The Physical Properties of Ceramides in Membranes.

Science.gov (United States)

Alonso, Alicia; Goñi, Félix M

2018-05-20

Ceramides are sphingolipids containing a sphingosine or a related base, to which a fatty acid is linked through an amide bond. When incorporated into a lipid bilayer, ceramides exhibit a number of properties not shared by almost any other membrane lipid: Ceramides ( a) are extremely hydrophobic and thus cannot exist in suspension in aqueous media; ( b) increase the molecular order (rigidity) of phospholipids in membranes; ( c) give rise to lateral phase separation and domain formation in phospholipid bilayers; ( d) possess a marked intrinsic negative curvature that facilitates formation of inverted hexagonal phases; ( e) make bilayers and cell membranes permeable to small and large (i.e., protein-size) solutes; and ( f) promote transmembrane (flip-flop) lipid motion. Unfortunately, there is hardly any link between the physical studies reviewed here and the mass of biological and clinical studies on the effects of ceramides in health and disease.

Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis.

Science.gov (United States)

Parra, Valentina; Eisner, Veronica; Chiong, Mario; Criollo, Alfredo; Moraga, Francisco; Garcia, Alejandra; Härtel, Steffen; Jaimovich, Enrique; Zorzano, Antonio; Hidalgo, Cecilia; Lavandero, Sergio

2008-01-15

In cells, mitochondria are organized as a network of interconnected organelles that fluctuate between fission and fusion events (mitochondrial dynamics). This process is associated with cell death. We investigated whether activation of apoptosis with ceramides affects mitochondrial dynamics and promotes mitochondrial fission in cardiomyocytes. Neonatal rat cardiomyocytes were incubated with C(2)-ceramide or the inactive analog dihydro-C(2)-ceramide for up to 6 h. Three-dimensional images of cells loaded with mitotracker green were obtained by confocal microscopy. Dynamin-related protein-1 (Drp-1) and mitochondrial fission protein 1 (Fis1) distribution and levels were studied by immunofluorescence and western blot. Mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c (cyt c) distribution were used as indexes of early activation of apoptosis. Cell viability and DNA fragmentation were determined by propidium iodide staining/flow cytometry, whereas cytotoxicity was evaluated by lactic dehydrogenase activity. To decrease the levels of the mitochondrial fusion protein mitofusin 2, we used an antisense adenovirus (AsMfn2). C(2)-ceramide, but not dihydro-C(2)-ceramide, promoted rapid fragmentation of the mitochondrial network in a concentration- and time-dependent manner. C(2)-ceramide also increased mitochondrial Drp-1 and Fis1 content, Drp-1 colocalization with Fis1, and caused early activation of apoptosis. AsMfn2 accentuated the decrease in DeltaPsi(m) and cyt c redistribution induced by C(2)-ceramide. Doxorubicin, which induces cardiomyopathy and apoptosis through ceramide generation, also stimulated mitochondrial fragmentation. Ceramides stimulate mitochondrial fission and this event is associated with early activation of cardiomyocyte apoptosis.

Structure of cholesterol/ceramide monolayer mixtures

DEFF Research Database (Denmark)

Scheffer, L.; Solomonov, I.; Weygand, M.J.

2005-01-01

The structure of monolayers of cholesterol/ ceramide mixtures was investigated using grazing incidence x-ray diffraction, immunofluorescence, and atomic force microscopy techniques. Grazing incidence x-ray diffraction measurements showed the existence of a crystalline mixed phase of the two....... As ceramide incorporates the lipid backbone common to all sphingolipids, this arrangement may be relevant to the understanding of the molecular organization of lipid rafts....

Anti-Plasmodium activity of ceramide analogs

Directory of Open Access Journals (Sweden)

Gatt Shimon

2004-12-01

Full Text Available Abstract Background Sphingolipids are key molecules regulating many essential functions in eukaryotic cells and ceramide plays a central role in sphingolipid metabolism. A sphingolipid metabolism occurs in the intraerythrocytic stages of Plasmodium falciparum and is associated with essential biological processes. It constitutes an attractive and potential target for the development of new antimalarial drugs. Methods The anti-Plasmodium activity of a series of ceramide analogs containing different linkages (amide, methylene or thiourea linkages between the fatty acid part of ceramide and the sphingoid core was investigated in culture and compared to the sphingolipid analog PPMP (d,1-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol. This analog is known to inhibit the parasite sphingomyelin synthase activity and block parasite development by preventing the formation of the tubovesicular network that extends from the parasitophorous vacuole to the red cell membrane and delivers essential extracellular nutrients to the parasite. Results Analogs containing methylene linkage showed a considerably higher anti-Plasmodium activity (IC50 in the low nanomolar range than PPMP and their counterparts with a natural amide linkage (IC50 in the micromolar range. The methylene analogs blocked irreversibly P. falciparum development leading to parasite eradication in contrast to PPMP whose effect is cytostatic. A high sensitivity of action towards the parasite was observed when compared to their effect on the human MRC-5 cell growth. The toxicity towards parasites did not correlate with the inhibition by methylene analogs of the parasite sphingomyelin synthase activity and the tubovesicular network formation, indicating that this enzyme is not their primary target. Conclusions It has been shown that ceramide analogs were potent inhibitors of P. falciparum growth in culture. Interestingly, the nature of the linkage between the fatty acid part and the

Synthesis and biological evaluation of conformationally restricted and nucleobase-modified analogs of the anticancer compound 3'-C-ethynylcytidine (ECyd)

DEFF Research Database (Denmark)

Hrdlicka, Patrick J; Jepsen, Jan S; Wengel, Jesper

2005-01-01

A series of conformationally restricted and nucleobase-modified analogs of the anticancer compound 3'-C-ethynylcytidine (ECyd) and its uracil analog (EUrd) have been synthesized. While none of the conformationally restricted analogs displayed anticancer activity, 5-iodo-EUrd and 5-bromo-EUrd disp......-EUrd displayed potent anticancer activity with IC50 values of 35 nM and 0. 73 microM....

Ceramide-Induced Apoptosis in Renal Tubular Cells: A Role of Mitochondria and Sphingosine-1-Phoshate

Science.gov (United States)

Ueda, Norishi

2015-01-01

Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability (MOMP). Ceramide enhances oligomerization of pro-apoptotic Bcl-2 family proteins, ceramide channel, and reduces anti-apoptotic Bcl-2 proteins in the MOM. This process alters MOMP, resulting in generation of reactive oxygen species (ROS), cytochrome C release into the cytosol, caspase activation, and apoptosis. Ceramide regulates apoptosis through mitogen-activated protein kinases (MAPKs)-dependent and -independent pathways. Conversely, MAPKs alter ceramide generation by regulating the enzymes involving ceramide metabolism, affecting ceramide-induced apoptosis. Crosstalk between Bcl-2 family proteins, ROS, and many signaling pathways regulates ceramide-induced apoptosis. Growth factors rescue ceramide-induced apoptosis by regulating the enzymes involving ceramide metabolism, S1P, and signaling pathways including MAPKs. This article reviews evidence supporting a role of ceramide for apoptosis and discusses a role of mitochondria, including MOMP, Bcl-2 family proteins, ROS, and signaling pathways, and crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. A balancing role between ceramide and S1P and the strategy for preventing ceramide-induced apoptosis by growth factors are also discussed. PMID:25751724

Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis.

Science.gov (United States)

Ferlazzo, Edoardo; Striano, Pasquale; Italiano, Domenico; Calarese, Tiziana; Gasparini, Sara; Vanni, Nicola; Fruscione, Floriana; Genton, Pierre; Zara, Federico

2016-09-01

Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis is an extremely rare condition, so far reported in a single family of Algerian origin presenting an unusual, severe form of progressive myoclonus epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment, with probable autosomal recessive inheritance. Disease onset was between 6 and 16 years of age. Genetic study allowed to identify a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. The mutation decreased C18-ceramide levels. In addition, downregulation of CerS1 in neuroblastoma cell line showed activation of ER stress response and induction of proapoptotic pathways. This observation demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.

Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis

DEFF Research Database (Denmark)

Tafesse, Fikadu G.; Vacaru, Ana M.; Bosma, Elleke Fenna

2014-01-01

ceramide-induced cell death and that SMSr-mediated ceramide homeostasis requires the N-terminal sterile a-motif, or SAM domain, of the enzyme. These results define ER ceramides as bona fide transducers of mitochondrial apoptosis and indicate a primary role of SMSr in monitoring ER ceramide levels...

Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy.

Science.gov (United States)

Vanni, Nicola; Fruscione, Floriana; Ferlazzo, Edoardo; Striano, Pasquale; Robbiano, Angela; Traverso, Monica; Sander, Thomas; Falace, Antonio; Gazzerro, Elisabetta; Bramanti, Placido; Bielawski, Jacek; Fassio, Anna; Minetti, Carlo; Genton, Pierre; Zara, Federico

2014-08-01

Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders. We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways. This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans. © 2014 American Neurological Association.

Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death.

Science.gov (United States)

Parra, Valentina; Moraga, Francisco; Kuzmicic, Jovan; López-Crisosto, Camila; Troncoso, Rodrigo; Torrealba, Natalia; Criollo, Alfredo; Díaz-Elizondo, Jessica; Rothermel, Beverly A; Quest, Andrew F G; Lavandero, Sergio

2013-08-01

Ceramides are important intermediates in the biosynthesis and degradation of sphingolipids that regulate numerous cellular processes, including cell cycle progression, cell growth, differentiation and death. In cardiomyocytes, ceramides induce apoptosis by decreasing mitochondrial membrane potential and promoting cytochrome-c release. Ca(2+) overload is a common feature of all types of cell death. The aim of this study was to determine the effect of ceramides on cytoplasmic Ca(2+) levels, mitochondrial function and cardiomyocyte death. Our data show that C2-ceramide induces apoptosis and necrosis in cultured cardiomyocytes by a mechanism involving increased Ca(2+) influx, mitochondrial network fragmentation and loss of the mitochondrial Ca(2+) buffer capacity. These biochemical events increase cytosolic Ca(2+) levels and trigger cardiomyocyte death via the activation of calpains. Copyright © 2013 Elsevier B.V. All rights reserved.

Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

Science.gov (United States)

Di Scala, Coralie; Fantini, Jacques; Yahi, Nouara; Barrantes, Francisco J; Chahinian, Henri

2018-05-22

Anandamide is a lipid neurotransmitter derived from arachidonic acid, a polyunsaturated fatty acid. The chemical differences between anandamide and arachidonic acid result in a slightly enhanced solubility in water and absence of an ionisable group for the neurotransmitter compared with the fatty acid. In this review, we first analyze the conformational flexibility of anandamide in aqueous and membrane phases. We next study the interaction of the neurotransmitter with membrane lipids and discuss the molecular basis of the unexpected selectivity of anandamide for cholesterol and ceramide from among other membrane lipids. We show that cholesterol behaves as a binding partner for anandamide, and that following an initial interaction mediated by the establishment of a hydrogen bond, anandamide is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu. The complex is then directed to the anandamide cannabinoid receptor (CB1) which displays a high affinity binding pocket for anandamide. We propose that cholesterol may regulate the entry and exit of anandamide in and out of CB1 by interacting with low affinity cholesterol recognition sites (CARC and CRAC) located in transmembrane helices. The mirror topology of cholesterol binding sites in the seventh transmembrane domain is consistent with the delivery, extraction and flip-flop of anandamide through a coordinated cholesterol-dependent mechanism. The binding of anandamide to ceramide illustrates another key function of membrane lipids which may occur independently of protein receptors. Interestingly, ceramide forms a tight complex with anandamide which blocks the degradation pathway of both lipids and could be exploited for anti-cancer therapies.

A conserved cysteine motif is critical for rice ceramide kinase activity and function.

Directory of Open Access Journals (Sweden)

Fang-Cheng Bi

Full Text Available Ceramide kinase (CERK is a key regulator of cell survival in dicotyledonous plants and animals. Much less is known about the roles of CERK and ceramides in mediating cellular processes in monocot plants. Here, we report the characterization of a ceramide kinase, OsCERK, from rice (Oryza sativa spp. Japonica cv. Nipponbare and investigate the effects of ceramides on rice cell viability.OsCERK can complement the Arabidopsis CERK mutant acd5. Recombinant OsCERK has ceramide kinase activity with Michaelis-Menten kinetics and optimal activity at 7.0 pH and 40°C. Mg2+ activates OsCERK in a concentration-dependent manner. Importantly, a CXXXCXXC motif, conserved in all ceramide kinases and important for the activity of the human enzyme, is critical for OsCERK enzyme activity and in planta function. In a rice protoplast system, inhibition of CERK leads to cell death and the ratio of added ceramide and ceramide-1-phosphate, CERK's substrate and product, respectively, influences cell survival. Ceramide-induced rice cell death has apoptotic features and is an active process that requires both de novo protein synthesis and phosphorylation, respectively. Finally, mitochondria membrane potential loss previously associated with ceramide-induced cell death in Arabidopsis was also found in rice, but it occurred with different timing.OsCERK is a bona fide ceramide kinase with a functionally and evolutionarily conserved Cys-rich motif that plays an important role in modulating cell fate in plants. The vital function of the conserved motif in both human and rice CERKs suggests that the biochemical mechanism of CERKs is similar in animals and plants. Furthermore, ceramides induce cell death with similar features in monocot and dicot plants.

Ceramide 1 and ceramide 3 act synergistically on skin hydration and the transepidermal water loss of sodium lauryl sulfate-irritated skin.

Science.gov (United States)

Huang, Huey-Chun; Chang, Tsong-Min

2008-08-01

Stratum corneum intercellular lipids, such as ceramides, play an important role in the regulation of skin water barrier homeostasis and water-holding capacity. Aim To evaluate the potential water retention capacity of control emulsion and three oil-in-water (o/w) emulsions containing ceramide 1, ceramide 3, or both. Fifteen healthy Asian women (age, 20-30 years) with healthy skin, pretreated with sodium lauryl sulfate (SLS), applied the tested emulsions twice daily over a period of 28 days. Skin hydration and transepidermal water loss (TEWL) values were measured on the indicated days with a Corneometer(R)825 and a TEWAMETER TM210, respectively. The maximum increase in skin humidity was reached after 4 weeks, with values of 21.9 +/- 1.8% and 8.9 +/- 0.9% for emulsion C and control emulsion, respectively. The maximum decrease in TEWL was also reached after 4 weeks, with values of 36.7 +/- 4.7% and 5.1 +/- 0.8% for the same emulsions. It can be concluded that all the tested ceramide-containing emulsions improved skin barrier function when compared with untreated skin. There was some indication that ceramides 1 and 3 contained in emulsion C might exert a beneficial synergistic effect on skin biochemical properties, such as skin hydration and TEWL, and play a key role in the protection mechanism against SLS irritation.

Undulating tubular liposomes through incorporation of a synthetic skin ceramide into phospholipid bilayers.

Science.gov (United States)

Xu, Peng; Tan, Grace; Zhou, Jia; He, Jibao; Lawson, Louise B; McPherson, Gary L; John, Vijay T

2009-09-15

Nonspherical liposomes were prepared by doping L-alpha-phosphatidylcholine (PC) with ceramide VI (a skin lipid). Cryo-transmission electron microscopy shows the liposome shape changing from spherical to an undulating tubular morphology, when the amount of ceramide VI is increased. The formation of tubular liposomes is energetically favorable and is attributed to the association of ceramide VI with PC creating regions of lower curvature. Since ceramides are the major component of skin lipids in the stratum corneum, tubular liposomes containing ceramide may potentially serve as self-enhanced nanocarriers for transdermal delivery.

Effect of pioglitazone on plasma ceramides in adults with metabolic syndrome.

Science.gov (United States)

Warshauer, Jeremy T; Lopez, Ximena; Gordillo, Ruth; Hicks, Jessica; Holland, William L; Anuwe, Estelle; Blankfard, Martin B; Scherer, Philipp E; Lingvay, Ildiko

2015-10-01

Metabolic syndrome (MetS) appears closely linked with ceramide accumulation, inducing insulin resistance and toxicity to multiple cell types. Animal studies demonstrate that thiazolidinediones (TZDs) reduce ceramide concentrations in plasma and skeletal muscle and support lowering of ceramide levels as a potential mediator of TZDs' mechanism of action in reducing insulin resistance; however, studies in humans have yet to be reported. This study investigated the effects of pioglitazone therapy on plasma ceramides to understand the mechanism by which TZDs improve insulin resistance in MetS. Thirty-seven subjects with MetS were studied in a single-centre, randomized, double-blind, placebo-controlled trial comparing pioglitazone to placebo. Data were collected at baseline and after 6 months of therapy. The primary endpoint was the change from baseline in plasma ceramide concentrations. Treatment with pioglitazone for 6 months, compared with placebo, significantly reduced multiple plasma ceramide concentrations: C18:0 (p = 0.001), C20:0 (p = 0.0004), C24 : 1 (p = 0.009), dihydroceramide C18 :0 (p = 0.005), dihydroceramide C24:1 (p = 0.004), lactosylceramide C16:0 (p = 0.02) and the hexosylceramides C16:0 (p = 0.0003), C18 : 0 (p = 0.00001), C22:0 (p = 0.00002) and C24:1 (p = 0.0006). Additionally, significant reductions were found when ceramides were grouped by species: ceramides (p = 0.03), dihydroceramides (p = 0.02), hexosylceramides (p = 0.00001) and lactosylceramides (p = 0.02). The total of all measured ceramides was also significantly reduced (p = 0.001). Following treatment with pioglitazone, the decrease in some ceramide species correlated negatively with the change in insulin sensitivity (dihydroceramide C16:0, r = -0.54; p = 0.02) and positively with total (lactosylceramide C24:0, r = 0.53; p = 0.02) and high molecular weight (lactosylceramide C24:0, r = 0.48; p = 0

Pressure-temperature phase behavior of mixtures of natural sphingomyelin and ceramide extracts.

Science.gov (United States)

Barriga, Hanna M G; Parsons, Edward S; McCarthy, Nicola L C; Ces, Oscar; Seddon, John M; Law, Robert V; Brooks, Nicholas J

2015-03-31

Ceramides are a group of sphingolipids that act as highly important signaling molecules in a variety of cellular processes including differentiation and apoptosis. The predominant in vivo synthetic pathway for ceramide formation is via sphingomyelinase catalyzed hydrolysis of sphingomyelin. The biochemistry of this essential pathway has been studied in detail; however, there is currently a lack of information on the structural behavior of sphingomyelin- and ceramide-rich model membrane systems, which is essential for developing a bottom-up understanding of ceramide signaling and platform formation. We have studied the lyotropic phase behavior of sphingomyelin-ceramide mixtures in excess water as a function of temperature (30-70 °C) and pressure (1-200 MPa) by small- and wide-angle X-ray scattering. At low ceramide concentrations the mixtures form the ripple gel phase (P(β)') below the gel transition temperature for sphingomyelin, and this observation has been confirmed by atomic force microscopy. Formation of the ripple gel phase can also be induced at higher temperatures via the application of hydrostatic pressure. At high ceramide concentration an inverse hexagonal phase (HII) is formed coexisting with a cubic phase.

Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice

Science.gov (United States)

Rotolo, Jimmy; Stancevic, Branka; Zhang, Jianjun; Hua, Guoqiang; Fuller, John; Yin, Xianglei; Haimovitz-Friedman, Adriana; Kim, Kisu; Qian, Ming; Cardó-Vila, Marina; Fuks, Zvi; Pasqualini, Renata; Arap, Wadih; Kolesnick, Richard

2012-01-01

Radiation gastrointestinal (GI) syndrome is a major lethal toxicity that may occur after a radiation/nuclear incident. Currently, there are no prophylactic countermeasures against radiation GI syndrome lethality for first responders, military personnel, or remediation workers entering a contaminated area. The pathophysiology of this syndrome requires depletion of stem cell clonogens (SCCs) within the crypts of Lieberkühn, which are a subset of cells necessary for postinjury regeneration of gut epithelium. Recent evidence indicates that SCC depletion is not exclusively a result of DNA damage but is critically coupled to ceramide-induced endothelial cell apoptosis within the mucosal microvascular network. Here we show that ceramide generated on the surface of endothelium coalesces to form ceramide-rich platforms that transmit an apoptotic signal. Moreover, we report the generation of 2A2, an anti-ceramide monoclonal antibody that binds to ceramide to prevent platform formation on the surface of irradiated endothelial cells of the murine GI tract. Consequently, we found that 2A2 protected against endothelial apoptosis in the small intestinal lamina propria and facilitated recovery of crypt SCCs, preventing the death of mice from radiation GI syndrome after high radiation doses. As such, we suggest that 2A2 represents a prototype of a new class of anti-ceramide therapeutics and an effective countermeasure against radiation GI syndrome mortality. PMID:22466649

Plasma Ceramides, Mediterranean Diet, and Incident Cardiovascular Disease in the PREDIMED Trial

Science.gov (United States)

Wang, Dong D.; Toledo, Estefanía; Hruby, Adela; Rosner, Bernard A.; Willett, Walter C.; Sun, Qi; Razquin, Cristina; Zheng, Yan; Ruiz-Canela, Miguel; Guasch-Ferré, Marta; Corella, Dolores; Gómez-Gracia, Enrique; Fiol, Miquel; Estruch, Ramón; Ros, Emilio; Lapetra, José; Fito, Montserrat; Aros, Fernando; Serra-Majem, Luis; Lee, Chih-Hao; Clish, Clary B.; Liang, Liming; Salas-Salvadó, Jordi; Martínez-González, Miguel A.; Hu, Frank B.

2017-01-01

Background Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between over-nutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. Methods The study population consisted of 980 participants from the PREDIMED trial, including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases), followed for up to 7.4 years. Participants were randomized to a Mediterranean diet (MedDiet) supplemented with extra-virgin olive oil, a MedDiet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of non-fatal acute myocardial infarction, non-fatal stroke, or cardiovascular death. Hazard Ratios (HRs) were estimated with weighted Cox regression models, using Barlow weights to account for the case-cohort design. Results The multivariable HRs [95% confidence interval (CI)] comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0 and C24:1 ceramides were 2.39 (1.49–3.83, P trend <0.001), 1.91 (1.21–3.01, P trend =0.003), 1.97 (1.21–3.01, P trend =0.004), and 1.73 (1.09–2.74, P trend =0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR =2.18, 95% CI, 1.36–3.49, P trend <0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (P interaction =0.010). Participants with a higher ceramide score and assigned to either of the two active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants

Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1.

Science.gov (United States)

Scarlatti, Francesca; Bauvy, Chantal; Ventruti, Annamaria; Sala, Giusy; Cluzeaud, Françoise; Vandewalle, Alain; Ghidoni, Riccardo; Codogno, Patrice

2004-04-30

The sphingolipid ceramide is involved in the cellular stress response. Here we demonstrate that ceramide controls macroautophagy, a major lysosomal catabolic pathway. Exogenous C(2)-ceramide stimulates macroautophagy (proteolysis and accumulation of autophagic vacuoles) in the human colon cancer HT-29 cells by increasing the endogenous pool of long chain ceramides as demonstrated by the use of the ceramide synthase inhibitor fumonisin B(1). Ceramide reverted the interleukin 13-dependent inhibition of macroautophagy by interfering with the activation of protein kinase B. In addition, C(2)-ceramide stimulated the expression of the autophagy gene product beclin 1. Ceramide is also the mediator of the tamoxifen-dependent accumulation of autophagic vacuoles in the human breast cancer MCF-7 cells. Monodansylcadaverine staining and electron microscopy showed that this accumulation was abrogated by myriocin, an inhibitor of de novo synthesis ceramide. The tamoxifen-dependent accumulation of vacuoles was mimicked by 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, an inhibitor of glucosylceramide synthase. 1-Phenyl-2-decanoylamino-3-morpholino-1-propanol, tamoxifen, and C(2)-ceramide stimulated the expression of beclin 1, whereas myriocin antagonized the tamoxifen-dependent up-regulation. Tamoxifen and C(2)-ceramide interfere with the activation of protein kinase B, whereas myriocin relieved the inhibitory effect of tamoxifen. In conclusion, the control of macroautophagy by ceramide provides a novel function for this lipid mediator in a cell process with major biological outcomes.

Effects of ceramide inhibition on radiation-induced apoptosis in human leukemia MOLT-4 cells

Energy Technology Data Exchange (ETDEWEB)

Takahashi, Eriko; Inanami, Osamu; Asanuma, Taketoshi; Kuwabara, Mikinori [Hokkaido Univ., Graduate School of Veterinary Medicine, Sapporo, Hokkaido (Japan)

2006-03-15

In the present study, using inhibitors of ceramide synthase (fumonisin B{sub 1}), ketosphinganine synthetase (L-cycloserine), acid sphingomyelinase (D609 and desipramine) and neutral sphingomyelinase (GW4869), the role of ceramide in X-ray-induced apoptosis was investigated in MOLT-4 cells. The diacylglycerol kinase (DGK) assay showed that the intracellular concentration of ceramide increased time-dependently after X irradiation of cells, and this radiation-induced accumulation of ceramide did not occur prior to the appearance of apoptotic cells. Treatment with D609 significantly inhibited radiation-induced apoptosis, but did not inhibit the increase of intracellular ceramide. Treatment with desipramine or GW4869 prevented neither radiation-induced apoptosis nor the induced increase of ceramide. On the other hand, fumonisin B{sub 1} and L-cycloserine had no effect on the radiation-induced induction of apoptosis, in spite of significant inhibition of the radiation-induced ceramide. From these results, it was suggested that the increase of the intracellular concentration of ceramide was not essential for radiation-induced apoptosis in MOLT-4 cells. (author)

Effects of ceramide inhibition on radiation-induced apoptosis in human leukemia MOLT-4 cells

International Nuclear Information System (INIS)

Takahashi, Eriko; Inanami, Osamu; Asanuma, Taketoshi; Kuwabara, Mikinori

2006-01-01

In the present study, using inhibitors of ceramide synthase (fumonisin B 1 ), ketosphinganine synthetase (L-cycloserine), acid sphingomyelinase (D609 and desipramine) and neutral sphingomyelinase (GW4869), the role of ceramide in X-ray-induced apoptosis was investigated in MOLT-4 cells. The diacylglycerol kinase (DGK) assay showed that the intracellular concentration of ceramide increased time-dependently after X irradiation of cells, and this radiation-induced accumulation of ceramide did not occur prior to the appearance of apoptotic cells. Treatment with D609 significantly inhibited radiation-induced apoptosis, but did not inhibit the increase of intracellular ceramide. Treatment with desipramine or GW4869 prevented neither radiation-induced apoptosis nor the induced increase of ceramide. On the other hand, fumonisin B 1 and L-cycloserine had no effect on the radiation-induced induction of apoptosis, in spite of significant inhibition of the radiation-induced ceramide. From these results, it was suggested that the increase of the intracellular concentration of ceramide was not essential for radiation-induced apoptosis in MOLT-4 cells. (author)

Ethnicity and stratum corneum ceramides

DEFF Research Database (Denmark)

Jungersted, J.M.; Høgh, Julie Kaae; Hellgren, Lars

2010-01-01

method and analysed using high-performance thin layer chromatography. RESULTS: For the ceramide/cholesterol ratio we found statistically significant differences between groups, with Asians having the highest ratio (P

Anandamide-ceramide interactions in a membrane environment: Molecular dynamic simulations data.

Science.gov (United States)

Di Scala, Coralie; Mazzarino, Morgane; Yahi, Nouara; Varini, Karine; Garmy, Nicolas; Fantini, Jacques; Chahinian, Henri

2017-10-01

Anandamide is a lipid neurotransmitter that interacts with various plasma membrane lipids. The data here consists of molecular dynamics simulations of anandamide, C18-ceramide and cholesterol performed in vacuo and within a hydrated palmitoyl-oleoyl-phosphatidylcholine (POPC)/cholesterol membrane. Several models of anandamide/cholesterol and anandamide/ceramide complexes are presented. The energy of interaction and the nature of the intermolecular forces involved in each of these complexes are detailed. The impact of water molecules hydrating the POPC/cholesterol membrane for the stability of the anandamide/cholesterol and anandamide/ceramide complexes is also analyzed. From a total number of 1920 water molecules stochatiscally merged with the lipid matrix, 48 were eventually redistributed around the polar head groups of the anandamide/ceramide complex, whereas only 15 reached with the anandamide/cholesterol complex. The interpretation of this dataset is presented in the accompanying article "Ceramide binding to anandamide increases its half-life and potentiates its cytotoxicity in human neuroblastoma cells" [1].

P53-dependent ceramide generation in response ro ionizing irradiation is caspase-dependent

International Nuclear Information System (INIS)

Dbaibo, G.; El-Assaad, W.

2000-01-01

Full text.We have previously reported that p53-dependent apoptosis is accompanied by ceramide accumulation. Lack of p53 prevents ceramide accumulation in response to induces such as ionizing irradiation. The mechanisms of ceramide accumulation have not been explored. P53 has been reported to function by inducing the death receptors Fas and DR5 both of which function by initiating a caspase cascade that results in apoptosis. We decided to examine the role of caspases in the elevation of cellular ceramide levels. We treated Molt-4 cells with 5Gy of ionizing irradiation and examined the effects of co-treatment with the general caspase inhibitor z-VAD-fmk at concentration of 50 and 100μM. We found that z-VAD blocked apoptosis induced by irradiation without interfering with p53 accumulation indicating that it was not functioning upstream of p53. However, z-VAD treatment resulted in a significant decrease in ceramide accumulation. Additionally, z-VAD partially blocked the loss of glutathione in response to irradiation. This was important since glutathione has been described as an inhibitor of neutral sphindomyelinase, a major source of cellular ceramide via sphingomyelin hydrolysis. These studies indicate that p53 induces ceramide accumulation in a caspase-dependent manner and that the regulation of cellular glutathione by caspases may be a mechanism by which they regulate ceramide accumulation

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

Science.gov (United States)

Moro, Kazuki; Kawaguchi, Tsutomu; Tsuchida, Junko; Gabriel, Emmanuel; Qi, Qianya; Yan, Li; Wakai, Toshifumi; Takabe, Kazuaki; Nagahashi, Masayuki

2018-01-01

Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients. PMID:29731990

Short-chain C6 ceramide sensitizes AT406-induced anti-pancreatic cancer cell activity

International Nuclear Information System (INIS)

Zhao, Xiaoguang; Sun, Baoyou; Zhang, Jingjing; Zhang, Ruishen; Zhang, Qing

2016-01-01

Our previous study has shown that AT406, a first-in-class small molecular antagonist of IAPs (inhibitor of apoptosis proteins), inhibits pancreatic cancer cell proliferation in vitro and in vivo. The aim of this research is to increase AT406's sensitivity by adding short-chain C6 ceramide. We show that co-treatment of C6 ceramide dramatically potentiated AT406-induced caspase/apoptosis activation and cytotoxicity in established (Panc-1 and Mia-PaCa-2 lines) and primary human pancreatic cancer cells. Reversely, caspase inhibitors largely attenuated C6 ceramide plus AT406-induced above cancer cell death. Molecularly, C6 ceramide downregulated Bcl-2 to increase AT406's sensitivity in pancreatic cancer cells. Intriguingly, C6 ceramide-mediated AT406 sensitization was nullified with Bcl-2 shRNA knockdown or pretreatment of the Bcl-2 inhibitor ABT-737. In vivo, liposomal C6 ceramide plus AT406 co-administration dramatically inhibited Panc-1 xenograft tumor growth in severe combined immunodeficient (SCID) mice. The combined anti-tumor activity was significantly more potent than either single treatment. Expressions of IAPs (cIAP1/XIAP) and Bcl-2 were downregulated in Panc-1 xenografts with the co-administration. Together, we demonstrate that C6 ceramide sensitizes AT406-mediated anti-pancreatic cancer cell activity possibly via downregulating Bcl-2. - Highlights: • C6 ceramide dramatically potentiates AT406-induced pancreatic cancer cell death. • C6 ceramide facilitates AT406-induced pancreatic cancer cell apoptosis. • C6 ceramide downregulates Bcl-2 to increase AT406's sensitivity in pancreatic cancer cells. • Liposomal C6 ceramide enhances AT406-induced anti-pancreatic cancer activity in vivo.

Ceramide binding to anandamide increases its half-life and potentiates its cytotoxicity in human neuroblastoma cells.

Science.gov (United States)

Di Scala, Coralie; Mazzarino, Morgane; Yahi, Nouara; Varini, Karine; Garmy, Nicolas; Fantini, Jacques; Chahinian, Henri

2017-06-01

Anandamide (AEA) is a ubiquitous lipid that exerts neurotransmitter functions but also controls important biological functions such as proliferation, survival, or programmed cell death. The latter effects are also regulated by ceramide, a lipid enzymatically generated from sphingomyelin hydrolysis by sphingomyelinase. Ceramide has been shown to increase the cellular toxicity of AEA, but the mechanisms controlling this potentiating effect remained unclear. Here we have used a panel of in silico, physicochemical, biochemical and cellular approaches to study the crosstalk between AEA and ceramide apoptotic pathways. Molecular dynamics simulations indicated that AEA and ceramide could form a stable complex in phosphatidylcholine membranes. Consistent with these data, we showed that AEA can specifically insert into ceramide monolayers whereas it did not penetrate into sphingomyelin membranes. Then we have studied the effects of ceramide on AEA-induced toxicity of human neuroblastoma cells. In these experiments, the cells have been either naturally enriched in ceramide by neutral sphingomyelinase pre-incubation or treated with C2-ceramide, a biologically active ceramide analog. Both treatments significantly increased the cytotoxicity of AEA as assessed by the MTS mitochondrial toxicity assay. This effect was correlated with the concomitant accumulation of natural ceramide (or its synthetic analog) and AEA in the cells. A kinetic study of AEA hydrolysis showed that ceramide inhibited the fatty acid amino hydrolase (FAAH) activity in cell extracts. Taken together, these data suggested that ceramide binds to AEA, increases its half-life and potentiates its cytotoxicity. Overall, these mechanisms account for a functional cross-talk between AEA and ceramide apoptotic pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

Ceramides and barrier function in healthy skin

DEFF Research Database (Denmark)

Jungerstedt, J; Hellgren, Lars; Drachmann, Tue

2010-01-01

Lipids in the stratum corneum are key components in the barrier function of the skin. Changes in lipid composition related to eczematous diseases are well known, but limited data are available on variations within healthy skin. The objective of the present study was to compare ceramide subgroups...... and ceramide/cholesterol ratios in young, old, male and female healthy skin. A total of 55 participants with healthy skin was included in the study. Lipid profiles were correlated with transepidermal water loss and with information on dry skin from a questionnaire including 16 people. No statistically...

Molecular dynamics modelling of EGCG clusters on ceramide bilayers

Energy Technology Data Exchange (ETDEWEB)

Yeo, Jingjie; Cheng, Yuan; Li, Weifeng; Zhang, Yong-Wei [Institute of High Performance Computing, A*STAR, 138632 (Singapore)

2015-12-31

A novel method of atomistic modelling and characterization of both pure ceramide and mixed lipid bilayers is being developed, using only the General Amber ForceField. Lipid bilayers modelled as pure ceramides adopt hexagonal packing after equilibration, and the area per lipid and bilayer thickness are consistent with previously reported theoretical results. Mixed lipid bilayers are modelled as a combination of ceramides, cholesterol, and free fatty acids. This model is shown to be stable after equilibration. Green tea extract, also known as epigallocatechin-3-gallate, is introduced as a spherical cluster on the surface of the mixed lipid bilayer. It is demonstrated that the cluster is able to bind to the bilayers as a cluster without diffusing into the surrounding water.

Distinct signaling roles of ceramide species in yeast revealed through systematic perturbation and systems biology analyses.

Science.gov (United States)

Montefusco, David J; Chen, Lujia; Matmati, Nabil; Lu, Songjian; Newcomb, Benjamin; Cooper, Gregory F; Hannun, Yusuf A; Lu, Xinghua

2013-10-29

Ceramide, the central molecule of sphingolipid metabolism, is an important bioactive molecule that participates in various cellular regulatory events and that has been implicated in disease. Deciphering ceramide signaling is challenging because multiple ceramide species exist, and many of them may have distinct functions. We applied systems biology and molecular approaches to perturb ceramide metabolism in the yeast Saccharomyces cerevisiae and inferred causal relationships between ceramide species and their potential targets by combining lipidomic, genomic, and transcriptomic analyses. We found that during heat stress, distinct metabolic mechanisms controlled the abundance of different groups of ceramide species and provided experimental support for the importance of the dihydroceramidase Ydc1 in mediating the decrease in dihydroceramides during heat stress. Additionally, distinct groups of ceramide species, with different N-acyl chains and hydroxylations, regulated different sets of functionally related genes, indicating that the structural complexity of these lipids produces functional diversity. The transcriptional modules that we identified provide a resource to begin to dissect the specific functions of ceramides.

Seasonal changes in epidermal ceramides are linked to impaired barrier function in acne patients.

Science.gov (United States)

Pappas, Apostolos; Kendall, Alexandra C; Brownbridge, Luke C; Batchvarova, Nikoleta; Nicolaou, Anna

2018-01-21

Acne skin demonstrates increased transepidermal water loss (TEWL) compared with healthy skin, which may be due, in part, to altered ceramide (CER) levels. We analysed ceramides in the stratum corneum of healthy and acne skin, and studied seasonal variation over the course of a year. Using ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry (UPLC/ESI-MS/MS), we identified 283 ceramides. Acne-affected skin demonstrated overall lower levels of ceramides, with notable reductions in CER[NH] and CER[AH] ceramides, as well as the acylceramides CER[EOS] and CER[EOH]; these differences were more apparent in the winter months. Lower ceramide levels reflected an increase in TEWL in acne, compared with healthy skin, which partly resolves in the summer. Individual ceramide species with 18-carbon 6-hydroxysphingosine (H) bases (including CER[N(24)H(18)], CER[N(26)H(18)], CER[A(24)H(18)], CER[A(26)H(18)]) were significantly reduced in acne skin, suggesting that CER[NH] and CER[AH] species may be particularly important in a healthy skin barrier. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hydration effects on the barrier function of stratum corneum lipids: Raman analysis of ceramides 2, III and 5.

Science.gov (United States)

Tfayli, Ali; Jamal, Dima; Vyumvuhore, Raoul; Manfait, Michel; Baillet-Guffroy, Arlette

2013-11-07

The stratum corneum is the outermost layer of the skin; its barrier function is highly dependent on the composition and the structure as well as the organization of lipids in its extracellular matrix. Ceramides, free fatty acids and cholesterol represent the major lipid classes present in this matrix. They play an important role in maintaining the normal hydration levels required for the normal physiological function. Despite the advancement in the understanding of the structure, composition and the function of the stratum corneum (SC), the concern of "dry skin" remains important in dermatology and care research. Most studies focus on the quantification of water in the skin using different techniques including Raman spectroscopy, while the studies that investigate the effect of hydration on the quality of the barrier function of the skin are limited. Raman spectroscopy provides structural, conformational and organizational information that could help elucidate the effect of hydration on the barrier function of the skin. In order to assess the effect of relative humidity on the lipid barrier function; we used Raman spectroscopy to follow-up the evolution of the conformation and the organization of three synthetic ceramides (CER) differing from each other by the nature of their polar heads (sphingosine, phytosphingosine and α hydroxyl sphingosine), CER 2, III and 5 respectively. CER III and 5 showed a more compact and ordered organization with stronger polar interactions at intermediate relative humidity values, while CER 2 showed opposite tendencies to those observed with CER III and 5.

Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis.

Science.gov (United States)

Aye, Irving L M H; Gao, Xiaoli; Weintraub, Susan T; Jansson, Thomas; Powell, Theresa L

2014-04-01

Maternal adiponectin (ADN) levels are inversely correlated with birth weight, and ADN infusion in pregnant mice down-regulates placental nutrient transporters and decreases fetal growth. In contrast to the insulin-sensitizing effects in adipose tissue and muscle, ADN inhibits insulin signaling in the placenta. However, the molecular mechanisms involved are unknown. We hypothesized that ADN inhibits insulin signaling and insulin-stimulated amino acid transport in primary human trophoblasts by peroxisome proliferator-activated receptor-α (PPARα)-mediated ceramide synthesis. Primary human term trophoblast cells were treated with ADN and/or insulin. ADN increased the phosphorylation of p38 MAPK and PPARα. ADN inhibited insulin signaling and insulin-stimulated amino acid transport. This effect was dependent on PPARα, because activation of PPARα with an agonist (GW7647) inhibited insulin signaling and function, whereas PPARα-small interfering RNA reversed the effects of ADN on the insulin response. ADN increased ceramide synthase expression and stimulated ceramide production. C2-ceramide inhibited insulin signaling and function, whereas inhibition of ceramide synthase (with Fumonisin B1) reversed the effects of ADN on insulin signaling and amino acid transport. These findings are consistent with the model that maternal ADN limits fetal growth mediated by activation of placental PPARα and ceramide synthesis, which inhibits placental insulin signaling and amino acid transport, resulting in reduced fetal nutrient availability.

Functional loss of two ceramide synthases elicits autophagy-dependent lifespan extension in C. elegans

DEFF Research Database (Denmark)

Mosbech, Mai-Britt; Kruse, Rikke; Harvald, Eva Bang

2013-01-01

Ceramide and its metabolites constitute a diverse group of lipids, which play important roles as structural entities of biological membranes as well as regulators of cellular growth, differentiation, and development. The C. elegans genome comprises three ceramide synthase genes; hyl-1, hyl-2...... that hyl-1;lagr-1 animals display reduced feeding, increased resistance to heat, and reduced reproduction. Collectively, our data suggest that specific sphingolipids produced by different ceramide synthases have opposing roles in determination of C. elegans lifespan. We propose that loss of HYL-1 and LAGR......, and lagr-1. HYL-1 function is required for synthesis of ceramides and sphingolipids containing very long acyl-chains (≥C24), while HYL-2 is required for synthesis of ceramides and sphingolipids containing shorter acyl-chains (≤C22). Here we show that functional loss of HYL-2 decreases lifespan, while loss...

Immobilization of phospholipase C for the production of ceramide from sphingomyelin hydrolysis

DEFF Research Database (Denmark)

Zhang, Long; Hellgren, Lars; Xu, Xuebing

2007-01-01

The immobilization of Clostridium perfringens phospholipase C was studied for the first time and the catalytic properties of the immobilized enzyme were investigated for the hydrolysis of sphingomyelin to produce ceramide. Ceramide is of great commercial potentials in cosmetic and pharmaceutical...... industries such as in hair and skin care products, due to its major role in maintaining the water-retaining properties of the epidermis. The feasibility of enzymatic production of ceramide through hydrolysis of sphingomyelin has previously been proven. In order to improve the reusability of the enzyme...

The impact of ultraviolet therapy on stratum corneum ceramides and barrier function

DEFF Research Database (Denmark)

Jungersted, Jakob Mutanu; Høgh, Julie Kaae; Hellgren, Lars

2011-01-01

therapy in dermatological patients on ceramides and skin barrier function.We found that UV light treatment does not change the ratio of important stratum corneum lipids, but we confirm earlier findings of decreased susceptibility to irritants after UV- therapy.......The ceramide profile as well as the barrier function is known to be deteriorated in atopic eczema and psoriasis, and ultraviolet (UV) light is known to improve the barrier function. The impact of UV light on ceramides, however, is not clarified.The aim of this study was to examine the effect of UV...

The impact of ultraviolet therapy on stratum corneum ceramides and barrier function

DEFF Research Database (Denmark)

Jungersted, Jakob Mutanu; Høgh, Julie Kaae; Hellgren, Lars

2011-01-01

therapy in dermatological patients on ceramides and skin barrier function. We found that UV light treatment does not change the ratio of important stratum corneum lipids, but we confirm earlier findings of decreased susceptibility to irritants after UV- therapy.......The ceramide profile as well as the barrier function is known to be deteriorated in atopic eczema and psoriasis, and ultraviolet (UV) light is known to improve the barrier function. The impact of UV light on ceramides, however, is not clarified. The aim of this study was to examine the effect of UV...

Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling.

Science.gov (United States)

Scarlatti, Francesca; Sala, Giusy; Somenzi, Giulia; Signorelli, Paola; Sacchi, Nicoletta; Ghidoni, Riccardo

2003-12-01

Resveratrol (3,4',5-trans-trihydroxystilbene), a phytoalexin present in grapes and red wine, is emerging as a natural compound with potential anticancer properties. Here we show that resveratrol can induce growth inhibition and apoptosis in MDA-MB-231, a highly invasive and metastatic breast cancer cell line, in concomitance with a dramatic endogenous increase of growth inhibitory/proapoptotic ceramide. We found that accumulation of ceramide derives from both de novo ceramide synthesis and sphingomyelin hydrolysis. More specifically we demonstrated that ceramide accumulation induced by resveratrol can be traced to the activation of serine palmitoyltransferase (SPT), the key enzyme of de novo ceramide biosynthetic pathway, and neutral sphingomyelinase (nSMase), a main enzyme involved in the sphingomyelin/ceramide pathway. However, by using specific inhibitors of SPT, myriocin and L-cycloserine, and nSMase, gluthatione and manumycin, we found that only the SPT inhibitors could counteract the biological effects induced by resveratrol. Thus, resveratrol seems to exert its growth inhibitory/apoptotic effect on the metastatic breast cancer cell line MDA-MB-231 by activating the de novo ceramide synthesis pathway.

Phospholipase C-catalyzed sphingomyelin hydrolysis in a membrane reactor for ceramide production

DEFF Research Database (Denmark)

Zhang, Long; Liang, Shanshan; Hellgren, Lars

2008-01-01

A membrane reactor for the production of ceramide through sphingomyelin hydrolysis with phospholipase C from Clostridium perfringens was studied for the first time. Ceramide has raised a large interest as an active component in both pharmaceutical and cosmetic industry. The enzymatic hydrolysis...

Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants.

Science.gov (United States)

Hebbar, Sarita; Sahoo, Ishtapran; Matysik, Artur; Argudo Garcia, Irene; Osborne, Kathleen Amy; Papan, Cyrus; Torta, Federico; Narayanaswamy, Pradeep; Fun, Xiu Hui; Wenk, Markus R; Shevchenko, Andrej; Schwudke, Dominik; Kraut, Rachel

2015-12-07

Sphingolipid metabolites are involved in the regulation of autophagy, a degradative recycling process that is required to prevent neuronal degeneration. Drosophila blue cheese mutants neurodegenerate due to perturbations in autophagic flux, and consequent accumulation of ubiquitinated aggregates. Here, we demonstrate that blue cheese mutant brains exhibit an elevation in total ceramide levels; surprisingly, however, degeneration is ameliorated when the pool of available ceramides is further increased, and exacerbated when ceramide levels are decreased by altering sphingolipid catabolism or blocking de novo synthesis. Exogenous ceramide is seen to accumulate in autophagosomes, which are fewer in number and show less efficient clearance in blue cheese mutant neurons. Sphingolipid metabolism is also shifted away from salvage toward de novo pathways, while pro-growth Akt and MAP pathways are down-regulated, and ER stress is increased. All these defects are reversed under genetic rescue conditions that increase ceramide generation from salvage pathways. This constellation of effects suggests a possible mechanism whereby the observed deficit in a potentially ceramide-releasing autophagic pathway impedes survival signaling and exacerbates neuronal death.

Plasma Ceramides as Prognostic Biomarkers and Their Arterial and Myocardial Tissue Correlates in Acute Myocardial Infarction

Directory of Open Access Journals (Sweden)

Leonardo P. de Carvalho, MD, PhD

2018-04-01

Full Text Available Summary: We identified a plasma signature of 11 C14 to C26 ceramides and 1 C16 dihydroceramide predictive of major adverse cardiovascular events in patients with acute myocardial infarction (AMI. Among patients undergoing coronary artery bypass surgery, those with recent AMI, compared with those without recent AMI, showed a significant increase in 5 of the signature’s 12 ceramides in plasma but not simultaneously-biopsied aortic tissue. In contrast, a rat AMI model, compared with sham control, showed a significant increase in myocardial concentrations of all 12 ceramides and up-regulation of 3 ceramide-producing enzymes, suggesting ischemic myocardium as a possible source of this ceramide signature. Key Words: acute coronary syndrome, ceramides, dihydroceramides, major adverse cardiovascular and cerebrovascular events, prognosis, risk prediction

Configurational assignments of conformationally restricted bis-monoterpene hydroquinones: utility in exploration of endangered plants.

Science.gov (United States)

Oh, Joonseok; Bowling, John J; Zou, Yike; Chittiboyina, Amar G; Doerksen, Robert J; Ferreira, Daneel; Leininger, Theodor D; Hamann, Mark T

2013-08-01

Endangered plant species are an important resource for new chemistry. Lindera melissifolia is native to the Southeastern U.S. and scarcely populates the edges of lakes and ponds. Quantum mechanics (QM) used in combination with NMR/ECD is a powerful tool for the assignment of absolute configuration in lieu of X-ray crystallography. The EtOAc extract of L. melissifolia was subject to chromatographic analysis by VLC and HPLC. Spin-spin coupling constant (SSCC) were calculated using DFT at the MPW1PW91/6-31G(d,p) level for all staggered rotamers. ECD calculations employed Amber* force fields followed by PM6 semi-empirical optimizations. Hetero- and homo-nuclear coupling constants were extracted from 1D (1)H, E.COSY and HETLOC experiments. Two meroterpenoids, melissifolianes A (1) and B (2) were purified and their 2-D structures elucidated using NMR and HRESIMS. The relative configuration of 1 was established using the combination of NOE-based distance restraints and the comparisons of experimental and calculated SSCCs. The comparison of calculated and experimental ECD assigned the absolute configuration of 1. The relative configuration of a racemic mixture, melissifoliane B (2) was established utilizing J-based analysis combined with QM and NMR techniques.Conclusion Our study of the Lindera melissifolia metabolome exemplifies how new chemistry remains undiscovered among the numerous endangered plant species and demonstrates how analysis by ECD and NMR combined with various QM calculations is a sensible approach to support the stereochemical assignment of molecules with conformationally restricted conformations. QM-NMR/ECD combined approaches are of utility for unambiguous assignment of 3-D structures, especially with limited plant material and when a molecule is conformationally restricted. Conservation of an endangered plant species can be supported through identification of its new chemistry and utilization of that chemistry for commercial purposes. Copyright © 2013

Conformal house

DEFF Research Database (Denmark)

Ryttov, Thomas Aaby; Sannino, Francesco

2010-01-01

fixed point. As a consistency check we recover the previously investigated bounds of the conformal windows when restricting to a single matter representation. The earlier conformal windows can be imagined to be part now of the new conformal house. We predict the nonperturbative anomalous dimensions...... at the infrared fixed points. We further investigate the effects of adding mass terms to the condensates on the conformal house chiral dynamics and construct the simplest instanton induced effective Lagrangian terms...

Complement Activation by Ceramide Transporter Proteins

NARCIS (Netherlands)

Bode, G.H.; Losen, M.; Buurman, W.A.; Veerhuis, R.; Molenaar, P.C.; Steinbusch, H.W.M.; De Baets, M.H.; Daha, MR; Martinez-Martinez, P.

2014-01-01

C1q is the initiator of the classical complement pathway and, as such, is essential for efficient opsonization and clearance of pathogens, altered self-structures, and apoptotic cells. The ceramide transporter protein (CERT) and its longer splicing isoform CERTL are known to interact with

Glioma cell death induced by irradiation or alkylating agent chemotherapy is independent of the intrinsic ceramide pathway.

Directory of Open Access Journals (Sweden)

Dorothee Gramatzki

Full Text Available Resistance to genotoxic therapy is a characteristic feature of glioma cells. Acid sphingomyelinase (ASM hydrolyzes sphingomyelin to ceramide and glucosylceramide synthase (GCS catalyzes ceramide metabolism. Increased ceramide levels have been suggested to enhance chemotherapy-induced death of cancer cells.Microarray and clinical data for ASM and GCS in astrocytomas WHO grade II-IV were acquired from the Rembrandt database. Moreover, the glioblastoma database of the Cancer Genome Atlas network (TCGA was used for survival data of glioblastoma patients. For in vitro studies, increases in ceramide levels were achieved either by ASM overexpression or by the GCS inhibitor DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP in human glioma cell lines. Combinations of alkylating chemotherapy or irradiation and ASM overexpression, PPMP or exogenous ceramide were applied in parental cells. The anti-glioma effects were investigated by assessing proliferation, metabolic activity, viability and clonogenicity. Finally, viability and clonogenicity were assessed in temozolomide (TMZ-resistant cells upon treatment with PPMP, exogenous ceramide, alkylating chemotherapy, irradiation or their combinations.Interrogations from the Rembrandt and TCGA database showed a better survival of glioblastoma patients with low expression of ASM or GCS. ASM overexpression or PPMP treatment alone led to ceramide accumulation but did not enhance the anti-glioma activity of alkylating chemotherapy or irradiation. PPMP or exogenous ceramide induced acute cytotoxicity in glioblastoma cells. Combined treatments with chemotherapy or irradiation led to additive, but not synergistic effects. Finally, no synergy was found when TMZ-resistant cells were treated with exogenous ceramide or PPMP alone or in combination with TMZ or irradiation.Modulation of intrinsic glioma cell ceramide levels by ASM overexpression or GCS inhibition does not enhance the anti-glioma activity of

Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol

DEFF Research Database (Denmark)

Lin, Hung-Yun; Delmas, Dominique; Vang, Ole

2013-01-01

-2 appears at the apex of the p38 kinase-mediated signaling cascade induced by ceramide. Induction of apoptosis by ceramide or resveratrol was inhibited by the endocytosis inhibitor, cytochalasin D (CytD); however, cells exposed to resveratrol showed greater sensitivity than ceramide-treated cells....... Ceramide-treated cells underwent a dose-dependent reduction in trans-membrane potential. Although both ceramide and resveratrol induced the expressions of caspase-3 and -7, the effect of inducible COX-2 was different in caspase-7 expression induced by ceramide compared to resveratrol. In summary......, resveratrol and ceramide converge on an endocytosis-requiring, ERK1/2-dependent signal transduction pathway and induction of COX-expression as an essential molecular antecedent for subsequent p53-dependent apoptosis. In addition, expressions of caspase-3 and -7 are observed. However, a p38 kinase...

Role of Intracellular Lipid Logistics in the Preferential Usage of Very Long Chain-Ceramides in Glucosylceramide

Directory of Open Access Journals (Sweden)

Toshiyuki Yamaji

2016-10-01

Full Text Available Ceramide is a common precursor of sphingomyelin (SM and glycosphingolipids (GSLs in mammalian cells. Ceramide synthase 2 (CERS2, one of the six ceramide synthase isoforms, is responsible for the synthesis of very long chain fatty acid (C20–26 fatty acids (VLC-containing ceramides (VLC-Cer. It is known that the proportion of VLC species in GSLs is higher than that in SM. To address the mechanism of the VLC-preference of GSLs, we used genome editing to establish three HeLa cell mutants that expressed different amounts of CERS2 and compared the acyl chain lengths of SM and GSLs by metabolic labeling experiments. VLC-sphingolipid expression was increased along with that of CERS2, and the proportion of VLC species in glucosylceramide (GlcCer was higher than that in SM for all expression levels of CERS2. This higher proportion was still maintained even when the proportion of C16-Cer to the total ceramides was increased by disrupting the ceramide transport protein (CERT-dependent C16-Cer delivery pathway for SM synthesis. On the other hand, merging the Golgi apparatus and the endoplasmic reticulum (ER by Brefeldin A decreased the proportion of VLC species in GlcCer probably due to higher accessibility of UDP-glucose ceramide glucosyltransferase (UGCG to C16-rich ceramides. These results suggest the existence of a yet-to-be-identified mechanism rendering VLC-Cer more accessible than C16-Cer to UGCG, which is independent of CERT.

Synthesis, anticancer activity, and inhibition of tubulin polymerization by conformationally restricted analogues of lavendustin A.

Science.gov (United States)

Mu, Fanrong; Hamel, Ernest; Lee, Debbie J; Pryor, Donald E; Cushman, Mark

2003-04-24

Compounds in the lavendustin A series have been shown to inhibit both protein-tyrosine kinases (PTKs) and tubulin polymerization. Since certain lavendustin A derivatives can exist in conformations that resemble both the trans-stilbene structure of the PTK inhibitor piceatannol and the cis-stilbene structure of the tubulin polymerization inhibitor combretastatin A-4, the possibility exists that the ratio of the two types of activities of the lavendustins could be influenced through the synthesis of conformationally restricted analogues. Accordingly, the benzylaniline structure of a series of pharmacologically active lavendustin A fragments was replaced by either their cis- or their trans-stilbene relatives, and effects on both inhibition of tubulin polymerization and cytotoxicity in cancer cell cultures were monitored. Both dihydrostilbene and 1,2-diphenylalkyne congeners were also prepared and evaluated biologically. Surprisingly, conformational restriction of the bridge between the two aromatic rings of the lavendustins had no significant effect on biological activity. On the other hand, conversion of the three phenolic hydroxyl groups of the lavendustin A derivatives to their corresponding methyl ethers consistently abolished their ability to inhibit tubulin polymerization and usually decreased cytotoxicity in cancer cell cultures as well, indicating the importance of at least one of the phenolic hydroxyl groups. Further investigation suggested that the phenolic hydroxyl group in the salicylamide ring was required for activity, while the two phenol moieties in the hydroquinone ring could be methylated with retention of activity. Two of the lavendustin A derivatives displayed IC(50) values of 1.4 microM for inhibition of tubulin polymerization, which ranks them among the most potent of the known tubulin polymerization inhibitors.

An Intestinal Farnesoid X Receptor–Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice

Science.gov (United States)

Xie, Cen; Shi, Jingmin; Gao, Xiaoxia; Sun, Dongxue; Sun, Lulu; Wang, Ting; Takahashi, Shogo; Anitha, Mallappa; Krausz, Kristopher W.; Patterson, Andrew D.

2017-01-01

Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota–FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-β-muricholic acid, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramide levels by suppressing expression of genes involved in ceramide synthesis specifically in the intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase (PC) activities and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondrial citrate synthase activities primarily through the induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and PC activities. These results reveal a mechanism by which the dietary supplement CAPE and intestinal FXR regulates hepatic gluconeogenesis and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia. PMID:28223344

Alkaline Ceramidase 3 (ACER3) Hydrolyzes Unsaturated Long-chain Ceramides, and Its Down-regulation Inhibits Both Cell Proliferation and Apoptosis*

OpenAIRE

Hu, Wei; Xu, Ruijuan; Sun, Wei; Szulc, Zdzislaw M.; Bielawski, Jacek; Obeid, Lina M.; Mao, Cungui

2010-01-01

Ceramides with different fatty acyl chains may vary in their physiological or pathological roles; however, it remains unclear how cellular levels of individual ceramide species are regulated. Here, we demonstrate that our previously cloned human alkaline ceramidase 3 (ACER3) specifically controls the hydrolysis of ceramides carrying unsaturated long acyl chains, unsaturated long-chain (ULC) ceramides. In vitro, ACER3 only hydrolyzed C18:1-, C20:1-, C20:4-ceramides, dihydroceramides, and phyto...

Ceramides in Alzheimer’s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation

Directory of Open Access Journals (Sweden)

Maja Jazvinšćak Jembrek

2015-01-01

Full Text Available Alzheimer’s disease (AD, the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloid β-peptides (Aβ and intracellular deposits of hyperphosphorylated tau (phospho-tau protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via Aβ generation. Enhanced levels of ceramides directly increase Aβ through stabilization of β-secretase, the key enzyme in the amyloidogenic processing of Aβ precursor protein (APP. As a positive feedback loop, the generated oligomeric and fibrillar Aβ induces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS, cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs. This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with Aβ in the cascade of events ending in neuronal degeneration.

The Permeability Enhancing Mechanism of DMSO in Ceramide Bilayers Simulated by Molecular Dynamics

Science.gov (United States)

Notman, Rebecca; den Otter, Wouter K.; Noro, Massimo G.; Briels, W. J.; Anwar, Jamshed

2007-01-01

The lipids of the topmost layer of the skin, the stratum corneum, represent the primary barrier to molecules penetrating the skin. One approach to overcoming this barrier for the purpose of delivery of active molecules into or via the skin is to employ chemical permeability enhancers, such as dimethylsulfoxide (DMSO). How these molecules exert their effect at the molecular level is not understood. We have investigated the interaction of DMSO with gel-phase bilayers of ceramide 2, the predominant lipid in the stratum corneum, by means of molecular dynamics simulations. The simulations satisfactorily reproduce the phase behavior and the known structural parameters of ceramide 2 bilayers in water. The effect of DMSO on the gel-phase bilayers was investigated at various concentrations over the range 0.0−0.6 mol fraction DMSO. The DMSO molecules accumulate in the headgroup region and weaken the lateral forces between the ceramides. At high concentrations of DMSO (≥0.4 mol fraction), the ceramide bilayers undergo a phase transition from the gel phase to the liquid crystalline phase. The liquid-crystalline phase of ceramides is expected to be markedly more permeable to solutes than the gel phase. The results are consistent with the experimental evidence that high concentrations of DMSO fluidize the stratum corneum lipids and enhance permeability. PMID:17513383

Brain Ceramide Metabolism in the Control of Energy Balance

Directory of Open Access Journals (Sweden)

Céline Cruciani-Guglielmacci

2017-10-01

Full Text Available The regulation of energy balance by the central nervous system (CNS is a key actor of energy homeostasis in mammals, and deregulations of the fine mechanisms of nutrient sensing in the brain could lead to several metabolic diseases such as obesity and type 2 diabetes (T2D. Indeed, while neuronal activity primarily relies on glucose (lactate, pyruvate, the brain expresses at high level enzymes responsible for the transport, utilization and storage of lipids. It has been demonstrated that discrete neuronal networks in the hypothalamus have the ability to detect variation of circulating long chain fatty acids (FA to regulate food intake and peripheral glucose metabolism. During a chronic lipid excess situation, this physiological lipid sensing is impaired contributing to type 2 diabetes in predisposed subjects. Recently, different studies suggested that ceramides levels could be involved in the regulation of energy balance in both hypothalamic and extra-hypothalamic areas. Moreover, under lipotoxic conditions, these ceramides could play a role in the dysregulation of glucose homeostasis. In this review we aimed at describing the potential role of ceramides metabolism in the brain in the physiological and pathophysiological control of energy balance.

The effect of ceramide-containing skin care products on eczema resolution duration.

Science.gov (United States)

Draelos, Zoe Diana

2008-01-01

Eczema is a common dermatologic condition that affects children as well as adults and is related to a defective skin barrier, which is most commonly caused by damage to the intercellular lipids from improper selection of skin cleansers and moisturizers. A new concept in skin care is the incorporation of ceramides into therapeutic cleansers and moisturizers. Ceramides are important components of the intercellular lipids that are necessary to link the protein-rich corneocytes into a waterproof barrier that is capable of protecting the underlying skin tissues and regulating body homeostasis. This study evaluated the effect of both a multilamellar vesicular emulsion (MVE) ceramide-containing liquid cleanser and moisturizing cream plus fluocinonide cream 0.05% compared with a bar cleanser plus fluocinonide cream 0.05% in the treatment of mild to moderate eczema. The addition of an MVE ceramide-containing liquid cleanser and moisturizing cream to a high-potency corticosteroid enhanced the treatment outcome of mild to moderate eczema compared with the use of a bar cleanser and high-potency corticosteroid in reducing disease duration, time to disease clearance, and symptoms. Thus, skin care product selection can have an important clinical effect on the clearance of mild to moderate eczema.

Influence of cholesterol and ceramide VI on the structure of multilamellar lipid membranes at water exchange

International Nuclear Information System (INIS)

Ryabova, N. Yu.; Kiselev, M. A.; Balagurov, A. M.

2010-01-01

The structural changes in the multilamellar lipid membranes of dipalmitoylphosphatidylcholine (DPPC)/cholesterol and DPPC/ceramide VI binary systems during hydration and dehydration have been studied by neutron diffraction. The effect of cholesterol and ceramide on the kinetics of water exchange in DPPC membranes is characterized. Compared to pure DPPC, membranes of binary systems swell faster during hydration (with a characteristic time of ∼30 min). Both compounds, ceramide VI and cholesterol, similarly affect the hydration of DPPC membranes, increasing the repeat distance due to the bilayer growth. However, in contrast to cholesterol, ceramide significantly reduces the thickness of the membrane water layer. The introduction of cholesterol into a DPPC membrane slows down the change in the parameters of the bilayer internal structure during dehydration. In the DPPC/ceramide VI/cholesterol ternary system (with a molar cholesterol concentration of 40%), cholesterol is partially released from the lamellar membrane structure into the crystalline phase.

PLC-dependent intracellular Ca2+ release was associated with C6-ceramide-induced inhibition of Na+ current in rat granule cells.

Science.gov (United States)

Liu, Zheng; Fei, Xiao-Wei; Fang, Yan-Jia; Shi, Wen-Jie; Zhang, Yu-Qiu; Mei, Yan-Ai

2008-09-01

In this report, the effects of C(6)-ceramide on the voltage-gated inward Na(+) currents (I(Na)), two types of main K(+) current [outward rectifier delayed K(+) current (I(K)) and outward transient K(+) current (I(A))], and cell death in cultured rat cerebellar granule cells were investigated. At concentrations of 0.01-100 microM, ceramide produced a dose-dependent and reversible inhibition of I(Na) without alteration of the steady-state activation and inactivation properties. Treatment with C(2)-ceramide caused a similar inhibitory effect on I(Na). However, dihydro-C(6)-ceramide failed to modulate I(Na). The effect of C(6)-ceramide on I(Na) was abolished by intracellular infusion of the Ca(2+)-chelating agent, 1,2-bis (2-aminophenoxy) ethane-N, N, N9, N9-tetraacetic acid, but was mimicked by application of caffeine. Blocking the release of Ca(2+) from the sarcoplasmic reticulum with ryanodine receptor blocker induced a gradual increase in I(Na) amplitude and eliminated the effect of ceramide on I(Na). In contrast, the blocker of the inositol 1,4,5-trisphosphate-sensitive Ca(2+) receptor did not affect the action of C(6)-ceramide. Intracellular application of GTPgammaS also induced a gradual decrease in I(Na) amplitude, while GDPbetaS eliminated the effect of C(6)-ceramide on I(Na). Furthermore, the C(6)-ceramide effect on I(Na) was abolished after application of the phospholipase C (PLC) blockers and was greatly reduced by the calmodulin inhibitors. Fluorescence staining showed that C(6)-ceramide decreased cell viability and blocking I(Na) by tetrodotoxin did not mimic the effect of C(6)-ceramide, and inhibiting intracellular Ca(2+) release by dantrolene could not decrease the C(6)-ceramide-induced cell death. We therefore suggest that increased PLC-dependent Ca(2+) release through the ryanodine-sensitive Ca(2+) receptor may be responsible for the C(6)-ceramide-induced inhibition of I(Na), which does not seem to be associated with C(6)-ceramide-induced granule

The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

International Nuclear Information System (INIS)

Xu, Weihong; Xu, Bin; Yao, Yiting; Yu, Xiaoling; Shen, Jie

2015-01-01

In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administration of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. - Highlights: • AR-42 is anti-proliferative against primary/established colon cancer cells. • AR-42 induces significant apoptotic death in primary/established colon cancer cells. • Ceramide production mediates AR-42-induced cytotoxicity in colon cancer cells. • AR-42 oral administration potently inhibits SW-620 xenograft growth in SCID mice

The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

Energy Technology Data Exchange (ETDEWEB)

Xu, Weihong; Xu, Bin; Yao, Yiting; Yu, Xiaoling [Department of Clinical Laboratory, Tongren Hospital, Shanghai (China); Shen, Jie, E-mail: tongrensj163@163.com [Department of Administrative, Tongren Hospital, No. 786 Yuyuan Road, Changning District, Shanghai (China)

2015-08-07

In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administration of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. - Highlights: • AR-42 is anti-proliferative against primary/established colon cancer cells. • AR-42 induces significant apoptotic death in primary/established colon cancer cells. • Ceramide production mediates AR-42-induced cytotoxicity in colon cancer cells. • AR-42 oral administration potently inhibits SW-620 xenograft growth in SCID mice.

Prohibitin (PHB) acts as a potent survival factor against ceramide induced apoptosis in rat granulosa cells.

Science.gov (United States)

Chowdhury, Indrajit; Branch, Alicia; Olatinwo, Moshood; Thomas, Kelwyn; Matthews, Roland; Thompson, Winston E

2011-08-29

Ceramide is a key factor in inducing germ cell apoptosis by translocating from cumulus cells into the adjacent oocyte and lipid rafts through gap junctions. Therefore studies designed to elucidate the mechanistic pathways in ceramide induced granulosa cell (GC) apoptosis and follicular atresia may potentially lead to the development of novel lipid-based therapeutic strategies that will prevent infertility and premature menopause associated with chemo and/or radiation therapy in female cancer patients. Our previous studies have shown that Prohibitin (PHB) is intimately involved in GCs differentiation, atresia, and luteolysis. In the present study, we have examined the functional effects of loss-/gain-of-function of PHB using adenoviral technology in delaying apoptosis induced by the physiological ligand ceramide in rat GCs. Under these experimental conditions, exogenous ceramide C-8 (50 μM) augmented the expression of mitochondrial PHB and subsequently cause the physical destruction of GC by the release of mitochondrial cytochrome c and activation of caspase-3. In further studies, silencing of PHB expression by adenoviral small interfering RNA (shRNA) sensitized GCs to ceramide C8-induce apoptosis. In contrast, adenovirus (Ad) directed overexpression of PHB in GCs resulted in increased PHB content in mitochondria and delayed the onset of ceramide induced apoptosis in the infected GCs. Taken together, these results provide novel evidences that a critical level of PHB expression within the mitochondria plays a key intra-molecular role in GC fate by mediating the inhibition of apoptosis and may therefore, contribute significantly to ceramide induced follicular atresia. Copyright © 2011 Elsevier Inc. All rights reserved.

Regulation of very-long acyl chain ceramide synthesis by acyl-CoA-binding protein

DEFF Research Database (Denmark)

Ferreira, Natalia Santos; Engelsby, Hanne; Neess, Ditte

2017-01-01

and cardiovascular diseases, as well as neurological disorders. Here we show that acyl-coenzyme A-binding protein (ACBP) potently facilitates very-long acyl chain ceramide synthesis. ACBP increases the activity of ceramide synthase 2 (CerS2) by more than 2-fold and CerS3 activity by 7-fold. ACBP binds very......-long-chain acyl-CoA esters, which is required for its ability to stimulate CerS activity. We also show that high-speed liver cytosol from wild-type mice activates CerS3 activity, whereas cytosol from ACBP knock-out mice does not. Consistently, CerS2 and CerS3 activities are significantly reduced in the testes...... of ACBP(-/-) mice, concomitant with a significant reduction in long- and very-long-chain ceramide levels. Importantly, we show that ACBP interacts with CerS2 and CerS3. Our data uncover a novel mode of regulation of very-long acyl chain ceramide synthesis by ACBP, which we anticipate is of crucial...

UDP-galactose: ceramide galactosyltransferase is a class I integral membrane protein of the endoplasmic reticulum

NARCIS (Netherlands)

Sprong, H.; Kruithof, B.; Leijendekker, R.L.; Slot, J.W.; van Meer, G.; van der Sluijs, P.

1998-01-01

UDP-galactose:ceramide galactosyltransferase (CGalT) transfers UDP-galactose to ceramide to form the glycosphingolipid galactosylceramide. Galactosylceramide is the major constituent of myelin and is also highly enriched in many epithelial cells, where it is thought to play an important role in

Killing tensors and conformal Killing tensors from conformal Killing vectors

International Nuclear Information System (INIS)

Rani, Raffaele; Edgar, S Brian; Barnes, Alan

2003-01-01

Koutras has proposed some methods to construct reducible proper conformal Killing tensors and Killing tensors (which are, in general, irreducible) when a pair of orthogonal conformal Killing vectors exist in a given space. We give the completely general result demonstrating that this severe restriction of orthogonality is unnecessary. In addition, we correct and extend some results concerning Killing tensors constructed from a single conformal Killing vector. A number of examples demonstrate that it is possible to construct a much larger class of reducible proper conformal Killing tensors and Killing tensors than permitted by the Koutras algorithms. In particular, by showing that all conformal Killing tensors are reducible in conformally flat spaces, we have a method of constructing all conformal Killing tensors, and hence all the Killing tensors (which will in general be irreducible) of conformally flat spaces using their conformal Killing vectors

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

OpenAIRE

Agnieszka Mikłosz; Bartłomiej Łukaszuk; Adrian Chabowski; Filip Rogowski; Krzysztof Kurek; Małgorzata Żendzian-Piotrowska

2015-01-01

Background: Thyroid hormones (THs) are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Methods: Male Wistar rats were treated for 10 days with triiodothyronine (T3) at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excise...

Stimulation of ceramide formation and suicidal erythrocyte death by vitamin K(3) (menadione).

Science.gov (United States)

Qadri, Syed M; Eberhard, Matthias; Mahmud, Hasan; Föller, Michael; Lang, Florian

2009-11-25

Vitamin K(3) is an essential micronutrient required for the activation of coagulation factors and thus hemostasis. Administration of vitamin K(3) analogues may cause anemia, which at least in theory could be due to stimulation of suicidal erythrocyte death or eryptosis characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane leading to exposure of phosphatidylserine at the erythrocyte surface. Eryptosis is triggered by an increase in the cytosolic Ca(2+) activity, by ceramide and by energy depletion (decrease of cytosolic ATP). The present experiments explored, whether vitamin K(3) may influence eryptosis. Hemolysis was estimated from the supernatant hemoglobin concentration, phosphatidylserine-exposing erythrocytes from annexin V-binding in fluorescence-activated cell sorter (FACS) analysis, erythrocyte volume from forward scatter in FACS analysis, ceramide formation from binding of fluorescent antibodies, and erythrocyte ATP content from a luciferin-luciferase assay. As a result, vitamin K(3) (> or =1microM) caused lysis of an only small fraction of erythrocytes, but significantly increased ceramide formation, significantly increased the percentage of annexin V-binding erythrocytes, significantly decreased forward scatter and, at higher concentrations, significantly decreased the cellular ATP content. In conclusion, vitamin K(3) stimulates suicidal erythrocyte death, an effect at least partially due to ceramide formation and ATP depletion.

Kinetic study of sphingomyelin hydrolysis for ceramide production

DEFF Research Database (Denmark)

Zhang, Long; Hellgren, Lars; Xu, Xuebing

2008-01-01

in cosmetic and pharmaceutical industries such as in hair and skin care products. The enzymatic hydrolysis of sphingomyelin has been proved to be a feasible method to produce ceramide. The kinetic performance of sphingomyelin hydrolysis in the optimal two-phase (water:organic solvent) reaction system...

Sphingomyelinase D activity in model membranes: structural effects of in situ generation of ceramide-1-phosphate.

Directory of Open Access Journals (Sweden)

Roberto P Stock

Full Text Available The toxicity of Loxosceles spider venom has been attributed to a rare enzyme, sphingomyelinase D, which transforms sphingomyelin to ceramide-1-phosphate. The bases of its inflammatory and dermonecrotic activity, however, remain unclear. In this work the effects of ceramide-1-phosphate on model membranes were studied both by in situ generation of this lipid using a recombinant sphingomyelinase D from the spider Loxosceles laeta and by pre-mixing it with sphingomyelin and cholesterol. The systems of choice were large unilamellar vesicles for bulk studies (enzyme kinetics, fluorescence spectroscopy and dynamic light scattering and giant unilamellar vesicles for fluorescence microscopy examination using a variety of fluorescent probes. The influence of membrane lateral structure on the kinetics of enzyme activity and the consequences of enzyme activity on the structure of target membranes containing sphingomyelin were examined. The findings indicate that: 1 ceramide-1-phosphate (particularly lauroyl ceramide-1-phosphate can be incorporated into sphingomyelin bilayers in a concentration-dependent manner and generates coexistence of liquid disordered/solid ordered domains, 2 the activity of sphingomyelinase D is clearly influenced by the supramolecular organization of its substrate in membranes and, 3 in situ ceramide-1-phosphate generation by enzymatic activity profoundly alters the lateral structure and morphology of the target membranes.

The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer

Directory of Open Access Journals (Sweden)

Nitai C. Hait

2017-01-01

Full Text Available Inflammation is part of our body’s response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P and ceramide-1-phosphate (C1P, contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs. Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.

High-Mobility Group Box 1 Disrupts Metabolic Function with Cigarette Smoke Exposure in a Ceramide-Dependent Manner

Directory of Open Access Journals (Sweden)

Oliver J. Taylor

2017-05-01

Full Text Available We have previously found that cigarette smoke disrupts metabolic function, in part, by increasing muscle ceramide accrual. To further our understanding of this, we sought to determine the role of the cytokine high-mobility group box 1 (HMGB1, which is increased with smoke exposure, in smoke-induced muscle metabolic perturbations. To test this theory, we determined HMGB1 from lungs of human smokers, as well as from lung cells from mice exposed to cigarette smoke. We also treated cells and mice directly with HMGB1, in the presence or absence of myriocin, an inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in ceramide biosynthesis. Outcomes included assessments of insulin resistance and muscle mitochondrial function. HMGB1 was significantly increased in both human lungs and rodent alveolar macrophages. Further testing revealed that HMGB1 treatment elicited a widespread increase in ceramide species and reduction in myotube mitochondrial respiration, an increase in reactive oxygen species, and reduced insulin-stimulated Akt phosphorylation. Inhibition of ceramide biosynthesis with myriocin was protective. In mice, by comparing treatments of HMGB1 injections with or without myriocin, we found that HMGB1 injections resulted in increased muscle ceramides, especially C16 and C24, which were necessary for reduced muscle mitochondrial respiration and compromised insulin and glucose tolerance. In conclusion, HMGB1 may be a necessary intermediate in the ceramide-dependent metabolic consequences of cigarette smoke exposure.

Influence of cholesterol and ceramide-VI on structure of the multilamellar lipid membrane at water exchange

International Nuclear Information System (INIS)

Ryabova, N.Yu.; Kiselev, M.A.; Balagurov, A.M.

2009-01-01

The results of neutron diffraction investigation of structure changes in multilamellar lipid membranes DPPC/cholesterol and DPPC/ceramide-VI (DPPC - dipalmitoylphosphatidylcholine) during the processes of hydration and dehydration are presented. The influence of cholesterol and ceramide-VI on kinetics of water exchange in DPPC membrane is characterized

Neutral sphingomyelinase-2, acid sphingomyelinase, and ceramide levels in COPD patients compared to controls

Directory of Open Access Journals (Sweden)

Lea SR

2016-09-01

Full Text Available Simon R Lea,1,* Hannah J Metcalfe,1,* Jonathan Plumb,1 Christian Beerli,2 Chris Poll,3 Dave Singh,1 Katharine H Abbott-Banner3 1Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK; 2Novartis Pharma AG, Postfach, Basel, Switzerland; 3Respiratory Diseases, Novartis Institute for Biomedical Research, Horsham, West Sussex, UK *These authors contributed equally to this work Background: Increased pulmonary ceramide levels are suggested to play a causative role in lung diseases including COPD. Neutral sphingomyelinase-2 (nSMase-2 and acid SMase (aSMase, which hydrolyze sphingomyelin to produce ceramide, are activated by a range of cellular stresses, including inflammatory cytokines and pathogens, but notably cigarette smoke appears to only activate nSMase-2. Our primary objective was to investigate nSMase-2 and aSMase protein localization and quantification in lung tissue from nonsmokers (NS, smokers (S, and COPD patients. In addition, various ceramide species (C16, C18, and C20 were measured in alveolar macrophages from COPD patients versus controls. Materials and methods: Patients undergoing surgical resection for suspected or confirmed lung cancer were recruited, and nSMase-2 and aSMase protein was investigated in different areas of lung tissue (small airways, alveolar walls, subepithelium, and alveolar macrophages by immunohistochemistry. Ceramide species were measured in alveolar macrophages from COPD patients and controls by mass spectrometry. Results: nSMase-2 and aSMase were detected in the majority of small airways. There was a significant increase in nSMase-2 immunoreactivity in alveolar macrophages from COPD patients (54% compared with NS (31.7% (P<0.05, and in aSMase immunoreactivity in COPD (68.2% and S (69.5% alveolar macrophages compared with NS (52.4% (P

Selective knockdown of ceramide synthases reveals complex interregulation of sphingolipid metabolism[S

OpenAIRE

Mullen, Thomas D.; Spassieva, Stefka; Jenkins, Russell W.; Kitatani, Kazuyuki; Bielawski, Jacek; Hannun, Yusuf A.; Obeid, Lina M.

2011-01-01

Mammalian ceramide synthases 1 to 6 (CerS1–6) generate Cer in an acyl-CoA-dependent manner, and expression of individual CerS has been shown to enhance the synthesis of ceramides with particular acyl chain lengths. However, the contribution of each CerS to steady-state levels of specific Cer species has not been evaluated. We investigated the knockdown of individual CerS in the MCF-7 human breast adenocarcinoma cell line by using small-interfering RNA (siRNA). We found that siRNA-induced down...

Modulation of ceramide metabolism in T-leukemia cell lines potentiates apoptosis induced by the cationic antimicrobial peptide bovine lactoferricin.

Science.gov (United States)

Furlong, Suzanne J; Ridgway, Neale D; Hoskin, David W

2008-03-01

Bovine lactoferricin (LfcinB) is a cationic antimicrobial peptide that selectively induces apoptosis in several different types of human cancer cells. However, the potential use of LfcinB as an anticancer agent is presently limited by the need for relatively high concentrations of the peptide to trigger apoptosis. Ceramide is a membrane sphingolipid that is believed to function as a second messenger during apoptosis. In this study, we investigated the role of ceramide in LfcinB-induced apoptosis in CCRF-CEM and Jurkat T-leukemia cell lines. Exposure to LfcinB caused nuclear condensation and fragmentation, poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation in CCRF-CEM and Jurkat T-cell acute lymphoblastic leukemia cell lines. Treatment with C6 ceramide, a cell-permeable, short-chain ceramide analog, also induced apoptotic nuclear morphology, PARP cleavage, and DNA fragmentation in T-leukemia cells. Although LfcinB treatment did not cause ceramide to accumulate in CCRF-CEM or Jurkat cells, the addition of C6 ceramide to LfcinB-treated T-leukemia cells resulted in increased DNA fragmentation. Furthermore, modulation of cellular ceramide metabolism either by inhibiting ceramidases with D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol or N-oleoylethanolamine, or by blocking glucosylceramide synthase activity with 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, enhanced the ability of LfcinB to trigger apoptosis in both Jurkat and CCRF-CEM cells. In addition, LfcinB-induced apoptosis of T-leukemia cells was enhanced in the presence of the antiestrogen tamoxifen, which has multiple effects on cancer cells, including inhibition of glucosylceramide synthase activity. We conclude that manipulation of cellular ceramide levels in combination with LfcinB therapy warrants further investigation as a novel strategy for the treatment of T cell-derived leukemias.

Lipid functions in skin: Differential effects of n-3 polyunsaturated fatty acids on cutaneous ceramides, in a human skin organ culture model.

Science.gov (United States)

Kendall, Alexandra C; Kiezel-Tsugunova, Magdalena; Brownbridge, Luke C; Harwood, John L; Nicolaou, Anna

2017-09-01

Ceramides are important for skin health, with a multitude of species found in both dermis and epidermis. The epidermis contains linoleic acid-Ester-linked Omega-hydroxylated ceramides of 6-Hydroxy-sphingosine, Sphingosine and Phytosphingosine bases (CER[EOH], CER[EOS] and CER[EOP], respectively), that are crucial for the formation of the epidermal barrier, conferring protection from environmental factors and preventing trans-epidermal water loss. Furthermore, a large number of ceramides, derivatives of the same sphingoid bases and various fatty acids, are produced by dermal and epidermal cells and perform signalling roles in cell functions ranging from differentiation to apoptosis. Supplementation with the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise as therapeutic agents in a number of inflammatory skin conditions, altering the lipid profile of the skin and production of bioactive lipids such as the eicosanoids, docosanoids and endocannabinoids. In this study we wished to investigate whether EPA and DHA could also affect the ceramide profile in epidermis and dermis, and, in this way, contribute to formation of a robust lipid barrier and ceramide-mediated regulation of skin functions. Ex vivo skin explants were cultured for 6days, and supplemented with EPA or DHA (50μM). Liquid chromatography coupled to tandem mass spectrometry with electrospray ionisation was used to assess the prevalence of 321 individual ceramide species, and a number of sphingoid bases, phosphorylated sphingoid bases, and phosphorylated ceramides, within the dermis and epidermis. EPA augmented dermal production of members of the ceramide families containing Non-hydroxy fatty acids and Sphingosine or Dihydrosphingosine bases (CER[NS] and CER[NDS], respectively), while epidermal CER[EOH], CER[EOS] and CER[EOP] ceramides were not affected. DHA did not significantly affect ceramide production. Ceramide-1-phosphate levels in

Expression and regulation of enzymes in the ceramide metabolic pathway in human retinal pigment epithelial cells and their relevance to retinal degeneration.

Science.gov (United States)

Zhu, DanHong; Sreekumar, Parameswaran G; Hinton, David R; Kannan, Ram

2010-03-31

Ceramide and its metabolic derivatives are important modulators of cellular apoptosis and proliferation. Dysregulation or imbalance of their metabolic pathways may promote the development of retinal degeneration. The aim of this study was to identify the expression and regulation of key enzymes of the ceramide pathway in retinal pigment epithelial (RPE) cells. RT-PCR was used to screen the enzymes involved in ceramide metabolism that are expressed in RPE. Over-expression of neutral sphingomyelinase-2 (SMPD3) or sphingosine kinase 1 (Sphk1) in ARPE-19 cells was achieved by transient transfection of SMPD3 or Sphk1 cDNA subcloned into an expression vector. The number of apoptotic or proliferating cells was determined using TUNEL and BrdU assays, respectively. Neutral sphingomyelinase-1, neutral sphingomyelinase-2, acidic ceramidase, ceramide kinase, SphK1 and Sphk2 were expressed in both ARPE-19 and early passage human fetal RPE (fRPE) cells, while alkaline ceramidase 2 was only expressed in fRPE cells. Over-expression of SMPD3 decreased RPE cell proliferation and increased cell apoptosis. The percentage of apoptotic cells increased proportionally with the amount of transfected SMPD3 DNA. Over-expression of SphK1 promoted cell proliferation and protected ARPE-19 cells from ceramide-induced apoptosis. The effect of C(2) ceramide on induction of apoptosis was evaluated in polarized vs. non-polarized RPE cultures; polarization of RPE was associated with much reduced apoptosis in response to ceramide. In conclusion, RPE cells possess the synthetic machinery for the production of ceramide, sphingosine, ceramide-1-phosphate (C1P), and sphingosine-1-phosphate (S1P). Over-expression of SMPD3 may increase cellular ceramide levels, leading to enhanced cell death and arrested cell proliferation. The selective induction of apoptosis in non-polarized RPE cultures by C(2) ceramide suggests that increased ceramide levels will preferentially affect non-polarized RPE, as are found in

The Human Skin Barrier Is Organized as Stacked Bilayers of Fully Extended Ceramides with Cholesterol Molecules Associated with the Ceramide Sphingoid Moiety

DEFF Research Database (Denmark)

Iwai, Ichiro; Han, Hongmei; Hollander, Lianne den

2012-01-01

not previously described in a biological system-stacked bilayers of fully extended ceramides (CERs) with cholesterol molecules associated with the CER sphingoid moiety. This arrangement rationalizes the skin's low permeability toward water and toward hydrophilic and lipophilic substances, as well as the skin...

How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer's beta amyloid peptide (Abeta1-40).

Science.gov (United States)

Yahi, Nouara; Aulas, Anaïs; Fantini, Jacques

2010-02-05

Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's beta-amyloid (Abeta) peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs) on the supramolecular assembly of Abeta peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Abeta(1-40) and chemically defined GSLs (GalCer, LacCer, GM1, GM3). Using the Langmuir monolayer technique, we show that Abeta(1-40) selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs). In contrast, Abeta(1-40) did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs). Cholesterol inhibited the interaction of Abeta(1-40) with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Abeta(1-40) binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Abeta(1-40) with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-pi stacking interactions involving residue Y10 of Abeta(1-40). We conclude that cholesterol can either inhibit or facilitate membrane-Abeta interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Abeta peptides, and on the influence

How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer's beta amyloid peptide (Abeta1-40.

Directory of Open Access Journals (Sweden)

Nouara Yahi

Full Text Available Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's beta-amyloid (Abeta peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs on the supramolecular assembly of Abeta peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Abeta(1-40 and chemically defined GSLs (GalCer, LacCer, GM1, GM3. Using the Langmuir monolayer technique, we show that Abeta(1-40 selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs. In contrast, Abeta(1-40 did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs. Cholesterol inhibited the interaction of Abeta(1-40 with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Abeta(1-40 binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Abeta(1-40 with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-pi stacking interactions involving residue Y10 of Abeta(1-40. We conclude that cholesterol can either inhibit or facilitate membrane-Abeta interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Abeta peptides, and on the

BcR-induced apoptosis involves differential regulation of C-16 and C-24-ceramide formation and sphingolipid-dependent activation of the proteasome

NARCIS (Netherlands)

Kroesen, BJ; Jacobs, Susan; Pettus, BJ; Sietsma, H; Kok, JW; Hannun, YA; de Leij, LFMH

2003-01-01

In this study, we describe an ordered formation of long- and very long-chain ceramide species in relation to the progression of B-cell receptor (BcR) triggering induced apoptosis. An early and caspase-independent increase in long-chain ceramide species, in which C-24-ceramide predominated, was

Chemoenzymatically prepared konjac ceramide inhibits NGF-induced neurite outgrowth by a semaphorin 3A-like action

Directory of Open Access Journals (Sweden)

Seigo Usuki

2016-03-01

Full Text Available Dietary sphingolipids such as glucosylceramide (GlcCer are potential nutritional factors associated with prevention of metabolic syndrome. Our current understanding is that dietary GlcCer is degraded to ceramide and further metabolized to sphingoid bases in the intestine. However, ceramide is only found in trace amounts in food plants and thus is frequently taken as GlcCer in a health supplement. In the present study, we successfully prepared konjac ceramide (kCer using endoglycoceramidase I (EGCase I. Konjac, a plant tuber, is an enriched source of GlcCer (kGlcCer, and has been commercialized as a dietary supplement to improve dry skin and itching that are caused by a deficiency of epidermal ceramide. Nerve growth factor (NGF produced by skin cells is one of the itch factors in the stratum corneum of the skin. Semaphorin 3A (Sema 3A has been known to inhibit NGF-induced neurite outgrowth of epidermal nerve fibers. It is well known that the itch sensation is regulated by the balance between NGF and Sema 3A. In the present study, while kGlcCer did not show an in vitro inhibitory effect on NGF-induced neurite outgrowth of PC12 cells, kCer was demonstrated to inhibit a remarkable neurite outgrowth. In addition, the effect of kCer was similar to that of Sema 3A in cell morphological changes and neurite retractions, but different from C2-Ceramide. kCer showed a Sema 3A-like action, causing CRMP2 phosphorylation, which results in a collapse of neurite growth cones. Thus, it is expected that kCer is an advanced konjac ceramide material that may have neurite outgrowth-specific action to relieve uncontrolled and serious itching, in particular, from atopic eczema.

Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy

DEFF Research Database (Denmark)

Mosbech, Mai-Britt; Olsen, Anne S B; Neess, Ditte

2014-01-01

between genes involved in SL metabolism and epilepsy. METHODS: We used quantitative real-time PCR, Western blotting, and enzymatic assays to determine the mRNA, protein, and activity levels of ceramide synthase 2 (CERS2) in fiibroblasts isolated from parental control subjects and from a patient diagnosed...... with progressive myoclonic epilepsy (PME). Mass spectrometry and fluorescence microscopy were used to examine the effects of reduced CERS2 activity on cellular lipid composition and plasma membrane functions. RESULTS: We identify a novel 27 kb heterozygous deletion including the CERS2 gene in a proband diagnosed...... with PME. Compared to parental controls, levels of CERS2 mRNA, protein, and activity were reduced by ˜50% in fibroblasts isolated from this proband, resulting in significantly reduced levels of ceramides and sphingomyelins containing the very long-chain fatty acids C24:0 and C26:0. The change in SL...

Conformal higher spin scattering amplitudes from twistor space

Energy Technology Data Exchange (ETDEWEB)

Adamo, Tim [Blackett Laboratory, Imperial College, London, SW7 2AZ (United Kingdom); Hähnel, Philipp; McLoughlin, Tristan [School of Mathematics, Trinity College Dublin, College Green, Dublin 2 (Ireland)

2017-04-04

We use the formulation of conformal higher spin (CHS) theories in twistor space to study their tree-level scattering amplitudes, finding expressions for all three-point (MHV)-bar amplitudes and all MHV amplitudes involving positive helicity conformal gravity particles and two negative helicity higher spins. This provides the on-shell analogue for the covariant coupling of CHS fields to a conformal gravity background. We discuss the restriction of the theory to a ghost-free unitary subsector, analogous to restricting conformal gravity to general relativity with a cosmological constant. We study the flat-space limit and show that the restricted amplitudes vanish, supporting the conjecture that in the unitary sector the S-matrix of CHS theories is trivial. However, by appropriately rescaling the amplitudes we find non-vanishing results which we compare with chiral flat-space higher spin theories.

Conformal higher spin scattering amplitudes from twistor space

International Nuclear Information System (INIS)

Adamo, Tim; Hähnel, Philipp; McLoughlin, Tristan

2017-01-01

We use the formulation of conformal higher spin (CHS) theories in twistor space to study their tree-level scattering amplitudes, finding expressions for all three-point (MHV)-bar amplitudes and all MHV amplitudes involving positive helicity conformal gravity particles and two negative helicity higher spins. This provides the on-shell analogue for the covariant coupling of CHS fields to a conformal gravity background. We discuss the restriction of the theory to a ghost-free unitary subsector, analogous to restricting conformal gravity to general relativity with a cosmological constant. We study the flat-space limit and show that the restricted amplitudes vanish, supporting the conjecture that in the unitary sector the S-matrix of CHS theories is trivial. However, by appropriately rescaling the amplitudes we find non-vanishing results which we compare with chiral flat-space higher spin theories.

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Directory of Open Access Journals (Sweden)

Agnieszka Mikłosz

2015-01-01

Full Text Available Background: Thyroid hormones (THs are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Methods: Male Wistar rats were treated for 10 days with triiodothyronine (T3 at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. Results: We have demonstrated that prolonged, in vivo, T3 treatment increased the content of sphinganine (SFA, sphingosine (SFO, ceramide (CER and sphingomyelin (SM, but decreased the level of sphingosine-1-phosphate (S1P in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV, β-hydroxyacyl-CoA dehydrogenase (β-HAD, carnityne palmitoyltransferase I (CPT I and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α. Conclusions: We conclude that prolonged T3 treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content.

Hyperthyroidism evokes myocardial ceramide accumulation.

Science.gov (United States)

Mikłosz, Agnieszka; Łukaszuk, Bartłomiej; Chabowski, Adrian; Rogowski, Filip; Kurek, Krzysztof; Żendzian-Piotrowska, Małgorzata

2015-01-01

Thyroid hormones (THs) are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Male Wistar rats were treated for 10 days with triiodothyronine (T3) at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. We have demonstrated that prolonged, in vivo, T3 treatment increased the content of sphinganine (SFA), sphingosine (SFO), ceramide (CER) and sphingomyelin (SM), but decreased the level of sphingosine-1-phosphate (S1P) in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK) with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV), β-hydroxyacyl-CoA dehydrogenase (β-HAD), carnityne palmitoyltransferase I (CPT I) and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). We conclude that prolonged T3 treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM) concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content. © 2015 S. Karger AG, Basel.

Synthesis and biological evaluation of branched and conformationally restricted analogs of the anticancer compounds 3'-C-ethynyluridine (EUrd) and 3'-C-ethynylcytidine (ECyd)

DEFF Research Database (Denmark)

Hrdlicka, Patrick J; Andersen, Nicolai K; Jepsen, Jan S

2005-01-01

The synthesis of branched and conformationally restricted analogs of the anticancer nucleosides 3'-C-ethynyluridine (EUrd) and 3'-C-ethynylcytidine (ECyd) is presented. Molecular modeling and (1)H NMR coupling constant analysis revealed that the furanose rings of all analogs except the LNA analog...

Inhibition of central de novo ceramide synthesis restores insulin signaling in hypothalamus and enhances β-cell function of obese Zucker rats

Directory of Open Access Journals (Sweden)

Mélanie Campana

2018-02-01

Full Text Available Objectives: Hypothalamic lipotoxicity has been shown to induce central insulin resistance and dysregulation of glucose homeostasis; nevertheless, elucidation of the regulatory mechanisms remains incomplete. Here, we aimed to determine the role of de novo ceramide synthesis in hypothalamus on the onset of central insulin resistance and the dysregulation of glucose homeostasis induced by obesity. Methods: Hypothalamic GT1-7 neuronal cells were treated with palmitate. De novo ceramide synthesis was inhibited either by pharmacological (myriocin or molecular (si-Serine Palmitoyl Transferase 2, siSPT2 approaches. Obese Zucker rats (OZR were intracerebroventricularly infused with myriocin to inhibit de novo ceramide synthesis. Insulin resistance was determined by quantification of Akt phosphorylation. Ceramide levels were quantified either by a radioactive kinase assay or by mass spectrometry analysis. Glucose homeostasis were evaluated in myriocin-treated OZR. Basal and glucose-stimulated parasympathetic tonus was recorded in OZR. Insulin secretion from islets and β-cell mass was also determined. Results: We show that palmitate impaired insulin signaling and increased ceramide levels in hypothalamic neuronal GT1-7 cells. In addition, the use of deuterated palmitic acid demonstrated that palmitate activated several enzymes of the de novo ceramide synthesis pathway in hypothalamic cells. Importantly, myriocin and siSPT2 treatment restored insulin signaling in palmitate-treated GT1-7 cells. Protein kinase C (PKC inhibitor or a dominant-negative PKCζ also counteracted palmitate-induced insulin resistance. Interestingly, attenuating the increase in levels of hypothalamic ceramides with intracerebroventricular infusion of myriocin in OZR improved their hypothalamic insulin-sensitivity. Importantly, central myriocin treatment partially restored glucose tolerance in OZR. This latter effect is related to the restoration of glucose-stimulated insulin

Lysosomal ceramide generated by acid sphingomyelinase triggers cytosolic cathepsin B-mediated degradation of X-linked inhibitor of apoptosis protein in natural killer/T lymphoma cell apoptosis.

Science.gov (United States)

Taniguchi, M; Ogiso, H; Takeuchi, T; Kitatani, K; Umehara, H; Okazaki, T

2015-04-09

We previously reported that IL-2 deprivation induced acid sphingomyelinase-mediated (ASM-mediated) ceramide elevation and apoptosis in an NK/T lymphoma cell line KHYG-1. However, the molecular mechanism of ASM-ceramide-mediated apoptosis during IL-2 deprivation is poorly understood. Here, we showed that IL-2 deprivation induces caspase-dependent apoptosis characterized by phosphatidylserine externalization, caspase-8, -9, and -3 cleavage, and degradation of X-linked inhibitor of apoptosis protein (XIAP). IL-2 re-supplementation rescued apoptosis via inhibition of XIAP degradation without affecting caspase cleavage. However, IL-2 deprivation induced ceramide elevation via ASM in lysosomes and activated lysosomal cathepsin B (CTSB) but not cathepsin D. A CTSB inhibitor CA-074 Me and knockdown of CTSB inhibited ceramide-mediated XIAP degradation and apoptosis. Inhibition of ceramide accumulation in lysosomes using an ASM inhibitor, desipramine, decreased cytosolic activation of CTSB by inhibiting its transfer into cytosol from the lysosome. Knockdown of ASM also inhibited XIAP degradation and apoptosis. Furthermore, cell permeable N-acetyl sphingosine (C2-ceramide), which increases mainly endogenous d18:1/16:0 and d18:1/24:1 ceramide-like IL-2 deprivation, induced caspase-dependent apoptosis with XIAP degradation through CTSB. These findings suggest that lysosomal ceramide produced by ASM mediates XIAP degradation by activation of cytosolic CTSB and caspase-dependent apoptosis. The ASM-ceramide-CTSB signaling axis is a novel pathway of ceramide-mediated apoptosis in IL-2-deprived NK/T lymphoma cells.

p53-independent early and late apoptosis is mediated by ceramide after exposure of tumor cells to photon or carbon ion irradiation

International Nuclear Information System (INIS)

Alphonse, Gersende; Maalouf, Mira; Battiston-Montagne, Priscillia; Ardail, Dominique; Beuve, Michaël; Rousson, Robert; Taucher-Scholz, Gisela; Fournier, Claudia; Rodriguez-Lafrasse, Claire

2013-01-01

To determine whether ceramide is responsible for the induction of p53-independent early or late apoptosis in response to high- and low-Linear-Energy-Transfer (LET) irradiation. Four cell lines displaying different radiosensitivities and p53-protein status were irradiated with photons or 33.4 or 184 keV/μm carbon ions. The kinetics of ceramide production was quantified by fluorescent microscopy or High-Performance-Liquid-Chromatogaphy and the sequence of events leading to apoptosis by flow cytometry. Regardless of the p53-status, both low and high-LET irradiation induced an early ceramide production in radiosensitive cells and late in the radioresistant. This production strongly correlated with the level of early apoptosis in radiosensitive cells and delayed apoptosis in the radioresistant ones, regardless of radiation quality, tumor type, radiosensitivity, or p53-status. Inhibition of caspase activity or ceramide production showed that, for both types of radiation, ceramide is essential for the initiation of early apoptosis in radiosensitive cells and late apoptosis following mitotic catastrophe in radioresistant cells. Ceramide is a determining factor in the onset of early and late apoptosis after low and high-LET irradiation and is the mediator of the p53-independent-apoptotic pathway. We propose that ceramide is the molecular bridge between mitotic catastrophe and the commitment phase of delayed apoptosis in response to irradiation

Accumulation of ceramide in slow-twitch muscle contributes to the development of insulin resistance in the obese JCR:LA-cp rat.

Science.gov (United States)

Fillmore, Natasha; Keung, Wendy; Kelly, Sandra E; Proctor, Spencer D; Lopaschuk, Gary D; Ussher, John R

2015-06-01

What is the central question of this study? The aim was to determine whether the accumulation of ceramide contributes to skeletal muscle insulin resistance in the JCR obese rat. What is the main finding and its importance? Our main new finding is that ceramides accumulate only in slow-twitch skeletal muscle in the JCR obese rat and that reducing ceramide content in this muscle type by inhibition of serine palmitoyl transferase-1 halts the progression of insulin resistance in this rat model predisposed to early development of type 2 diabetes. Our findings highlight the importance of assessing insulin signalling/sensitivity and lipid intermediate accumulation in different muscle fibre types. It has been postulated that insulin resistance results from the accumulation of cytosolic lipid metabolites (i.e. diacylglycerol/ceramide) that impede insulin signalling and impair glucose homeostasis. De novo ceramide synthesis is catalysed by serine palmitoyl transferase-1. Our aim was to determine whether de novo ceramide synthesis plays a role during development of insulin resistance in the JCR:LA-cp obese rat. Ten-week-old JCR:LA-cp obese rats were supplemented with either vehicle or the serine palmitoyl transferase-1 inhibitor l-cycloserine (360 mg l(-1) ) in their drinking water for a 2 week period, and glycaemia was assessed by meal tolerance testing. Treatment of JCR:LA-cp obese rats with l-cycloserine improved their plasma glucose and insulin levels during a meal tolerance test. Examination of muscle lipid metabolites and protein phosphorylation patterns revealed differential signatures in slow-twitch (soleus) versus fast-twitch muscle (gastrocnemius), in that ceramide levels were increased in soleus but not gastrocnemius muscles of JCR:LA-cp obese rats. Likewise, improved glycaemia in l-cycloserine-treated JCR:LA-cp obese rats was associated with enhanced Akt and pyruvate dehydrogenase signalling in soleus but not gastrocnemius muscles, probably as a result of l

Topical effects of N-acetyl-L-hydroxyproline on ceramide synthesis and alleviation of pruritus

Directory of Open Access Journals (Sweden)

Hashizume E

2013-02-01

Full Text Available Erika Hashizume,1 Tetsuo Nakano,2 Ayako Kamimura,1 Koji Morishita31Healthcare Products Development Center, Kyowa Hakko Bio, Tsukuba, Ibaraki, 2Technical Research Laboratories, Kyowa Hakko Bio, Hofu, Yamaguchi, 3Technology Development and Research Department, Kyowa Hakko Bio, Tokyo, JapanPurpose: N-acetyl-l-hydroxyproline (AHYP is an acetylated form of l-hydroxyproline that is used to treat skin ulcers and porphyria cutanea tarda. Its other biological and physiological effects on the skin have not been elucidated. We investigated the effects of AHYP on the skin-barrier function, focusing on ceramide synthesis and the effects of topical AHYP on atopic dermatitis.Materials and methods: AHYP was applied to a three-dimensional cultured skin model. Ceramides were quantified by high-performance thin-layer chromatography. Serine palmitoyltransferase (SPT is the rate-limiting enzyme in de novo ceramide synthesis, and the mRNA of its long-chain base subunit 1 (SPTLC1 was evaluated by quantitative reverse-transcription polymerase chain reaction. A clinical trial in the form of an intraindividual, comparative, double-blind, randomized, vehicle-controlled test involving 15 female subjects suffering from slight atopic dermatitis was performed. Subjects applied 1% (w/w AHYP cream to one forearm and a control cream to the other forearm twice daily for 4 weeks. Skin condition was evaluated by measuring transepidermal water loss (TEWL. Dermatological observations were made by a dermatologist, and subjects evaluated their own pruritus intensity before beginning treatment and 4 weeks after the start of treatment.Results: SPTLC1 expression and ceramide synthesis were significantly increased in an AHYP-treated skin model (P < 0.05. In the clinical trial, no adverse effects were observed in any subjects. TEWL was increased in the control-treated region of the forearm (P < 0.05 after 4 weeks' application, whereas there was no change in the AHYP-treated region of the

Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter

DEFF Research Database (Denmark)

Våbenø, Jon; Nielsen, Carsten Uhd; Steffansen, Bente

2005-01-01

The aim of the present study was to develop a computational method aiding the design of dipeptidomimetic pro-moieties targeting the human intestinal di-/tripeptide transporter hPEPT1. First, the conformation in which substrates bind to hPEPT1 (the bioactive conformation) was identified...... to change the peptide backbone conformation (DeltaE(bbone)) from the global energy minimum conformation to the identified bioactive conformation was calculated for 20 hPEPT1 targeted model prodrugs with known K(i) values. Quantitatively, an inverse linear relationship (r(2)=0.81, q(2)=0.80) was obtained...

A ceramide sensor hiding in a family of sphingomyelin synthases

NARCIS (Netherlands)

Tafesse, F.G.

2009-01-01

Sphingolipids are vital components of cellular membranes that provide mechanical stability and play key roles in signal transduction, cell recognition and molecular sorting. They are synthesized from ceramide, a potent mediator of programmed cell death. Hence, cells face the dilemma of how to

Plasma ceramides are elevated in overweight Holstein dairy cows experiencing greater lipolysis and insulin resistance during the transition from late pregnancy to early lactation.

Science.gov (United States)

Rico, J E; Bandaru, V V R; Dorskind, J M; Haughey, N J; McFadden, J W

2015-11-01

Insulin resistance is a homeorhetic adaptation to parturition in dairy cows transitioning from late pregnancy to early lactation. An increase in prepartum adiposity can predispose periparturient cows to greater lipolysis and insulin resistance, thus increasing the risk for metabolic disease. Mechanisms mediating the development of insulin resistance in overweight peripartal dairy cows may depend on ceramide metabolism. The sphingolipid ceramide accumulates in plasma and tissues of overweight monogastric animals, and facilitates saturated fatty acid-induced insulin resistance. Considering this evidence, we hypothesized that plasma ceramides would be elevated in periparturient dairy cattle and that these sphingolipids would correlate with the magnitude of lipolysis and insulin resistance. To test our central hypothesis, multiparous Holstein cows were allocated into 2 groups according to their body condition score (BCS) at d -30 prepartum: lean (BCS 4.0; n=11). Blood samples were collected at d -45, -30, -15, and -7, relative to expected parturition, and at d 4 postpartum. Plasma glucose, insulin, nonesterified fatty acids (NEFA), and β-hydroxybutyrate (BHBA) concentrations were measured, and insulin sensitivity was estimated. The concentrations of individual plasma ceramide and glycosylated ceramide were determined using liquid chromatography-based mass spectrometry. Results demonstrated that greater adiposity was associated with a greater loss in body condition during late pregnancy. Overweight cows had greater circulating concentrations of glucose, insulin, and NEFA, and lower insulin sensitivity relative to lean cows. We detected 30 different sphingolipids across 6 lipid classes with acyl chains ranging from 16 to 26 carbons. The most abundant plasma sphingolipids detected were C24:0-ceramide, C24:0-monohexosylceramide, and C16:0-lactosylceramide. Plasma concentrations of total ceramide and monohexosylceramide increased as lactation approached, and saturated

A novel pathway of ceramide metabolism in Saccharomyces cerevisiae

DEFF Research Database (Denmark)

Voynova, Natalia S; Vionnet, Christine; Ejsing, Christer S.

2012-01-01

The hydrolysis of ceramides in yeast is catalysed by the alkaline ceramidases Ypc1p and Ydc1p, two highly homologous membrane proteins localized to the ER (endoplasmic reticulum). As observed with many enzymes, Ypc1p can also catalyse the reverse reaction, i.e. condense a non-esterified fatty aci...

Lipid functions in skin: differential effects of n-3 polyunsaturated fatty acids on cutaneous ceramides, in a human skin organ culture model

OpenAIRE

Kendall, Alexandra; Kiezel-Tsugunova, Magdalena; Brownbridge, Luke; Harwood, John L.; Nicolaou, Anna

2017-01-01

Ceramides are important for skin health, with a multitude of species found in both dermis and epidermis. The epidermis contains linoleic acid-Ester-linked Omega-hydroxylated ceramides of 6-Hydroxy-sphingosine, Sphingosine and Phytosphingosine bases (CER[EOH], CER[EOS] and CER[EOP], respectively), that are crucial for the formation of the epidermal barrier, conferring protection from environmental factors and preventing trans-epidermal water loss. Furthermore, a large number of ceramides, deri...

A Hypothesis Concerning a Potential Involvement of Ceramide in Apoptosis and Acantholysis Induced by Pemphigus Autoantibodies

Directory of Open Access Journals (Sweden)

Wendy B. Bollag

2010-01-01

Full Text Available Autoimmune diseases affect more than 50 million Americans, resulting in significant healthcare costs. Most autoimmune diseases occur sporadically; however, endemic pemphigus foliaceus (EPF is an autoimmune skin disease localized to specific geographic loci. EPF, and the related diseases pemphigus vulgaris (PV and pemphigus foliaceus (PF, are characterized by skin lesions and autoantibodies to molecules found on epidermal keratinocytes. A variant of EPF in patients from El Bagre, Colombia, South America, has recently been reported to be distinct from previously described loci in Brazil and Tunisia epidemiologically and immunologically. As in PF and EPF, El Bagre EPF patients exhibit autoantibodies towards desmoglein-1, a cell adhesion molecule critical for maintaining epidermal integrity. An association of El Bagre EPF with sun exposure has been detected, and ultraviolet irradiation also exacerbates symptoms in PV, PF and EPF. Our hypothesis is that: (1 the autoantibodies generate pathology through an alteration in ceramide metabolism in targeted keratinocytes, resulting in apoptosis and/or cell death and acantholysis, but only when the cell's ability to metabolize ceramide is exceeded, and (2 apoptosis in response to this altered ceramide metabolism is initiated and/or exacerbated by other agents that increase ceramide levels, such as cytokines, ultraviolet irradiation, and senescence.

A hypothesis concerning a potential involvement of ceramide in apoptosis and acantholysis induced by pemphigus autoantibodies.

Science.gov (United States)

Bollag, Wendy B

2010-01-01

Autoimmune diseases affect more than 50 million Americans, resulting in significant healthcare costs. Most autoimmune diseases occur sporadically; however, endemic pemphigus foliaceus (EPF) is an autoimmune skin disease localized to specific geographic loci. EPF, and the related diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are characterized by skin lesions and autoantibodies to molecules found on epidermal keratinocytes. A variant of EPF in patients from El Bagre, Colombia, South America, has recently been reported to be distinct from previously described loci in Brazil and Tunisia epidemiologically and immunologically. As in PF and EPF, El Bagre EPF patients exhibit autoantibodies towards desmoglein-1, a cell adhesion molecule critical for maintaining epidermal integrity. An association of El Bagre EPF with sun exposure has been detected, and ultraviolet irradiation also exacerbates symptoms in PV, PF and EPF. Our hypothesis is that: (1) the autoantibodies generate pathology through an alteration in ceramide metabolism in targeted keratinocytes, resulting in apoptosis and/or cell death and acantholysis, but only when the cell's ability to metabolize ceramide is exceeded, and (2) apoptosis in response to this altered ceramide metabolism is initiated and/or exacerbated by other agents that increase ceramide levels, such as cytokines, ultraviolet irradiation, and senescence.

Training Does Not Alter Muscle Ceramide and Diacylglycerol in Offsprings of Type 2 Diabetic Patients Despite Improved Insulin Sensitivity

DEFF Research Database (Denmark)

Sogaard, Ditte; Ostergard, Torben; Blachnio-Zabielska, Agnieszka U.

2016-01-01

not change in response to the endurance training except for an overall reduction in C22:0-Cer (). Finally, the intervention induced an increase in AKT protein expression (Off: %; Con: %, ). This study showed no relation between insulin sensitivity and ceramide or DAG content suggesting that ceramide and DAG...

Association of the golgi UDP-galactose transporter with UDP-galactose: ceramide galactosyltransferase allows UDP-galactose import in the endoplasmic reticulum

NARCIS (Netherlands)

Sprong, H.; Degroote, S.; Nilsson, T.; Kawakita, M.; Ishida, N.; van der Sluijs, P.; van Meer, G.

2003-01-01

UDP-galactose reaches the Golgi lumen through the UDP-galactose transporter (UGT) and is used for the galactosylation of proteins and lipids. Ceramides and diglycerides are galactosylated within the endoplasmic reticulum by the UDP-galactose: ceramide galactosyltransferase. It is not known how

Plasma Ceramides, Mediterranean Diet, and Incident Cardiovascular Disease in the PREDIMED Trial (Prevención con Dieta Mediterránea).

Science.gov (United States)

Wang, Dong D; Toledo, Estefanía; Hruby, Adela; Rosner, Bernard A; Willett, Walter C; Sun, Qi; Razquin, Cristina; Zheng, Yan; Ruiz-Canela, Miguel; Guasch-Ferré, Marta; Corella, Dolores; Gómez-Gracia, Enrique; Fiol, Miquel; Estruch, Ramón; Ros, Emilio; Lapetra, José; Fito, Montserrat; Aros, Fernando; Serra-Majem, Luis; Lee, Chih-Hao; Clish, Clary B; Liang, Liming; Salas-Salvadó, Jordi; Martínez-González, Miguel A; Hu, Frank B

2017-05-23

Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ≤7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49-3.83, P trend Mediterranean diet and control groups during the first year of follow-up. Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. URL: http://www.isrctn.com. Unique identifier: ISRCTN35739639. © 2017 American Heart Association, Inc.

Simulations of Skin Barrier Function: Free Energies of Hydrophobic and Hydrophilic Transmembrane Pores in Ceramide Bilayers

OpenAIRE

Notman, Rebecca; Anwar, Jamshed; Briels, W. J.; Noro, Massimo G.; den Otter, Wouter K.

2008-01-01

Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel pha...

Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P Rats.

Directory of Open Access Journals (Sweden)

Jessica Godfrey

Full Text Available Heavy alcohol consumption has detrimental neurologic effects, inducing widespread neuronal loss in both fetuses and adults. One proposed mechanism of ethanol-induced cell loss with sufficient exposure is an elevation in concentrations of bioactive lipids that mediate apoptosis, including the membrane sphingolipid metabolites ceramide and sphingosine. While these naturally-occurring lipids serve as important modulators of normal neuronal development, elevated levels resulting from various extracellular insults have been implicated in pathological apoptosis of neurons and oligodendrocytes in several neuroinflammatory and neurodegenerative disorders. Prior work has shown that acute administration of ethanol to developing mice increases levels of ceramide in multiple brain regions, hypothesized to be a mediator of fetal alcohol-induced neuronal loss. Elevated ceramide levels have also been implicated in ethanol-mediated neurodegeneration in adult animals and humans. Here, we determined the effect of chronic voluntary ethanol consumption on lipid profiles in brain and peripheral tissues from adult alcohol-preferring (P rats to further examine alterations in lipid composition as a potential contributor to ethanol-induced cellular damage. P rats were exposed for 13 weeks to a 20% ethanol intermittent-access drinking paradigm (45 ethanol sessions total or were given access only to water (control. Following the final session, tissues were collected for subsequent chromatographic analysis of lipid content and enzymatic gene expression. Contrary to expectations, ethanol-exposed rats displayed substantial reductions in concentrations of ceramides in forebrain and heart relative to non-exposed controls, and modest but significant decreases in liver cholesterol. qRT-PCR analysis showed a reduction in the expression of sphingolipid delta(4-desaturase (Degs2, an enzyme involved in de novo ceramide synthesis. These findings indicate that ethanol intake levels

Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease.

Science.gov (United States)

Luukkonen, Panu K; Zhou, You; Sädevirta, Sanja; Leivonen, Marja; Arola, Johanna; Orešič, Matej; Hyötyläinen, Tuulia; Yki-Järvinen, Hannele

2016-05-01

Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver. Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3(148MM/MI), n=61 vs. PNPLA3(148II), n=64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither. Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. 'Low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI)vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups. Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner.

Science.gov (United States)

Nelson, Michael B; Swensen, Adam C; Winden, Duane R; Bodine, Jared S; Bikman, Benjamin T; Reynolds, Paul R

2015-07-01

Cigarette smoke exposure is associated with an increased risk of cardiovascular complications. The role of advanced glycation end products (AGEs) is already well established in numerous comorbidities, including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with the AGE carboxy-methyllysine before mitochondrial respiration assessment. We discovered that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when cotreated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed wild-type and RAGE knockout mice to secondhand cigarette smoke and found reduced mitochondrial respiration in the left ventricular myocardium from wild-type mice, but RAGE knockout mice were protected from this effect. Finally, conditional overexpression of RAGE in the lungs of transgenic mice elicited a robust increase in left ventricular ceramides in the absence of smoke exposure. Taken together, these findings suggest a RAGE-ceramide axis as an important contributor to AGE-mediated disrupted cardiomyocyte mitochondrial function. Copyright © 2015 the American Physiological Society.

Increased killing of SCCVII squamous cell carcinoma cells after the combination of Pc 4 photodynamic therapy and dasatinib is associated with enhanced caspase-3 activity and ceramide synthase 1 upregulation

Science.gov (United States)

SEPAROVIC, DUSKA; BREEN, PAUL; BOPPANA, NITHIN B.; VAN BUREN, ERIC; JOSEPH, NICHOLAS; KRAVEKA, JACQUELINE M.; RAHMANIYAN, MEHRDAD; LI, LI; GUDZ, TATYANA I.; BIELAWSKA, ALICJA; BAI, AIPING; BIELAWSKI, JACEK; PIERCE, JASON S.; KORBELIK, MLADEN

2013-01-01

Photodynamic therapy (PDT) is not always effective as an anticancer treatment, therefore, PDT is combined with other anticancer agents for improved efficacy. The combination of dasatinib and PDT with the silicone phthalocyanine photosensitizer Pc 4 was assessed for increased killing of SCCVII mouse squamous cell carcinoma cells, a preclinical model of head and neck squamous cell carcinoma, using apoptotic markers and colony formation as experimental end-points. Because each of these treatments regulates the metabolism of the sphingolipid ceramide, their effects on mRNA levels of ceramide synthase, a ceramide-producing enzyme, and the sphingolipid profile were determined. PDT + dasatinib induced an additive loss of clonogenicity. Unlike PDT alone or PDT + dasatinib, dasatinib induced zVAD-fmk-dependent cell killing. PDT or dasatinib-induced caspase-3 activation was potentiated after the combination. PDT alone induced mitochondrial depolarization, and the effect was inhibited after the combination. Annexin V+ and propidium iodide+ cells remained at control levels after treatments. In contrast to PDT alone, dasatinib induced upregulation of ceramide synthase 1 mRNA, and the effect was enhanced after the combination. Dasatinib induced a modest increase in C20:1-and C22-ceramide but had no effect on total ceramide levels. PDT increased the levels of 12 individual ceramides and total ceramides, and the addition of dasatinib did not affect these increases. PDT alone decreased substantially sphingosine levels and inhibited the activity of acid ceramidase, an enzyme that converts ceramide to sphingosine. The data suggest that PDT-induced increases in ceramide levels do not correlate with ceramide synthase mRNA levels but rather with inhibition of ceramidase. Cell killing was zVAD-fmk-sensitive after dasatinib but not after either PDT or the combination and enhanced cell killing after the combination correlated with potentiated caspase-3 activation and upregulation of

Ceramide in lipid emulsions used in parenteral nutrition: an innocent bystander?

NARCIS (Netherlands)

Groener, Johanna E.; Serlie, Mireille J.; Poppema, Aldi; Mirzaian, Mina; Aerts, Johannes M.

2011-01-01

Parenteral nutrition-associated liver disease is a prevalent and severe complication of long term parenteral nutrition. We present here for the first time data on the presence of ceramide, a bioactive compound involved in a variety of metabolic processes, in different lipid emulsions used in

Ceramide-Enriched Membrane Domains in Red Blood Cells and the Mechanism ofSphingomyelinase-Induced Hot-Cold Hemolysis

DEFF Research Database (Denmark)

Montes, Ruth; Lopez, David; Sot, Jesus

2008-01-01

Hot-cold hemolysis is the phenomenon whereby red blood cells, preincubated at 37 °C in the presence of certain agents, undergo rapid hemolysis when transferred to 4 °C. The mechanism of this phenomenon is not understood. PlcHR2, a phospholipase C/sphingomyelinase from Pseudomonas aeruginosa......) but also in goat erythrocytes, which lack PC. However, in horse erythrocytes, with a large proportion of PC and almost no SM, hot-cold hemolysis induced by PlcHR2 is not observed. Fluorescence microscopy observations confirm the formation of ceramide-enriched domains as a result of PlcHR2 activity. After......-cold hemolysis. Differential scanning calorimetry of erytrocyte membranes treated with PlcHR2 demonstrates the presence of ceramide-rich domains that are rigid at 4 °C but fluid at 37 °C. Ceramidase treatment causes the disapperance of the calorimetric signal assigned to ceramide-rich domains. Finally...

Impact of the ceramide subspecies on the nanostructure of stratum corneum lipids using neutron scattering and molecular dynamics simulations. Part I: impact of CER[NS].

Science.gov (United States)

Schmitt, Thomas; Gupta, Rakesh; Lange, Stefan; Sonnenberger, Stefan; Dobner, Bodo; Hauß, Thomas; Rai, Beena; Neubert, Reinhard H H

2018-05-30

For this study mixtures based on the ceramides [NS] (NS = non-hydroxy-sphingosine) and [AP] (AP = α-hydroxy-phytosphingosine) in a 2:1 and 1:2 ratio, together with cholesterol and lignoceric acid, were investigated. These mixtures are modelling the uppermost skin layer, the stratum corneum. Neutron diffraction, utilizing specifically deuterated ceramide molecules, was used to obtain a maximum amount of experimental detail. Highly detailed molecular dynamics simulations were used to generate even more information from the experimental data. It was possible to observe a single lamellar phase for both systems. They had a lamellar repeat distance of 5.43 ± 0.05 nm for the [NS]/[AP] 2:1 and a slightly shorter one of 5.34 ± 0.05 nm for the 1:2 system. The structure and water content was uninfluenced by excess humidity. Both the experimental and simulation data indicated slightly tilted ceramides, with their C24 chains overlapping in the lamellar mid-plane. This arrangement is well comparable to systems investigated before. The structure of both systems, except for the differing repeat distance, looks similar at first. However, on a smaller scale there were various distinct differences, demonstrating only low redundancy between the different ceramide species, despite only minor chemical differences. The mainly ceramide [AP] determined 1:2 system has a slightly smaller repeat distance. This is a result of a tighter arrangement of the lipids chain along the bilayer normal and increased overlapping of the long chains in the lamellar middle. For the CER[NS] some novel features could be shown, despite it being the overall most investigated ceramide. These include the low adaptability to changed lateral interactions, leading to an increased chain opening. This effect could explain its low miscibility with other lipids. The investigated model systems allows it to directly compare results from the literature which have used ceramide [NS] to the most recent

Conformal superalgebras via tractor calculus

Science.gov (United States)

Lischewski, Andree

2015-01-01

We use the manifestly conformally invariant description of a Lorentzian conformal structure in terms of a parabolic Cartan geometry in order to introduce a superalgebra structure on the space of twistor spinors and normal conformal vector fields formulated in purely algebraic terms on parallel sections in tractor bundles. Via a fixed metric in the conformal class, one reproduces a conformal superalgebra structure that has been considered in the literature before. The tractor approach, however, makes clear that the failure of this object to be a Lie superalgebra in certain cases is due to purely algebraic identities on the spinor module and to special properties of the conformal holonomy representation. Moreover, it naturally generalizes to higher signatures. This yields new formulas for constructing new twistor spinors and higher order normal conformal Killing forms out of existing ones, generalizing the well-known spinorial Lie derivative. Moreover, we derive restrictions on the possible dimension of the space of twistor spinors in any metric signature.

Plasma ceramide levels are altered in low and normal birth weight men in response to short-term high-fat overfeeding

DEFF Research Database (Denmark)

Ribel-Madsen, Amalie; Ribel-Madsen, Rasmus; Nielsen, Kristian Fog

2018-01-01

Low birth weight (LBW) individuals have an increased risk of developing insulin resistance and type 2 diabetes compared with normal birth weight (NBW) individuals. We hypothesised that LBW individuals exhibit an increased fatty acid flux into lipogenesis in non-adipose tissue with a resulting...... accumulation of lipotoxic lipids, including ceramides, in the blood. Therefore, we measured fasting plasma levels of 27 ceramides in 18 young, healthy, LBW men and 25 NBW controls after an isocaloric control diet and a 5-day high-fat, high-calorie diet by HPLC-HRMS. LBW men did not show elevated plasma......:0–18:1/d18:1–18:0 and d18:1–24:2/d18:2–24:1 levels and increased the d18:0–24:1a level in response to overfeeding. Plasma d18:0–24:1a and total ceramide levels were positively associated with the fasting blood glucose level and endogenous glucose production after the control diet, and the total ceramide...

Sphingosine Kinase 2 and Ceramide Transport as Key Targets of the Natural Flavonoid Luteolin to Induce Apoptosis in Colon Cancer Cells.

Directory of Open Access Journals (Sweden)

Loubna Abdel Hadi

Full Text Available The plant flavonoid luteolin exhibits different biological effects, including anticancer properties. Little is known on the molecular mechanisms underlying its actions in colorectal cancer (CRC. Here we investigated the effects of luteolin on colon cancer cells, focusing on the balance between ceramide and sphingosine-1-phosphate (S1P, two sphingoid mediators with opposite roles on cell fate. Using cultured cells, we found that physiological concentrations of luteolin induce the elevation of ceramide, followed by apoptotic death of colon cancer cells, but not of differentiated enterocytes. Pulse studies revealed that luteolin inhibits ceramide anabolism to complex sphingolipids. Further experiments led us to demonstrate that luteolin induces an alteration of the endoplasmic reticulum (ER-Golgi flow of ceramide, pivotal to its metabolic processing to complex sphingolipids. We report that luteolin exerts its action by inhibiting both Akt activation, and sphingosine kinase (SphK 2, with the consequent reduction of S1P, an Akt stimulator. S1P administration protected colon cancer cells from luteolin-induced apoptosis, most likely by an intracellular, receptor-independent mechanism. Overall this study reveals for the first time that the dietary flavonoid luteolin exerts toxic effects on colon cancer cells by inhibiting both S1P biosynthesis and ceramide traffic, suggesting its dietary introduction/supplementation as a potential strategy to improve existing treatments in CRC.

Behavior of sphingomyelin and ceramide in a tear film lipid layer model

Czech Academy of Sciences Publication Activity Database

Olžyńska, A.; Cwiklik, Lukasz

2017-01-01

Roč. 210, March (2017), s. 128-134 ISSN 0940-9602 Institutional support: RVO:61388963 Keywords : tear film lipid layer * molecular dynamics simulations * Langmuir balance * sphingomyelin * ceramide Subject RIV: CF - Physical ; Theoretical Chemistry OBOR OECD: Physical chemistry Impact factor: 1.864, year: 2016

Extending the Glucosyl Ceramide Cassette Approach: Application in the Total Synthesis of Ganglioside GalNAc-GM1b

Directory of Open Access Journals (Sweden)

Miku Konishi

2013-12-01

Full Text Available The development of a novel cyclic glucosyl ceramide cassette acceptor for efficient glycolipid syntheses was investigated. p-Methoxybenzyl (PMB groups were selected as protecting groups at C2 and C3 of the glucose residue with the aim of improving the functionality of the cassette acceptor. The choice of the PMB group resulted in a loss of β-selectivity, which was corrected by using an appropriate tether to control the spatial arrangement and the nitrile solvent effect. To investigate the effect of linker structure on the β-selectivity of intramolecular glycosylation, several linkers for tethering the glucose and ceramide moiety were designed and prepared, namely, succinyl, glutaryl, dimethylmalonyl, and phthaloyl esters. The succinyl ester linker was the best for accessing the cassette form. The newly designed glucosyl ceramide cassette acceptor was then applied in the total synthesis of ganglioside GalNAc-GM1b.

Ceramide transport from endoplasmic reticulum to Golgi apparatus is not vesicle-mediated

NARCIS (Netherlands)

Kok, JW; Babia, T; Klappe, K; Egea, G; Hoekstra, D

1998-01-01

Ceramide (Cer) transfer from the endoplasmic reticulum (ER) to the Golgi apparatus was measured under conditions that block vesicle-mediated protein transfer. This was done either in intact cells by reducing the incubation temperature to 15 degrees C, or in streptolysin O-permeabilized cells by

Ceramide content is higher in type I compared to type II fibers in obesity and type 2 diabetes mellitus

DEFF Research Database (Denmark)

Kristensen, Ditte Bech; Prats Gavalda, Clara; Larsen, Steen

2012-01-01

This study investigated fiber-type-specific muscle ceramide content in obese subjects and type 2 diabetes patients. Two substudies, one which compared type 2 diabetes patients to both lean- and obese BMI-matched subjects and the other study which compared lean body-matched post-obese, obese......, and control subjects, were performed. A fasting blood sample was obtained and plasma insulin and glucose determined. A muscle biopsy was obtained from deltoideus and vastus lateralis, and fiber-type ceramide content was determined by fluorescence immunohistochemistry. Insulin sensitivity estimated by Quicki...... index was higher in lean compared to type 2 diabetes patients and obese controls. Also in control and post-obese subjects, a higher insulin sensitivity was observed compared to obese subjects. Ceramide content was consistently higher in type I than in type II muscle fibers and higher in deltoideus than...

Interleukin-2-induced survival of natural killer (NK) cells involving phosphatidylinositol-3 kinase-dependent reduction of ceramide through acid sphingomyelinase, sphingomyelin synthase, and glucosylceramide synthase.

Science.gov (United States)

Taguchi, Yoshimitsu; Kondo, Tadakazu; Watanabe, Mitsumasa; Miyaji, Michihiko; Umehara, Hisanori; Kozutsumi, Yasunori; Okazaki, Toshiro

2004-11-15

Interleukin 2 (IL-2) rescued human natural killer (NK) KHYG-1 cells from apoptosis along with a reduction of ceramide. Conversely, an increase of ceramide inhibited IL-2-rescued survival. IL-2 deprivation-induced activation of acid sphingomyelinase (SMase) and inhibition of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) were normalized by IL-2 supplementation. A phosphatidyl inositol-3 (PI-3) kinase inhibitor, LY294002, inhibited IL-2-rescued survival, but a mitogen-activated protein kinase inhibitor, PD98059, and an inhibitor of Janus tyrosine kinase/signal transducer and activator of transcription pathway, AG490, did not. LY294002 inhibited IL-2-induced reduction of ceramide through activation of acid SMase and inhibition of GCS and SMS, suggesting the positive involvement of PI-3 kinase in ceramide reduction through enzymatic regulation. Indeed, a constitutively active PI-3 kinase enhanced growth rate and ceramide reduction through inhibition of acid SMase and activation of GCS and SMS. Further, LY294002 inhibited IL-2-induced changes of transcriptional level as well as mRNA and protein levels in acid SMase and GCS but did not affect the stability of the mRNAs. These results suggest that PI-3 kinase-dependent reduction of ceramide through regulation of acid SMase, GCS, and SMS plays a role in IL-2-rescued survival of NK cells.

Ceramide-induced TCR up-regulation

DEFF Research Database (Denmark)

Menné, C; Lauritsen, Jens Peter Holst; Dietrich, J

2000-01-01

to increase T cell responsiveness. The purpose of this study was to identify and characterize potential pathways for TCR up-regulation. We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concentration- and time-dependent manner. Experiments applying phosphatase......The TCR is a constitutively recycling receptor meaning that a constant fraction of TCR from the plasma membrane is transported inside the cell at the same time as a constant fraction of TCR from the intracellular pool is transported to the plasma membrane. TCR recycling is affected by protein...... kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected...

The use of chemomodification for tumor apoptosis ceramide pathway induction

International Nuclear Information System (INIS)

Myitryajeva, N.A.; Bakaj, T.S.; Segeda, T.V.; Staren'kij, V.P.

2012-01-01

Comparative analysis of the clinical findings of pre-operative radiation therapy in patients with non-small-cell lung cancer with chemomodification (Taxotere, Etoposide, Cisplatin) and without it demonstrated the advantages of the combination therapy. Experimental investigation of chemomodifying effect of chemotherapy drugs (Taxotere, Etoposide, Cisplatin) on Guerin's carcinoma showed various mechanisms of accumulation of pro-apoptosis ceramides and their potential role in apoptosis induction and tumor regression.

Flat connection, conformal field theory and quantum group

International Nuclear Information System (INIS)

Kato, Mitsuhiro.

1989-07-01

General framework of linear first order differential equation for four-point conformal block is studied by using flat connection. Integrability and SL 2 invariance restrict possible form of flat connection. Under a special ansatz classical Yang-Baxter equation appears as an integrability condition and the WZW model turns to be unique conformal field theory in that case. Monodromy property of conformal block can be easily determined by the flat connection. 11 refs

Dynamics of ceramide channels detected using a microfluidic system.

Directory of Open Access Journals (Sweden)

Chenren Shao

Full Text Available Ceramide, a proapoptotic sphingolipid, has been shown to form channels, in mitochondrial outer membranes, large enough to translocate proteins. In phospholipid membranes, electrophysiological studies and electron microscopic visualization both report that these channels form in a range of sizes with a modal value of 10 nm in diameter. A hydrogen bonded barrel-like structure consisting of hundreds of ceramide molecules has been proposed for the structure of the channel and this is supported by electrophysiological studies and molecular dynamic simulations. To our knowledge, the mechanical strength and deformability of such a large diameter but extremely thin cylindrical structure has never been reported. Here we present evidence for a reversible mechanical distortion of the cylinder following the addition of La(3+. A microfluidic system was used to repeatedly lower and then restore the conductance by alternatively perfusing La(3+ and EDTA. Although aspects of the kinetics of conductance drop and recovery are consistent with a disassembly/diffusion/reassembly model, others are inconsistent with the expected time scale of lateral diffusion of disassembled channel fragments in the membrane. The presence of a residual conductance following La(3+ treatment and the relationship between the residual conductance and the initial conductance were both indicative of a distortion/recovery process in analogy with a pressure-induced distortion of a flexible cylinder.

Cholesterol Depletion from a Ceramide/Cholesterol Mixed Monolayer: A Brewster Angle Microscope Study

KAUST Repository

Mandal, Pritam; Noutsi, Bakiza Kamal; Chaieb, Saharoui

2016-01-01

to deplete cholesterol (Chol) from biomembranes. Here, we focus on the depletion of cholesterol from a C16 ceramide/cholesterol (C16-Cer/Chol) mixed monolayer using MβCD. While the removal of cholesterol by MβCD depends on the cholesterol concentration

Endurance and Resistance Training Affect High Fat Diet-Induced Increase of Ceramides, Inflammasome Expression, and Systemic Inflammation in Mice

Directory of Open Access Journals (Sweden)

Cornelia Mardare

2016-01-01

Full Text Available The study aimed to investigate the effects of differentiated exercise regimes on high fat-induced metabolic and inflammatory pathways. Mice were fed a standard diet (ST or a high fat diet (HFD and subjected to regular endurance training (ET or resistance training (RT. After 10 weeks body weight, glucose tolerance, fatty acids (FAs, circulating ceramides, cytokines, and immunological mediators were determined. The HFD induced a significant increase in body weight and a disturbed glucose tolerance (p<0.05. An increase of plasma FA, ceramides, and inflammatory mediators in adipose tissue and serum was found (p<0.05. Both endurance and resistance training decreased body weight (p<0.05 and reduced serum ceramides (p<0.005. While RT attenuated the increase of NLRP-3 (RT expression in adipose tissue, ET was effective in reducing TNF-α and IL-18 expression. Furthermore, ET reduced levels of MIP-1γ, while RT decreased levels of IL-18, MIP-1γ, Timp-1, and CD40 in serum (p<0.001, respectively. Although both exercise regimes improved glucose tolerance (p<0.001, ET was more effective than RT. These results suggest that exercise improves HFD-induced complications possibly through a reduction of ceramides, the reduction of inflammasome activation in adipose tissues, and a systemic downregulation of inflammatory cytokines.

Metabolism and apoptotic properties of elevated ceramide in HT29(rev) cells

NARCIS (Netherlands)

Veldman, R J; Klappe, K; Hoekstra, D; Kok, J W

1998-01-01

Ceramide (Cer) has been implicated in the regulation of apoptosis. In this study, we elevated cellular Cer levels in human colon-carcinoma (HT29(rev)) cells by incubating the cells in the presence of bacterial sphingomyelinase (bSMase) or, alternatively, in the presence of C2-Cer, a short-chain

Interaction between the PH and START domains of ceramide transfer protein competes with phosphatidylinositol 4-phosphate binding by the PH domain.

Science.gov (United States)

Prashek, Jennifer; Bouyain, Samuel; Fu, Mingui; Li, Yong; Berkes, Dusan; Yao, Xiaolan

2017-08-25

De novo synthesis of the sphingolipid sphingomyelin requires non-vesicular transport of ceramide from the endoplasmic reticulum to the Golgi by the multidomain protein ceramide transfer protein (CERT). CERT's N-terminal pleckstrin homology (PH) domain targets it to the Golgi by binding to phosphatidylinositol 4-phosphate (PtdIns(4)P) in the Golgi membrane, whereas its C-terminal StAR-related lipid transfer domain (START) carries out ceramide transfer. Hyperphosphorylation of a serine-rich motif immediately after the PH domain decreases both PtdIns(4)P binding and ceramide transfer by CERT. This down-regulation requires both the PH and START domains, suggesting a possible inhibitory interaction between the two domains. In this study we show that isolated PH and START domains interact with each other. The crystal structure of a PH-START complex revealed that the START domain binds to the PH domain at the same site for PtdIns(4)P-binding, suggesting that the START domain competes with PtdIns(4)P for association with the PH domain. We further report that mutations disrupting the PH-START interaction increase both PtdIns(4)P-binding affinity and ceramide transfer activity of a CERT-serine-rich phosphorylation mimic. We also found that these mutations increase the Golgi localization of CERT inside the cell, consistent with enhanced PtdIns(4)P binding of the mutant. Collectively, our structural, biochemical, and cellular investigations provide important structural insight into the regulation of CERT function and localization. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Comparative tissue distribution of conformationally restricted radioiodinated vesamicol receptor ligands

Energy Technology Data Exchange (ETDEWEB)

Efange, S M.N.; Khare, A B; Langason, R B

1995-05-01

Three conformationally restricted analogs of vesamicol, 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-spirol[1H-indene-1,4'- piperidine] (5), 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-3,4-dihydrospiro[indene-1,4'- piperidine] (6) and 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl)]-3,4-dihydrospiro[naphthalene- 1(2H),4'-piperidine] (7), were labelled with iodine-125 and evaluated as potential radioligands for mapping vesamicol receptor (VR) density and cholinergic function in vivo. All compounds showed similar kinetics in most tissues. However, differences were observed in the brain. Although comparable levels of each corresponding enantiomeric pair were obtained initially in the brain, the levels of the dextrorotatory enantiomers (+)-5, (+)-6 and (+)-7 were found to decrease by 72-82% over a period of 3 h. In contrast, the brain levels of the corresponding levorotatory isomers were maintained throughout the duration of the experiment. Among the dextrorotatory isomers, (+)-6 showed the highest brain extraction, while (+)-7 showed the lowest. In tissue dissection experiments, the levels of (+)-5, (+)-6 and (+)-7 were highest in the striatum and moderate to low in the cortex and cerebellum. Co-administration of haloperidol with (+)-6 decreased the levels of the latter in the striatum by 27%, while the levels in the cortex and cerebellum were each reduced by 60%. In addition, haloperidol failed to affect the regional distribution of (+)-7 in the brain. However, both haloperidol and spiperone increased the striatal levels of (+)-5 by 67 and 76%, respectively, suggesting that the binding of this radioligand is related to cholinergic function. Furthermore, haloperidol reduced the concentration of (+)-5 in the cortex and cerebellum by 25 and 33%, respectively, thereby implicating the sigma site as a secondary target for this ligand in the cortex.

Comparative tissue distribution of conformationally restricted radioiodinated vesamicol receptor ligands

International Nuclear Information System (INIS)

Efange, S.M.N.; Khare, A.B.; Langason, R.B.

1995-01-01

Three conformationally restricted analogs of vesamicol, 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-spirol[1H-indene-1,4'- piperidine] (5), 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-3,4-dihydrospiro[indene-1,4'- piperidine] (6) and 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl)-3,4-dihydrospiro[naphthalene- 1(2H),4'-piperidine] (7), were labelled with iodine-125 and evaluated as potential radioligands for mapping vesamicol receptor (VR) density and cholinergic function in vivo. All compounds showed similar kinetics in most tissues. However, differences were observed in the brain. Although comparable levels of each corresponding enantiomeric pair were obtained initially in the brain, the levels of the dextrorotatory enantiomers (+)-5, (+)-6 and (+)-7 were found to decrease by 72-82% over a period of 3 h. In contrast, the brain levels of the corresponding levorotatory isomers were maintained throughout the duration of the experiment. Among the dextrorotatory isomers, (+)-6 showed the highest brain extraction, while (+)-7 showed the lowest. In tissue dissection experiments, the levels of (+)-5, (+)-6 and (+)-7 were highest in the striatum and moderate to low in the cortex and cerebellum. Co-administration of haloperidol with (+)-6 decreased the levels of the latter in the striatum by 27%, while the levels in the cortex and cerebellum were each reduced by 60%. In addition, haloperidol failed to affect the regional distribution of (+)-7 in the brain. However, both haloperidol and spiperone increased the striatal levels of (+)-5 by 67 and 76%, respectively, suggesting that the binding of this radioligand is related to cholinergic function. Furthermore, haloperidol reduced the concentration of (+)-5 in the cortex and cerebellum by 25 and 33%, respectively, thereby implicating the sigma site as a secondary target for this ligand in the cortex

Enzymatic production of ceramide from sphingomyelin

DEFF Research Database (Denmark)

Zhang, Long; Hellgren, Lars; Xu, Xuebing

2006-01-01

-saturated organic solvent) system. Among the screened phospholipase C, the Clostridium petfringens enzyme had the highest sphingomyetin conversion rate, with very small temperature dependence. Addition of ethanol to the system markedly enhanced the rate of ceramide formation, and a mixture of ethyl acetate: hexane...... (50:50) was the best organic solvent tested. Other factors such as (NH4)(2)SO4, MCI and CaCl, were also tested but excluded for further consideration. On the basis of the initial experiments, the reaction system was optimized using response surface methodology including five factors (enzyme amount...... systern evaluation and optimization, with the optimal conditions at 75 min reaction time, 3 U ml(-1) enzyme amount, 6% water amount, 1.8% ethanol arnount and 46% hexane in ethylacetate. (c) 2005 Elsevier B.V. All rights reserved....

Restricted conformal invariance in QCD and its predictive power for virtual two-photon processes

CERN Document Server

Müller, D

1998-01-01

The conformal algebra provides powerful constraints, which guarantee that renormalized conformally covariant operators exist in the hypothetical conformal limit of the theory, where the $\\beta$-function vanishes. Thus, in this limit also the conformally covariant operator product expansion on the light cone holds true. This operator product expansion has predictive power for two-photon processes in the generalized Bjorken region. Only the Wilson coefficients and the anomalous dimensions that are known from deep inelastic scattering are required for the prediction of all other two-photon processes in terms of the process-dependent off-diagonal expectation values of conformal operators. It is checked that the next-to-leading order calculations for the flavour non-singlet meson transition form factors are consistent with the corrections to the corresponding Wilson coefficients in deep inelasitic scattering.

Dimyristoylphosphatidylcholine/C16 : 0-ceramide binary liposomes studied by differential scanning calorimetry and wide- and small-angle X-ray scattering

DEFF Research Database (Denmark)

Holopainen, J. M.; Lemmich, Jesper; Richter, F.

2000-01-01

hydrated binary membranes composed of dimyristoylphosphatidylcholine (DMPC) and N-palmitoyl-ceramide (C16:0-ceramide, up to a mole fraction X-cer = 0.35) were resolved in further detail by high-sensitivity differential scanning calorimetry (DSC) and x-ray diffraction. Both methods reveal very strong...... hysteresis in the thermal phase behavior of ceramide-containing membranes. A partial phase diagram was constructed based on results from a combination of these two methods. DSC heating scans show that with increased X-cer the pretransition temperature T-P first increases, whereafter at X-cer > 0.06 it can...... no longer be resolved. The main transition enthalpy Delta H remains practically unaltered while its width increases significantly, and the upper phase boundary temperature of the mixture shifts to similar to 63 degrees C at X-cer = 0.30. Upon cooling, profound phase separation is evident, and for all...

Non-local Effects of Conformal Anomaly

Science.gov (United States)

Meissner, Krzysztof A.; Nicolai, Hermann

2018-03-01

It is shown that the nonlocal anomalous effective actions corresponding to the quantum breaking of the conformal symmetry can lead to observable modifications of Einstein's equations. The fact that Einstein's general relativity is in perfect agreement with all observations including cosmological or recently observed gravitational waves imposes strong restrictions on the field content of possible extensions of Einstein's theory: all viable theories should have vanishing conformal anomalies. It is shown that a complete cancellation of conformal anomalies in D=4 for both the C^2 invariant and the Euler (Gauss-Bonnet) invariant can only be achieved for N-extended supergravity multiplets with N ≥ 5.

Microbubble-based enhancement of radiation effect: Role of cell membrane ceramide metabolism.

Directory of Open Access Journals (Sweden)

Azza Al-Mahrouki

Full Text Available Ultrasound (US stimulated microbubbles (MB is a new treatment approach that sensitizes cancer cells to radiation (XRT. The molecular pathways in this response remain unelucidated, however, previous data has supported a role for cell membrane-metabolism related pathways including an up regulation of UDP glycosyltransferase 8 (UGT8, which catalyzes the transfer of galactose to ceramide, a lipid that is associated with the induction of apoptotic signalling. In this study, the role of UGT8 in responses of prostate tumours to ultrasound-stimulated microbubble radiation enhancement therapy is investigated. Experiments were carried out with cells in vitro and tumours in vivo in which UGT8 levels had been up regulated or down regulated. Genetically modified PC3 cells were treated with XRT, US+MB, or a combination of XRT+US+MB. An increase in the immunolabelling of ceramide was observed in cells where UGT8 was down-regulated as opposed to cells where UGT8 was either not regulated or was up-regulated. Clonogenic assays have revealed a decreased level of cellular survival with the down-regulation of UGT8. Xenograft tumours generated from stably transfected PC3 cells were also treated with US+MB, XRT or US+MB+XRT. Histology demonstrated more cellular damage in tumours with down-regulated UGT8 in comparison with control tumours. In contrast, tumours with up-regulated UGT8 had less damage than control tumours. Power Doppler imaging indicated a reduction in the vascular index with UGT8 down-regulation and photoacoustic imaging revealed a reduction in oxygen saturation. This was contrary to when UGT8 was up regulated. The down regulation of UGT8 led to the accumulation of ceramide resulting in more cell death signalling and therefore, a greater enhancement of radiation effect when vascular disruption takes place through the use of ultrasound-stimulated microbubbles.

Improved insulin sensitivity after exercise training is linked to reduced plasma C14:0 ceramide in obesity and type 2 diabetes.

Science.gov (United States)

Kasumov, Takhar; Solomon, Thomas P J; Hwang, Calvin; Huang, Hazel; Haus, Jacob M; Zhang, Renliang; Kirwan, John P

2015-07-01

To assess the effect of exercise training on insulin sensitivity and plasma ceramides in obesity and type 2 diabetes (T2D). Twenty-four adults with obesity and normal glucose tolerance (NGT, n = 14) or diabetes (n = 10) were studied before and after a 12-week supervised exercise-training program (5 days/week, 1 h/day, 80-85% of maximum heart rate). Changes in body composition were assessed using hydrostatic weighing and computed tomography. Peripheral tissue insulin sensitivity was assessed by a 40 mU/m(2) /min hyperinsulinemic euglycemic clamp. Plasma ceramides (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1) were quantified using electrospray ionization tandem mass spectrometry after separation with HPLC. Plasma ceramides were similar for the subjects with obesity and NGT and the subjects with diabetes, despite differences in glucose tolerance. Exercise significantly reduced body weight and adiposity and increased peripheral insulin sensitivity in both groups (P exercise training-induced improvements in insulin sensitivity, and plasma C14:0 ceramide may provide a specific target for investigating lipid-related insulin resistance in obesity and T2D. © 2015 The Obesity Society.

Stinging Nettle (Urtica dioica L.) Attenuates FFA Induced Ceramide Accumulation in 3T3-L1 Adipocytes in an Adiponectin Dependent Manner.

Science.gov (United States)

Obanda, Diana N; Zhao, Peng; Richard, Allison J; Ribnicky, David; Cefalu, William T; Stephens, Jacqueline M

2016-01-01

Excess dietary lipids result in the accumulation of lipid metabolites including ceramides that can attenuate insulin signaling. There is evidence that a botanical extract of Urtica dioica L. (stinging nettle) improves insulin action, yet the precise mechanism(s) are not known. Hence, we examined the effects of Urtica dioica L. (UT) on adipocytes. We investigated the effects of an ethanolic extract of UT on free fatty acid (palmitic acid) induced inhibition of insulin-stimulated Akt serine phosphorylation and modulation of ceramidase expression in 3T3-L1 adipocytes. Adipocytes were exposed to excess FFAs in the presence or absence of UT. Effects on adiponectin expression, ceramidase expression, ceramidase activity, ceramide accumulation and insulin signaling were determined. As expected, FFAs reduced adiponectin expression and increased the expression of ceramidase enzymes but not their activity. FFA also induced the accumulation of ceramides and reduced insulin-stimulated phosphorylation of Akt in adipocytes. The effects of FFA were partially reversed by UT. UT enhanced adiponectin expression and ceramidase activity in the presence of excess FFAs. UT abated ceramide accumulation and increased insulin sensitivity via enhanced Akt phosphorylation. A siRNA knockdown of adiponectin expression prevented UT from exerting positive effects on ceramidase activity but not Akt phosphorylation. In adipocytes, the ability of UT to antagonize the negative effects of FFA by modulating ceramidase activity and ceramide accumulation is dependent on the presence of adiponectin. However, the ability of UT to enhance Akt phosphorylation is independent of adiponectin expression. These studies demonstrate direct effects of UT on adipocytes and suggest this botanical extract is metabolically beneficial.

A Framework for Online Conformance Checking

DEFF Research Database (Denmark)

Burattin, Andrea; Carmona, Josep

2017-01-01

is quantified after the completion of the process instance. In this paper we propose a framework for online conformance checking: not only do we quantify (non-)conformant behavior as the execution is running, we also restrict the computation to constant time complexity per event analyzed, thus enabling...... the online analysis of a stream of events. The framework is instantiated with ideas coming from the theory of regions, and state similarity. An implementation is available in ProM and promising results have been obtained....

Biological functionalization of drug delivery carriers to bypass size restrictions of receptor-mediated endocytosis independently from receptor targeting.

Science.gov (United States)

Ansar, Maria; Serrano, Daniel; Papademetriou, Iason; Bhowmick, Tridib Kumar; Muro, Silvia

2013-12-23

Targeting of drug carriers to cell-surface receptors involved in endocytosis is commonly used for intracellular drug delivery. However, most endocytic receptors mediate uptake via clathrin or caveolar pathways associated with ≤200-nm vesicles, restricting carrier design. We recently showed that endocytosis mediated by intercellular adhesion molecule 1 (ICAM-1), which differs from clathrin- and caveolae-mediated pathways, allows uptake of nano- and microcarriers in cell culture and in vivo due to recruitment of cellular sphingomyelinases to the plasmalemma. This leads to ceramide generation at carrier binding sites and formation of actin stress-fibers, enabling engulfment and uptake of a wide size-range of carriers. Here we adapted this paradigm to enhance uptake of drug carriers targeted to receptors associated with size-restricted pathways. We coated sphingomyelinase onto model (polystyrene) submicro- and microcarriers targeted to clathrin-associated mannose-6-phosphate receptor. In endothelial cells, this provided ceramide enrichment at the cell surface and actin stress-fiber formation, modifying the uptake pathway and enhancing carrier endocytosis without affecting targeting, endosomal transport, cell-associated degradation, or cell viability. This improvement depended on the carrier size and enzyme dose, and similar results were observed for other receptors (transferrin receptor) and cell types (epithelial cells). This phenomenon also enhanced tissue accumulation of carriers after intravenous injection in mice. Hence, it is possible to maintain targeting toward a selected receptor while bypassing natural size restrictions of its associated endocytic route by functionalization of drug carriers with biological elements mimicking the ICAM-1 pathway. This strategy holds considerable promise to enhance flexibility of design of targeted drug delivery systems.

Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity

DEFF Research Database (Denmark)

Skovbro, M; Baranowski, M; Skov-Jensen, C

2008-01-01

-hyperinsulinaemic clamp was performed for 120 and 90 min for step 1 and step 2, respectively. Muscle biopsies were obtained from vastus lateralis at baseline, and after steps 1 and 2. RESULTS: Glucose infusion rates increased in response to insulin infusion, and significant differences were present between groups (T2D......AIMS/HYPOTHESIS: In skeletal muscle, ceramides may be involved in the pathogenesis of insulin resistance through an attenuation of insulin signalling. This study investigated total skeletal muscle ceramide fatty acid content in participants exhibiting a wide range of insulin sensitivities. METHODS......: The middle-aged male participants (n=33) were matched for lean body mass and divided into four groups: type 2 diabetes (T2D, n=8), impaired glucose tolerance (IGT, n=9), healthy controls (CON, n=8) and endurance-trained (TR, n=8). A two step (28 and 80 mU m(-2) min(-1)) sequential euglycaemic...

Muscle ceramide content is similar after 3 weeks’ consumption of fat or carbohydrate diet in a crossover design in patients with type 2 diabetes

DEFF Research Database (Denmark)

Helge, J. W.; Tobin, L.; Drachmann, Tue

2012-01-01

This study aimed at investigating the effect of prolonged adaptation to fat- or carbohydrate-rich diet on muscle ceramide in type 2 diabetes patients, using a longitudinal crossover study. Eleven type 2 diabetes patients consumed isocaloric fat- or carbohydrate-rich diet for 3 weeks in random order...... sensitivity, muscle glycogen, triacylglycerol and ceramide content were similar. Plasma adiponectin concentration was significantly higher after fat compared with carbohydrate-rich diet. Results indicated that following fat-rich diet intake muscle ceramide and triacylglycerol concentrations were not different...... compared with that after carbohydrate-rich diet. Furthermore, plasma adiponectin concentration was higher after fat-rich compared with carbohydrate-rich diet, but insulin sensitivity remained similar despite the major difference in dietary macronutrient composition....

Diagonal Limit for Conformal Blocks in d Dimensions

CERN Document Server

Hogervorst, Matthijs; Rychkov, Slava

2013-01-01

Conformal blocks in any number of dimensions depend on two variables z, zbar. Here we study their restrictions to the special "diagonal" kinematics z = zbar, previously found useful as a starting point for the conformal bootstrap analysis. We show that conformal blocks on the diagonal satisfy ordinary differential equations, third-order for spin zero and fourth-order for the general case. These ODEs determine the blocks uniquely and lead to an efficient numerical evaluation algorithm. For equal external operator dimensions, we find closed-form solutions in terms of finite sums of 3F2 functions.

Hsp70 and ceramide release by diode laser-treated mouse skin cells in vivo

Science.gov (United States)

Sokolovskii, G. S.; Onikienko, S. B.; Zemlyanoi, A. V.; Soboleva, K. K.; Pikhtin, N. A.; Tarasov, I. S.; Guzova, I. V.; Margulis, B. A.

2014-12-01

We report experimental study of generation of extracellular heat shock proteins (Hsp70) and ceramides under pulsed irradiation by quantum-well laser diodes. Our results are of great promise for applications in practical medicine such as protection against biopathogenes and abiotic stress factor challenges.

Stinging Nettle (Urtica dioica L. Attenuates FFA Induced Ceramide Accumulation in 3T3-L1 Adipocytes in an Adiponectin Dependent Manner.

Directory of Open Access Journals (Sweden)

Diana N Obanda

Full Text Available Excess dietary lipids result in the accumulation of lipid metabolites including ceramides that can attenuate insulin signaling. There is evidence that a botanical extract of Urtica dioica L. (stinging nettle improves insulin action, yet the precise mechanism(s are not known. Hence, we examined the effects of Urtica dioica L. (UT on adipocytes.We investigated the effects of an ethanolic extract of UT on free fatty acid (palmitic acid induced inhibition of insulin-stimulated Akt serine phosphorylation and modulation of ceramidase expression in 3T3-L1 adipocytes. Adipocytes were exposed to excess FFAs in the presence or absence of UT. Effects on adiponectin expression, ceramidase expression, ceramidase activity, ceramide accumulation and insulin signaling were determined.As expected, FFAs reduced adiponectin expression and increased the expression of ceramidase enzymes but not their activity. FFA also induced the accumulation of ceramides and reduced insulin-stimulated phosphorylation of Akt in adipocytes. The effects of FFA were partially reversed by UT. UT enhanced adiponectin expression and ceramidase activity in the presence of excess FFAs. UT abated ceramide accumulation and increased insulin sensitivity via enhanced Akt phosphorylation. A siRNA knockdown of adiponectin expression prevented UT from exerting positive effects on ceramidase activity but not Akt phosphorylation.In adipocytes, the ability of UT to antagonize the negative effects of FFA by modulating ceramidase activity and ceramide accumulation is dependent on the presence of adiponectin. However, the ability of UT to enhance Akt phosphorylation is independent of adiponectin expression. These studies demonstrate direct effects of UT on adipocytes and suggest this botanical extract is metabolically beneficial.

Simulations of skin barrier function: free energies of hydrophobic and hydrophilic transmembrane pores in ceramide bilayers.

Science.gov (United States)

Notman, Rebecca; Anwar, Jamshed; Briels, W J; Noro, Massimo G; den Otter, Wouter K

2008-11-15

Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy profile of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening.

Mitomycin C, ceramide, and 5-fluorouracil inhibit corneal haze and apoptosis after PRK.

Science.gov (United States)

Kim, Tae-im; Lee, Sun Young; Pak, Jhang Ho; Tchah, Hungwon; Kook, Michael S

2006-01-01

To investigate the effects of mitomycin C (MMC), ceramide, and 5-fluororacil (5-FU) on haze after photorefractive keratectomy (PRK) and exposure to ultraviolet B (UVB) radiation. The right eyes of 42 New Zealand white rabbits were treated with PRK to correct -10 diopter with a 5-mm optical zone. Sponges soaked in 0.02% MMC, 10 or 40 micromol/L ceramide, or 0.5% 5-FU were applied to the right eyes of 6 rabbits each, and a tarsorrhaphy was performed. Eight weeks after complete healing, topical 0.02% MMC or 0.5% 5-FU was applied twice daily to the right eyes of 6 rabbits that had previously received PRK but no topical medication. The control group of 6 rabbits was treated only with PRK. Three weeks after PRK, all the laser-treated eyes were exposed to 100 mJ/cm UVB radiation. Corneal haze was assessed biomicroscopically every 2 weeks using the Fantes scale. Eyes were enucleated 2, 7, and 13 weeks after PRK, and tissue specimens were stained with hematoxylin and eosin and with Apostain. Corneal haze was observed in all rabbits after PRK and was aggravated by UVB irradiation. When applied immediately after PRK, MMC induced corneal opacity and apoptosis of keratocytes, but, at later times, this reagent significantly suppressed opacity, Apostain-positive keratocytes and reactivation of keratocytes, even after UVB irradiation. In contrast, ceramide and 5-FU suppressed corneal opacity after PRK, but this effect was not sustained after UVB irradiation. MMC is a potent inhibitor of haze induced by PRK and UVB irradiation. Throughout the process of corneal wound healing, the severity of apoptosis and reactivation of keratocytes was closely correlated with haze formation.

Sphingomyelinase D activity in model membranes: structural effects of in situ generation of ceramide-1-phosphate

DEFF Research Database (Denmark)

Stock, Roberto; Brewer, Jonathan R.; Wagner, Kerstin

2012-01-01

The toxicity of Loxosceles spider venom has been attributed to a rare enzyme, sphingomyelinase D, which transforms sphingomyelin to ceramide-1-phosphate. The bases of its inflammatory and dermonecrotic activity, however, remain unclear. In this work the effects of ceramide-1-phosphate on model...... membranes were studied both by in situ generation of this lipid using a recombinant sphingomyelinase D from the spider Loxosceles laeta and by pre-mixing it with sphingomyelin and cholesterol. The systems of choice were large unilamellar vesicles for bulk studies (enzyme kinetics, fluorescence spectroscopy...... and dynamic light scattering) and giant unilamellar vesicles for fluorescence microscopy examination using a variety of fluorescent probes. The influence of membrane lateral structure on the kinetics of enzyme activity and the consequences of enzyme activity on the structure of target membranes containing...

Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi

Science.gov (United States)

2013-01-01

Background Ceramide accumulation is considered a contributing factor to neuronal dysfunction and damage. However, the underlying mechanisms that occur following ischemic insult are still unclear. Methods In the present study, we established cerebral ischemia models using four-vessel occlusion and oxygen-glucose deprivation methods. The hippocampus neural cells were subjected to immunohistochemistry and immunofluorescence staining for ceramide and neutral sphingomyelinase 2 (nSMase2) levels; immunoprecipitation and immunoblot analysis for nSMase2, receptor for activated C kinase 1 (RACK1), embryonic ectoderm development (EED), p38 mitogen-activated protein kinase (p38MAPK) and phosphorylated p38MAPK expression; SMase assay for nSMase and acid sphingomyelinase (aSMase) activity; real-time reverse transcription polymerase chain reaction for cytokine expression; and Nissl, microtubule-associated protein 2 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining. Results We found considerable production of ceramide in astrocytes, but not in neurons, during early cerebral ischemia. This was accompanied by the induction of nSMase (but not aSMase) activity in the rat hippocampi. The inhibition of nSMase2 activity effectively reduced ceramide accumulation in astrocytes and alleviated neuronal damage to some extent. Meanwhile, the expression levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6, were found to be upregulated, which may have played an import role in neuronal damage mediated by the nSMase2/ceramide pathway. Although enhanced binding of nSMase2 with RACK1 and EED were also observed after cerebral ischemia, nSMase2 activity was not blocked by the TNF-α receptor inhibitor through RACK1/EED signaling. p38MAPK, but not protein kinase Cζ or protein phosphatase 2B, was able to induce nSMase2 activation after ischemia. p38MAPK can be induced by A2B adenosine

Conformal invariance of extended spinning particle mechanics

International Nuclear Information System (INIS)

Siegel, W.

1988-01-01

Recently a mechanics action has been considered with extended, local, one-dimensional supersymmetry. The authors show this action is conformally invariant in arbitrary spacetime dimensions, and derive the corresponding quantum mechanical restriction on the Lorentz representations it describes

Conformal field theories, Coulomb gas picture and integrable models

International Nuclear Information System (INIS)

Zuber, J.B.

1988-01-01

The aim of the study is to present the links between some results of conformal field theory, the conventional Coulomb gas picture in statistical mechanics and the approach of integrable models. It is shown that families of conformal theories, related by the coset construction to the SU(2) Kac-Moody algebra, may be regarded as obtained from some free field, and modified by the coupling of its winding numbers to floating charges. This representation reflects the procedure of restriction of the corresponding integrable lattice models. The work may be generalized to models based on the coset construction with higher rank algebras. The corresponding integrable models are identified. In the conformal field description, generalized parafermions appear, and are coupled to free fields living on a higher-dimensional torus. The analysis is not as exhaustive as in the SU(2) case: all the various restrictions have not been identified, nor the modular invariants completely classified

Cameroonemide A: a new ceramide from Helichrysum cameroonense.

Science.gov (United States)

Antoine, Kakam Zanetsie; Hussain, Hidayat; Dongo, Etienne; Kouam, Simeon F; Schulz, Barbara; Krohn, Karsten

2010-07-01

From the extracts of all parts of the plant Helichrysum cameroonense, five compounds were isolated and identified. One of them, a ceramide, named cameroonemide A (1), is reported for the first time as a new natural product. Its structure was determined by comprehensive analyses of their 1D and 2D NMR and HR-EI-MS spectral data. The remaining four known compounds were identified by comparing their spectroscopic data with those reported in the literature as kaurenoic acid (2), 3-acetyloxykaurenoic acid (3), beta-sitosterol (4), and beta-sitosterol glucopyranoside (5). Preliminary studies showed that 3-acetyloxykaurenoic acid (3) inhibited the alga Chlorella fusca, while kaurenoic acid (2) showed strong antibacterial activity against Bacillus megaterium.

Functions of Ceramide Synthase Paralogs YPR114w and YJR116w of Saccharomyces cerevisiae.

Directory of Open Access Journals (Sweden)

Shamroop K Mallela

Full Text Available Ceramide is synthesized in yeast by two redundant acyl-CoA dependent synthases, Lag1 and Lac1. In lag1∆ lac1∆ cells, free fatty acids and sphingoid bases are elevated, and ceramides are produced through the redundant alkaline ceramidases Ypc1 and Ydc1, working backwards. Even with all four of these genes deleted, cells are surviving and continue to contain small amounts of complex sphingolipids. Here we show that these residual sphingolipids are not synthesized by YPR114w or YJR116w, proteins of unknown function showing a high degree of homology to Lag1 and Lac1. Indeed, the hextuple lag1∆ lac1∆ ypc1∆ ydc1∆ ypr114w∆ yjr116w∆ mutant still contains ceramides and complex sphingolipids. Yjr116w∆ exhibit an oxygen-dependent hypersensitivity to Cu2+ due to an increased mitochondrial production of reactive oxygen species (ROS and a mitochondrially orchestrated programmed cell death in presence of copper, but also a general copper hypersensitivity that cannot be counteracted by the antioxidant N-acetyl-cysteine (NAC. Myriocin efficiently represses the synthesis of sphingoid bases of ypr114w∆, but not its growth. Both yjr116w∆ and ypr114w∆ have fragmented vacuoles and produce less ROS than wild type, before and after diauxic shift. Ypr114w∆/ypr114w∆ have an increased chronological life span. Thus, Yjr116w and Ypr114w are related, but not functionally redundant.

Ceramide formation is involved in Lactobacillus acidophilus-induced IFN-beta response in dendritic cells

DEFF Research Database (Denmark)

Fuglsang, Eva; Henningsen, Louise; Frøkiær, Hanne

of sphingomyelin to ceramide by acid sphingomyelinase (ASMase) at the outer leaflet of the PM is a key event in endocytosis of gram-positive Lactobacillus acidophilus (L. acidophilus) and the subsequent induction of IFN-beta in DCs and, as the gram-negative Escherichia coli (E. coli) does not induce appreciable...

Differential protection by wildtype vs. organelle-specific Bcl-2 suggests a combined requirement of both the ER and mitochondria in ceramide-mediated caspase-independent programmed cell death

International Nuclear Information System (INIS)

Deerberg, Andrea; Sosna, Justyna; Thon, Lutz; Belka, Claus; Adam, Dieter

2009-01-01

Programmed cell death (PCD) is essential for development and homeostasis of multicellular organisms and can occur by caspase-dependent apoptosis or alternatively, by caspase-independent PCD (ciPCD). Bcl-2, a central regulator of apoptosis, localizes to both mitochondria and the endoplasmic reticulum (ER). Whereas a function of mitochondrial and ER-specific Bcl-2 in apoptosis has been established in multiple studies, corresponding data for ciPCD do not exist. We utilized Bcl-2 constructs specifically localizing to mitochondria (Bcl-2 ActA), the ER (Bcl-2 cb5), both (Bcl-2 WT) or the cytosol/nucleus (Bcl-2 ΔTM) and determined their protective effect on ceramide-mediated ciPCD in transiently and stably transfected Jurkat cells. Expression of the constructs was verified by immunoblots. Ceramide-mediated ciPCD was induced by treatment with human recombinant tumor necrosis factor and determined by flow cytometric measurement of propidium iodide uptake as well as by optical analysis of cell morphology. Only wildtype Bcl-2 had the ability to efficiently protect from ceramide-mediated ciPCD, whereas expression of Bcl-2 solely at mitochondria, the ER, or the cytosol/nucleus did not prevent ceramide-mediated ciPCD. Our data suggest a combined requirement for both mitochondria and the ER in the induction and the signaling pathways of ciPCD mediated by ceramide

Differential protection by wildtype vs. organelle-specific Bcl-2 suggests a combined requirement of both the ER and mitochondria in ceramide-mediated caspase-independent programmed cell death

Directory of Open Access Journals (Sweden)

Belka Claus

2009-10-01

Full Text Available Abstract Background Programmed cell death (PCD is essential for development and homeostasis of multicellular organisms and can occur by caspase-dependent apoptosis or alternatively, by caspase-independent PCD (ciPCD. Bcl-2, a central regulator of apoptosis, localizes to both mitochondria and the endoplasmic reticulum (ER. Whereas a function of mitochondrial and ER-specific Bcl-2 in apoptosis has been established in multiple studies, corresponding data for ciPCD do not exist. Methods We utilized Bcl-2 constructs specifically localizing to mitochondria (Bcl-2 ActA, the ER (Bcl-2 cb5, both (Bcl-2 WT or the cytosol/nucleus (Bcl-2 ΔTM and determined their protective effect on ceramide-mediated ciPCD in transiently and stably transfected Jurkat cells. Expression of the constructs was verified by immunoblots. Ceramide-mediated ciPCD was induced by treatment with human recombinant tumor necrosis factor and determined by flow cytometric measurement of propidium iodide uptake as well as by optical analysis of cell morphology. Results Only wildtype Bcl-2 had the ability to efficiently protect from ceramide-mediated ciPCD, whereas expression of Bcl-2 solely at mitochondria, the ER, or the cytosol/nucleus did not prevent ceramide-mediated ciPCD. Conclusion Our data suggest a combined requirement for both mitochondria and the ER in the induction and the signaling pathways of ciPCD mediated by ceramide.

Conformal radiotherapy: principles and classification

International Nuclear Information System (INIS)

Rosenwald, J.C.; Gaboriaud, G.; Pontvert, D.

1999-01-01

'Conformal radiotherapy' is the name fixed by usage and given to a new form of radiotherapy resulting from the technological improvements observed during the last ten years. While this terminology is now widely used, no precise definition can be found in the literature. Conformal radiotherapy refers to an approach in which the dose distribution is more closely 'conformed' or adapted to the actual shape of the target volume. However, the achievement of a consensus on a more specific definition is hampered by various difficulties, namely in characterizing the degree of 'conformality'. We have therefore suggested a classification scheme be established on the basis of the tools and the procedures actually used for all steps of the process, i.e., from prescription to treatment completion. Our classification consists of four levels: schematically, at level 0, there is no conformation (rectangular fields); at level 1, a simple conformation takes place, on the basis of conventional 2D imaging; at level 2, a 3D reconstruction of the structures is used for a more accurate conformation; and level 3 includes research and advanced dynamic techniques. We have used our personal experience, contacts with colleagues and data from the literature to analyze all the steps of the planning process, and to define the tools and procedures relevant to a given level. The corresponding tables have been discussed and approved at the European level within the Dynarad concerted action. It is proposed that the term 'conformal radiotherapy' be restricted to procedures where all steps are at least at level 2. (author)

Complement activation by ceramide transporter proteins.

Science.gov (United States)

Bode, Gerard H; Losen, Mario; Buurman, Wim A; Veerhuis, Robert; Molenaar, Peter C; Steinbusch, Harry W M; De Baets, Marc H; Daha, Mohamed R; Martinez-Martinez, Pilar

2014-02-01

C1q is the initiator of the classical complement pathway and, as such, is essential for efficient opsonization and clearance of pathogens, altered self-structures, and apoptotic cells. The ceramide transporter protein (CERT) and its longer splicing isoform CERTL are known to interact with extracellular matrix components, such as type IV collagen, and with the innate immune protein serum amyloid P. In this article, we report a novel function of CERT in the innate immune response. Both CERT isoforms, when immobilized, were found to bind the globular head region of C1q and to initiate the classical complement pathway, leading to activation of C4 and C3, as well as generation of the membrane attack complex C5b-9. In addition, C1q was shown to bind to endogenous CERTL on the surface of apoptotic cells. These results demonstrate the role of CERTs in innate immunity, especially in the clearance of apoptotic cells.

Fliposomes: pH-triggered conformational flip of new trans-2-aminocyclohexanol-based amphiphiles causes instant cargo release in liposomes.

Science.gov (United States)

Liu, Xin; Zheng, Yu; Samoshina, Nataliya M; Franz, Andreas H; Guo, Xin; Samoshin, Vyacheslav V

2012-12-01

A new type of pH-sensitive liposomes (fliposomes) was designed based on the amphiphiles that are able to perform a pH-triggered conformational flip (flipids). This flip disrupts the liposome membrane and causes rapid release of the liposome cargo, specifically in response to lowered pH. The flipids (1) and (2) are equipped with a trans-2-aminocyclohexanol conformational switch. pH-sensitive fliposomes containing one or both of these flipids, as well as POPC and PEG ceramide, were constructed and characterized. These compositions were stable at 4°C and pH 7.4 for several months. Fliposomes loaded with ANTS/DPX performed an unusually quick content release within a few seconds at pH below 8.5 (in case of 2) and 6.0 (in case of 1). This difference in pH sensitivity demonstrates a potential for the custom design of flipids by variation of the amino group to target areas with specific pH values. The pH titration curves for the fliposome leakage parallel the curves for the acid-induced conformational flip of 1 and 2 studied by ¹H NMR. A plausible mechanism of pH sensitivity starts with an acid-triggered conformational flip of 1 or 2, which changes the molecular size and shape, shortens the lipid tails, and perturbs the liposome membrane, resulting in the content leakage.

Simulations of Skin Barrier Function: Free Energies of Hydrophobic and Hydrophilic Transmembrane Pores in Ceramide Bilayers

NARCIS (Netherlands)

Notman, Rebecca; Anwar, Jamshed; Briels, Willem J.; Noro, Massimo G.; den Otter, Wouter K.

2008-01-01

Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO)

Conformational Restriction of Peptides Using Dithiol Bis-Alkylation.

Science.gov (United States)

Peraro, L; Siegert, T R; Kritzer, J A

2016-01-01

Macrocyclic peptides are highly promising as inhibitors of protein-protein interactions. While many bond-forming reactions can be used to make cyclic peptides, most have limitations that make this chemical space challenging to access. Recently, a variety of cysteine alkylation reactions have been used in rational design and library approaches for cyclic peptide discovery and development. We and others have found that this chemistry is versatile and robust enough to produce a large variety of conformationally constrained cyclic peptides. In this chapter, we describe applications, methods, mechanistic insights, and troubleshooting for dithiol bis-alkylation reactions for the production of cyclic peptides. This method for efficient solution-phase macrocyclization is highly useful for the rapid production and screening of loop-based inhibitors of protein-protein interactions. © 2016 Elsevier Inc. All rights reserved.

Expression of ceramide glucosyltransferases, which are essential for glycosphingolipid synthesis, is only required in a small subset of C. elegans cells

DEFF Research Database (Denmark)

Marza, Esther; Simonsen, Karina T; Færgeman, Nils J

2009-01-01

mutants with essentially no GSLs. The C. elegans genome encodes three ceramide glucosyltransferase (CGT) genes, which encode enzymes required for GSL biosynthesis. Animals lacking CGT do not synthesize GSLs, arrest growth at the first larval stage, and display defects in a subset of cells...... suggest that GSLs are dispensable in most C. elegans cells, including those of the nervous system.......Glycosphingolipids (GSLs) are glycosylated derivatives of ceramide in the lipid bilayer. Their ubiquitous distribution and complexity suggest that they have important functions, but what these are in vivo is still poorly understood. Here, we characterize the phenotype of Caenorhabditis elegans...

Intrinsic, pro-apoptotic effects of IGFBP-3 on breast cancer cells are reversible: Involvement of PKA, Rho and ceramide.

Directory of Open Access Journals (Sweden)

Claire M Perks

2011-05-01

Full Text Available We established previously that IGFBP-3 could exert positive or negative effects on cell function depending upon the extracellular matrix composition and by interacting with integrin signalling. To elicit its pro-apoptotic effects IGFBP-3 bound to caveolin-1 and the beta 1 integrin receptor and increased their association culminating in MAPK activation. Disruption of these complexes or blocking the beta 1 integrin receptor reversed these intrinsic actions of IGFBP-3. In this study we have examined the signalling pathway between integrin receptor binding and MAPK activation that mediates the intrinsic, pro-apoptotic actions of IGFBP-3. We found on inhibiting protein kinase A(PKA, Rho associated kinase (ROCK and ceramide, the accentuating effects of IGFBP-3 on apoptotic triggers were reversed, such that IGFBP-3 then conferred cell survival. We established that IGFBP-3 activated Rho, the upstream regulator of ROCK and that beta1 integrin and PKA were upstream of Rho activation, whereas the involvement of ceramide was downstream. The beta 1 integrin, PKA, Rho and ceramide were all upstream of MAPK activation. These data highlight key components involved in the pro-apoptotic effects of IGFBP-3 and that inhibiting them leads to a reversal in the action of IGFBP-3.

Exotic Galilean conformal symmetry and its dynamical realisations

International Nuclear Information System (INIS)

Lukierski, J.; Stichel, P.C.; Zakrzewski, W.J.

2006-01-01

The six-dimensional exotic Galilean algebra in (2+1) dimensions with two central charges m and θ, is extended when m=0, to a ten-dimensional Galilean conformal algebra with dilatation, expansion, two acceleration generators and the central charge θ. A realisation of such a symmetry is provided by a model with higher derivatives recently discussed in [P.C. Stichel, W.J. Zakrzewski, Ann. Phys. 310 (2004) 158]. We consider also a realisation of the Galilean conformal symmetry for the motion with a Coulomb potential and a magnetic vortex interaction. Finally, we study the restriction, as well as the modification, of the Galilean conformal algebra obtained after the introduction of the minimally coupled constant electric and magnetic fields

Application of a non-invasive method to study the moisturizing effect of formulations containing vitamins A or E or ceramide on human skin.

Science.gov (United States)

Leonardi, Gislaine Ricci; Gaspar, Lorena Rigo; Maia Campos, Patrícia M B G

2002-01-01

Moisturizers containing vitamins A and E as well as ceramides are believed to improve the skin condition by increasing the water content of the stratum corneum. The aim of this research was to evaluate, through the capacitance method (a non-invasive method), the moisturizing effect of an O/W emulsion (non-ionic self-emulsifying base) containing vitamin A palmitate, vitamin E acetate, and ceramide III on human skin. The studies were carried out on a group of 40 healthy Caucasian female test subjects between 30 and 45 years of age, using the Corneometer CM 825 PC. Skin measurements were taken from the volunteers at 7 and 30 days after daily use (twice a day) of the tested products. The presence of vitamins A and E or ceramide III did not cause an improvement in the hydration of the stratum corneum, which means that none of those compounds strengthens the hydration effectiveness of the base formulations used, at least at the doses tested. The interpretation of electrical measurement regarding skin moisture should be made with caution; thus the results observed in this study show the importance of using different approaches (or methodologies) to verify the performance of the formulas tested. We conclude that, at the low doses typically used in cosmetic formulations, vitamins A and E and ceramide III are not likely to contribute to the hydrating effects of the base moisturizing formulation when assessed by capacitance.

Resveratrol sensitization of DU145 prostate cancer cells to ionizing radiation is associated to ceramide increase.

Science.gov (United States)

Scarlatti, Francesca; Sala, Giusy; Ricci, Clara; Maioli, Claudio; Milani, Franco; Minella, Marco; Botturi, Marco; Ghidoni, Riccardo

2007-08-08

Radiotherapy is an established therapeutic modality for prostate cancer. Since it is well known that radiotherapy is limited due to its severe toxicity towards normal cells at high dose and minimal effect at low dose, the search for biological compounds that increase the sensitivity of tumors cells to radiation may improve the efficacy of therapy. Resveratrol, a natural antioxidant, was shown to inhibit carcinogenesis in animal models, and to block the process of tumor initiation and progression. The purpose of this study was to examine whether or not resveratrol can sensitize DU145, an androgen-independent human prostate cancer cell line, to ionizing radiation. We report here that DU145 cells are resistant to ionizing radiation-induced cell death, but pretreatment with resveratrol significantly enhances cell death. Resveratrol acts synergistically with ionizing radiation to inhibit cell survival in vitro. Resveratrol also potentiates ionizing radiation-induced ceramide accumulation, by promoting its de novo biosynthesis. This confirms ceramide as an effective mediator of the anticancer potential induced by resveratrol.

Palyosulfonoceramides A and B: Unique Sulfonylated Ceramides from the Brazilian Zoanthids Palythoa caribaeorum and Protopalyhtoa variabilis

Directory of Open Access Journals (Sweden)

Otília Deusdenia L. Pessoa

2012-12-01

Full Text Available The zoanthids Palythoa caribaeorum and Protopalythoa variabilis are among the most abundant marine species along the Brazilian coast. We now report the isolation and structure elucidation of two unprecedented sulfonylated ceramides, palyosulfonoceramide A (1 and palyosulfonoceramide B (2 from specimens collected off Brazil’s northeastern coast. The structures of 1 and 2 were established using a combination of NMR analyses, including: evaluation of 1H, 13C, 1H–1H COSY, 1H–13C HSQC, 1H–13C HMBC, and 1H–15N HMBC NMR spectra, high-resolution mass spectrometry and chemical degradation. In addition, we also isolated the corresponding known ceramides, N-((2S,3R,4E,8E-1, 3-dihydroxyoctadeca-4,8-dien-2-yl-hexadecanamide (3 and N-((2S,3R,4E-1,3-dihydroxy octadeca-4-en-2-yl-hexadecanamide (4, which provided further support for the assignments of 1 and 2.

Palyosulfonoceramides A and B: Unique Sulfonylated Ceramides from the Brazilian Zoanthids Palythoa caribaeorum and Protopalyhtoa variabilis

Science.gov (United States)

Almeida, Jose Gustavo L.; Maia, Ana Isabel V.; Wilke, Diego V.; Silveira, Edilberto R.; Braz-Filho, Raimundo; La Clair, James J.; Costa-Lotufo, Leticia V.; Pessoa, Otília Deusdenia L.

2012-01-01

The zoanthids Palythoa caribaeorum and Protopalythoa variabilis are among the most abundant marine species along the Brazilian coast. We now report the isolation and structure elucidation of two unprecedented sulfonylated ceramides, palyosulfonoceramide A (1) and palyosulfonoceramide B (2) from specimens collected off Brazil’s northeastern coast. The structures of 1 and 2 were established using a combination of NMR analyses, including: evaluation of 1H, 13C, 1H–1H COSY, 1H–13C HSQC, 1H–13C HMBC, and 1H–15N HMBC NMR spectra, high-resolution mass spectrometry and chemical degradation. In addition, we also isolated the corresponding known ceramides, N-((2S,3R,4E,8E)-1,3-dihydroxyoctadeca-4,8-dien-2-yl)-hexadecanamide (3) and N-((2S,3R,4E)-1,3-dihydroxyoctadeca-4-en-2-yl)-hexadecanamide (4), which provided further support for the assignments of 1 and 2. PMID:23242205

Palyosulfonoceramides A and B: unique sulfonylated ceramides from the Brazilian zoanthids Palythoa caribaeorum and Protopalythoa variabilis.

Science.gov (United States)

Almeida, Jose Gustavo L; Maia, Ana Isabel V; Wilke, Diego V; Silveira, Edilberto R; Braz-Filho, Raimundo; La Clair, James J; Costa-Lotufo, Leticia V; Pessoa, Otília Deusdenia L

2012-12-14

The zoanthids Palythoa caribaeorum and Protopalythoa variabilis are among the most abundant marine species along the Brazilian coast. We now report the isolation and structure elucidation of two unprecedented sulfonylated ceramides, palyosulfonoceramide A (1) and palyosulfonoceramide B (2) from specimens collected off Brazil's northeastern coast. The structures of 1 and 2 were established using a combination of NMR analyses, including: evaluation of 1H, 13C, ¹H--¹H COSY, ¹H--¹³C HSQC, ¹H--¹³C HMBC, and ¹H--¹⁵N HMBC NMR spectra, high-resolution mass spectrometry and chemical degradation. In addition, we also isolated the corresponding known ceramides, N-((2S,3R,4E,8E)-1, 3-dihydroxyoctadeca-4,8-dien-2-yl)-hexadecanamide (3) and N-((2S,3R,4E)-1,3-dihydroxy octadeca-4-en-2-yl)-hexadecanamide (4), which provided further support for the assignments of 1 and 2.

Novel phytoceramides containing fatty acids of diverse chain lengths are better than a single C18-ceramide N-stearoyl phytosphingosine to improve the physiological properties of human stratum corneum

Directory of Open Access Journals (Sweden)

Oh MJ

2017-09-01

Full Text Available Myoung Jin Oh,1 Young Hoon Cho,1 So Yoon Cha,1 Eun Ok Lee,2 Jin Wook Kim,2 Sun Ki Kim,2 Chang Seo Park1 1Department of Chemical and Biochemical Engineering, Dongguk University, Chung-gu, Seoul, 2LCS Biotech, Gwonseon-gu, Suwon-si, Gyeonggi-do, Republic of Korea Abstract: Ceramides in the human stratum corneum (SC are a mixture of diverse N-acylated fatty acids (FAs with different chain lengths. C24 is the major class of FAs of ceramides. However, there are also other classes of ceramides with diverse chain lengths of FAs, and these lengths generally range from C16 to C26. This study aimed to prepare several types of phytoceramide containing diverse chain lengths of N-acylated FAs and compare them with C18-ceramide N-stearoyl phytosphingosine (NP in terms of their effects on the physiological properties of the SC. We chose natural oils, such as horse fat oil, shea butter, sunflower oil, and a mixture of macadamia nut, shea butter, moringa, and meadowfoam seed oil, as sources of FAs and phytosphingosine as a sphingoid backbone to synthesize diverse phytoceramides. Each phytoceramide exhibited a distinctive formation of the lamellar structure, and their FA profiles were similar to those of their respective natural oil. The skin barrier properties, as analyzed in human skin, clearly demonstrated that all the phytoceramides improved the recovery rate of the damaged SC and enhanced hydration better than C18-ceramide NP did. In conclusion, natural oil-derived phytoceramides could represent a novel class of ceramides for cosmetic applications in the development of an ideal skin barrier moisturizer. Keywords: fatty acid, chain length, phytoceramide, skin barrier, natural oil

Effect of C2 ceramide on the inositol phospholipid metabolism (uptake of 32P, 3H-serine and 3H-palmitic acid) and apoptosis-related morphological changes in Tetrahymena

International Nuclear Information System (INIS)

Kovacs, P.; Hegyesi, H.; Koehidai, L.; Nemes, P.; Csaba, G.

1999-01-01

Sphingomyelin metabolites have significant role in the regulation of many life processes of mammalian cells. In the present experiments the influence of phospholipid turnover and apoptosis related morphologic signs by one of this metabolite, C 2 ceramide was studied, and compared to the control, untreated cells, in the unicellular Tetrahymena. The incorporation of phospholipid head group components (serine, phosphorus) show a clear time-dependence; while the incorporation of fatty acid component (palmitic acid) is very fast: no significant alterations were found between 5- and 60-min incubations. C 2 ceramide treatment didn't alter 3 H-palmitic acid incorporation into phospholipids, however 3 H-serine incorporation was mainly inhibited. The amount of total incorporated 32 P was also decreased, on the other hand the lover concentration C 2 ceramide (10 μM) elevated the synthesis of inositol phospholipids. The higher concentration of C 2 ceramide (50 μM) had inhibitory effect on the synthesis of each phospholipids examined. This means that in the presence of the C 2 ceramide the synthesis, recovery and turnover of phospholipids, participating in signal transduction, are altered. However these observations were based the uptake of labeled phospholipid precursors, which gives information on the dynamics of the process, without using lipid mass measurements. C 2 ceramide also caused the rounding off the cells, DNA degradation and nuclear condensation. These latter observations point to morphological signs of apoptosis. The results call attention to the role of sphingomyelin metabolites on signalization of unicellulars, to the cross-talk between the inositol phospholipids and sphingomyelin metabolites, and the role of these molecules in the apoptotic processes at a low evolutionary level. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

Asymptotic mass degeneracies in conformal field theories

International Nuclear Information System (INIS)

Kani, I.; Vafa, C.

1990-01-01

By applying a method of Hardy and Ramanujan to characters of rational conformal field theories, we find an asymptotic expansion for degeneracy of states in the limit of large mass which is exact for strings propagating in more than two uncompactified space-time dimensions. Moreover we explore how the rationality of the conformal theory is reflected in the degeneracy of states. We also consider the one loop partition function for strings, restricted to physical states, for arbitrary (irrational) conformal theories, and obtain an asymptotic expansion for it in the limit that the torus degenerates. This expansion depends only on the spectrum of (physical and unphysical) relevant operators in the theory. We see how rationality is consistent with the smoothness of mass degeneracies as a function of moduli. (orig.)

Analysis of the Involvement of Different Ceramide Variants in the Response to Hydroxyurea Stress in Baker's Yeast.

Directory of Open Access Journals (Sweden)

Po-Wei Chen

Full Text Available Sphingolipids have been identified as important signaling compounds in stress responses. However, it is not always clear how different sphingolipid profiles are achieved in a particular stress situation. Here we propose a detailed mass action model, containing 42 dependent variables and 137 reactions, that offers explanations of the roles of variant ceramides species, which differ in the lengths of their fatty acyl chains and their saturation state, in the response to hydroxyurea stress. The simulations demonstrate that the cells manage to achieve hydroxyurea tolerance through a well-coordinated, differential usage of the variant ceramide species. Moreover, the results suggest that key enzymes have different affinities toward saturated and unsaturated fatty acyl chains, which implies that the saturation state affords the cells with an additional mode of regulation that had not been recognized so far. These conclusions from our computational analysis are yet to be validated experimentally.

Lysosomal ceramide generated by acid sphingomyelinase triggers cytosolic cathepsin B-mediated degradation of X-linked inhibitor of apoptosis protein in natural killer/T lymphoma cell apoptosis

OpenAIRE

Taniguchi, M; Ogiso, H; Takeuchi, T; Kitatani, K; Umehara, H; Okazaki, T

2015-01-01

We previously reported that IL-2 deprivation induced acid sphingomyelinase-mediated (ASM-mediated) ceramide elevation and apoptosis in an NK/T lymphoma cell line KHYG-1. However, the molecular mechanism of ASM?ceramide-mediated apoptosis during IL-2 deprivation is poorly understood. Here, we showed that IL-2 deprivation induces caspase-dependent apoptosis characterized by phosphatidylserine externalization, caspase-8, -9, and -3 cleavage, and degradation of X-linked inhibitor of apoptosis pro...

A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease.

Science.gov (United States)

Toda, Narihiro; Tago, Keiko; Marumoto, Shinji; Takami, Kazuko; Ori, Mayuko; Yamada, Naho; Koyama, Kazuo; Naruto, Shunji; Abe, Kazumi; Yamazaki, Reina; Hara, Takao; Aoyagi, Atsushi; Abe, Yasuyuki; Kaneko, Tsugio; Kogen, Hiroshi

2003-10-01

Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101 nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM).

Homothetic and conformal motions in spacelike slices of solutions of Einstein's equations

International Nuclear Information System (INIS)

Berger, B.K.

1976-01-01

Components of Killing's equation are used to obtain constraints satisfied in a spacelike hypersurface by the intrinsic metric and extrinsic curvature in the presence of a spacetime conformal motion for a solution of Einstein's equations. If the conformal motion is either a homothetic motion or a motion, it is shown that these Killing constraints are preserved by the Einstein evolution equations. It is then shown that the generator of the homothetic motion (homothetic Killing vector) can be constructed if the Killing constraints are satisfied by a set of initial data. It is shown that a homothetic motion in the intrinsic metric is a spacetime homothetic motion if the extrinsic curvature is transformed correctly under the spatial homothetic motion. Further restrictions on a proper conformal motion due to the fact that it is not identically a curvature collineation are obtained. Restrictions on the matter--stress--energy tensor are discussed. Examples are presented

Restricted N-glycan conformational space in the PDB and its implication in glycan structure modeling.

Science.gov (United States)

Jo, Sunhwan; Lee, Hui Sun; Skolnick, Jeffrey; Im, Wonpil

2013-01-01

Understanding glycan structure and dynamics is central to understanding protein-carbohydrate recognition and its role in protein-protein interactions. Given the difficulties in obtaining the glycan's crystal structure in glycoconjugates due to its flexibility and heterogeneity, computational modeling could play an important role in providing glycosylated protein structure models. To address if glycan structures available in the PDB can be used as templates or fragments for glycan modeling, we present a survey of the N-glycan structures of 35 different sequences in the PDB. Our statistical analysis shows that the N-glycan structures found on homologous glycoproteins are significantly conserved compared to the random background, suggesting that N-glycan chains can be confidently modeled with template glycan structures whose parent glycoproteins share sequence similarity. On the other hand, N-glycan structures found on non-homologous glycoproteins do not show significant global structural similarity. Nonetheless, the internal substructures of these N-glycans, particularly, the substructures that are closer to the protein, show significantly similar structures, suggesting that such substructures can be used as fragments in glycan modeling. Increased interactions with protein might be responsible for the restricted conformational space of N-glycan chains. Our results suggest that structure prediction/modeling of N-glycans of glycoconjugates using structure database could be effective and different modeling approaches would be needed depending on the availability of template structures.

Restricted N-glycan conformational space in the PDB and its implication in glycan structure modeling.

Directory of Open Access Journals (Sweden)

Sunhwan Jo

Full Text Available Understanding glycan structure and dynamics is central to understanding protein-carbohydrate recognition and its role in protein-protein interactions. Given the difficulties in obtaining the glycan's crystal structure in glycoconjugates due to its flexibility and heterogeneity, computational modeling could play an important role in providing glycosylated protein structure models. To address if glycan structures available in the PDB can be used as templates or fragments for glycan modeling, we present a survey of the N-glycan structures of 35 different sequences in the PDB. Our statistical analysis shows that the N-glycan structures found on homologous glycoproteins are significantly conserved compared to the random background, suggesting that N-glycan chains can be confidently modeled with template glycan structures whose parent glycoproteins share sequence similarity. On the other hand, N-glycan structures found on non-homologous glycoproteins do not show significant global structural similarity. Nonetheless, the internal substructures of these N-glycans, particularly, the substructures that are closer to the protein, show significantly similar structures, suggesting that such substructures can be used as fragments in glycan modeling. Increased interactions with protein might be responsible for the restricted conformational space of N-glycan chains. Our results suggest that structure prediction/modeling of N-glycans of glycoconjugates using structure database could be effective and different modeling approaches would be needed depending on the availability of template structures.

Distinct roles of two ceramide synthases, CaLag1p and CaLac1p, in the morphogenesis of Candida albicans

DEFF Research Database (Denmark)

Cheon, Seon Ah; Bal, Jyotiranjan; Song, Yunkyoung

2012-01-01

p) and Lac1p (CaLac1p) are functionally distinct. Lack of CaLag1p, but not CaLac1p, caused severe defects in the growth and hyphal morphogenesis of C. albicans. Deletion of CaLAG1 decreased expression of the hypha-specific HWP1 and ECE1 genes. Moreover, overexpression of CaLAG1 induced pseudohyphal...... growth in this organism under non-hypha-inducing conditions, suggesting that CaLag1p is necessary for relaying signals to induce hypha-specific gene expression. Analysis of ceramide and sphingolipid composition revealed that CaLag1p predominantly synthesizes ceramides with C24:0/C26:0 fatty acid moieties...

Fusion and braiding in W-algebra extended conformal theories

International Nuclear Information System (INIS)

Bilal, A.

1990-01-01

We define the chiral conformal blocks of integer-spin extended (W-algebra) conformal theories by the fusion of elementary ones. The braid group representation matrices which realize the exchange algebra are computed. They are shown to coincide with the Boltzmann weights - in a certain limit of the spectral parameter - of the critical face models of Jimbo et al. In the unitary cases, where the extended conformal theories can be realized as cosets g k + g 1 /g k+1 , we relate the braiding matrices of the former to those of the g WZW models. In this article we restrict ourselves to the case corresponding to symmetric tensor representations of A n . (orig.)

Causality Constraints in Conformal Field Theory

CERN Multimedia

CERN. Geneva

2015-01-01

Causality places nontrivial constraints on QFT in Lorentzian signature, for example fixing the signs of certain terms in the low energy Lagrangian. In d-dimensional conformal field theory, we show how such constraints are encoded in crossing symmetry of Euclidean correlators, and derive analogous constraints directly from the conformal bootstrap (analytically). The bootstrap setup is a Lorentzian four-point function corresponding to propagation through a shockwave. Crossing symmetry fixes the signs of certain log terms that appear in the conformal block expansion, which constrains the interactions of low-lying operators. As an application, we use the bootstrap to rederive the well known sign constraint on the (∂φ)4 coupling in effective field theory, from a dual CFT. We also find constraints on theories with higher spin conserved currents. Our analysis is restricted to scalar correlators, but we argue that similar methods should also impose nontrivial constraints on the interactions of spinni...

Causality constraints in conformal field theory

Energy Technology Data Exchange (ETDEWEB)

Hartman, Thomas; Jain, Sachin; Kundu, Sandipan [Department of Physics, Cornell University,Ithaca, New York (United States)

2016-05-17

Causality places nontrivial constraints on QFT in Lorentzian signature, for example fixing the signs of certain terms in the low energy Lagrangian. In d dimensional conformal field theory, we show how such constraints are encoded in crossing symmetry of Euclidean correlators, and derive analogous constraints directly from the conformal bootstrap (analytically). The bootstrap setup is a Lorentzian four-point function corresponding to propagation through a shockwave. Crossing symmetry fixes the signs of certain log terms that appear in the conformal block expansion, which constrains the interactions of low-lying operators. As an application, we use the bootstrap to rederive the well known sign constraint on the (∂ϕ){sup 4} coupling in effective field theory, from a dual CFT. We also find constraints on theories with higher spin conserved currents. Our analysis is restricted to scalar correlators, but we argue that similar methods should also impose nontrivial constraints on the interactions of spinning operators.

Evidence for Fumonisin inhibition of ceramide synthase in humans: validation in follow-up studies in Guatemala

Science.gov (United States)

Fumonisins (FB) are mycotoxins found in corn. FB1 is the most common FB. It is the cause of farm animal diseases and is carcinogenic in rodents. The mode of action is the inhibition of ceramide synthase (CerS). Inhibition of CerS in mice causes a dose-dependent accumulation of sphinganine 1-phosphat...

Conformal field theory on surfaces with boundaries and nondiagonal modular invariants

International Nuclear Information System (INIS)

Bern, Z.; Dunbar, D.C.

1990-01-01

This paper shows that the operator content of a conformal field theory defined on surfaces with boundaries and crosscaps is more restricted when the periodic sector is described by nondiagonal modular invariants than in the case of diagonal modular invariants. By tensoring, the restrictions can be alleviated, leading to a rich structure. Such constrictions are useful, for example, in lower- dimensional open superstring models

Conformal invariance and pion wave functions of nonleading twist

International Nuclear Information System (INIS)

Braun, V.M.; Filyanov, I.E.

1989-01-01

The restrictions are studied for the general structure of pion wave functions of twist 3 and twist 4 imposed by the conformal symmetry and the equations of motion. A systematic expansion of wave functions in the conformal spin is built and the first order corrections to asymptotic formulae are calculated by the QCD sum rule method. In particular, we have found a multiplicatively renormalizable contribution into the two-particle wave function of twist 4 which cannot be expanded in a finite set of Gegenbauer polynomials. 19 refs.; 5 figs

Conformally symmetric traversable wormholes

International Nuclear Information System (INIS)

Boehmer, Christian G.; Harko, Tiberiu; Lobo, Francisco S. N.

2007-01-01

Exact solutions of traversable wormholes are found under the assumption of spherical symmetry and the existence of a nonstatic conformal symmetry, which presents a more systematic approach in searching for exact wormhole solutions. In this work, a wide variety of solutions are deduced by considering choices for the form function, a specific linear equation of state relating the energy density and the pressure anisotropy, and various phantom wormhole geometries are explored. A large class of solutions impose that the spatial distribution of the exotic matter is restricted to the throat neighborhood, with a cutoff of the stress-energy tensor at a finite junction interface, although asymptotically flat exact solutions are also found. Using the 'volume integral quantifier', it is found that the conformally symmetric phantom wormhole geometries may, in principle, be constructed by infinitesimally small amounts of averaged null energy condition violating matter. Considering the tidal acceleration traversability conditions for the phantom wormhole geometry, specific wormhole dimensions and the traversal velocity are also deduced

Conformal field theories near a boundary in general dimensions

International Nuclear Information System (INIS)

McAvity, D.M.

1995-01-01

The implications of restricted conformal invariance under conformal transformations preserving a plane boundary are discussed for general dimensions d. Calculations of the universal function of a conformal invariant ξ which appears in the two-point function of scalar operators in conformally invariant theories with a plane boundary are undertaken to first order in the ε=4-d expansion for the operator φ 2 in φ 4 theory. The form for the associated functions of ξ for the two-point functions for the basic field φ α and the auxiliary field λ in the N→∞ limit of the O(N) non-linear sigma model for any d in the range 2 α φ β and λλ. Using this method the form of the two-point function for the energy-momentum tensor in the conformal O(N) model with a plane boundary is also found. General results for the sum of the contributions of all derivative operators appearing in the operator product expansion, and also in a corresponding boundary operator expansion, to the two-point functions are also derived making essential use of conformal invariance. (orig.)

The Role of Ceramide Synthases in the Pathogenicity of Cryptococcus neoformans.

Science.gov (United States)

Munshi, Mansa A; Gardin, Justin M; Singh, Ashutosh; Luberto, Chiara; Rieger, Robert; Bouklas, Tejas; Fries, Bettina C; Del Poeta, Maurizio

2018-02-06

Cryptococcus neoformans (C. neoformans) is estimated to cause about 220,000 new cases every year in patients with AIDS, despite advances in antifungal treatments. C. neoformans possesses a remarkable ability to disseminate through an immunocompromised host, making treatment difficult. Here, we examine the mechanism of survival of C. neoformans under varying host conditions and find a role for ceramide synthase in C. neoformans virulence. This study also provides a detailed lipidomics resource for the fungal lipid research community in addition to discovering a potential target for antifungal therapy. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Conformal Nets II: Conformal Blocks

Science.gov (United States)

Bartels, Arthur; Douglas, Christopher L.; Henriques, André

2017-08-01

Conformal nets provide a mathematical formalism for conformal field theory. Associated to a conformal net with finite index, we give a construction of the `bundle of conformal blocks', a representation of the mapping class groupoid of closed topological surfaces into the category of finite-dimensional projective Hilbert spaces. We also construct infinite-dimensional spaces of conformal blocks for topological surfaces with smooth boundary. We prove that the conformal blocks satisfy a factorization formula for gluing surfaces along circles, and an analogous formula for gluing surfaces along intervals. We use this interval factorization property to give a new proof of the modularity of the category of representations of a conformal net.

Influence of palmitoyl pentapeptide and Ceramide III B on the droplet size of nanoemulsion

Science.gov (United States)

Sondari, Dewi; Haryono, Agus; Harmami, Sri Budi; Randy, Ahmad

2010-05-01

The influence of the Palmitoyl Pentapeptide (PPp) and Ceramide IIIB (Cm III B) as active ingredients on the droplet size of nano-emulsion was studied using different kinds of oil (avocado oil, sweet almond oil, jojoba oil, mineral oil and squalene). The formation of nano-emulsions were prepared in water mixed non ionic surfactant/oils system using the spontaneous emulsification mechanism. The aqueous solution, which consist of water and Tween® 20 as a hydrophilic surfactant was mixed homogenously. The organic solution, which consist of oil and Span® 80 as a lipophilic surfactant was mixed homogenously in ethanol. Ethanol was used as a water miscible solvent, which can help the formation of nano-emulsion. The oil phase (containing the blend of surfactant Span® 80, ethanol, oil and active ingredient) and the aqueous phase (containing water and Tween® 20) were separately prepared at room temperatures. The oil phase was slowly added into aqueous phase under continuous mechanical agitation (18000 rpm). All samples were subsequently homogenized with Ultra-Turrax for 30 minutes. The characterizations of nano-emulsion were carried out using photo-microscope and particle size analyzer. Addition of active ingredients on the formation of nano-emulsion gave smallest droplet size compared without active ingredients addition on the formation of nano-emulsion. Squalene oil with Palmitoyl Pentapeptide (PPm) and Ceramide IIIB (Cm IIIB) gave smallest droplet size (184.0 nm) compared without Palmitoyl Pentapeptide and Ceramide IIIB (214.9 nm), however the droplets size of the emulsion prepared by the other oils still in the range of nano-emulsion (below 500 nm). The stability of nano-emulsion was observed using two methods. In one method, the stability of nano-emulsion was observed for three months at temperature of 5°C and 50°C, while in the other method, the stability nano-emulsion was observed by centrifuged at 12000 rpm for 30 minutes. Nanoemulsion with active ingredient

Modest phenotypic improvements in ASA-deficient mice with only one UDP-galactose:ceramide-galactosyltransferase gene

OpenAIRE

Franken, S; Wittke, D; Mansson, JE; D'Hooge, R; De Deyn, PP; Lüllmann-Rauch, R; Matzner, U; Gieselmann, V

2006-01-01

Summary Background Arylsulfatase A (ASA)-deficient mice are a model for the lysosomal storage disorder metachromatic leukodystrophy. This lipidosis is characterised by the lysosomal accumulation of the sphingolipid sulfatide. Storage of this lipid is associated with progressive demyelination. We have mated ASA-deficient mice with mice heterozygous for a non-functional allele of UDP-galactose:ceramide-galactosyltransferase (CGT). This deficiency is known to lead to a decreased synthesis of gal...

Rationalization of reduced penetration of drugs through ceramide gel phase membrane.

Science.gov (United States)

Paloncýová, Markéta; DeVane, Russell H; Murch, Bruce P; Berka, Karel; Otyepka, Michal

2014-11-25

Since computing resources have advanced enough to allow routine molecular simulation studies of drug molecules interacting with biologically relevant membranes, a considerable amount of work has been carried out with fluid phospholipid systems. However, there is very little work in the literature on drug interactions with gel phase lipids. This poses a significant limitation for understanding permeation through the stratum corneum where the primary pathway is expected to be through a highly ordered lipid matrix. To address this point, we analyzed the interactions of p-aminobenzoic acid (PABA) and its ethyl (benzocaine) and butyl (butamben) esters with two membrane bilayers, which differ in their fluidity at ambient conditions. We considered a dioleoylphosphatidylcholine (DOPC) bilayer in a fluid state and a ceramide 2 (CER2, ceramide NS) bilayer in a gel phase. We carried out unbiased (100 ns long) and biased z-constraint molecular dynamics simulations and calculated the free energy profiles of all molecules along the bilayer normal. The free energy profiles converged significantly slower for the gel phase. While the compounds have comparable affinities for both membranes, they exhibit penetration barriers almost 3 times higher in the gel phase CER2 bilayer. This elevated barrier and slower diffusion in the CER2 bilayer, which are caused by the high ordering of CER2 lipid chains, explain the low permeability of the gel phase membranes. We also compared the free energy profiles from MD simulations with those obtained from COSMOmic. This method provided the same trends in behavior for the guest molecules in both bilayers; however, the penetration barriers calculated by COSMOmic did not differ between membranes. In conclusion, we show how membrane fluid properties affect the interaction of drug-like molecules with membranes.

A tendem mass spectrometric approach for determining the structure of molecular species of ceramide in the marine sponge, Haliclona cribricutis

Digital Repository Service at National Institute of Oceanography (India)

Tilvi, S.; Majik, M.; Naik, C.G.

, “Squid nerve Sphingomyelin containing an unusual sphingoid base”, J. Lipid Res. 41, 1118 (2000). 24. J.D. Watts, M. Gu, A.J. Polverino, S.D. Patterson and R. Aebersold, “Fas-induced apoptosis of T cells occurs independently of ceramide generation...

Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines

Energy Technology Data Exchange (ETDEWEB)

Vethakanraj, Helen Shiphrah; Babu, Thabraz Ahmed; Sudarsanan, Ganesh Babu; Duraisamy, Prabhu Kumar; Ashok Kumar, Sekar, E-mail: sekarashok@gmail.com

2015-08-28

The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER{sup +} and ER{sup −} breast cancer cell lines. - Highlights: • Acid Ceramidase inhibitor, Ceranib 2 induced apoptosis in Breast cancer cell lines (MCF 7 and MDA MB 231 cell lines). • Apoptosis is mediated by DNA fragmentation and cell cycle arrest. • Ceranib 2 upregulated the expression of pro-apoptotic genes and down regulated anti-apoptotic gene expression. • More potent compared to the standard drug Tamoxifen.

Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines

International Nuclear Information System (INIS)

Vethakanraj, Helen Shiphrah; Babu, Thabraz Ahmed; Sudarsanan, Ganesh Babu; Duraisamy, Prabhu Kumar; Ashok Kumar, Sekar

2015-01-01

The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER + and ER − breast cancer cell lines. - Highlights: • Acid Ceramidase inhibitor, Ceranib 2 induced apoptosis in Breast cancer cell lines (MCF 7 and MDA MB 231 cell lines). • Apoptosis is mediated by DNA fragmentation and cell cycle arrest. • Ceranib 2 upregulated the expression of pro-apoptotic genes and down regulated anti-apoptotic gene expression. • More potent compared to the standard drug Tamoxifen

C2-Ceramide Induces Cell Death and Protective Autophagy in Head and Neck Squamous Cell Carcinoma Cells

Directory of Open Access Journals (Sweden)

Wenyuan Zhu

2014-02-01

Full Text Available Ceramides are second messengers involved in several intracellular processes in cancer cells, amongst others. The aim of this study was to evaluate the anti-tumor efficacy of C2-ceramide (C2-Cer; N-acetyl-D-sphingosine by investigating cell death and autophagy in head and neck squamous cell carcinoma (HNSCC cells. C2-Cer showed concentration-dependent cytotoxicity in HN4 and HN30 cell lines. It simultaneously induced caspase-3-independent apoptosis and programmed necrosis. C2-Cer markedly increased the expression level of microtubule-associated protein 1 light chain 3B (LC3B type II associated with protective autophagy. An autophagy inhibitor enhanced C2-Cer-mediated cytotoxicity, while a programmed-necrosis inhibitor produced the opposite effect. Furthermore, C2-Cer up-regulated the phosphorylation of extracellular signal-regulated kinase 1/2, but down-regulated its downstream substrate phospho-mammalian target of rapamycin (p-mTOR during the autophagy process. These results suggested that C2-Cer exerts anti-tumor effects by inducing programmed apoptosis and necrosis in HNSCC, and these cytotoxic effects are enhanced by an autophagy inhibitor.

Conformal coupling of gravitational wave field to curvature

International Nuclear Information System (INIS)

Grishchuk, L.P.; Yudin, V.

1980-01-01

Conformal properties of the equations for weak gravitational waves in a curved space--time are investigated. The basic equations are derived in the linear approximation from Einstein's equations. They represent, in fact, the equations for the second-rank tensor field h/sub alphabeta/, restricted by the auxiliary conditions h/sub α//sup β//sub ;/α =0, hequivalentγ/sub alphabeta/h/sup alphabeta/=0, and embedded into the background space--time with the metric tensor γ/sub alphabeta/. It is shown that the equations for h/sub alphabeta/ are not conformally invariant under the transformations gamma-circumflex/sub alphabeta/ =e/sup 2sigma/γ/sub alphabeta/ and h/sub alphabeta/ =e/sup sigma/h/sub alphabeta/, except for those metric rescalings which transform the Ricci scalar R of the original background space--time into e/sup -2sigma/R, where R is the Ricci scalar of the conformally related background space--time. The general form of the equations for h/sub alphabeta/ which are conformally invariant have been deduced. It is shown that these equations cannot be derived in the linear approximation from any tensor equations which generalize the Einstein equations

Braided structure in 4-dimensional conformal quantum field theory

International Nuclear Information System (INIS)

Schroer, Bert

2001-03-01

Higher dimensional conformal QFT possesses an intersting braided structure which different from the d=1+1 models, is restricted to the timelike region and therefore easily escapes euclidean action methods. It lies behind the spectrum of anamalous which may be viewed as a kind of substitute for a missing particle interpretation in the presence of interactions. (author)

Plasma glucosylceramide and ceramide in type 1 Gaucher disease patients: correlations with disease severity and response to therapeutic intervention

NARCIS (Netherlands)

Groener, J. E. M.; Poorthuis, B. J. H. M.; Kuiper, S.; Hollak, C. E. M.; Aerts, J. M. F. G.

2008-01-01

The concentrations of plasma glucosylceramide (GlcCer) and ceramide (Cer) were determined in a cohort of type 1 Gaucher disease patients. In plasma of untreated patients, GlcCer concentrations were on average 3-fold increased (median Gaucher: 17.5 nmol/ml, range: 6.5-45.5 (n=27); median control: 5.9

Palyosulfonoceramides A and B: Unique Sulfonylated Ceramides from the Brazilian Zoanthids Palythoa caribaeorum and Protopalyhtoa variabilis

OpenAIRE

Almeida, Jose Gustavo L.; Maia, Ana Isabel V.; Wilke, Diego V.; Silveira, Edilberto R.; Braz-Filho, Raimundo; La Clair, James J.; Costa-Lotufo, Leticia V.; Pessoa, Otília Deusdenia L.

2012-01-01

The zoanthids Palythoa caribaeorum and Protopalythoa variabilis are among the most abundant marine species along the Brazilian coast. We now report the isolation and structure elucidation of two unprecedented sulfonylated ceramides, palyosulfonoceramide A (1) and palyosulfonoceramide B (2) from specimens collected off Brazil’s northeastern coast. The structures of 1 and 2 were established using a combination of NMR analyses, including: evaluation of 1H, 13C, 1H–1H COSY, 1H...

Water Orientation at Ceramide/Water Interfaces Studied by Heterodyne-Detected Vibrational Sum Frequency Generation Spectroscopy and Molecular Dynamics Simulation

KAUST Repository

Adhikari, Aniruddha

2016-10-10

Lipid/water interaction is essential for many biological processes. The water structure at the nonionic lipid interface remains little known, and there is no scope of a priori prediction of water orientation at nonionic interfaces, either. Here, we report our study combining advanced nonlinear spectroscopy and molecular dynamics simulation on the water orientation at the ceramide/water interface. We measured χ spectrum in the OH stretch region of ceramide/isotopically diluted water interface using heterodyne-detected vibrational sum-frequency generation spectroscopy and found that the interfacial water prefers an overall hydrogen-up orientation. Molecular dynamics simulation indicates that this preferred hydrogen-up orientation of water is determined by a delicate balance between hydrogen-up and hydrogen-down orientation induced by lipid-water and intralipid hydrogen bonds. This mechanism also suggests that water orientation at neutral lipid interfaces depends highly on the chemical structure of the lipid headgroup, in contrast to the charged lipid interfaces where the net water orientation is determined solely by the charge of the lipid headgroup.

Conformal field theory in conformal space

International Nuclear Information System (INIS)

Preitschopf, C.R.; Vasiliev, M.A.

1999-01-01

We present a new framework for a Lagrangian description of conformal field theories in various dimensions based on a local version of d + 2-dimensional conformal space. The results include a true gauge theory of conformal gravity in d = (1, 3) and any standard matter coupled to it. An important feature is the automatic derivation of the conformal gravity constraints, which are necessary for the analysis of the matter systems

Local Order in the Unfolded State: Conformational Biases and Nearest Neighbor Interactions

Directory of Open Access Journals (Sweden)

Siobhan Toal

2014-07-01

Full Text Available The discovery of Intrinsically Disordered Proteins, which contain significant levels of disorder yet perform complex biologically functions, as well as unwanted aggregation, has motivated numerous experimental and theoretical studies aimed at describing residue-level conformational ensembles. Multiple lines of evidence gathered over the last 15 years strongly suggest that amino acids residues display unique and restricted conformational preferences in the unfolded state of peptides and proteins, contrary to one of the basic assumptions of the canonical random coil model. To fully understand residue level order/disorder, however, one has to gain a quantitative, experimentally based picture of conformational distributions and to determine the physical basis underlying residue-level conformational biases. Here, we review the experimental, computational and bioinformatic evidence for conformational preferences of amino acid residues in (mostly short peptides that can be utilized as suitable model systems for unfolded states of peptides and proteins. In this context particular attention is paid to the alleged high polyproline II preference of alanine. We discuss how these conformational propensities may be modulated by peptide solvent interactions and so called nearest-neighbor interactions. The relevance of conformational propensities for the protein folding problem and the understanding of IDPs is briefly discussed.

Co-encapsulation of paclitaxel and C6 ceramide in tributyrin-containing nanocarriers improve co-localization in the skin and potentiate cytotoxic effects in 2D and 3D models.

Science.gov (United States)

Carvalho, Vanessa F M; Migotto, Amanda; Giacone, Daniela V; de Lemos, Débora P; Zanoni, Thalita B; Maria-Engler, Silvya S; Costa-Lotufo, Leticia V; Lopes, Luciana B

2017-11-15

Considering that tumor development is generally multifactorial, therapy with a combination of agents capable of potentiating cytotoxic effects is promising. In this study, we co-encapsulated C6 ceramide (0.35%) and paclitaxel (0.50%) in micro and nanoemulsions containing tributyrin (a butyric acid pro-drug included for potentiation of cytotoxicity), and compared their ability to co-localize the drugs in viable skin layers. The nanoemulsion delivered 2- and 2.4-fold more paclitaxel into viable skin layers of porcine skin in vitro at 4 and 8h post-application than the microemulsion, and 1.9-fold more C6 ceramide at 8h. The drugs were co-localized mainly in the epidermis, suggesting the nanoemulsion ability for a targeted delivery. Based on this result, the nanoemulsion was selected for evaluation of the nanocarrier-mediated cytotoxicity against cells in culture (2D model) and histological changes in a 3D melanoma model. Encapsulation of the drugs individually decreased the concentration necessary to reduce melanoma cells viability to 50% (EC 50 ) by approximately 4- (paclitaxel) and 13-fold (ceramide), demonstrating an improved nanoemulsion-mediated drug delivery. Co-encapsulation of paclitaxel and ceramide further decreased EC 50 by 2.5-4.5-fold, and calculation of the combination index indicated a synergistic effect. Nanoemulsion topical administration on 3D bioengineered melanoma models for 48h promoted marked epidermis destruction, with only few cells remaining in this layer. This result demonstrates the efficacy of the nanoemulsion, but also suggests non-selective cytotoxic effects, which highlights the importance of localizing the drugs within cutaneous layers where the lesions develop to avoid adverse effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Ceramides and cytotoxic constituents from Ficus glumosa Del. (Moraceae)

Energy Technology Data Exchange (ETDEWEB)

Nana, Frederic; Sandjo, Louis Pergaud; Keumedjio, Felix; Ambassa, Pantaleon [Department of Organic Chemistry, University of Yaounde I, Yaounde (Cameroon); Malik, Rizwana [H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi (Pakistan); Kuete, Victor; Choudhary, Muhammad Iqbal [Department of Biochemistry, University of Dschang, Dschang (Cameroon); Rincheval, Vincent [Laboratoire de Genetique et Biologie Cellulaire Batiment Fermat, University of Versailles, St Quentin-en-Yvelines (France); Ngadjui, Bonaventure Tchaleu [Department of Pharmaceutical Sciences and Traditional Pharmacopeia, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Yaounde (Cameroon)

2012-03-15

Chemical investigation of the stem bark of Ficus glumosa (Moraceae) yielded two new ceramides (2R,7E)-2-hydroxy-N-[(2S,3S,4R)-1,3,4-trihydroxyhexadecan-2-yl] hexacos-7-enamide and (2R)-N-{l_brace}(2S,3S,4R,9Z)-1-O-[({beta}-D-glucopyranosyl]-3,4-dihydroxyheptadec -9-en-2-yl{r_brace}-2-hydroxypentacosanamide together with twenty one known compounds. The structures were established using NMR data, mass spectrometry, chemical transformation and by comparison with the reported data. Twenty one compounds were further tested against the prostate cancer PC-3 cell line and six of them revealed cytotoxic effect. Dongnoside E was the most active compound with an IC{sub 50} 0.75 {mu}mol L{sup -1}against the cancer cells line PC-3 while the reference drug doxorubicin displayed 0.91 {mu}mol L{sup -1}. This compound also proved to inhibit the cell growth of the fibrosarcoma cancer HT1080 (IC{sub 50} 0.7 {mu}mol L{sup -1}). (author)

Imaging mass spectrometry visualizes ceramides and the pathogenesis of dorfman-chanarin syndrome due to ceramide metabolic abnormality in the skin.

Directory of Open Access Journals (Sweden)

Naoko Goto-Inoue

Full Text Available Imaging mass spectrometry (IMS is a useful cutting edge technology used to investigate the distribution of biomolecules such as drugs and metabolites, as well as to identify molecular species in tissues and cells without labeling. To protect against excess water loss that is essential for survival in a terrestrial environment, mammalian skin possesses a competent permeability barrier in the stratum corneum (SC, the outermost layer of the epidermis. The key lipids constituting this barrier in the SC are the ceramides (Cers comprising of a heterogeneous molecular species. Alterations in Cer composition have been reported in several skin diseases that display abnormalities in the epidermal permeability barrier function. Not only the amounts of different Cers, but also their localizations are critical for the barrier function. We have employed our new imaging system, capable of high-lateral-resolution IMS with an atmospheric-pressure ionization source, to directly visualize the distribution of Cers. Moreover, we show an ichthyotic disease pathogenesis due to abnormal Cer metabolism in Dorfman-Chanarin syndrome, a neutral lipid storage disorder with ichthyosis in human skin, demonstrating that IMS is a novel diagnostic approach for assessing lipid abnormalities in clinical setting, as well as for investigating physiological roles of lipids in cells/tissues.

Platelet activating factor-induced ceramide micro-domains drive endothelial NOS activation and contribute to barrier dysfunction.

Directory of Open Access Journals (Sweden)

Sanda Predescu

Full Text Available The spatial and functional relationship between platelet activating factor-receptor (PAF-R and nitric oxide synthase (eNOS in the lateral plane of the endothelial plasma membrane is poorly characterized. In this study, we used intact mouse pulmonary endothelial cells (ECs as well as endothelial plasma membrane patches and subcellular fractions to define a new microdomain of plasmalemma proper where the two proteins colocalize and to demonstrate how PAF-mediated nitric oxide (NO production fine-tunes ECs function as gatekeepers of vascular permeability. Using fluorescence microscopy and immunogold labeling electron microscopy (EM on membrane patches we demonstrate that PAF-R is organized as clusters and colocalizes with a subcellular pool of eNOS, outside recognizable vesicular profiles. Moreover, PAF-induced acid sphingomyelinase activation generates a ceramide-based microdomain on the external leaflet of plasma membrane, inside of which a signalosome containing eNOS shapes PAF-stimulated NO production. Real-time measurements of NO after PAF-R ligation indicated a rapid (5 to 15 min increase in NO production followed by a > 45 min period of reduction to basal levels. Moreover, at the level of this new microdomain, PAF induces a dynamic phosphorylation/dephosphorylation of Ser, Thr and Tyr residues of eNOS that correlates with NO production. Altogether, our findings establish the existence of a functional partnership PAF-R/eNOS on EC plasma membrane, at the level of PAF-induced ceramide plasma membrane microdomains, outside recognized vesicular profiles.

The Chevreton tensor and Einstein-Maxwell spacetimes conformal to Einstein spaces

International Nuclear Information System (INIS)

Bergqvist, Goeran; Eriksson, Ingemar

2007-01-01

In this paper, we characterize the source-free Einstein-Maxwell spacetimes which have a trace-free Chevreton tensor. We show that this is equivalent to the Chevreton tensor being of pure radiation type and that it restricts the spacetimes to Petrov type N or O. We prove that the trace of the Chevreton tensor is related to the Bach tensor and use this to find all Einstein-Maxwell spacetimes with a zero cosmological constant that have a vanishing Bach tensor. Among these spacetimes we then look for those which are conformal to Einstein spaces. We find that the electromagnetic field and the Weyl tensor must be aligned, and in the case that the electromagnetic field is null, the spacetime must be conformally Ricci-flat and all such solutions are known. In the non-null case, since the general solution is not known on a closed form, we settle by giving the integrability conditions in the general case, but we do give new explicit examples of Einstein-Maxwell spacetimes that are conformal to Einstein spaces, and we also find examples where the vanishing of the Bach tensor does not imply that the spacetime is conformal to a C-space. The non-aligned Einstein-Maxwell spacetimes with vanishing Bach tensor are conformally C-spaces, but none of them are conformal to Einstein spaces

The effect of synthetic ceramide analogues on gastritis and esophagitis in rats.

Science.gov (United States)

Kim, Sung Hyo; Um, Seung In; Nam, Yoonjin; Park, Sun Young; Dong, Je Hyun; Ko, Sung Kwon; Sohn, Uy Dong; Lee, Sang Joon

2016-09-01

The effects of ceremide analogues on esophagitis and gastritis in rats were examined. Gastritis induced by indomethacin was significantly reduced after CY3325 and CY3723 treatment, whereas other analogues had no effect. The amount of malondialdehyde in gastritis was significantly reduced by CY3325 or CY 3723. CY3325 or CY 3723 decreased the glutathione levels in gastritis. The myeloperoxidase level in gastritis is increased, and its increment was decreased by CY3325 and CY3723. In reflux esophagitis, the ulceration was decreased by CY3325, CY3723. The gastric volume and acid output are reduced, whereas the pH value is increased by CY3325 or CY3723 after esophagitis. These results suggest that ceramide analogues, CY3325 and CY3723, can prevent the development of gastritis and reflux esophagitis in rats.

Quantifying polypeptide conformational space: sensitivity to conformation and ensemble definition.

Science.gov (United States)

Sullivan, David C; Lim, Carmay

2006-08-24

Quantifying the density of conformations over phase space (the conformational distribution) is needed to model important macromolecular processes such as protein folding. In this work, we quantify the conformational distribution for a simple polypeptide (N-mer polyalanine) using the cumulative distribution function (CDF), which gives the probability that two randomly selected conformations are separated by less than a "conformational" distance and whose inverse gives conformation counts as a function of conformational radius. An important finding is that the conformation counts obtained by the CDF inverse depend critically on the assignment of a conformation's distance span and the ensemble (e.g., unfolded state model): varying ensemble and conformation definition (1 --> 2 A) varies the CDF-based conformation counts for Ala(50) from 10(11) to 10(69). In particular, relatively short molecular dynamics (MD) relaxation of Ala(50)'s random-walk ensemble reduces the number of conformers from 10(55) to 10(14) (using a 1 A root-mean-square-deviation radius conformation definition) pointing to potential disconnections in comparing the results from simplified models of unfolded proteins with those from all-atom MD simulations. Explicit waters are found to roughen the landscape considerably. Under some common conformation definitions, the results herein provide (i) an upper limit to the number of accessible conformations that compose unfolded states of proteins, (ii) the optimal clustering radius/conformation radius for counting conformations for a given energy and solvent model, (iii) a means of comparing various studies, and (iv) an assessment of the applicability of random search in protein folding.

77 FR 11384 - Removal of Oman from the Restricted Destinations List

Science.gov (United States)

2012-02-27

... NUCLEAR REGULATORY COMMISSION 10 CFR Part 110 [NRC-2011-0264] RIN 3150-AJ06 Removal of Oman from... regulations by removing Oman from the list of restricted destinations. This amendment is necessary to conform... regard to U.S. Government law and policy on Oman. The Executive Branch recommended, in light of current...

Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity.

Directory of Open Access Journals (Sweden)

Laura M J Ylinen

2010-08-01

Full Text Available TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5alpha but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations.

Comparison of the Simple Patient-Centric Atopic Dermatitis Scoring System PEST with SCORAD in Young Children Using a Ceramide Dominant Therapeutic Moisturizer.

Science.gov (United States)

Koh, Mark Jean-Ann; Giam, Yoke Chin; Liew, Hui Min; Foong, Alice Yee-Wah; Chong, Jin Ho; Wong, Sharon Mun Yee; Tang, Mark Boon Yang; Ho, Madeline Sheun Ling; Tan, Lucinda Siyun; Mason, James M; Cork, Michael J

2017-09-01

Patient eczema severity time (PEST) is a new atopic dermatitis (AD) scoring system based on patients' own perception of their disease. Conventional scales such as SCORing of atopic dermatitis (SCORAD) reflect the clinician's observations during the clinic visit. Instead, the PEST score captures eczema severity, relapse and recovery as experienced by the patient or caregiver on a daily basis, promoting patient engagement, compliance with treatment and improved outcomes. This study aims to determine the correlation between carer-assessed PEST and clinician-assessed SCORAD in paediatric AD patients after 12 weeks of treatment using a ceramide-dominant therapeutic moisturizer. Prospective, open-label, observational, multi-centre study in which children with AD aged 6 months to 6 years were treated with a ceramide dominant therapeutic moisturizer twice daily for 12 weeks; 58 children with mild-to-moderate AD were included. Correlation between the 7-day averaged PEST and SCORAD scores for assessment of AD severity was measured within a general linear model. PEST and SCORAD were compared in week 4 and week 12. At week 12, a moderate correlation was found between the SCORAD and PEST scores (r = 0.51). The mean change in SCORAD and PEST scores from baseline to week 12 was -11.46 [95% confidence interval (CI) -14.99 to -7.92, p PEST demonstrated greater responsiveness to change (33.3% of scale) compared to SCORAD (13.8% of scale). The PEST score correlates well with the SCORAD score and may have improved sensitivity when detecting changes in the severity of AD. The ceramide-dominant therapeutic moisturizer used was safe and effective in the management of AD in young children. Hyphens Pharma Pte Ltd. clinicaltrials.gov identifier, NCT02073591.

Workers’ Conformism

Directory of Open Access Journals (Sweden)

Nikolay Ivantchev

2013-10-01

Full Text Available Conformism was studied among 46 workers with different kinds of occupations by means of two modified scales measuring conformity by Santor, Messervey, and Kusumakar (2000 – scale for perceived peer pressure and scale for conformism in antisocial situations. The hypothesis of the study that workers’ conformism is expressed in a medium degree was confirmed partly. More than a half of the workers conform in a medium degree for taking risk, and for the use of alcohol and drugs, and for sexual relationships. More than a half of the respondents conform in a small degree for anti-social activities (like a theft. The workers were more inclined to conform for risk taking (10.9%, then – for the use of alcohol, drugs and for sexual relationships (8.7%, and in the lowest degree – for anti-social activities (6.5%. The workers who were inclined for the use of alcohol and drugs tended also to conform for anti-social activities.

Effects of Topical Corticosteroid and Tacrolimus on Ceramides and Irritancy to Sodium Lauryl Sulphate in Healthy Skin

DEFF Research Database (Denmark)

Jungersted, Jakob Mutanu; Høgh, Julie Kaae; Hellgren, Lars

2011-01-01

twice daily for one week with betamethasone, tacrolimus, emollient, or left untreated, respectively. After one week each area was challenged with a 24 h sodium lauryl sulphate patch test. The lipids were collected using the cyanoacrylate method and evaluated by high performance thin layer chromatography...... found between treatment regimes. Pretreatment with betamethasone (p = 0.01) or with tacrolimus (p = 0.001) causes a decreased inflammatory response to sodium lauryl sulphate compared with emollient. In conclusion, treatment with betamethasone and tacrolimus has a positive effect on the ceramide...

Effect of Ceramide Tail Length on the Structure of Model Stratum Corneum Lipid Bilayers.

Science.gov (United States)

Moore, Timothy C; Hartkamp, Remco; Iacovella, Christopher R; Bunge, Annette L; McCabe, Clare

2018-01-09

Lipid bilayers composed of non-hydroxy sphingosine ceramide (CER NS), cholesterol (CHOL), and free fatty acids (FFAs), which are components of the human skin barrier, are studied via molecular dynamics simulations. Since mixtures of these lipids exist in dense gel phases with little molecular mobility at physiological conditions, care must be taken to ensure that the simulations become decorrelated from the initial conditions. Thus, we propose and validate an equilibration protocol based on simulated tempering, in which the simulation takes a random walk through temperature space, allowing the system to break out of metastable configurations and hence become decorrelated from its initial configuration. After validating the equilibration protocol, which we refer to as random-walk molecular dynamics, the effects of the lipid composition and ceramide tail length on bilayer properties are studied. Systems containing pure CER NS, CER NS + CHOL, and CER NS + CHOL + FFA, with the CER NS fatty acid tail length varied within each CER NS-CHOL-FFA composition, are simulated. The bilayer thickness is found to depend on the structure of the center of the bilayer, which arises as a result of the tail-length asymmetry between the lipids studied. The hydrogen bonding between the lipid headgroups and with water is found to change with the overall lipid composition, but is mostly independent of the CER fatty acid tail length. Subtle differences in the lateral packing of the lipid tails are also found as a function of CER tail length. Overall, these results provide insight into the experimentally observed trend of altered barrier properties in skin systems where there are more CERs with shorter tails present. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Membrane Restructuring Events during the Enzymatic Generation of Ceramides with Very Long-Chain Polyunsaturated Fatty Acids.

Science.gov (United States)

Peñalva, Daniel A; Antollini, Silvia S; Ambroggio, Ernesto E; Aveldaño, Marta I; Fanani, María L

2018-04-10

In rat sperm heads, sphingomyelin (SM) species that contain very long-chain polyunsaturated fatty acid (V-SM) become ceramides (V-Cer) after inducing in vitro the acrosomal reaction. The reason for such a specific location of this conversion, catalyzed by a sphingomyelinase (SMase), has received little investigation so far. Here, the effects of SMase were compared in unilamellar vesicles (large unilamellar vesicles (LUVs), giant unilamellar vesicles (GUVs)) containing phosphatidylcholine, and either V-SM or a palmitate-rich SM (P-SM). In uniformly sized LUVs at 37 °C, more V-Cer was generated and more rapidly than P-Cer. Nephelometry and dynamic light scattering showed that LUVs tended to form large lipid particles more intensely, and Förster resonance energy transfer (FRET) increases suggested that lateral lipid mixing was more marked when V-Cer rather than P-Cer was produced. As reported by 6-dodecanoyl-2-dimethyl-aminopnaphthalene (Laurdan) and 1,6-diphenyl-1,3,5,-hexatriene (DPH), the production of V-Cer resulted in higher and faster restriction in lipid mobility than that of P-Cer, implying a stronger increase in membrane dehydration and microviscosity. Moreover, DPH anisotropy suggested a higher solubility of V-Cer than that of P-Cer in the liquid-disordered phase. At room temperature, liquid-condensed lateral domains appeared in P-SM- but not in V-SM-containing GUVs. The former maintained their size while losing their contents gradually during SMase action, whereas the latter became permeable earlier and reduced their size in few minutes until suddenly collapsing. The fast and potent generation of V-Cer may contribute to the membrane restructuring events that occur on the acrosome-reacted sperm head.

Conformation radiotherapy and conformal radiotherapy

International Nuclear Information System (INIS)

Morita, Kozo

1999-01-01

In order to coincide the high dose region to the target volume, the 'Conformation Radiotherapy Technique' using the multileaf collimator and the device for 'hollow-out technique' was developed by Prof. S. Takahashi in 1960. This technique can be classified a type of 2D-dynamic conformal RT techniques. By the clinical application of this technique, the late complications of the lens, the intestine and the urinary bladder after radiotherapy for the maxillary cancer and the cervical cancer decreased. Since 1980's the exact position and shape of the tumor and the surrounding normal tissues can be easily obtained by the tremendous development of the CT/MRI imaging technique. As a result, various kinds of new conformal techniques such as the 3D-CRT, the dose intensity modulation, the tomotherapy have been developed since the beginning of 1990'. Several 'dose escalation study with 2D-/3D conformal RT' is now under way to improve the treatment results. (author)

Gromwell (Lithospermum erythrorhizon) Supplementation Enhances Epidermal Levels of Ceramides, Glucosylceramides, β-Glucocerebrosidase, and Acidic Sphingomyelinase in NC/Nga Mice

OpenAIRE

Kim, Jungmin; Cho, Yunhi

2013-01-01

We have previously reported that dietary gromwell (Lithospermum erythrorhizon; LE) prevents the development of atopic dermatitis (AD) with increased epidermal levels of total ceramide (Cer), the major lipid maintaining epidermal barrier. In this study, we investigated whether the increased level of total Cer induced by dietary LE would be related to the altered metabolism of glucosylceramide (GlcCer) and sphingomyelin (SM), two major precursor lipids in Cer generation. NC/Nga mice, an animal ...

DNA-tension dependence of restriction enzyme activity reveals mechanochemical properties of the reaction pathway

NARCIS (Netherlands)

van den Broek, B.; Noom, M.C.; Wuite, G.J.L.

2005-01-01

Type II restriction endonucleases protect bacteria against phage infections by cleaving recognition sites on foreign double-stranded DNA (dsDNA) with extraordinary specificity. This capability arises primarily from large conformational changes in enzyme and/or DNA upon target sequence recognition.

Exercise and training effects on ceramide metabolism in human skeletal muscle

DEFF Research Database (Denmark)

Helge, Jørn Wulff; Dobrzyn, Agnieszka; Saltin, Bengt

2004-01-01

in skeletal muscle in untrained and trained subjects before and after prolonged exercise. Healthy male subjects were recruited into an untrained (n = 8, VO2,max 3.8 +/- 0.2 1 min1) and a trained (n = 8, Vo2,max 5.1 +/- 0.1 1 min2) group. Before and after a 3-h exercise bout (58 +/- 1% VO2,max) a muscle biopsy...... was measured using N-[14CH3]-sphingomyelin as a substrate. Prior to exercise, the muscle total ceramide fatty acid content in both groups was similar (201 +/- 18 and 197 +/- 9 nmol g(-1) in the untrained and trained group, respectively) and after exercise a 25% increase in the content was observed in each...... group. At rest, the muscle total sphingomyelin fatty acid content was higher in untrained than in trained subjects (456 +/- 10, 407 +/- 7 nmol g(-1), respectively; P trained subjects. The muscle neutral, Mg...

Abscinazole-F1, a conformationally restricted analogue of the plant growth retardant uniconazole and an inhibitor of ABA 8'-hydroxylase CYP707A with no growth-retardant effect.

Science.gov (United States)

Todoroki, Yasushi; Kobayashi, Kyotaro; Shirakura, Minaho; Aoyama, Hikaru; Takatori, Kokichi; Nimitkeatkai, Hataitip; Jin, Mei-Hong; Hiramatsu, Saori; Ueno, Kotomi; Kondo, Satoru; Mizutani, Masaharu; Hirai, Nobuhiro

2009-09-15

To develop a specific inhibitor of abscisic acid (ABA) 8'-hydroxylase, a key enzyme in the catabolism of ABA, a plant hormone involved in stress tolerance, seed dormancy, and other various physiological events, we designed and synthesized conformationally restricted analogues of uniconazole (UNI), a well-known plant growth retardant, which inhibits a biosynthetic enzyme (ent-kaurene oxidase) of gibberellin as well as ABA 8'-hydroxylase. Although most of these analogues were less effective than UNI in inhibition of ABA 8'-hydroxylase and rice seedling growth, we found that a lactol-bridged analogue with an imidazole is a potent inhibitor of ABA 8'-hydroxylase but not of plant growth. This compound, abscinazole-F1, induced drought tolerance in apple seedlings upon spray treatment with a 10 microM solution.

Replacement between conformity and counter-conformity in consumption decisions.

Science.gov (United States)

Chou, Ting-Jui; Chang, En-Chung; Dai, Qi; Wong, Veronica

2013-02-01

This study assessed, in a Chinese context, how self-esteem interacts with perceived similarity and uniqueness to yield cognitive dissonance, and whether the dissonance leads to self-reported conformity or counter-conformity behavior. Participants were 408 respondents from 4 major Chinese cities (M age = 33.0 yr., SD = 4.3; 48% men). Self-perceptions of uniqueness, similarity, cognitive dissonance, self-esteem and need to behave in conformity or counter-conformity were measured. A theoretical model was assessed in four situations, relating the ratings of self-esteem and perceived similarity/uniqueness to the way other people at a wedding were dressed, and the resultant cognitive dissonance and conformity/ counter-conformity behavior. Regardless of high or low self-esteem, all participants reported cognitive dissonance when they were told that they were dressed extremely similarly to or extremely differently from the other people attending the wedding. However, the conforming/counter-conforming strategies used by participants to resolve the cognitive dissonance differed. When encountering dissonance induced by the perceived extreme uniqueness of dress, participants with low self-esteem tended to say they would dress next time so as to conform with the way others were dressed, while those with high self-esteem indicated they would continue their counter-conformity in attire. When encountering dissonance induced by the perceived extreme similarity to others, both those with high and low self-esteem tended to say they would dress in an unorthodox manner to surprise other people in the future.

The Dynameomics Entropy Dictionary: A Large-Scale Assessment of Conformational Entropy across Protein Fold Space.

Science.gov (United States)

Towse, Clare-Louise; Akke, Mikael; Daggett, Valerie

2017-04-27

Molecular dynamics (MD) simulations contain considerable information with regard to the motions and fluctuations of a protein, the magnitude of which can be used to estimate conformational entropy. Here we survey conformational entropy across protein fold space using the Dynameomics database, which represents the largest existing data set of protein MD simulations for representatives of essentially all known protein folds. We provide an overview of MD-derived entropies accounting for all possible degrees of dihedral freedom on an unprecedented scale. Although different side chains might be expected to impose varying restrictions on the conformational space that the backbone can sample, we found that the backbone entropy and side chain size are not strictly coupled. An outcome of these analyses is the Dynameomics Entropy Dictionary, the contents of which have been compared with entropies derived by other theoretical approaches and experiment. As might be expected, the conformational entropies scale linearly with the number of residues, demonstrating that conformational entropy is an extensive property of proteins. The calculated conformational entropies of folding agree well with previous estimates. Detailed analysis of specific cases identifies deviations in conformational entropy from the average values that highlight how conformational entropy varies with sequence, secondary structure, and tertiary fold. Notably, α-helices have lower entropy on average than do β-sheets, and both are lower than coil regions.

A plant oil-containing pH 4 emulsion improves epidermal barrier structure and enhances ceramide levels in aged skin.

Science.gov (United States)

Blaak, J; Dähnhardt, D; Dähnhardt-Pfeiffer, S; Bielfeldt, S; Wilhelm, K-P; Wohlfart, R; Staib, P

2017-06-01

Xerosis is a serious problem among the very old. It is a dermatological challenge caused by significant alterations in stratum corneum (SC) function and structure. Two negative changes in aged skin are (i) the enhanced skin surface pH and (ii) the altered SC lipid content, composition and ordering. Therefore, we investigated the way in which an acidic skin care product with different plant oils affects SC function, structure and lipid profile in older subjects with dry skin. Before and after a 3-week application period, different biophysical measurements were performed: transepidermal water loss, SC hydration and skin surface pH. In addition, the SC lipid matrix was evaluated by analysis of the intercellular lipid lamellae and the SC lipid profile. After treatment, a significant increase in lipid lamellae in the intercellular space of the SC was observed in the area treated with the test product compared to the untreated area. Furthermore, the ceramide level was found to be increased, although ceramides were not provided by the acidic test formulation. In summary, topical application of a pH 4.0 product containing plant oils improves epidermal barrier formation and SC lipid ordering and ratio in aged dry skin. © 2016 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Efficacy of a Cream Containing Ceramides and Magnesium in the Treatment of Mild to Moderate Atopic Dermatitis: A Randomized, Double-blind, Emollient- and Hydrocortisone-controlled Trial

NARCIS (Netherlands)

Koppes, Sjors A.; Charles, Frank; Lammers, Laureen; Frings-Dresen, Monique; Kezic, Sanja; Rustemeyer, Thomas

2016-01-01

The aim of this randomized controlled trial was to assess the efficacy of a cream containing ceramides and magnesium (Cer-Mg) in the treatment of mild to moderate atopic dermatitis and to compare it with hydrocortisone and a commonly used emollient (unguentum leniens; cold cream). A total of 100

Quantum Conformal Algebras and Closed Conformal Field Theory

CERN Document Server

Anselmi, D

1999-01-01

We investigate the quantum conformal algebras of N=2 and N=1 supersymmetric gauge theories. Phenomena occurring at strong coupling are analysed using the Nachtmann theorem and very general, model-independent, arguments. The results lead us to introduce a novel class of conformal field theories, identified by a closed quantum conformal algebra. We conjecture that they are the exact solution to the strongly coupled large-N_c limit of the open conformal field theories. We study the basic properties of closed conformal field theory and work out the operator product expansion of the conserved current multiplet T. The OPE structure is uniquely determined by two central charges, c and a. The multiplet T does not contain just the stress-tensor, but also R-currents and finite mass operators. For this reason, the ratio c/a is different from 1. On the other hand, an open algebra contains an infinite tower of non-conserved currents, organized in pairs and singlets with respect to renormalization mixing. T mixes with a se...

C-metric solution for conformal gravity with a conformally coupled scalar field

Energy Technology Data Exchange (ETDEWEB)

Meng, Kun, E-mail: mengkun@tjpu.edu.cn [School of Science, Tianjin Polytechnic University, Tianjin 300387 (China); Zhao, Liu, E-mail: lzhao@nankai.edu.cn [School of Physics, Nankai University, Tianjin 300071 (China)

2017-02-15

The C-metric solution of conformal gravity with a conformally coupled scalar field is presented. The solution belongs to the class of Petrov type D spacetimes and is conformal to the standard AdS C-metric appeared in vacuum Einstein gravity. For all parameter ranges, we identify some of the physically interesting static regions and the corresponding coordinate ranges. The solution may contain a black hole event horizon, an acceleration horizon, either of which may be cut by the conformal infinity or be hidden behind the conformal infinity. Since the model is conformally invariant, we also discussed the possible effects of the conformal gauge choices on the structure of the spacetime.

Non-conformable, partial and conformable transposition

DEFF Research Database (Denmark)

König, Thomas; Mäder, Lars Kai

2013-01-01

and the Commission regarding a directive’s outcome, play a much more strategic role than has to date acknowledged in the transposition literature. Whereas disagreement of a member state delays conformable transposition, it speeds up non-conformable transposition. Disagreement of the Commission only prolongs...... the transposition process. We therefore conclude that a stronger focus on an effective sanctioning mechanism is warranted for safeguarding compliance with directives....

Novel analogues of bradykinin conformationally restricted in the C-terminal part of the molecule

Czech Academy of Sciences Publication Activity Database

Sleszynska, M.; Wierzba, T. H.; Malinowski, K.; Borovičková, Lenka; Maluch, I.; Sobolewski, D.; Lammek, B.; Slaninová, Jiřina; Prahl, A.

2011-01-01

Roč. 17, č. 5 (2011), s. 366-372 ISSN 1075-2617 Institutional research plan: CEZ:AV0Z40550506 Keywords : bradykinin analogues * B2 receptor antagonists * sterically restricted residue * in vivo rat blood pressure test * in vitro rat uterus Subject RIV: CC - Organic Chemistry Impact factor: 1.799, year: 2011

Conformal Einstein spaces

International Nuclear Information System (INIS)

Kozameh, C.N.; Newman, E.T.; Tod, K.P.

1985-01-01

Conformal transformations in four-dimensional. In particular, a new set of two necessary and sufficient conditions for a space to be conformal to an Einstein space is presented. The first condition defines the class of spaces conformal to C spaces, whereas the last one (the vanishing of the Bach tensor) gives the particular subclass of C spaces which are conformally related to Einstein spaces. (author)

Conformal Gravity

International Nuclear Information System (INIS)

Hooft, G.

2012-01-01

The dynamical degree of freedom for the gravitational force is the metric tensor, having 10 locally independent degrees of freedom (of which 4 can be used to fix the coordinate choice). In conformal gravity, we split this field into an overall scalar factor and a nine-component remainder. All unrenormalizable infinities are in this remainder, while the scalar component can be handled like any other scalar field such as the Higgs field. In this formalism, conformal symmetry is spontaneously broken. An imperative demand on any healthy quantum gravity theory is that black holes should be described as quantum systems with micro-states as dictated by the Hawking-Bekenstein theory. This requires conformal symmetry that may be broken spontaneously but not explicitly, and this means that all conformal anomalies must cancel out. Cancellation of conformal anomalies yields constraints on the matter sector as described by some universal field theory. Thus black hole physics may eventually be of help in the construction of unified field theories. (author)

Enzymatic monoesterification of symmetric diols: restriction of molecular conformations influences selectivity.

Science.gov (United States)

Tomer, Sanjiv O; Soni, Hemant P

2017-10-31

We have experimentally demonstrated that by 'locking' the molecular conformation through the introduction of a double or triple bond in the center of a symmetric diol, enzymatic monoesterification can be achieved selectively. The enzyme Candida antarctica lipase B, generally used for the transesterification of diols, can be effectively used for the monoesterification of symmetrical diols in an unbuffered system also. By varying the chain length of a carboxylic acid moiety, we have established that optimum selectivity and efficiency can be achieved in the range of 4.8 to 5.0 pK a values. Selectivity can be improved up to 98.75% for a monoester in an overall 73% yield (mixture of a monoester and a diester) when but-2-yne-1,4-diol reacted with hexanoic acid. Water, a by-product, provides an interfacial environment for the enzyme to work in the organic reaction medium. The uniqueness of the reported monoesterification protocol is that it involves only the mechanical stirring of the reaction mixture at room temperature in the presence of the enzyme for 24 h. High percentage yield with selectivity for a monoester, easier product isolation and overall, environmental sustainability are added advantages. The synthesized monoesters are characterized by using HNMR and high resolution mass spectrometry (HRMS).

A new ceramide from Suillus luteus and its cytotoxic activity against human melanoma cells.

Science.gov (United States)

León, Francisco; Brouard, Ignacio; Torres, Fernando; Quintana, José; Rivera, Augusto; Estévez, Francisco; Bermejo, Jaime

2008-01-01

A new phytosphingosine-type ceramide, suillumide (1), was isolated from the EtOH extract of the basidiomycete Suillus luteus (L.) S. F. Gray, along with ten known compounds: ergosta-4,6,8(14),22-tetraen-3-one, ergosterol, ergosterol peroxide, suillin, (E)-3,4,5-trimethoxycinnamic alcohol, 5 alpha,6 alpha-epoxyergosta-8,22-diene-3beta,7 beta-diol, (R)-1-palmitoylglycerol, ergosta-7,9(11),22-triene-3beta,5 alpha,6 beta-triol, cerevisterol, and 4-hydroxybenzoic acid. The structure of 1 was determined on the basis of spectroscopic and mass-spectrometric analyses, as well as by chemical methods. Compound 1 and its synthetic diacetyl derivative 2 were tested for their cytotoxic activities against the human melanoma cell line SK-MEL-1. Both drugs showed IC(50) values of ca. 10 microM after 72 h of exposure.

Implications of conformal invariance in momentum space

Science.gov (United States)

Bzowski, Adam; McFadden, Paul; Skenderis, Kostas

2014-03-01

We present a comprehensive analysis of the implications of conformal invariance for 3-point functions of the stress-energy tensor, conserved currents and scalar operators in general dimension and in momentum space. Our starting point is a novel and very effective decomposition of tensor correlators which reduces their computation to that of a number of scalar form factors. For example, the most general 3-point function of a conserved and traceless stress-energy tensor is determined by only five form factors. Dilatations and special conformal Ward identities then impose additional conditions on these form factors. The special conformal Ward identities become a set of first and second order differential equations, whose general solution is given in terms of integrals involving a product of three Bessel functions (`triple- K integrals'). All in all, the correlators are completely determined up to a number of constants, in agreement with well-known position space results. In odd dimensions 3-point functions are finite without renormalisation while in even dimensions non-trivial renormalisation in required. In this paper we restrict ourselves to odd dimensions. A comprehensive analysis of renormalisation will be discussed elsewhere. This paper contains two parts that can be read independently of each other. In the first part, we explain the method that leads to the solution for the correlators in terms of triple- K integrals while the second part contains a self-contained presentation of all results. Readers interested only in results may directly consult the second part of the paper.

Facile synthesis of new carbon-11 labeled conformationally restricted rivastigmine analogues as potential PET agents for imaging AChE and BChE enzymes

International Nuclear Information System (INIS)

Wang Min; Wang Jiquan; Gao Mingzhang; Zheng Qihuang

2008-01-01

Rivastigmine is a newer-generation inhibitor with a dual inhibitory action on both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes, and is used for the treatment of AChE- and BChE-related diseases such as brain Alzheimer's disease and cardiovascular disease. New carbon-11 labeled conformationally restricted rivastigmine analogues radiolabeled quaternary ammonium triflate salts, (3aR,9bS)-1-[ 11 C]methyl-1-methyl-6-(methylcarbamoyloxy)-2,3,3a,4,5, 9b-hexahy dro-1H-benzo[g]indolium triflate ([ 11 C]8) and (3aR,9bS)-1-[ 11 C]methyl-1-methyl-6-(heptylcarbamoyloxy)-2,3,3a,4,5, 9b-hexahy dro-1H-benzo[g]indolium triflate ([ 11 C]9), were designed and synthesized as potential positron emission tomography (PET) agents for imaging AChE and BChE enzymes. The appropriate precursors were labeled with [ 11 C]CH 3 OTf through N-[ 11 C]methylation, and the target tracers were isolated by solid-phase extraction (SPE) using a cation-exchange CM Sep-Pak cartridge in 40-50% radiochemical yields decay corrected to end of bombardment (EOB), 15-20 min overall synthesis time, and 148-222 GBq/μmol specific activity at EOB

Transmission of HBV DNA Mediated by Ceramide-Triggered Extracellular Vesicles.

Science.gov (United States)

Sanada, Takahiro; Hirata, Yuichi; Naito, Yutaka; Yamamoto, Naoki; Kikkawa, Yoshiaki; Ishida, Yuji; Yamasaki, Chihiro; Tateno, Chise; Ochiya, Takahiro; Kohara, Michinori

2017-03-01

An extracellular vesicle (EV) is a nanovesicle that shuttles proteins, nucleic acids, and lipids, thereby influencing cell behavior. A recent crop of reports have shown that EVs are involved in infectious biology, influencing host immunity and playing a role in the viral life cycle. In the present work, we investigated the EV-mediated transmission of hepatitis B virus (HBV) infection. We investigated the EV-mediated transmission of HBV infection by using a HBV infectious culture system that uses primary human hepatocytes derived from humanized chimeric mice (PXB-cells). Purified EVs were isolated by ultracentrifugation. To analyze the EVs and virions, we used stimulated emission depletion microscopy. Purified EVs from HBV-infected PXB-cells were shown to contain HBV DNA and to be capable of transmitting HBV DNA to naive PXB-cells. These HBV-DNA-transmitting EVs were shown to be generated through a ceramide-triggered EV production pathway. Furthermore, we showed that these HBV-DNA-transmitting EVs were resistant to antibody neutralization; stimulated emission depletion microscopy showed that EVs lacked hepatitis B surface antigen, the target of neutralizing antibodies. These findings suggest that EVs harbor a DNA cargo capable of transmitting viral DNA into hepatocytes during HBV infection, representing an additional antibody-neutralization-resistant route of HBV infection.

Cholesterol Depletion from a Ceramide/Cholesterol Mixed Monolayer: A Brewster Angle Microscope Study

KAUST Repository

Mandal, Pritam

2016-06-01

Cholesterol is crucial to the mechanical properties of cell membranes that are important to cells’ behavior. Its depletion from the cell membranes could be dramatic. Among cyclodextrins (CDs), methyl beta cyclodextrin (MβCD) is the most efficient to deplete cholesterol (Chol) from biomembranes. Here, we focus on the depletion of cholesterol from a C16 ceramide/cholesterol (C16-Cer/Chol) mixed monolayer using MβCD. While the removal of cholesterol by MβCD depends on the cholesterol concentration in most mixed lipid monolayers, it does not depend very much on the concentration of cholesterol in C16-Cer/Chol monolayers. The surface pressure decay during depletion were described by a stretched exponential that suggested that the cholesterol molecules are unable to diffuse laterally and behave like static traps for the MβCD molecules. Cholesterol depletion causes morphology changes of domains but these disrupted monolayers domains seem to reform even when cholesterol level was low.

Conformal symmetry in two-dimensional space: recursion representation of conformal block

International Nuclear Information System (INIS)

Zamolodchikov, A.B.

1988-01-01

The four-point conformal block plays an important part in the analysis of the conformally invariant operator algebra in two-dimensional space. The behavior of the conformal block is calculated in the present paper in the limit in which the dimension Δ of the intermediate operator tends to infinity. This makes it possible to construct a recursion relation for this function that connects the conformal block at arbitrary Δ to the blocks corresponding to the dimensions of the zero vectors in the degenerate representations of the Virasoro algebra. The relation is convenient for calculating the expansion of the conformal block in powers of the uniformizing parameters q = i π tau

SU-E-T-278: Dose Conformity Index for the Target in a Multitarget Environment

Energy Technology Data Exchange (ETDEWEB)

Harikrishnaperumal, Sudahar [Apollo Speciality Hospital, Chennai, Tamil Nadu (India)

2015-06-15

Purpose: The existing conformity index formulations are failing when multiple targets present outside the target of interest with same or different dose prescriptions. In the present study a novel methodology is introduced to solve this issue. Methods: The conformity index used by Nakamura et al (Int J Radiat Oncol Biol Phys 2001; 51(5):1313–1319) is taken as the base for this methodology. In this proposal, the prescription isodose volume (PIV) which normally includes the normal tissue and other target regions is restricted as PIV in annular regions of different thickness around the target of interest. The graphical line plotted between the thickness of annular region and the corresponding conformity index, will increase in the beginning and will reach a flat region, then it will increase again. The second increase in the conformity index depends basically on the distance between the targets, dose prescriptions, and size of the targets. The conformity index in the flat region should be the conformity index of the target of interest. This methodology was validated on dual target environment on a skull phantom in Multiplan planning system (Accuray Inc. Sunnyvale, USA) Results: When the surrounding target’s (sphere) size is changed from 1.5cm to 6cm diameter, the conformity index of the target of interest (3cm diameter) changed from 1.09 to 1.25. When the distance between the targets changed from 7.5cm to 2.5cm, the conformity index changed from 1.10 to 1.17. Similarly, when the prescribed dose changed from 25Gy to 50Gy the conformity index changed from 1.09 to 1.42. These values were above 2.0 when Nakamura et al formula was used. Conclusion: The proposed conformity index methodology eliminates the influence of surrounding targets to a greater extend. However, the limitations of this method should be studied further. Application of this method in clinical situations is the future scope.

Conformal Infinity

Directory of Open Access Journals (Sweden)

Frauendiener Jörg

2000-08-01

Full Text Available The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, ``conformal infinity'' is related with almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved out of physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation and how it lends itself very naturally to solve radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

Conformal Infinity.

Science.gov (United States)

Frauendiener, Jörg

2004-01-01

The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, "conformal infinity" is related to almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved from physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation, and how it lends itself very naturally to the solution of radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

24 +24 real scalar multiplet in four dimensional N =2 conformal supergravity

Science.gov (United States)

Hegde, Subramanya; Lodato, Ivano; Sahoo, Bindusar

2018-03-01

Starting from the 48 +48 component multiplet of supercurrents for a rigid N =2 tensor multiplet in four spacetime dimensions, we obtain the transformation of the linearized supergravity multiplet which couples to this supercurrent multiplet. At the linearized level, this 48 +48 component supergravity multiplet decouples into the 24 +24 component linearized standard Weyl multiplet and a 24 +24 component irreducible matter multiplet containing a real scalar field. By a consistent application of the supersymmetry algebra with field-dependent structure constants appropriate to N =2 conformal supergravity, we find the full transformation law for this multiplet in a conformal supergravity background. By performing a suitable field redefinition, we find that the multiplet is a generalization of the flat space multiplet, obtained by Howe et al. in Nucl. Phys. B214, 519 (1983), 10.1016/0550-3213(83)90249-3, to a conformal supergravity background. We also present a set of constraints which can be consistently imposed on this multiplet to obtain a restricted minimal 8 +8 off-shell matter multiplet. We also show, as an example, the precise embedding of the tensor multiplet inside this multiplet.

Conformal Infinity

Directory of Open Access Journals (Sweden)

Frauendiener Jörg

2004-01-01

Full Text Available The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, 'conformal infinity' is related to almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved from physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation, and how it lends itself very naturally to the solution of radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

Halo histories versus galaxy properties at z = 0 II: large-scale galactic conformity

Science.gov (United States)

Tinker, Jeremy L.; Hahn, ChangHoon; Mao, Yao-Yuan; Wetzel, Andrew R.; Conroy, Charlie

2018-06-01

Using group catalogues from the Sloan Digital Sky Survey (SDSS) Data Release 7, we measure galactic conformity in the local universe. We measure the quenched fraction of neighbour galaxies around isolated primary galaxies, dividing the isolated sample into star-forming and quiescent objects. We restrict our measurements to scales >1 Mpc to probe the correlations between halo formation histories. Over the stellar mass range 109.7 ≤ M*/M⊙ ≤ 1010.9, we find minimal evidence for conformity. We further compare these data to predictions of the halo age-matching model, in which the oldest galaxies are associated with the oldest haloes. For models with strong correlations between halo and stellar age, the conformity is too large to be consistent with the data. Weaker implementations of the age-matching model would not produce a detectable signal in SDSS data. We reproduce the results of Kauffmann et al., in which the star formation rates of neighbour galaxies are reduced around primary galaxies when the primaries are low star formers. However, we find this result is mainly driven by contamination in the isolation criterion; when removing the small fraction of satellite galaxies in the sample, the conformity signal largely goes away. Lastly, we show that small conformity signals, i.e. 2-5 per cent differences in the quenched fractions of neighbour galaxies, can be produced by mechanisms other than halo assembly bias. For example, if passive galaxies occupy more massive haloes than star-forming galaxies of the same stellar mass, a conformity signal that is consistent with recent measurements from PRIMUS (Berti et al.) can be produced.

Logarithmic conformal field theory through nilpotent conformal dimensions

International Nuclear Information System (INIS)

Moghimi-Araghi, S.; Rouhani, S.; Saadat, M.

2001-01-01

We study logarithmic conformal field theories (LCFTs) through the introduction of nilpotent conformal weights. Using this device, we derive the properties of LCFTs such as the transformation laws, singular vectors and the structure of correlation functions. We discuss the emergence of an extra energy momentum tensor, which is the logarithmic partner of the energy momentum tensor

Viscous conformal gauge theories

DEFF Research Database (Denmark)

Toniato, Arianna; Sannino, Francesco; Rischke, Dirk H.

2017-01-01

We present the conformal behavior of the shear viscosity-to-entropy density ratio and the fermion-number diffusion coefficient within the perturbative regime of the conformal window for gauge-fermion theories.......We present the conformal behavior of the shear viscosity-to-entropy density ratio and the fermion-number diffusion coefficient within the perturbative regime of the conformal window for gauge-fermion theories....

Generation of reactive oxygen species (ROS) is a key factor for stimulation of macrophage proliferation by ceramide 1-phosphate

International Nuclear Information System (INIS)

Arana, Lide; Gangoiti, Patricia; Ouro, Alberto; Rivera, Io-Guané; Ordoñez, Marta; Trueba, Miguel; Lankalapalli, Ravi S.; Bittman, Robert; Gomez-Muñoz, Antonio

2012-01-01

We previously demonstrated that ceramide 1-phosphate (C1P) is mitogenic for fibroblasts and macrophages. However, the mechanisms involved in this action were only partially described. Here, we demonstrate that C1P stimulates reactive oxygen species (ROS) formation in primary bone marrow-derived macrophages, and that ROS are required for the mitogenic effect of C1P. ROS production was dependent upon prior activation of NADPH oxidase by C1P, which was determined by measuring phosphorylation of the p40phox subunit and translocation of p47phox from the cytosol to the plasma membrane. In addition, C1P activated cytosolic calcium-dependent phospholipase A 2 and protein kinase C-α, and NADPH oxidase activation was blocked by selective inhibitors of these enzymes. These inhibitors, and inhibitors of ROS production, blocked the mitogenic effect of C1P. By using BHNB-C1P (a photolabile caged-C1P analog), we demonstrate that all of these C1P actions are caused by intracellular C1P. It can be concluded that the enzyme responsible for C1P-stimulated ROS generation in bone marrow-derived macrophages is NADPH oxidase, and that this enzyme is downstream of PKC-α and cPLA 2 -α in this pathway. -- Highlights: ► Ceramide 1-phosphate (C1P) stimulates reactive oxygen species (ROS) formation. ► The enzyme responsible for ROS generation by C1P in macrophages is NADPH oxidase. ► NADPH oxidase lies downstream of cPLA 2 -α and PKC-α in this pathway. ► ROS generation is essential for the stimulation of macrophage proliferation by C1P.

Palmitic Acid Reduces Circulating Bone Formation Markers in Obese Animals and Impairs Osteoblast Activity via C16-Ceramide Accumulation.

Science.gov (United States)

Alsahli, Ahmad; Kiefhaber, Kathryn; Gold, Tziporah; Muluke, Munira; Jiang, Hongfeng; Cremers, Serge; Schulze-Späte, Ulrike

2016-05-01

Obesity and impaired lipid metabolism increase circulating and local fatty acid (FA) levels. Our previous studies showed that a high high-saturated -fat diet induced greater bone loss in mice than a high high-unsaturated-fat diet due to increased osteoclast numbers and activity. The impact of elevated FA levels on osteoblasts is not yet clear. We induced obesity in 4 week old male mice using a palmitic acid (PA)- or oleic acid (OA)-enriched high fat high-fat diet (HFD) (20 % of calories from FA), and compared them to mice on a normal (R) caloric diet (10 % of calories from FA). We collected serum to determine FA and bone metabolism marker levels. Primary osteoblasts were isolated; cultured in PA, OA, or control (C) medium; and assessed for mineralization activity, gene expression, and ceramide levels. Obese animals in the PA and OA groups had significantly lower serum levels of bone formation markers P1NP and OC compared to normal weight animals (*p < 0.001), with the lowest marker levels in animals on an PA-enriched HFD (*p < 0.001). Accordingly, elevated levels of PA significantly reduced osteoblast mineralization activity in vitro (*p < 0.05). Elevated PA intake significantly increased C16 ceramide accumulation. This accumulation was preventable through inhibition of SPT2 (serine palmitoyl transferase 2) using myriocin. Elevated levels of PA reduce osteoblast function in vitro and bone formation markers in vivo. Our findings suggest that saturated PA can compromise bone health by affecting osteoblasts, and identify a potential mechanism through which obesity promotes bone loss.

Dissecting the dynamic conformations of the metamorphic protein lymphotactin.

Science.gov (United States)

Harvey, Sophie R; Porrini, Massimiliano; Konijnenberg, Albert; Clarke, David J; Tyler, Robert C; Langridge-Smith, Patrick R R; MacPhee, Cait E; Volkman, Brian F; Barran, Perdita E

2014-10-30

A mass spectrometer provides an ideal laboratory to probe the structure and stability of isolated protein ions. Interrogation of each discrete mass/charge-separated species enables the determination of the intrinsic stability of a protein fold, gaining snapshots of unfolding pathways. In solution, the metamorphic protein lymphotactin (Ltn) exists in equilibrium between two distinct conformations, a monomeric (Ltn10) and a dimeric (Ltn40) fold. Here, we use electron capture dissociation (ECD) and drift tube ion mobility-mass spectrometry (DT IM-MS) to analyze both forms and use molecular dynamics (MD) to consider how the solution fold alters in a solvent-free environment. DT IM-MS reveals significant conformational flexibility for the monomer, while the dimer appears more conformationally restricted. These findings are supported by MD calculations, which reveal how salt bridges stabilize the conformers in vacuo. Following ECD experiments, a distinctive fragmentation pattern is obtained for both the monomer and dimer. Monomer fragmentation becomes more pronounced with increasing charge state especially in the disordered regions and C-terminal α-helix in the solution fold. Lower levels of fragmentation are seen in the β-sheet regions and in regions that contain salt bridges, identified by MD simulations. The lowest charge state of the dimer for which we obtain ECD data ([D+9H](9+)) exhibits extensive fragmentation with no relationship to the solution fold and has a smaller collision cross section (CCS) than charge states 10-13+, suggesting a "collapsed" encounter complex. Other charge states of the dimer, as for the monomer, are resistant to fragmentation in regions of β-sheets in the solution fold. This study provides evidence for preservation and loss of global fold and secondary structural elements, providing a tantalizing glimpse into the power of the emerging field of native top-down mass spectrometry.

Conformal invariance in supergravity

International Nuclear Information System (INIS)

Bergshoeff, E.A.

1983-01-01

In this thesis the author explains the role of conformal invariance in supergravity. He presents the complete structure of extended conformal supergravity for N <= 4. The outline of this work is as follows. In chapter 2 he briefly summarizes the essential properties of supersymmetry and supergravity and indicates the use of conformal invariance in supergravity. The idea that the introduction of additional symmetry transformations can make clear the structure of a field theory is not reserved to supergravity only. By means of some simple examples it is shown in chapter 3 how one can always introduce additional gauge transformations in a theory of massive vector fields. Moreover it is shown how the gauge invariant formulation sometimes explains the quantum mechanical properties of the theory. In chapter 4 the author defines the conformal transformations and summarizes their main properties. He explains how these conformal transformations can be used to analyse the structure of gravity. The supersymmetric extension of these results is discussed in chapter 5. Here he describes as an example how N=1 supergravity can be reformulated in a conformally-invariant way. He also shows that beyond N=1 the gauge fields of the superconformal symmetries do not constitute an off-shell field representation of extended conformal supergravity. Therefore, in chapter 6, a systematic method to construct the off-shell formulation of all extended conformal supergravity theories with N <= 4 is developed. As an example he uses this method to construct N=1 conformal supergravity. Finally, in chapter 7 N=4 conformal supergravity is discussed. (Auth.)

Loss of Ceramide Synthases Elicits a PHA-4/FoxA-, SKN-1-, and Autophagy-Dependent Lifespan Extension in C. elegans

DEFF Research Database (Denmark)

Jensen, Mai-Britt Mosbech; Færgeman, Nils J.; Ejsing, Christer S.

2011-01-01

, these lipid species are recognized as bioactive signalling molecules involved in regulation of cell growth, differentiation, senescence, and apoptosis, and thus a delicate equilibrium between the levels of these interconvertible lipid species underlies the balance between cell survival and death. The C....... elegans genome comprises three ceramide synthase genes; hyl-1, hyl-2, and lagr-1. Here we show that functional loss of HYL-1 and LAGR-1 depletes 43:1;3 sphingolipids and extends lifespan in a PHA-4-, SKN-1-, and ATG-12-dependent manner. The transcription factors PHA-4 and SKN-1 as well as ATG-12, which...

Atropisomerism about aryl-Csp(3) bonds: the electronic and steric influence of ortho-substituents on conformational exchange in cannabidiol and linderatin derivatives.

Science.gov (United States)

Berber, Hatice; Lameiras, Pedro; Denhez, Clément; Antheaume, Cyril; Clayden, Jonathan

2014-07-03

Terpenylation reactions of substituted phenols were used to prepare cannabidiol and linderatin derivatives, and their structure and conformational behavior in solution were investigated by NMR and, for some representative examples, by DFT. VT-NMR spectra and DFT calculations were used to determine the activation energies of the conformational change arising from restricted rotation about the aryl-Csp(3) bond that lead to two unequally populated rotameric epimers. The NBO calculation was applied to explain the electronic stabilization of one conformer over another by donor-acceptor charge transfer interactions. Conformational control arises from a combination of stereoelectronic and steric effects between substituents in close contact with each other on the two rings of the endocyclic epoxide atropisomers. This study represents the first exploration of the stereoelectronic origins of atropisomerism around C(sp(2))-C(sp(3)) single bonds through theoretical calculations.

Comparison of structure and organization of cutaneous lipids in a reconstructed skin model and human skin: spectroscopic imaging and chromatographic profiling.

Science.gov (United States)

Tfayli, Ali; Bonnier, Franck; Farhane, Zeineb; Libong, Danielle; Byrne, Hugh J; Baillet-Guffroy, Arlette

2014-06-01

The use of animals for scientific research is increasingly restricted by legislation, increasing the demand for human skin models. These constructs present comparable bulk lipid content to human skin. However, their permeability is significantly higher, limiting their applicability as models of barrier function, although the molecular origins of this reduced barrier function remain unclear. This study analyses the stratum corneum (SC) of one such commercially available reconstructed skin model (RSM) compared with human SC by spectroscopic imaging and chromatographic profiling. Total lipid composition was compared by chromatographic analysis (HPLC). Raman spectroscopy was used to evaluate the conformational order, lateral packing and distribution of lipids in the surface and skin/RSM sections. Although HPLC indicates that all SC lipid classes are present, significant differences are observed in ceramide profiles. Raman imaging demonstrated that the RSM lipids are distributed in a non-continuous matrix, providing a better understanding of the limited barrier function. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Modest phenotypic improvements in ASA-deficient mice with only one UDP-galactose:ceramide-galactosyltransferase gene

Directory of Open Access Journals (Sweden)

De Deyn PP

2006-08-01

Full Text Available Summary Background Arylsulfatase A (ASA-deficient mice are a model for the lysosomal storage disorder metachromatic leukodystrophy. This lipidosis is characterised by the lysosomal accumulation of the sphingolipid sulfatide. Storage of this lipid is associated with progressive demyelination. We have mated ASA-deficient mice with mice heterozygous for a non-functional allele of UDP-galactose:ceramide-galactosyltransferase (CGT. This deficiency is known to lead to a decreased synthesis of galactosylceramide and sulfatide, which should reduce sulfatide storage and improve pathology in ASA-deficient mice. Results ASA-/- CGT+/- mice, however, showed no detectable decrease in sulfatide storage. Neuronal degeneration of cells in the spiral ganglion of the inner ear, however, was decreased. Behavioural tests showed small but clear improvements of the phenotype in ASA-/- CGT+/- mice. Conclusion Thus the reduction of galactosylceramide and sulfatide biosynthesis by genetic means overall causes modest improvements of pathology.

Influence of calcium on ceramide-1-phosphate monolayers

Directory of Open Access Journals (Sweden)

Joana S. L. Oliveira

2016-02-01

Full Text Available Ceramide-1-phosphate (C1P plays an important role in several biological processes, being identified as a key regulator of many protein functions. For instance, it acts as a mediator of inflammatory responses. The mediation of the inflammation process happens due to the interaction of C1P with the C2 domain of cPLA2α, an effector protein that needs the presence of submicromolar concentrations of calcium ions. The aim of this study was to determine the phase behaviour and structural properties of C1P in the presence and absence of millimolar quantities of calcium in a well-defined pH environment. For that purpose, we used monomolecular films of C1P at the soft air/liquid interface with calcium ions in the subphase. The pH was varied to change the protonation degree of the C1P head group. We used surface pressure versus molecular area isotherms coupled with other monolayer techniques as Brewster angle microscopy (BAM, infrared reflection–absorption spectroscopy (IRRAS and grazing incidence X-ray diffraction (GIXD. The isotherms indicate that C1P monolayers are in a condensed state in the presence of calcium ions, regardless of the pH. At higher pH without calcium ions, the monolayer is in a liquid-expanded state due to repulsion between the negatively charged phosphate groups of the C1P molecules. When divalent calcium ions are added, they are able to bridge the highly charged phosphate groups, enhancing the regular arrangement of the head groups. Similar solidification of the monolayer structure can be seen in the presence of a 150 times larger concentration of monovalent sodium ions. Therefore, calcium ions have clearly a strong affinity for the phosphomonoester of C1P.

National Law Restrictions on Family Reunification Rights of International Protection Beneficiaries from a ECHR/EU Perspective

DEFF Research Database (Denmark)

Storgaard, Louise Halleskov

n light of the refugee crisis, European countries are exploring new ways to restrict access of migrants to their territory. One such restriction relates to family reunification rights of international protection beneficiaries. Proposals in this area have already been adopted or are currently being...... considered in countries such as Norway, Denmark, Sweden, Austria and Germany most commonly in the form of waiting periods before applications for family reunification can be submitted and/or age requirements. The personal scope of these proposals differs. In some countries the restrictions apply/are intended...... to apply to international beneficiaries in general while they in other countries are applicable/envisaged applicable only to persons with subsidiary protection status or persons fleeing from generalised violence. The intention of the paper is to examine whether this legislative trend is in conformity...

Conformal expansions and renormalons

Energy Technology Data Exchange (ETDEWEB)

Rathsman, J.

2000-02-07

The coefficients in perturbative expansions in gauge theories are factorially increasing, predominantly due to renormalons. This type of factorial increase is not expected in conformal theories. In QCD conformal relations between observables can be defined in the presence of a perturbative infrared fixed-point. Using the Banks-Zaks expansion the authors study the effect of the large-order behavior of the perturbative series on the conformal coefficients. The authors find that in general these coefficients become factorially increasing. However, when the factorial behavior genuinely originates in a renormalon integral, as implied by a postulated skeleton expansion, it does not affect the conformal coefficients. As a consequence, the conformal coefficients will indeed be free of renormalon divergence, in accordance with previous observations concerning the smallness of these coefficients for specific observables. The authors further show that the correspondence of the BLM method with the skeleton expansion implies a unique scale-setting procedure. The BLM coefficients can be interpreted as the conformal coefficients in the series relating the fixed-point value of the observable with that of the skeleton effective charge. Through the skeleton expansion the relevance of renormalon-free conformal coefficients extends to real-world QCD.

Low Serum Levels of (Dihydro-Ceramides Reflect Liver Graft Dysfunction in a Real-World Cohort of Patients Post Liver Transplantation

Directory of Open Access Journals (Sweden)

Victoria Therese Mücke

2018-03-01

Full Text Available Patients after orthopic liver transplantation (OLT are at risk of developing graft dysfunction. Sphingolipids (SL’s have been identified to play a pivotal role in the regulation of hepatocellular apoptosis, inflammation and immunity. We aimed to investigate the serum SL profile in a prospective real-world cohort of post-OLT patients. From October 2015 until July 2016, 149 well-characterized post-OLT patients were analyzed. SL’s were assessed in serum probes via Liquid Chromatography/Tandem Mass Spectrometry. Twenty-nine (20% patients had a biopsy proven graft rejection with decreased C20-ceramide (Cer (p = 0.042, C18-dihydroceramide (DHC (p = 0.022 and C24DHC (p = 0.060 levels. Furthermore, C18DHC (p = 0.044 and C24DHC (p = 0.011 were significantly down-regulated in patients with ischemic type biliary lesions (ITBL; n = 15; 10%. One-hundred and thirty-three patients (89% have so far received tacrolimus as the main immunosuppressive agent with observed elevations of C14Cer (p = 0.052, C18Cer (p = 0.049 and C18:1Cer (p = 0.024. Hepatocellular carcinoma (HCC pre-OLT was associated with increases in C24:1Cer (p = 0.024 and C24:1DHC (p = 0.024. In this large prospective cross-sectional study of patients, post-OLT serum levels of (very-long chain (dihydro-ceramides associate with graft rejection, ITBL, tacrolimus intake and HCC pre-OLT. Hence, serum SL’s may be indicative of graft complications. Further research is necessary to identify their diverse mechanistic role in regulating immunity and inflammation in patients post-OLT.

On the effects of basis set truncation and electron correlation in conformers of 2-hydroxy-acetamide

Science.gov (United States)

Szarecka, A.; Day, G.; Grout, P. J.; Wilson, S.

Ab initio quantum chemical calculations have been used to study the differences in energy between two gas phase conformers of the 2-hydroxy-acetamide molecule that possess intramolecular hydrogen bonding. In particular, rotation around the central C-C bond has been considered as a factor determining the structure of the hydrogen bond and stabilization of the conformer. Energy calculations include full geometiy optimization using both the restricted matrix Hartree-Fock model and second-order many-body perturbation theory with a number of commonly used basis sets. The basis sets employed ranged from the minimal STO-3G set to [`]split-valence' sets up to 6-31 G. The effects of polarization functions were also studied. The results display a strong basis set dependence.

Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants.

Directory of Open Access Journals (Sweden)

Thomas L Prince

Full Text Available The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90β, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90α and HSP90β with the transcription factors HSF1 and HIF1α, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90α binding each client protein with greater apparent affinity compared to HSP90β, while HSP90β bound each inhibitor with greater relative interaction strength compared to HSP90α. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states.

The influence of the preparations with the glucocorticosteroids and ceramides on the morphological state of the rats’ skin with the nonspecific dermatitis

Directory of Open Access Journals (Sweden)

Ya. O. Butko

2013-04-01

Full Text Available Introduction. Local therapy is an important method for treatment of dermatitis used to suppress the skin inflammation and the main related symptoms: hyperemia, edema, pruritus, lichenification etc. However today it is important to pay more attention to elimination of the skin dryness, restoration of the damaged epithelium and improvement of the skin barrier functions in dermatitis therapy. Considering all the requirements mentioned above, cream and ointment that correspond to the modern requirements of the local therapy were developed. They promote the decrease of inflammatory processes in skin (Mometasone furoate and Methylprednisolone atseponat are strong GCS with antipruritic, anti-inflammatory, vasoconstrictive, antiproliferative action and with minimum side effects, eliminate excessive skin dryness, restore the damaged epithelium, improve the skin condition and normalize the barrier functions of the skin (ceramides are the natural ceramides of the human’s skin. The purpose of this work was morphological study of the rats’ skin during treatment with cream “Mometasone with ceramides” and ointment “Methyl­prednisolone with ceramides” in the conditions of contact dermatitis inducted by turpentine. Materials and methods. Skin of animals was an object of the research after its treatment with cream “Mometasone with ceramides” and ointment “Methylprednisolone with ceramides”. The comparator preparations were cream “Elocom” and ointment “Advantan”. In the experiment 36 rats divided into groups were used. All the preparations were applied on the skin in a thin layer once a day. After the 5th day of the treatment animals were taken out of the experiment and all the tissue materials were fixed in 10% solution of formalin for morphological studies carrying out. Sections were stained with hematoxylin and eosine. An examination was carried out under the microscope Micros 400. Results of the research. The results showed that

Conformational analysis by intersection: CONAN.

Science.gov (United States)

Smellie, Andrew; Stanton, Robert; Henne, Randy; Teig, Steve

2003-01-15

As high throughput techniques in chemical synthesis and screening improve, more demands are placed on computer assisted design and virtual screening. Many of these computational methods require one or more three-dimensional conformations for molecules, creating a demand for a conformational analysis tool that can rapidly and robustly cover the low-energy conformational spaces of small molecules. A new algorithm of intersection is presented here, which quickly generates (on average heuristics are applied after intersection to generate a small representative collection of conformations that span the conformational space. In a study of approximately 97,000 randomly selected molecules from the MDDR, results are presented that explore these conformations and their ability to cover low-energy conformational space. Copyright 2002 Wiley Periodicals, Inc. J Comput Chem 24: 10-20, 2003

Black Hole Entropy from Conformal Field Theory in Any Dimension

International Nuclear Information System (INIS)

Carlip, S.

1999-01-01

Restricted to a black hole horizon, the open-quotes gaugeclose quotes algebra of surface deformations in general relativity contains a Virasoro subalgebra with a calculable central charge. The fields in any quantum theory of gravity must transform accordingly, i.e., they must admit a conformal field theory description. Applying Cardy close-quote s formula for the asymptotic density of states, I use this result to derive the Bekenstein-Hawking entropy. This method is universal it holds for any black hole, and requires no details of quantum gravity but it is also explicitly statistical mechanical, based on counting microscopic states. copyright 1999 The American Physical Society

The conformal method and the conformal thin-sandwich method are the same

International Nuclear Information System (INIS)

Maxwell, David

2014-01-01

The conformal method developed in the 1970s and the more recent Lagrangian and Hamiltonian conformal thin-sandwich methods are techniques for finding solutions of the Einstein constraint equations. We show that they are manifestations of a single conformal method: there is a straightforward way to convert back and forth between the parameters for these methods so that the corresponding solutions of the Einstein constraint equations agree. The unifying idea is the need to clearly distinguish tangent and cotangent vectors to the space of conformal classes on a manifold, and we introduce a vocabulary for working with these objects without reference to a particular representative background metric. As a consequence of these conceptual advantages, we demonstrate how to strengthen previous near-CMC (constant mean curvature) existence and non-existence theorems for the original conformal method to include metrics with scalar curvatures that change sign. (paper)

Superspace conformal field theory

Energy Technology Data Exchange (ETDEWEB)

Quella, Thomas [Koeln Univ. (Germany). Inst. fuer Theoretische Physik; Schomerus, Volker [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

2013-07-15

Conformal sigma models and WZW models on coset superspaces provide important examples of logarithmic conformal field theories. They possess many applications to problems in string and condensed matter theory. We review recent results and developments, including the general construction of WZW models on type I supergroups, the classification of conformal sigma models and their embedding into string theory.

Superspace conformal field theory

International Nuclear Information System (INIS)

Quella, Thomas

2013-07-01

Conformal sigma models and WZW models on coset superspaces provide important examples of logarithmic conformal field theories. They possess many applications to problems in string and condensed matter theory. We review recent results and developments, including the general construction of WZW models on type I supergroups, the classification of conformal sigma models and their embedding into string theory.

Exciplex and excimer molecular probes: detection of conformational flip in a myo-inositol chair.

Science.gov (United States)

Kadirvel, Manikandan; Arsic, Biljana; Freeman, Sally; Bichenkova, Elena V

2008-06-07

2-O-tert-Butyldimethylsilyl-4,6-bis-O-pyrenoyl-myo-inositol-1,3,5-orthoformate (6) and 2-O-tert-butyldimethylsilyl-4-O-[4-(dimethylamino)benzoyl]-6-O-pyrenoyl-myo-inositol-1,3,5-orthoacetate (10) adopt conformationally restricted unstable chairs with five axial substituents. In the symmetrical diester 6, the two pi-stacked pyrenoyl groups are electron acceptor-donor partners, giving a strong intramolecular excimer emission. In the mixed ester 10, the pyrenoyl group is the electron acceptor and the 4-(dimethylamino)benzoyl ester is the electron donor, giving a strong intramolecular exciplex emission. The conformation of the mixed ester 10 was assessed using 1H NMR spectroscopy (1H-NOESY) and computational studies. which showed the minimum inter-centroid distance between the two aromatic systems to be approximately 3.9 A. Upon addition of acid, the orthoformate/orthoacetate trigger in 6 and 10 was cleaved, which caused a switch of the conformation of the myo-inositol ring to the more stable penta-equatorial chair, leading to separation of the aromatic ester groups and loss of excimer and exciplex fluorescence, respectively. This study provides proof of principle for the development of novel fluorescent molecular probes.

Conformal Infinity

OpenAIRE

Frauendiener, J?rg

2000-01-01

The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, 'conformal infinity' is related to almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved from physical issues, namely the need to understand gravitational radiation and isolated systems within the theory...

End-to-end Structural Restriction of α-Synuclein and Its Influence on Amyloid Fibril Formation

International Nuclear Information System (INIS)

Hong, Chul Suk; Park, Jae Hyung; Choe, Young Jun; Paik, Seung R.

2014-01-01

Relationship between molecular freedom of amyloidogenic protein and its self-assembly into amyloid fibrils has been evaluated with α-synuclein, an intrinsically unfolded protein related to Parkinson's disease, by restricting its structural plasticity through an end-to-end disulfide bond formation between two newly introduced cysteine residues on the N- and C-termini. Although the resulting circular form of α-synuclein exhibited an impaired fibrillation propensity, the restriction did not completely block the protein's interactive core since co-incubation with wild-type α-synuclein dramatically facilitated the fibrillation by producing distinctive forms of amyloid fibrils. The suppressed fibrillation propensity was instantly restored as the structural restriction was unleashed with β-mercaptoethanol. Conformational flexibility of the accreting amyloidogenic protein to pre-existing seeds has been demonstrated to be critical for fibrillar extension process by exerting structural adjustment to a complementary structure for the assembly

End-to-end Structural Restriction of α-Synuclein and Its Influence on Amyloid Fibril Formation

Energy Technology Data Exchange (ETDEWEB)

Hong, Chul Suk; Park, Jae Hyung; Choe, Young Jun; Paik, Seung R. [Seoul National University, Seoul (Korea, Republic of)

2014-09-15

Relationship between molecular freedom of amyloidogenic protein and its self-assembly into amyloid fibrils has been evaluated with α-synuclein, an intrinsically unfolded protein related to Parkinson's disease, by restricting its structural plasticity through an end-to-end disulfide bond formation between two newly introduced cysteine residues on the N- and C-termini. Although the resulting circular form of α-synuclein exhibited an impaired fibrillation propensity, the restriction did not completely block the protein's interactive core since co-incubation with wild-type α-synuclein dramatically facilitated the fibrillation by producing distinctive forms of amyloid fibrils. The suppressed fibrillation propensity was instantly restored as the structural restriction was unleashed with β-mercaptoethanol. Conformational flexibility of the accreting amyloidogenic protein to pre-existing seeds has been demonstrated to be critical for fibrillar extension process by exerting structural adjustment to a complementary structure for the assembly.

Conformal sequestering simplified

International Nuclear Information System (INIS)

Schmaltz, Martin; Sundrum, Raman

2006-01-01

Sequestering is important for obtaining flavor-universal soft masses in models where supersymmetry breaking is mediated at high scales. We construct a simple and robust class of hidden sector models which sequester themselves from the visible sector due to strong and conformally invariant hidden dynamics. Masses for hidden matter eventually break the conformal symmetry and lead to supersymmetry breaking by the mechanism recently discovered by Intriligator, Seiberg and Shih. We give a unified treatment of subtleties due to global symmetries of the CFT. There is enough review for the paper to constitute a self-contained account of conformal sequestering

Conformity index: A review

International Nuclear Information System (INIS)

Feuvret, Loic; Noel, Georges; Mazeron, Jean-Jacques; Bey, Pierre

2006-01-01

We present a critical analysis of the conformity indices described in the literature and an evaluation of their field of application. Three-dimensional conformal radiotherapy, with or without intensity modulation, is based on medical imaging techniques, three-dimensional dosimetry software, compression accessories, and verification procedures. It consists of delineating target volumes and critical healthy tissues to select the best combination of beams. This approach allows better adaptation of the isodose to the tumor volume, while limiting irradiation of healthy tissues. Tools must be developed to evaluate the quality of proposed treatment plans. Dosimetry software provides the dose distribution in each CT section and dose-volume histograms without really indicating the degree of conformity. The conformity index is a complementary tool that attributes a score to a treatment plan or that can compare several treatment plans for the same patient. The future of conformal index in everyday practice therefore remains unclear

Conformation and stability of intramolecular telomeric G-quadruplexes: sequence effects in the loops.

Directory of Open Access Journals (Sweden)

Giovanna Sattin

Full Text Available Telomeres are guanine-rich sequences that protect the ends of chromosomes. These regions can fold into G-quadruplex structures and their stabilization by G-quadruplex ligands has been employed as an anticancer strategy. Genetic analysis in human telomeres revealed extensive allelic variation restricted to loop bases, indicating that the variant telomeric sequences maintain the ability to fold into G-quadruplex. To assess the effect of mutations in loop bases on G-quadruplex folding and stability, we performed a comprehensive analysis of mutant telomeric sequences by spectroscopic techniques, molecular dynamics simulations and gel electrophoresis. We found that when the first position in the loop was mutated from T to C or A the resulting structure adopted a less stable antiparallel topology; when the second position was mutated to C or A, lower thermal stability and no evident conformational change were observed; in contrast, substitution of the third position from A to C induced a more stable and original hybrid conformation, while mutation to T did not significantly affect G-quadruplex topology and stability. Our results indicate that allelic variations generate G-quadruplex telomeric structures with variable conformation and stability. This aspect needs to be taken into account when designing new potential anticancer molecules.

Fermion-scalar conformal blocks

Energy Technology Data Exchange (ETDEWEB)

Iliesiu, Luca [Joseph Henry Laboratories, Princeton University,Washington Road, Princeton, NJ 08544 (United States); Kos, Filip [Department of Physics, Yale University,217 Prospect Street, New Haven, CT 06520 (United States); Poland, David [Department of Physics, Yale University,217 Prospect Street, New Haven, CT 06520 (United States); School of Natural Sciences, Institute for Advanced Study,1 Einstein Dr, Princeton, New Jersey 08540 (United States); Pufu, Silviu S. [Joseph Henry Laboratories, Princeton University,Washington Road, Princeton, NJ 08544 (United States); Simmons-Duffin, David [School of Natural Sciences, Institute for Advanced Study,1 Einstein Dr, Princeton, New Jersey 08540 (United States); Yacoby, Ran [Joseph Henry Laboratories, Princeton University,Washington Road, Princeton, NJ 08544 (United States)

2016-04-13

We compute the conformal blocks associated with scalar-scalar-fermion-fermion 4-point functions in 3D CFTs. Together with the known scalar conformal blocks, our result completes the task of determining the so-called ‘seed blocks’ in three dimensions. Conformal blocks associated with 4-point functions of operators with arbitrary spins can now be determined from these seed blocks by using known differential operators.

Fabrication challenges associated with conformal optics

Science.gov (United States)

Schaefer, John; Eichholtz, Richard A.; Sulzbach, Frank C.

2001-09-01

A conformal optic is typically an optical window that conforms smoothly to the external shape of a system platform to improve aerodynamics. Conformal optics can be on-axis, such as an ogive missile dome, or off-axis, such as in a free form airplane wing. A common example of conformal optics is the automotive head light window that conforms to the body of the car aerodynamics and aesthetics. The unusual shape of conformal optics creates tremendous challenges for design, manufacturing, and testing. This paper will discuss fabrication methods that have been successfully demonstrated to produce conformal missile domes and associated wavefront corrector elements. It will identify challenges foreseen with more complex free-form configurations. Work presented in this paper was directed by the Precision Conformal Optics Consortium (PCOT). PCOT is comprised of both industrial and academic members who teamed to develop and demonstrate conformal optical systems suitable for insertion into future military programs. The consortium was funded under DARPA agreement number MDA972-96-9-08000.

The Fab Conformations in the Solution Structure of Human Immunoglobulin G4 (IgG4) Restrict Access to Its Fc Region

Science.gov (United States)

Rayner, Lucy E.; Hui, Gar Kay; Gor, Jayesh; Heenan, Richard K.; Dalby, Paul A.; Perkins, Stephen J.

2014-01-01

Human IgG4 antibody shows therapeutically useful properties compared with the IgG1, IgG2, and IgG3 subclasses. Thus IgG4 does not activate complement and shows conformational variability. These properties are attributable to its hinge region, which is the shortest of the four IgG subclasses. Using high throughput scattering methods, we studied the solution structure of wild-type IgG4(Ser222) and a hinge mutant IgG4(Pro222) in different buffers and temperatures where the proline substitution suppresses the formation of half-antibody. Analytical ultracentrifugation showed that both IgG4 forms were principally monomeric with sedimentation coefficients s20,w0 of 6.6–6.8 S. A monomer-dimer equilibrium was observed in heavy water buffer at low temperature. Scattering showed that the x-ray radius of gyration Rg was unchanged with concentration in 50–250 mm NaCl buffers, whereas the neutron Rg values showed a concentration-dependent increase as the temperature decreased in heavy water buffers. The distance distribution curves (P(r)) revealed two peaks, M1 and M2, that shifted below 2 mg/ml to indicate concentration-dependent IgG4 structures in addition to IgG4 dimer formation at high concentration in heavy water. Constrained x-ray and neutron scattering modeling revealed asymmetric solution structures for IgG4(Ser222) with extended hinge structures. The IgG4(Pro222) structure was similar. Both IgG4 structures showed that their Fab regions were positioned close enough to the Fc region to restrict C1q binding. Our new molecular models for IgG4 explain its inability to activate complement and clarify aspects of its stability and function for therapeutic applications. PMID:24876381

Reactions driving conformational movements (molecular motors) in gels: conformational and structural chemical kinetics.

Science.gov (United States)

Otero, Toribio F

2017-01-18

In this perspective the empirical kinetics of conducting polymers exchanging anions and solvent during electrochemical reactions to get dense reactive gels is reviewed. The reaction drives conformational movements of the chains (molecular motors), exchange of ions and solvent with the electrolyte and structural (relaxation, swelling, shrinking and compaction) gel changes. Reaction-driven structural changes are identified and quantified from electrochemical responses. The empirical reaction activation energy (E a ), the reaction coefficient (k) and the reaction orders (α and β) change as a function of the conformational energy variation during the reaction. This conformational energy becomes an empirical magnitude. E a , k, α and β include and provide quantitative conformational and structural information. The chemical kinetics becomes structural chemical kinetics (SCK) for reactions driving conformational movements of the reactants. The electrochemically stimulated conformational relaxation model describes empirical results and some results from the literature for biochemical reactions. In parallel the development of an emerging technological world of soft, wet, multifunctional and biomimetic tools and anthropomorphic robots driven by reactions of the constitutive material, as in biological organs, can be now envisaged being theoretically supported by the kinetic model.

Axiomatic conformal field theory

International Nuclear Information System (INIS)

Gaberdiel, M.R.; Goddard, P.

2000-01-01

A new rigourous approach to conformal field theory is presented. The basic objects are families of complex-valued amplitudes, which define a meromorphic conformal field theory (or chiral algebra) and which lead naturally to the definition of topological vector spaces, between which vertex operators act as continuous operators. In fact, in order to develop the theory, Moebius invariance rather than full conformal invariance is required but it is shown that every Moebius theory can be extended to a conformal theory by the construction of a Virasoro field. In this approach, a representation of a conformal field theory is naturally defined in terms of a family of amplitudes with appropriate analytic properties. It is shown that these amplitudes can also be derived from a suitable collection of states in the meromorphic theory. Zhu's algebra then appears naturally as the algebra of conditions which states defining highest weight representations must satisfy. The relationship of the representations of Zhu's algebra to the classification of highest weight representations is explained. (orig.)

Conformal description of spinning particles

International Nuclear Information System (INIS)

Todorov, I.T.

1986-01-01

This book is an introduction to the application of the conformal group to quantum field theory of particles with spin. After an introduction to the twistor representations of the conformal group of a conformally flat space-time and twistor flag manifolds with Su(2,2) orbits the classical phase space of conformal spinning particles is described. Thereafter the twistor description of classical zero mass fields is considered together with the quantization. (HSI)

Conformal boundaries of warped products

DEFF Research Database (Denmark)

Kokkendorff, Simon Lyngby

2006-01-01

In this note we prove a result on how to determine the conformal boundary of a type of warped product of two length spaces in terms of the individual conformal boundaries. In the situation, that we treat, the warping and conformal distortion functions are functions of distance to a base point....... The result is applied to produce examples of CAT(0)-spaces, where the conformal and ideal boundaries differ in interesting ways....

Conformally connected universes

International Nuclear Information System (INIS)

Cantor, M.; Piran, T.

1983-01-01

A well-known difficulty associated with the conformal method for the solution of the general relativistic Hamiltonian constraint is the appearance of an aphysical ''bag of gold'' singularity at the nodal surface of the conformal factor. This happens whenever the background Ricci scalar is too large. Using a simple model, it is demonstrated that some of these singular solutions do have a physical meaning, and that these can be considered as initial data for Universe containing black holes, which are connected, in a conformally nonsingular way with each other. The relation between the ADM mass and the horizon area in this solution supports the cosmic censorship conjecture. (author)

Binding induced conformational changes of proteins correlate with their intrinsic fluctuations: a case study of antibodies

Directory of Open Access Journals (Sweden)

Keskin Ozlem

2007-05-01

Full Text Available Abstract Background How antibodies recognize and bind to antigens can not be totally explained by rigid shape and electrostatic complimentarity models. Alternatively, pre-existing equilibrium hypothesis states that the native state of an antibody is not defined by a single rigid conformation but instead with an ensemble of similar conformations that co-exist at equilibrium. Antigens bind to one of the preferred conformations making this conformation more abundant shifting the equilibrium. Results Here, two antibodies, a germline antibody of 36–65 Fab and a monoclonal antibody, SPE7 are studied in detail to elucidate the mechanism of antibody-antigen recognition and to understand how a single antibody recognizes different antigens. An elastic network model, Anisotropic Network Model (ANM is used in the calculations. Pre-existing equilibrium is not restricted to apply to antibodies. Intrinsic fluctuations of eight proteins, from different classes of proteins, such as enzymes, binding and transport proteins are investigated to test the suitability of the method. The intrinsic fluctuations are compared with the experimentally observed ligand induced conformational changes of these proteins. The results show that the intrinsic fluctuations obtained by theoretical methods correlate with structural changes observed when a ligand is bound to the protein. The decomposition of the total fluctuations serves to identify the different individual modes of motion, ranging from the most cooperative ones involving the overall structure, to the most localized ones. Conclusion Results suggest that the pre-equilibrium concept holds for antibodies and the promiscuity of antibodies can also be explained this hypothesis: a limited number of conformational states driven by intrinsic motions of an antibody might be adequate to bind to different antigens.

On Associative Conformal Algebras of Linear Growth

OpenAIRE

Retakh, Alexander

2000-01-01

Lie conformal algebras appear in the theory of vertex algebras. Their relation is similar to that of Lie algebras and their universal enveloping algebras. Associative conformal algebras play a role in conformal representation theory. We introduce the notions of conformal identity and unital associative conformal algebras and classify finitely generated simple unital associative conformal algebras of linear growth. These are precisely the complete algebras of conformal endomorphisms of finite ...

Conformal algebra of Riemann surfaces

International Nuclear Information System (INIS)

Vafa, C.

1988-01-01

It has become clear over the last few years that 2-dimensional conformal field theories are a crucial ingredient of string theory. Conformal field theories correspond to vacuum solutions of strings; or more precisely we know how to compute string spectrum and scattering amplitudes by starting from a formal theory (with a proper value of central charge of the Virasoro algebra). Certain non-linear sigma models do give rise to conformal theories. A lot of progress has been made in the understanding of conformal theories. The author discusses a different view of conformal theories which was motivated by the development of operator formalism on Riemann surfaces. The author discusses an interesting recent work from this point of view

Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics.

Directory of Open Access Journals (Sweden)

Barry J Grant

2009-03-01

Full Text Available Ras mediates signaling pathways controlling cell proliferation and development by cycling between GTP- and GDP-bound active and inactive conformational states. Understanding the complete reaction path of this conformational change and its intermediary structures is critical to understanding Ras signaling. We characterize nucleotide-dependent conformational transition using multiple-barrier-crossing accelerated molecular dynamics (aMD simulations. These transitions, achieved for the first time for wild-type Ras, are impossible to observe with classical molecular dynamics (cMD simulations due to the large energetic barrier between end states. Mapping the reaction path onto a conformer plot describing the distribution of the crystallographic structures enabled identification of highly populated intermediate structures. These structures have unique switch orientations (residues 25-40 and 57-75 intermediate between GTP and GDP states, or distinct loop3 (46-49, loop7 (105-110, and alpha5 C-terminus (159-166 conformations distal from the nucleotide-binding site. In addition, these barrier-crossing trajectories predict novel nucleotide-dependent correlated motions, including correlations of alpha2 (residues 66-74 with alpha3-loop7 (93-110, loop2 (26-37 with loop10 (145-151, and loop3 (46-49 with alpha5 (152-167. The interconversion between newly identified Ras conformations revealed by this study advances our mechanistic understanding of Ras function. In addition, the pattern of correlated motions provides new evidence for a dynamic linkage between the nucleotide-binding site and the membrane interacting C-terminus critical for the signaling function of Ras. Furthermore, normal mode analysis indicates that the dominant collective motion that occurs during nucleotide-dependent conformational exchange, and captured in aMD (but absent in cMD simulations, is a low-frequency motion intrinsic to the structure.

sup(1)H-NMR study of restricted rotation in dithiophosphoromethyl acetanilides

International Nuclear Information System (INIS)

Kovacs, Zs.

1985-01-01

sup(1)H-NMR spectra of a series of dithiophosphoromethyl acetanilide derivatives were investigated. The presence of an ortho substituted aryl group bonded to the nitrogen atom of the amide group allowed the observation of restricted internal rotation around the aryl-nitrogen bond. Coalescence temperature and the values of the free energy of activation were determined from the temperature dependent NMR behaviour of these molecules. The possibility of cis-trans isomerism about the nitrogen carbonyl bond was also studied, and the assignment of the conformation of the existing isomer was also made using the aromatic solvent induced shift. (author)

Conformality lost

International Nuclear Information System (INIS)

Kaplan, David B.; Lee, Jong-Wan; Son, Dam T.; Stephanov, Mikhail A.

2009-01-01

We consider zero-temperature transitions from conformal to nonconformal phases in quantum theories. We argue that there are three generic mechanisms for the loss of conformality in any number of dimensions: (i) fixed point goes to zero coupling, (ii) fixed point runs off to infinite coupling, or (iii) an IR fixed point annihilates with a UV fixed point and they both disappear into the complex plane. We give both relativistic and nonrelativistic examples of the last case in various dimensions and show that the critical behavior of the mass gap behaves similarly to the correlation length in the finite temperature Berezinskii-Kosterlitz-Thouless (BKT) phase transition in two dimensions, ξ∼exp(c/|T-T c | 1/2 ). We speculate that the chiral phase transition in QCD at large number of fermion flavors belongs to this universality class, and attempt to identify the UV fixed point that annihilates with the Banks-Zaks fixed point at the lower end of the conformal window.

40 CFR 93.154 - Conformity analysis.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Conformity analysis. 93.154 Section 93...) DETERMINING CONFORMITY OF FEDERAL ACTIONS TO STATE OR FEDERAL IMPLEMENTATION PLANS Determining Conformity of General Federal Actions to State or Federal Implementation Plans § 93.154 Conformity analysis. Any Federal...

Recursion Relations for Conformal Blocks

CERN Document Server

Penedones, João; Yamazaki, Masahito

2016-09-12

In the context of conformal field theories in general space-time dimension, we find all the possible singularities of the conformal blocks as functions of the scaling dimension $\\Delta$ of the exchanged operator. In particular, we argue, using representation theory of parabolic Verma modules, that in odd spacetime dimension the singularities are only simple poles. We discuss how to use this information to write recursion relations that determine the conformal blocks. We first recover the recursion relation introduced in 1307.6856 for conformal blocks of external scalar operators. We then generalize this recursion relation for the conformal blocks associated to the four point function of three scalar and one vector operator. Finally we specialize to the case in which the vector operator is a conserved current.

The logarithmic conformal field theories

International Nuclear Information System (INIS)

Rahimi Tabar, M.R.; Aghamohammadi, A.; Khorrami, M.

1997-01-01

We study the correlation functions of logarithmic conformal field theories. First, assuming conformal invariance, we explicitly calculate two- and three-point functions. This calculation is done for the general case of more than one logarithmic field in a block, and more than one set of logarithmic fields. Then we show that one can regard the logarithmic field as a formal derivative of the ordinary field with respect to its conformal weight. This enables one to calculate any n-point function containing the logarithmic field in terms of ordinary n-point functions. Finally, we calculate the operator product expansion (OPE) coefficients of a logarithmic conformal field theory, and show that these can be obtained from the corresponding coefficients of ordinary conformal theory by a simple derivation. (orig.)

Transmission of HBV DNA Mediated by Ceramide-Triggered Extracellular VesiclesSummary

Directory of Open Access Journals (Sweden)

Takahiro Sanada

2017-03-01

Full Text Available Background & Aims: An extracellular vesicle (EV is a nanovesicle that shuttles proteins, nucleic acids, and lipids, thereby influencing cell behavior. A recent crop of reports have shown that EVs are involved in infectious biology, influencing host immunity and playing a role in the viral life cycle. In the present work, we investigated the EV-mediated transmission of hepatitis B virus (HBV infection. Methods: We investigated the EV-mediated transmission of HBV infection by using a HBV infectious culture system that uses primary human hepatocytes derived from humanized chimeric mice (PXB-cells. Purified EVs were isolated by ultracentrifugation. To analyze the EVs and virions, we used stimulated emission depletion microscopy. Results: Purified EVs from HBV-infected PXB-cells were shown to contain HBV DNA and to be capable of transmitting HBV DNA to naive PXB-cells. These HBV-DNA–transmitting EVs were shown to be generated through a ceramide-triggered EV production pathway. Furthermore, we showed that these HBV-DNA–transmitting EVs were resistant to antibody neutralization; stimulated emission depletion microscopy showed that EVs lacked hepatitis B surface antigen, the target of neutralizing antibodies. Conclusions: These findings suggest that EVs harbor a DNA cargo capable of transmitting viral DNA into hepatocytes during HBV infection, representing an additional antibody-neutralization–resistant route of HBV infection. Keywords: HBV, Extracellular Vesicles, Transmission Pathway

Atropisomerism about Aryl-C(sp(3)) Bonds: Conformational Behavior of Substituted Phenylcyclohexanes in Solution.

Science.gov (United States)

Flos, Manon; Lameiras, Pedro; Denhez, Clément; Mirand, Catherine; Berber, Hatice

2016-03-18

A catalytic hydrogenation of cannabidiol derivatives known as phenylcyclohexenes was used to prepare epimeric (1R,1S) and/or rotameric (M,P) phenylcyclohexanes. The reaction is diastereoselective, in favor of the 1S epimer, when large groups are attached to the phenyl ring. For each epimer, variable-temperature NMR experiments, including EXSY spectroscopy and DFT calculations, were used to determine the activation energies of the conformational exchange arising from the restricted rotation about the aryl-C(sp(3)) bond that led to two unequally populated rotamers. The conformational preference arises essentially from steric interactions between substituents vicinal to the pivot bond. The conformers of epimers (1S)-2e,f show high rotational barriers of up to 92 kJ mol(-1), unlike those of (1R)-2e,f and with much lower barriers of ∼72 kJ mol(-1). The height of the barriers not only depends on the substituents at the axis of chirality but also is influenced by the position of a methyl group on the monoterpene ring. The feature most favorable to high rotational barriers is when the methyl at C1 lies equatorially. This additional substituent effect, highlighted for the first time, seems fundamental to allowing atropisomerism in hindered ortho-substituted phenylcyclohexanes.

Recent advancements in conformal gravity

International Nuclear Information System (INIS)

O’Brien, James G.; Chaykov, Spasen S.; Moss, Robert J.; Dentico, Jeremy; Stulge, Modestas; Stefanski, Brian

2017-01-01

In recent years, due to the lack of direct observed evidence of cold dark matter, coupled with the shrinking parameter space to search for new dark matter particles, there has been increased interest in Alternative Gravitational theories. This paper, addresses three recent advances in conformal gravity, a fourth order renormalizable metric theory of gravitation originally formulated by Weyl, and later advanced by Mannheim and Kazanas. The first section of the paper applies conformal gravity to the rotation curves of the LITTLE THINGS survey, extending the total number of rotation curves successfully fit by conformal gravity to well over 200 individual data sets without the need for additional dark matter. Further, in this rotation curve study, we show how MOND and conformal gravity compare for each galaxy in the sample. Second, we look at the original Zwicky problem of applying the virial theorem to the Coma cluster in order to get an estimate for the cluster mass. However, instead of using the standard Newtonian potential, here we use the weak field approximation of conformal gravity. We show that in the conformal case we can get a much smaller mass estimate and thus there is no apparent need to include dark matter. We then show that this calculation is in agreement with the observational data from other well studied clusters. Last, we explore the calculation of the deflection of starlight through conformal gravity, as a first step towards applying conformal gravity to gravitaitonal lensing. (paper)

Conformally invariant processes in the plane

International Nuclear Information System (INIS)

Lawler, G.F.

2004-01-01

These lectures will focus on recent rigorous work on continuum limits of planar lattice models from statistical physics at criticality. For an introduction, I would like to discuss the general problem of critical exponents and scaling limits for lattice models in equilibrium statistical mechanics. There are a number of models, [e.g., self-avoiding walk (polymers), percolation, loop-erased random walk (uniform spanning trees, domino tilings), Ising model, Potts model, nonintersecting simple random walks] that fall under this general framework. These lectures will consider the case d = 2. Mathematicians are now starting to understand rigorously the scaling limit of two-dimensional systems. For most of these models, the general strategy can be described as: Construct possible continuum limits for these models. Show that there are only a limited number of such limits that are conformally invariant. Prove that the lattice model approaches the continuum limit. We should think of the first step as being similar for all of these models. We will spend the next couple of lectures discussing the continuum limits. One example you should already know - the scaling limit of simple random walk is Brownian motion (which in two dimensions is conformally invariant). The important new ideas are restriction measures and stochastic Loewner evolution (SLE). The later lectures will discuss rigorous results about lattice models approaching the continuum limit - we will discuss nonintersecting random walks (which can be shown to be equivalent to problems about exceptional sets of Brownian paths), percolation on the triangular lattice, and the loop-erased random walk. As a rule, the methods used for the second step are particular to each model

PDMP, a ceramide analogue, acts as an inhibitor of mTORC1 by inducing its translocation from lysosome to endoplasmic reticulum

Energy Technology Data Exchange (ETDEWEB)

Ode, Takashi [Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Research Fellow of the Japan Society for the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083 (Japan); Podyma-Inoue, Katarzyna A.; Terasawa, Kazue [Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Inokuchi, Jin-ichi [Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558 (Japan); Kobayashi, Toshihide [Lipid Biology Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch (France); Watabe, Tetsuro [Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Izumi, Yuichi [Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Hara-Yokoyama, Miki, E-mail: m.yokoyama.bch@tmd.ac.jp [Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan)

2017-01-01

Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism, and cell differentiation. Recent studies have revealed that the recruitment of mTORC1 to lysosomes is essential for its activation. The ceramide analogue 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a well known glycosphingolipid synthesis inhibitor, also affects the structures and functions of various organelles, including lysosomes and endoplasmic reticulum (ER). We investigated whether PDMP regulates the mTORC1 activity through its effects on organellar behavior. PDMP induced the translocation of mTORC1 from late endosomes/lysosomes, leading to the dissociation of mTORC1 from its activator Rheb in MC3T3-E1 cells. Surprisingly, we found mTORC1 translocation to the ER upon PDMP treatment. This effect of PDMP was independent of its action as the inhibitor, since two stereoisomers of PDMP, with and without the inhibitor activity, showed essentially the same effect. We confirmed that PDMP inhibits the mTORC1 activity based on the decrease in the phosphorylation of ribosomal S6 kinase, a downstream target of mTORC1, and the increase in LC3 puncta, reflecting autophagosome formation. Furthermore, PDMP inhibited the mTORC1-dependent osteoblastic cell proliferation and differentiation of MC3T3-E1 cells. Accordingly, the present results reveal a novel mechanism of PDMP, which inhibits the mTORC1 activity by inducing the translocation of mTOR from lysosomes to the ER. - Highlights: • The ceramide analogue, PDMP, suppressed the activation of mTORC1. • PDMP induced the translocation of mTOR from lysosomes to ER. • PDMP led to the dissociation of mTOR from its activator Rheb. • PDMP inhibited the mTORC1-dependent osteoblastic cell proliferation.

Benchmarking Commercial Conformer Ensemble Generators.

Science.gov (United States)

Friedrich, Nils-Ole; de Bruyn Kops, Christina; Flachsenberg, Florian; Sommer, Kai; Rarey, Matthias; Kirchmair, Johannes

2017-11-27

We assess and compare the performance of eight commercial conformer ensemble generators (ConfGen, ConfGenX, cxcalc, iCon, MOE LowModeMD, MOE Stochastic, MOE Conformation Import, and OMEGA) and one leading free algorithm, the distance geometry algorithm implemented in RDKit. The comparative study is based on a new version of the Platinum Diverse Dataset, a high-quality benchmarking dataset of 2859 protein-bound ligand conformations extracted from the PDB. Differences in the performance of commercial algorithms are much smaller than those observed for free algorithms in our previous study (J. Chem. Inf. 2017, 57, 529-539). For commercial algorithms, the median minimum root-mean-square deviations measured between protein-bound ligand conformations and ensembles of a maximum of 250 conformers are between 0.46 and 0.61 Å. Commercial conformer ensemble generators are characterized by their high robustness, with at least 99% of all input molecules successfully processed and few or even no substantial geometrical errors detectable in their output conformations. The RDKit distance geometry algorithm (with minimization enabled) appears to be a good free alternative since its performance is comparable to that of the midranked commercial algorithms. Based on a statistical analysis, we elaborate on which algorithms to use and how to parametrize them for best performance in different application scenarios.

Accumulation of long-chain glycosphingolipids during aging is prevented by caloric restriction.

Directory of Open Access Journals (Sweden)

María José Hernández-Corbacho

Full Text Available Chronic kidney disease and end-stage renal disease are major causes of morbidity and mortality that are seen far more commonly in the aged population. Interestingly, kidney function declines during aging even in the absence of underlying renal disease. Declining renal function has been associated with age-related cellular damage and dysfunction with reports of increased levels of apoptosis, necrosis, and inflammation in the aged kidney. Bioactive sphingolipids have been shown to regulate these same cellular processes, and have also been suggested to play a role in aging and cellular senescence.We hypothesized that alterations in kidney sphingolipids play a role in the declining kidney function that occurs during aging. To begin to address this, the sphingolipid profile was measured in young (3 mo, middle aged (9 mo and old (17 mo C57BL/6 male mice. Interestingly, while modest changes in ceramides and sphingoid bases were evident in kidneys from older mice, the most dramatic elevations were seen in long-chain hexosylceramides (HexCer and lactosylceramides (LacCer, with C14- and C16-lactosylceramides elevated as much as 8 and 12-fold, respectively. Increases in long-chain LacCers during aging are not exclusive to the kidney, as they also occur in the liver and brain. Importantly, caloric restriction, previously shown to prevent the declining kidney function seen in aging, inhibits accumulation of long-chain HexCer/LacCers and prevents the age-associated elevation of enzymes involved in their synthesis. Additionally, long-chain LacCers are also significantly elevated in human fibroblasts isolated from elderly individuals.This study demonstrates accumulation of the glycosphingolipids HexCer and LacCer in several different organs in rodents and humans during aging. In addition, data demonstrate that HexCer and LacCer metabolism is regulated by caloric restriction. Taken together, data suggest that HexCer/LacCers are important mediators of cellular

Enhancement of ceramide formation increases endocytosis of Lactobacillus acidophilus and leads to increased IFN-β and IL-12 production in dendritic cells

DEFF Research Database (Denmark)

Fuglsang, Eva; Boye, Louise; Frøkiær, Hanne

2017-01-01

, and induced macropinocytosis in the bmDCs. Addition of SMase increased the phagocytosis of L. acidophilus and L. acidophilus-induced IL-12/IFN-β but showed no effect on the uptake of E. coli nor on E.coli induced IL-12/IFN-β production. Also, SMase did not affect Pam3CSK4-induced macropinocytosis of FITC......-dextran. Inhibition of both acid SMase and ceramidase by CPZ increased constitutive macropinocytosis of dextran and slightly increased L.acidophilus induced Il12/Ifn-β expression and E.coli induced Ifnβ expression. Our results confirm a role for ceramide in the L.acidophilus induced IL-12/IFN-β production but also...

Conformal and Nearly Conformal Theories at Large N

Science.gov (United States)

Tarnoplskiy, Grigory M.

In this thesis we present new results in conformal and nearly conformal field theories in various dimensions. In chapter two, we study different properties of the conformal Quantum Electrodynamics (QED) in continuous dimension d. At first we study conformal QED using large Nf methods, where Nf is the number of massless fermions. We compute its sphere free energy as a function of d, ignoring the terms of order 1/Nf and higher. For finite Nf we use the epsilon-expansion. Next we use a large Nf diagrammatic approach to calculate the leading corrections to CT, the coefficient of the two-point function of the stress-energy tensor, and CJ, the coefficient of the two-point function of the global symmetry current. We present explicit formulae as a function of d and check them versus the expectations in 2 and 4 - epsilon dimensions. In chapter three, we discuss vacuum stability in 1 + 1 dimensional conformal field theories with external background fields. We show that the vacuum decay rate is given by a non-local two-form. This two-form is a boundary term that must be added to the effective in/out Lagrangian. The two-form is expressed in terms of a Riemann-Hilbert decomposition for background gauge fields, and is given by its novel "functional'' version in the gravitational case. In chapter four, we explore Tensor models. Such models possess the large N limit dominated by the melon diagrams. The quantum mechanics of a real anti-commuting rank-3 tensor has a large N limit similar to the Sachdev-Ye-Kitaev (SYK) model. We also discuss the quantum mechanics of a complex 3-index anti-commuting tensor and argue that it is equivalent in the large N limit to a version of SYK model with complex fermions. Finally, we discuss models of a commuting tensor in dimension d. We study the spectrum of the large N quantum field theory of bosonic rank-3 tensors using the Schwinger-Dyson equations. We compare some of these results with the 4 - epsilon expansion, finding perfect agreement. We

S-Adenosylmethionine conformations in solution and in protein complexes: Conformational influences of the sulfonium group

DEFF Research Database (Denmark)

Markham, George D.; Norrby, Per-Ola; Bock, Charles W.

2002-01-01

S-Adenosylmethionine (AdoMet) and other sulfonium ions play central roles in the metabolism of all organisms. The conformational preferences of AdoMet and two other biologically important sulfonium ions, S-methylmethionine and dimethylsulfonioproprionic acid, have been investigated by NMR...... and computational studies. Molecular mechanics parameters for the sulfonium center have been developed for the AMBER force field to permit analysis of NMR results and to enable comparison of the relative energies of the different conformations of AdoMet that have been found in crystal structures of complexes...... with proteins. S-Methylmethionine and S-dimethylsulfonioproprionate adopt a variety of conformations in aqueous solution; a conformation with an electrostatic interaction between the sulfonium sulfur and the carboxylate group is not noticeably favored, in contrast to the preferred conformation found by in vacuo...

Conformal Killing vectors in Robertson-Walker spacetimes

International Nuclear Information System (INIS)

Maartens, R.; Maharaj, S.d.

1986-01-01

It is well known that Robertson-Walker spacetimes admit a conformal Killingl vector normal to the spacelike homogeneous hypersurfaces. Because these spacetimes are conformally flat, there are a further eight conformal Killing vectors, which are neither normal nor tangent to the homogeneous hypersurfaces. The authors find these further conformal Killing vectors and the Lie algebra of the full G 15 of conformal motions. Conditions on the metric scale factor are determined which reduce some of the conformal Killing vectors to homothetic Killing vectors or Killing vectors, allowing one to regain in a unified way the known special geometries. The non-normal conformal Killing vectors provide a counter-example to show that conformal motions do not, in general, map a fluid flow conformally. These non-normal vectors are also used to find the general solution of the null geodesic equation and photon Liouville equation. (author)

Conformal transformations in superspace

International Nuclear Information System (INIS)

Dao Vong Duc

1977-01-01

The spinor extension of the conformal algebra is investigated. The transformation law of superfields under the conformal coordinate inversion R defined in the superspace is derived. Using R-technique, the superconformally covariant two-point and three-point correlation functions are found

Towards conformal loop quantum gravity

International Nuclear Information System (INIS)

Wang, Charles H-T

2006-01-01

A discussion is given of recent developments in canonical gravity that assimilates the conformal analysis of gravitational degrees of freedom. The work is motivated by the problem of time in quantum gravity and is carried out at the metric and the triad levels. At the metric level, it is shown that by extending the Arnowitt-Deser-Misner (ADM) phase space of general relativity (GR), a conformal form of geometrodynamics can be constructed. In addition to the Hamiltonian and Diffeomorphism constraints, an extra first class constraint is introduced to generate conformal transformations. This phase space consists of York's mean extrinsic curvature time, conformal three-metric and their momenta. At the triad level, the phase space of GR is further enlarged by incorporating spin-gauge as well as conformal symmetries. This leads to a canonical formulation of GR using a new set of real spin connection variables. The resulting gravitational constraints are first class, consisting of the Hamiltonian constraint and the canonical generators for spin-gauge and conformorphism transformations. The formulation has a remarkable feature of being parameter-free. Indeed, it is shown that a conformal parameter of the Barbero-Immirzi type can be absorbed by the conformal symmetry of the extended phase space. This gives rise to an alternative approach to loop quantum gravity that addresses both the conceptual problem of time and the technical problem of functional calculus in quantum gravity

A single-center, prospective, randomized, open-label, clinical trial of ceramide 2-containing hydrocolloid dressings versus polyurethane film dressings for pressure ulcer prevention in high-risk surgical patients

Directory of Open Access Journals (Sweden)

Kohta M

2015-11-01

Full Text Available Masushi Kohta,1 Kazumi Sakamoto,2 Yasuhiro Kawachi,3 Tsunao Oh-i4 1Medical Engineering Laboratory, ALCARE Co, Ltd, Tokyo, 2Department of Nursing, 3Department of Dermatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, 4Department of Dermatology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan Purpose: There have been previous clinical studies regarding the impact of dressings on the prevention of pressure ulcer development. However, it remains unclear whether one type of dressing is better than any other type for preventing ulcer development during surgery. Therefore, we compared the effects of ceramide 2-containing hydrocolloid dressing with film dressings in high-risk patients with regard to reducing the incidence of pressure ulcer development during surgery. Patients and methods: A prospective, randomized, open-label, clinical trial was conducted involving patients who were at a high risk of developing pressure ulcers at a Japanese hospital. The intervention group received ceramide 2-containing hydrocolloid dressings (n=66, and the control group received film dressings (n=64. The primary end point was the incidence rate of pressure ulcer development in both groups; skin damage, such as blanchable erythema, skin discoloration, contact dermatitis, and stripped skin, was recorded as the secondary end point. The relative risk (RR and 95% confidence interval (CI were assessed to compare the probability ratios of pressure ulcer development between the groups. Results: There were significantly fewer patients who developed pressure ulcers in the intervention group than in the control group (RR, 0.37; 95% CI, 0.05–0.99; P=0.04. In the post hoc subgroup analysis, the superiority of the intervention group was more marked when patients had a lower body mass index (P=0.02, lower albumin values (P=0.07, and operation time of 3 hours or more and less than 6 hours (P=0.03. There was no evidence of any statistically significant

Mass generation within conformal invariant theories

International Nuclear Information System (INIS)

Flato, M.; Guenin, M.

1981-01-01

The massless Yang-Mills theory is strongly conformally invariant and renormalizable; however, when masses are introduced the theory becomes nonrenormalizable and weakly conformally invariant. Conditions which recover strong conformal invariance are discussed in the letter. (author)

Conformal group actions and Segal's cosmology

International Nuclear Information System (INIS)

Werth, J.-E.

1984-01-01

A mathematical description of Segal's cosmological model in the framework of conformal group actions is presented. The relation between conformal and causal group actions on time-orientable Lorentzian manifolds is analysed and several examples are discussed. A criterion for the conformality of a map between Lorentzian manifolds is given. The results are applied to Segal's 'conformal compactification' of Minkowski space. Furthermore, the 'unitary formulation' of Segal's cosmology is regarded. (Author) [pt

Conformal field theories and critical phenomena

International Nuclear Information System (INIS)

Xu, Bowei

1993-01-01

In this article we present a brief review of the conformal symmetry and the two dimensional conformal quantum field theories. As concrete applications of the conformal theories to the critical phenomena in statistical systems, we calculate the value of central charge and the anomalous scale dimensions of the Z 2 symmetric quantum chain with boundary condition. The results are compatible with the prediction of the conformal field theories

New conformations of linear polyubiquitin chains from crystallographic and solution-scattering studies expand the conformational space of polyubiquitin.

Science.gov (United States)

Thach, Trung Thanh; Shin, Donghyuk; Han, Seungsu; Lee, Sangho

2016-04-01

The conformational flexibility of linkage-specific polyubiquitin chains enables ubiquitylated proteins and their receptors to be involved in a variety of cellular processes. Linear or Met1-linked polyubiquitin chains, associated with nondegradational cellular signalling pathways, have been known to adopt multiple conformations from compact to extended conformations. However, the extent of such conformational flexibility remains open. Here, the crystal structure of linear Ub2 was determined in a more compact conformation than that of the previously known structure (PDB entry 3axc). The two structures differ significantly from each other, as shown by an r.m.s.d. between C(α) atoms of 3.1 Å. The compactness of the linear Ub2 structure in comparison with PDB entry 3axc is supported by smaller values of the radius of gyration (Rg; 18 versus 18.9 Å) and the maximum interatomic distance (Dmax; 55.5 versus 57.8 Å). Extra intramolecular hydrogen bonds formed among polar residues between the distal and proximal ubiquitin moieties seem to contribute to stabilization of the compact conformation of linear Ub2. An ensemble of three semi-extended and extended conformations of linear Ub2 was also observed by small-angle X-ray scattering (SAXS) analysis in solution. In addition, the conformational heterogeneity in linear polyubiquitin chains is clearly manifested by SAXS analyses of linear Ub3 and Ub4: at least three distinct solution conformations are observed in each chain, with the linear Ub3 conformations being compact. The results expand the extent of conformational space of linear polyubiquitin chains and suggest that changes in the conformational ensemble may be pivotal in mediating multiple signalling pathways.

Ward identities for conformal models

International Nuclear Information System (INIS)

Lazzarini, S.; Stora, R.

1988-01-01

Ward identities which express the symmetry of conformal models are treated. Diffeomorphism invariance or locally holomorphic coordinate transformations are used. Diffeomorphism invariance is then understood in terms of Riemannian geometry. Two different sets of Ward identities expressing diffeomorphism invariance in a conformally invariant way are found for the free bosonic string. Using a geometrical argument, the correct invariance for a large class of conformal models is given

Conformity and statistical tolerancing

Science.gov (United States)

Leblond, Laurent; Pillet, Maurice

2018-02-01

Statistical tolerancing was first proposed by Shewhart (Economic Control of Quality of Manufactured Product, (1931) reprinted 1980 by ASQC), in spite of this long history, its use remains moderate. One of the probable reasons for this low utilization is undoubtedly the difficulty for designers to anticipate the risks of this approach. The arithmetic tolerance (worst case) allows a simple interpretation: conformity is defined by the presence of the characteristic in an interval. Statistical tolerancing is more complex in its definition. An interval is not sufficient to define the conformance. To justify the statistical tolerancing formula used by designers, a tolerance interval should be interpreted as the interval where most of the parts produced should probably be located. This tolerance is justified by considering a conformity criterion of the parts guaranteeing low offsets on the latter characteristics. Unlike traditional arithmetic tolerancing, statistical tolerancing requires a sustained exchange of information between design and manufacture to be used safely. This paper proposes a formal definition of the conformity, which we apply successively to the quadratic and arithmetic tolerancing. We introduce a concept of concavity, which helps us to demonstrate the link between tolerancing approach and conformity. We use this concept to demonstrate the various acceptable propositions of statistical tolerancing (in the space decentring, dispersion).

Dissecting the large-scale galactic conformity

Science.gov (United States)

Seo, Seongu

2018-01-01

Galactic conformity is an observed phenomenon that galaxies located in the same region have similar properties such as star formation rate, color, gas fraction, and so on. The conformity was first observed among galaxies within in the same halos (“one-halo conformity”). The one-halo conformity can be readily explained by mutual interactions among galaxies within a halo. Recent observations however further witnessed a puzzling connection among galaxies with no direct interaction. In particular, galaxies located within a sphere of ~5 Mpc radius tend to show similarities, even though the galaxies do not share common halos with each other ("two-halo conformity" or “large-scale conformity”). Using a cosmological hydrodynamic simulation, Illustris, we investigate the physical origin of the two-halo conformity and put forward two scenarios. First, back-splash galaxies are likely responsible for the large-scale conformity. They have evolved into red galaxies due to ram-pressure stripping in a given galaxy cluster and happen to reside now within a ~5 Mpc sphere. Second, galaxies in strong tidal field induced by large-scale structure also seem to give rise to the large-scale conformity. The strong tides suppress star formation in the galaxies. We discuss the importance of the large-scale conformity in the context of galaxy evolution.

Entanglement evolution across a conformal interface

Science.gov (United States)

Wen, Xueda; Wang, Yuxuan; Ryu, Shinsei

2018-05-01

For two-dimensional conformal field theories (CFTs) in the ground state, it is known that a conformal interface along the entanglement cut can suppress the entanglement entropy from to , where L is the length of the subsystem A, and is the effective central charge which depends on the transmission property of the conformal interface. In this work, by making use of conformal mappings, we show that a conformal interface has the same effect on entanglement evolution in non-equilibrium cases, including global, local and certain inhomogeneous quantum quenches. I.e. a conformal interface suppresses the time evolution of entanglement entropy by effectively replacing the central charge c with , where is exactly the same as that in the ground state case. We confirm this conclusion by a numerical study on a critical fermion chain. Furthermore, based on the quasi-particle picture, we conjecture that this conclusion holds for an arbitrary quantum quench in CFTs, as long as the initial state can be described by a regularized conformal boundary state.

Re-evaluating the kinetics of ATP hydrolysis during initiation of DNA sliding by Type III restriction enzymes.

Science.gov (United States)

Tóth, Júlia; Bollins, Jack; Szczelkun, Mark D

2015-12-15

DNA cleavage by the Type III restriction enzymes requires long-range protein communication between recognition sites facilitated by thermally-driven 1D diffusion. This 'DNA sliding' is initiated by hydrolysis of multiple ATPs catalysed by a helicase-like domain. Two distinct ATPase phases were observed using short oligoduplex substrates; the rapid consumption of ∼10 ATPs coupled to a protein conformation switch followed by a slower phase, the duration of which was dictated by the rate of dissociation from the recognition site. Here, we show that the second ATPase phase is both variable and only observable when DNA ends are proximal to the recognition site. On DNA with sites more distant from the ends, a single ATPase phase coupled to the conformation switch was observed and subsequent site dissociation required little or no further ATP hydrolysis. The overall DNA dissociation kinetics (encompassing site release, DNA sliding and escape via a DNA end) were not influenced by the second phase. Although the data simplifies the ATP hydrolysis scheme for Type III restriction enzymes, questions remain as to why multiple ATPs are hydrolysed to prepare for DNA sliding. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Long, partial-short, and special conformal fields

Energy Technology Data Exchange (ETDEWEB)

Metsaev, R.R. [Department of Theoretical Physics, P.N. Lebedev Physical Institute,Leninsky prospect 53, Moscow 119991 (Russian Federation)

2016-05-17

In the framework of metric-like approach, totally symmetric arbitrary spin bosonic conformal fields propagating in flat space-time are studied. Depending on the values of conformal dimension, spin, and dimension of space-time, we classify all conformal field as long, partial-short, short, and special conformal fields. An ordinary-derivative (second-derivative) Lagrangian formulation for such conformal fields is obtained. The ordinary-derivative Lagrangian formulation is realized by using double-traceless gauge fields, Stueckelberg fields, and auxiliary fields. Gauge-fixed Lagrangian invariant under global BRST transformations is obtained. The gauge-fixed BRST Lagrangian is used for the computation of partition functions for all conformal fields. Using the result for the partition functions, numbers of propagating D.o.F for the conformal fields are also found.

Maxwell equations in conformal invariant electrodynamics

International Nuclear Information System (INIS)

Fradkin, E.S.; AN SSSR, Novosibirsk. Inst. Avtomatiki i Ehlektrometrii); Kozhevnikov, A.A.; Palchik, M.Ya.; Pomeransky, A.A.

1983-01-01

We consider a conformal invariant formulation of quantum electrodynamics. Conformal invariance is achieved with a specific mathematical construction based on the indecomposable representations of the conformal group associated with the electromagnetic potential and current. As a corolary of this construction modified expressions for the 3-point Green functions are obtained which both contain transverse parts. They make it possible to formulate a conformal invariant skeleton perturbation theory. It is also shown that the Euclidean Maxwell equations in conformal electrodynamics are manifestations of its kinematical structure: in the case of the 3-point Green functions these equations follow (up to constants) from the conformal invariance while in the case of higher Green functions they are equivalent to the equality of the kernels of the partial wave expansions. This is the manifestation of the mathematical fast of a (partial) equivalence of the representations associated with the potential, current and the field tensor. (orig.)

Conformal symmetries of FRW accelerating cosmologies

International Nuclear Information System (INIS)

Kehagias, A.; Riotto, A.

2014-01-01

We show that any accelerating Friedmann–Robertson–Walker (FRW) cosmology with equation of state w<−1/3 (and therefore not only a de Sitter stage with w=−1) exhibits three-dimensional conformal symmetry on future constant-time hypersurfaces if the bulk theory is invariant under bulk conformal Killing vectors. We also offer an alternative derivation of this result in terms of conformal Killing vectors and show that long wavelength comoving curvature perturbations of the perturbed FRW metric are just conformal Killing motions of the FRW background. We then extend the boundary conformal symmetry to the bulk for accelerating cosmologies. Our findings indicate that one can easily generate perturbations of scalar fields which are not only scale invariant, but also fully conformally invariant on super-Hubble scales. Measuring a scale-invariant power spectrum for the cosmological perturbation does not automatically imply that the universe went through a de Sitter stage

Conformers, infrared spectrum, UV-induced photochemistry, and near-IR-induced generation of two rare conformers of matrix-isolated phenylglycine

Science.gov (United States)

Borba, Ana; Gómez-Zavaglia, Andrea; Fausto, Rui

2014-10-01

The conformational space of α-phenylglycine (PG) have been investigated theoretically at both the DFT/B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of approximation. Seventeen different minima were found on the investigated potential energy surfaces, which are characterized by different dominant intramolecular interactions: type I conformers are stabilized by hydrogen bonds of the type N-H...O=C, type II by a strong O-H...N hydrogen bond, type III by weak N-H...O-H hydrogen bonds, and type IV by a C=O...H-C contact. The calculations indicate also that entropic effects are relevant in determining the equilibrium populations of the conformers of PG in the gas phase, in particular in the case of conformers of type II, where the strong intramolecular O-H...N hydrogen bond considerably diminishes entropy by reducing the conformational mobility of the molecule. In consonance with the relative energies of the conformers and barriers for conformational interconversion, only 3 conformers of PG were observed for the compound isolated in cryogenic Ar, Xe, and N2 matrices: the conformational ground state (ICa), and forms ICc and IITa. All other significantly populated conformers existing in the gas phase prior to deposition convert either to conformer ICa or to conformer ICc during matrix deposition. The experimental observation of ICc had never been achieved hitherto. Narrowband near-IR irradiation of the first overtone of νOH vibrational mode of ICa and ICc in nitrogen matrices (at 6910 and 6930 cm-1, respectively) led to selective generation of two additional conformers of high-energy, ITc and ITa, respectively, which were also observed experimentally for the first time. In addition, these experiments also provided the key information for the detailed vibrational characterization of the 3 conformers initially present in the matrices. On the other hand, UV irradiation (λ = 255 nm) of PG isolated in a xenon matrix revealed that PG undergoes facile photofragmentation

Conformers, infrared spectrum, UV-induced photochemistry, and near-IR-induced generation of two rare conformers of matrix-isolated phenylglycine

International Nuclear Information System (INIS)

Borba, Ana; Fausto, Rui; Gómez-Zavaglia, Andrea

2014-01-01

The conformational space of α-phenylglycine (PG) have been investigated theoretically at both the DFT/B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of approximation. Seventeen different minima were found on the investigated potential energy surfaces, which are characterized by different dominant intramolecular interactions: type I conformers are stabilized by hydrogen bonds of the type N–H···O=C, type II by a strong O–H···N hydrogen bond, type III by weak N–H···O–H hydrogen bonds, and type IV by a C=O···H–C contact. The calculations indicate also that entropic effects are relevant in determining the equilibrium populations of the conformers of PG in the gas phase, in particular in the case of conformers of type II, where the strong intramolecular O–H···N hydrogen bond considerably diminishes entropy by reducing the conformational mobility of the molecule. In consonance with the relative energies of the conformers and barriers for conformational interconversion, only 3 conformers of PG were observed for the compound isolated in cryogenic Ar, Xe, and N 2 matrices: the conformational ground state (ICa), and forms ICc and IITa. All other significantly populated conformers existing in the gas phase prior to deposition convert either to conformer ICa or to conformer ICc during matrix deposition. The experimental observation of ICc had never been achieved hitherto. Narrowband near-IR irradiation of the first overtone of νOH vibrational mode of ICa and ICc in nitrogen matrices (at 6910 and 6930 cm −1 , respectively) led to selective generation of two additional conformers of high-energy, ITc and ITa, respectively, which were also observed experimentally for the first time. In addition, these experiments also provided the key information for the detailed vibrational characterization of the 3 conformers initially present in the matrices. On the other hand, UV irradiation (λ = 255 nm) of PG isolated in a xenon matrix revealed that PG

40 CFR 52.2133 - General conformity.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 4 2010-07-01 2010-07-01 false General conformity. 52.2133 Section 52...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Carolina § 52.2133 General conformity. The General Conformity regulations adopted into the South Carolina State Implementation Plan which...

40 CFR 91.106 - Certificate of conformity.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Certificate of conformity. 91.106... Provisions § 91.106 Certificate of conformity. (a) Every manufacturer of a new marine SI engine produced... obtain a certificate of conformity covering each engine family. The certificate of conformity must be...

In Vitro Palmitate Treatment of Myotubes from Postmenopausal Women Leads to Ceramide Accumulation, Inflammation and Affected Insulin Signaling

DEFF Research Database (Denmark)

Abildgaard, Julie; Henstridge, Darren C; Pedersen, Anette Tønnes

2014-01-01

Menopause is associated with an increased incidence of insulin resistance and metabolic diseases. In a chronic palmitate treatment model, we investigated the role of skeletal muscle fatty acid exposure in relation to the metabolic deterioration observed with menopause. Human skeletal muscle......, post-myotubes showed a blunted insulin stimulated phosphorylation of AS160 in response to chronic palmitate treatment compared with pre-myotubes (p = 0.02). The increased intramyocellular ceramide content in the post-myotubes was associated with a significantly higher mRNA expression of Serine...... Palmitoyltransferase1 (SPT1) after one day of palmitate treatment (p = 0.03) in post-myotubes compared with pre-myotubes. Our findings indicate that post-myotubes are more prone to develop lipid accumulation and defective insulin signaling following chronic saturated fatty acid exposure as compared to pre-myotubes....

40 CFR 52.938 - General conformity.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 3 2010-07-01 2010-07-01 false General conformity. 52.938 Section 52...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Kentucky § 52.938 General conformity. The General Conformity regulations were submitted on November 10, 1995, and adopted into the Kentucky State...

40 CFR 51.854 - Conformity analysis.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 2 2010-07-01 2010-07-01 false Conformity analysis. 51.854 Section 51... FOR PREPARATION, ADOPTION, AND SUBMITTAL OF IMPLEMENTATION PLANS Determining Conformity of General Federal Actions to State or Federal Implementation Plans § 51.854 Conformity analysis. Link to an...

Lie algebra of conformal Killing–Yano forms

International Nuclear Information System (INIS)

Ertem, Ümit

2016-01-01

We provide a generalization of the Lie algebra of conformal Killing vector fields to conformal Killing–Yano forms. A new Lie bracket for conformal Killing–Yano forms that corresponds to slightly modified Schouten–Nijenhuis bracket of differential forms is proposed. We show that conformal Killing–Yano forms satisfy a graded Lie algebra in constant curvature manifolds. It is also proven that normal conformal Killing–Yano forms in Einstein manifolds also satisfy a graded Lie algebra. The constructed graded Lie algebras reduce to the graded Lie algebra of Killing–Yano forms and the Lie algebras of conformal Killing and Killing vector fields in special cases. (paper)

Universal hydrodynamics of non-conformal branes

International Nuclear Information System (INIS)

Kanitscheider, Ingmar; Skenderis, Kostas

2009-01-01

We examine the hydrodynamic limit of non-conformal branes using the recently developed precise holographic dictionary. We first streamline the discussion of holography for backgrounds that asymptote locally to non-conformal brane solutions by showing that all such solutions can be obtained from higher dimensional asymptotically locally AdS solutions by suitable dimensional reduction and continuation in the dimension. As a consequence, many holographic results for such backgrounds follow from the corresponding results of the Asymptotically AdS case. In particular, the hydrodynamics of non-conformal branes is fully determined in terms of conformal hydrodynamics. Using previous results on the latter we predict the form of the non-conformal hydrodynamic stress tensor to second order in derivatives. Furthermore we show that the ratio between bulk and shear viscosity is fixed by the generalized conformal structure to be ζ/η = 2(1/(d-1)-c s 2 ), where c s is the speed of sound in the fluid.

Operator algebras and conformal field theory

International Nuclear Information System (INIS)

Gabbiani, F.; Froehlich, J.

1993-01-01

We define and study two-dimensional, chiral conformal field theory by the methods of algebraic field theory. We start by characterizing the vacuum sectors of such theories and show that, under very general hypotheses, their algebras of local observables are isomorphic to the unique hyperfinite type III 1 factor. The conformal net determined by the algebras of local observables is proven to satisfy Haag duality. The representation of the Moebius group (and presumably of the entire Virasoro algebra) on the vacuum sector of a conformal field theory is uniquely determined by the Tomita-Takesaki modular operators associated with its vacuum state and its conformal net. We then develop the theory of Mebius covariant representations of a conformal net, using methods of Doplicher, Haag and Roberts. We apply our results to the representation theory of loop groups. Our analysis is motivated by the desire to find a 'background-independent' formulation of conformal field theories. (orig.)

47 CFR 2.906 - Declaration of Conformity.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Declaration of Conformity. 2.906 Section 2.906... Conformity. (a) A Declaration of Conformity is a procedure where the responsible party, as defined in § 2.909... of Conformity attaches to all items subsequently marketed by the responsible party which are...

Synergistic Enhancement of Cancer Therapy Using a Combination of Ceramide and Docetaxel

Directory of Open Access Journals (Sweden)

Li-Xia Feng

2014-03-01

Full Text Available Ceramide (CE-based combination therapy (CE combination as a novel therapeutic strategy has attracted great attention in the field of anti-cancer therapy. The principal purposes of this study were to investigate the synergistic effect of CE in combination with docetaxel (DTX (CE + DTX and to explore the synergy mechanisms of CE + DTX. The 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT and combination index (CI assay showed that simultaneous administration of CE and DTX with a molar ratio of 0.5:1 could generate the optimal synergistic effect on murine malignant melanoma cell (B16, CI = 0.31 and human breast carcinoma cell (MCF-7, CI = 0.48. The apoptosis, cell cycle, and cytoskeleton destruction study demonstrated that CE could target and destruct the microfilament actin, subsequently activate Caspase-3 and induce apoptosis. Meanwhile, DTX could target and disrupt the microtubules cytoskeleton, leading to a high proportion of cancer cells in G2/M-phase arrest. Moreover, CE plus DTX could cause a synergistic destruction of cytoskeleton, which resulted in a significantly higher apoptosis and a significantly higher arrest in G2/M arrest comparing with either agent alone (p < 0.01. The in vivo antitumor study evaluated in B16 tumor-bearing mice also validated the synergistic effects. All these results suggested that CE could enhance the antitumor activity of DTX in a synergistic manner, which suggest promising application prospects of CE + DTX combination treatment.

Characterization of the human UDP-galactose:ceramide galactosyltransferase gene promoter.

Science.gov (United States)

Tencomnao, T; Yu, R K; Kapitonov, D

2001-02-16

UDP-galactose:ceramide galactosyltransferase (CGT, EC 2.4.1.45) is a key enzyme in the biosynthesis of galactocerebroside, the most abundant glycosphingolipid in the myelin sheath. An 8 kb fragment upstream from the transcription initiation site of CGT gene was isolated from a human genomic DNA library. Primer extension analysis revealed a single transcription initiation site 329 bp upstream from the ATG start codon. Neither a consensus TATA nor a CCAAT box was identified in the proximity to the transcription start site; however, this region contains a high GC content and multiple putative regulatory elements. To investigate the transcriptional regulation of CGT, a series of 5' deletion constructs of the 5'-flanking region were generated and cloned upstream from the luciferase reporter gene. By comparing promoter activity in the human oligodendroglioma (HOG) and human neuroblastoma (LAN-5) cell lines, we found that the CGT promoter functions in a cell type-specific manner. Three positive cis-acting regulatory regions were identified, including a proximal region at -292/-256 which contains the potential binding sites for known transcription factors (TFs) such as Ets and SP1 (GC box), a distal region at -747/-688 comprising a number of binding sites such as the ERE half-site, NF1-like, TGGCA-BP, and CRE, and a third positive cis-acting region distally localized at -1325/-1083 consisting of binding sites for TFs such as nitrogen regulatory, TCF-1, TGGCA-BP, NF-IL6, CF1, bHLH, NF1-like, GATA, and gamma-IRE. A negative cis-acting domain localized in a far distal region at -1594/-1326 was also identified. Our results suggest the presence of both positive and negative cis-regulatory regions essential for the cell-specific expression in the TATA-less promoter of the human CGT gene.

Naturality in conformal field theory

International Nuclear Information System (INIS)

Moore, G.; Seiberg, N.

1989-01-01

We discuss constraints on the operator product coefficients in diagonal and nondiagonal rational conformal field theories. Nondiagonal modular invariants always arise from automorphisms of the fusion rule algebra or from extensions of the chiral algebra. Moreover, when the chiral algebra has been maximally extended a strong form of the naturality principle of field theory can be proven for rational conformal field theory: operator product coefficients vanish if and only if the corresponding fusion rules vanish; that is, if and only if the vanishing can be understood in terms of a symmetry. We illustrate these ideas with several examples. We also generalize our ideas about rational conformal field theories to a larger class of theories: 'quasi-rational conformal field theories' and we explore some of their properties. (orig.)

Challenges of Agro-Food Standards Conformity: Lessons from East Africa and Policy Implications

DEFF Research Database (Denmark)

Bolwig, Simon; Riisgaard, Lone; Gibbon, Peter

2013-01-01

Standards are used to govern an increasing share of global food trade, and have been interpreted by academics both as market access barriers and opportunities for low-income country producers, exporters and workers. Donors have mostly chosen to treat them as opportunities and today finance...... of a research programme on standards conformity in East Africa. These demonstrate that most interventions underestimate the nature of the challenges faced and that significant impacts are achieved only under rather restricted conditions. The solutions lay not only in more selective support to standard...... development and better-informed interventions, but also to focus more squarely on supply capacity and welfare outcomes in project planning....

21 CFR 26.70 - Conformity assessment bodies.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Conformity assessment bodies. 26.70 Section 26.70...Frameworkâ Provisions § 26.70 Conformity assessment bodies. Each party recognizes that the conformity... conformity in relation to its requirements as specified in subpart B of this part. The parties shall specify...

Conformational analysis of lignin models

International Nuclear Information System (INIS)

Santos, Helio F. dos

2001-01-01

The conformational equilibrium for two 5,5' biphenyl lignin models have been analyzed using a quantum mechanical semiempirical method. The gas phase and solution structures are discussed based on the NMR and X-ray experimental data. The results obtained showed that the observed conformations are solvent-dependent, being the geometries and the thermodynamic properties correlated with the experimental information. This study shows how a systematic theoretical conformational analysis can help to understand chemical processes at a molecular level. (author)

On the linear conformal gravitation

International Nuclear Information System (INIS)

Pal'chik, M.Ya.; Fradkin, E.S.

1984-01-01

Conformal gravitation is analyzed under the assumption that its solution possesses the property of conformal symmetry. This assumption has sense in the case of small distances and only for definite types of matter fields, namely: at special choice of matter fields and their interactions, providing a lack of conformal anomalies; or at definite magnitudes of binding constants, coinciding with the zeroes of the Gell-Mann-Low function. The field equations, of the group-theoretical natura are obtained

Conformal Symmetry Patterns in Baryon Spectra

International Nuclear Information System (INIS)

Kirchbach, Mariana; Compean, Cliffor B

2011-01-01

Attention is drawn to the fact that the spectra of the baryons of the lightest flavors, the nucleon and the Δ, carry quantum numbers characteristic for an unitary representation of the conformal group. We show that the above phenomenon is well explained for baryons whose internal structure is dominated by a quark-diquark configuration that resides in a conformally compactified Minkowski space time, R 1 x S 3 , and is described by means of the conformal scale equation there. The R 1 x S 3 space-time represents the boundary of the conformally compactified AdS 5 , on which one expects to encounter a conformal theory in accord with the gauge-gravity duality. Within this context, our model is congruent with AdS 5 /CFT 4 .

Conformational cooling and conformation selective aggregation in dimethyl sulfite isolated in solid rare gases

OpenAIRE

Borba, Ana; Gómez-Zavaglia, Andrea; Fausto, Rui

2006-01-01

Dimethyl sulfite has three conformers of low energy, GG, GT and GG0, which have significant populations in the gas phase at room temperature. According to theoretical predictions, the GT and GG0 conformers are higher in energy than the GG conformer by 0.83 and 1.18 kJ molK1, respectively, while the barriers associated with the GG0/GT and GT/GG isomerizations are 1.90 and 9.64 kJ molK1, respectively. Experimental data obtained for the compound isolated in solid argon, krypton and xenon demonst...

Conformational Clusters of Phosphorylated Tyrosine.

Science.gov (United States)

Abdelrasoul, Maha; Ponniah, Komala; Mao, Alice; Warden, Meghan S; Elhefnawy, Wessam; Li, Yaohang; Pascal, Steven M

2017-12-06

Tyrosine phosphorylation plays an important role in many cellular and intercellular processes including signal transduction, subcellular localization, and regulation of enzymatic activity. In 1999, Blom et al., using the limited number of protein data bank (PDB) structures available at that time, reported that the side chain structures of phosphorylated tyrosine (pY) are partitioned into two conserved conformational clusters ( Blom, N.; Gammeltoft, S.; Brunak, S. J. Mol. Biol. 1999 , 294 , 1351 - 1362 ). We have used the spectral clustering algorithm to cluster the increasingly growing number of protein structures with pY sites, and have found that the pY residues cluster into three distinct side chain conformations. Two of these pY conformational clusters associate strongly with a narrow range of tyrosine backbone conformation. The novel cluster also highly correlates with the identity of the n + 1 residue, and is strongly associated with a sequential pYpY conformation which places two adjacent pY side chains in a specific relative orientation. Further analysis shows that the three pY clusters are associated with distinct distributions of cognate protein kinases.

Thickenings and conformal gravity

Science.gov (United States)

Lebrun, Claude

1991-07-01

A twistor correspondence is given for complex conformal space-times with vanishing Bach and Eastwood-Dighton tensors; when the Weyl curvature is algebraically general, these equations are precisely the conformal version of Einstein's vacuum equations with cosmological constant. This gives a fully curved version of the linearized correspondence of Baston and Mason [B-M].

Thickenings and conformal gravity

International Nuclear Information System (INIS)

LeBrun, C.

1991-01-01

A twistor correspondence is given for complex conformal space-times with vanishing Bach and Eastwood-Dighton tensors; when the Weyl curvature is algebraically general, these equations are precisely the conformal version of Einstein's vacuum equations with cosmological constant. This gives a fully curved version of the linearized correspondence of Baston and Mason [B-M]. (orig.)

Analysis of fluorescently labeled glycosphingolipid-derived oligosaccharides following ceramide glycanase digestion and anthranilic acid labeling.

Science.gov (United States)

Neville, David C A; Coquard, Virginie; Priestman, David A; te Vruchte, Danielle J M; Sillence, Daniel J; Dwek, Raymond A; Platt, Frances M; Butters, Terry D

2004-08-15

Interest in cellular glycosphingolipid (GSL) function has necessitated the development of a rapid and sensitive method to both analyze and characterize the full complement of structures present in various cells and tissues. An optimized method to characterize oligosaccharides released from glycosphingolipids following ceramide glycanase digestion has been developed. The procedure uses the fluorescent compound anthranilic acid (2-aminobenzoic acid; 2-AA) to label oligosaccharides prior to analysis using normal-phase high-performance liquid chromatography. The labeling procedure is rapid, selective, and easy to perform and is based on the published method of Anumula and Dhume [Glycobiology 8 (1998) 685], originally used to analyze N-linked oligosaccharides. It is less time consuming than a previously published 2-aminobenzamide labeling method [Anal. Biochem. 298 (2001) 207] for analyzing GSL-derived oligosaccharides, as the fluorescent labeling is performed on the enzyme reaction mixture. The purification of 2-AA-labeled products has been improved to ensure recovery of oligosaccharides containing one to four monosaccharide units, which was not previously possible using the Anumula and Dhume post-derivatization purification procedure. This new approach may also be used to analyze both N- and O-linked oligosaccharides.

Conformal symmetry inheritance in null fluid spacetimes

International Nuclear Information System (INIS)

Tupper, B O J; Keane, A J; Hall, G S; Coley, A A; Carot, J

2003-01-01

We define inheriting conformal Killing vectors for null fluid spacetimes and find the maximum dimension of the associated inheriting Lie algebra. We show that for non-conformally flat null fluid spacetimes, the maximum dimension of the inheriting algebra is seven and for conformally flat null fluid spacetimes the maximum dimension is eight. In addition, it is shown that there are two distinct classes of non-conformally flat generalized plane wave spacetimes which possess the maximum dimension, and one class in the conformally flat case

Conformal maps between pseudo-Finsler spaces

Science.gov (United States)

Voicu, Nicoleta

The paper aims to initiate a systematic study of conformal mappings between Finsler spacetimes and, more generally, between pseudo-Finsler spaces. This is done by extending several results in pseudo-Riemannian geometry which are necessary for field-theoretical applications and by proposing a technique that reduces some problems involving pseudo-Finslerian conformal vector fields to their pseudo-Riemannian counterparts. Also, we point out, by constructing classes of examples, that conformal groups of flat (locally Minkowskian) pseudo-Finsler spaces can be much richer than both flat Finslerian and pseudo-Euclidean conformal groups.

Transportation Conformity

Science.gov (United States)

This section provides information on: current laws, regulations and guidance, policy and technical guidance, project-level conformity, general information, contacts and training, adequacy review of SIP submissions

Extended conformal algebras

International Nuclear Information System (INIS)

Goddard, Peter

1990-01-01

The algebra of the group of conformal transformations in two dimensions consists of two commuting copies of the Virasoro algebra. In many mathematical and physical contexts, the representations of ν which are relevant satisfy two conditions: they are unitary and they have the ''positive energy'' property that L o is bounded below. In an irreducible unitary representation the central element c takes a fixed real value. In physical contexts, the value of c is a characteristic of a theory. If c < 1, it turns out that the conformal algebra is sufficient to ''solve'' the theory, in the sense of relating the calculation of the infinite set of physically interesting quantities to a finite subset which can be handled in principle. For c ≥ 1, this is no longer the case for the algebra alone and one needs some sort of extended conformal algebra, such as the superconformal algebra. It is these algebras that this paper aims at addressing. (author)

Families and degenerations of conformal field theories

Energy Technology Data Exchange (ETDEWEB)

Roggenkamp, D.

2004-09-01

In this work, moduli spaces of conformal field theories are investigated. In the first part, moduli spaces corresponding to current-current deformation of conformal field theories are constructed explicitly. For WZW models, they are described in detail, and sigma model realizations of the deformed WZW models are presented. The second part is devoted to the study of boundaries of moduli spaces of conformal field theories. For this purpose a notion of convergence of families of conformal field theories is introduced, which admits certain degenerated conformal field theories to occur as limits. To such a degeneration of conformal field theories, a degeneration of metric spaces together with additional geometric structures can be associated, which give rise to a geometric interpretation. Boundaries of moduli spaces of toroidal conformal field theories, orbifolds thereof and WZW models are analyzed. Furthermore, also the limit of the discrete family of Virasoro minimal models is investigated. (orig.)

Thickenings and conformal gravity

Energy Technology Data Exchange (ETDEWEB)

LeBrun, C. (State Univ. of New York, Stony Brook, NY (USA). Dept. of Mathematics)

1991-07-01

A twistor correspondence is given for complex conformal space-times with vanishing Bach and Eastwood-Dighton tensors; when the Weyl curvature is algebraically general, these equations are precisely the conformal version of Einstein's vacuum equations with cosmological constant. This gives a fully curved version of the linearized correspondence of Baston and Mason (B-M). (orig.).

Conformational stability of calreticulin

DEFF Research Database (Denmark)

Jørgensen, C.S.; Trandum, C.; Larsen, N.

2005-01-01

The conformational stability of calreticulin was investigated. Apparent unfolding temperatures (T-m) increased from 31 degrees C at pH 5 to 51 degrees C at pH 9, but electrophoretic analysis revealed that calreticulin oligomerized instead of unfolding. Structural analyses showed that the single C......-terminal a-helix was of major importance to the conformational stability of calreticulin....

Conformity in Christ | Waaijman | Acta Theologica

African Journals Online (AJOL)

This essay investigates the notion of conformity in Christ as it is part of a comprehensive, multilayered process of transformation. In the first part it focuses on the process of transformation in creation, re-creation, conformity, love and glory. In the second part it discusses transformation in Christ by looking at conformation and ...

Gauge fixing problem in the conformal QED

International Nuclear Information System (INIS)

Ichinose, Shoichi

1986-01-01

The gauge fixing problem in the conformal (spinor and scalar) QED is examined. For the analysis, we generalize Dirac's manifestly conformal-covariant formalism. It is shown that the (vector and matter) fields must obey a certain mixed (conformal and gauge) type of transformation law in order to fix the local gauge symmetry preserving the conformal invariance in the Lagrangian. (orig.)

Critical Role of Interdomain Interactions in the Conformational Change and Catalytic Mechanism of Endoplasmic Reticulum Aminopeptidase 1.

Science.gov (United States)

Stamogiannos, Athanasios; Maben, Zachary; Papakyriakou, Athanasios; Mpakali, Anastasia; Kokkala, Paraskevi; Georgiadis, Dimitris; Stern, Lawrence J; Stratikos, Efstratios

2017-03-14

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that is important for the generation of antigenic epitopes and major histocompatibility class I-restricted adaptive immune responses. ERAP1 processes a vast variety of different peptides but still shows length and sequence selectivity, although the mechanism behind these properties is poorly understood. X-ray crystallographic analysis has revealed that ERAP1 can assume at least two distinct conformations in which C-terminal domain IV is either proximal or distal to active site domain II. To improve our understanding of the role of this conformational change in the catalytic mechanism of ERAP1, we used site-directed mutagenesis to perturb key salt bridges between domains II and IV. Enzymatic analysis revealed that these mutations, although located away from the catalytic site, greatly reduce the catalytic efficiency and change the allosteric kinetic behavior. The variants were more efficiently activated by small peptides and bound a competitive inhibitor with weaker affinity and faster dissociation kinetics. Molecular dynamics analysis suggested that the mutations affect the conformational distribution of ERAP1, reducing the population of closed states. Small-angle X-ray scattering indicated that both the wild type and the ERAP1 variants are predominantly in an open conformational state in solution. Overall, our findings suggest that electrostatic interactions between domains II and IV in ERAP1 are crucial for driving a conformational change that regulates the structural integrity of the catalytic site. The extent of domain opening in ERAP1 probably underlies its specialization for antigenic peptide precursors and should be taken into account in inhibitor development efforts.

Transportation Conformity Training and Presentations

Science.gov (United States)

EPA's OTAQ has provided multiple conformity training sessions in the past to assist state and local governments in implementing conformity requirements. As training information is prepared for other venues, it will be posted on this page.

Two dimensional infinite conformal symmetry

International Nuclear Information System (INIS)

Mohanta, N.N.; Tripathy, K.C.

1993-01-01

The invariant discontinuous (discrete) conformal transformation groups, namely the Kleinian and Fuchsian groups Gamma (with an arbitrary signature) of H (the Poincare upper half-plane l) and the unit disc Delta are explicitly constructed from the fundamental domain D. The Riemann surface with signatures of Gamma and conformally invariant automorphic forms (functions) with Peterson scalar product are discussed. The functor, where the category of complex Hilbert spaces spanned by the space of cusp forms constitutes the two dimensional conformal field theory. (Author) 7 refs

Virtual and solution conformations of oligosaccharides

International Nuclear Information System (INIS)

Cumming, D.A.; Carver, J.P.

1987-01-01

The possibility that observed nuclear Overhauser enhancements and bulk longitudinal relaxation times, parameters measured by 1 H NMR and often employed in determining the preferred solution conformation of biologically important molecules, are the result of averaging over many conformational states is quantitatively evaluated. Of particular interest was to ascertain whether certain 1 H NMR determined conformations are virtual in nature; i.e., the fraction of the population of molecules actually found at any time within the subset of conformational space defined as the solution conformation is vanishingly small. A statistical mechanics approach was utilized to calculate an ensemble average relaxation matrix from which (NOE)'s and (T 1 )'s are calculated. Model glycosidic linkages in four oligosaccharides were studied. The nature of the resultant population distributions is such that 50% of the molecular population is found within 1% of available microstates, while 99% of the molecular population occupies about 10% of the ensemble microstates, a number roughly equal to that sterically allowed. From this analysis the authors conclude that in many cases quantitative interpretation of NMR relaxation data, which attempts to define a single set of allowable torsion angle values consistent with the observed data, will lead to solution conformations that are either virtual or reflect torsion angle values possessed by a minority of the molecular population. Observed values of NMR relaxation data are the result of the complex interdependence of the population distribution and NOE (or T 1 ) surfaces in conformational space. In conformational analyses, NMR data can therefore be used to test different population distributions calculated from empirical potential energy functions

Identification of a nuclear localization signal in the retinitis pigmentosa-mutated RP26 protein, ceramide kinase-like protein

International Nuclear Information System (INIS)

Inagaki, Yuichi; Mitsutake, Susumu; Igarashi, Yasuyuki

2006-01-01

Retinitis pigmentosa (RP) is a genetically heterogeneous disease characterized by degeneration of the retina. A mutation in a new ceramide kinase (CERK) homologous gene, named CERK-like protein (CERKL), was found to cause autosomal recessive retinitis pigmentosa (RP26). Here, we show a point mutation of one of two putative nuclear localization signal (NLS) sequences inhibited the nuclear localization of the protein. Furthermore, the tetra-GFP-tagged NLS, which cannot passively enter the nucleus, was observed not only in the nucleus but also in the nucleolus. Our results provide First evidence of the active nuclear import of CERKL and suggest that the identified NLS might be responsible for nucleolar retention of the protein. As recent studies have shown other RP-related proteins are localized in the nucleus or the nucleolus, our identification of NLS in CERKL suggests that CERKL likely plays important roles for retinal functions in the nucleus and the nucleolus

Uniform stable conformal convolutional perfectly matched layer for enlarged cell technique conformal finite-difference time-domain method

International Nuclear Information System (INIS)

Wang Yue; Wang Jian-Guo; Chen Zai-Gao

2015-01-01

Based on conformal construction of physical model in a three-dimensional Cartesian grid, an integral-based conformal convolutional perfectly matched layer (CPML) is given for solving the truncation problem of the open port when the enlarged cell technique conformal finite-difference time-domain (ECT-CFDTD) method is used to simulate the wave propagation inside a perfect electric conductor (PEC) waveguide. The algorithm has the same numerical stability as the ECT-CFDTD method. For the long-time propagation problems of an evanescent wave in a waveguide, several numerical simulations are performed to analyze the reflection error by sweeping the constitutive parameters of the integral-based conformal CPML. Our numerical results show that the integral-based conformal CPML can be used to efficiently truncate the open port of the waveguide. (paper)

Noncommutative geometry and twisted conformal symmetry

International Nuclear Information System (INIS)

Matlock, Peter

2005-01-01

The twist-deformed conformal algebra is constructed as a Hopf algebra with twisted coproduct. This allows for the definition of conformal symmetry in a noncommutative background geometry. The twisted coproduct is reviewed for the Poincare algebra and the construction is then extended to the full conformal algebra. The case of Moyal-type noncommutativity of the coordinates is considered. It is demonstrated that conformal invariance need not be viewed as incompatible with noncommutative geometry; the noncommutativity of the coordinates appears as a consequence of the twisting, as has been shown in the literature in the case of the twisted Poincare algebra

Superintegrability of d-dimensional conformal blocks

International Nuclear Information System (INIS)

Isachenkov, Mikhail

2016-02-01

We observe that conformal blocks of scalar 4-point functions in a d-dimensional conformal field theory can mapped to eigenfunctions of a 2-particle hyperbolic Calogero-Sutherland Hamiltonian. The latter describes two coupled Poeschl-Teller particles. Their interaction, whose strength depends smoothly on the dimension d, is known to be superintegrable. Our observation enables us to exploit the rich mathematical literature on Calogero-Sutherland models in deriving various results for conformal field theory. These include an explicit construction of conformal blocks in terms of Heckman-Opdam hypergeometric functions and a remarkable duality that relates the blocks of theories in different dimensions.

Superintegrability of d-dimensional conformal blocks

Energy Technology Data Exchange (ETDEWEB)

Isachenkov, Mikhail [Weizmann Institute of Science, Rehovot (Israel). Dept. of Particle Physics and Astronomy; Schomerus, Volker [DESY Theory Group, Hamburg (Germany)

2016-02-15

We observe that conformal blocks of scalar 4-point functions in a d-dimensional conformal field theory can mapped to eigenfunctions of a 2-particle hyperbolic Calogero-Sutherland Hamiltonian. The latter describes two coupled Poeschl-Teller particles. Their interaction, whose strength depends smoothly on the dimension d, is known to be superintegrable. Our observation enables us to exploit the rich mathematical literature on Calogero-Sutherland models in deriving various results for conformal field theory. These include an explicit construction of conformal blocks in terms of Heckman-Opdam hypergeometric functions and a remarkable duality that relates the blocks of theories in different dimensions.

Induced quantum conformal gravity

International Nuclear Information System (INIS)

Novozhilov, Y.V.; Vassilevich, D.V.

1988-11-01

Quantum gravity is considered as induced by matter degrees of freedom and related to the symmetry breakdown in the low energy region of a non-Abelian gauge theory of fundamental fields. An effective action for quantum conformal gravity is derived where both the gravitational constant and conformal kinetic term are positive. Relation with induced classical gravity is established. (author). 15 refs

Conformal invariance in harmonic superspace

International Nuclear Information System (INIS)

Galperin, A.; Ivanov, E.; Ogievetsky, V.; Sokatchev, E.

1987-01-01

In the present paper we show how the N = 2 superconformal group is realised in harmonic superspace and examine conformal invariance of N = 2 off-shell theories. We believe that the example of N = O self-dual Yang-Mills equations can serve as an instructive introduction to the subject of harmonic superspace and this is examined. The rigid N = 2 conformal supersymmetry and its local version, i.e. N = 2 conformal supergravity is also discussed. The paper is a contribution to the book commemorating the sixtieth birthday of E.S. Fradkin. (author)

Harmony of spinning conformal blocks

Energy Technology Data Exchange (ETDEWEB)

Schomerus, Volker [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group; Sobko, Evgeny [Stockholm Univ. (Sweden); Nordita, Stockholm (Sweden); Isachenkov, Mikhail [Weizmann Institute of Science, Rehovoth (Israel). Dept. of Particle Physics and Astrophysics

2016-12-07

Conformal blocks for correlation functions of tensor operators play an increasingly important role for the conformal bootstrap programme. We develop a universal approach to such spinning blocks through the harmonic analysis of certain bundles over a coset of the conformal group. The resulting Casimir equations are given by a matrix version of the Calogero-Sutherland Hamiltonian that describes the scattering of interacting spinning particles in a 1-dimensional external potential. The approach is illustrated in several examples including fermionic seed blocks in 3D CFT where they take a very simple form.

Harmony of spinning conformal blocks

Energy Technology Data Exchange (ETDEWEB)

Schomerus, Volker [DESY Hamburg, Theory Group,Notkestraße 85, 22607 Hamburg (Germany); Sobko, Evgeny [Nordita and Stockholm University,Roslagstullsbacken 23, SE-106 91 Stockholm (Sweden); Isachenkov, Mikhail [Department of Particle Physics and Astrophysics, Weizmann Institute of Science,Rehovot 7610001 (Israel)

2017-03-15

Conformal blocks for correlation functions of tensor operators play an increasingly important role for the conformal bootstrap programme. We develop a universal approach to such spinning blocks through the harmonic analysis of certain bundles over a coset of the conformal group. The resulting Casimir equations are given by a matrix version of the Calogero-Sutherland Hamiltonian that describes the scattering of interacting spinning particles in a 1-dimensional external potential. The approach is illustrated in several examples including fermionic seed blocks in 3D CFT where they take a very simple form.

Conformational cooling and conformation selective aggregation in dimethyl sulfite isolated in solid rare gases

Science.gov (United States)

Borba, Ana; Gómez-Zavaglia, Andrea; Fausto, Rui

2006-08-01

Dimethyl sulfite has three conformers of low energy, GG, GT and GG', which have significant populations in the gas phase at room temperature. According to theoretical predictions, the GT and GG' conformers are higher in energy than the GG conformer by 0.83 and 1.18 kJ mol -1, respectively, while the barriers associated with the GG'→GT and GT→GG isomerizations are 1.90 and 9.64 kJ mol -1, respectively. Experimental data obtained for the compound isolated in solid argon, krypton and xenon demonstrated that the GG'→GT energy barrier is low enough to allow an extensive conversion of the GG' form into the GT conformer during deposition of the matrices, the extent of the conversion increasing along the series Arconformers could be trapped in both argon and krypton matrices, but, at a given temperature, the amount of GG' form trapped in krypton is considerably smaller than in argon, while the amount of GT form increases in relation to the most stable GG form. In addition, when xenon is used, no bands due to GG' are observed in the as-deposited spectra ( Tsubstrate≥10 K, the minimum substrate temperature accessible to our experimental set up), indicating that when the best relaxant gas is used the GG'→GT conversion during deposition of the matrix is complete even at 10 K. Annealing of the argon and krypton matrices shows that the increase of the temperature of the matrix first promotes the GG'→GT isomerization, and only at higher temperatures the GT→GG conversion starts to occur, in consonance with the relative energy barriers associated with these two processes. The results also indicate that dimethyl sulfite exhibits conformation selective aggregation, with the most stable form, which has the highest dipole moment, aggregating more easily than the remaining experimentally relevant conformers (GT and GG').

Conformal hyperbolicity of Lorentzian warped products

International Nuclear Information System (INIS)

Markowitz, M.J.

1982-01-01

A space-time M is said to be conformally hyperbolic if the intrinsic conformal Lorentz pseudodistance dsub(M) is a true distance. In this paper criteria are derived which insure the conformal hyperbolicity of certain space-times which are generalizations of the Robertson-Walker spaces. Then dsub(M) is determined explicitly for Einstein-de Sitter space, and important cosmological model. (author)

Conformal hyperbolicity of Lorentzian warped products

Energy Technology Data Exchange (ETDEWEB)

Markowitz, M.J. (Chicago Univ., IL (USA). Dept. of Mathematics)

1982-12-01

A space-time M is said to be conformally hyperbolic if the intrinsic conformal Lorentz pseudodistance dsub(M) is a true distance. In this paper criteria are derived which insure the conformal hyperbolicity of certain space-times which are generalizations of the Robertson-Walker spaces. Then dsub(M) is determined explicitly for Einstein-de Sitter space, and important cosmological model.

Non-linear realizations of conformal symmetry and effective field theory for the pseudo-conformal universe

International Nuclear Information System (INIS)

Hinterbichler, Kurt; Joyce, Austin; Khoury, Justin

2012-01-01

The pseudo-conformal scenario is an alternative to inflation in which the early universe is described by an approximate conformal field theory on flat, Minkowski space. Some fields acquire a time-dependent expectation value, which breaks the flat space so(4,2) conformal algebra to its so(4,1) de Sitter subalgebra. As a result, weight-0 fields acquire a scale invariant spectrum of perturbations. The scenario is very general, and its essential features are determined by the symmetry breaking pattern, irrespective of the details of the underlying microphysics. In this paper, we apply the well-known coset technique to derive the most general effective lagrangian describing the Goldstone field and matter fields, consistent with the assumed symmetries. The resulting action captures the low energy dynamics of any pseudo-conformal realization, including the U(1)-invariant quartic model and the Galilean Genesis scenario. We also derive this lagrangian using an alternative method of curvature invariants, consisting of writing down geometric scalars in terms of the conformal mode. Using this general effective action, we compute the two-point function for the Goldstone and a fiducial weight-0 field, as well as some sample three-point functions involving these fields

General Conformity

Science.gov (United States)

The General Conformity requirements ensure that the actions taken by federal agencies in nonattainment and maintenance areas do not interfere with a state’s plans to meet national standards for air quality.

Posterior Reversible Encephalopathy Syndrome (PRES): Restricted Diffusion does not Necessarily Mean Irreversibility.

Science.gov (United States)

Wagih, Alaa; Mohsen, Laila; Rayan, Moustafa M; Hasan, Mo'men M; Al-Sherif, Ashraf H

2015-01-01

Restricted diffusion is the second most common atypical presentation of PRES. This has a very important implication, as lesions with cytotoxic edema may progress to infarction. Several studies suggested the role of DWI in the prediction of development of infarctions in these cases. Other studies, however, suggested that PRES is reversible even with cytotoxic patterns. Our aim was to evaluate whether every restricted diffusion in PRES is reversible and what factors affect this reversibility. Thirty-six patients with acute neurological symptoms suggestive of PRES were included in our study. Inclusion criteria comprised imaging features of atypical PRES where DWI images and ADC maps show restricted diffusion. Patients were imaged with 0.2-T and 1.5-T machines. FLAIR images were evaluated for the severity of the disease and a FLAIR/DWI score was used. ADC values were selectively recorded from the areas of diffusion restriction. A follow-up MRI study was carried out in all patients after 2 weeks. Patients were classified according to reversibility into: Group 1 (reversible PRES; 32 patients) and Group 2 (irreversible changes; 4 patients). The study was approved by the University's research ethics committee, which conforms to the declaration of Helsinki. The age and blood pressure did not vary significantly between both groups. The total number of regions involved and the FLAIR/DWI score did not vary significantly between both groups. Individual regions did not reveal any tendency for the development of irreversible lesions. Similarly, ADC values did not reveal any significant difference between both groups. PRES is completely reversible in the majority of patients, even with restricted diffusion. None of the variables under study could predict the reversibility of PRES lesions. It seems that this process is individual-dependent.

Epigenetic dominance of prion conformers.

Directory of Open Access Journals (Sweden)

Eri Saijo

2013-10-01

Full Text Available Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP primary structures interact with distinct prion conformations to influence pathogenesis, we produced transgenic (Tg mice expressing different sheep scrapie susceptibility alleles, varying only at a single amino acid at PrP residue 136. Tg mice expressing ovine PrP with alanine (A at (OvPrP-A136 infected with SSBP/1 scrapie prions propagated a relatively stable (S prion conformation, which accumulated as punctate aggregates in the brain, and produced prolonged incubation times. In contrast, Tg mice expressing OvPrP with valine (V at 136 (OvPrP-V136 infected with the same prions developed disease rapidly, and the converted prion was comprised of an unstable (U, diffusely distributed conformer. Infected Tg mice co-expressing both alleles manifested properties consistent with the U conformer, suggesting a dominant effect resulting from exclusive conversion of OvPrP-V136 but not OvPrP-A136. Surprisingly, however, studies with monoclonal antibody (mAb PRC5, which discriminates OvPrP-A136 from OvPrP-V136, revealed substantial conversion of OvPrP-A136. Moreover, the resulting OvPrP-A136 prion acquired the characteristics of the U conformer. These results, substantiated by in vitro analyses, indicated that co-expression of OvPrP-V136 altered the conversion potential of OvPrP-A136 from the S to

Conformational analysis of GT1B ganglioside and its interaction with botulinum neurotoxin type B: a study by molecular modeling and molecular dynamics.

Science.gov (United States)

Venkateshwari, Sureshkumar; Veluraja, Kasinadar

2012-01-01

The conformational property of oligosaccharide GT1B in aqueous environment was studied by molecular dynamics (MD) simulation using all-atom model. Based on the trajectory analysis, three prominent conformational models were proposed for GT1B. Direct and water-mediated hydrogen bonding interactions stabilize these structures. The molecular modeling and 15 ns MD simulation of the Botulinum Neuro Toxin/B (BoNT/B) - GT1B complex revealed that BoNT/B can accommodate the GT1B in the single binding mode. Least mobility was seen for oligo-GT1B in the binding pocket. The bound conformation of GT1B obtained from the MD simulation of the BoNT/B-GT1B complex bear a close conformational similarity with the crystal structure of BoNT/A-GT1B complex. The mobility noticed for Arg 1268 in the dynamics was accounted for its favorable interaction with terminal NeuNAc. The internal NeuNAc1 tends to form 10 hydrogen bonds with BoNT/B, hence specifying this particular site as a crucial space for the therapeutic design that can restrict the pathogenic activity of BoNT/B.

Conformal Dimensions via Large Charge Expansion.

Science.gov (United States)

Banerjee, Debasish; Chandrasekharan, Shailesh; Orlando, Domenico

2018-02-09

We construct an efficient Monte Carlo algorithm that overcomes the severe signal-to-noise ratio problems and helps us to accurately compute the conformal dimensions of large-Q fields at the Wilson-Fisher fixed point in the O(2) universality class. Using it, we verify a recent proposal that conformal dimensions of strongly coupled conformal field theories with a global U(1) charge can be obtained via a series expansion in the inverse charge 1/Q. We find that the conformal dimensions of the lowest operator with a fixed charge Q are almost entirely determined by the first few terms in the series.

Some Progress in Conformal Geometry

Directory of Open Access Journals (Sweden)

Sun-Yung A. Chang

2007-12-01

Full Text Available This is a survey paper of our current research on the theory of partial differential equations in conformal geometry. Our intention is to describe some of our current works in a rather brief and expository fashion. We are not giving a comprehensive survey on the subject and references cited here are not intended to be complete. We introduce a bubble tree structure to study the degeneration of a class of Yamabe metrics on Bach flat manifolds satisfying some global conformal bounds on compact manifolds of dimension 4. As applications, we establish a gap theorem, a finiteness theorem for diffeomorphism type for this class, and diameter bound of the $sigma_2$-metrics in a class of conformal 4-manifolds. For conformally compact Einstein metrics we introduce an eigenfunction compactification. As a consequence we obtain some topological constraints in terms of renormalized volumes.

Algebraic conformal field theory

International Nuclear Information System (INIS)

Fuchs, J.; Nationaal Inst. voor Kernfysica en Hoge-Energiefysica

1991-11-01

Many conformal field theory features are special versions of structures which are present in arbitrary 2-dimensional quantum field theories. So it makes sense to describe 2-dimensional conformal field theories in context of algebraic theory of superselection sectors. While most of the results of the algebraic theory are rather abstract, conformal field theories offer the possibility to work out many formulae explicitly. In particular, one can construct the full algebra A-bar of global observables and the endomorphisms of A-bar which represent the superselection sectors. Some explicit results are presented for the level 1 so(N) WZW theories; the algebra A-bar is found to be the enveloping algebra of a Lie algebra L-bar which is an extension of the chiral symmetry algebra of the WZW theory. (author). 21 refs., 6 figs

47 CFR 68.320 - Supplier's Declaration of Conformity.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 3 2010-10-01 2010-10-01 false Supplier's Declaration of Conformity. 68.320... Approval § 68.320 Supplier's Declaration of Conformity. (a) Supplier's Declaration of Conformity is a... Supplier's Declaration of Conformity attaches to all items subsequently marketed by the responsible party...

Conformational effects in photoelectron circular dichroism

Science.gov (United States)

Turchini, S.

2017-12-01

Photoelectron circular dichroism (PECD) is a novel type of spectroscopy, which presents surprising sensitivity to conformational effects in chiral systems. While classical photoelectron spectroscopy mainly responds to conformational effects in terms of energy level shifts, PECD provides a rich and detailed response to tiny changes in electronic and structural properties by means of the intensity dispersion of the circular dichroism as a function of photoelectron kinetic energy. In this work, the basics of PECD will be outlined, emphasizing the role of interference from the l,l+/- 1 outgoing partial wave of the photoelectron in the PECD transition matrix element, which is responsible for the extreme sensitivity to conformational effects. Examples using molecular systems and interfaces will shed light on the powerful application of PECD to classical conformational effects such as group substitution, isomerism, conformer population and clustering. Moreover, the PECD results will be reported in challenging new fields where conformations play a key role, such as vibrational effects, transient chirality and time- resolved experiments. To date, PECD has mostly been based on synchrotron radiation facilities, but it also has a future as a table-top lab experiment by means of multiphoton ionization. An important application of PECD as an analytical tool will be reported. The aim of this review is to illustrate that in PECD, the presence of conformational effects is essential for understanding a wide range of effects from a new perspective, making it different from classical spectroscopy.

Understanding modern magnets through conformal mapping

International Nuclear Information System (INIS)

Halbach, K.

1989-10-01

I want to show with the help of a number of examples that conformal mapping is a unique and enormously powerful tool for thinking about, and solving, problems. Usually one has to write down only a few equations, and sometimes none at all exclamation point When I started getting involved in work for which conformal mapping seemed to be a powerful tool, I did not think that I would ever be able to use that technique successfully because it seemed to require a nearly encyclopedic memory, an impression that was strengthened when I saw K. Kober's Dictionary of Conformal Representations. This attitude changed when I started to realize that beyond the basics of the theory of a function of a complex variable, I needed to know only about a handful of conformal maps and procedures. Consequently, my second goal for this talk is to show that in most cases conformal mapping functions can be obtained by formulating the underlying physics appropriately. This means particularly that encyclopedic knowledge of conformal maps is not necessary for successful use of conformal mapping techniques. To demonstrate these facts I have chosen examples from an area of physics/engineering in which I am active, namely accelerator physics. In order to do that successfully I start with a brief introduction into high energy charged particle storage ring technology, even though not all examples used in this paper to elucidate my points come directly from this particular field of accelerator technology

Restricted Interval Valued Neutrosophic Sets and Restricted Interval Valued Neutrosophic Topological Spaces

Directory of Open Access Journals (Sweden)

Anjan Mukherjee

2016-08-01

Full Text Available In this paper we introduce the concept of restricted interval valued neutrosophic sets (RIVNS in short. Some basic operations and properties of RIVNS are discussed. The concept of restricted interval valued neutrosophic topology is also introduced together with restricted interval valued neutrosophic finer and restricted interval valued neutrosophic coarser topology. We also define restricted interval valued neutrosophic interior and closer of a restricted interval valued neutrosophic set. Some theorems and examples are cites. Restricted interval valued neutrosophic subspace topology is also studied.

Higher-derivative generalization of conformal mechanics

Science.gov (United States)

Baranovsky, Oleg

2017-08-01

Higher-derivative analogs of multidimensional conformal particle and many-body conformal mechanics are constructed. Their Newton-Hooke counterparts are derived by applying appropriate coordinate transformations.

Gluon amplitudes as 2 d conformal correlators

Science.gov (United States)

Pasterski, Sabrina; Shao, Shu-Heng; Strominger, Andrew

2017-10-01

Recently, spin-one wave functions in four dimensions that are conformal primaries of the Lorentz group S L (2 ,C ) were constructed. We compute low-point, tree-level gluon scattering amplitudes in the space of these conformal primary wave functions. The answers have the same conformal covariance as correlators of spin-one primaries in a 2 d CFT. The Britto-Cachazo-Feng-Witten (BCFW) recursion relation between three- and four-point gluon amplitudes is recast into this conformal basis.

Identification of potential small molecule allosteric modulator sites on IL-1R1 ectodomain using accelerated conformational sampling method.

Directory of Open Access Journals (Sweden)

Chao-Yie Yang

Full Text Available The interleukin-1 receptor (IL-1R is the founding member of the interleukin 1 receptor family which activates innate immune response by its binding to cytokines. Reports showed dysregulation of cytokine production leads to aberrant immune cells activation which contributes to auto-inflammatory disorders and diseases. Current therapeutic strategies focus on utilizing antibodies or chimeric cytokine biologics. The large protein-protein interaction interface between cytokine receptor and cytokine poses a challenge in identifying binding sites for small molecule inhibitor development. Based on the significant conformational change of IL-1R type 1 (IL-1R1 ectodomain upon binding to different ligands observed in crystal structures, we hypothesized that transient small molecule binding sites may exist when IL-1R1 undergoes conformational transition and thus suitable for inhibitor development. Here, we employed accelerated molecular dynamics (MD simulation to efficiently sample conformational space of IL-1R1 ectodomain. Representative IL-1R1 ectodomain conformations determined from the hierarchy cluster analysis were analyzed by the SiteMap program which leads to identify small molecule binding sites at the protein-protein interaction interface and allosteric modulator locations. The cosolvent mapping analysis using phenol as the probe molecule further confirms the allosteric modulator site as a binding hotspot. Eight highest ranked fragment molecules identified from in silico screening at the modulator site were evaluated by MD simulations. Four of them restricted the IL-1R1 dynamical motion to inactive conformational space. The strategy from this study, subject to in vitro experimental validation, can be useful to identify small molecule compounds targeting the allosteric modulator sites of IL-1R and prevent IL-1R from binding to cytokine by trapping IL-1R in inactive conformations.

Multichannel conformal blocks for scattering amplitudes

Science.gov (United States)

Belitsky, A. V.

2018-05-01

By performing resummation of small fermion-antifermion pairs within the pentagon form factor program to scattering amplitudes in planar N = 4 superYang-Mills theory, we construct multichannel conformal blocks within the flux-tube picture for N-sided NMHV polygons. This procedure is equivalent to summation of descendants of conformal primaries in the OPE framework. The resulting conformal partial waves are determined by multivariable hypergeometric series of Lauricella-Saran type.

Conformation Generation: The State of the Art.

Science.gov (United States)

Hawkins, Paul C D

2017-08-28

The generation of conformations for small molecules is a problem of continuing interest in cheminformatics and computational drug discovery. This review will present an overview of methods used to sample conformational space, focusing on those methods designed for organic molecules commonly of interest in drug discovery. Different approaches to both the sampling of conformational space and the scoring of conformational stability will be compared and contrasted, with an emphasis on those methods suitable for conformer sampling of large numbers of drug-like molecules. Particular attention will be devoted to the appropriate utilization of information from experimental solid-state structures in validating and evaluating the performance of these tools. The review will conclude with some areas worthy of further investigation.

The pseudo-conformal universe: scale invariance from spontaneous breaking of conformal symmetry

International Nuclear Information System (INIS)

Hinterbichler, Kurt; Khoury, Justin

2012-01-01

We present a novel theory of the very early universe which addresses the traditional horizon and flatness problems of big bang cosmology and predicts a scale invariant spectrum of perturbations. Unlike inflation, this scenario requires no exponential accelerated expansion of space-time. Instead, the early universe is described by a conformal field theory minimally coupled to gravity. The conformal fields develop a time-dependent expectation value which breaks the flat space so(4,2) conformal symmetry down to so(4,1), the symmetries of de Sitter, giving perturbations a scale invariant spectrum. The solution is an attractor, at least in the case of a single time-dependent field. Meanwhile, the metric background remains approximately flat but slowly contracts, which makes the universe increasingly flat, homogeneous and isotropic, akin to the smoothing mechanism of ekpyrotic cosmology. Our scenario is very general, requiring only a conformal field theory capable of developing the appropriate time-dependent expectation values, and encompasses existing incarnations of this idea, specifically the U(1) model of Rubakov and the Galileon Genesis scenario. Its essential features depend only on the symmetry breaking pattern and not on the details of the underlying lagrangian. It makes generic observational predictions that make it potentially distinguishable from standard inflation, in particular significant non-gaussianities and the absence of primordial gravitational waves

Arbitrary spin conformal fields in (A)dS

International Nuclear Information System (INIS)

Metsaev, R.R.

2014-01-01

Totally symmetric arbitrary spin conformal fields in (A)dS space of even dimension greater than or equal to four are studied. Ordinary-derivative and gauge invariant Lagrangian formulation for such fields is obtained. Gauge symmetries are realized by using auxiliary fields and Stueckelberg fields. We demonstrate that Lagrangian of conformal field is decomposed into a sum of gauge invariant Lagrangians for massless, partial-massless, and massive fields. We obtain a mass spectrum of the partial-massless and massive fields and confirm the conjecture about the mass spectrum made in the earlier literature. In contrast to conformal fields in flat space, the kinetic terms of conformal fields in (A)dS space turn out to be diagonal with respect to fields entering the Lagrangian. Explicit form of conformal transformation which maps conformal field in flat space to conformal field in (A)dS space is obtained. Covariant Lorentz-like and de-Donder like gauge conditions leading to simple gauge-fixed Lagrangian of conformal fields are proposed. Using such gauge-fixed Lagrangian, which is invariant under global BRST transformations, we explain how the partition function of conformal field is obtained in the framework of our approach

Inversion theory and conformal mapping

CERN Document Server

Blair, David E

2000-01-01

It is rarely taught in an undergraduate or even graduate curriculum that the only conformal maps in Euclidean space of dimension greater than two are those generated by similarities and inversions in spheres. This is in stark contrast to the wealth of conformal maps in the plane. The principal aim of this text is to give a treatment of this paucity of conformal maps in higher dimensions. The exposition includes both an analytic proof in general dimension and a differential-geometric proof in dimension three. For completeness, enough complex analysis is developed to prove the abundance of conformal maps in the plane. In addition, the book develops inversion theory as a subject, along with the auxiliary theme of circle-preserving maps. A particular feature is the inclusion of a paper by Carath�odory with the remarkable result that any circle-preserving transformation is necessarily a M�bius transformation, not even the continuity of the transformation is assumed. The text is at the level of advanced undergr...

Inverse bootstrapping conformal field theories

Science.gov (United States)

Li, Wenliang

2018-01-01

We propose a novel approach to study conformal field theories (CFTs) in general dimensions. In the conformal bootstrap program, one usually searches for consistent CFT data that satisfy crossing symmetry. In the new method, we reverse the logic and interpret manifestly crossing-symmetric functions as generating functions of conformal data. Physical CFTs can be obtained by scanning the space of crossing-symmetric functions. By truncating the fusion rules, we are able to concentrate on the low-lying operators and derive some approximate relations for their conformal data. It turns out that the free scalar theory, the 2d minimal model CFTs, the ϕ 4 Wilson-Fisher CFT, the Lee-Yang CFTs and the Ising CFTs are consistent with the universal relations from the minimal fusion rule ϕ 1 × ϕ 1 = I + ϕ 2 + T , where ϕ 1 , ϕ 2 are scalar operators, I is the identity operator and T is the stress tensor.

On functional representations of the conformal algebra

Energy Technology Data Exchange (ETDEWEB)

Rosten, Oliver J.

2017-07-15

Starting with conformally covariant correlation functions, a sequence of functional representations of the conformal algebra is constructed. A key step is the introduction of representations which involve an auxiliary functional. It is observed that these functionals are not arbitrary but rather must satisfy a pair of consistency equations corresponding to dilatation and special conformal invariance. In a particular representation, the former corresponds to the canonical form of the exact renormalization group equation specialized to a fixed point whereas the latter is new. This provides a concrete understanding of how conformal invariance is realized as a property of the Wilsonian effective action and the relationship to action-free formulations of conformal field theory. Subsequently, it is argued that the conformal Ward Identities serve to define a particular representation of the energy-momentum tensor. Consistency of this construction implies Polchinski's conditions for improving the energy-momentum tensor of a conformal field theory such that it is traceless. In the Wilsonian approach, the exactly marginal, redundant field which generates lines of physically equivalent fixed points is identified as the trace of the energy-momentum tensor. (orig.)

40 CFR 89.105 - Certificate of conformity.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Certificate of conformity. 89.105... and Certification Provisions § 89.105 Certificate of conformity. Every manufacturer of a new nonroad compression-ignition engine must obtain a certificate of conformity covering the engine family, as described...

Changes in ceramide metabolism are essential in Madin-Darby canine kidney cell differentiation.

Science.gov (United States)

Pescio, Lucila Gisele; Santacreu, Bruno Jaime; Lopez, Vanina Gisela; Paván, Carlos Humberto; Romero, Daniela Judith; Favale, Nicolás Octavio; Sterin-Speziale, Norma Beatriz

2017-07-01

Ceramides (Cers) and complex sphingolipids with defined acyl chain lengths play important roles in numerous cell processes. Six Cer synthase (CerS) isoenzymes (CerS1-6) are the key enzymes responsible for the production of the diversity of molecular species. In this study, we investigated the changes in sphingolipid metabolism during the differentiation of Madin-Darby canine kidney (MDCK) cells. By MALDI TOF TOF MS, we analyzed the molecular species of Cer, glucosylceramide (GlcCer), lactosylceramide (LacCer), and SM in nondifferentiated and differentiated cells (cultured under hypertonicity). The molecular species detected were the same, but cells subjected to hypertonicity presented higher levels of C24:1 Cer, C24:1 GlcCer, C24:1 SM, and C16:0 LacCer. Consistently with the molecular species, MDCK cells expressed CerS2, CerS4, and CerS6, but with no differences during cell differentiation. We next evaluated the different synthesis pathways with sphingolipid inhibitors and found that cells subjected to hypertonicity in the presence of amitriptyline, an inhibitor of acid sphingomyelinase, showed decreased radiolabeled incorporation in LacCer and cells did not develop a mature apical membrane. These results suggest that hypertonicity induces the endolysosomal degradation of SM, generating the Cer used as substrate for the synthesis of specific molecular species of glycosphingolipids that are essential for MDCK cell differentiation. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

A note on fashion cycles, novelty and conformity

OpenAIRE

Federica Alberti

2013-01-01

We develop a model in which novelty and conformity motivate fashion behavior. Fashion cycles occur if conformity is not too high. The duration of fashion cycles depends on individual-specific conformity, novelty, and the number of available styles. The use of individual-specific novelty and conformity allows us to also identify fashion leaders.

Nonperturbative results for two-index conformal windows

Energy Technology Data Exchange (ETDEWEB)

Bergner, Georg [Albert Einstein Center for Fundamental Physics,Institute for Theoretical Physics, University of Bern,Sidlerstrasse 5, CH-3012 Bern (Switzerland); Ryttov, Thomas A.; Sannino, Francesco [CP-Origins and the Danish IAS, University of Southern Denmark,5230 Odense M (Denmark)

2015-12-10

Via large and small N{sub c} relations we derive nonperturbative results about the conformal window of two-index theories. Using Schwinger-Dyson methods as well as four-loops results we estimate subleading corrections and show that naive large number of colors extrapolations are unreliable when N{sub c} is less than about six. Nevertheless useful nonperturbative inequalities for the size of the conformal windows, for any number of colors, can be derived. By further observing that the adjoint conformal window is independent of the number of colors we argue, among other things, that: the large N{sub c} two-index conformal window is twice the conformal window of the adjoint representation (which can be determined at small N{sub c}) expressed in terms of Dirac fermions; lattice results for adjoint matter can be used to provide independent information on the conformal dynamics of two-index theories such as SU(N{sub c}) with two and four symmetric Dirac flavors.

Nonperturbative results for two-index conformal windows

International Nuclear Information System (INIS)

Bergner, Georg; Ryttov, Thomas A.; Sannino, Francesco

2015-01-01

Via large and small N c relations we derive nonperturbative results about the conformal window of two-index theories. Using Schwinger-Dyson methods as well as four-loops results we estimate subleading corrections and show that naive large number of colors extrapolations are unreliable when N c is less than about six. Nevertheless useful nonperturbative inequalities for the size of the conformal windows, for any number of colors, can be derived. By further observing that the adjoint conformal window is independent of the number of colors we argue, among other things, that: the large N c two-index conformal window is twice the conformal window of the adjoint representation (which can be determined at small N c ) expressed in terms of Dirac fermions; lattice results for adjoint matter can be used to provide independent information on the conformal dynamics of two-index theories such as SU(N c ) with two and four symmetric Dirac flavors.

Measuring the mechanical properties of molecular conformers

Science.gov (United States)

Jarvis, S. P.; Taylor, S.; Baran, J. D.; Champness, N. R.; Larsson, J. A.; Moriarty, P.

2015-09-01

Scanning probe-actuated single molecule manipulation has proven to be an exceptionally powerful tool for the systematic atomic-scale interrogation of molecular adsorbates. To date, however, the extent to which molecular conformation affects the force required to push or pull a single molecule has not been explored. Here we probe the mechanochemical response of two tetra(4-bromophenyl)porphyrin conformers using non-contact atomic force microscopy where we find a large difference between the lateral forces required for manipulation. Remarkably, despite sharing very similar adsorption characteristics, variations in the potential energy surface are capable of prohibiting probe-induced positioning of one conformer, while simultaneously permitting manipulation of the alternative conformational form. Our results are interpreted in the context of dispersion-corrected density functional theory calculations which reveal significant differences in the diffusion barriers for each conformer. These results demonstrate that conformational variation significantly modifies the mechanical response of even simple porpyhrins, potentially affecting many other flexible molecules.

Counselor Identity: Conformity or Distinction?

Science.gov (United States)

McLaughlin, Jerry E.; Boettcher, Kathryn

2009-01-01

The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

Peer influence: neural mechanisms underlying in-group conformity.

Science.gov (United States)

Stallen, Mirre; Smidts, Ale; Sanfey, Alan G

2013-01-01

People often conform to the behavior of others with whom they identify. However, it is unclear what fundamental mechanisms underlie this type of conformity. Here, we investigate the processes mediating in-group conformity by using functional magnetic resonance imaging (fMRI). Participants completed a perceptual decision-making task while undergoing fMRI, during which they were exposed to the judgments of both in-group and out-group members. Our data suggest that conformity to the in-group is mediated by both positive affect as well as the cognitive capacity of perspective taking. Examining the processes that drive in-group conformity by utilizing a basic decision-making paradigm combined with neuroimaging methods provides important insights into the potential mechanisms of conformity. These results may provide an integral step in developing more effective campaigns using group conformity as a tool for behavioral change.

47 CFR 2.1072 - Limitation on Declaration of Conformity.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Limitation on Declaration of Conformity. 2.1072... Conformity § 2.1072 Limitation on Declaration of Conformity. (a) The Declaration of Conformity signifies that...'s rules. (b) A Declaration of Conformity by the responsible party is effective until a termination...

Conformity index for brain cancer patients

International Nuclear Information System (INIS)

Petkovska, Sonja; Tolevska, Cveta; Kraleva, Slavica; Petreska, Elena

2010-01-01

The purpose of this study is to present the level of conformity achieved by using 3D conformal radiotherapy for brain cancer patients. Conformity index is a helpful quantitative tool for assessing (evaluating) the quality of a treatment plan. Treatment plans made for ninety patients with brain tumor are worked on this paper. The patients are in supine position and immobilized with thermoplastic masks for the head. Computed tomography data sets with 5 mm scan thickness are used to create a 3D image. All structures of interest are contoured. In order to obtain an optimal dose distribution, treatment fields are fit around target volume with set-up margins of 7mm in each direction. The conformity index values are between 1.21 and 2.04. Value of 1.8 is exceeded in eighteen cases; nine of them are bigger than 1.9 and only three of them are above 2. The target volume for each of these extreme CI values is ideal covered (between 95% and 105% of the prescribed dose). The most acceptable conformity index value in this paper belongs to the plan with the lowest minimal dose (84.7%). It can be concluded that conformity index is necessary but not sufficient factor for assessing radiation treatment plan conformity. To be able to estimate the acceptability of some treatment plan in daily practice, additional information as minimal, maximal and mean dose into target volume, as well as health tissues coverage must be taken into account.(Author)

Renormalization, conformal ward identities and the origin of a conformal anomaly pole

Science.gov (United States)

Corianò, Claudio; Maglio, Matteo Maria

2018-06-01

We investigate the emergence of a conformal anomaly pole in conformal field theories in the case of the TJJ correlator. We show how it comes to be generated in dimensional renormalization, using a basis of 13 form factors (the F-basis), where only one of them requires renormalization (F13), extending previous studies. We then combine recent results on the structure of the non-perturbative solutions of the conformal Ward identities (CWI's) for the TJJ in momentum space, expressed in terms of a minimal set of 4 form factors (A-basis), with the properties of the F-basis, and show how the singular behaviour of the corresponding form factors in both basis can be related. The result proves the centrality of such massless effective interactions induced by the anomaly, which have recently found realization in solid state, in the theory of topological insulators and of Weyl semimetals. This pattern is confirmed in massless abelian and nonabelian theories (QED and QCD) investigated at one-loop.

Conformable variational iteration method

Directory of Open Access Journals (Sweden)

Omer Acan

2017-02-01

Full Text Available In this study, we introduce the conformable variational iteration method based on new defined fractional derivative called conformable fractional derivative. This new method is applied two fractional order ordinary differential equations. To see how the solutions of this method, linear homogeneous and non-linear non-homogeneous fractional ordinary differential equations are selected. Obtained results are compared the exact solutions and their graphics are plotted to demonstrate efficiency and accuracy of the method.

40 CFR 90.106 - Certificate of conformity.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Certificate of conformity. 90.106... Standards and Certification Provisions § 90.106 Certificate of conformity. (a)(1) Except as provided in § 90... certificate of conformity covering such engines; however, engines manufactured during an annual production...

SCit: web tools for protein side chain conformation analysis

OpenAIRE

Gautier, R.; Camproux, A.-C.; Tufféry, P.

2004-01-01

SCit is a web server providing services for protein side chain conformation analysis and side chain positioning. Specific services use the dependence of the side chain conformations on the local backbone conformation, which is described using a structural alphabet that describes the conformation of fragments of four-residue length in a limited library of structural prototypes. Based on this concept, SCit uses sets of rotameric conformations dependent on the local backbone conformation of each...

The structure, function, and importance of ceramides in skin and their use as therapeutic agents in skin-care products.

Science.gov (United States)

Meckfessel, Matthew H; Brandt, Staci

2014-07-01

Ceramides (CERs) are epidermal lipids that are important for skin barrier function. Much research has been devoted to identifying the numerous CERs found in human skin and their function. Alterations in CER content are associated with a number of skin diseases such as atopic dermatitis. Newer formulations of skin-care products have incorporated CERs into their formulations with the goal of exogenously applying CERs to help skin barrier function. CERs are a complex class of molecules and because of their growing ubiquity in skin-care products, a clear understanding of their role in skin and use in skin-care products is essential for clinicians treating patients with skin diseases. This review provides an overview of the structure, function, and importance of skin CERs in diseased skin and how CERs are being used in skin-care products to improve or restore skin barrier function. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

SCit: web tools for protein side chain conformation analysis.

Science.gov (United States)

Gautier, R; Camproux, A-C; Tufféry, P

2004-07-01

SCit is a web server providing services for protein side chain conformation analysis and side chain positioning. Specific services use the dependence of the side chain conformations on the local backbone conformation, which is described using a structural alphabet that describes the conformation of fragments of four-residue length in a limited library of structural prototypes. Based on this concept, SCit uses sets of rotameric conformations dependent on the local backbone conformation of each protein for side chain positioning and the identification of side chains with unlikely conformations. The SCit web server is accessible at http://bioserv.rpbs.jussieu.fr/SCit.

Conformal Killing horizons and their thermodynamics

Science.gov (United States)

Nielsen, Alex B.; Shoom, Andrey A.

2018-05-01

Certain dynamical black hole solutions can be mapped to static spacetimes by conformal metric transformations. This mapping provides a physical link between the conformal Killing horizon of the dynamical black hole and the Killing horizon of the static spacetime. Using the Vaidya spacetime as an example, we show how this conformal relation can be used to derive thermodynamic properties of such dynamical black holes. Although these horizons are defined quasi-locally and can be located by local experiments, they are distinct from other popular notions of quasi-local horizons such as apparent horizons. Thus in the dynamical Vaidya spacetime describing constant accretion of null dust, the conformal Killing horizon, which is null by construction, is the natural horizon to describe the black hole.

Molecular dynamics studies of the conformation of sorbitol

Science.gov (United States)

Lerbret, A.; Mason, P.E.; Venable, R.M.; Cesàro, A.; Saboungi, M.-L.; Pastor, R.W.; Brady, J.W.

2009-01-01

Molecular dynamics simulations of a 3 m aqueous solution of D-sorbitol (also called D-glucitol) have been performed at 300 K, as well as at two elevated temperatures to promote conformational transitions. In principle, sorbitol is more flexible than glucose since it does not contain a constraining ring. However, a conformational analysis revealed that the sorbitol chain remains extended in solution, in contrast to the bent conformation found experimentally in the crystalline form. While there are 243 staggered conformations of the backbone possible for this open-chain polyol, only a very limited number were found to be stable in the simulations. Although many conformers were briefly sampled, only eight were significantly populated in the simulation. The carbon backbones of all but two of these eight conformers were completely extended, unlike the bent crystal conformation. These extended conformers were stabilized by a quite persistent intramolecular hydrogen bond between the hydroxyl groups of carbon C-2 and C-4. The conformational populations were found to be in good agreement with the limited available NMR data except for the C-2–C-3 torsion (spanned by the O-2–O-4 hydrogen bond), where the NMR data supports a more bent structure. PMID:19744646

Lattice models and conformal field theories

International Nuclear Information System (INIS)

Saleur, H.

1988-01-01

Theoretical studies concerning the connection between critical physical systems and the conformal theories are reviewed. The conformal theory associated to a critical (integrable) lattice model is derived. The obtention of the central charge, critical exponents and torus partition function, using renormalization group arguments, is shown. The quantum group structure, in the integrable lattice models, and the theory of Visaro algebra representations are discussed. The relations between off-critical integrable models and conformal theories, in finite geometries, are studied

14 CFR 21.130 - Statement of conformity.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Statement of conformity. 21.130 Section 21... conformity. Each holder or licensee of a type certificate only, for a product manufactured in the United... Administrator a statement of conformity (FAA Form 317). This statement must be signed by an authorized person...

14 CFR 21.53 - Statement of conformity.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Statement of conformity. 21.53 Section 21... CERTIFICATION PROCEDURES FOR PRODUCTS AND PARTS Type Certificates § 21.53 Statement of conformity. Link to an... conformity (FAA Form 317) to the Administrator for each aircraft engine and propeller presented to the...

Delineating the conformal window

DEFF Research Database (Denmark)

Frandsen, Mads Toudal; Pickup, Thomas; Teper, Michael

2011-01-01

We identify and characterise the conformal window in gauge theories relevant for beyond the standard model building, e.g. Technicolour, using the criteria of metric confinement and causal analytic couplings, which are known to be consistent with the phase diagram of supersymmetric QCD from Seiberg...... duality. Using these criteria we find perturbation theory to be consistent throughout the predicted conformal window for several of these gauge theories and we discuss recent lattice results in the light of our findings....

Rapid roll inflation with conformal coupling

International Nuclear Information System (INIS)

Kofman, Lev; Mukohyama, Shinji

2008-01-01

Usual inflation is realized with a slow rolling scalar field minimally coupled to gravity. In contrast, we consider dynamics of a scalar with a flat effective potential, conformally coupled to gravity. Surprisingly, it contains an attractor inflationary solution with the rapidly rolling inflaton field. We discuss models with the conformal inflaton with a flat potential (including hybrid inflation). There is no generation of cosmological fluctuations from the conformally coupled inflaton. We consider realizations of modulated (inhomogeneous reheating) or curvaton cosmological fluctuations in these models. We also implement these unusual features for the popular string-theoretic warped inflationary scenario, based on the interacting D3-D3 branes. The original warped brane inflation suffers a large inflaton mass due to conformal coupling to 4-dimensional gravity. Instead of considering this as a problem and trying to cure it with extra engineering, we show that warped inflation with the conformally coupled, rapidly rolling inflaton is yet possible with N=37 efoldings, which requires low-energy scales 1-100 TeV of inflation. Coincidentally, the same warping numerology can be responsible for the hierarchy. It is shown that the scalars associated with angular isometries of the warped geometry of compact manifold (e.g. S 3 of Klebanov-Strassler (KS) geometry) have solutions identical to conformally coupled modes and also cannot be responsible for cosmological fluctuations. We discuss other possibilities

Rapid roll inflation with conformal coupling

Science.gov (United States)

Kofman, Lev; Mukohyama, Shinji

2008-02-01

Usual inflation is realized with a slow rolling scalar field minimally coupled to gravity. In contrast, we consider dynamics of a scalar with a flat effective potential, conformally coupled to gravity. Surprisingly, it contains an attractor inflationary solution with the rapidly rolling inflaton field. We discuss models with the conformal inflaton with a flat potential (including hybrid inflation). There is no generation of cosmological fluctuations from the conformally coupled inflaton. We consider realizations of modulated (inhomogeneous reheating) or curvaton cosmological fluctuations in these models. We also implement these unusual features for the popular string-theoretic warped inflationary scenario, based on the interacting D3-D¯3 branes. The original warped brane inflation suffers a large inflaton mass due to conformal coupling to 4-dimensional gravity. Instead of considering this as a problem and trying to cure it with extra engineering, we show that warped inflation with the conformally coupled, rapidly rolling inflaton is yet possible with N=37 efoldings, which requires low-energy scales 1 100 TeV of inflation. Coincidentally, the same warping numerology can be responsible for the hierarchy. It is shown that the scalars associated with angular isometries of the warped geometry of compact manifold (e.g. S3 of Klebanov-Strassler (KS) geometry) have solutions identical to conformally coupled modes and also cannot be responsible for cosmological fluctuations. We discuss other possibilities.

Conformal collineations and anisotropic fluids in general relativity

International Nuclear Information System (INIS)

Duggal, K.L.; Sharma, R.

1986-01-01

Recently, Herrera et al. [L. Herrera, J. Jimenez, L. Leal, J. Ponce de Leon, M. Esculpi, and V. Galino, J. Math. Phys. 25, 3274 (1984)] studied the consequences of the existence of a one-parameter group of conformal motions for anisotropic matter. They concluded that for special conformal motions, the stiff equation of state (p = μ) is singled out in a unique way, provided the generating conformal vector field is orthogonal to the four-velocity. In this paper, the same problem is studied by using conformal collineations (which include conformal motions as subgroups). It is shown that, for a special conformal collineation, the stiff equation of state is not singled out. Non-Einstein Ricci-recurrent spaces are considered as physical models for the fluid matter

Genetic polymorphism of toll-like receptors 4 gene by polymerase chain reaction-restriction fragment length polymorphisms, polymerase chain reaction-single-strand conformational polymorphism to correlate with mastitic cows

Directory of Open Access Journals (Sweden)

Pooja H. Gupta

2015-05-01

Full Text Available Aim: An attempt has been made to study the toll-like receptors 4 (TLR4 gene polymorphism from cattle DNA to correlate with mastitis cows. Materials and Methods: In present investigation, two fragments of TLR4 gene named T4CRBR1 and T4CRBR2 of a 316 bp and 382 bp were amplified by polymerase chain reaction (PCR, respectively from Kankrej (22 and Triple cross (24 cattle. The genetic polymorphisms in the two populations were detected by a single-strand conformational polymorphism in the first locus and by digesting the fragments with restriction endonuclease Alu I in the second one. Results: Results showed that both alleles (A and B of two loci were found in all the two populations and the value of polymorphism information content indicated that these were highly polymorphic. Statistical results of χ2 test indicated that two polymorphism sites in the two populations fit with Hardy–Weinberg equilibrium (p˂0.05. Meanwhile, the effect of polymorphism of TLR4 gene on the somatic cell score (SCS indicated the cattle with allele a in T4CRBR1 showed lower SCS than that of allele B (p<0.05. Thus, the allele A might play an important role in mastitis resistance in cows. Conclusion: The relationship between the bovine mastitis trait and the polymorphism of TLR4 gene indicated that the bovine TLR4 gene may play an important role in mastitis resistance.

Bioactive focus in conformational ensembles: a pluralistic approach

Science.gov (United States)

Habgood, Matthew

2017-12-01

Computational generation of conformational ensembles is key to contemporary drug design. Selecting the members of the ensemble that will approximate the conformation most likely to bind to a desired target (the bioactive conformation) is difficult, given that the potential energy usually used to generate and rank the ensemble is a notoriously poor discriminator between bioactive and non-bioactive conformations. In this study an approach to generating a focused ensemble is proposed in which each conformation is assigned multiple rankings based not just on potential energy but also on solvation energy, hydrophobic or hydrophilic interaction energy, radius of gyration, and on a statistical potential derived from Cambridge Structural Database data. The best ranked structures derived from each system are then assembled into a new ensemble that is shown to be better focused on bioactive conformations. This pluralistic approach is tested on ensembles generated by the Molecular Operating Environment's Low Mode Molecular Dynamics module, and by the Cambridge Crystallographic Data Centre's conformation generator software.

CONFORMITY IN CHRIST 1. THE TRANSFORMATION PROCESS

African Journals Online (AJOL)

This essay investigates the notion of conformity in Christ as it is part of a compre- hensive, multilayered process of transformation. In the first part it focuses on the process of transformation in creation, re-creation, conformity, love and glory. In the second part it discusses transformation in Christ by looking at conformation and ...

Conformal invariance in harmonic superspace

International Nuclear Information System (INIS)

Galperin, A.; Ivanov, E.; Ogievetsky, V.; Sokatchev, E.

1985-01-01

N=2 conformal supersymmetry is realized in harmonic superspace, its peculiarities are analyzed. The coordinate group and analytical prepotentials for N=2 conformal supergravity are found. A new version of the N=2 Einstein supergravity with infinite number of auxiliary fields is suggested. A hypermultiplet without central charges and constraints is used as a compensator

New open conformation of SMYD3 implicates conformational selection and allostery

Directory of Open Access Journals (Sweden)

Nicholas Spellmon

2016-12-01

Full Text Available SMYD3 plays a key role in cancer cell viability, adhesion, migration and invasion. SMYD3 promotes formation of inducible regulatory T cells and is involved in reducing autoimmunity. However, the nearly “closed” substrate-binding site and poor in vitro H3K4 methyltransferase activity have obscured further understanding of this oncogenically related protein. Here we reveal that SMYD3 can adopt an “open” conformation using molecular dynamics simulation and small-angle X-ray scattering. This ligand-binding-capable open state is related to the crystal structure-like closed state by a striking clamshell-like inter-lobe dynamics. The two states are characterized by many distinct structural and dynamical differences and the conformational transition pathway is mediated by a reversible twisting motion of the C-terminal domain (CTD. The spontaneous transition from the closed to open states suggests two possible, mutually non-exclusive models for SMYD3 functional regulation and the conformational selection mechanism and allostery may regulate the catalytic or ligand binding competence of SMYD3. This study provides an immediate clue to the puzzling role of SMYD3 in epigenetic gene regulation.

Reciprocity Outperforms Conformity to Promote Cooperation.

Science.gov (United States)

Romano, Angelo; Balliet, Daniel

2017-10-01

Evolutionary psychologists have proposed two processes that could give rise to the pervasiveness of human cooperation observed among individuals who are not genetically related: reciprocity and conformity. We tested whether reciprocity outperformed conformity in promoting cooperation, especially when these psychological processes would promote a different cooperative or noncooperative response. To do so, across three studies, we observed participants' cooperation with a partner after learning (a) that their partner had behaved cooperatively (or not) on several previous trials and (b) that their group members had behaved cooperatively (or not) on several previous trials with that same partner. Although we found that people both reciprocate and conform, reciprocity has a stronger influence on cooperation. Moreover, we found that conformity can be partly explained by a concern about one's reputation-a finding that supports a reciprocity framework.

Irreversibility and higher-spin conformal field theory

Science.gov (United States)

Anselmi, Damiano

2000-08-01

I discuss the properties of the central charges c and a for higher-derivative and higher-spin theories (spin 2 included). Ordinary gravity does not admit a straightforward identification of c and a in the trace anomaly, because it is not conformal. On the other hand, higher-derivative theories can be conformal, but have negative c and a. A third possibility is to consider higher-spin conformal field theories. They are not unitary, but have a variety of interesting properties. Bosonic conformal tensors have a positive-definite action, equal to the square of a field strength, and a higher-derivative gauge invariance. There exists a conserved spin-2 current (not the canonical stress tensor) defining positive central charges c and a. I calculate the values of c and a and study the operator-product structure. Higher-spin conformal spinors have no gauge invariance, admit a standard definition of c and a and can be coupled to Abelian and non-Abelian gauge fields in a renormalizable way. At the quantum level, they contribute to the one-loop beta function with the same sign as ordinary matter, admit a conformal window and non-trivial interacting fixed points. There are composite operators of high spin and low dimension, which violate the Ferrara-Gatto-Grillo theorem. Finally, other theories, such as conformal antisymmetric tensors, exhibit more severe internal problems. This research is motivated by the idea that fundamental quantum field theories should be renormalization-group (RG) interpolations between ultraviolet and infrared conformal fixed points, and quantum irreversibility should be a general principle of nature.

Essential role of conformational selection in ligand binding.

Science.gov (United States)

Vogt, Austin D; Pozzi, Nicola; Chen, Zhiwei; Di Cera, Enrico

2014-02-01

Two competing and mutually exclusive mechanisms of ligand recognition - conformational selection and induced fit - have dominated our interpretation of ligand binding in biological macromolecules for almost six decades. Conformational selection posits the pre-existence of multiple conformations of the macromolecule from which the ligand selects the optimal one. Induced fit, on the other hand, postulates the existence of conformational rearrangements of the original conformation into an optimal one that are induced by binding of the ligand. In the former case, conformational transitions precede the binding event; in the latter, conformational changes follow the binding step. Kineticists have used a facile criterion to distinguish between the two mechanisms based on the dependence of the rate of relaxation to equilibrium, kobs, on the ligand concentration, [L]. A value of kobs decreasing hyperbolically with [L] has been seen as diagnostic of conformational selection, while a value of kobs increasing hyperbolically with [L] has been considered diagnostic of induced fit. However, this simple conclusion is only valid under the rather unrealistic assumption of conformational transitions being much slower than binding and dissociation events. In general, induced fit only produces values of kobs that increase with [L] but conformational selection is more versatile and is associated with values of kobs that increase with, decrease with or are independent of [L]. The richer repertoire of kinetic properties of conformational selection applies to kinetic mechanisms with single or multiple saturable relaxations and explains the behavior of nearly all experimental systems reported in the literature thus far. Conformational selection is always sufficient and often necessary to account for the relaxation kinetics of ligand binding to a biological macromolecule and is therefore an essential component of any binding mechanism. On the other hand, induced fit is never necessary and

Rotational Spectroscopy Unveils Eleven Conformers of Adrenaline

Science.gov (United States)

Cabezas, C.; Cortijo, V.; Mata, S.; Lopez, J. C.; Alonso, J. L.

2013-06-01

Recent improvements in our LA-MB-FTMW instrumentation have allowed the characterization of eleven and eight conformers for the neurotransmitters adrenaline and noradrenaline respectively. The observation of this rich conformational behavior is in accordance with the recent observation of seven conformers for dopamine and in sharp contrast with the conformational reduction proposed for catecholamines. C. Cabezas, I. Peña, J. C. López, J. L. Alonso J. Phys. Chem. Lett. 2013, 4, 486. H. Mitsuda, M. Miyazaki, I. B. Nielsen, P. Carcabal,C. Dedonder, C. Jouvet, S. Ishiuchi, M. Fujii J. Phys. Chem. Lett. 2010, 1, 1130.

Dilogarithm identities in conformal field theory

International Nuclear Information System (INIS)

Nahm, W.; Recknagel, A.; Terhoeven, M.

1992-11-01

Dilogarithm identities for the central charges and conformal dimensions exist for at least large classes of rational conformally invariant quantum field theories in two dimensions. In many cases, proofs are not yet known but the numerical and structural evidence is convincing. In particular, close relations exist to fusion rules and partition identities. We describe some examples and ideas, and present conjectures useful for the classification of conformal theories. The mathematical structures seem to be dual to Thurston's program for the classification of 3-manifolds. (orig.)

Efficient CT simulation of the four-field technique for conformal radiotherapy of prostate carcinoma

International Nuclear Information System (INIS)

Valicenti, Richard K.; Waterman, Frank M.; Croce, Raymond J.; Corn, Benjamin; Suntharalingam, Nagalingam; Curran, Walter J.

1997-01-01

Purpose: Conformal radiotherapy of prostate carcinoma relies on contouring of individual CT slices for target and normal tissue localization. This process can be very time consuming. In the present report, we describe a method to more efficiently localize pelvic anatomy directly from digital reconstructed radiographs (DRRs). Materials and Methods: Ten patients with prostate carcinoma underwent CT simulation (the spiral mode at 3 mm separation) for conformal four-field 'box' radiotherapy. The bulbous urethra and bladder were opacified with iodinated contrast media. On lateral and anteroposterior DRRs, the volume of interest (VOI) was restricted to 1.0-1.5 cm tissue thickness to optimize digital radiograph reconstruction of the prostate and seminal vesicles. By removing unessential voxel elements, this method provided direct visualization of those structures. For comparison, the targets of each patient were also obtained by contouring CT axial slices. Results: The method was successfully performed if the target structures were readily visualized and geometrically corresponded to those generated by contouring axial images. The targets in 9 of 10 patients were reliable representations of the CT-contoured volumes. One patient had 18 mm variation due to the lack of bladder opacification. Using VOIs to generate thin tissue DRRs, the time required for target and normal tissue localization was on the average less than 5 min. Conclusion: In CT simulation of the four-field irradiation technique for prostate carcinoma, thin-tissue DRRs allowed for efficient and accurate target localization without requiring individual axial image contouring. This method may facilitate positioning of the beam isocenter and provide reliable conformal radiotherapy

Conformational dynamics data bank: a database for conformational dynamics of proteins and supramolecular protein assemblies.

Science.gov (United States)

Kim, Do-Nyun; Altschuler, Josiah; Strong, Campbell; McGill, Gaël; Bathe, Mark

2011-01-01

The conformational dynamics data bank (CDDB, http://www.cdyn.org) is a database that aims to provide comprehensive results on the conformational dynamics of high molecular weight proteins and protein assemblies. Analysis is performed using a recently introduced coarse-grained computational approach that is applied to the majority of structures present in the electron microscopy data bank (EMDB). Results include equilibrium thermal fluctuations and elastic strain energy distributions that identify rigid versus flexible protein domains generally, as well as those associated with specific functional transitions, and correlations in molecular motions that identify molecular regions that are highly coupled dynamically, with implications for allosteric mechanisms. A practical web-based search interface enables users to easily collect conformational dynamics data in various formats. The data bank is maintained and updated automatically to include conformational dynamics results for new structural entries as they become available in the EMDB. The CDDB complements static structural information to facilitate the investigation and interpretation of the biological function of proteins and protein assemblies essential to cell function.

Conformational Analysis of Contrast Media for X-Ray Diagnostic Radiology

International Nuclear Information System (INIS)

Solieman, A.H.M.

2010-01-01

The conformational analysis of iodinated non-ionic contrast agent, Iobitridol, was carried out using theoretical calculations to explore its conformational space, and to study different aspects connected with application of different search techniques. Monte Carlo (MC), random search (RS) and molecular dynamics (MD) based conformational search techniques were used to extract a reasonable-size sample that adequately represents and has an average behavior of the entire conformational ensemble.While MC is good for quick search for lowest energy conformer, RS is better in obtaining conformational sample that cover the whole conformational space and MD is the best for investigation of isomeric preferences inside the conformational ensemble at thermal equilibrium. Conformational analysis of the produced gas phase samples reveals that RS and MD methods could sufficiently present the 18 distinct isomeric classes that constitute the total conformational space of the Iobitridol. S samples of conformational space of Iobitridol are extensively studied, as it hypothetically cover the total conformational space. They are used to test the suitability of different methods (charge distribution methods, energy calculation methods) for Iobitridol molecular computations and internal structure forces (steric hindrance, resonance interaction), as well as dependences among the internal coordinates (dihedral angles correlations and coincidences). The atomic partial charge distribution is found to greatly affect the energy calculation for the molecular mechanics based conformational energy distributions. Further energy minimization of conformational sample by the quantum molecular orbital methods is crucial to obtain charge independent as well as energy balanced conformational sample.

Static validation of licence conformance policies

DEFF Research Database (Denmark)

Hansen, Rene Rydhof; Nielson, Flemming; Nielson, Hanne Riis

2008-01-01

Policy conformance is a security property gaining importance due to commercial interest like Digital Rights Management. It is well known that static analysis can be used to validate a number of more classical security policies, such as discretionary and mandatory access control policies, as well...... as communication protocols using symmetric and asymmetric cryptography. In this work we show how to develop a Flow Logic for validating the conformance of client software with respect to a licence conformance policy. Our approach is sufficiently flexible that it extends to fully open systems that can admit new...

The decomposition of global conformal invariants

CERN Document Server

Alexakis, Spyros

2012-01-01

This book addresses a basic question in differential geometry that was first considered by physicists Stanley Deser and Adam Schwimmer in 1993 in their study of conformal anomalies. The question concerns conformally invariant functionals on the space of Riemannian metrics over a given manifold. These functionals act on a metric by first constructing a Riemannian scalar out of it, and then integrating this scalar over the manifold. Suppose this integral remains invariant under conformal re-scalings of the underlying metric. What information can one then deduce about the Riemannian scalar? Dese

77 FR 14979 - Transportation Conformity Rule Restructuring Amendments

Science.gov (United States)

2012-03-14

... Transportation Conformity Rule Restructuring Amendments AGENCY: Environmental Protection Agency (EPA). ACTION: Final rule. SUMMARY: EPA is amending the transportation conformity rule to finalize provisions that were proposed on August 13, 2010. These amendments restructure several sections of the transportation conformity...

Solid state conformational classification of eight-membered rings

DEFF Research Database (Denmark)

Pérez, J.; García, L.; Kessler, M.

2005-01-01

A statistical classification of the solid state conformation in the title complexes using data retrieved from the Cambridge Structural Database (CSD) has been made. Phosphate and phosphinate complexes show a chair conformation preferably. In phosphonate complexes, the most frequent conformations...

Conformational analysis of 9β,19-cyclopropyl sterols: Detection of the pseudoplanar conformer by nuclear Overhauser effects and its functional implications

International Nuclear Information System (INIS)

Nes, W.D.; Benson, M.; Lundin, R.E.; Le, P.H.

1988-01-01

Nuclear Overhauser difference spectroscopy and variable temperature studies of the 9β,19-cyclopropyl sterols 24,25-dehydropollinastanol (4,4-desmethyl-5α-cycloart-24-en-3β-ol) and cyclolaudenol [(24S)-24-methyl-5α-cycloart-25(27)-en-3β-ol] have shown the solution conformation of the B/C rings to be twist-chair/twist-boat rather than boat/chair as suggested in the literature. This is very similar to the known crystal structure conformation of 9β,19-cyclopropyl sterols. The effect of these conformations on the molecular shape is highly significant; the first conformation orients into a pseudoplanar or flat shape analogous to lanosterol, whereas the latter conformation exhibits a bent shape. The results are interpreted to imply that, for conformational reasons, cyclopropyl sterols can be expected to maintain the pseudoplanar shape in membrane bilayers

Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase.

Science.gov (United States)

Cingolani, Francesca; Simbari, Fabio; Abad, Jose Luis; Casasampere, Mireia; Fabrias, Gemma; Futerman, Anthony H; Casas, Josefina

2017-08-01

Sphingolipids (SLs) have been extensively investigated in biomedical research due to their role as bioactive molecules in cells. Here, we describe the effect of a SL analog, jaspine B (JB), a cyclic anhydrophytosphingosine found in marine sponges, on the gastric cancer cell line, HGC-27. JB induced alterations in the sphingolipidome, mainly the accumulation of dihydrosphingosine, sphingosine, and their phosphorylated forms due to inhibition of ceramide synthases. Moreover, JB provoked atypical cell death in HGC-27 cells, characterized by the formation of cytoplasmic vacuoles in a time and dose-dependent manner. Vacuoles appeared to originate from macropinocytosis and triggered cytoplasmic disruption. The pan-caspase inhibitor, z-VAD, did not alter either cytotoxicity or vacuole formation, suggesting that JB activates a caspase-independent cell death mechanism. The autophagy inhibitor, wortmannin, did not decrease JB-stimulated LC3-II accumulation. In addition, cell vacuolation induced by JB was characterized by single-membrane vacuoles, which are different from double-membrane autophagosomes. These findings suggest that JB-induced cell vacuolation is not related to autophagy and it is also independent of its action on SL metabolism. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Application of Conformational Space Search in Drug Action | Adikwu ...

African Journals Online (AJOL)

The role of conformational space in drug action is presented. Two examples of molecules in different therapeutic groups are presented. Conformational space search will lead to isolating the exact conformation with the desired medicinal properties. Many conformations of a plant isolate may exist which are active, weakly ...

Ceramide and Its Related Neurochemical Networks as Targets for Some Brain Disorder Therapies.

Science.gov (United States)

Brodowicz, Justyna; Przegaliński, Edmund; Müller, Christian P; Filip, Malgorzata

2018-02-01

Correlational and causal comparative research link ceramide (Cer), the precursor of complex sphingolipids, to some psychiatric (e.g., depression, schizophrenia (SZ), alcohol use disorder, and morphine antinociceptive tolerance) and neurological (e.g., Alzheimer's disease (AD), Parkinson disease (PD)) disorders. Cer generation can occur through the de novo synthesis pathway, the sphingomyelinase pathways, and the salvage pathway. The discoveries that plasma Cer concentration increase during depressive episodes in patients and that tricyclic and tetracyclic antidepressants functionally inhibit acid sphingomyelinase (ASM), the enzyme that catalyzes the degradation of sphingomyelin to Cer, have initiated a series of studies on the role of the ASM-Cer system in depressive disorder. Disturbances in the metabolism of Cer or SM are associated with the occurrence of SZ and PD. In both PD and SZ patients, the elevated levels of Cer or SM in the brain regions were associated with the disease. AD patients showed also an abnormal metabolism of brain Cer at early stages of the disease which may suggest Cer as an AD biomarker. In plasma of AD patients and in AD transgenic mice, ASM activity was increased. In contrast, partial ASM inhibition of Aβ deposition improved memory deficits. Furthermore, in clinical and preclinical research, ethanol enhanced activation of ASM followed by Cer production. Limited data have shown that Cer plays an important role in the development of morphine antinociceptive tolerance. In summary, clinical and preclinical findings provide evidence that targeting the Cer system should be considered as an innovative translational strategy for some brain disorders.

Defects in conformal field theory

International Nuclear Information System (INIS)

Billò, Marco; Gonçalves, Vasco; Lauria, Edoardo; Meineri, Marco

2016-01-01

We discuss consequences of the breaking of conformal symmetry by a flat or spherical extended operator. We adapt the embedding formalism to the study of correlation functions of symmetric traceless tensors in the presence of the defect. Two-point functions of a bulk and a defect primary are fixed by conformal invariance up to a set of OPE coefficients, and we identify the allowed tensor structures. A correlator of two bulk primaries depends on two cross-ratios, and we study its conformal block decomposition in the case of external scalars. The Casimir equation in the defect channel reduces to a hypergeometric equation, while the bulk channel blocks are recursively determined in the light-cone limit. In the special case of a defect of codimension two, we map the Casimir equation in the bulk channel to the one of a four-point function without defect. Finally, we analyze the contact terms of the stress-tensor with the extended operator, and we deduce constraints on the CFT data. In two dimensions, we relate the displacement operator, which appears among the contact terms, to the reflection coefficient of a conformal interface, and we find unitarity bounds for the latter.

Defects in conformal field theory

Energy Technology Data Exchange (ETDEWEB)

Billò, Marco [Dipartimento di Fisica, Università di Torino, and Istituto Nazionale di Fisica Nucleare - sezione di Torino,Via P. Giuria 1 I-10125 Torino (Italy); Gonçalves, Vasco [Centro de Física do Porto,Departamento de Física e Astronomia Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto (Portugal); ICTP South American Institute for Fundamental Research Instituto de Física Teórica,UNESP - University Estadual Paulista,Rua Dr. Bento T. Ferraz 271, 01140-070, São Paulo, SP (Brazil); Lauria, Edoardo [Institute for Theoretical Physics, KU Leuven, Celestijnenlaan 200D, B-3001 Leuven (Belgium); Meineri, Marco [Perimeter Institute for Theoretical Physics,Waterloo, Ontario, N2L 2Y5 (Canada); Scuola Normale Superiore, and Istituto Nazionale di Fisica Nucleare - sezione di Pisa,Piazza dei Cavalieri 7 I-56126 Pisa (Italy)

2016-04-15

We discuss consequences of the breaking of conformal symmetry by a flat or spherical extended operator. We adapt the embedding formalism to the study of correlation functions of symmetric traceless tensors in the presence of the defect. Two-point functions of a bulk and a defect primary are fixed by conformal invariance up to a set of OPE coefficients, and we identify the allowed tensor structures. A correlator of two bulk primaries depends on two cross-ratios, and we study its conformal block decomposition in the case of external scalars. The Casimir equation in the defect channel reduces to a hypergeometric equation, while the bulk channel blocks are recursively determined in the light-cone limit. In the special case of a defect of codimension two, we map the Casimir equation in the bulk channel to the one of a four-point function without defect. Finally, we analyze the contact terms of the stress-tensor with the extended operator, and we deduce constraints on the CFT data. In two dimensions, we relate the displacement operator, which appears among the contact terms, to the reflection coefficient of a conformal interface, and we find unitarity bounds for the latter.

UV conformal window for asymptotic safety

Science.gov (United States)

Bond, Andrew D.; Litim, Daniel F.; Vazquez, Gustavo Medina; Steudtner, Tom

2018-02-01

Interacting fixed points in four-dimensional gauge theories coupled to matter are investigated using perturbation theory up to three loop order. It is shown how fixed points, scaling exponents, and anomalous dimensions are obtained as a systematic power series in a small parameter. The underlying ordering principle is explained and contrasted with conventional perturbation theory and Weyl consistency conditions. We then determine the conformal window with asymptotic safety from the complete next-to-next-to-leading order in perturbation theory. Limits for the conformal window arise due to fixed point mergers, the onset of strong coupling, or vacuum instability. A consistent picture is uncovered by comparing various levels of approximation. The theory remains perturbative in the entire conformal window, with vacuum stability dictating the tightest constraints. We also speculate about a secondary conformal window at strong coupling and estimate its lower limit. Implications for model building and cosmology are indicated.

Irregular conformal block, spectral curve and flow equations

International Nuclear Information System (INIS)

Choi, Sang Kwan; Rim, Chaiho; Zhang, Hong

2016-01-01

Irregular conformal block is motivated by the Argyres-Douglas type of N=2 super conformal gauge theory. We investigate the classical/NS limit of irregular conformal block using the spectral curve on a Riemann surface with irregular punctures, which is equivalent to the loop equation of irregular matrix model. The spectral curve is reduced to the second order (Virasoro symmetry, SU(2) for the gauge theory) and third order (W_3 symmetry, SU(3)) differential equations of a polynomial with finite degree. The conformal and W symmetry generate the flow equations in the spectral curve and determine the irregular conformal block, hence the partition function of the Argyres-Douglas theory ala AGT conjecture.

Scalar perturbations and conformal transformation

International Nuclear Information System (INIS)

Fabris, J.C.; Tossa, J.

1995-11-01

The non-minimal coupling of gravity to a scalar field can be transformed into a minimal coupling through a conformal transformation. We show how to connect the results of a perturbation calculation, performed around a Friedman-Robertson-Walker background solution, before and after the conformal transformation. We work in the synchronous gauge, but we discuss the implications of employing other frames. (author). 16 refs

49 CFR 577.9 - Conformity to statutory requirements.

Science.gov (United States)

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Conformity to statutory requirements. 577.9 Section 577.9 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY... NOTIFICATION § 577.9 Conformity to statutory requirements. A notification that does not conform to the...

20 CFR 604.6 - Conformity and substantial compliance.

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Conformity and substantial compliance. 604.6... FOR ELIGIBILITY FOR UNEMPLOYMENT COMPENSATION § 604.6 Conformity and substantial compliance. (a) In... for the administration of its UC program. (b) Resolving Issues of Conformity and Substantial...

Vertex operator algebras and conformal field theory

International Nuclear Information System (INIS)

Huang, Y.Z.

1992-01-01

This paper discusses conformal field theory, an important physical theory, describing both two-dimensional critical phenomena in condensed matter physics and classical motions of strings in string theory. The study of conformal field theory will deepen the understanding of these theories and will help to understand string theory conceptually. Besides its importance in physics, the beautiful and rich mathematical structure of conformal field theory has interested many mathematicians. New relations between different branches of mathematics, such as representations of infinite-dimensional Lie algebras and Lie groups, Riemann surfaces and algebraic curves, the Monster sporadic group, modular functions and modular forms, elliptic genera and elliptic cohomology, Calabi-Yau manifolds, tensor categories, and knot theory, are revealed in the study of conformal field theory. It is therefore believed that the study of the mathematics involved in conformal field theory will ultimately lead to new mathematical structures which would be important to both mathematics and physics

Restrictions and Proportionality

DEFF Research Database (Denmark)

Werlauff, Erik

2009-01-01

The article discusses three central aspects of the freedoms under European Community law, namely 1) the prohibition against restrictions as an important extension of the prohibition against discrimination, 2) a prohibition against exit restrictions which is just as important as the prohibition...... against host country restrictions, but which is often not recognised to the same extent by national law, and 3) the importance of also identifying and recognising an exit restriction, so that it is possible to achieve the required test of appropriateness and proportionality in relation to the rule...

The butane condensed matter conformational problem

NARCIS (Netherlands)

Weber, A.C.J.; de Lange, C.A.; Meerts, W.L.; Burnell, E.E.

2010-01-01

From the dipolar couplings of orientationally ordered n-butane obtained by NMR spectroscopy we have calculated conformer probabilities using the modified Chord (Cd) and Size-and-Shape (CI) models to estimate the conformational dependence of the order matrix. All calculation methods make use of

Conformal invariance and two-dimensional physics

International Nuclear Information System (INIS)

Zuber, J.B.

1993-01-01

Actually, physicists and mathematicians are very interested in conformal invariance: geometric transformations which keep angles. This symmetry is very important for two-dimensional systems as phase transitions, string theory or node mathematics. In this article, the author presents the conformal invariance and explains its usefulness

Geometrical formulation of the conformal Ward identity

International Nuclear Information System (INIS)

Kachkachi, M.

2002-08-01

In this paper we use deep ideas in complex geometry that proved to be very powerful in unveiling the Polyakov measure on the moduli space of Riemann surfaces and lead to obtain the partition function of perturbative string theory for 2, 3, 4 loops. Indeed, a geometrical interpretation of the conformal Ward identity in two dimensional conformal field theory is proposed: the conformal anomaly is interpreted as a deformation of the complex structure of the basic Riemann surface. This point of view is in line with the modern trend of geometric quantizations that are based on deformations of classical structures. Then, we solve the conformal Ward identity by using this geometrical formalism. (author)

Riemann monodromy problem and conformal field theories

International Nuclear Information System (INIS)

Blok, B.

1989-01-01

A systematic analysis of the use of the Riemann monodromy problem for determining correlators (conformal blocks) on the sphere is presented. The monodromy data is constructed in terms of the braid matrices and gives a constraint on the noninteger part of the conformal dimensions of the primary fields. To determine the conformal blocks we need to know the order of singularities. We establish a criterion which tells us when the knowledge of the conformal dimensions of primary fields suffice to determine the blocks. When zero modes of the extended algebra are present the analysis is more difficult. In this case we give a conjecture that works for the SU(2) WZW case. (orig.)

Conformal field theories and tensor categories. Proceedings

Energy Technology Data Exchange (ETDEWEB)

Bai, Chengming [Nankai Univ., Tianjin (China). Chern Institute of Mathematics; Fuchs, Juergen [Karlstad Univ. (Sweden). Theoretical Physics; Huang, Yi-Zhi [Rutgers Univ., Piscataway, NJ (United States). Dept. of Mathematics; Kong, Liang [Tsinghua Univ., Beijing (China). Inst. for Advanced Study; Runkel, Ingo; Schweigert, Christoph (eds.) [Hamburg Univ. (Germany). Dept. of Mathematics

2014-08-01

First book devoted completely to the mathematics of conformal field theories, tensor categories and their applications. Contributors include both mathematicians and physicists. Some long expository articles are especially suitable for beginners. The present volume is a collection of seven papers that are either based on the talks presented at the workshop ''Conformal field theories and tensor categories'' held June 13 to June 17, 2011 at the Beijing International Center for Mathematical Research, Peking University, or are extensions of the material presented in the talks at the workshop. These papers present new developments beyond rational conformal field theories and modular tensor categories and new applications in mathematics and physics. The topics covered include tensor categories from representation categories of Hopf algebras, applications of conformal field theories and tensor categories to topological phases and gapped systems, logarithmic conformal field theories and the corresponding non-semisimple tensor categories, and new developments in the representation theory of vertex operator algebras. Some of the papers contain detailed introductory material that is helpful for graduate students and researchers looking for an introduction to these research directions. The papers also discuss exciting recent developments in the area of conformal field theories, tensor categories and their applications and will be extremely useful for researchers working in these areas.

Conformal field theories and tensor categories. Proceedings

International Nuclear Information System (INIS)

Bai, Chengming; Fuchs, Juergen; Huang, Yi-Zhi; Kong, Liang; Runkel, Ingo; Schweigert, Christoph

2014-01-01

First book devoted completely to the mathematics of conformal field theories, tensor categories and their applications. Contributors include both mathematicians and physicists. Some long expository articles are especially suitable for beginners. The present volume is a collection of seven papers that are either based on the talks presented at the workshop ''Conformal field theories and tensor categories'' held June 13 to June 17, 2011 at the Beijing International Center for Mathematical Research, Peking University, or are extensions of the material presented in the talks at the workshop. These papers present new developments beyond rational conformal field theories and modular tensor categories and new applications in mathematics and physics. The topics covered include tensor categories from representation categories of Hopf algebras, applications of conformal field theories and tensor categories to topological phases and gapped systems, logarithmic conformal field theories and the corresponding non-semisimple tensor categories, and new developments in the representation theory of vertex operator algebras. Some of the papers contain detailed introductory material that is helpful for graduate students and researchers looking for an introduction to these research directions. The papers also discuss exciting recent developments in the area of conformal field theories, tensor categories and their applications and will be extremely useful for researchers working in these areas.

Conformal anomaly actions for dilaton interactions

Directory of Open Access Journals (Sweden)

Rose Luigi Delle

2014-01-01

Full Text Available We discuss, in conformally invariant field theories such as QCD with massless fermions, a possible link between the perturbative signature of the conformal anomaly, in the form of anomaly poles of the 1-particle irreducible effective action, and its descrip- tion in terms of Wess-Zumino actions with a dilaton. The two descriptions are expected to capture the UV and IR behaviour of the conformal anomaly, in terms of fundamental and effective degrees of freedom respectively, with the dilaton effective state appearing in a nonlinear realization. As in the chiral case, conformal anomalies seem to be related to the appearance of these effective interactions in the 1PI action in all the gauge-invariant sectors of the Standard Model. We show that, as a consequence of the underlying anomalous symmetry, the infinite hierarchy of recurrence relations involving self-interactions of the dilaton is entirely determined only by the first four of them. This relation can be generalized to any even space-time dimension.

Invariants for minimal conformal supergravity in six dimensions

Energy Technology Data Exchange (ETDEWEB)

Butter, Daniel [Nikhef Theory Group,Science Park 105, 1098 XG Amsterdam (Netherlands); Kuzenko, Sergei M. [School of Physics M013, The University of Western Australia,35 Stirling Highway, Crawley W.A. 6009 (Australia); Novak, Joseph; Theisen, Stefan [Max-Planck-Institut für Gravitationsphysik, Albert-Einstein-Institut,Am Mühlenberg 1, D-14476 Golm (Germany)

2016-12-15

We develop a new off-shell formulation for six-dimensional conformal supergravity obtained by gauging the 6D N=(1,0) superconformal algebra in superspace. This formulation is employed to construct two invariants for 6D N=(1,0) conformal supergravity, which contain C{sup 3} and C◻C terms at the component level. Using a conformal supercurrent analysis, we prove that these exhaust all such invariants in minimal conformal supergravity. Finally, we show how to construct the supersymmetric F◻F invariant in curved superspace.

A Mediated Moderation Model of Conformative Peer Bullying

Science.gov (United States)

Cho, Yoonju; Chung, Ock-Boon

2012-01-01

We investigated the relationship between conformative peer bullying and issues of peer conformity among adolescents. This relationship is examined through the establishment of a mediated moderation model for conformative peer bullying using structural equation modeling in a sample of 391 second-year middle school students in Seoul, South Korea. We…

{kappa}-deformed realization of D=4 conformal algebra

Energy Technology Data Exchange (ETDEWEB)

Klimek, M. [Technical Univ. of Czestochowa, Inst. of Mathematics and Computer Science, Czestochowa (Poland); Lukierski, J. [Universite de Geneve, Department de Physique Theorique, Geneve (Switzerland)

1995-07-01

We describe the generators of {kappa}-conformal transformations, leaving invariant the {kappa}-deformed d`Alembert equation. In such a way one obtains the conformal extension of-shell spin spin zero realization of {kappa}-deformed Poincare algebra. Finally the algebraic structure of {kappa}-deformed conformal algebra is discussed. (author). 23 refs.

Selective stimulation of conformational conversions in free molecules

International Nuclear Information System (INIS)

Ismailzade, G.I.; Movsumov, I.Z.; Menzeleev, M.R.; Kazymova, S.B.

2014-01-01

Application of double-resonance (RF-MW, IR-MW, MW-MW) methods to enhance studies of unstable isomeric structures was discussed. The use of infrared pump radiation to excite conformational energy levels in order to stimulate selectively conformational conversions and to correct spectral line intensities of separate conformations was substantiated. (authors)

Elementary introduction to conformal invariance

International Nuclear Information System (INIS)

Grandati, Y.

1992-01-01

These notes constitute an elementary introduction to the concept of conformal invariance and its applications to the study of bidimensional critical phenomena. The aim is to give an access as pedestrian as possible to this vast subject. After a brief account of the general properties of conformal transformation in D dimensions, we study more specifically the case D = 2. The center of the discussion is then the consequences of the action of this symmetry group on bidimensional field theories, and in particular the links between the representations of the Virasoro algebra and the structure of the correlation functions of conformal field theories. Finally after showing how the Ising model reduces to a Majorana fermionic field theory, we see how the general formalism previously discussed can be applied to the Ising case at the critical point. (orig.)

Conformational changes in glycine tri- and hexapeptide

DEFF Research Database (Denmark)

Yakubovich, Alexander V.; Solov'yov, Ilia; Solov'yov, Andrey V.

2006-01-01

conformations and calculated the energy barriers for transitions between them. Using a thermodynamic approach, we have estimated the times of the characteristic transitions between these conformations. The results of our calculations have been compared with those obtained by other theoretical methods...... also investigated the influence of the secondary structure of polypeptide chains on the formation of the potential energy landscape. This analysis has been performed for the sheet and the helix conformations of chains of six amino acids....

Conformal invariance in the quantum field theory

International Nuclear Information System (INIS)

Kurak, V.

1975-09-01

Basic features concerning the present knowledge of conformal symmetry are illustrated in a simple model. Composite field dimensions of this model are computed and related to the conformal group. (author) [pt

R Factor-Controlled Restriction and Modification of Deoxyribonucleic Acid: Restriction Mutants

Science.gov (United States)

Yoshimori, Robert; Roulland-Dussoix, Daisy; Boyer, Herbert W.

1972-01-01

Restriction mutants of two different R factor-controlled host specificities (RI and RII) were isolated. All of the restriction mutants examined had a normal modification phenotype. No complementation was observed between the RI and RII host specificities. It is concluded that for each host specificity no protein subunit is shared by the restriction endonuclease and modification methylase. PMID:4565538

Seed conformal blocks in 4D CFT

Energy Technology Data Exchange (ETDEWEB)

Echeverri, Alejandro Castedo; Elkhidir, Emtinan; Karateev, Denis [SISSA and INFN,Via Bonomea 265, I-34136 Trieste (Italy); Serone, Marco [SISSA and INFN,Via Bonomea 265, I-34136 Trieste (Italy); ICTP,Strada Costiera 11, I-34151 Trieste (Italy)

2016-02-29

We compute in closed analytical form the minimal set of “seed' conformal blocks associated to the exchange of generic mixed symmetry spinor/tensor operators in an arbitrary representation (ℓ,ℓ̄) of the Lorentz group in four dimensional conformal field theories. These blocks arise from 4-point functions involving two scalars, one (0,|ℓ−ℓ̄|) and one (|ℓ−ℓ̄|,0) spinors or tensors. We directly solve the set of Casimir equations, that can elegantly be written in a compact form for any (ℓ,ℓ̄), by using an educated ansatz and reducing the problem to an algebraic linear system. Various details on the form of the ansatz have been deduced by using the so called shadow formalism. The complexity of the conformal blocks depends on the value of p=|ℓ−ℓ̄| and grows with p, in analogy to what happens to scalar conformal blocks in d even space-time dimensions as d increases. These results open the way to bootstrap 4-point functions involving arbitrary spinor/tensor operators in four dimensional conformal field theories.

Conformal invariance in the long-range Ising model

Directory of Open Access Journals (Sweden)

Miguel F. Paulos

2016-01-01

Full Text Available We consider the question of conformal invariance of the long-range Ising model at the critical point. The continuum description is given in terms of a nonlocal field theory, and the absence of a stress tensor invalidates all of the standard arguments for the enhancement of scale invariance to conformal invariance. We however show that several correlation functions, computed to second order in the epsilon expansion, are nontrivially consistent with conformal invariance. We proceed to give a proof of conformal invariance to all orders in the epsilon expansion, based on the description of the long-range Ising model as a defect theory in an auxiliary higher-dimensional space. A detailed review of conformal invariance in the d-dimensional short-range Ising model is also included and may be of independent interest.

Conformal Invariance in the Long-Range Ising Model

CERN Document Server

Paulos, Miguel F; van Rees, Balt C; Zan, Bernardo

2016-01-01

We consider the question of conformal invariance of the long-range Ising model at the critical point. The continuum description is given in terms of a nonlocal field theory, and the absence of a stress tensor invalidates all of the standard arguments for the enhancement of scale invariance to conformal invariance. We however show that several correlation functions, computed to second order in the epsilon expansion, are nontrivially consistent with conformal invariance. We proceed to give a proof of conformal invariance to all orders in the epsilon expansion, based on the description of the long-range Ising model as a defect theory in an auxiliary higher-dimensional space. A detailed review of conformal invariance in the d-dimensional short-range Ising model is also included and may be of independent interest.

Conformal invariance in the long-range Ising model

Energy Technology Data Exchange (ETDEWEB)

Paulos, Miguel F. [CERN, Theory Group, Geneva (Switzerland); Rychkov, Slava, E-mail: slava.rychkov@lpt.ens.fr [CERN, Theory Group, Geneva (Switzerland); Laboratoire de Physique Théorique de l' École Normale Supérieure (LPTENS), Paris (France); Faculté de Physique, Université Pierre et Marie Curie (UPMC), Paris (France); Rees, Balt C. van [CERN, Theory Group, Geneva (Switzerland); Zan, Bernardo [Institute of Physics, Universiteit van Amsterdam, Amsterdam (Netherlands)

2016-01-15

We consider the question of conformal invariance of the long-range Ising model at the critical point. The continuum description is given in terms of a nonlocal field theory, and the absence of a stress tensor invalidates all of the standard arguments for the enhancement of scale invariance to conformal invariance. We however show that several correlation functions, computed to second order in the epsilon expansion, are nontrivially consistent with conformal invariance. We proceed to give a proof of conformal invariance to all orders in the epsilon expansion, based on the description of the long-range Ising model as a defect theory in an auxiliary higher-dimensional space. A detailed review of conformal invariance in the d-dimensional short-range Ising model is also included and may be of independent interest.

Conformational stability and self-association equilibrium in biologics.

Science.gov (United States)

Clarkson, Benjamin R; Schön, Arne; Freire, Ernesto

2016-02-01

Biologics exist in equilibrium between native, partially denatured, and denatured conformational states. The population of any of these states is dictated by their Gibbs energy and can be altered by changes in physical and solution conditions. Some conformations have a tendency to self-associate and aggregate, an undesirable phenomenon in protein therapeutics. Conformational equilibrium and self-association are linked thermodynamic functions. Given that any associative reaction is concentration dependent, conformational stability studies performed at different protein concentrations can provide early clues to future aggregation problems. This analysis can be applied to the selection of protein variants or the identification of better formulation solutions. In this review, we discuss three different aggregation situations and their manifestation in the observed conformational equilibrium of a protein. Copyright © 2015 Elsevier Ltd. All rights reserved.

Conformal Cosmology and Supernova Data

OpenAIRE

Behnke, Danilo; Blaschke, David; Pervushin, Victor; Proskurin, Denis

2000-01-01

We define the cosmological parameters $H_{c,0}$, $\\Omega_{m,c}$ and $\\Omega_{\\Lambda, c}$ within the Conformal Cosmology as obtained by the homogeneous approximation to the conformal-invariant generalization of Einstein's General Relativity theory. We present the definitions of the age of the universe and of the luminosity distance in the context of this approach. A possible explanation of the recent data from distant supernovae Ia without a cosmological constant is presented.

Conformationally locked aryl C-nucleosides: synthesis of phosphoramidite monomers and incorporation into single-stranded DNA and LNA (locked nucleic acid)

DEFF Research Database (Denmark)

Babu, B. Ravindra; Prasad, Ashok K.; Trikha, Smriti

2002-01-01

. The phosphoramidite approach was used for automated incorporation of the LNA-type beta-configured C-aryl monomers 17a-17e into short DNA and 2'-OMe-RNA/LNA strands. It is shown that universal hybridization can be obtained with a conformationally restricted monomer as demonstrated most convincingly for the pyrene LNA...... monomer 17d, both in a DNA context and in an RNA-like context. Increased binding affinity of oligonucleotide probes for universal hybridization can be induced by combining the pyrene LNA monomer 17d with affinity-enhancing 2'-OMe-RNA/LNA monomers....

Conformal Symmetry as a Template for QCD

Energy Technology Data Exchange (ETDEWEB)

Brodsky, S

2004-08-04

Conformal symmetry is broken in physical QCD; nevertheless, one can use conformal symmetry as a template, systematically correcting for its nonzero {beta} function as well as higher-twist effects. For example, commensurate scale relations which relate QCD observables to each other, such as the generalized Crewther relation, have no renormalization scale or scheme ambiguity and retain a convergent perturbative structure which reflects the underlying conformal symmetry of the classical theory. The ''conformal correspondence principle'' also dictates the form of the expansion basis for hadronic distribution amplitudes. The AdS/CFT correspondence connecting superstring theory to superconformal gauge theory has important implications for hadron phenomenology in the conformal limit, including an all-orders demonstration of counting rules for hard exclusive processes as well as determining essential aspects of hadronic light-front wavefunctions. Theoretical and phenomenological evidence is now accumulating that QCD couplings based on physical observables such as {tau} decay become constant at small virtuality; i.e., effective charges develop an infrared fixed point in contradiction to the usual assumption of singular growth in the infrared. The near-constant behavior of effective couplings also suggests that QCD can be approximated as a conformal theory even at relatively small momentum transfer. The importance of using an analytic effective charge such as the pinch scheme for unifying the electroweak and strong couplings and forces is also emphasized.

Conformal Symmetry as a Template for QCD

International Nuclear Information System (INIS)

Brodsky, S

2004-01-01

Conformal symmetry is broken in physical QCD; nevertheless, one can use conformal symmetry as a template, systematically correcting for its nonzero β function as well as higher-twist effects. For example, commensurate scale relations which relate QCD observables to each other, such as the generalized Crewther relation, have no renormalization scale or scheme ambiguity and retain a convergent perturbative structure which reflects the underlying conformal symmetry of the classical theory. The ''conformal correspondence principle'' also dictates the form of the expansion basis for hadronic distribution amplitudes. The AdS/CFT correspondence connecting superstring theory to superconformal gauge theory has important implications for hadron phenomenology in the conformal limit, including an all-orders demonstration of counting rules for hard exclusive processes as well as determining essential aspects of hadronic light-front wavefunctions. Theoretical and phenomenological evidence is now accumulating that QCD couplings based on physical observables such as τ decay become constant at small virtuality; i.e., effective charges develop an infrared fixed point in contradiction to the usual assumption of singular growth in the infrared. The near-constant behavior of effective couplings also suggests that QCD can be approximated as a conformal theory even at relatively small momentum transfer. The importance of using an analytic effective charge such as the pinch scheme for unifying the electroweak and strong couplings and forces is also emphasized

Investigation of calcium-dependent activity and conformational dynamics of zebra fish 12-lipoxygenase.

Science.gov (United States)

Mittal, Monica; Hasan, Mahmudul; Balagunaseelan, Navisraj; Fauland, Alexander; Wheelock, Craig; Rådmark, Olof; Haeggström, Jesper Z; Rinaldo-Matthis, Agnes

2017-08-01

A 12-lipoxygenase in zebra fish (zf12-LOX) was found to be required for normal embryonic development and LOXs are of great interest for targeted drug designing. In this study, we investigate the structural-functional aspects of zf12-LOX in response to calcium. A soluble version of zf12-LOX was created by mutagenesis. Based on multiple sequence alignment, we mutated the putative calcium-responsive amino acids in N-PLAT domain of soluble zf12-LOX. Using a series of biophysical methods, we ascertained the oligomeric state, stability, structural integrity and conformational changes of zf12-LOX in response to calcium. We also compared the biophysical properties of soluble zf12-LOX with the mutant in the absence and presence of calcium. Here we provide a detailed characterization of soluble zf12-LOX and the mutant. Both proteins exist as compact monomers in solution, however the enzyme activity of soluble zf12-LOX is significantly increased in presence of calcium. We find that the stimulatory effect of calcium on zf12-LOX is related to a change in protein structure as observed by SAXS, adopting an open-state. In contrast, enzyme with a mutated calcium regulatory site has reduced activity-response to calcium and restricted large re-modeling, suggesting that it retains a closed-state in response to calcium. Taken together, our study suggests that Ca 2+ -dependent regulation is associated with different domain conformation(s) that might change the accessibility to substrate-binding site in response to calcium. The study can be broadly implicated in better understanding the mode(s) of action of LOXs, and the enzymes regulated by calcium in general. Copyright © 2017 Elsevier B.V. All rights reserved.

Z/NZ conformal field theories

International Nuclear Information System (INIS)

Degiovanni, P.

1990-01-01

We compute the modular properties of the possible genus-one characters of some Rational Conformal Field Theories starting from their fusion rules. We show that the possible choices of S matrices are indexed by some automorphisms of the fusion algebra. We also classify the modular invariant partition functions of these theories. This gives the complete list of modular invariant partition functions of Rational Conformal Field Theories with respect to the A N (1) level one algebra. (orig.)

Structural alphabets derived from attractors in conformational space

Directory of Open Access Journals (Sweden)

Kleinjung Jens