nestler, Eric J

    2013-12-01

    DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. Here, we review the types of molecular and cellular adaptations that occur in specific brain regions to mediate addiction-associated behavioral abnormalities. These include alterations in gene expression achieved in part via epigenetic mechanisms, plasticity in the neurophysiological functioning of neurons and synapses, and associated plasticity in neuronal and synaptic morphology mediated in part by altered neurotrophic factor signaling. Each of these types of drug-induced modifications can be viewed as a form of "cellular or molecular memory." Moreover, it is striking that most addiction-related forms of plasticity are very similar to the types of plasticity that have been associated with more classic forms of "behavioral memory," perhaps reflecting the finite repertoire of adaptive mechanisms available to neurons when faced with environmental challenges. Finally, addiction-related molecular and cellular adaptations involve most of the same brain regions that mediate more classic forms of memory, consistent with the view that abnormal memories are important drivers of addiction syndromes. The goal of these studies which aim to explicate the molecular and cellular basis of drug addiction is to eventually develop biologically based diagnostic tests, as well as more effective treatments for addiction disorders. PMID:24459410

  17. Modeling mechanical restriction differences between car and heavy truck in two-lane cellular automata traffic flow model

    Science.gov (United States)

    Li, Xin; Li, Xingang; Xiao, Yao; Jia, Bin

    2016-06-01

    Real traffic is heterogeneous with car and truck. Due to mechanical restrictions, the car and the truck have different limited deceleration capabilities, which are important factors in safety driving. This paper extends the single lane safety driving (SD) model with limited deceleration capability to two-lane SD model, in which car-truck heterogeneous traffic is considered. A car has a larger limited deceleration capability while a heavy truck has a smaller limited deceleration capability as a result of loaded goods. Then the safety driving conditions are different as the types of the following and the leading vehicles vary. In order to eliminate the well-known plug in heterogeneous two-lane traffic, it is assumed that heavy truck has active deceleration behavior when the heavy truck perceives the forming plug. The lane-changing decisions are also determined by the safety driving conditions. The fundamental diagram, spatiotemporal diagram, and lane-changing frequency were investigated to show the effect of mechanical restriction on heterogeneous traffic flow. It was shown that there would be still three traffic phases in heterogeneous traffic condition; the active deceleration of the heavy truck could well eliminate the plug; the lane-changing frequency was low in synchronized flow; the flow and velocity would decrease as the proportion of heavy truck grows or the limited deceleration capability of heavy truck drops; and the flow could be improved with lane control measures.

  18. Chromic-P32 phosphate treatment of implanted pancreatic carcinoma: Mechanism involved

    Institute of Scientific and Technical Information of China (English)

    Lu Liu; Guo-Sheng Feng; Hong Gao; Guan-Sheng Tong; Yu Wang; Wen Gao; Ying Huang; Cheng Li

    2005-01-01

    AIM: To study the effects of chromic-P32 phosphate (32p colloids) interstitial administration in Pc-3 implanted pancreatic carcinoma, and investigate its anticancer mechanism.METHODS: Ninety-eight tumor bearing nude mice werekilled at different time points after the injection of 32Pcolloids to the tumor core with observed radioactivity. The light microscopy, transmission electron microscopy (TEM) and immuno-histochemistry and flow cytometry were used to study the rates of tumor cell necrosis, proliferating cell nuclear antigen index, the micro vessel density (MVD). The changes of the biological response to the lymphatic transported 32p colloids in the inguinal lymph node (ILN) were dynamically observed, and the percentage of tumor cell apoptosis, and Apo2.7, caspase-3, Bcl-2, Baxrelated gene expression were observed too.RESULTS: The half-life of effective medication is 13 dafter injection of 32P colloids to the tumor stroma, in 1-6groups, the tumor cell necrosis rates were 20%, 45%,65%, 70%, 95% and 4%, respectively (F= 4.14-105.36, P<0.01). MVD were 38.5±4.0, 28.0±2.9, 17.0±2.9, 8.8±1.5,5.7±2.3 and 65.0±5.2 (t= 11.9-26.1, P<0.01), respectively.Under TEM fairly differentiated Pc-3 cells were found. Thirty days after medication, tumors were shrunk and dried with scabs detached, and those in control group increased in size prominently with plenty of hypodermic blood vessels. In all animals the ILN were enlarged but in medicated animals they appeared later and smaller than those in control group. The extent of irradiative injury in ILN was positively correlated to the dosage of medication. Typical tumor cell apoptosis could be found under TEM inanimals with intra-tumoral injection of low dosed 32P colloids. The peak of apoptosis occurred in 2.96 MBq group and 24 h after irradiation. In the course of irradiationinduced apoptosis, the value of Bcl-2/Bax was down regulated; Apo2.7 and caspase-3 protein expression were prominently increased dose dependently

  19. Cytotoxicity of CdTe quantum dots in human umbilical vein endothelial cells: the involvement of cellular uptake and induction of pro-apoptotic endoplasmic reticulum stress

    Directory of Open Access Journals (Sweden)

    Yan M

    2016-02-01

    Full Text Available Ming Yan,1,* Yun Zhang,2,* Haiyan Qin,3 Kezhou Liu,1 Miao Guo,1 Yakun Ge,1 Mingen Xu,1 Yonghong Sun,4 Xiaoxiang Zheng4 1Department of Biomedical Engineering, College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, 2Basic Medical Sciences, College of Medicine, Shaoxing University, Shaoxing, 3Department of Chemistry, Zhejiang University, 4Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Department of Biomedical Engineering, Zhejiang University, Hangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Cadmium telluride quantum dots (CdTe QDs have been proposed to induce oxidative stress, which plays a crucial role in CdTe QDs-mediated mitochondrial-dependent apoptosis in human umbilical vein endothelial cells (HUVECs. However, the direct interactions of CdTe QDs with HUVECs and their potential impairment of other organelles like endoplasmic reticulum (ER in HUVECs are poorly understood. In this study, we reported that the negatively charged CdTe QDs (–21.63±0.91 mV, with good dispersity and fluorescence stability, were rapidly internalized via endocytosis by HUVECs, as the notable internalization could be inhibited up to 95.52% by energy depletion (NaN3/deoxyglucose or low temperature. The endocytosis inhibitors (methyl-β-cyclodextrin, genistein, sucrose, chlorpromazine, and colchicine dramatically decreased the uptake of CdTe QDs by HUVECs, suggesting that both caveolae/raft- and clathrin-mediated endocytosis were involved in the endothelial uptake of CdTe QDs. Using immunocytochemistry, a striking overlap of the internalized CdTe QDs and ER marker was observed, which indicates that QDs may be transported to ER. The CdTe QDs also caused remarkable ER stress responses in HUVECs, confirmed by significant dilatation of ER cisternae, upregulation of ER stress markers GRP78/GRP94, and

  20. Loss and recovery of Mgat3 and GnT-III Mediated E-cadherin N-glycosylation is a mechanism involved in epithelial-mesenchymal-epithelial transitions.

    Directory of Open Access Journals (Sweden)

    Salomé S Pinho

    Full Text Available BACKGROUND: N-acetylglucosaminyltransferase-III (GnT-III is a glycosyltransferase encoded by Mgat3 that catalyzes the addition of β1,4-bisecting-N-acetylglucosamine on N-glycans. GnT-III has been pointed as a metastases suppressor having varying effects on cell adhesion and migration. We have previously described the existence of a functional feedback loop between E-cadherin expression and GnT-III-mediated glycosylation. The effects of GnT-III-mediated glycosylation on E-cadherin expression and cellular phenotype lead us to evaluate Mgat3 and GnT-III-glycosylation role during Epithelial-Mesenchymal-Transition (EMT and the reverted process, Mesenchymal-Epithelial-Transition (MET. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the expression profile and genetic mechanism controlling Mgat3 expression as well as GnT-III-mediated glycosylation, in general and specifically on E-cadherin, during EMT/MET. We found that during EMT, Mgat3 expression was dramatically decreased and later recovered when cells returned to an epithelial-like phenotype. We further identified that Mgat3 promoter methylation/demethylation is involved in this expression regulation. The impact of Mgat3 expression variation, along EMT/MET, leads to a variation in the expression levels of the enzymatic product of GnT-III (bisecting GlcNAc structures, and more importantly, to the specific modification of E-cadherin glycosylation with bisecting GlcNAc structures. CONCLUSIONS/SIGNIFICANCE: Altogether, this work identifies for the first time Mgat3 glycogene expression and GnT-III-mediated glycosylation, specifically on E-cadherin, as a novel and major component of the EMT/MET mechanism signature, supporting its role during EMT/MET.

  1. Report on NCI symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. II. Cellular and animal models

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1984-01-01

    The point at which the common final pathway for induction of cancer by chemical carcinogens and ionizing radiation has not been identified. Although common molecular targets are suggested by recent findings about the role of oncogenes, the mechanism by which the deposition of radiation energy and the formation of adducts or other DNA lesions induced by chemicals affects the changes in the relevant targets may be quite different. The damage to DNA that plays no part in the transformation events, but that influences the stability of the genome, and therefore, the probability of subsequent changes that influence tumorigenesis may be more readily induced by some agents than others. Similarly, the degree of cytotoxic effects that disrupt tissue integrity and increase the probability of expression of initiated cells may be dependent on the type of carcinogen. Also, evidence was presented that repair of the initial lesions could be demonstrated after exposure to low-LET radiation but not after exposure to chemical carcinogens.

  2. Report on NCI symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. II. Cellular and animal models

    International Nuclear Information System (INIS)

    The point at which the common final pathway for induction of cancer by chemical carcinogens and ionizing radiation has not been identified. Although common molecular targets are suggested by recent findings about the role of oncogenes, the mechanism by which the deposition of radiation energy and the formation of adducts or other DNA lesions induced by chemicals affects the changes in the relevant targets may be quite different. The damage to DNA that plays no part in the transformation events, but that influences the stability of the genome, and therefore, the probability of subsequent changes that influence tumorigenesis may be more readily induced by some agents than others. Similarly, the degree of cytotoxic effects that disrupt tissue integrity and increase the probability of expression of initiated cells may be dependent on the type of carcinogen. Also, evidence was presented that repair of the initial lesions could be demonstrated after exposure to low-LET radiation but not after exposure to chemical carcinogens

  3. Cellular mechanisms for the treatment of chronic heart failure: the nitric oxide- and adenosine-dependent pathways.

    Science.gov (United States)

    Minamino, Tetsuo; Kitakaze, Masafumi

    2002-05-01

    Accumulated evidence suggests that several drugs proven to improve survival in patients with chronic heart failure (CHF) enhance endogenous nitric oxide (NO)- and/or adenosine-dependent pathways. Indeed, we and others have demonstrated that: i) antagonists of either renin-angiotensin-aldosterone or beta-adrenergic systems enhance NO-dependent pathways; ii) although carvedilol and amlodipine belong to different drug classes, both of them can increase cardiac adenosine levels; iii) increased adenosine levels by dipyridamole are associated with the improvement of CHF. Interestingly, both NO and adenosine have multifactorial beneficial actions in cardiovascular systems. First of all, both of them induce vasodilation and decrease myocardial hypercontractility, which may contribute to a reduction in the severity of myocardial ischaemia. Both adenosine and NO are also involved in cardioprotection attributable to acute and late phases of ischaemic preconditioning, respectively. Secondly, they can modulate the neurohormonal systems that contribute to the progression of CHF. Thus, we propose that enhancement of endogenous NO and/or adenosine as potential therapeutic targets in a new strategy for the treatment for CHF. PMID:15989539

  4. A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence.

    Science.gov (United States)

    Bukhari, Syed I A; Truesdell, Samuel S; Lee, Sooncheol; Kollu, Swapna; Classon, Anthony; Boukhali, Myriam; Jain, Esha; Mortensen, Richard D; Yanagiya, Akiko; Sadreyev, Ruslan I; Haas, Wilhelm; Vasudevan, Shobha

    2016-03-01

    MicroRNAs predominantly decrease gene expression; however, specific mRNAs are translationally upregulated in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes by an FXR1a-associated microRNA-protein complex (microRNP) that lacks the microRNP repressor, GW182. Their mechanism in these conditions of decreased mTOR signaling, and therefore reduced canonical (cap-and-poly(A)-tail-mediated) translation, remains undiscovered. Our data reveal that mTOR inhibition in human THP1 cells enables microRNA-mediated activation. Activation requires shortened/no poly(A)-tail targets; polyadenylated mRNAs are partially activated upon PAIP2 overexpression, which interferes with poly(A)-bound PABP, precluding PABP-enhanced microRNA-mediated inhibition and canonical translation. Consistently, inhibition of PARN deadenylase prevents activation. P97/DAP5, a homolog of canonical translation factor, eIF4G, which lacks PABP- and cap binding complex-interacting domains, is required for activation, and thereby for the oocyte immature state. P97 interacts with 3' UTR-binding FXR1a-associated microRNPs and with PARN, which binds mRNA 5' caps, forming a specialized complex to translate recruited mRNAs in these altered canonical translation conditions. PMID:26942679

  5. Cellular mechanisms of reduced sarcoplasmic reticulum Ca2+ content in L-thyroxin-induced rat ventricular hypertrophy

    Institute of Scientific and Technical Information of China (English)

    Lai-jing SONG; Guan-lei WANG; Jie LIU; Qin-ying QIU; Jing-hua OU; Yong-yuan GUAN

    2008-01-01

    Aim:To examine how the sarcoplasmic reticulum (SR) Ca2+ content changes and the underlying mechanism in L-thyroxin-induced cardiac hypertrophy. Methods:Echocardiography was used to confirm the establishment of the cardiac hypertro-phy model. The confocal microscopy and fluorescent indicator Fluo-3 was ap-plied to examine the intracellular Ca2+ concentration ([Ca2+]I), the Ca2+ sparks, and the caffeine-induced Ca2+ transient in freshly isolated cardiac ventricular myocytes. The activity of sarcolemmal and SR Ca2+-ATPase 2a (SERCA2a) in the ventricular tissue was also measured, respectively. Results:L-thyroxin (1 mg/kg injection for 10 d) induces left ventricular cardiac hypertrophy with normal myocardial function. The decreased caffeine-induced Ca2+ transient in the Ca2+-free solution was detected. The spontaneous Ca2+ sparks in hypertrophied myocytes occurred more frequently than in normal cells, with similar duration and spatial spread, but smaller amplitude. Then the basal [Ca2+]I increase was observed in quiescent left ventricular myocytes from hyperthyroidism rats. The activity of sarcolemmal and SR Ca2+-ATPase was decreased in the hypertrophied ventricle tissue. Conclusion:The results suggested that the reduced SR Ca2+ content may be associated with an increased Ca2+ leak and reduced SERCA2a activity, contributing to abnormal intracellular Ca2+ handling during hypertrophy in hyperthyroidism rats.

  6. The phosphoinositide 3-kinase signaling pathway in normal and malignant B cells: activation mechanisms, regulation and impact on cellular functions.

    Science.gov (United States)

    Pauls, Samantha D; Lafarge, Sandrine T; Landego, Ivan; Zhang, Tingting; Marshall, Aaron J

    2012-01-01

    The phosphoinositide 3-kinase (PI3K) pathway is a central signal transduction axis controlling normal B cell homeostasis and activation in humoral immunity. The p110δ PI3K catalytic subunit has emerged as a critical mediator of multiple B cell functions. The activity of this pathway is regulated at multiple levels, with inositol phosphatases PTEN and SHIP both playing critical roles. When deregulated, the PI3K pathway can contribute to B cell malignancies and autoantibody production. This review summarizes current knowledge on key mechanisms that activate and regulate the PI3K pathway and influence normal B cell functional responses including the development of B cell subsets, antigen presentation, immunoglobulin isotype switch, germinal center responses, and maintenance of B cell anergy. We also discuss PI3K pathway alterations reported in select B cell malignancies and highlight studies indicating the functional significance of this pathway in malignant B cell survival and growth within tissue microenvironments. Finally, we comment on early clinical trial results, which support PI3K inhibition as a promising treatment of chronic lymphocytic leukemia. PMID:22908014

  7. Visual loss in HIV-associated cryptococcal meningitis: A case series and review of the mechanisms involved

    Directory of Open Access Journals (Sweden)

    Anand Moodley

    2015-04-01

    Full Text Available Permanent visual loss is a devastating yet preventable complication of cryptococcal meningitis. Early and aggressive management of cerebrospinal fluid pressure in conjunction with antifungal therapy is required. Historically, the mechanisms of visual loss in cryptococcal meningitis have included optic neuritis and papilloedema. Hence, the basis of visual loss therapy has been steroid therapy and intracranial pressure lowering without clear guidelines. With the use of high-resolution magnetic resonance imaging of the optic nerve, an additional mechanism has emerged, namely an optic nerve sheath compartment syndrome (ONSCS caused by severely elevated intracranial pressure and fungal loading in the peri-optic space. An improved understanding of these mechanisms and recognition of the important role played by raised intracranial pressure allows for more targeted treatment measures and better outcomes. In the present case series of 90 HIV co-infected patients with cryptococcal meningitis, we present the clinical and electrophysiological manifestations of Cryptococcus-induced visual loss and review the mechanisms involved.

  8. Arbuscular Mycorrhizal Fungi for the Biocontrol of Plant-Parasitic Nematodes: A Review of the Mechanisms Involved

    Science.gov (United States)

    Schouteden, Nele; De Waele, Dirk; Panis, Bart; Vos, Christine M.

    2015-01-01

    Arbuscular mycorrhizal fungi (AMF) are obligate root symbionts that can protect their host plant against biotic stress factors such as plant-parasitic nematode (PPN) infection. PPN consist of a wide range of species with different life styles that can cause major damage in many important crops worldwide. Various mechanisms have been proposed to play a role in the biocontrol effect of AMF against PPN. This review presents an overview of the different mechanisms that have been proposed, and discusses into more detail the plausibility of their involvement in the biocontrol against PPN specifically. The proposed mechanisms include enhanced plant tolerance, direct competition for nutrients and space, induced systemic resistance (ISR) and altered rhizosphere interactions. Recent studies have emphasized the importance of ISR in biocontrol and are increasingly placing rhizosphere effects on the foreground as well, both of which will be the focal point of this review. Though AMF are not yet widely used in conventional agriculture, recent data help to develop a better insight into the modes of action, which will eventually lead toward future field applications of AMF against PPN. The scientific community has entered an exciting era that provides the tools to actually unravel the underlying molecular mechanisms, making this a timely opportunity for a review of our current knowledge and the challenges ahead. PMID:26635750

  9. Biokinetics of a transuranic (238PU) and a rare earth element (152Eu) in the lobster (Homarus gammarus): transfer mechanisms (accumulation and detoxification) in organs and at the cellular level

    International Nuclear Information System (INIS)

    The work presented here is an experimental investigation of the biokinetics of transfer of a transuranic and a rare earth element (238Pu and 152Eu) in the lobster Homarus gammarus. The study of 238Pu biokinetics forms part of a wider framework of research concerning the transfer of transuranic elements in marine species, while the study of 152Eu is carried out with a view to supporting the analogy between the behaviour of transuranics and rare earths in living organisms. Exactly the same experimental protocol, based on techniques from various disciplines (biology, biochemistry and metrology), was used to Investigate the biokinetics of transfer of these two radionuclides. The Individual lobsters were radiolabelled by means of one-shot or chronic ingestion of spiked meals. As the first approach, the kinetics and transfer mechanisms were studied In whole animal samples and in different organs distinct series of pathways through the different organs were identified in the case of both radionuclides, being mainly linked to digestive processes induced by the meal as well as the transport function of hemo-lymph in this way, the Important role of the digestive gland was picked out, with two of four cellular types displaying a successive involvement In the fixation and then the retention of the studied radionuclides. As a corroborative approach, the digestive gland was subjected to a more detailed investigation with the aim of describing the mechanisms of Incorporation and elucidating transfer processes at the cellular and molecular levels. 238Pu is preferentially partitioned into the cytosol, where it is associated with various constituents such as ferritin (iron-storing protein). 152Eu is more diffusely distributed in the hepato-pancreatic cells, while the lysosomes appear to play a more important role during transfer. The results obtained in this study, both on the macroscopic scale (i.e. the whole animal and different organs) as well as the cellular and molecular levels

  10. Cellular Automata

    OpenAIRE

    Bagnoli, Franco

    1998-01-01

    An introduction to cellular automata (both deterministic and probabilistic) with examples. Definition of deterministic automata, dynamical properties, damage spreading and Lyapunov exponents; probabilistic automata and Markov processes, nonequilibrium phase transitions, directed percolation, diffusion; simulation techniques, mean field. Investigation themes: life, epidemics, forest fires, percolation, modeling of ecosystems and speciation. They represent my notes for the school "Dynamical Mod...

  11. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons.

    Science.gov (United States)

    Balkowiec, Agnieszka; Katz, David M

    2002-12-01

    Brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent modifications of neuronal connectivity and synaptic strength, including establishment of hippocampal long-term potentiation (LTP). To shed light on mechanisms underlying BDNF-dependent synaptic plasticity, the present study was undertaken to characterize release of native BDNF from newborn rat hippocampal neurons in response to physiologically relevant patterns of electrical field stimulation in culture, including tonic stimulation at 5 Hz, bursting stimulation at 25 and 100 Hz, and theta-burst stimulation (TBS). Release was measured using the ELISA in situ technique, developed in our laboratory to quantify secretion of native BDNF without the need to first overexpress the protein to nonphysiological levels. Each stimulation protocol resulted in a significant increase in BDNF release that was tetrodotoxin sensitive and occurred in the absence of glutamate receptor activation. However, 100 Hz tetanus and TBS, stimulus patterns that are most effective in inducing hippocampal LTP, were significantly more effective in releasing native BDNF than lower-frequency stimulation. For all stimulation protocols tested, removal of extracellular calcium, or blockade of N-type calcium channels, prevented BDNF release. Similarly, depletion of intracellular calcium stores with thapsigargin and treatment with dantrolene, an inhibitor of calcium release from caffeine-ryanodine-sensitive stores, markedly inhibited activity-dependent BDNF release. Our results indicate that BDNF release can encode temporal features of hippocampal neuronal activity. The dual requirement for calcium influx through N-type calcium channels and calcium mobilization from intracellular stores strongly implicates a role for calcium-induced calcium release in activity-dependent BDNF secretion. PMID:12451139

  12. Genetic Dominance & Cellular Processes

    Science.gov (United States)

    Seager, Robert D.

    2014-01-01

    In learning genetics, many students misunderstand and misinterpret what "dominance" means. Understanding is easier if students realize that dominance is not a mechanism, but rather a consequence of underlying cellular processes. For example, metabolic pathways are often little affected by changes in enzyme concentration. This means that…

  13. The New Cellular Immunology

    Science.gov (United States)

    Claman, Henry N.

    1973-01-01

    Discusses the nature of the immune response and traces many of the discoveries that have led to the present state of knowledge in immunology. The new cellular immunology is directing its efforts toward improving health by proper manipulation of the immune mechanisms of the body. (JR)

  14. On the Path of Election and Martyrdom: Some Psychic Mechanisms Involved in the Anders Behring Breivik's Determination as a Terrorist.

    Science.gov (United States)

    Cotti, Patricia

    2015-08-01

    On 22 July 2011, the Norwegian Anders Behring Breivik carried out two attacks in Oslo that cost the lives of 77 people, injured many others, and plunged the entire Norwegian nation into mourning. When he was arrested, Breivik presented himself as a member of the Knights Templar, whose mission is to defend the Christian Western world. He considers that he has sacrificed himself by his actions for his people and says that he has prepared himself for martyrdom. In analysing Breivik's words and writings, this article attempts to identify the thought mechanisms involved in Breivik's idea of election (megalomania) and martyrology. It highlights the importance of a mechanism of "return to the sender," whereby Breivik returns the reproaches directed at him by an agency of judgment (ego ideal or superegoic object). It emphasizes the existence of a "burning desire" and yearning (Sehnsucht) for this same persecuting superegoic object, an object that Breivik constantly wants to find again, even if in death. Taking into consideration Searles's hypothesis that the sense of being persecuted is a defence against the impossibility of mourning, and also H. Blum's hypothesis that persecutory feelings are indicative of fears of a "regressive loss of object constancy," the different psychic mechanisms and modes of functioning underlying Breivik's terrorist determination are related here to what we know about his affective development and infantile relationships. PMID:26290947

  15. Dynamin-2 regulates fusion pore expansion and quantal release through a mechanism that involves actin dynamics in neuroendocrine chromaffin cells.

    Directory of Open Access Journals (Sweden)

    Arlek M González-Jamett

    Full Text Available Over the past years, dynamin has been implicated in tuning the amount and nature of transmitter released during exocytosis. However, the mechanism involved remains poorly understood. Here, using bovine adrenal chromaffin cells, we investigated whether this mechanism rely on dynamin's ability to remodel actin cytoskeleton. According to this idea, inhibition of dynamin GTPase activity suppressed the calcium-dependent de novo cortical actin and altered the cortical actin network. Similarly, expression of a small interfering RNA directed against dynamin-2, an isoform highly expressed in chromaffin cells, changed the cortical actin network pattern. Disruption of dynamin-2 function, as well as the pharmacological inhibition of actin polymerization with cytochalasine-D, slowed down fusion pore expansion and increased the quantal size of individual exocytotic events. The effects of cytochalasine-D and dynamin-2 disruption were not additive indicating that dynamin-2 and F-actin regulate the late steps of exocytosis by a common mechanism. Together our data support a model in which dynamin-2 directs actin polymerization at the exocytosis site where both, in concert, adjust the hormone quantal release to efficiently respond to physiological demands.

  16. MeCP2 post-translational modifications: a mechanism to control its involvement in synaptic plasticity and homeostasis?

    Directory of Open Access Journals (Sweden)

    Elisa Bellini

    2014-08-01

    Full Text Available Although Rett syndrome (RTT represents one of the most frequent forms of severe intellectual disability in females worldwide, we still have an inadequate knowledge of the many roles played by MeCP2 (whose mutations are responsible for most cases of RTT and their relevance for RTT pathobiology. Several studies support a role of MeCP2 in the regulation of synaptic plasticity and homeostasis. At the molecular level, MeCP2 is described as a repressor capable of inhibiting gene transcription through chromatin compaction. Indeed, it interacts with several chromatin remodeling factors, such as HDAC-containing complexes and ATRX. Other studies have inferred that MeCP2 functions also as an activator; a role in regulating mRNA splicing and in modulating protein synthesis has also been proposed. Further, MeCP2 avidly binds both 5-methyl- and 5-hydroxymethyl-cytosine. Recent evidence suggests that it is the highly disorganized structure of MeCP2, together with its post-translational modifications (PTMs that generate and regulate this functional versatility. Indeed, several reports have demonstrated that differential phosphorylation of MeCP2 is a key mechanism by which the methyl binding protein modulates its affinity for its partners, gene expression and cellular adaptations to stimuli and neuronal plasticity. As logic consequence, generation of phospho-defective Mecp2 knock-in mice has permitted associating alterations in neuronal morphology, circuit formation, and mouse behavioral phenotypes with specific phosphorylation events. MeCP2 undergoes various other PTMs, including acetylation, ubiquitination and sumoylation, whose functional roles remain largely unexplored. These results, together with the genome-wide distribution of MeCP2 and its capability to substitute histone H1, recall the complex regulation of histones and suggest the relevance of quickly gaining a deeper comprehension of MeCP2 PTMs, the respective writers and readers and the consequent

  17. Metal and metalloid foliar uptake by various plant species exposed to atmospheric industrial fallout: Mechanisms involved for lead

    Energy Technology Data Exchange (ETDEWEB)

    Schreck, E., E-mail: eva.schreck@ensat.fr [Universite de Toulouse (France); INP, UPS (France); EcoLab (Laboratoire Ecologie Fonctionnelle et Environnement) (France); ENSAT, Avenue de l' Agrobiopole, 31326 Castanet Tolosan (France); CNRS (France); EcoLab, 31326 Castanet Tolosan (France); Foucault, Y. [Universite de Toulouse (France); INP, UPS (France); EcoLab (Laboratoire Ecologie Fonctionnelle et Environnement) (France); ENSAT, Avenue de l' Agrobiopole, 31326 Castanet Tolosan (France); CNRS (France); EcoLab, 31326 Castanet Tolosan (France); STCM, Societe de Traitements Chimiques des Metaux, 30 Avenue de Fondeyre 31200 Toulouse (France); Sarret, G. [ISTerre (UMR 5275), Universite J. Fourier and CNRS, BP 53, 38041 Grenoble cedex 9 (France); Sobanska, S. [LASIR (UMR CNRS 8516), Universite de Lille 1, Bat. C5, 59655 Villeneuve d' Ascq cedex (France); Cecillon, L. [ISTerre (UMR 5275), Universite J. Fourier and CNRS, BP 53, 38041 Grenoble cedex 9 (France); Castrec-Rouelle, M. [Universite Pierre and Marie Curie (UPMC-Paris 6), Bioemco (Biogeochimie et Ecologie des Milieux Continentaux), Site Jussieu, Tour 56, 4 Place Jussieu, 75252 Paris cedex 05 (France); Uzu, G. [Laboratoire d' Aerologie (UMR 5560), OMP, UPS 14, Avenue Edouard Belin, 31400 Toulouse (France); GET (UMR 5563), IRD, 14, Avenue Edouard Belin, 31400 Toulouse (France); Dumat, C. [Universite de Toulouse (France); INP, UPS (France); EcoLab (Laboratoire Ecologie Fonctionnelle et Environnement) (France); ENSAT, Avenue de l' Agrobiopole, 31326 Castanet Tolosan (France); CNRS (France); EcoLab, 31326 Castanet Tolosan (France)

    2012-06-15

    Fine and ultrafine metallic particulate matters (PMs) are emitted from metallurgic activities in peri-urban zones into the atmosphere and can be deposited in terrestrial ecosystems. The foliar transfer of metals and metalloids and their fate in plant leaves remain unclear, although this way of penetration may be a major contributor to the transfer of metals into plants. This study focused on the foliar uptake of various metals and metalloids from enriched PM (Cu, Zn, Cd, Sn, Sb, As, and especially lead (Pb)) resulting from the emissions of a battery-recycling factory. Metal and metalloid foliar uptake by various vegetable species, exhibiting different morphologies, use (food or fodder) and life-cycle (lettuce, parsley and rye-grass) were studied. The mechanisms involved in foliar metal transfer from atmospheric particulate matter fallout, using lead (Pb) as a model element was also investigated. Several complementary techniques (micro-X-ray fluorescence, scanning electron microscopy coupled with energy dispersive X-ray microanalysis and time-of-flight secondary ion mass spectrometry) were used to investigate the localization and the speciation of lead in their edible parts, i.e. leaves. The results showed lead-enriched PM on the surface of plant leaves. Biogeochemical transformations occurred on the leaf surfaces with the formation of lead secondary species (PbCO{sub 3} and organic Pb). Some compounds were internalized in their primary form (PbSO{sub 4}) underneath an organic layer. Internalization through the cuticle or penetration through stomata openings are proposed as two major mechanisms involved in foliar uptake of particulate matter. - Graphical abstract: Overall picture of performed observations and mechanisms potentially involved in lead foliar uptake. Highlights: Black-Right-Pointing-Pointer Foliar uptake of metallic particulate matter (PM) is of environmental and health concerns. Black-Right-Pointing-Pointer The leaf morphology influences the adsorption

  18. Never-ageing cellular senescence

    OpenAIRE

    Ogrunc, Müge; d’Adda di Fagagna, Fabrizio

    2011-01-01

    Cellular senescence was historically discovered as a form of cellular ageing of in vitro cultured cells. It has been under the spotlight following the evidence of oncogene-induced senescence in vivo and its role as a potent tumour suppressor mechanism. Presently, a PubMed search using keywords ‘cellular senescence and cancer’ reveals 8398 number of references (by April 2011) showing that while our knowledge of senescence keeps expanding, the complexity of the phenomenon keeps us – researchers...

  19. Mechanism of action of peptidoglycan O-acetyltransferase B involves a Ser-His-Asp catalytic triad.

    Science.gov (United States)

    Moynihan, Patrick J; Clarke, Anthony J

    2014-10-01

    The O-acetylation of the essential cell wall polymer peptidoglycan is essential in many bacteria for their integrity and survival, and it is catalyzed by peptidoglycan O-acetlytransferase B (PatB). Using PatB from Neisseria gonorrhoeae as the model, we have shown previously that the enzyme has specificity for polymeric muropeptides that possess tri- and tetrapeptide stems and that rates of reaction increase with increasing degrees of polymerization. Here, we present the catalytic mechanism of action of PatB, the first to be described for an O-acetyltransferase of any bacterial exopolysaccharide. The influence of pH on PatB activity was investigated, and pKa values of 6.4-6.45 and 6.25-6.35 for the enzyme-substrate complex (kcat vs pH) and the free enzyme (kcat·KM(-1) vs pH), respectively, were determined for the respective cosubstrates. The enzyme is partially inactivated by sulfonyl fluorides but not by EDTA, suggesting the participation of a serine residue in its catalytic mechanism. Alignment of the known and hypothetical PatB amino acid sequences identified Ser133, Asp302, and His305 as three invariant amino acid residues that could potentially serve as a catalytic triad. Replacement of Asp302 with Ala resulted in an enzyme with less than 20% residual activity, whereas activity was barely detectable with (His305 → Ala)PatB and (Ser133 → Ala)PatB was totally inactive. The reaction intermediate of the transferase reaction involving acetyl- and propionyl-acyl donors was trapped on both the wild-type and (Asp302 → Ala) enzymes and LC-MS/MS analysis of tryptic peptides identified Ser133 as the catalytic nucleophile. A transacetylase mechanism is proposed based on the mechanism of action of serine esterases. PMID:25215566

  20. Study of the mechanisms involved in the laser superficial hardening process of metallic alloys; Estudo dos mecanismos envolvidos no processo de endurecimento superficial a laser de ligas metalicas

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Edmara Marques Rodrigues da

    2001-07-01

    The laser superficial hardening process of a ferrous alloy (gray cast iron) and of an aluminum-silicon alloy was investigated in this work. These metallic alloys are used in the automobile industry for manufacturing cylinders and pistons, respectively. By application of individual pulses and single tracks, the involved mechanisms during the processing were studied. Variables such as energy density, power density, temporal width, beam diameter on the sample surface, atmosphere of the processing region, overlapping and scanning velocity. The hardened surface was characterized by optical and scanning electronic microscopy, dispersive energy microanalysis, X-ray mapping, X-ray diffraction, and measurements of roughness and Vickers microhardness. Depending on the processing parameters, it is possible to obtain different microstructures. The affected area of gray cast iron, can be hardened by remelting or transformation hardening (total or partial) if the reached temperature is higher or not that of melting temperature. Laser treatment originated new structures such as retained austenite, martensite and, occasionally, eutectic of cellular dendritic structure. Aluminum-silicon alloy does not have phase transformation in solid state, it can be hardened only by remelting. The increase of hardness is a function of the precipitation hardening process, which makes the silicon particles smaller and more disperse in the matrix. Maximal values of microhardness (700-1000 HV) were reached with the laser treatment in gray cast iron samples. The initial microhardness is of 242 HV. For aluminum-silicon alloy, the laser remelting increases the initial microhardness of 128 HV to the range of 160-320 HV. The found results give a new perspective for using the CLA/IPEN's laser in the heat treatment area. Besides providing a higher absorptivity to the materials, compared with the CO{sub 2} laser, and optical fiber access, the superficial hardening with Nd:YAG laser, depending on the