Synthesis and in vivo evaluation of [11C]SA6298 as a PET sigma1 receptor ligand

International Nuclear Information System (INIS)

Kawamura, Kazunori; Ishiwata, Kiichi; Tajima, Hisashi; Ishii, Shin-Ichi; Shimada, Yuhei; Matsuno, Kiyoshi; Homma, Yoshio; Senda, Michio

1999-01-01

The potential of a 11 C-labeled selective sigma 1 receptor ligand, 1-(3,4-dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([ 11 C]SA6298), was evaluated as a positron emission tomography (PET) ligand for mapping sigma 1 receptors in the central nervous system and peripheral organs. [ 11 C]SA6298 was synthesized by methylation of the desmethyl SA6298 with [ 11 C]CH 3 I, with the decay-corrected radiochemical yield of 39±5% based on [ 11 C]CH 3 I and with the specific activity of 53±17 TBq/mmol within 20 min from end of bombardment (EOB). In mice, the uptake of [ 11 C]SA6298 was significantly decreased by carrier loading in the brain, liver, spleen, heart, lung, small intestine, and kidney in which sigma receptors are present as well as in the skeletal muscle. Pretreatment with SA6298 also blocked the uptake of [ 11 C]SA6298 by these organs except for the small intestine, but significant displacement of [ 11 C]SA6298 by posttreatment with SA6298 was observed only in the heart, lung, and muscle. In the blocking study with one of the eight sigma receptor ligands, including haloperidol, SA6298, NE-100, (+)-pentazocine, SA4503, (-)-pentazocine, (+)-3-PPP, and (+)-SKF 10,047 (in the order of the affinity for sigma 1 receptor subtype), only SA6298 and an analog SA4503 significantly reduced the brain uptake of [ 11 C]SA6298 to approximately 80% of the control, but the other six ligands did not. Peripherally, the uptake of [ 11 C]SA6298 by the organs described above was decreased predominantly by SA6298 or SA4503, but the blocking effects of the other five ligands except for NE-100 depended on their affinity for sigma 1 receptors. The saturable brain uptake of [ 11 C]SA6298, approximately 20%, was also observed by tissue dissection method in rats and by PET in a cat. Ex vivo autoradiography of the rat brain showed a high uptake in the cortex and thalamus. In the cat brain a relatively high uptake was found in the cortex, thalamus, striatum, and cerebellum

Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy

International Nuclear Information System (INIS)

Ogawa, Kazuma; Mizuno, Yoshiaki; Washiyama, Kohshin; Shiba, Kazuhiro; Takahashi, Naruto; Kozaka, Takashi; Watanabe, Shigeki; Shinohara, Atsushi; Odani, Akira

2015-01-01

Introduction: Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated 131 I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[ 131 I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[ 131 I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[ 211 At]pAtV, an 211 At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy. Methods: The radiolabeled sigma receptor ligand (+)-[ 211 At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[ 211 At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[ 211 At]pAtV and (+)-[ 125 I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. Results: The lipophilicity of (+)-[ 211 At]pAtV was similar to that of (+)-[ 125 I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1 h post-injection were also similar between (+)-[ 211 At]pAtV and (+)-[ 125 I]pIV. Namely, (+)-[ 211 At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors. Conclusion: These results indicate that (+)-[ 211 At]pAtV could function as an new agent for alpha-radionuclide receptor therapy.

Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy.

Science.gov (United States)

Ogawa, Kazuma; Mizuno, Yoshiaki; Washiyama, Kohshin; Shiba, Kazuhiro; Takahashi, Naruto; Kozaka, Takashi; Watanabe, Shigeki; Shinohara, Atsushi; Odani, Akira

2015-11-01

Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated (131)I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[(131)I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[(131)I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[(211)At]pAtV, an (211)At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy. The radiolabeled sigma receptor ligand (+)-[(211)At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[(211)At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[(211)At]pAtV and (+)-[(125)I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. The lipophilicity of (+)-[(211)At]pAtV was similar to that of (+)-[(125)I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+)-[(211)At]pAtV and (+)-[(125)I]pIV. Namely, (+)-[(211)At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors. These results indicate that (+)-[(211)At]pAtV could function as an new agent for alpha-radionuclide receptor therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

AutoSite: an automated approach for pseudo-ligands prediction—from ligand-binding sites identification to predicting key ligand atoms

Science.gov (United States)

Ravindranath, Pradeep Anand; Sanner, Michel F.

2016-01-01

Motivation: The identification of ligand-binding sites from a protein structure facilitates computational drug design and optimization, and protein function assignment. We introduce AutoSite: an efficient software tool for identifying ligand-binding sites and predicting pseudo ligand corresponding to each binding site identified. Binding sites are reported as clusters of 3D points called fills in which every point is labelled as hydrophobic or as hydrogen bond donor or acceptor. From these fills AutoSite derives feature points: a set of putative positions of hydrophobic-, and hydrogen-bond forming ligand atoms. Results: We show that AutoSite identifies ligand-binding sites with higher accuracy than other leading methods, and produces fills that better matches the ligand shape and properties, than the fills obtained with a software program with similar capabilities, AutoLigand. In addition, we demonstrate that for the Astex Diverse Set, the feature points identify 79% of hydrophobic ligand atoms, and 81% and 62% of the hydrogen acceptor and donor hydrogen ligand atoms interacting with the receptor, and predict 81.2% of water molecules mediating interactions between ligand and receptor. Finally, we illustrate potential uses of the predicted feature points in the context of lead optimization in drug discovery projects. Availability and Implementation: http://adfr.scripps.edu/AutoDockFR/autosite.html Contact: sanner@scripps.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27354702

N-(N-benzylpiperidin-4-yl)-2-[{sup 18}F]fluorobenzamide: A potential ligand for PET imaging of {sigma} receptors

Energy Technology Data Exchange (ETDEWEB)

Chyngyann, Shiue; Shiue, Grace G; Zhang, Sue X; Wilder, Susan; Greenberg, Joel H; Benard, Francois; Wortman, Jeffrey A; Alavi, Abass A

1997-10-01

Four nitro- and fluorobenzamides (1-4) have been synthesized in good yields from nitro- and fluoro-substituted benzoyl chloride with 4-amino-1-benzylpiperidine. In vitro studies showed that these compounds have high affinities to {sigma} receptors. N-(N-Benzylpiperidin-4-yl)-2-fluorobenzamide (3), in particular, bound to {sigma} receptors with high affinity (K{sub i} = 3.4 nM, guinea pig brain membranes) and high selectivity ({sigma}-2/{sigma}-1 = 120). It was, therefore, labeled with {sup 18}F and evaluated as a {sigma} receptor radioligand. N-(N-Benzylpiperidin-4-yl)-2-[{sup 18}F]fluorobenzamide (3a) was synthesized in one step by nucleophilic substitution of the 2-nitro precursor (1) with [{sup 18}F]fluoride in DMSO at 140 deg. C for 20 min followed by purification with HPLC in 4-10% yield (decay corrected). The synthesis time was 90 min and the specific activity was 0.4-1.0 Ci/{mu}mol. Tissue distribution in mice revealed that the uptakes of 3a in the brain, heart, liver, lungs, spleen, kidneys and small intestine were high, and the radioactivity in these organs remained constant from 60 to 120 min post-injection. The radioactivity in the bone did not significantly increase, suggesting in vivo defluorination may not be the major route of metabolism of 3a in mice. Blocking studies with haloperidol in rats indicated that the uptake of compound 3a in the rat brain was selective to haloperidol-sensitive {sigma} sites. These results suggest that compound 3a is a potent {sigma} receptor radioligand and may be a potential ligand for PET imaging of {sigma} receptors in humans.

Inhibition by sigma receptor ligand, MS-377, of N-methyl- D-aspartate-induced currents in dopamine neurons of the rat ventral tegmental area.

Science.gov (United States)

Yamazaki, Yuu; Ishioka, Miwa; Matsubayashi, Hiroaki; Amano, Taku; Sasa, Masashi

2002-04-01

MS-377 [( R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl) piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate] is a novel anti-psychotic drug candidate with high affinity for sigma receptors but devoid of binding affinity for PCP binding site of NMDA receptor/ion channel complex. The effects of MS-377 on NMDA receptor and/or its ion channel complex were examined to elucidate the antipsychotic properties of MS-377. We examined the effect of MS-377 on NMDA ( N-methyl- D-aspartate)-induced current in acutely dissociated dopamine neurons of rat ventral tegmental area (VTA) using patch clamp whole cell recording. MS-377 applied in a bath inhibited the peak current evoked by NMDA applied via the U-tube method for 2 s in a concentration-dependent manner. Other sigma receptor ligands, BD-1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), NE-100 ( N, N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride) and haloperidol also inhibited NMDA-induced current in a concentration-dependent manner. Interestingly, concomitant application of MS-377 with BD-1063, NE-100 or haloperidol at concentrations that had no effects on NMDA-induced current, potentiated the MS-377-induced inhibition. The results suggest that MS-377, as well as other sigma receptor ligands, indirectly acts on the sigma receptor to inhibit glutaminergic transmission mediated by NMDA receptor/ion channel complex in VTA dopamine neurons, thereby inhibiting dopamine release in target VTA areas.

Heterogeneous binding of sigma radioligands in the rat brain and liver

International Nuclear Information System (INIS)

Ross, S.B.

1991-01-01

The binding of four sigma receptor ligands, 3 H-(+)-N-allyl-N-normetazocine ( 3 H-(+)-SKF 10,047), 3 H-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ( 3 H-(+)-3-PPP), 3 H-haloperidol and 3 H-N,N'-di(o-totyl)guanidine ( 3 H-DTG), and the cytochrome P450IID6 ligand and dopamine uptake inhibitor 3 H-1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine ( 3 H-GBR 12935) to membranal preparations of rat liver or whole rat brain was examined regarding kinetical properties and inhibition by various compounds with affinity for sigma binding sites or cytochrome P-450. In rat brain the density of binding sites was increased in order (+)-SKF 10,047 3 H-(+)-SKF 10,047 there were quite marked differences between the ligands studied. Multiple binding sites were also indicated by the low Hill coefficients found for most of the compounds studied. It was found that the cytochrome P-450 inhibitor proadifen (SKF 525A), like haloperidol, was a potent inhibitor of the binding of 3 H-(+)-SKF 10,047, 3 H-(+)-3-PPP and 3 H-haloperidol to the liver and brain preparations, less active in inhibiting the binding of 3 H-DTG and least effective on the binding of 3 H-GBR 12935. Another cytochrome P-450 inhibitor, L-lobeline, was particularly potent in inhibiting the binding of 3 H-DTG but was also quite potent inhibitor of the binding of the other sigma ligands. It was less potent in inhibiting the binding of 3 H-GBR 12935. The binding of the latter ligand was potently inhibited by the analogous compound GBR 12909 but of the other compounds examined only L-lobeline, proadifen, haloperidol, DTG and (+)-3-PPP had IC50 values below 10 μM. The possibility that the sigma binding sites are identical with some subforms of cytochrome P-450 is discussed. (author)

Bitopic Ligands and Metastable Binding Sites

DEFF Research Database (Denmark)

Fronik, Philipp; Gaiser, Birgit I; Sejer Pedersen, Daniel

2017-01-01

of orthosteric binding sites. Bitopic ligands have been employed to address the selectivity problem by combining (linking) an orthosteric ligand with an allosteric modulator, theoretically leading to high-affinity subtype selective ligands. However, it remains a challenge to identify suitable allosteric binding...... that have been reported to date, this type of bitopic ligands would be composed of two identical pharmacophores. Herein, we outline the concept of bitopic ligands, review metastable binding sites, and discuss their potential as a new source of allosteric binding sites....

LIBRA: LIgand Binding site Recognition Application.

Science.gov (United States)

Hung, Le Viet; Caprari, Silvia; Bizai, Massimiliano; Toti, Daniele; Polticelli, Fabio

2015-12-15

In recent years, structural genomics and ab initio molecular modeling activities are leading to the availability of a large number of structural models of proteins whose biochemical function is not known. The aim of this study was the development of a novel software tool that, given a protein's structural model, predicts the presence and identity of active sites and/or ligand binding sites. The algorithm implemented by ligand binding site recognition application (LIBRA) is based on a graph theory approach to find the largest subset of similar residues between an input protein and a collection of known functional sites. The algorithm makes use of two predefined databases for active sites and ligand binding sites, respectively, derived from the Catalytic Site Atlas and the Protein Data Bank. Tests indicate that LIBRA is able to identify the correct binding/active site in 90% of the cases analyzed, 90% of which feature the identified site as ranking first. As far as ligand binding site recognition is concerned, LIBRA outperforms other structure-based ligand binding sites detection tools with which it has been compared. The application, developed in Java SE 7 with a Swing GUI embedding a JMol applet, can be run on any OS equipped with a suitable Java Virtual Machine (JVM), and is available at the following URL: http://www.computationalbiology.it/software/LIBRAv1.zip. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Sigma-1 receptor: The novel intracellular target of neuropsychotherapeutic drugs

Directory of Open Access Journals (Sweden)

Teruo Hayashi

2015-01-01

Full Text Available Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane. In specific types of neurons (e.g., those at the spinal cord, sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.

Steroid hormones affect binding of the sigma ligand 11C-SA4503 in tumour cells and tumour-bearing rats

International Nuclear Information System (INIS)

Rybczynska, Anna A.; Elsinga, Philip H.; Sijbesma, Jurgen W.; Jong, Johan R. de; Vries, Erik F. de; Dierckx, Rudi A.; Waarde, Aren van; Ishiwata, Kiichi

2009-01-01

Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist 11 C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. 11 C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Binding of 11 C-SA4503 to C6 cells was increased (∝50%) upon removal and decreased (∝60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC 50 progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of 11 C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. The binding of 11 C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids. (orig.)

Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites.

Science.gov (United States)

Marsh, Lorraine

2015-01-01

Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorable ΔG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorable ΔG because of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total binding ΔG arising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where "nonspecific" interactions contribute to biological function.

Synthesis, in vitro validation and in vivo pharmacokinetics of [{sup 125}I]N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-piperidinyl) ethylamine: A high-affinity ligand for imaging sigma receptor positive tumors

Energy Technology Data Exchange (ETDEWEB)

John, Christy S; Gulden, Mary E; Vilner, Bertold J; Bowen, Wayne D

1996-08-01

N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-piperidinyl)ethylamine, IPEMP, and the corresponding bromo derivative, BrPEMP, have been synthesized and characterized. Both BrPEMP and IPEMP were evaluated for sigma-1 and sigma-2 subtype receptor affinities and found to possess very high affinities for both receptor subtypes. The precursor for radioiodination n-tributylstannylphenylethylpiperidinylethylamine was prepared from its bromo derivative by palladium-catalyzed stannylation reaction. Radioiodinated 4-[{sup 125}I]PEMP was readily prepared in high yields and high specific activity by oxidative iododestannylation reaction using chloramine-T as oxidizing agent. Sites labeled by 4-[{sup 125}I]PEMP in guinea pig brain membranes showed high affinity for BD1008, haloperidol, and (+)-pentazocine (Ki = 5.06 {+-} 0.40, 32.6 {+-} 2.75, and 48.1 {+-} 8.60 nM, respectively), which is consistent with sigma receptor pharmacology. Competition binding studies of 4-[{sup 125}I]PEMP in melanoma (A375) and MCF-7 breast cancer cells showed a high affinity, dose-dependent inhibition of binding with known sigma ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl) ethylamine, BD1008 (Ki = 5, 11 nM, respectively), supporting the labeling of sigma sites in these cells. Haloperidol, however showed a weaker (Ki 100-200 nM) affinity for the sites labeled by 4-[{sup 125}I]PEMP in these cells. Biodistribution studies of 4-[{sup 125}I]PEMP in rats showed a fast clearance of this radiopharmaceutical from blood, liver, lung, and other organs. A co-injection of 4-IPEMP with 4-[{sup 125}I]PEMP resulted in 37%, 69%, and 35% decrease in activity in liver, kidney, and brain (organs possessing sigma receptors), respectively at 1-h postinjection. These results suggest that 4-[{sup 125}I]PEMP is a promising radiopharmaceutical for pursuing further studies in animal models with tumors.

Binding of kappa- and sigma-opiates in rat brain

International Nuclear Information System (INIS)

Wolozin, B.L.; Nishimura, S.; Pasternak, G.W.

1982-01-01

Detailed displacements of [ 3 H]dihydromorphine by ketocyclazocine and SKF 10,047, [ 3 H]ethylketocyclazocine by SKF 10,047, and [ 3 H]SKF 10,047 by ketocyclazocine are all multiphasic, suggesting multiple binding sites. After treating brain tissue in vitro with naloxazone, all displacements lose the initial inhibition of 3 H-ligand binding by low concentrations of unlabeled drugs. Together with Scatchard analysis of saturation experiments, these studies suggest a common site which binds mu-, kappa, and sigma-opiates and enkephalins equally well and with highest affinity (KD less than 1 nM). The ability of unlabeled drugs to displace the low affinity binding of [ 3 H]dihydromorphine (KD . 3 nM), [ 3 H]ethylketocyclazocine (KD . 4 nM), [ 3 H]SKF 10,047 (KD . 6 nM), and D-Ala2-D-Leu5-[ 3 H]enkephalin (KD . 5 nM) remaining after treating tissue with naloxazone demonstrates unique pharmacological profiles for each. These results suggest the existence of distinct binding sites for kappa- and sigma-opiates which differ from those sites which selectively bind morphine (mu) and enkephalin

Receptor-ligand binding sites and virtual screening.

Science.gov (United States)

Hattotuwagama, Channa K; Davies, Matthew N; Flower, Darren R

2006-01-01

Within the pharmaceutical industry, the ultimate source of continuing profitability is the unremitting process of drug discovery. To be profitable, drugs must be marketable: legally novel, safe and relatively free of side effects, efficacious, and ideally inexpensive to produce. While drug discovery was once typified by a haphazard and empirical process, it is now increasingly driven by both knowledge of the receptor-mediated basis of disease and how drug molecules interact with receptors and the wider physiome. Medicinal chemistry postulates that to understand a congeneric ligand series, or set thereof, is to understand the nature and requirements of a ligand binding site. Likewise, structural molecular biology posits that to understand a binding site is to understand the nature of ligands bound therein. Reality sits somewhere between these extremes, yet subsumes them both. Complementary to rules of ligand design, arising through decades of medicinal chemistry, structural biology and computational chemistry are able to elucidate the nature of binding site-ligand interactions, facilitating, at both pragmatic and conceptual levels, the drug discovery process.

ProBiS-ligands: a web server for prediction of ligands by examination of protein binding sites.

Science.gov (United States)

Konc, Janez; Janežič, Dušanka

2014-07-01

The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query protein. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at http://probis.cmm.ki.si/ligands. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Steroid hormones affect binding of the sigma ligand {sup 11}C-SA4503 in tumour cells and tumour-bearing rats

Energy Technology Data Exchange (ETDEWEB)

Rybczynska, Anna A.; Elsinga, Philip H.; Sijbesma, Jurgen W.; Jong, Johan R. de; Vries, Erik F. de; Dierckx, Rudi A.; Waarde, Aren van [University of Groningen, Nuclear Medicine and Molecular Imaging, University of Groningen Medical Center, Groningen (Netherlands); Ishiwata, Kiichi [Tokyo Metropolitan Institute of Gerontology, Positron Medical Center, Tokyo (Japan)

2009-07-15

Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist {sup 11}C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. {sup 11}C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Binding of {sup 11}C-SA4503 to C6 cells was increased ({proportional_to}50%) upon removal and decreased ({proportional_to}60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC{sub 50} progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of {sup 11}C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. The binding of {sup 11}C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids. (orig.)

Cloud computing for protein-ligand binding site comparison.

Science.gov (United States)

Hung, Che-Lun; Hua, Guan-Jie

2013-01-01

The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.

Multiple [3H]-nemonapride binding sites in calf brain.

Science.gov (United States)

Helmeste, D M; Tang, S W; Li, M; Fang, H

1997-07-01

[3H]-Nemonapride has been the ligand of choice to label D4 dopamine receptors. Its specificity was questioned when it was discovered that sigma (sigma) sites were also labeled by [3H]-nemonapride. To further characterize the binding of [3H]-nemonapride, three areas of calf brain (striatum, frontal cortex and cerebellum) were examined. In all three areas, [3H]-nemonapride labeled multiple sites. Dopaminergic and sigma sites were the most prominent. The sigma binding profile was sigma-1 like with a Ki binding profile as follows (in order of decreasing potency): haloperidol, PPAP, pentazocine, DTG, U-50488, R(+)-3-PPP. Experiments using sulpiride and pentazocine to block striatal dopaminergic and sigma sites, respectively, revealed additional, not previously characterized binding sites for [3H]-nemonapride. One component which was present in striatum but not in frontal cortex or cerebellum, had affinity for some neuroleptics and WB-4101, but not for typical serotonergic agents. Thus, [3H]-nemonapride has no selectivity for dopamine receptors unless stringent experimental conditions are met.

Synthesis and evaluation of fluorine-18-labeled SA4503 as a selective sigma1 receptor ligand for positron emission tomography

International Nuclear Information System (INIS)

Kawamura, Kazunori; Tsukada, Hideo; Shiba, Kazuhiro; Tsuji, Chieko; Harada, Norihiro; Kimura, Yuichi; Ishiwata, Kiichi

2007-01-01

The [ 18 F]fluoromethyl analog of the sigma 1 selective ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) ([ 18 F]FM-SA4503) was prepared and its potential evaluated for the in vivo measurement of sigma 1 receptors with positron emission tomography (PET). FM-SA4503 had selective affinity for the sigma 1 receptor ( K i for sigma 1 receptor, 6.4 nM; K i for sigma 2 receptor, 250 nM) that was compatible with the affinity of SA4503 ( K i for sigma 1 receptor, 4.4 nM; K i for sigma 2 receptor, 242 nM). [ 18 F]FM-SA4503 was synthesized by 18 F-fluoromethylation of O-demethyl SA4503 in the radiochemical yield of 2.9-16.6% at the end of bombardment with a specific activity of 37.8-283 TBq/mmol at the end of synthesis. In mice, the uptake of [ 18 F]FM-SA4503 in the brain was gradually increased for 30 min after injection, and then decreased. In the blocking study, brain uptake was significantly decreased by co-injection of haloperidol to 32% of control, and FM-SA4503 to 52% of control. In PET study of the monkey brain, high uptake was found in the cerebral cortex, thalamus and striatum. The radioactivity level of [ 18 F]FM-SA4503 in the brain regions gradually increased over a period of 120 min after injection, followed by a stable plateau phase until 180 min after injection. In pretreatment with haloperidol measurement of the monkey brain, the radioactivity level was 22-32% and 11-25% of the baseline at 60 and 180 min, respectively, after injection, suggesting high receptor-specific binding. [ 18 F]FM-SA4503 showed specific binding to sigma 1 receptors in mice and monkeys; therefore, [ 18 F]FM-SA4503 has the potential for mapping sigma 1 receptors in the brain

Synthesis and evaluation of fluorine-18-labeled SA4503 as a selective sigma{sub 1} receptor ligand for positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Kawamura, Kazunori [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0022 (Japan) and Center for Integrated Human Brain Science, Brain Research Institute, University of Niigata, Niigata, Niigata 951-8585 (Japan)]. E-mail: kawamurak@bri.niigata-u.ac.jp; Tsukada, Hideo [Central Research Laboratory, Hamamatsu Photonics, K.K., Hamamatsu, Shizuoka 434-8601 (Japan); Shiba, Kazuhiro [Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8640 (Japan); Tsuji, Chieko [NARD Institute, Ltd., Amagasaki, Hyogo 660-0805 (Japan); Harada, Norihiro [Central Research Laboratory, Hamamatsu Photonics, K.K., Hamamatsu, Shizuoka 434-8601 (Japan); Kimura, Yuichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0022 (Japan); Ishiwata, Kiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0022 (Japan)

2007-07-15

The [{sup 18}F]fluoromethyl analog of the sigma{sub 1} selective ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) ([{sup 18}F]FM-SA4503) was prepared and its potential evaluated for the in vivo measurement of sigma{sub 1} receptors with positron emission tomography (PET). FM-SA4503 had selective affinity for the sigma{sub 1} receptor ( K {sub i} for sigma{sub 1} receptor, 6.4 nM; K {sub i} for sigma{sub 2} receptor, 250 nM) that was compatible with the affinity of SA4503 ( K {sub i} for sigma{sub 1} receptor, 4.4 nM; K {sub i} for sigma{sub 2} receptor, 242 nM). [{sup 18}F]FM-SA4503 was synthesized by {sup 18}F-fluoromethylation of O-demethyl SA4503 in the radiochemical yield of 2.9-16.6% at the end of bombardment with a specific activity of 37.8-283 TBq/mmol at the end of synthesis. In mice, the uptake of [{sup 18}F]FM-SA4503 in the brain was gradually increased for 30 min after injection, and then decreased. In the blocking study, brain uptake was significantly decreased by co-injection of haloperidol to 32% of control, and FM-SA4503 to 52% of control. In PET study of the monkey brain, high uptake was found in the cerebral cortex, thalamus and striatum. The radioactivity level of [{sup 18}F]FM-SA4503 in the brain regions gradually increased over a period of 120 min after injection, followed by a stable plateau phase until 180 min after injection. In pretreatment with haloperidol measurement of the monkey brain, the radioactivity level was 22-32% and 11-25% of the baseline at 60 and 180 min, respectively, after injection, suggesting high receptor-specific binding. [{sup 18}F]FM-SA4503 showed specific binding to sigma{sub 1} receptors in mice and monkeys; therefore, [{sup 18}F]FM-SA4503 has the potential for mapping sigma{sub 1} receptors in the brain.

Small-Molecule Sigma1 Modulator Induces Autophagic Degradation of PD-L1.

Science.gov (United States)

Maher, Christina M; Thomas, Jeffrey D; Haas, Derick A; Longen, Charles G; Oyer, Halley M; Tong, Jane Y; Kim, Felix J

2018-02-01

Emerging evidence suggests that Sigma1 ( SIGMAR1 , also known as sigma-1 receptor) is a unique ligand-regulated integral membrane scaffolding protein that contributes to cellular protein and lipid homeostasis. Previously, we demonstrated that some small-molecule modulators of Sigma1 alter endoplasmic reticulum (ER)-associated protein homeostasis pathways in cancer cells, including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type I integral membrane glycoprotein that is cotranslationally inserted into the ER and is processed and transported through the secretory pathway. Once at the surface of cancer cells, PD-L1 acts as a T-cell inhibitory checkpoint molecule and suppresses antitumor immunity. Here, we demonstrate that in Sigma1-expressing triple-negative breast and androgen-independent prostate cancer cells, PD-L1 protein levels were suppressed by RNAi knockdown of Sigma1 and by small-molecule inhibition of Sigma1. Sigma1-mediated action was confirmed by pharmacologic competition between Sigma1-selective inhibitor and activator ligands. When administered alone, the Sigma1 inhibitor decreased cell surface PD-L1 expression and suppressed functional interaction of PD-1 and PD-L1 in a coculture of T cells and cancer cells. Conversely, the Sigma1 activator increased PD-L1 cell surface expression, demonstrating the ability to positively and negatively modulate Sigma1 associated PD-L1 processing. We discovered that the Sigma1 inhibitor induced degradation of PD-L1 via autophagy, by a mechanism distinct from bulk macroautophagy or general ER stress-associated autophagy. Finally, the Sigma1 inhibitor suppressed IFNγ-induced PD-L1. Our data demonstrate that small-molecule Sigma1 modulators can be used to regulate PD-L1 in cancer cells and trigger its degradation by selective autophagy. Implications: Sigma1 modulators sequester and eliminate PD-L1 by autophagy, thus preventing functional PD-L1 expression at the cell surface. This

Heterogeneous binding of sigma radioligands in the rat brain and liver; Possible relationship to subforms of cytochrome P-450

Energy Technology Data Exchange (ETDEWEB)

Ross, S B [Research Laboratories, Astra Research Centre AB, Soedertaejle (Sweden)

1991-01-01

The binding of four sigma receptor ligands, {sup 3}H-(+)-N-allyl-N-normetazocine ({sup 3}H-(+)-SKF 10,047), {sup 3}H-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ({sup 3}H-(+)-3-PPP), {sup 3}H-haloperidol and {sup 3}H-N,N'-di(o-totyl)guanidine ({sup 3}H-DTG), and the cytochrome P450IID6 ligand and dopamine uptake inhibitor {sup 3}H-1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine ({sup 3}H-GBR 12935) to membranal preparations of rat liver or whole rat brain was examined regarding kinetical properties and inhibition by various compounds with affinity for sigma binding sites or cytochrome P-450. In rat brain the density of binding sites was increased in order (+)-SKF 10,047<(+)-3-PPPligand was similar in brain and liver. With the exception of {sup 3}H-(+)-SKF 10,047 there were quite marked differences between the ligands studied. Multiple binding sites were also indicated by the low Hill coefficients found for most of the compounds studied. It was found that the cytochrome P-450 inhibitor proadifen (SKF 525A), like haloperidol, was a potent inhibitor of the binding of {sup 3}H-(+)-SKF 10,047, {sup 3}H-(+)-3-PPP and {sup 3}H-haloperidol to the liver and brain preparations, less active in inhibiting the binding of {sup 3}H-DTG and least effective on the binding of {sup 3}H-GBR 12935. Another cytochrome P-450 inhibitor, L-lobeline, was particularly potent in inhibiting the binding of {sup 3}H-DTG but was also quite potent inhibitor of the binding of the other sigma ligands. It was less potent in inhibiting the binding of {sup 3}H-GBR 12935. The binding of the latter ligand was potently inhibited by the analogous compound GBR 12909 but of the other compounds examined only L-lobeline, proadifen, haloperidol, DTG and (+)-3-PPP had IC50 values below 10 {mu}M. (Abstract Truncated)

A prototypical Sigma-1 receptor antagonist protects against brain ischemia

OpenAIRE

Schetz, John A.; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W.

2007-01-01

Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this s...

Distinct roles of beta1 metal ion-dependent adhesion site (MIDAS), adjacent to MIDAS (ADMIDAS), and ligand-associated metal-binding site (LIMBS) cation-binding sites in ligand recognition by integrin alpha2beta1.

Science.gov (United States)

Valdramidou, Dimitra; Humphries, Martin J; Mould, A Paul

2008-11-21

Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as alpha2beta1, ligand recognition takes place exclusively at the alpha subunit I domain. However, activation of the alphaI domain depends on its interaction with a structurally similar domain in the beta subunit known as the I-like or betaI domain. The top face of the betaI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding site). The role of these sites in controlling ligand binding to the alphaI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to alpha2beta1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between alphaI and betaI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of betaI. An activating mutation in the alpha2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca(2+), Mg(2+), and Mn(2+) on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn(2+) stimulates ligand binding, whereas the LIMBS is a stimulatory Ca(2+)-binding site, occupancy of which increases the affinity of Mg(2+) for the MIDAS.

In vivo binding of [11C]nemonapride to sigma receptors in the cortex and cerebellum.

Science.gov (United States)

Ishiwata, K; Senda, M

1999-08-01

Radiolabeled nemonapride (NEM, YM-09151-2) is widely used as a representative dopamine D2-like receptor ligand in pharmacological and neurological studies, and 11C-labeled analog ([11C]NEM) has been developed for positron emission tomography (PET) studies. The aim of this study was to evaluate whether [11C]NEM binds in vivo to sigma receptors. [11C]NEM and one of six dopamine D2-like receptor ligands or seven sigma receptor ligands were co-injected into mice, and the regional brain uptake of [11C]NEM was measured by a tissue dissection method. The striatal uptake of [11C]NEM was reduced by D2-like receptor ligands, NEM, haloperidol, (+)-butaclamol, raclopride, and sulpiride, but not by a D4 receptor ligand clozapine. In the cortex and cerebellum the uptake was also reduced by D2-like receptor ligands with affinity for sigma receptors, but not by raclopride. Although none of seven sigma receptor ligands, SA6298, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (NE-100), (+)-pentazocine, R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ([-]-PPAP), (-)-pentazocine, R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ([+]-3-PPP), and (+)-N-allylnormetazocine hydrochloride ([+]-SKF 10047), blocked the striatal uptake, five of them with relatively higher affinity significantly reduced the [11C]NEM uptake by the cortex, and four of them reduced that by the cerebellum. We concluded that [11C]NEM binds in vivo not only to dopamine D2-like receptors in the striatum but also to sigma receptors in other regions such as cortex and cerebellum.

In vivo binding of [11C]nemonapride to sigma receptors in the cortex and cerebellum

International Nuclear Information System (INIS)

Ishiwata, Kiichi; Senda, Michio

1999-01-01

Radiolabeled nemonapride (NEM, YM-09151-2) is widely used as a representative dopamine D 2 -like receptor ligand in pharmacological and neurological studies, and 11 C-labeled analog ([ 11 C]NEM) has been developed for positron emission tomography (PET) studies. The aim of this study was to evaluate whether [ 11 C]NEM binds in vivo to sigma receptors. [ 11 C]NEM and one of six dopamine D 2 -like receptor ligands or seven sigma receptor ligands were co-injected into mice, and the regional brain uptake of [ 11 C]NEM was measured by a tissue dissection method. The striatal uptake of [ 11 C]NEM was reduced by D 2 -like receptor ligands, NEM, haloperidol, (+)-butaclamol, raclopride, and sulpiride, but not by a D 4 receptor ligand clozapine. In the cortex and cerebellum the uptake was also reduced by D 2 -like receptor ligands with affinity for sigma receptors, but not by raclopride. Although none of seven sigma receptor ligands, SA6298, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (NE-100), (+)-pentazocine, R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ([-]-PPAP), (-)-pentazocine, R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ([+]-3-PPP), and (+)-N-allylnormetazocine hydrochloride ([+]-SKF 10047), blocked the striatal uptake, five of them with relatively higher affinity significantly reduced the [ 11 C]NEM uptake by the cortex, and four of them reduced that by the cerebellum. We concluded that [ 11 C]NEM binds in vivo not only to dopamine D 2 -like receptors in the striatum but also to sigma receptors in other regions such as cortex and cerebellum

A web server for analysis, comparison and prediction of protein ligand binding sites.

Science.gov (United States)

Singh, Harinder; Srivastava, Hemant Kumar; Raghava, Gajendra P S

2016-03-25

One of the major challenges in the field of system biology is to understand the interaction between a wide range of proteins and ligands. In the past, methods have been developed for predicting binding sites in a protein for a limited number of ligands. In order to address this problem, we developed a web server named 'LPIcom' to facilitate users in understanding protein-ligand interaction. Analysis, comparison and prediction modules are available in the "LPIcom' server to predict protein-ligand interacting residues for 824 ligands. Each ligand must have at least 30 protein binding sites in PDB. Analysis module of the server can identify residues preferred in interaction and binding motif for a given ligand; for example residues glycine, lysine and arginine are preferred in ATP binding sites. Comparison module of the server allows comparing protein-binding sites of multiple ligands to understand the similarity between ligands based on their binding site. This module indicates that ATP, ADP and GTP ligands are in the same cluster and thus their binding sites or interacting residues exhibit a high level of similarity. Propensity-based prediction module has been developed for predicting ligand-interacting residues in a protein for more than 800 ligands. In addition, a number of web-based tools have been integrated to facilitate users in creating web logo and two-sample between ligand interacting and non-interacting residues. In summary, this manuscript presents a web-server for analysis of ligand interacting residue. This server is available for public use from URL http://crdd.osdd.net/raghava/lpicom .

Development and evaluation of a radiobromine-labeled sigma ligand for tumor imaging

International Nuclear Information System (INIS)

Ogawa, Kazuma; Kanbara, Hiroya; Kiyono, Yasushi; Kitamura, Yoji; Kiwada, Tatsuto; Kozaka, Takashi; Kitamura, Masanori; Mori, Tetsuya; Shiba, Kazuhiro; Odani, Akira

2013-01-01

Introduction: Sigma receptors are appropriate targets for tumor imaging because they are highly expressed in a variety of human tumors. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with high affinity for sigma receptors, and prepared radioiodinated (+)-pIV. In this study, to develop a radiobromine-labeled vesamicol analog as a sigma receptor imaging agent for PET, nonradioactive and radiobromine-labeled (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol ((+)-pBrV) was prepared and evaluated in vitro and in vivo. In these initial studies, 77 Br was used because of its longer half-life. Methods: (+)-[ 77 Br]pBrV was prepared by a bromodestannylation reaction with radiochemical purity of 98.8% after HPLC purification. The partition coefficient of (+)-[ 77 Br]pBrV was measured. In vitro binding characteristics of (+)-pBrV to sigma receptors were assayed. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[ 77 Br]pBrV and (+)-[ 125 I]pIV into DU-145 tumor-bearing mice. Results: The lipophilicity of (+)-[ 77 Br]pBrV was lower than that of (+)-[ 125 I]pIV. As a result of in vitro binding assay to sigma receptors, the affinities of (+)-pBrV to sigma receptors were competitive to those of (+)-pIV. In biodistribution experiments, (+)-[ 77 Br]pBrV and (+)-[ 125 I]pIV showed high uptake in tumor via sigma receptors. The biodistributions of both radiotracers showed similar patterns. However, the accumulation of radioactivity in liver after injection of (+)-[ 77 Br]pBrV was significantly lower compared to that of (+)-[ 125 I]pIV. Conclusion: These results indicate that radiobromine-labeled pBrV possesses great potential as a sigma receptor imaging agent for PET

Development and evaluation of a radiobromine-labeled sigma ligand for tumor imaging.

Science.gov (United States)

Ogawa, Kazuma; Kanbara, Hiroya; Kiyono, Yasushi; Kitamura, Yoji; Kiwada, Tatsuto; Kozaka, Takashi; Kitamura, Masanori; Mori, Tetsuya; Shiba, Kazuhiro; Odani, Akira

2013-05-01

Sigma receptors are appropriate targets for tumor imaging because they are highly expressed in a variety of human tumors. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with high affinity for sigma receptors, and prepared radioiodinated (+)-pIV. In this study, to develop a radiobromine-labeled vesamicol analog as a sigma receptor imaging agent for PET, nonradioactive and radiobromine-labeled (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol ((+)-pBrV) was prepared and evaluated in vitro and in vivo. In these initial studies, (77)Br was used because of its longer half-life. (+)-[(77)Br]pBrV was prepared by a bromodestannylation reaction with radiochemical purity of 98.8% after HPLC purification. The partition coefficient of (+)-[(77)Br]pBrV was measured. In vitro binding characteristics of (+)-pBrV to sigma receptors were assayed. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[(77)Br]pBrV and (+)-[(125)I]pIV into DU-145 tumor-bearing mice. The lipophilicity of (+)-[(77)Br]pBrV was lower than that of (+)-[(125)I]pIV. As a result of in vitro binding assay to sigma receptors, the affinities of (+)-pBrV to sigma receptors were competitive to those of (+)-pIV. In biodistribution experiments, (+)-[(77)Br]pBrV and (+)-[(125)I]pIV showed high uptake in tumor via sigma receptors. The biodistributions of both radiotracers showed similar patterns. However, the accumulation of radioactivity in liver after injection of (+)-[(77)Br]pBrV was significantly lower compared to that of (+)-[(125)I]pIV. These results indicate that radiobromine-labeled pBrV possesses great potential as a sigma receptor imaging agent for PET. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of sigma(1) receptor ligand, MS-377 on apomorphine- or phencyclidine-induced disruption of prepulse inhibition of acoustic startle in rats.

Science.gov (United States)

Yamada, S; Yamauchi, K; Hisatomi, S; Annoh, N; Tanaka, M

2000-08-25

To evaluate the antipsychotic property of a sigma(1) receptor ligand, (R)-(+)-1-(4-chlorophenyl)-3-¿4-(2-methoxyethyl)piperazin-1-yl¿ methyl-2-pyrrolidinone-L-tartrate (MS-377), an antagonistic effect of MS-377 on the disruption of prepulse inhibition (PPI) of the acoustic startle by apomorphine or phencyclidine (PCP) was investigated in rats. MS-377 antagonized the PCP-induced disruption of PPI. The ED(50) value of MS-377 for this effect was 0.66 mg/kg. In contrast, apomorphine-induced disruption of PPI was not attenuated by MS-377. These data indicate that the PCP-induced disruption of PPI in rats would be, at least partially, mediated by sigma receptors and MS-377 could be a novel anti-psychotic agent with clinical efficacy for the sensorimotor-gating deficit in schizophrenia.

Synthesis and binding properties of new selective ligands for the nucleobase opposite the AP site.

Science.gov (United States)

Abe, Yukiko; Nakagawa, Osamu; Yamaguchi, Rie; Sasaki, Shigeki

2012-06-01

DNA is continuously damaged by endogenous and exogenous factors such as oxidative stress or DNA alkylating agents. These damaged nucleobases are removed by DNA N-glycosylase and form apurinic/apyrimidinic sites (AP sites) as intermediates in the base excision repair (BER) pathway. AP sites are also representative DNA damages formed by spontaneous hydrolysis. The AP sites block DNA polymerase and a mismatch nucleobase is inserted opposite the AP sites by polymerization to cause acute toxicities and mutations. Thus, AP site specific compounds have attracted much attention for therapeutic and diagnostic purposes. In this study, we have developed nucleobase-polyamine conjugates as the AP site binding ligand by expecting that the nucleobase part would play a role in the specific recognition of the nucleobase opposite the AP site by the Watson-Crick base pair formation and that the polyamine part should contribute to the access of the ligand to the AP site by a non-specific interaction to the DNA phosphate backbone. The nucleobase conjugated with 3,3'-diaminodipropylamine (A-ligand, G-ligand, C-ligand, T-ligand and U-ligand) showed a specific stabilization of the duplex containing the AP site depending on the complementary combination with the nucleobase opposite the AP site; that is A-ligand to T, G-ligand to C, C-ligand to G, T- and U-ligand to A. The thermodynamic binding parameters clearly indicated that the specific stabilization is due to specific binding of the ligands to the complementary AP site. These results have suggested that the complementary base pairs of the Watson-Crick type are formed at the AP site. Copyright © 2012 Elsevier Ltd. All rights reserved.

Identification of D3 and sigma receptors in the rat striatum and nucleus accumbens using (+/-)-7-hydroxy-N,N-di-n-[3H]propyl-2-aminotetralin and carbetapentane.

Science.gov (United States)

Wallace, D R; Booze, R M

1995-02-01

Cross-reactions between dopamine D3 and sigma receptor ligands were investigated using (+/-)-7-hydroxy-N,N-di-n-[3H]propyl-2-aminotetralin [(+/-)-7-OH-[3H]-DPAT], a putative D3-selective radioligand, in conjunction with the unlabeled sigma ligands 1,3-di(2-tolyl)guanidine (DTG), carbetapentane, and R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane [R(-)-PPAP]. In transfected CCL1.3 mouse fibroblasts expressing the human D3 receptor, neither DTG nor carbetapentane (0.1 microM) displaced (+/-)-7-OH-[3H]DPAT binding. R(-)-PPAP (0.1 microM) displaced 39.6 +/- 1.0% of total (+/-)-7-OH-[3H]DPAT binding. In striatal and nucleus accumbens homogenates, (+/-)-7-OH-[3H]DPAT labeled a single site (15-20 fmol/mg of protein) with high (1 nM) affinity. Competition analysis with carbetapentane defined both high- and low-affinity sites in striatal (35 and 65%, respectively) and nucleus accumbens (59 and 41%, respectively) tissue, yet R(-)-PPAP identified two sites in equal proportion. Carbetapentane and R(-)-PPAP (0.1 microM) displaced approximately 20-50% of total (+/-)-7-OH-[3H]DPAT binding in striatum, nucleus accumbens, and olfactory tubercle in autoradiographic studies, with the nucleus accumbens shell subregion exhibiting the greatest displacement. To determine directly (+)-7-OH-[3H]DPAT binding to sigma receptors, saturation analysis was performed in the cerebellum while masking D3 receptors with 1 microM dopamine. Under these conditions (+)-7-OH-[3H]DPAT labeled sigma receptors with an affinity of 24 nM. These results suggest that (a) (+/-)-7-OH-[3H]DPAT binds D3 receptors with high affinity in rat brain and (b) a significant proportion of (+/-)-7-OH-[3H]DPAT binding consists of sigma 1 sites and the percentages of these sites differ among the subregions of the striatum and nucleus accumbens.

In vivo binding of [{sup 11}C]nemonapride to sigma receptors in the cortex and cerebellum

Energy Technology Data Exchange (ETDEWEB)

Ishiwata, Kiichi E-mail: ishiwata@pet.tmig.or.jp; Senda, Michio

1999-08-01

Radiolabeled nemonapride (NEM, YM-09151-2) is widely used as a representative dopamine D{sub 2}-like receptor ligand in pharmacological and neurological studies, and {sup 11}C-labeled analog ([{sup 11}C]NEM) has been developed for positron emission tomography (PET) studies. The aim of this study was to evaluate whether [{sup 11}C]NEM binds in vivo to sigma receptors. [{sup 11}C]NEM and one of six dopamine D{sub 2}-like receptor ligands or seven sigma receptor ligands were co-injected into mice, and the regional brain uptake of [{sup 11}C]NEM was measured by a tissue dissection method. The striatal uptake of [{sup 11}C]NEM was reduced by D{sub 2}-like receptor ligands, NEM, haloperidol, (+)-butaclamol, raclopride, and sulpiride, but not by a D{sub 4} receptor ligand clozapine. In the cortex and cerebellum the uptake was also reduced by D{sub 2}-like receptor ligands with affinity for sigma receptors, but not by raclopride. Although none of seven sigma receptor ligands, SA6298, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (NE-100), (+)-pentazocine, R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ([-]-PPAP), (-)-pentazocine, R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ([+]-3-PPP), and (+)-N-allylnormetazocine hydrochloride ([+]-SKF 10047), blocked the striatal uptake, five of them with relatively higher affinity significantly reduced the [{sup 11}C]NEM uptake by the cortex, and four of them reduced that by the cerebellum. We concluded that [{sup 11}C]NEM binds in vivo not only to dopamine D{sub 2}-like receptors in the striatum but also to sigma receptors in other regions such as cortex and cerebellum.

In vivo evaluation of [123I]-4-iodo-N-(4-(4-(2-methoxyphenyl)-piperazin-1-yl)butyl)-benzamide: a potential sigma receptor ligand for SPECT studies

International Nuclear Information System (INIS)

Staelens, Ludovicus; Oltenfreiter, Ruth; Dumont, Filip; Waterhouse, Rikki N.; Vandenbulcke, Katia; Blanckaert, Peter; Dierckx, Rudi A.; Slegers, Guido

2005-01-01

In this study, in vivo evaluation in mice and rabbits of [ 123 I]-4-iodo-N-(4-(4-(2-methoxyphenyl)-piperazin-1-yl)butyl)-benzamide ([ 123 I]-BPB), a potential radioligand for visualisation of the sigma receptor by single photon emission computed tomography (SPECT), is reported. The compound possesses appropriate lipophilicity (log P=2.2) and binds sigma-1 and sigma-2 receptors (pKi=6.51 and 6.79, respectively). In mice, this new radioiodinated tracer exhibited high brain uptake (4.99% ID/g tissue at 10 min postinjection) and saturable binding (3.06% ID/g tissue at 10 min postinjection) as determined by pretreatment with unlabeled [ 123 I]-BPB. A metabolite study demonstrated no (less than 5%) labeled metabolites in the brain. In rabbits, regional brain distribution was investigated and the tracer displayed high, homogeneous central nervous system uptake. Selectivity was assessed by competition experiments with known sigma ligands. Metabolite analysis showed no (less than 8%) labeled metabolites in the rabbit brain. In conclusion, our findings indicate that [ 123 I]-BPB is not a suitable tracer for visualisation of D 3 receptors while its potential for sigma receptor imaging is severely hampered by its affinity for dopamine receptors

MS-377, a selective sigma receptor ligand, indirectly blocks the action of PCP in the N-methyl-D-aspartate receptor ion-channel complex in primary cultured rat neuronal cells.

Science.gov (United States)

Karasawa, Jun-ichi; Yamamoto, Hideko; Yamamoto, Toshifumi; Sagi, Naoki; Horikomi, Kazutoshi; Sora, Ichiro

2002-02-22

MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate) is a antipsychotic agent that binds to sigma-1 receptor. MS-377 showed anti-dopaminergic and anti-serotonergic activities and antagonistic action against phencyclidine (PCP)-induced behaviors in an animal model. These anti-psychotic activities of MS-377 are attributable to association with sigma-1 receptor. However, the mechanism by which the sigma-1 receptor ligands exact those numerous effects remains to be elucidated. In the present study, we evaluated the effect of MS-377 on N-methyl-D-aspartate (NMDA) receptor ion-channel complex in primary cultured rat neuronal cells. First, we examined the effect of MS-377 on NMDA-induced Ca2+ influx with fura-2/ AM loaded cells. MS-377 showed no effects on the basal Ca2+ concentration and NMDA-induced Ca2+ influx by itself PCP and SKF-10047 reduced the NMDA-induced increase in intracellular Ca2+ concentration. Pre-incubation of 1 microM MS-377 was found to significantly block the reduction by PCP or SKF-10047 of the NMDA-induced Ca2+ influx. Second, the effect of MS-377 on [3H]MK-801 intact cell binding was examined. PCP, haloperidol and (+)-pentazocine inhibited [3H]MK-801 binding, although MS-377 showed no effect by itself Pre-treatment of MS-377 markedly reversed the inhibition of [3H]MK-801 binding by PCP in a dose-dependent manner. These effects of MS-377 may depend on its affinity for the sigma-1 receptor, because MS-377 is a selective sigma-1 receptor ligand without any affinity for NMDA receptor ion-channel complex. These observations suggest that the MS-377 indirectly modulated the NMDA receptor ion-channel complex, and the anti-psychotic activities of MS-377, in part, are attributable to such on action via sigma-1 receptor.

Exploring the composition of protein-ligand binding sites on a large scale.

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Nickolay A Khazanov

Full Text Available The residue composition of a ligand binding site determines the interactions available for diffusion-mediated ligand binding, and understanding general composition of these sites is of great importance if we are to gain insight into the functional diversity of the proteome. Many structure-based drug design methods utilize such heuristic information for improving prediction or characterization of ligand-binding sites in proteins of unknown function. The Binding MOAD database if one of the largest curated sets of protein-ligand complexes, and provides a source of diverse, high-quality data for establishing general trends of residue composition from currently available protein structures. We present an analysis of 3,295 non-redundant proteins with 9,114 non-redundant binding sites to identify residues over-represented in binding regions versus the rest of the protein surface. The Binding MOAD database delineates biologically-relevant "valid" ligands from "invalid" small-molecule ligands bound to the protein. Invalids are present in the crystallization medium and serve no known biological function. Contacts are found to differ between these classes of ligands, indicating that residue composition of biologically relevant binding sites is distinct not only from the rest of the protein surface, but also from surface regions capable of opportunistic binding of non-functional small molecules. To confirm these trends, we perform a rigorous analysis of the variation of residue propensity with respect to the size of the dataset and the content bias inherent in structure sets obtained from a large protein structure database. The optimal size of the dataset for establishing general trends of residue propensities, as well as strategies for assessing the significance of such trends, are suggested for future studies of binding-site composition.

Synthesis and in vivo evaluation of [123I]-4-iodo-N-(4-(4-(2-methoxyphenyl)-piperazin-1-yl)butyl)-benzamide, a potential sigma receptor ligand for SPECT studies

International Nuclear Information System (INIS)

Staelens, L.; Dumont, F.; Oltenfreiter, R.; Slegers, G.; Vos, F. de; Goethals, I.; Dierckx, R.A.

2002-01-01

Aim: Sigma receptors which are expressed in the brain as well as in endocrine and immune systems have been the focus of research in the past few years due to their implicated role in psychosis. Many widely used antipsychotics interact with sigma receptors, some exhibit sigma receptor antagonism as their predominant mode of action. There is evidence that sigma receptors modulate several neuroreceptors, including dopaminergic and other catecholaminergic systems. Furthermore there are indications that a decrease of cortical sigma receptors occurs in schizophrenia. They are also present in high densities in various human and rodent cancer cell lines. In light of these findings we report the synthesis and in vivo evaluation of a 123 I-labelled selective sigma ligand. Materials and Methods: The 123 I-labelled compound was synthesized by electrophilic iododestannylation of the tributyltin derivative. For biodistribution studies 37 kBq of the 123 I-labelled compound dissolved in a mixture water/ethanol (99/1) was injected i.v. into the tail vein of NMRI mice. At various time points p.i. the mice were sacrificed and dissected. Biodistribution studies were performed until 48 hours p.i.. For blocking studies the mice were injected with cold product (1mg/kg) 10 minutes before tracer injection. Regional brain distributions were carried out in New Zealand rabbits, for this study 9,25 MBq of the 123 I-labelled compound dissolved in a mixture water/ethanol (90/10) was injected i.v. into the ear vein. At various time points up to 1 hour post injection the rabbits were sacrificed and their brain was dissected. Subsequently a regional blocking study was preformed in rabbits using the sigma ligand 1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)-piperidine (FPS)(0,5 mg/kg) which was injected 5 minutes before tracer injection. Results: Radiochemical yield was 70% ± 5%. Radiochemical purity was >95%. Biodistribution studies showed penetration through the blood brain barrier and accumulation

Allosteric ligands and their binding sites define γ-aminobutyric acid (GABA) type A receptor subtypes.

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Olsen, Richard W

2015-01-01

GABAA receptors (GABA(A)Rs) mediate rapid inhibitory transmission in the brain. GABA(A)Rs are ligand-gated chloride ion channel proteins and exist in about a dozen or more heteropentameric subtypes exhibiting variable age and brain regional localization and thus participation in differing brain functions and diseases. GABA(A)Rs are also subject to modulation by several chemotypes of allosteric ligands that help define structure and function, including subtype definition. The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABA(A)Rs. This ligand site is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Two classes of pharmacologically important allosteric modulatory ligand binding sites reside in the extracellular domain at modified agonist sites at other subunit interfaces: the benzodiazepine site and the high-affinity, relevant to intoxication, ethanol site. The benzodiazepine site is specific for certain GABA(A)R subtypes, mainly synaptic, while the ethanol site is found at a modified benzodiazepine site on different, extrasynaptic, subtypes. In the transmembrane domain are allosteric modulatory ligand sites for diverse chemotypes of general anesthetics: the volatile and intravenous agents, barbiturates, etomidate, propofol, long-chain alcohols, and neurosteroids. The last are endogenous positive allosteric modulators. X-ray crystal structures of prokaryotic and invertebrate pentameric ligand-gated ion channels, and the mammalian GABA(A)R protein, allow homology modeling of GABA(A)R subtypes with the various ligand sites located to suggest the structure and function of these proteins and their pharmacological modulation. © 2015 Elsevier Inc. All rights reserved.

Evidence for a non-opioid sigma binding site din the guinea-pig myenteric plexus

International Nuclear Information System (INIS)

Roman, F.; Pascaud, X.; Vauche, D.; Junien, J.

1988-01-01

The presence of a binding site to (+)-( 3 H)SKF 10,047 was demonstrated in a guinea-pig myenteric plexus (MYP) membrane preparation. Specific binding to this receptor was saturable, reversible, linear with protein concentration and consisted of two components, a high affinity site and a low affinity site. Morphine and naloxone 10 -4 M were unable to displace (+)-( 3 H)SKF 10,047 binding. Haloperidol, imipramine, ethylketocyclazocine and propranolol were among the most potent compounds to inhibit this specific binding. These results suggest the presence of a non-opioid haloperidol sensitive sigma receptor in the MYP of the guinea-pig

Evaluation of radioiodinated vesamicol analogs for sigma receptor imaging in tumor and radionuclide receptor therapy.

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Ogawa, Kazuma; Shiba, Kazuhiro; Akhter, Nasima; Yoshimoto, Mitsuyoshi; Washiyama, Kohshin; Kinuya, Seigo; Kawai, Keiichi; Mori, Hirofumi

2009-11-01

It has been reported that sigma receptors are highly expressed in a variety of human tumors. In this study, we selected (+)-2-[4-(4-iodophenyl)piperidino] cyclohexanol [(+)-pIV] as a sigma receptor ligand and evaluated the potential of radioiodinated (+)-pIV for tumor imaging and therapy. (+)-[(125/131)I]pIV was prepared by an iododestannylation reaction under no-carrier-added conditions with radiochemical purity over 99% after HPLC purification. Biodistribution experiments were performed by the intravenous injection of (+)-[(125)I]pIV into mice bearing human prostate tumors (DU-145). Blocking studies were performed by intravenous injection of (+)-[(125)I]pIV mixed with an excess amount of unlabeled sigma ligand into DU-145 tumor-bearing mice. For therapeutic study, (+)-[(131)I]pIV was injected at a dose of 7.4 MBq followed by measurement of the tumor size. In biodistribution experiments, (+)-[(125)I]pIV showed high uptake and long residence in the tumor. High tumor to blood and muscle ratios were achieved because the radioactivity levels of blood and muscle were low. However, the accumulations of radioactivity in non-target tissues, such as liver and kidney, were high. The radioactivity in the non-target tissues slowly decreased over time. Co-injection of (+)-[(125)I]pIV with an excess amount of unlabeled sigma ligand resulted in a significant decrease in the tumor/blood ratio, indicating sigma receptor-mediated tumor uptake. In therapeutic study, tumor growth in mice treated with (+)-[(131)I]pIV was significantly inhibited compared to that of an untreated group. These results indicate that radioiodinated (+)-pIV has a high potential for sigma receptor imaging in tumor and radionuclide receptor therapy.

LIGAND-BINDING SITES ON THE MYCOBACTERIUM TUBERCULOSIS UREASE

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Lisnyak Yu. V.

2017-10-01

Full Text Available Introduction. Mycobacterium tuberculosis is the causative agent of tuberculosis that remains a serious medical and social health problem. Despite intensive efforts have been made in the past decade, there are no new efficient anti-tuberculosis drugs today, and that need is growing due to the spread of drug-resistant strains of M.tuberculosis. M. tuberculosis urease (MTU, being an important factor of the bacterium viability and virulence, is an attractive target for anti-tuberculosis drugs acting by inhibition of urease activity. However, the commercially available urease inhibitors are toxic and unstable, that prevent their clinical use. Therefore, new more potent anti-tuberculosis drugs inhibiting new targets are urgently needed. A useful tool for the search of novel inhibitors is a computational drug design. The inhibitor design is significantly easier if binding sites on the enzyme are identified in advance. This paper aimed to determine the probable ligand binding sites on the surface of M. tuberculosis urease. Methods. To identify ligand binding sites on MTU surface, сomputational solvent mapping method FTSite was applied by the use of MTU homology model we have built earlier. The method places molecular probes (small organic molecules containing various functional groups on a dense grid defined around the enzyme, and for each probe finds favorable positions. The selected poses are refined by free energy minimization, the low energy conformations are clustered, and the clusters are ranked on the basis of the average free energy. FTSite server outputs the protein residues delineating a binding sites and the probe molecules representing each cluster. To predict allosteric pockets on MTU, AlloPred and AlloSite servers were applied. AlloPred uses the normal mode analysis (NMA and models how the dynamics of a protein would be altered in the presence of a modulator at a specific pocket. Pockets on the enzyme are predicted using the Fpocket

Elimination of a ligand gating site generates a supersensitive olfactory receptor.

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Sharma, Kanika; Ahuja, Gaurav; Hussain, Ashiq; Balfanz, Sabine; Baumann, Arnd; Korsching, Sigrun I

2016-06-21

Olfaction poses one of the most complex ligand-receptor matching problems in biology due to the unparalleled multitude of odor molecules facing a large number of cognate olfactory receptors. We have recently deorphanized an olfactory receptor, TAAR13c, as a specific receptor for the death-associated odor cadaverine. Here we have modeled the cadaverine/TAAR13c interaction, exchanged predicted binding residues by site-directed mutagenesis, and measured the activity of the mutant receptors. Unexpectedly we observed a binding site for cadaverine at the external surface of the receptor, in addition to an internal binding site, whose mutation resulted in complete loss of activity. In stark contrast, elimination of the external binding site generated supersensitive receptors. Modeling suggests this site to act as a gate, limiting access of the ligand to the internal binding site and thereby downregulating the affinity of the native receptor. This constitutes a novel mechanism to fine-tune physiological sensitivity to socially relevant odors.

Evaluation of (+)-p-[11C]methylvesamicol for mapping sigma1 receptors: a comparison with [11C]SA4503

International Nuclear Information System (INIS)

Ishiwata, Kiichi; Kawamura, Kazunori; Yajima, Kazuyoshi; QingGeLeTu; Mori, Hirofumi; Shiba, Kazuhiro

2006-01-01

Vesamicol is a leading compound for positron emission tomography (PET) and single photon emission computed tomography (SPECT) tracers for mapping the vesicular acetylcholine transporter (VAChT). Recently, we found that (+)-p-methylvesamicol ((+)-PMV) has low affinity for VAChT (K i =199 nM), but has moderate to high affinity for sigma receptors: K i =3.0 nM for sigma 1 and K i =40.7 nM for sigma 2 , and that sigma 1 -selective SA4503 (K i =4.4 nM for sigma 1 and K i =242 nM for sigma 2 ) has moderate affinity for VAChT (K i =50.2 nM). In the present study, we examined the potential of (+)-[ 11 C]PMV as a PET radioligand for mapping sigma 1 receptors as compared with [ 11 C]SA4503. In rat brain, similar regional distribution patterns of (+)-[ 11 C]PMV and [ 11 C]SA4503 were shown by tissue dissection and by ex vivo autoradiography. Blocking experiments using (±)-PMV (-)-vesamicol, SA4503, haloperidol and (±)-pentazocine showed that the two tracers specifically bound to sigma 1 receptors, and that [ 11 C]SA4503 exhibited greater specific binding than (+)-[ 11 C]PMV. No sign of VAChT-specific binding by [ 11 C]SA4503 was observed in the striatum, which is rich in VAChT sites. In conclusion, (+)-[ 11 C]PMV specifically bound to sigma 1 receptors in the brain, but to a lesser extent than [ 11 C]SA4503, suggesting that (+)-[ 11 C]PMV is a less preferable PET ligand than [ 11 C]SA4503. On the other hand, the moderate affinity of [ 11 C]SA4503 for VAChT is negligible in vivo

Sigma and opioid receptors in human brain tumors

International Nuclear Information System (INIS)

Thomas, G.E.; Szuecs, M.; Mamone, J.Y.; Bem, W.T.; Rush, M.D.; Johnson, F.E.; Coscia, C.J.

1990-01-01

Human brain tumors and nude mouse-borne human neuroblastomas and gliomas were analyzed for sigma and opioid receptor content. Sigma binding was assessed using [ 3 H] 1, 3-di-o-tolylguanidine (DTG), whereas opioid receptor subtypes were measured with tritiated forms of the following: μ, [D-ala 2 , mePhe 4 , gly-ol 5 ] enkephalin (DAMGE); κ, ethylketocyclazocine (EKC) or U69,593; δ, [D-pen 2 , D-pen 5 ] enkephalin (DPDPE) or [D-ala 2 , D-leu 5 ] enkephalin (DADLE) with μ suppressor present. Binding parameters were estimated by homologous displacement assays followed by analysis using the LIGAND program. Sigma binding was detected in 15 of 16 tumors examined with very high levels found in a brain metastasis from an adenocarcinoma of lung and a human neuroblastoma (SK-N-MC) passaged in nude mice. κ opioid receptor binding was detected in 4 of 4 glioblastoma multiforme specimens and 2 of 2 human astrocytoma cell lines tested but not in the other brain tumors analyzed

Development of a Tc-99m labeled sigma-2 receptor-specific ligand as a potential breast tumor imaging agent

International Nuclear Information System (INIS)

Choi, Seok-Rye; Yang, Biao; Ploessl, Karl; Chumpradit, Sumalee; Wey, Shiaw-Pyng; Acton, Paul D.; Wheeler, Kenneth; Mach, Robert H.; Kung, Hank F.

2001-01-01

, but the blood and peripheral tissue content for the isomer in peak B was higher than that for the isomer in peak A. It is evident that the isomer in peak A displayed significantly better tumor/blood and tumor/muscle ratios. The higher rate of in vivo metabolism was also confirmed by the higher thyroid uptake values for the isomer in peak B as compared to peak A. In summary, a 99m Tc-labeled sigma receptor imaging agent, [ 99m Tc]2, has demonstrated the feasibility of using a 99m Tc-labeled agent for imaging sigma receptor expression in tumor cells. This is the first time a subtype-selective 99m Tc-labeled agent for imaging sigma receptor sites is reported

SU-E-T-760: Tolerance Design for Site-Specific Range in Proton Patient QA Process Using the Six Sigma Model

International Nuclear Information System (INIS)

Lah, J; Shin, D; Kim, G

2015-01-01

Purpose: To show how tolerance design and tolerancing approaches can be used to predict and improve the site-specific range in patient QA process in implementing the Six Sigma. Methods: In this study, patient QA plans were selected according to 6 site-treatment groups: head &neck (94 cases), spine (76 cases), lung (89 cases), liver (53 cases), pancreas (55 cases), and prostate (121 cases), treated between 2007 and 2013. We evaluated a model of the Six Sigma that determines allowable deviations in design parameters and process variables in patient-specific QA, where possible, tolerance may be loosened, then customized if it necessary to meet the functional requirements. A Six Sigma problem-solving methodology is known as DMAIC phases, which are used stand for: Define a problem or improvement opportunity, Measure process performance, Analyze the process to determine the root causes of poor performance, Improve the process by fixing root causes, Control the improved process to hold the gains. Results: The process capability for patient-specific range QA is 0.65 with only ±1 mm of tolerance criteria. Our results suggested the tolerance level of ±2–3 mm for prostate and liver cases and ±5 mm for lung cases. We found that customized tolerance between calculated and measured range reduce that patient QA plan failure and almost all sites had failure rates less than 1%. The average QA time also improved from 2 hr to less than 1 hr for all including planning and converting process, depth-dose measurement and evaluation. Conclusion: The objective of tolerance design is to achieve optimization beyond that obtained through QA process improvement and statistical analysis function detailing to implement a Six Sigma capable design

SU-E-T-760: Tolerance Design for Site-Specific Range in Proton Patient QA Process Using the Six Sigma Model

Energy Technology Data Exchange (ETDEWEB)

Lah, J [Myongji Hospital, Goyang, Gyeonggi-do (Korea, Republic of); Shin, D [National Cancer Center, Goyang-si, Gyeonggi-do (Korea, Republic of); Kim, G [University of California, San Diego, La Jolla, CA (United States)

2015-06-15

Purpose: To show how tolerance design and tolerancing approaches can be used to predict and improve the site-specific range in patient QA process in implementing the Six Sigma. Methods: In this study, patient QA plans were selected according to 6 site-treatment groups: head &neck (94 cases), spine (76 cases), lung (89 cases), liver (53 cases), pancreas (55 cases), and prostate (121 cases), treated between 2007 and 2013. We evaluated a model of the Six Sigma that determines allowable deviations in design parameters and process variables in patient-specific QA, where possible, tolerance may be loosened, then customized if it necessary to meet the functional requirements. A Six Sigma problem-solving methodology is known as DMAIC phases, which are used stand for: Define a problem or improvement opportunity, Measure process performance, Analyze the process to determine the root causes of poor performance, Improve the process by fixing root causes, Control the improved process to hold the gains. Results: The process capability for patient-specific range QA is 0.65 with only ±1 mm of tolerance criteria. Our results suggested the tolerance level of ±2–3 mm for prostate and liver cases and ±5 mm for lung cases. We found that customized tolerance between calculated and measured range reduce that patient QA plan failure and almost all sites had failure rates less than 1%. The average QA time also improved from 2 hr to less than 1 hr for all including planning and converting process, depth-dose measurement and evaluation. Conclusion: The objective of tolerance design is to achieve optimization beyond that obtained through QA process improvement and statistical analysis function detailing to implement a Six Sigma capable design.

Model studies of the Cu(B) site of cytochrome c oxidase utilizing a Zn(II) complex containing an imidazole-phenol cross-linked ligand.

Science.gov (United States)

Pesavento, Russell P; Pratt, Derek A; Jeffers, Jerry; van der Donk, Wilfred A

2006-07-21

Cytochrome c oxidase, the enzyme complex responsible for the four-electron reduction of O2 to H2O, contains an unusual histidine-tyrosine cross-link in its bimetallic heme a3-CuB active site. We have synthesised an unhindered, tripodal chelating ligand, BPAIP, containing the unusual ortho-imidazole-phenol linkage, which mimics the coordination environment of the CuB center. The ligand was used to investigate the physicochemical (pKa, oxidation potential) and coordination properties of the imidazole-phenol linkage when bound to a dication. Zn(II) coordination lowers the pKa of the phenol by 0.6 log units, and increases the potential of the phenolate/phenoxyl radical couple by approximately 50 mV. These results are consistent with inductive withdrawal of electron density from the phenolic ring. Spectroscopic data and theoretical calculations (DFT) were used to establish that the cationic complex [Zn(BPAIP)Br]+ has an axially distorted trigonal bipyramidal structure, with three coordinating nitrogen ligands (two pyridine and one imidazole) occupying the equatorial plane and the bromide and the tertiary amine nitrogen of the tripod in the axial positions. Interestingly, the Zn-Namine bonding interaction is weak or absent in [Zn(BPAIP)Br]+ and the complex gains stability in basic solutions, as indicated by 1H NMR spectroscopy. These observations are supported by theoretical calculations (DFT), which suggest that the electron-donating capacity of the equatorial imidazole ligand can be varied by modulation of the protonation and/or redox state of the cross-linked phenol. Deprotonation of the phenol makes the equatorial imidazole a stronger sigma-donor, resulting in an increased Zn-Nimd interaction and thereby leading to distortion of the axial ligand axis toward a more tetrahedral geometry.

PATTERN BASED DETECTION OF POTENTIALLY DRUGGABLE BINDING SITES BY LIGAND SCREENING

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Uttam Pal

2018-03-01

Full Text Available This article describes an innovative way of finding the potentially druggable sites on a target protein, which can be used for orthosteric and allosteric lead detection in a single virtual screening setup. Druggability estimation for an alternate binding site other than the canonical ligand-binding pocket of an enzyme is rewarding for several inherent benefits. Allostery is a direct and efficient way of regulating biomacromolecule function. The allosteric modulators can fine-tune protein mechanics. Besides, allosteric sites are evolutionarily less conserved/more diverse even in very similarly related proteins, thus, provides high degree of specificity in targeting a particular protein. Therefore, targeting of allosteric sites is gaining attention as an emerging strategy in rational drug design. However, the experimental approaches provide a limited degree of characterization of new allosteric sites. Computational approaches are useful to analyze and select potential allosteric sites for drug discovery. Here, the use of molecular docking, which has become an integral part of the drug discovery process, has been discussed to predict the druggability of novel allosteric sites as well as the active site on target proteins by ligand screening. Genetic algorithm was used for docking and the whole protein was placed in the search space. For each ligand in the library of small molecules, the genetic algorithm was run for multiple times to populate all the druggable sites in the target protein, which was then translated into two dimensional density maps or “patterns”. High density clusters were observed for lead like molecules in these pattern diagrams. Each cluster in such a pattern diagram indicated a plausible binding site and the density gave its druggability score in terms of weighted probabilities. The patterns were filtered to find the leads for each of the druggable sites on the target protein. Such a novel pattern based analysis of the

Sigma and opioid receptors in human brain tumors

Energy Technology Data Exchange (ETDEWEB)

Thomas, G.E.; Szuecs, M.; Mamone, J.Y.; Bem, W.T.; Rush, M.D.; Johnson, F.E.; Coscia, C.J. (St. Louis Univ. School of Medicine, MO (USA))

1990-01-01

Human brain tumors and nude mouse-borne human neuroblastomas and gliomas were analyzed for sigma and opioid receptor content. Sigma binding was assessed using ({sup 3}H) 1, 3-di-o-tolylguanidine (DTG), whereas opioid receptor subtypes were measured with tritiated forms of the following: {mu}, (D-ala{sup 2}, mePhe{sup 4}, gly-ol{sup 5}) enkephalin (DAMGE); {kappa}, ethylketocyclazocine (EKC) or U69,593; {delta}, (D-pen{sup 2}, D-pen{sup 5}) enkephalin (DPDPE) or (D-ala{sup 2}, D-leu{sup 5}) enkephalin (DADLE) with {mu} suppressor present. Binding parameters were estimated by homologous displacement assays followed by analysis using the LIGAND program. Sigma binding was detected in 15 of 16 tumors examined with very high levels found in a brain metastasis from an adenocarcinoma of lung and a human neuroblastoma (SK-N-MC) passaged in nude mice. {kappa} opioid receptor binding was detected in 4 of 4 glioblastoma multiforme specimens and 2 of 2 human astrocytoma cell lines tested but not in the other brain tumors analyzed.

Ligand-tailored single-site silica supported titanium catalysts: Synthesis, characterization and towards cyanosilylation reaction

International Nuclear Information System (INIS)

Xu, Wei; Li, Yani; Yu, Bo; Yang, Jindou; Zhang, Ying; Chen, Xi; Zhang, Guofang; Gao, Ziwei

2015-01-01

A successive anchoring of Ti(NMe 2 ) 4 , cyclopentadiene and a O-donor ligand, 1-hydroxyethylbenzene (PEA), 1,1′-bi-2-naphthol (Binol) or 2,3-dihydroxybutanedioic acid diethyl ester (Tartrate), on silica was conducted by SOMC strategy in moderate conditions. The silica, monitored by in-situ Fourier transform infrared spectroscopy (in-situ FT-IR), was pretreated at different temperatures (200, 500 and 800 °C). The ligand tailored silica-supported titanium complexes were characterized by in-situ FT-IR, 13 C CP MAS-NMR, X-ray photoelectron spectroscopy (XPS), X-ray absorption near edge structure (XANES) and elemental analysis in detail, verifying that the surface titanium species are single sited. The catalytic activity of the ligand tailored single-site silica supported titanium complexes was evaluated by a cyanosilylation of benzaldehyde. The results showed that the catalytic activity is dependent strongly on the dehydroxylation temperatures of silica and the configuration of the ligands. - Graphical abstract: The ligand-tailored silica supported “single site” titanium complexes were synthesized by SOMC strategy and fully characterized. Their catalytic activity were evaluated by benzaldehyde silylcyanation. - Highlights: • Single-site silica supported Ti active species was prepared by SOMC technique. • O-donor ligand tailored Ti surface species was synthesized. • The surface species was characterized by XPS, 13 C CP-MAS NMR, XANES etc. • Catalytic activity of the Ti active species in silylcyanation reaction was evaluated

Ligand-tailored single-site silica supported titanium catalysts: Synthesis, characterization and towards cyanosilylation reaction

Energy Technology Data Exchange (ETDEWEB)

Xu, Wei; Li, Yani; Yu, Bo; Yang, Jindou; Zhang, Ying; Chen, Xi; Zhang, Guofang, E-mail: gfzhang@snnu.edu.cn; Gao, Ziwei, E-mail: zwgao@snnu.edu.cn

2015-01-15

A successive anchoring of Ti(NMe{sub 2}){sub 4}, cyclopentadiene and a O-donor ligand, 1-hydroxyethylbenzene (PEA), 1,1′-bi-2-naphthol (Binol) or 2,3-dihydroxybutanedioic acid diethyl ester (Tartrate), on silica was conducted by SOMC strategy in moderate conditions. The silica, monitored by in-situ Fourier transform infrared spectroscopy (in-situ FT-IR), was pretreated at different temperatures (200, 500 and 800 °C). The ligand tailored silica-supported titanium complexes were characterized by in-situ FT-IR, {sup 13}C CP MAS-NMR, X-ray photoelectron spectroscopy (XPS), X-ray absorption near edge structure (XANES) and elemental analysis in detail, verifying that the surface titanium species are single sited. The catalytic activity of the ligand tailored single-site silica supported titanium complexes was evaluated by a cyanosilylation of benzaldehyde. The results showed that the catalytic activity is dependent strongly on the dehydroxylation temperatures of silica and the configuration of the ligands. - Graphical abstract: The ligand-tailored silica supported “single site” titanium complexes were synthesized by SOMC strategy and fully characterized. Their catalytic activity were evaluated by benzaldehyde silylcyanation. - Highlights: • Single-site silica supported Ti active species was prepared by SOMC technique. • O-donor ligand tailored Ti surface species was synthesized. • The surface species was characterized by XPS, {sup 13}C CP-MAS NMR, XANES etc. • Catalytic activity of the Ti active species in silylcyanation reaction was evaluated.

Ground Motion Uncertainty and Variability (single-station sigma): Insights from Euroseistest, Greece

Science.gov (United States)

Ktenidou, O. J.; Roumelioti, Z.; Abrahamson, N. A.; Cotton, F.; Pitilakis, K.

2014-12-01

Despite recent improvements in networks and data, the global aleatory uncertainty (sigma) in GMPEs is still large. One reason is the ergodic approach, where we combine data in space to make up for lack of data in time. By estimating the systematic site response, we can make site-specific GMPEs and use a lower, site-specific uncertainty: single-station sigma. In this study we use the EUROSEISTEST database (http://euroseisdb.civil.auth.gr), which has two distinct advantages: good existing knowledge of site conditions at all stations, and careful relocation of the recorded events. Constraining the site and source parameters as best we can, we minimise the within- and between-events components of the global, ergodic sigma. Following that, knowledge of the site response from empirical and theoretical approaches permits us to move on to single-station sigma. The variability per site is not clearly correlated to the site class. We show that in some cases knowledge of Vs30 is not sufficient, and that site-specific data are needed to capture the response, possibly due to 2D/3D effects from complex geometry. Our values of single-station sigma are low compared to the literature. This may be due to the good ray coverage we have in all directions for small, nearby records. Indeed, our single-station sigma values are similar to published single-path values, which means that they may correspond to a fully -rather than partially- non-ergodic approach. We find larger ground motion variability for short distances and small magnitudes. This may be related to the uncertainty in the depth affecting nearby records more, or to stress drop and causing trade-offs between the source and site terms for small magnitudes.

Effects of sigma(1) receptor ligand MS-377 on D(2) antagonists-induced behaviors.

Science.gov (United States)

Karasawa, Jun-ichi; Takahashi, Shinji; Takagi, Kaori; Horikomi, Kazutoshi

2002-10-01

(R)-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377) is a novel antipsychotic agent with selective and high affinity for sigma(1) receptor. The present study was carried out to clarify the interaction of MS-377 with dopamine D(2) receptor antagonists (D(2) antagonists) in concurrent administration, and then the involvement of sigma receptors in the interaction. The effects of MS-377 on haloperidol- or sultopride-induced inhibition of apomorphine-induced climbing behavior and catalepsy were investigated in mice and rats, respectively. In addition, the effects of (+)-SKF-10,047 and SA4503, both of which are sigma receptor agonists, and WAY-100,635, which is a 5-HT(1A) receptor antagonist, on the interaction due to the concurrent use were also investigated. MS-377 potentiated the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior in a dose-dependent manner. In contrast, MS-377 did not affect the catalepsy induction by these drugs. The potentiation of the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior by MS-377 was not inhibited by WAY-100,635, but was inhibited by (+)-SKF-10,047 and SA4503. These findings showed that MS-377 potentiates the efficacy of D(2) antagonists, but it does not deteriorate the adverse effect. Moreover, sigma(1) receptors are involved in this potentiation of the efficacy of D(2) antagonists by MS-377.

eMatchSite: sequence order-independent structure alignments of ligand binding pockets in protein models.

Directory of Open Access Journals (Sweden)

Michal Brylinski

2014-09-01

Full Text Available Detecting similarities between ligand binding sites in the absence of global homology between target proteins has been recognized as one of the critical components of modern drug discovery. Local binding site alignments can be constructed using sequence order-independent techniques, however, to achieve a high accuracy, many current algorithms for binding site comparison require high-quality experimental protein structures, preferably in the bound conformational state. This, in turn, complicates proteome scale applications, where only various quality structure models are available for the majority of gene products. To improve the state-of-the-art, we developed eMatchSite, a new method for constructing sequence order-independent alignments of ligand binding sites in protein models. Large-scale benchmarking calculations using adenine-binding pockets in crystal structures demonstrate that eMatchSite generates accurate alignments for almost three times more protein pairs than SOIPPA. More importantly, eMatchSite offers a high tolerance to structural distortions in ligand binding regions in protein models. For example, the percentage of correctly aligned pairs of adenine-binding sites in weakly homologous protein models is only 4-9% lower than those aligned using crystal structures. This represents a significant improvement over other algorithms, e.g. the performance of eMatchSite in recognizing similar binding sites is 6% and 13% higher than that of SiteEngine using high- and moderate-quality protein models, respectively. Constructing biologically correct alignments using predicted ligand binding sites in protein models opens up the possibility to investigate drug-protein interaction networks for complete proteomes with prospective systems-level applications in polypharmacology and rational drug repositioning. eMatchSite is freely available to the academic community as a web-server and a stand-alone software distribution at http://www.brylinski.org/ematchsite.

Evaluation of (+)-p-[{sup 11}C]methylvesamicol for mapping sigma{sub 1} receptors: a comparison with [{sup 11}C]SA4503

Energy Technology Data Exchange (ETDEWEB)

Ishiwata, Kiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022 (Japan)]. E-mail: ishiwata@pet.tmig.or.jp; Kawamura, Kazunori [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022 (Japan); SHI Accelerator Service Ltd., Tokyo 141-0032 (Japan); Yajima, Kazuyoshi [The Medical and Pharmacological Research Center Foundation, Hakui 920-0631 (Japan); QingGeLeTu [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022 (Japan); Mori, Hirofumi [Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640 (Japan); Shiba, Kazuhiro [Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640 (Japan)

2006-05-15

Vesamicol is a leading compound for positron emission tomography (PET) and single photon emission computed tomography (SPECT) tracers for mapping the vesicular acetylcholine transporter (VAChT). Recently, we found that (+)-p-methylvesamicol ((+)-PMV) has low affinity for VAChT (K {sub i}=199 nM), but has moderate to high affinity for sigma receptors: K {sub i}=3.0 nM for sigma{sub 1} and K {sub i}=40.7 nM for sigma{sub 2}, and that sigma{sub 1}-selective SA4503 (K {sub i}=4.4 nM for sigma{sub 1} and K {sub i}=242 nM for sigma{sub 2}) has moderate affinity for VAChT (K {sub i}=50.2 nM). In the present study, we examined the potential of (+)-[{sup 11}C]PMV as a PET radioligand for mapping sigma{sub 1} receptors as compared with [{sup 11}C]SA4503. In rat brain, similar regional distribution patterns of (+)-[{sup 11}C]PMV and [{sup 11}C]SA4503 were shown by tissue dissection and by ex vivo autoradiography. Blocking experiments using ({+-})-PMV (-)-vesamicol, SA4503, haloperidol and ({+-})-pentazocine showed that the two tracers specifically bound to sigma{sub 1} receptors, and that [{sup 11}C]SA4503 exhibited greater specific binding than (+)-[{sup 11}C]PMV. No sign of VAChT-specific binding by [{sup 11}C]SA4503 was observed in the striatum, which is rich in VAChT sites. In conclusion, (+)-[{sup 11}C]PMV specifically bound to sigma{sub 1} receptors in the brain, but to a lesser extent than [{sup 11}C]SA4503, suggesting that (+)-[{sup 11}C]PMV is a less preferable PET ligand than [{sup 11}C]SA4503. On the other hand, the moderate affinity of [{sup 11}C]SA4503 for VAChT is negligible in vivo.

Numerical simulation of extreme snowmelt observed at the SIGMA-A site, northwest Greenland, during summer 2012

Directory of Open Access Journals (Sweden)

M. Niwano

2015-05-01

Full Text Available The surface energy balance (SEB from 30 June to 14 July 2012 at site SIGMA (Snow Impurity and Glacial Microbe effects on abrupt warming in the Arctic-A, (78°03' N, 67°38' W; 1490 m a.s.l. on the northwest Greenland Ice Sheet (GrIS was investigated by using in situ atmospheric and snow measurements as well as numerical modeling with a one-dimensional multi-layered physical snowpack model called SMAP (Snow Metamorphism and Albedo Process. At SIGMA-A, remarkable near-surface snowmelt and continuous heavy rainfall (accumulated precipitation between 10 and 14 July was estimated to be 100 mm were observed after 10 July 2012. Application of the SMAP model to the GrIS snowpack was evaluated based on the snow temperature profile, snow surface temperature, surface snow grain size, and shortwave albedo, all of which the model simulated reasonably well. Above all, the fact that the SMAP model successfully reproduced frequently observed rapid increases in snow albedo under cloudy conditions highlights the advantage of the physically based snow albedo model (PBSAM incorporated in the SMAP model. Using such data and model, we estimated the SEB at SIGMA-A from 30 June to 14 July 2012. Radiation-related fluxes were obtained from in situ measurements, whereas other fluxes were calculated with the SMAP model. By examining the components of the SEB, we determined that low-level clouds accompanied by a significant temperature increase played an important role in the melt event observed at SIGMA-A. These conditions induced a remarkable surface heating via cloud radiative forcing in the polar region.

Molecular imaging of {sigma} receptors: synthesis and evaluation of the potent {sigma}{sub 1} selective radioligand [{sup 18}F]fluspidine

Energy Technology Data Exchange (ETDEWEB)

Fischer, Steffen; Hiller, Achim; Deuther-Conrad, Winnie; Scheunemann, Matthias; Steinbach, Joerg; Brust, Peter [Institute of Radiopharmacy, Forschungszentrum Dresden-Rossendorf, Research Site Leipzig, Interdisciplinary Isotope Research, Leipzig (Germany); Wiese, Christian; Grosse Maestrup, Eva; Schepmann, Dirk; Wuensch, Bernhard [Institut fuer Pharmazeutische und Medizinische Chemie der Westfaelischen Wilhelms-Universitaet Muenster, Muenster (Germany)

2011-03-15

Neuroimaging of {sigma}{sub 1} receptors in the human brain has been proposed for the investigation of the pathophysiology of neurodegenerative and psychiatric diseases. However, there is a lack of suitable {sup 18}F-labelled PET radioligands for that purpose. The selective {sigma}{sub 1} receptor ligand [{sup 18}F]fluspidine (1'-benzyl-3-(2-[{sup 18}F]fluoroethyl)-3H-spiro[[2]benzofuran-1,4'-piperidine]) was synthesized by nucleophilic {sup 18}F{sup -} substitution of the tosyl precursor. In vitro receptor binding affinity and selectivity were assessed by radioligand competition in tissue homogenate and autoradiographic approaches. In female CD-1 mice, in vivo properties of [{sup 18}F]fluspidine were evaluated by ex vivo brain section imaging and organ distribution of intravenously administered radiotracer. Target specificity was validated by organ distribution of [{sup 18}F]fluspidine after treatment with 1 mg/kg i.p. of the {sigma} receptor antagonist haloperidol or the emopamil binding protein (EBP) inhibitor tamoxifen. In vitro metabolic stability and in vivo metabolism were investigated by LC-MS{sup n} and radio-HPLC analysis. [{sup 18}F]Fluspidine was obtained with a radiochemical yield of 35-45%, a radiochemical purity of {>=} 99.6% and a specific activity of 150-350 GBq/{mu}mol (n = 6) within a total synthesis time of 90-120 min. In vitro, fluspidine bound specifically and with high affinity to {sigma}{sub 1} receptors (K{sub i} = 0.59 nM). In mice, [{sup 18}F]fluspidine rapidly accumulated in brain with uptake values of 3.9 and 4.7%ID/g and brain to blood ratios of 7 and 13 at 5 and 30 min after intravenous application of the radiotracer, respectively. By ex vivo autoradiography of brain slices, resemblance between binding site occupancy of [{sup 18}F]fluspidine and the expression of {sigma}{sub 1} receptors was shown. The radiotracer uptake in the brain as well as in peripheral {sigma}{sub 1} receptor expressing organs was significantly

Ligand-tailored single-site silica supported titanium catalysts: Synthesis, characterization and towards cyanosilylation reaction

Science.gov (United States)

Xu, Wei; Li, Yani; Yu, Bo; Yang, Jindou; Zhang, Ying; Chen, Xi; Zhang, Guofang; Gao, Ziwei

2015-01-01

A successive anchoring of Ti(NMe2)4, cyclopentadiene and a O-donor ligand, 1-hydroxyethylbenzene (PEA), 1,1‧-bi-2-naphthol (Binol) or 2,3-dihydroxybutanedioic acid diethyl ester (Tartrate), on silica was conducted by SOMC strategy in moderate conditions. The silica, monitored by in-situ Fourier transform infrared spectroscopy (in-situ FT-IR), was pretreated at different temperatures (200, 500 and 800 °C). The ligand tailored silica-supported titanium complexes were characterized by in-situ FT-IR, 13C CP MAS-NMR, X-ray photoelectron spectroscopy (XPS), X-ray absorption near edge structure (XANES) and elemental analysis in detail, verifying that the surface titanium species are single sited. The catalytic activity of the ligand tailored single-site silica supported titanium complexes was evaluated by a cyanosilylation of benzaldehyde. The results showed that the catalytic activity is dependent strongly on the dehydroxylation temperatures of silica and the configuration of the ligands.

G-LoSA for Prediction of Protein-Ligand Binding Sites and Structures.

Science.gov (United States)

Lee, Hui Sun; Im, Wonpil

2017-01-01

Recent advances in high-throughput structure determination and computational protein structure prediction have significantly enriched the universe of protein structure. However, there is still a large gap between the number of available protein structures and that of proteins with annotated function in high accuracy. Computational structure-based protein function prediction has emerged to reduce this knowledge gap. The identification of a ligand binding site and its structure is critical to the determination of a protein's molecular function. We present a computational methodology for predicting small molecule ligand binding site and ligand structure using G-LoSA, our protein local structure alignment and similarity measurement tool. All the computational procedures described here can be easily implemented using G-LoSA Toolkit, a package of standalone software programs and preprocessed PDB structure libraries. G-LoSA and G-LoSA Toolkit are freely available to academic users at http://compbio.lehigh.edu/GLoSA . We also illustrate a case study to show the potential of our template-based approach harnessing G-LoSA for protein function prediction.

Single-Station Sigma for the Iranian Strong Motion Stations

Science.gov (United States)

Zafarani, H.; Soghrat, M. R.

2017-11-01

In development of ground motion prediction equations (GMPEs), the residuals are assumed to have a log-normal distribution with a zero mean and a standard deviation, designated as sigma. Sigma has significant effect on evaluation of seismic hazard for designing important infrastructures such as nuclear power plants and dams. Both aleatory and epistemic uncertainties are involved in the sigma parameter. However, ground-motion observations over long time periods are not available at specific sites and the GMPEs have been derived using observed data from multiple sites for a small number of well-recorded earthquakes. Therefore, sigma is dominantly related to the statistics of the spatial variability of ground motion instead of temporal variability at a single point (ergodic assumption). The main purpose of this study is to reduce the variability of the residuals so as to handle it as epistemic uncertainty. In this regard, it is tried to partially apply the non-ergodic assumption by removing repeatable site effects from total variability of six GMPEs driven from the local, Europe-Middle East and worldwide data. For this purpose, we used 1837 acceleration time histories from 374 shallow earthquakes with moment magnitudes ranging from M w 4.0 to 7.3 recorded at 370 stations with at least two recordings per station. According to estimated single-station sigma for the Iranian strong motion stations, the ratio of event-corrected single-station standard deviation ( Φ ss) to within-event standard deviation ( Φ) is about 0.75. In other words, removing the ergodic assumption on site response resulted in 25% reduction of the within-event standard deviation that reduced the total standard deviation by about 15%.

DISTINCT ROLES OF β1 MIDAS, ADMIDAS AND LIMBS CATION-BINDING SITES IN LIGAND RECOGNITION BY INTEGRIN α2β1*

Science.gov (United States)

Valdramidou, Dimitra; Humphries, Martin J.; Mould, A. Paul

2012-01-01

Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as α2β1, ligand recognition takes place exclusively at the α subunit I domain. However, activation of the αI domain depends on its interaction with a structurally similar domain in the β subunit known as the I-like or βI domain. The top face of the βI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS) and LIMBS (ligand-associated metal binding site). The role of these sites in controlling ligand binding to the αI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to α2β1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating mAb TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between αI and βI whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of βI. An activating mutation in the α2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca2+, Mg2+ and Mn2+ on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn2+ stimulates ligand binding, whereas the LIMBS is a stimulatory Ca2+-binding site, occupancy of which increases the affinity of Mg2+ for the MIDAS. PMID:18820259

Quantitation of species differences in albumin–ligand interactions for bovine, human and rat serum albumins using fluorescence spectroscopy: A test case with some Sudlow's site I ligands

International Nuclear Information System (INIS)

Poór, Miklós; Li, Yin; Matisz, Gergely; Kiss, László; Kunsági-Máté, Sándor; Kőszegi, Tamás

2014-01-01

Albumin, the most abundant plasma protein is an approximately 67 kDa sized water-soluble macromolecule. Since several drugs and xenobiotics circulate in the blood at least partially in albumin-bound form, albumin plays a key role in the pharmacokinetics/toxicokinetics of these chemicals. Most of the drugs and xenobiotics are Sudlow's site I ligands. In numerous studies, bovine serum albumin (BSA) is used for modeling albumin–ligand interactions and the results are extrapolated to human serum albumin (HSA). Furthermore, only limited information is available related to albumin–ligand interactions of different albumin species. Therefore, in our study, we have focused on the quantification of differences between bovine, human and rat serum albumin (RSA) using four Sudlow's site I ligands (luteolin, ochratoxin A, phenylbutazone and warfarin). Interactions were analyzed by fluorescence spectroscopy. Stability constants as well as competing capacities of the ligands were determined, and thermodynamic study was also performed. Our results highlight that there could be major differences between BSA, HSA and RSA in their ligand binding properties. Based on our observations we emphasize that in molecular aspects BSA behaves considerably differently from HSA or from albumins of other species therefore, it is strongly recommended to apply at least some confirmatory measurements when data obtained from other species are attempted to be extrapolated to HSA. -- Highlights: • Albumin–ligand interactions of human, bovine and rat albumins were studied. • Four Sudlow's site I ligands were tested by fluorescence spectroscopy. • Substantial differences were found in stability constants among albumin complexes. • Competing capacity of ligands showed major differences in the studied species. • Data obtained for BSA cannot be directly extrapolated to human albumin

Sigma virus and mutation in Drosophila melanogaster

International Nuclear Information System (INIS)

Paquin, S.L.A.

1977-01-01

- The objectives of these experiments have been (1) to verify and evidence more fully the action of sigma in causing recessive lethal mutation on the X chromosome of Drosophila, both in the male and the female germ line; (2) to extend the study of sigma-induced recessive lethal mutation to the Drosophila autosomes; (3) to explore the possibility that this mutagenesis is site-directed; (4) to study the effects of sigma virus in conjunction with radiation in increasing non-disjunction and dominant lethality. The virus increases the rate of radiation-induced nondisjunction by altering meiotic chromosomal behavior. Percentage of non-disjunction with 500 rads of x-rays in the virus-free flies was 0.176, while in sigma-containing lines it was 0.333. With high doses of either x or neutron radiation, the presence of the virus enhances the frequency of dominant lethality. The difference is especially significant with the fast neutrons. The results indicate that sigma, and presumably other viruses, are indeed environmental mutagens and are, therefore, factors in the rate of background or spontaneous mutation

LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

KAUST Repository

Chen, Peng

2014-12-03

Background Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction for protein-ligand binding sites, the state-of-the-art methods search for similar, known structures of the query and predict the binding sites based on the solved structures. However, such structural information is not commonly available. Results In this paper, we propose a sequence-based approach to identify protein-ligand binding residues. We propose a combination technique to reduce the effects of different sliding residue windows in the process of encoding input feature vectors. Moreover, due to the highly imbalanced samples between the ligand-binding sites and non ligand-binding sites, we construct several balanced data sets, for each of which a random forest (RF)-based classifier is trained. The ensemble of these RF classifiers forms a sequence-based protein-ligand binding site predictor. Conclusions Experimental results on CASP9 and CASP8 data sets demonstrate that our method compares favorably with the state-of-the-art protein-ligand binding site prediction methods.

Inclusive $\\Sigma^{+}$ and $\\Sigma^{0}$ Production in Hadronic Z Decays

CERN Document Server

Acciarri, M.; Adriani, O.; Aguilar-Benitez, M.; Alcaraz, J.; Alemanni, G.; Allaby, J.; Aloisio, A.; Alviggi, M.G.; Ambrosi, G.; Anderhub, H.; Andreev, Valery P.; Angelescu, T.; Anselmo, F.; Arefev, A.; Azemoon, T.; Aziz, T.; Bagnaia, P.; Bajo, A.; Baksay, L.; Balandras, A.; Banerjee, S.; Banerjee, Sw.; Barczyk, A.; Barillere, R.; Barone, L.; Bartalini, P.; Basile, M.; Battiston, R.; Bay, A.; Becattini, F.; Becker, U.; Behner, F.; Bellucci, L.; Berbeco, R.; Berdugo, J.; Berges, P.; Bertucci, B.; Betev, B.L.; Bhattacharya, S.; Biasini, M.; Biland, A.; Blaising, J.J.; Blyth, S.C.; Bobbink, G.J.; Bohm, A.; Boldizsar, L.; Borgia, B.; Bourilkov, D.; Bourquin, M.; Braccini, S.; Branson, J.G.; Brigljevic, V.; Brochu, F.; Buffini, A.; Buijs, A.; Burger, J.D.; Burger, W.J.; Cai, X.D.; Campanelli, Mario; Capell, M.; Cara Romeo, G.; Carlino, G.; Cartacci, A.M.; Casaus, J.; Castellini, G.; Cavallari, F.; Cavallo, N.; Cecchi, C.; Cerrada, M.; Cesaroni, F.; Chamizo, M.; Chang, Y.H.; Chaturvedi, U.K.; Chemarin, M.; Chen, A.; Chen, G.; Chen, G.M.; Chen, H.F.; Chen, H.S.; Chiefari, G.; Cifarelli, L.; Cindolo, F.; Civinini, C.; Clare, I.; Clare, R.; Coignet, G.; Colijn, A.P.; Colino, N.; Costantini, S.; Cotorobai, F.; Cozzoni, B.; de la Cruz, B.; Csilling, A.; Cucciarelli, S.; Dai, T.S.; van Dalen, J.A.; D'Alessandro, R.; de Asmundis, R.; Deglon, P.; Degre, A.; Deiters, K.; della Volpe, D.; Denes, P.; DeNotaristefani, F.; De Salvo, A.; Diemoz, M.; van Dierendonck, D.; Di Lodovico, F.; Dionisi, C.; Dittmar, M.; Dominguez, A.; Doria, A.; Dova, M.T.; Duchesneau, D.; Dufournaud, D.; Duinker, P.; Duran, I.; El Mamouni, H.; Engler, A.; Eppling, F.J.; Erne, F.C.; Extermann, P.; Fabre, M.; Faccini, R.; Falagan, M.A.; Falciano, S.; Favara, A.; Fay, J.; Fedin, O.; Felcini, M.; Ferguson, T.; Ferroni, F.; Fesefeldt, H.; Fiandrini, E.; Field, J.H.; Filthaut, F.; Fisher, P.H.; Fisk, I.; Forconi, G.; Fredj, L.; Freudenreich, K.; Furetta, C.; Galaktionov, Iouri; Ganguli, S.N.; Garcia-Abia, Pablo; Gataullin, M.; Gau, S.S.; Gentile, S.; Gheordanescu, N.; Giagu, S.; Gong, Z.F.; Grenier, Gerald Jean; Grimm, O.; Gruenewald, M.W.; Guida, M.; van Gulik, R.; Gupta, V.K.; Gurtu, A.; Gutay, L.J.; Haas, D.; Hasan, A.; Hatzifotiadou, D.; Hebbeker, T.; Herve, Alain; Hidas, P.; Hirschfelder, J.; Hofer, H.; Holzner, G.; Hoorani, H.; Hou, S.R.; Hu, Y.; Iashvili, I.; Jin, B.N.; Jones, Lawrence W.; de Jong, P.; Josa-Mutuberria, I.; Khan, R.A.; Kaur, M.; Kienzle-Focacci, M.N.; Kim, D.; Kim, J.K.; Kirkby, Jasper; Kiss, D.; Kittel, W.; Klimentov, A.; Konig, A.C.; Kopp, A.; Koutsenko, V.; Kraber, M.; Kraemer, R.W.; Krenz, W.; Kruger, A.; Kunin, A.; Ladron Ladron de Guevara, P.; Laktineh, I.; Landi, G.; Lassila-Perini, K.; Lebeau, M.; Lebedev, A.; Lebrun, P.; Lecomte, P.; Lecoq, P.; Le Coultre, P.; Lee, H.J.; Le Goff, J.M.; Leiste, R.; Leonardi, Emanuele; Levtchenko, P.; Li, C.; Likhoded, S.; Lin, C.H.; Lin, W.T.; Linde, F.L.; Lista, L.; Liu, Z.A.; Lohmann, W.; Longo, E.; Lu, Y.S.; Lubelsmeyer, K.; Luci, C.; Luckey, David; Lugnier, L.; Luminari, L.; Lustermann, W.; Ma, W.G.; Maity, M.; Malgeri, L.; Malinin, A.; Mana, C.; Mangeol, D.; Mans, J.; Marchesini, P.; Marian, G.; Martin, J.P.; Marzano, F.; Massaro, G.G.G.; Mazumdar, K.; McNeil, R.R.; Mele, S.; Merola, L.; Meschini, M.; Metzger, W.J.; von der Mey, M.; Mihul, A.; Milcent, H.; Mirabelli, G.; Mnich, J.; Mohanty, G.B.; Molnar, P.; Monteleoni, B.; Moulik, T.; Muanza, G.S.; Muheim, F.; Muijs, A.J.M.; Musy, M.; Napolitano, M.; Nessi-Tedaldi, F.; Newman, H.; Niessen, T.; Nisati, A.; Kluge, Hannelies; Organtini, G.; Oulianov, A.; Palomares, C.; Pandoulas, D.; Paoletti, S.; Paolucci, P.; Paramatti, R.; Park, H.K.; Park, I.H.; Pascale, G.; Passaleva, G.; Patricelli, S.; Paul, Thomas Cantzon; Pauluzzi, M.; Paus, C.; Pauss, F.; Pedace, M.; Pensotti, S.; Perret-Gallix, D.; Petersen, B.; Piccolo, D.; Pierella, F.; Pieri, M.; Piroue, P.A.; Pistolesi, E.; Plyaskin, V.; Pohl, M.; Pojidaev, V.; Postema, H.; Pothier, J.; Produit, N.; Prokofev, D.O.; Prokofev, D.; Quartieri, J.; Rahal-Callot, G.; Rahaman, M.A.; Raics, P.; Raja, N.; Ramelli, R.; Rancoita, P.G.; Raspereza, A.; Raven, G.; Razis, P.; Ren, D.; Rescigno, M.; Reucroft, S.; van Rhee, T.; Riemann, S.; Riles, Keith; Robohm, A.; Rodin, J.; Roe, B.P.; Romero, L.; Rosca, A.; Rosier-Lees, S.; Rubio, J.A.; Ruschmeier, D.; Rykaczewski, H.; Saremi, S.; Sarkar, S.; Salicio, J.; Sanchez, E.; Sanders, M.P.; Sarakinos, M.E.; Schafer, C.; Schegelsky, V.; Schmidt-Kaerst, S.; Schmitz, D.; Schopper, H.; Schotanus, D.J.; Schwering, G.; Sciacca, C.; Sciarrino, D.; Seganti, A.; Servoli, L.; Shevchenko, S.; Shivarov, N.; Shoutko, V.; Shumilov, E.; Shvorob, A.; Siedenburg, T.; Son, D.; Smith, B.; Spillantini, P.; Steuer, M.; Stickland, D.P.; Stone, A.; Stone, H.; Stoyanov, B.; Straessner, A.; Sudhakar, K.; Sultanov, G.; Sun, L.Z.; Suter, H.; Swain, J.D.; Szillasi, Z.; Sztaricskai, T.; Tang, X.W.; Tauscher, L.; Taylor, L.; Tellili, B.; Timmermans, Charles; Ting, Samuel C.C.; Ting, S.M.; Tonwar, S.C.; Toth, J.; Tully, C.; Tung, K.L.; Uchida, Y.; Ulbricht, J.; Valente, E.; Vesztergombi, G.; Vetlitsky, I.; Vicinanza, D.; Viertel, G.; Villa, S.; Vivargent, M.; Vlachos, S.; Vodopianov, I.; Vogel, H.; Vogt, H.; Vorobev, I.; Vorobov, A.A.; Vorvolakos, A.; Wadhwa, M.; Wallraff, W.; Wang, M.; Wang, X.L.; Wang, Z.M.; Weber, A.; Weber, M.; Wienemann, P.; Wilkens, H.; Wu, S.X.; Wynhoff, S.; Xia, L.; Xu, Z.Z.; Yamamoto, J.; Yang, B.Z.; Yang, C.G.; Yang, H.J.; Yang, M.; Ye, J.B.; Yeh, S.C.; Zalite, A.; Zalite, Yu.; Zhang, Z.P.; Zhu, G.Y.; Zhu, R.Y.; Zichichi, A.; Zilizi, G.; Zoller, M.

2000-01-01

We report on measurements of the inclusive production rate of $\\Sigma^+$ and $\\Sigma^0$ baryons in hadronic Z decays collected with the L3 detector at LEP. The $\\Sigma^+$ baryons are detected through the decay $\\Sigma^+ \\rightarrow {\\rm p} \\pi^0$, while the $\\Sigma^0$ baryons are detected via the decay mode $\\Sigma^0 \\rightarrow \\Lambda \\gamma$. The average numbers of $\\Sigma^+$ and $\\Sigma^0$ per hadronic Z decay are measured to be: \\begin{eqnarray*} \\left + \\left & = & 0.114 \\pm 0.011_{\\mbox{\\it \\small stat}} \\pm 0.009_{\\mbox{\\it \\small syst}} \\\\ \\left + \\left & = & 0.095 \\pm 0.015_{\\mbox{\\it \\small stat}} \\pm 0.013_{\\mbox{\\it \\small syst}} \\ \\mbox{.} \\end{eqnarray*} These rates are found to be higher than the predictions from Monte Carlo hadronization models and analytical parameterizations of strange baryon production.

Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series.

Science.gov (United States)

Güssregen, Stefan; Matter, Hans; Hessler, Gerhard; Lionta, Evanthia; Heil, Jochen; Kast, Stefan M

2017-07-24

Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three-dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design. Unlike molecular dynamics-based approaches, 3D RISM theory allows for fast and noise-free calculations using the same detailed level of solute-solvent interaction description. Here we correlate molecular water entities instead of mere site density maxima with local contributions to the solvation free energy using novel algorithms. Distinct water molecules and hydration sites are investigated in multiple protein-ligand X-ray structures, namely streptavidin, factor Xa, and factor VIIa, based on 3D RISM-derived free energy density fields. Our approach allows the semiquantitative assessment of whether a given structural water molecule can potentially be targeted for replacement in structure-based design. Finally, PLS-based regression models from free energy density fields used within a 3D-QSAR approach (CARMa - comparative analysis of 3D RISM Maps) are shown to be able to extract relevant information for the interpretation of structure-activity relationship (SAR) trends, as demonstrated for a series of serine protease inhibitors.

6 sigma quality performance

International Nuclear Information System (INIS)

Yu, Yeong Hak

2000-03-01

This deals with 6 sigma quality performance introducing company which has 6 sigma quality management, 6 sigma quality activity and customer, secret of success of 6 sigma quality management, what 6 sigma is, 6 sigma quality management propel system 5 propel steps of project like point of 6 sigma, flow of problem solution, tool for propel of project, performance of CTQ and total customer satisfaction, and quality management system and 6 sigma quality.

The point of 6 sigma

International Nuclear Information System (INIS)

An, Yeong Jin

2000-07-01

This book gives descriptions of the point of 6 sigma. These are the titles of this : what 6 sigma is, sigma conception, motor roller 3.4 ppm, centering error, 6 sigma purpose, 6 sigma principle, eight steps of innovation strategy, 6 sigma innovation strategy of easy system step, measurement standard of 6 sigma outcome, the main role of 6 sigma, acknowledgment and reword, 6 sigma characteristic, 6 sigma effect, 6 sigma application and problems which happen when 6 sigma introduces.

In vitro and in vivo binding of neuroactive steroids to the sigma-1 receptor as measured with the positron emission tomography radioligand [18F]FPS.

Science.gov (United States)

Waterhouse, Rikki N; Chang, Raymond C; Atuehene, Nana; Collier, Thomas Lee

2007-07-01

Sigma-1 receptors are widely expressed in the mammalian brain and also in organs of the immune, endocrine and reproductive systems. Based on behavioral and pharmacological assessments, sigma-1 receptors are important in memory and cognitive processes, and are thought to be involved in specific psychiatric illnesses, including schizophrenia, depression, and drug addiction. It is thought that specific neuroactive steroids are endogenous ligands for these sites. In addition, several sigma-1 receptor binding steroids including progesterone, dihydroepiandrosterone (DHEA), and testosterone are being examined clinically for specific therapeutic purposes; however, their mechanisms of action have not been clearly defined. We previously described the high affinity sigma-1 receptor selective PET tracer [(18)F]FPS. This study examines the effect of neuroactive steroids on [(18)F]FPS binding in vitro and in vivo. Inhibition constants were determined in vitro for progesterone, testosterone, DHEA, estradiol, and estriol binding to the [(18)F]FPS labeled receptor. The affinity order (K(i) values) for these steroids ranged from 36 nM for progesterone to >10,000 nM for estrodiol and estriol. Biodistribution studies revealed that i.v. coadministration of progesterone (10 mg/kg), testosterone (20 mg/kg), or DHEA (20 mg/kg) significantly decreased [(18)F]FPS uptake (%ID/g) by up to 50% in nearly all of eight brain regions examined. [(18)F]FPS uptake in several peripheral organs that express sigma-1 receptors (heart, spleen, muscle, lung) was also reduced (54-85%). These studies clearly demonstrate that exogenously administered steroids can occupy sigma-1 receptors in vivo, and that [(18)F]FPS may provide an effective tool for monitoring sigma-1 receptor occupancy of specific therapeutic steroids during clinical trials.

Ligand Binding Site Detection by Local Structure Alignment and Its Performance Complementarity

Science.gov (United States)

Lee, Hui Sun; Im, Wonpil

2013-01-01

Accurate determination of potential ligand binding sites (BS) is a key step for protein function characterization and structure-based drug design. Despite promising results of template-based BS prediction methods using global structure alignment (GSA), there is a room to improve the performance by properly incorporating local structure alignment (LSA) because BS are local structures and often similar for proteins with dissimilar global folds. We present a template-based ligand BS prediction method using G-LoSA, our LSA tool. A large benchmark set validation shows that G-LoSA predicts drug-like ligands’ positions in single-chain protein targets more precisely than TM-align, a GSA-based method, while the overall success rate of TM-align is better. G-LoSA is particularly efficient for accurate detection of local structures conserved across proteins with diverse global topologies. Recognizing the performance complementarity of G-LoSA to TM-align and a non-template geometry-based method, fpocket, a robust consensus scoring method, CMCS-BSP (Complementary Methods and Consensus Scoring for ligand Binding Site Prediction), is developed and shows improvement on prediction accuracy. The G-LoSA source code is freely available at http://im.bioinformatics.ku.edu/GLoSA. PMID:23957286

Comparative Analysis between Lean, Six Sigma and Lean Six Sigma Concepts

OpenAIRE

Alexandra Mirela Cristina MUNTEANU

2017-01-01

This paper analyzes the benefits of Lean Six Sigma in comparison with Lean and Six Sigma, traditional improvement methodologies. The introduction highlights the appearance of Lean Six Sigma, early 2000s, as well as the benefits brought by the integrated approach. The following parts of the study emphasize the main differences between methodologies and their commonalities based on their synergy. Finally the advantages of Lean Six Sigma versus Lean and Six Sigma are analyzed and systematized by...

Quantitation of species differences in albumin–ligand interactions for bovine, human and rat serum albumins using fluorescence spectroscopy: A test case with some Sudlow's site I ligands

Energy Technology Data Exchange (ETDEWEB)

Poór, Miklós [Institute of Laboratory Medicine, University of Pécs, Ifjúság u. 13, Pécs H-7624 (Hungary); Li, Yin; Matisz, Gergely [Department of General and Physical Chemistry, University of Pécs, Pécs H-7624 (Hungary); János Szentágothai Research Center, Pécs H-7624 (Hungary); Kiss, László [Department of General and Physical Chemistry, University of Pécs, Pécs H-7624 (Hungary); Kunsági-Máté, Sándor [Department of General and Physical Chemistry, University of Pécs, Pécs H-7624 (Hungary); János Szentágothai Research Center, Pécs H-7624 (Hungary); Kőszegi, Tamás, E-mail: koszegit@freemail.hu [Institute of Laboratory Medicine, University of Pécs, Ifjúság u. 13, Pécs H-7624 (Hungary)

2014-01-15

Albumin, the most abundant plasma protein is an approximately 67 kDa sized water-soluble macromolecule. Since several drugs and xenobiotics circulate in the blood at least partially in albumin-bound form, albumin plays a key role in the pharmacokinetics/toxicokinetics of these chemicals. Most of the drugs and xenobiotics are Sudlow's site I ligands. In numerous studies, bovine serum albumin (BSA) is used for modeling albumin–ligand interactions and the results are extrapolated to human serum albumin (HSA). Furthermore, only limited information is available related to albumin–ligand interactions of different albumin species. Therefore, in our study, we have focused on the quantification of differences between bovine, human and rat serum albumin (RSA) using four Sudlow's site I ligands (luteolin, ochratoxin A, phenylbutazone and warfarin). Interactions were analyzed by fluorescence spectroscopy. Stability constants as well as competing capacities of the ligands were determined, and thermodynamic study was also performed. Our results highlight that there could be major differences between BSA, HSA and RSA in their ligand binding properties. Based on our observations we emphasize that in molecular aspects BSA behaves considerably differently from HSA or from albumins of other species therefore, it is strongly recommended to apply at least some confirmatory measurements when data obtained from other species are attempted to be extrapolated to HSA. -- Highlights: • Albumin–ligand interactions of human, bovine and rat albumins were studied. • Four Sudlow's site I ligands were tested by fluorescence spectroscopy. • Substantial differences were found in stability constants among albumin complexes. • Competing capacity of ligands showed major differences in the studied species. • Data obtained for BSA cannot be directly extrapolated to human albumin.

[3H]opipramol labels a novel binding site and sigma receptors in rat brain membranes

International Nuclear Information System (INIS)

Ferris, C.D.; Hirsch, D.J.; Brooks, B.P.; Snowman, A.M.; Snyder, S.H.

1991-01-01

Opipramol (OP), a clinically effective antidepressant with a tricyclic structure, is inactive as an inhibitor of biogenic amine uptake. [ 3 H]Opipramol binds saturably to rat brain membranes (apparent KD = 4 nM, Bmax = 3 pmol/mg of protein). [ 3 H]Opipramol binding can be differentiated into haloperidol-sensitive and -resistant components, with Ki values for haloperidol of 1 nM (Bmax = 1 pmol/mg of protein) and 350 nM (Bmax = 1.9 pmol/mg of protein), respectively. The drug specificity of the haloperidol-sensitive component is the same as that of sigma receptors labeled with (+)-[ 3 H]3-(3-hydroxyphenyl)-N-(1-propyl)piperdine. The haloperidol-resistant component does not correspond to any known neurotransmitter receptor or uptake recognition site. It displays high affinity for phenothiazines and related structures such as perphenazine, clopenthixol, and flupenthixol, whose potencies are comparable to that of opipramol. Because certain of these drugs are more potent at the haloperidol-resistant opipramol site than in exerting any other action, it is possible that this opipramol-selective site may mediate their therapeutic effects

Comparative Analysis between Lean, Six Sigma and Lean Six Sigma Concepts

Directory of Open Access Journals (Sweden)

Alexandra Mirela Cristina MUNTEANU

2017-06-01

Full Text Available This paper analyzes the benefits of Lean Six Sigma in comparison with Lean and Six Sigma, traditional improvement methodologies. The introduction highlights the appearance of Lean Six Sigma, early 2000s, as well as the benefits brought by the integrated approach. The following parts of the study emphasize the main differences between methodologies and their commonalities based on their synergy. Finally the advantages of Lean Six Sigma versus Lean and Six Sigma are analyzed and systematized by author in order to reveal Lean Six Sigma’s benefits.

Synthesis and evaluation of ligands with mixed amide and phosphonate, phosphinoxide, and phosphonothioate sites for An(III)/Ln(III) extraction

NARCIS (Netherlands)

Iqbal, M.; Struijk, R.G.; Huskens, Jurriaan; Sypula, M.; Wilden, A.; Modolo, G.; Verboom, Willem

2012-01-01

Various organophosphorus ligands with a combination of different donor sites were synthesized and evaluated by solvent extraction studies for the complexation of Am(III)/Eu(III). Among the ligands with a glycolamide backbone, those with mixed amide and PO donor sites and a central oxygen or nitrogen

The met axial ligand determines the redox potential in Cu-A sites

DEFF Research Database (Denmark)

Ledesma, G.N.; Murgida, D.H.; Ly, H.K.

2007-01-01

The replacement of the axial methionine ligand in a native Cu-A protein rendered a series of stable mutants with spectroscopic features of a mixed valence center. The mutations resulted in minor perturbations of the electronic structure of this site but led to significant changes in the redox pot...

Observation of the Heavy Baryons Sigma b and Sigma b*.

Science.gov (United States)

Aaltonen, T; Abulencia, A; Adelman, J; Affolder, T; Akimoto, T; Albrow, M G; Amerio, S; Amidei, D; Anastassov, A; Anikeev, K; Annovi, A; Antos, J; Aoki, M; Apollinari, G; Arisawa, T; Artikov, A; Ashmanskas, W; Attal, A; Aurisano, A; Azfar, F; Azzi-Bacchetta, P; Azzurri, P; Bacchetta, N; Badgett, W; Barbaro-Galtieri, A; Barnes, V E; Barnett, B A; Baroiant, S; Bartsch, V; Bauer, G; Beauchemin, P-H; Bedeschi, F; Behari, S; Bellettini, G; Bellinger, J; Belloni, A; Benjamin, D; Beretvas, A; Beringer, J; Berry, T; Bhatti, A; Binkley, M; Bisello, D; Bizjak, I; Blair, R E; Blocker, C; Blumenfeld, B; Bocci, A; Bodek, A; Boisvert, V; Bolla, G; Bolshov, A; Bortoletto, D; Boudreau, J; Boveia, A; Brau, B; Brigliadori, L; Bromberg, C; Brubaker, E; Budagov, J; Budd, H S; Budd, S; Burkett, K; Busetto, G; Bussey, P; Buzatu, A; Byrum, K L; Cabrera, S; Campanelli, M; Campbell, M; Canelli, F; Canepa, A; Carillo, S; Carlsmith, D; Carosi, R; Carron, S; Casal, B; Casarsa, M; Castro, A; Catastini, P; Cauz, D; Cavalli-Sforza, M; Cerri, A; Cerrito, L; Chang, S H; Chen, Y C; Chertok, M; Chiarelli, G; Chlachidze, G; Chlebana, F; Cho, I; Cho, K; Chokheli, D; Chou, J P; Choudalakis, G; Chuang, S H; Chung, K; Chung, W H; Chung, Y S; Cilijak, M; Ciobanu, C I; Ciocci, M A; Clark, A; Clark, D; Coca, M; Compostella, G; Convery, M E; Conway, J; Cooper, B; Copic, K; Cordelli, M; Cortiana, G; Crescioli, F; Cuenca Almenar, C; Cuevas, J; Culbertson, R; Cully, J C; DaRonco, S; Datta, M; D'Auria, S; Davies, T; Dagenhart, D; de Barbaro, P; De Cecco, S; Deisher, A; De Lentdecker, G; De Lorenzo, G; Dell'Orso, M; Delli Paoli, F; Demortier, L; Deng, J; Deninno, M; De Pedis, D; Derwent, P F; Di Giovanni, G P; Dionisi, C; Di Ruzza, B; Dittmann, J R; D'Onofrio, M; Dörr, C; Donati, S; Dong, P; Donini, J; Dorigo, T; Dube, S; Efron, J; Erbacher, R; Errede, D; Errede, S; Eusebi, R; Fang, H C; Farrington, S; Fedorko, I; Fedorko, W T; Feild, R G; Feindt, M; Fernandez, J P; Field, R; Flanagan, G; Forrest, R; Forrester, S; Franklin, M; Freeman, J C; Furic, I; Gallinaro, M; Galyardt, J; Garcia, J E; Garberson, F; Garfinkel, A F; Gay, C; Gerberich, H; Gerdes, D; Giagu, S; Giannetti, P; Gibson, K; Gimmell, J L; Ginsburg, C; Giokaris, N; Giordani, M; Giromini, P; Giunta, M; Giurgiu, G; Glagolev, V; Glenzinski, D; Gold, M; Goldschmidt, N; Goldstein, J; Golossanov, A; Gomez, G; Gomez-Ceballos, G; Goncharov, M; González, O; Gorelov, I; Goshaw, A T; Goulianos, K; Gresele, A; Grinstein, S; Grosso-Pilcher, C; Grundler, U; Guimaraes da Costa, J; Gunay-Unalan, Z; Haber, C; Hahn, K; Hahn, S R; Halkiadakis, E; Hamilton, A; Han, B-Y; Han, J Y; Handler, R; Happacher, F; Hara, K; Hare, D; Hare, M; Harper, S; Harr, R F; Harris, R M; Hartz, M; Hatakeyama, K; Hauser, J; Hays, C; Heck, M; Heijboer, A; Heinemann, B; Heinrich, J; Henderson, C; Herndon, M; Heuser, J; Hidas, D; Hill, C S; Hirschbuehl, D; Hocker, A; Holloway, A; Hou, S; Houlden, M; Hsu, S-C; Huffman, B T; Hughes, R E; Husemann, U; Huston, J; Incandela, J; Introzzi, G; Iori, M; Ivanov, A; Iyutin, B; James, E; Jang, D; Jayatilaka, B; Jeans, D; Jeon, E J; Jindariani, S; Johnson, W; Jones, M; Joo, K K; Jun, S Y; Jung, J E; Junk, T R; Kamon, T; Karchin, P E; Kato, Y; Kemp, Y; Kephart, R; Kerzel, U; Khotilovich, V; Kilminster, B; Kim, D H; Kim, H S; Kim, J E; Kim, M J; Kim, S B; Kim, S H; Kim, Y K; Kimura, N; Kirsch, L; Klimenko, S; Klute, M; Knuteson, B; Ko, B R; Kondo, K; Kong, D J; Konigsberg, J; Korytov, A; Kotwal, A V; Kraan, A C; Kraus, J; Kreps, M; Kroll, J; Krumnack, N; Kruse, M; Krutelyov, V; Kubo, T; Kuhlmann, S E; Kuhr, T; Kulkarni, N P; Kusakabe, Y; Kwang, S; Laasanen, A T; Lai, S; Lami, S; Lammel, S; Lancaster, M; Lander, R L; Lannon, K; Lath, A; Latino, G; Lazzizzera, I; LeCompte, T; Lee, J; Lee, J; Lee, Y J; Lee, S W; Lefèvre, R; Leonardo, N; Leone, S; Levy, S; Lewis, J D; Lin, C; Lin, C S; Lindgren, M; Lipeles, E; Lister, A; Litvintsev, D O; Liu, T; Lockyer, N S; Loginov, A; Loreti, M; Lu, R-S; Lucchesi, D; Lujan, P; Lukens, P; Lungu, G; Lyons, L; Lys, J; Lysak, R; Lytken, E; Mack, P; MacQueen, D; Madrak, R; Maeshima, K; Makhoul, K; Maki, T; Maksimovic, P; Malde, S; Malik, S; Manca, G; Manousakis, A; Margaroli, F; Marginean, R; Marino, C; Marino, C P; Martin, A; Martin, M; Martin, V; Martínez, M; Martínez-Ballarín, R; Maruyama, T; Mastrandrea, P; Masubuchi, T; Matsunaga, H; Mattson, M E; Mazini, R; Mazzanti, P; McFarland, K S; McIntyre, P; McNulty, R; Mehta, A; Mehtala, P; Menzemer, S; Menzione, A; Merkel, P; Mesropian, C; Messina, A; Miao, T; Miladinovic, N; Miles, J; Miller, R; Mills, C; Milnik, M; Mitra, A; Mitselmakher, G; Miyamoto, A; Moed, S; Moggi, N; Mohr, B; Moon, C S; Moore, R; Morello, M; Movilla Fernandez, P; Mülmenstädt, J; Mukherjee, A; Muller, Th; Mumford, R; Murat, P; Mussini, M; Nachtman, J; Nagano, A; Naganoma, J; Nakamura, K; Nakano, I; Napier, A; Necula, V; Neu, C; Neubauer, M S; Nielsen, J; Nodulman, L; Norniella, O; Nurse, E; Oh, S H; Oh, Y D; Oksuzian, I; Okusawa, T; Oldeman, R; Orava, R; Osterberg, K; Pagliarone, C; Palencia, E; Papadimitriou, V; Papaikonomou, A; Paramonov, A A; Parks, B; Pashapour, S; Patrick, J; Pauletta, G; Paulini, M; Paus, C; Pellett, D E; Penzo, A; Phillips, T J; Piacentino, G; Piedra, J; Pinera, L; Pitts, K; Plager, C; Pondrom, L; Portell, X; Poukhov, O; Pounder, N; Prakoshyn, F; Pronko, A; Proudfoot, J; Ptohos, F; Punzi, G; Pursley, J; Rademacker, J; Rahaman, A; Ramakrishnan, V; Ranjan, N; Redondo, I; Reisert, B; Rekovic, V; Renton, P; Rescigno, M; Richter, S; Rimondi, F; Ristori, L; Robson, A; Rodrigo, T; Rogers, E; Rolli, S; Roser, R; Rossi, M; Rossin, R; Roy, P; Ruiz, A; Russ, J; Rusu, V; Saarikko, H; Safonov, A; Sakumoto, W K; Salamanna, G; Saltó, O; Santi, L; Sarkar, S; Sartori, L; Sato, K; Savard, P; Savoy-Navarro, A; Scheidle, T; Schlabach, P; Schmidt, E E; Schmidt, M A; Schmidt, M P; Schmitt, M; Schwarz, T; Scodellaro, L; Scott, A L; Scribano, A; Scuri, F; Sedov, A; Seidel, S; Seiya, Y; Semenov, A; Sexton-Kennedy, L; Sfyrla, A; Shalhout, S Z; Shapiro, M D; Shears, T; Shepard, P F; Sherman, D; Shimojima, M; Shochet, M; Shon, Y; Shreyber, I; Sidoti, A; Sinervo, P; Sisakyan, A; Slaughter, A J; Slaunwhite, J; Sliwa, K; Smith, J R; Snider, F D; Snihur, R; Soderberg, M; Soha, A; Somalwar, S; Sorin, V; Spalding, J; Spinella, F; Spreitzer, T; Squillacioti, P; Stanitzki, M; Staveris-Polykalas, A; St Denis, R; Stelzer, B; Stelzer-Chilton, O; Stentz, D; Strologas, J; Stuart, D; Suh, J S; Sukhanov, A; Sun, H; Suslov, I; Suzuki, T; Taffard, A; Takashima, R; Takeuchi, Y; Tanaka, R; Tecchio, M; Teng, P K; Terashi, K; Tesarek, R J; Thom, J; Thompson, A S; Thomson, E; Tipton, P; Tiwari, V; Tkaczyk, S; Toback, D; Tokar, S; Tollefson, K; Tomura, T; Tonelli, D; Torre, S; Torretta, D; Tourneur, S; Trischuk, W; Tsuno, S; Tu, Y; Turini, N; Ukegawa, F; Uozumi, S; Vallecorsa, S; van Remortel, N; Varganov, A; Vataga, E; Vazquez, F; Velev, G; Vellidis, C; Veramendi, G; Veszpremi, V; Vidal, M; Vidal, R; Vila, I; Vilar, R; Vine, T; Vogel, M; Vollrath, I; Volobouev, I; Volpi, G; Würthwein, F; Wagner, P; Wagner, R G; Wagner, R L; Wagner, J; Wagner, W; Wallny, R; Wang, S M; Warburton, A; Waters, D; Weinberger, M; Wester, W C; Whitehouse, B; Whiteson, D; Wicklund, A B; Wicklund, E; Williams, G; Williams, H H; Wilson, P; Winer, B L; Wittich, P; Wolbers, S; Wolfe, C; Wright, T; Wu, X; Wynne, S M; Yagil, A; Yamamoto, K; Yamaoka, J; Yamashita, T; Yang, C; Yang, U K; Yang, Y C; Yao, W M; Yeh, G P; Yoh, J; Yorita, K; Yoshida, T; Yu, G B; Yu, I; Yu, S S; Yun, J C; Zanello, L; Zanetti, A; Zaw, I; Zhang, X; Zhou, J; Zucchelli, S

2007-11-16

We report an observation of new bottom baryons produced in pp collisions at the Tevatron. Using 1.1 fb(-1) of data collected by the CDF II detector, we observe four Lambda b 0 pi+/- resonances in the fully reconstructed decay mode Lambda b 0-->Lambda c + pi-, where Lambda c+-->pK* pi+. We interpret these states as the Sigma b(*)+/- baryons and measure the following masses: m Sigma b+=5807.8 -2.2 +2.0(stat.)+/-1.7(syst.) MeV/c2, m Sigma b- =5815.2+/-1.0(stat.)+/-1.7(syst.) MeV/c2, and m(Sigma b*)-m(Sigma b)=21.2-1.9 +2.0(stat.)-0.3+0.4(syst.) MeV/c2.

Simple Ligand-Receptor Interaction Descriptor (SILIRID) for alignment-free binding site comparison.

Science.gov (United States)

Chupakhin, Vladimir; Marcou, Gilles; Gaspar, Helena; Varnek, Alexandre

2014-06-01

We describe SILIRID (Simple Ligand-Receptor Interaction Descriptor), a novel fixed size descriptor characterizing protein-ligand interactions. SILIRID can be obtained from the binary interaction fingerprints (IFPs) by summing up the bits corresponding to identical amino acids. This results in a vector of 168 integer numbers corresponding to the product of the number of entries (20 amino acids and one cofactor) and 8 interaction types per amino acid (hydrophobic, aromatic face to face, aromatic edge to face, H-bond donated by the protein, H-bond donated by the ligand, ionic bond with protein cation and protein anion, and interaction with metal ion). Efficiency of SILIRID to distinguish different protein binding sites has been examined in similarity search in sc-PDB database, a druggable portion of the Protein Data Bank, using various protein-ligand complexes as queries. The performance of retrieval of structurally and evolutionary related classes of proteins was comparable to that of state-of-the-art approaches (ROC AUC ≈ 0.91). SILIRID can efficiently be used to visualize chemogenomic space covered by sc-PDB using Generative Topographic Mapping (GTM): sc-PDB SILIRID data form clusters corresponding to different protein types.

Tumor imaging with 2 sigma-receptor ligands, F-18-FE-SA5845 and C-11-SA4503 : A feasibility study

NARCIS (Netherlands)

van Waarde, A; Buursma, AR; Hospers, GAP; Kawamura, K; Kobayashi, T; Ishii, K; Oda, K; Ishiwata, K; Vaalburg, W; Elsinga, PH

Our objective was to study 2 radioligands for visualization of sigma-receptors with PET. Methods: Two radioligands--sigma(1)-selective C-11-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (C-11-SA4503) and nonsubtype-selective

Predicting Ligand Binding Sites on Protein Surfaces by 3-Dimensional Probability Density Distributions of Interacting Atoms

Science.gov (United States)

Jian, Jhih-Wei; Elumalai, Pavadai; Pitti, Thejkiran; Wu, Chih Yuan; Tsai, Keng-Chang; Chang, Jeng-Yih; Peng, Hung-Pin; Yang, An-Suei

2016-01-01

Predicting ligand binding sites (LBSs) on protein structures, which are obtained either from experimental or computational methods, is a useful first step in functional annotation or structure-based drug design for the protein structures. In this work, the structure-based machine learning algorithm ISMBLab-LIG was developed to predict LBSs on protein surfaces with input attributes derived from the three-dimensional probability density maps of interacting atoms, which were reconstructed on the query protein surfaces and were relatively insensitive to local conformational variations of the tentative ligand binding sites. The prediction accuracy of the ISMBLab-LIG predictors is comparable to that of the best LBS predictors benchmarked on several well-established testing datasets. More importantly, the ISMBLab-LIG algorithm has substantial tolerance to the prediction uncertainties of computationally derived protein structure models. As such, the method is particularly useful for predicting LBSs not only on experimental protein structures without known LBS templates in the database but also on computationally predicted model protein structures with structural uncertainties in the tentative ligand binding sites. PMID:27513851

MS-377, a novel selective sigma(1) receptor ligand, reverses phencyclidine-induced release of dopamine and serotonin in rat brain.

Science.gov (United States)

Takahashi, S; Horikomi, K; Kato, T

2001-09-21

A novel selective sigma(1) receptor ligand, (R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377), inhibits phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP)-induced behaviors in animal models. In this study, we measured extracellular dopamine and serotonin levels in the rat brain after treatment with MS-377 alone, using in vivo microdialysis. We also examined the effects of MS-377 on extracellular dopamine and serotonin levels in the rat medial prefrontal cortex after treatment with PCP. MS-377 itself had no significant effects on dopamine release in the striatum (10 mg/kg, p.o.) nor on dopamine or serotonin release in the medial prefrontal cortex (1 and 10 mg/kg, p.o.). PCP (3 mg/kg, i.p.) markedly increased dopamine and serotonin release in the medial prefrontal cortex. MS-377 (1 mg/kg, p.o.), when administered 60 min prior to PCP, significantly attenuated this effect of PCP. These results suggest that the inhibitory effects of MS-377 on PCP-induced behaviors are partly mediated by inhibition of the increase in dopamine and serotonin release in the rat medial prefrontal cortex caused by PCP.

Bifunctional avidin with covalently modifiable ligand binding site.

Directory of Open Access Journals (Sweden)

Jenni Leppiniemi

Full Text Available The extensive use of avidin and streptavidin in life sciences originates from the extraordinary tight biotin-binding affinity of these tetrameric proteins. Numerous studies have been performed to modify the biotin-binding affinity of (streptavidin to improve the existing applications. Even so, (streptavidin greatly favours its natural ligand, biotin. Here we engineered the biotin-binding pocket of avidin with a single point mutation S16C and thus introduced a chemically active thiol group, which could be covalently coupled with thiol-reactive molecules. This approach was applied to the previously reported bivalent dual chain avidin by modifying one binding site while preserving the other one intact. Maleimide was then coupled to the modified binding site resulting in a decrease in biotin affinity. Furthermore, we showed that this thiol could be covalently coupled to other maleimide derivatives, for instance fluorescent labels, allowing intratetrameric FRET. The bifunctional avidins described here provide improved and novel tools for applications such as the biofunctionalization of surfaces.

IgG-Fc-mediated effector functions: molecular definition of interaction sites for effector ligands and the role of glycosylation.

Science.gov (United States)

Jefferis, R; Lund, J; Pound, J D

1998-06-01

The Fc region of human IgG expresses interaction sites for many effector ligands. In this review the topographical distributions of ten of these sites are discussed in relation to functional requirement. It is apparent that interaction sites localised to the inter-CH2-CH3 domain region of the Fc allow for functional divalency, whereas sites localised to the hinge proximal region of the CH2 domain are functionally monovalent, with expression of the latter sites being particularly dependent on glycosylation. All x-ray crystal structures for Fc and Fc-ligand complexes report that the protein structure of the hinge proximal region of the CH2 domain is "disordered", suggesting "internal mobility". We propose a model in which such "internal mobility" results in the generation of a dynamic equilibrium between multiple conformers, certain of which express interaction sites specific to individual ligands. The emerging understanding of the influence of oligosaccharide/protein interactions on protein conformation and biological function of IgG antibodies suggests a potential to generate novel glycoforms of antibody molecules having unique profiles of effector functions.

Cyanide does more to inhibit heme enzymes, than merely serving as an active-site ligand

Energy Technology Data Exchange (ETDEWEB)

Parashar, Abhinav [Center for Biomedical Research, VIT University, Vellore, Tamil Nadu, 632014 India (India); Venkatachalam, Avanthika [REDOx Lab, PSG Institute of Advanced Studies, Avinashi Road, Peelamedu, Coimbatore, Tamil Nadu, 641004 (India); Gideon, Daniel Andrew [Center for Biomedical Research, VIT University, Vellore, Tamil Nadu, 632014 India (India); Manoj, Kelath Murali, E-mail: satyamjayatu@yahoo.com [REDOx Lab, PSG Institute of Advanced Studies, Avinashi Road, Peelamedu, Coimbatore, Tamil Nadu, 641004 (India)

2014-12-12

Highlights: • Cyanide (CN) is a well-studied toxic principle, known to inhibit heme-enzymes. • Inhibition is supposed to result from CN binding at the active site as a ligand. • Diverse heme enzymes’ CN inhibition profiles challenge prevailing mechanism. • Poor binding efficiency of CN at low enzyme concentrations and ligand pressures. • CN-based diffusible radicals cause ‘non-productive electron transfers’ (inhibition). - Abstract: The toxicity of cyanide is hitherto attributed to its ability to bind to heme proteins’ active site and thereby inhibit their activity. It is shown herein that the long-held interpretation is inadequate to explain several observations in heme-enzyme reaction systems. Generation of cyanide-based diffusible radicals in heme-enzyme reaction milieu could shunt electron transfers (by non-active site processes), and thus be detrimental to the efficiency of oxidative outcomes.

Serotoninergic receptors in brain tissue: properties and identification of various 3H-ligand binding sites in vitro

International Nuclear Information System (INIS)

Leysen, J.E.

1981-01-01

In vitro binding studies to serotoninergic receptors were performed using 3 H-LSD, 3 H-5-HT and 3 H-spiperone. An overwiew is given on findings using these three ligands with respect to the following: localization of specific binding sites, in various animal species, the regional distribution in the brain and periphery, the subcellular and cellular distribution. Properties of the binding sites, influence of the composition of the assay medium, binding kinetic properties, receptor regulation in vivo. Identity of the binding sites, differences between site for various 3 H-ligands, pharmacological specificity of the membranous binding sites, chemical composition of the macromolecular complex constituting the binding site. Function of the receptor. Binding affinities of 44 compounds were measured in binding assays using 3 H-spiperone and 3 H-LSD with rat frontal cortex membrane preparations and using 3 H-5-HT and 3 H-LSD with rat hippocampal membrane preparations

Removal and recovery of toxic metal ions from aqueous waste sites using polymer pendant ligands

International Nuclear Information System (INIS)

Fish, D.

1996-01-01

The purpose of this project is to investigate the use of polymer pendant ligand technology to remove and recover toxic metal ions from DOE aqueous waste sites. Polymer pendant lgiands are organic ligands, anchored to crosslinked, modified divinylbenzene-polystyrene beads, that can selectively complex metal ions. The metal ion removal step usually occurs through a complexation or ion exchange phenomena, thus recovery of the metal ions and reuse of the beads is readily accomplished

SIGMA without effort

International Nuclear Information System (INIS)

Hagedorn, R.; Reinfelds, J.

1978-01-01

SIGMA (System for Interactive Graphical Analysis) is an interactive computing language with automatic array handling and graphical facilities. It is designed as a tool for mathematical problem solving. The SIGMA language is simple, almost obvious, yet flexible and powerful. This tutorial introduces the beginner to SIGMA. It is supposed to be used at a graphics terminal having access to SIGMA. The user will learn the language in dialogue with the system in sixteen sessions of about one hour. The first session enables him already to compute and display functions of one or two variables. (Auth.)

Long chain fatty acids alter the interactive binding of ligands to the two principal drug binding sites of human serum albumin.

Directory of Open Access Journals (Sweden)

Keishi Yamasaki

Full Text Available A wide variety of drugs bind to human serum albumin (HSA at its two principal sites, namely site I and site II. A number of reports indicate that drug binding to these two binding sites are not completely independent, and that interactions between ligands of these two discrete sites can play a role. In this study, the effect of the binding of long-chain fatty acids on the interactive binding between dansyl-L-asparagine (DNSA; site I ligand and ibuprofen (site II ligand at pH6.5 was examined. Binding experiments showed that the binding of sodium oleate (Ole to HSA induces conformational changes in the molecule, which, in turn, changes the individual binding of DNSA and ibuprofen, as well as the mode of interaction between these two ligands from a 'competitive-like' allosteric interaction in the case of the defatted HSA conformer to a 'nearly independent' binding in the case of non-defatted HSA conformer. Circular dichroism measurements indicated that ibuprofen and Ole are likely to modify the spatial orientation of DNSA at its binding site. Docking simulations suggest that the long-distance electric repulsion between DNSA and ibuprofen on defatted HSA contributes to a 'competitive-like' allosteric interaction, whereas extending the distance between ligands and/or increasing the flexibility or size of the DNSA binding site in fatted HSA evokes a change in the interaction mode to 'nearly independent' binding. The present findings provide further insights into the structural dynamics of HSA upon the binding of fatty acids, and its effects on drug binding and drug-drug interactions that occur on HSA.

( sup 3 H)opipramol labels a novel binding site and sigma receptors in rat brain membranes

Energy Technology Data Exchange (ETDEWEB)

Ferris, C.D.; Hirsch, D.J.; Brooks, B.P.; Snowman, A.M.; Snyder, S.H. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (USA))

1991-02-01

Opipramol (OP), a clinically effective antidepressant with a tricyclic structure, is inactive as an inhibitor of biogenic amine uptake. ({sup 3}H)Opipramol binds saturably to rat brain membranes (apparent KD = 4 nM, Bmax = 3 pmol/mg of protein). ({sup 3}H)Opipramol binding can be differentiated into haloperidol-sensitive and -resistant components, with Ki values for haloperidol of 1 nM (Bmax = 1 pmol/mg of protein) and 350 nM (Bmax = 1.9 pmol/mg of protein), respectively. The drug specificity of the haloperidol-sensitive component is the same as that of sigma receptors labeled with (+)-({sup 3}H)3-(3-hydroxyphenyl)-N-(1-propyl)piperdine. The haloperidol-resistant component does not correspond to any known neurotransmitter receptor or uptake recognition site. It displays high affinity for phenothiazines and related structures such as perphenazine, clopenthixol, and flupenthixol, whose potencies are comparable to that of opipramol. Because certain of these drugs are more potent at the haloperidol-resistant opipramol site than in exerting any other action, it is possible that this opipramol-selective site may mediate their therapeutic effects.

LIGSITEcsc: predicting ligand binding sites using the Connolly surface and degree of conservation

Directory of Open Access Journals (Sweden)

Schroeder Michael

2006-09-01

Full Text Available Abstract Background Identifying pockets on protein surfaces is of great importance for many structure-based drug design applications and protein-ligand docking algorithms. Over the last ten years, many geometric methods for the prediction of ligand-binding sites have been developed. Results We present LIGSITEcsc, an extension and implementation of the LIGSITE algorithm. LIGSITEcsc is based on the notion of surface-solvent-surface events and the degree of conservation of the involved surface residues. We compare our algorithm to four other approaches, LIGSITE, CAST, PASS, and SURFNET, and evaluate all on a dataset of 48 unbound/bound structures and 210 bound-structures. LIGSITEcsc performs slightly better than the other tools and achieves a success rate of 71% and 75%, respectively. Conclusion The use of the Connolly surface leads to slight improvements, the prediction re-ranking by conservation to significant improvements of the binding site predictions. A web server for LIGSITEcsc and its source code is available at scoppi.biotec.tu-dresden.de/pocket.

The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca2+ homeostasis.

Science.gov (United States)

Gueguinou, M; Crottès, D; Chantôme, A; Rapetti-Mauss, R; Potier-Cartereau, M; Clarysse, L; Girault, A; Fourbon, Y; Jézéquel, P; Guérin-Charbonnel, C; Fromont, G; Martin, P; Pellissier, B; Schiappa, R; Chamorey, E; Mignen, O; Uguen, A; Borgese, F; Vandier, C; Soriani, O

2017-06-22

The remodeling of calcium homeostasis contributes to the cancer hallmarks and the molecular mechanisms involved in calcium channel regulation in tumors remain to be characterized. Here, we report that SigmaR1, a stress-activated chaperone, is required to increase calcium influx by triggering the coupling between SK3, a Ca 2+ -activated K + channel (KCNN3) and the voltage-independent calcium channel Orai1. We show that SigmaR1 physically binds SK3 in BC cells. Inhibition of SigmaR1 activity, either by molecular silencing or by the use of sigma ligand (igmesine), decreased SK3 current and Ca 2+ entry in breast cancer (BC) and colorectal cancer (CRC) cells. Interestingly, SigmaR1 inhibition diminished SK3 and/or Orai1 levels in lipid nanodomains isolated from BC cells. Analyses of tissue microarray from CRC patients showed higher SigmaR1 expression levels in cancer samples and a correlation with tumor grade. Moreover, the exploration of a cohort of 4937 BC patients indicated that high expression of SigmaR1 and Orai1 channels was significantly correlated to a lower overall survival. As the SK3/Orai1 tandem drives invasive process in CRC and bone metastasis progression in BC, our results may inaugurate innovative therapeutic approaches targeting SigmaR1 to control the remodeling of Ca 2+ homeostasis in epithelial cancers.

Searching the protein structure database for ligand-binding site similarities using CPASS v.2

Directory of Open Access Journals (Sweden)

Caprez Adam

2011-01-01

Full Text Available Abstract Background A recent analysis of protein sequences deposited in the NCBI RefSeq database indicates that ~8.5 million protein sequences are encoded in prokaryotic and eukaryotic genomes, where ~30% are explicitly annotated as "hypothetical" or "uncharacterized" protein. Our Comparison of Protein Active-Site Structures (CPASS v.2 database and software compares the sequence and structural characteristics of experimentally determined ligand binding sites to infer a functional relationship in the absence of global sequence or structure similarity. CPASS is an important component of our Functional Annotation Screening Technology by NMR (FAST-NMR protocol and has been successfully applied to aid the annotation of a number of proteins of unknown function. Findings We report a major upgrade to our CPASS software and database that significantly improves its broad utility. CPASS v.2 is designed with a layered architecture to increase flexibility and portability that also enables job distribution over the Open Science Grid (OSG to increase speed. Similarly, the CPASS interface was enhanced to provide more user flexibility in submitting a CPASS query. CPASS v.2 now allows for both automatic and manual definition of ligand-binding sites and permits pair-wise, one versus all, one versus list, or list versus list comparisons. Solvent accessible surface area, ligand root-mean square difference, and Cβ distances have been incorporated into the CPASS similarity function to improve the quality of the results. The CPASS database has also been updated. Conclusions CPASS v.2 is more than an order of magnitude faster than the original implementation, and allows for multiple simultaneous job submissions. Similarly, the CPASS database of ligand-defined binding sites has increased in size by ~ 38%, dramatically increasing the likelihood of a positive search result. The modification to the CPASS similarity function is effective in reducing CPASS similarity scores

How the early sporulation sigma factor sigmaF delays the switch to late development in Bacillus subtilis.

Science.gov (United States)

Karmazyn-Campelli, Céline; Rhayat, Lamya; Carballido-López, Rut; Duperrier, Sandra; Frandsen, Niels; Stragier, Patrick

2008-03-01

Sporulation in Bacillus subtilis is a primitive differentiation process involving two cell types, the forespore and the mother cell. Each cell implements two successive transcription programmes controlled by specific sigma factors. We report that activity of sigma(G), the late forespore sigma factor, is kept in check by Gin, the product of csfB, a gene controlled by sigma(F), the early forespore sigma factor. Gin abolishes sigma(G) transcriptional activity when sigma(G) is artificially synthesized during growth, but has no effect on sigma(F). Gin interacts strongly with sigma(G) but not with sigma(F) in a yeast two-hybrid experiment. The absence of Gin allows sigma(G) to be active during sporulation independently of the mother-cell development to which it is normally coupled. Premature sigma(G) activity leads to the formation of slow-germinating spores, and complete deregulation of sigma(G) synthesis is lethal when combined with gin inactivation. Gin allows sigma(F) to delay the switch to the late forespore transcription programme by preventing sigma(G) to take over before the cell has reached a critical stage of development. A similar strategy, following a completely unrelated route, is used by the mother cell.

Study of the reactions $\\bar{p}p \\rightarrow \\bar{\\Lambda} \\Lambda , \\bar{\\Lambda} \\Sigma^{0}$ or $\\bar{\\Sigma^{0}} \\Lambda , \\bar{\\Sigma^{+}} \\Sigma^{+}$ at 3.6 GeV/c

CERN Document Server

Atherton, Henry W; Moebes, J P; Quercigh, Emanuele

1974-01-01

The reactions $\\bar{p}p \\rightarrow \\bar{\\Lambda} \\Lambda , \\bar{\\Lambda} \\Sigma^{0}$ or $\\bar{\\Sigma^{0}} \\Lambda , \\bar{\\Sigma^{+}} \\Sigma^{+}$ are studied at an incident momentum of 3.6 GeV/c in a 35.4 event/$\\mu$ b experiment performed in the CERN 2m HBC. Total and differential cross sections are presented. The polarization of the hyperons is measured as a function of $t$ and for the reaction $\\bar{p}p \\rightarrow \\bar{\\Lambda} \\Lambda$ the complete spin correlation matrix is given. (23 refs).

Effect of the methionine ligand on the reorganization energy of the type-1 copper site of nitrite Reductase

DEFF Research Database (Denmark)

Farver, Ole; Wijma, Hein J.; MacPherson, Iain

2007-01-01

Copper-containing nitrite reductase harbors a type-1 and a type-2 Cu site. The former acts as the electron acceptor site of the enzyme, and the latter is the site of catalytic action. The effect of the methionine ligand on the reorganization energy of the type-1 site was explored by studying...

Naloxone-sensitive, haloperidol-sensitive, [3H](+)SKF-10047-binding protein partially purified from rat liver and rat brain membranes: an opioid/sigma receptor?

Science.gov (United States)

Tsao, L I; Su, T P

1997-02-01

A naloxone-sensitive, haloperidol-sensitive, [3H](+)SKF-10047-binding protein was partially purified from rat liver and rat brain membranes in an affinity chromatography originally designed to purify sigma receptors. Detergent-solubilized extracts from membranes were adsorbed to Sephadex G-25 resin containing an affinity ligand for sigma receptors: N-(2- 3,4-dichlorophenyl]ethyl)-N-(6-aminohexyl)-(2-[1-pyrrolidinyl]) ethylamine (DAPE). After eluting the resin with haloperidol, a protein that bound [3H](+)SKF-10047 was detected in the eluates. However, the protein was not the sigma receptor. [3H](+)SKF-10047 binding to the protein was inhibited by the following compounds in the order of decreasing potency: (+)pentazocine > (-) pentazocine > (+/-)cyclazocine > (-)morphine > (-)naloxone > haloperidol > (+)SKF-10047 > DADLE > (-)SKF-10047. Further, the prototypic sigma receptor ligands, such as 1,3-di-o-tolylguanidine (DTG), (+)3-PPP, and progesterone, bound poorly to the protein. Tryptic digestion and heat treatment of the affinity-purified protein abolished radioligand binding. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) of the partially-purified protein from the liver revealed a major diffuse band with a molecular mass of 31 kDa, a polypeptide of 65 kDa, and another polypeptide of > 97 kDa. This study demonstrates the existence of a novel protein in the rat liver and rat brain which binds opioids, benzomorphans, and haloperidol with namomolar affinity. The protein resembles the opioid/sigma receptor originally proposed by Martin et al. [(1976): J. Pharmacol. Exp. Ther., 197:517-532.]. A high degree of purification of this protein has been achieved in the present study.

Topological massive sigma models

International Nuclear Information System (INIS)

Lambert, N.D.

1995-01-01

In this paper we construct topological sigma models which include a potential and are related to twisted massive supersymmetric sigma models. Contrary to a previous construction these models have no central charge and do not require the manifold to admit a Killing vector. We use the topological massive sigma model constructed here to simplify the calculation of the observables. Lastly it is noted that this model can be viewed as interpolating between topological massless sigma models and topological Landau-Ginzburg models. ((orig.))

Study of Sigma Phase in Duplex SAF 2507

Science.gov (United States)

Fellicia, D. M.; Sutarsis; Kurniawan, B. A.; Wulanari, D.; Purniawan, A.; Wibisono, A. T.

2017-05-01

Super duplex stainless steel is one of the stainless steel which has a combination between high strength properties and excellent corrosion resistance. However, the resistance can decrease by precipitation of sigma phase which is formed at high temperature, for example after welding processes. A series of experiments has been performed to study the effect of solution annealing to existence of sigma phase on super duplex SAF 2507. Variations of solution-annealing temperatures were 1000 °C, 1065 °C and 1125 °C with holding time of 15 and 30 minutes for each temperature. Effect of solution annealing process was characterized by using XRD, SEM, and Optical Microscopy. The result showed precipitation of sigma phase completely dissolved at 1065 °C and 1125 °C because it reformed to austenite. After it was heated at 1065 °C, chromium carbide appeared in ferrite site and grain boundary. The amount of chromium carbide increased with the increasing of solution annealing temperature.

Characterization and autoradiographic visualization of (+)-[3H]SKF10,047 binding in rat and mouse brain: further evidence for phencyclidine/sigma opiate receptor commonality

International Nuclear Information System (INIS)

Sircar, R.; Nichtenhauser, R.; Ieni, J.R.; Zukin, S.R.

1986-01-01

The binding specificity of (+)-[ 3 H]N-allylnormetazocine, the dextrorotatory isomer of the prototypical sigma opiate SKF10,047, was determined in rat and mouse brain and the neuroanatomical distribution of its binding sites elucidated by quantitative autoradiography in sections of rat brain. Computer-assisted Scatchard analysis revealed an apparent two-site fit of the binding data in both species and in all rat brain regions examined. In whole rat brain, the Kd values were 3.6 and 153 nM and the maximum binding values were 40 fmol and 1.6 pmol/mg of protein for the apparent high- and low-affinity binding sites, respectively. (+)-SKF10,047, haloperidol and pentazocine were among the most potent inhibitors of 7 nM (+)-[ 3 H]SKF10,047 binding to the higher affinity sites; rank orders of ligand potencies at these sites differ sharply from those that have been reported for the [ 3 H]phencyclidine (PCP) site, or for eliciting PCP-like or SKF10,047-like behaviors. By contrast, rank orders of potency of sigma opiods, PCP derivatives and dioxolanes for displacement of 100 nM (+)-[ 3 H]SKF10,047 from the more numerous lower affinity sites in the presence of 100 nM haloperidol agreed closely with their potencies in the [ 3 H]PCP binding assay as well as their potencies in exerting PCP- or SKF10,047-like behavioral effects. In order to compare directly the anatomical localizations of PCP and (+)-SKF10,047 binding sites, quantitative light microscopy autoradiography utilizing tritium-labeled PCP and (+)-SKF10,047 was carried out in rat brain sections. (+)-[ 3 H]SKF10,047 binding was observed to follow the regional pattern of [3H]PCP binding but also to bind in other regions not associated with PCP receptors

Translating 10 lessons from lean six sigma project in paper-based training site to electronic health record-based primary care practice: challenges and opportunities.

Science.gov (United States)

Aleem, Sohaib

2013-01-01

Lean Six Sigma is a well-proven methodology to enhance the performance of any business, including health care. The strategy focuses on cutting out waste and variation from the processes to improve the value and efficiency of work. This article walks through the journey of "green belt" training using a Lean Six Sigma approach and the implementation of a process improvement project that focused on wait time for patients to be examined in an urban academic primary care clinic without requiring added resources. Experiences of the training and the project at an urban paper-based satellite clinic have informed the planning efforts of a data and performance team, including implementing a 15-minute nurse "pre-visit" at primary care sites of an accountable care organization.

LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

KAUST Repository

Chen, Peng; Huang, Jianhua Z; Gao, Xin

2014-01-01

Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction

[3H]CGP 61594, the first photoaffinity ligand for the glycine site of NMDA receptors

International Nuclear Information System (INIS)

Benke, D.; Honer, M.; Mohler, H.; Heckendorn, R.; Pozza, M.F.; Allgeier, H.; Angst, C.

1999-01-01

Activation of NMDA receptors requires the presence of glycine as a coagonist which binds to a site that is allosterically linked to the glutamate binding site. To identify the protein constituents of the glycine binding site in situ the photoaffinity label [ 3 H]CGP 61594 was synthesized. In reversible binding assays using crude rat brain membranes, [ 3 H]CGP 61594 labeled with high affinity (K D =23 nM) the glycine site of the NMDA receptor. This was evident from the Scatchard analysis, the displacing potencies of various glycine site ligands and the allosteric modulation of [ 3 H]CGP 61594 binding by ligands of the glutamate and polyamine sites. Electrophysiological experiments in a neocortical slice preparation identified CGP 61594 as a glycine antagonist. Upon UV-irradiation, a protein band of 115 kDa was specifically photolabeled by [ 3 H]CGP 61594 in brain membrane preparations. The photolabeled protein was identified as the NR1 subunit of the NMDA receptor by NR1 subunit-specific immunoaffinity chromatography. Thus, [ 3 H]CGP 61594 is the first photoaffinity label for the glycine site of NMDA receptors. It will serve as a tool for the identification of structural elements that are involved in the formation of the glycine binding domain of NMDA receptors in situ and will thereby complement the mutational analysis of recombinant receptors. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

Exploring the role of water in molecular recognition: predicting protein ligandability using a combinatorial search of surface hydration sites

Science.gov (United States)

Vukovic, Sinisa; Brennan, Paul E.; Huggins, David J.

2016-09-01

The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule. This is referred to as ligandability. In the study, we describe a method to predict ligandability by performing a search of all possible combinations of hydration sites on protein surfaces. We predict ligandability as the summed binding free energy for each of the constituent hydration sites, computed using inhomogeneous fluid solvation theory. We compared the predicted ligandability with the maximum observed binding affinity for 20 proteins in the human bromodomain family. Based on this comparison, it was determined that effective inhibitors have been developed for the majority of bromodomains, in the range from 10 to 100 nM. However, we predict that more potent inhibitors can be developed for the bromodomains BPTF and BRD7 with relative ease, but that further efforts to develop inhibitors for ATAD2 will be extremely challenging. We have also made predictions for the 14 bromodomains with no reported small molecule K d values by isothermal titration calorimetry. The calculations predict that PBRM1(1) will be a challenging target, while others such as TAF1L(2), PBRM1(4) and TAF1(2), should be highly ligandable. As an outcome of this work, we assembled a database of experimental maximal K d that can serve as a community resource assisting medicinal chemistry efforts focused on BRDs. Effective prediction of ligandability would be a very useful tool in the drug discovery process.

Exploring the role of water in molecular recognition: predicting protein ligandability using a combinatorial search of surface hydration sites.

Science.gov (United States)

Vukovic, Sinisa; Brennan, Paul E; Huggins, David J

2016-09-01

The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule. This is referred to as ligandability. In the study, we describe a method to predict ligandability by performing a search of all possible combinations of hydration sites on protein surfaces. We predict ligandability as the summed binding free energy for each of the constituent hydration sites, computed using inhomogeneous fluid solvation theory. We compared the predicted ligandability with the maximum observed binding affinity for 20 proteins in the human bromodomain family. Based on this comparison, it was determined that effective inhibitors have been developed for the majority of bromodomains, in the range from 10 to 100 nM. However, we predict that more potent inhibitors can be developed for the bromodomains BPTF and BRD7 with relative ease, but that further efforts to develop inhibitors for ATAD2 will be extremely challenging. We have also made predictions for the 14 bromodomains with no reported small molecule K d values by isothermal titration calorimetry. The calculations predict that PBRM1(1) will be a challenging target, while others such as TAF1L(2), PBRM1(4) and TAF1(2), should be highly ligandable. As an outcome of this work, we assembled a database of experimental maximal K d that can serve as a community resource assisting medicinal chemistry efforts focused on BRDs. Effective prediction of ligandability would be a very useful tool in the drug discovery process.

Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent.

Science.gov (United States)

Ogawa, Kazuma; Kanbara, Hiroya; Shiba, Kazuhiro; Kitamura, Yoji; Kozaka, Takashi; Kiwada, Tatsuto; Odani, Akira

2012-09-28

Sigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)-pIV. As a result, (+)-[125I]pIV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-pIV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH). (+)-[125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[125I]IV-OH and (+)-[131I]pIV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice. The hydrophilicity of (+)-[125I]IV-OH was much higher than that of (+)-[125I]pIV. In biodistribution experiments, (+)-[125I]IV-OH and (+)-[131I]pIV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[131I]pIV tended to be retained in most tissues, (+)-[125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[125I]IV-OH was significantly lower at all time points compared to those of (+)-[131I]pIV. In the blocking studies, co-injection of an excess amount of sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[125I]IV-OH. The results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent.

SVM prediction of ligand-binding sites in bacterial lipoproteins employing shape and physio-chemical descriptors.

Science.gov (United States)

Kadam, Kiran; Prabhakar, Prashant; Jayaraman, V K

2012-11-01

Bacterial lipoproteins play critical roles in various physiological processes including the maintenance of pathogenicity and numbers of them are being considered as potential candidates for generating novel vaccines. In this work, we put forth an algorithm to identify and predict ligand-binding sites in bacterial lipoproteins. The method uses three types of pocket descriptors, namely fpocket descriptors, 3D Zernike descriptors and shell descriptors, and combines them with Support Vector Machine (SVM) method for the classification. The three types of descriptors represent shape-based properties of the pocket as well as its local physio-chemical features. All three types of descriptors, along with their hybrid combinations are evaluated with SVM and to improve classification performance, WEKA-InfoGain feature selection is applied. Results obtained in the study show that the classifier successfully differentiates between ligand-binding and non-binding pockets. For the combination of three types of descriptors, 10 fold cross-validation accuracy of 86.83% is obtained for training while the selected model achieved test Matthews Correlation Coefficient (MCC) of 0.534. Individually or in combination with new and existing methods, our model can be a very useful tool for the prediction of potential ligand-binding sites in bacterial lipoproteins.

Six Sigma software development

CERN Document Server

Tayntor, Christine B

2002-01-01

Since Six Sigma has had marked success in improving quality in other settings, and since the quality of software remains poor, it seems a natural evolution to apply the concepts and tools of Six Sigma to system development and the IT department. Until now however, there were no books available that applied these concepts to the system development process. Six Sigma Software Development fills this void and illustrates how Six Sigma concepts can be applied to all aspects of the evolving system development process. It includes the traditional waterfall model and in the support of legacy systems,

Interaction of sigma factor sigmaN with Escherichia coli RNA polymerase core enzyme.

Science.gov (United States)

Scott, D J; Ferguson, A L; Gallegos, M T; Pitt, M; Buck, M; Hoggett, J G

2000-12-01

The equilibrium binding and kinetics of assembly of the DNA-dependent RNA polymerase (RNAP) sigma(N)-holoenzyme has been investigated using biosynthetically labelled 7-azatryptophyl- (7AW)sigma(N). The spectroscopic properties of such 7AW proteins allows their absorbance and fluorescence to be monitored selectively, even in the presence of high concentrations of other tryptophan-containing proteins. The 7AWsigma(N) retained its biological activity in stimulating transcription from sigma(N)-specific promoters, and in in vitro gel electrophoresis assays of binding to core RNAP from Escherichia coli. Furthermore, five Trp-->Ala single mutants of sigma(N) were shown to support growth under conditions of nitrogen limitation, and showed comparable efficiency in activating the sigma(N)-dependent nifH promoter in vivo, indicating that none of the tryptophan residues were essential for activity. The equilibrium binding of 7AWsigma(N) to core RNAP was examined by analytical ultracentrifugation. In sedimentation equilibrium experiments, absorbance data at 315 nm (which reports selectively on the distribution of free and bound 7AWsigma(N)) established that a 1:1 complex was formed, with a dissociation constant lower than 2 microM. The kinetics of the interaction between 7AWsigma(N) and core RNAP was investigated using stopped-flow spectrofluorimetry. A biphasic decrease in fluorescence intensity was observed when samples were excited at 280 nm, whereas only the slower of the two phases was observed at 315 nm. The kinetic data were analysed in terms of a mechanism in which a fast bimolecular association of sigma(N) with core RNAP is followed by a relatively slow isomerization step. The consequences of these findings on the competition between sigma(N) and the major sigma factor, sigma(70), in Escherichia coli are discussed.

Detecting local ligand-binding site similarity in nonhomologous proteins by surface patch comparison.

Science.gov (United States)

Sael, Lee; Kihara, Daisuke

2012-04-01

Functional elucidation of proteins is one of the essential tasks in biology. Function of a protein, specifically, small ligand molecules that bind to a protein, can be predicted by finding similar local surface regions in binding sites of known proteins. Here, we developed an alignment free local surface comparison method for predicting a ligand molecule which binds to a query protein. The algorithm, named Patch-Surfer, represents a binding pocket as a combination of segmented surface patches, each of which is characterized by its geometrical shape, the electrostatic potential, the hydrophobicity, and the concaveness. Representing a pocket by a set of patches is effective to absorb difference of global pocket shape while capturing local similarity of pockets. The shape and the physicochemical properties of surface patches are represented using the 3D Zernike descriptor, which is a series expansion of mathematical 3D function. Two pockets are compared using a modified weighted bipartite matching algorithm, which matches similar patches from the two pockets. Patch-Surfer was benchmarked on three datasets, which consist in total of 390 proteins that bind to one of 21 ligands. Patch-Surfer showed superior performance to existing methods including a global pocket comparison method, Pocket-Surfer, which we have previously introduced. Particularly, as intended, the accuracy showed large improvement for flexible ligand molecules, which bind to pockets in different conformations. Copyright © 2011 Wiley Periodicals, Inc.

CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction.

Science.gov (United States)

Xu, Youjun; Wang, Shiwei; Hu, Qiwan; Gao, Shuaishi; Ma, Xiaomin; Zhang, Weilin; Shen, Yihang; Chen, Fangjin; Lai, Luhua; Pei, Jianfeng

2018-05-10

CavityPlus is a web server that offers protein cavity detection and various functional analyses. Using protein three-dimensional structural information as the input, CavityPlus applies CAVITY to detect potential binding sites on the surface of a given protein structure and rank them based on ligandability and druggability scores. These potential binding sites can be further analysed using three submodules, CavPharmer, CorrSite, and CovCys. CavPharmer uses a receptor-based pharmacophore modelling program, Pocket, to automatically extract pharmacophore features within cavities. CorrSite identifies potential allosteric ligand-binding sites based on motion correlation analyses between cavities. CovCys automatically detects druggable cysteine residues, which is especially useful to identify novel binding sites for designing covalent allosteric ligands. Overall, CavityPlus provides an integrated platform for analysing comprehensive properties of protein binding cavities. Such analyses are useful for many aspects of drug design and discovery, including target selection and identification, virtual screening, de novo drug design, and allosteric and covalent-binding drug design. The CavityPlus web server is freely available at http://repharma.pku.edu.cn/cavityplus or http://www.pkumdl.cn/cavityplus.

Hadron properties in chiral sigma model

International Nuclear Information System (INIS)

Shen Hong

2005-01-01

The modification of hadron masses in nuclear medium is studied by using the chiral sigma model, which is extended to generate the omega meson mass by the sigma condensation in the vacuum in the same way as the nucleon mass. The chiral sigma model provides proper equilibrium properties of nuclear matter. It is shown that the effective masses of both nucleons and omega mesons decrease in nuclear medium, while the effective mass of sigma mesons increases oat finite density in the chiral sigma model. The results obtained in the chiral sigma model are compared with those obtained in the Walecka model, which includes sigma and omega mesons in a non-chiral fashion. (author)

Intraoperative detection of 18F-FDG-avid tissue sites using the increased probe counting efficiency of the K-alpha probe design and variance-based statistical analysis with the three-sigma criteria

International Nuclear Information System (INIS)

Povoski, Stephen P; Chapman, Gregg J; Murrey, Douglas A; Lee, Robert; Martin, Edward W; Hall, Nathan C

2013-01-01

Intraoperative detection of 18 F-FDG-avid tissue sites during 18 F-FDG-directed surgery can be very challenging when utilizing gamma detection probes that rely on a fixed target-to-background (T/B) ratio (ratiometric threshold) for determination of probe positivity. The purpose of our study was to evaluate the counting efficiency and the success rate of in situ intraoperative detection of 18 F-FDG-avid tissue sites (using the three-sigma statistical threshold criteria method and the ratiometric threshold criteria method) for three different gamma detection probe systems. Of 58 patients undergoing 18 F-FDG-directed surgery for known or suspected malignancy using gamma detection probes, we identified nine 18 F-FDG-avid tissue sites (from amongst seven patients) that were seen on same-day preoperative diagnostic PET/CT imaging, and for which each 18 F-FDG-avid tissue site underwent attempted in situ intraoperative detection concurrently using three gamma detection probe systems (K-alpha probe, and two commercially-available PET-probe systems), and then were subsequently surgical excised. The mean relative probe counting efficiency ratio was 6.9 (± 4.4, range 2.2–15.4) for the K-alpha probe, as compared to 1.5 (± 0.3, range 1.0–2.1) and 1.0 (± 0, range 1.0–1.0), respectively, for two commercially-available PET-probe systems (P < 0.001). Successful in situ intraoperative detection of 18 F-FDG-avid tissue sites was more frequently accomplished with each of the three gamma detection probes tested by using the three-sigma statistical threshold criteria method than by using the ratiometric threshold criteria method, specifically with the three-sigma statistical threshold criteria method being significantly better than the ratiometric threshold criteria method for determining probe positivity for the K-alpha probe (P = 0.05). Our results suggest that the improved probe counting efficiency of the K-alpha probe design used in conjunction with the three-sigma

[{sup 3}H]CGP 61594, the first photoaffinity ligand for the glycine site of NMDA receptors

Energy Technology Data Exchange (ETDEWEB)

Benke, D.; Honer, M.; Mohler, H. [Institute of Pharmacology, ETH and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich (Switzerland); Heckendorn, R.; Pozza, M.F.; Allgeier, H.; Angst, C. [NS Research, Novartis Pharma AG, CH-4002 Basle (Switzerland)

1999-02-01

Activation of NMDA receptors requires the presence of glycine as a coagonist which binds to a site that is allosterically linked to the glutamate binding site. To identify the protein constituents of the glycine binding site in situ the photoaffinity label [{sup 3}H]CGP 61594 was synthesized. In reversible binding assays using crude rat brain membranes, [{sup 3}H]CGP 61594 labeled with high affinity (K{sub D}=23 nM) the glycine site of the NMDA receptor. This was evident from the Scatchard analysis, the displacing potencies of various glycine site ligands and the allosteric modulation of [{sup 3}H]CGP 61594 binding by ligands of the glutamate and polyamine sites. Electrophysiological experiments in a neocortical slice preparation identified CGP 61594 as a glycine antagonist. Upon UV-irradiation, a protein band of 115 kDa was specifically photolabeled by [{sup 3}H]CGP 61594 in brain membrane preparations. The photolabeled protein was identified as the NR1 subunit of the NMDA receptor by NR1 subunit-specific immunoaffinity chromatography. Thus, [{sup 3}H]CGP 61594 is the first photoaffinity label for the glycine site of NMDA receptors. It will serve as a tool for the identification of structural elements that are involved in the formation of the glycine binding domain of NMDA receptors in situ and will thereby complement the mutational analysis of recombinant receptors. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

Correcting binding parameters for interacting ligand-lattice systems

Science.gov (United States)

Hervy, Jordan; Bicout, Dominique J.

2017-07-01

Binding of ligands to macromolecules is central to many functional and regulatory biological processes. Key parameters characterizing ligand-macromolecule interactions are the stoichiometry, inducing the number of ligands per macromolecule binding site, and the dissociation constant, quantifying the ligand-binding site affinity. Both these parameters can be obtained from analyses of classical saturation experiments using the standard binding equation that offers the great advantage of mathematical simplicity but becomes an approximation for situations of interest when a ligand binds and covers more than one single binding site on the macromolecule. Using the framework of car-parking problem with latticelike macromolecules where each ligand can cover simultaneously several consecutive binding sites, we showed that employing the standard analysis leads to underestimation of binding parameters, i.e., ligands appear larger than they actually are and their affinity is also greater than it is. Therefore, we have derived expressions allowing to determine the ligand size and true binding parameters (stoichiometry and dissociation constant) as a function of apparent binding parameters retrieved from standard saturation experiments.

Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo.

Science.gov (United States)

Kaushal, Nidhi; Seminerio, Michael J; Robson, Matthew J; McCurdy, Christopher R; Matsumoto, Rae R

2013-08-01

Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

The structure of the .sigma.-ideal of .sigma.-porous sets

Czech Academy of Sciences Publication Activity Database

Zelený, M.; Pelant, Jan

2004-01-01

Roč. 45, č. 1 (2004), s. 37-72 ISSN 0010-2628 R&D Projects: GA ČR GA201/97/1161; GA ČR GA201/97/0216; GA ČR GA201/00/1466; GA AV ČR KSK1019101 Institutional research plan: CEZ:AV0Z1019905 Keywords : .sigma. proposity * descriptive set theory * .sigma.-ideal Subject RIV: BA - General Mathematics

Intraoperative detection of ¹⁸F-FDG-avid tissue sites using the increased probe counting efficiency of the K-alpha probe design and variance-based statistical analysis with the three-sigma criteria.

Science.gov (United States)

Povoski, Stephen P; Chapman, Gregg J; Murrey, Douglas A; Lee, Robert; Martin, Edward W; Hall, Nathan C

2013-03-04

Intraoperative detection of (18)F-FDG-avid tissue sites during 18F-FDG-directed surgery can be very challenging when utilizing gamma detection probes that rely on a fixed target-to-background (T/B) ratio (ratiometric threshold) for determination of probe positivity. The purpose of our study was to evaluate the counting efficiency and the success rate of in situ intraoperative detection of (18)F-FDG-avid tissue sites (using the three-sigma statistical threshold criteria method and the ratiometric threshold criteria method) for three different gamma detection probe systems. Of 58 patients undergoing (18)F-FDG-directed surgery for known or suspected malignancy using gamma detection probes, we identified nine (18)F-FDG-avid tissue sites (from amongst seven patients) that were seen on same-day preoperative diagnostic PET/CT imaging, and for which each (18)F-FDG-avid tissue site underwent attempted in situ intraoperative detection concurrently using three gamma detection probe systems (K-alpha probe, and two commercially-available PET-probe systems), and then were subsequently surgical excised. The mean relative probe counting efficiency ratio was 6.9 (± 4.4, range 2.2-15.4) for the K-alpha probe, as compared to 1.5 (± 0.3, range 1.0-2.1) and 1.0 (± 0, range 1.0-1.0), respectively, for two commercially-available PET-probe systems (P < 0.001). Successful in situ intraoperative detection of 18F-FDG-avid tissue sites was more frequently accomplished with each of the three gamma detection probes tested by using the three-sigma statistical threshold criteria method than by using the ratiometric threshold criteria method, specifically with the three-sigma statistical threshold criteria method being significantly better than the ratiometric threshold criteria method for determining probe positivity for the K-alpha probe (P = 0.05). Our results suggest that the improved probe counting efficiency of the K-alpha probe design used in conjunction with the three-sigma statistical

Pion--nucleon sigma-commutator

International Nuclear Information System (INIS)

Banerjee, M.K.; Cammarata, J.B.

1977-07-01

The reasons for the large discrepancies in the magnitude of the πN sigma-commutator, sigma(πN), obtained by several authors are discussed using dynamic theory of the πN scattering amplitude. With sigma(πN) approximately 25 MeV this theory reproduces reasonably well both the experimental S-wave phase shifts at low energies and the amplitudes C approximately/sup(+)/(ν=0,t less than or equal to 0) determined by Langbein. In the method of Cheng and Dashen the value of sigma(πN) is obtained from these amplitudes by extrapolation to t = 2m 2 /sub π/. A study of the experimental D-wave ''scattering lengths'' implies that the coefficient of the term quadratic in t in the Hoehler expansion of C approximately/sup(+)/(0,t) is negative. Adding such a term to the results of the S-wave theory will tend to improve the agreement for C approximately/sup (+)/(0,t less than or equal to 0). These results suggest that the large ''world value'' sigma(πN) = 65 +- 5 MeV obtained using the Cheng-Dashen method is a consequence of errors in the extrapolation of amplitudes to the unphysical point ν = 0, t = 2m 2 /sub π/. Only the smaller value sigma(πN) approximately 25 MeV appears to be consistent with the experimental data and theoretical constraints

Running Head: Implementing Six Sigma Efforts

Science.gov (United States)

Lindsay, Jamie Eleaitia Mae

2005-01-01

Six Sigma is an organization wide program that provides common set of goals, language, and methodology for improving the overall quality of the processes within the organization (Davis & Heineke 2004). Six Sigma main concern is for the customer. What will the customers want? Need? Six Sigma has a model that helps Sigma get implemented DMAIC model…

Detecting Local Ligand-Binding Site Similarity in Non-Homologous Proteins by Surface Patch Comparison

Science.gov (United States)

Sael, Lee; Kihara, Daisuke

2012-01-01

Functional elucidation of proteins is one of the essential tasks in biology. Function of a protein, specifically, small ligand molecules that bind to a protein, can be predicted by finding similar local surface regions in binding sites of known proteins. Here, we developed an alignment free local surface comparison method for predicting a ligand molecule which binds to a query protein. The algorithm, named Patch-Surfer, represents a binding pocket as a combination of segmented surface patches, each of which is characterized by its geometrical shape, the electrostatic potential, the hydrophobicity, and the concaveness. Representing a pocket by a set of patches is effective to absorb difference of global pocket shape while capturing local similarity of pockets. The shape and the physicochemical properties of surface patches are represented using the 3D Zernike descriptor, which is a series expansion of mathematical 3D function. Two pockets are compared using a modified weighted bipartite matching algorithm, which matches similar patches from the two pockets. Patch-Surfer was benchmarked on three datasets, which consist in total of 390 proteins that bind to one of 21 ligands. Patch-Surfer showed superior performance to existing methods including a global pocket comparison method, Pocket-Surfer, which we have previously introduced. Particularly, as intended, the accuracy showed large improvement for flexible ligand molecules, which bind to pockets in different conformations. PMID:22275074

Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression.

Science.gov (United States)

Aguinaga, David; Medrano, Mireia; Vega-Quiroga, Ignacio; Gysling, Katia; Canela, Enric I; Navarro, Gemma; Franco, Rafael

2018-01-01

Sigma σ 1 and σ 2 receptors are targets of cocaine. Despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is unknown. Cocaine increases the level of dopamine, a key neurotransmitter in CNS motor control and reward areas. While the drug also affects dopaminergic signaling by allosteric modulations exerted by σ 1 R interacting with dopamine D 1 and D 2 receptors, the potential regulation of dopaminergic transmission by σ 2 R is also unknown. We here demonstrate that σ 2 R may form heteroreceptor complexes with D 1 but not with D 2 receptors. Remarkably σ 1 , σ 2 , and D 1 receptors may form heterotrimers with particular signaling properties. Determination of cAMP levels, MAP kinase activation and label-free assays demonstrate allosteric interactions within the trimer. Importantly, the presence of σ 2 R induces bias in signal transduction as σ 2 R ligands increase cAMP signaling whereas reduce MAP kinase activation. These effects, which are opposite to those exerted via σ 1 R, suggest that the D 1 receptor-mediated signaling depends on the degree of trimer formation and the differential balance of sigma receptor and heteroreceptor expression in acute versus chronic cocaine consumption. Although the physiological role is unknown, the heteroreceptor complex formed by σ 1 , σ 2 , and D 1 receptors arise as relevant to convey the cocaine actions on motor control and reward circuits and as a key factor in acquisition of the addictive habit.

Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression

Directory of Open Access Journals (Sweden)

David Aguinaga

2018-02-01

Full Text Available Sigma σ1 and σ2 receptors are targets of cocaine. Despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is unknown. Cocaine increases the level of dopamine, a key neurotransmitter in CNS motor control and reward areas. While the drug also affects dopaminergic signaling by allosteric modulations exerted by σ1R interacting with dopamine D1 and D2 receptors, the potential regulation of dopaminergic transmission by σ2R is also unknown. We here demonstrate that σ2R may form heteroreceptor complexes with D1 but not with D2 receptors. Remarkably σ1, σ2, and D1 receptors may form heterotrimers with particular signaling properties. Determination of cAMP levels, MAP kinase activation and label-free assays demonstrate allosteric interactions within the trimer. Importantly, the presence of σ2R induces bias in signal transduction as σ2R ligands increase cAMP signaling whereas reduce MAP kinase activation. These effects, which are opposite to those exerted via σ1R, suggest that the D1 receptor-mediated signaling depends on the degree of trimer formation and the differential balance of sigma receptor and heteroreceptor expression in acute versus chronic cocaine consumption. Although the physiological role is unknown, the heteroreceptor complex formed by σ1, σ2, and D1 receptors arise as relevant to convey the cocaine actions on motor control and reward circuits and as a key factor in acquisition of the addictive habit.

Narrow Sigma -hypernuclear states

CERN Document Server

Gal, A

1980-01-01

It is shown that the spin-isospin dependence of low-energy Sigma N to Lambda N conversion leads to substantial quenching of nuclear-matter estimates of the widths of some Sigma -hypernuclear states produced in (K/sup -/, pi ) reactions, to a level below 10 MeV. The estimated widths compare favorably with those of the Sigma -hypernuclear peaks recently observed at CERN for /sup 7/Li, /sup 9/Be, and /sup 12/C. Tentative quantum number assignments are suggested for these states. (10 refs).

Evaluation of the state of stress at the Forsmark site. Preliminary site investigation Forsmark area - version 1.2

Energy Technology Data Exchange (ETDEWEB)

Sjoeberg, Jonny; Lindfors, Ulf; Perman, Fredrik; Ask, Daniel [SwedPower AB, Stockholm (Sweden)

2005-09-15

This report presents an evaluation of the state of stress at the Forsmark site, based on all conducted stress measurements to date at the site, indirect stress estimates, geological and tectonic description of the site, and regional stress data from nearby locations. The work included (i) compilation of measurement results from Forsmark, as well as from nearby (regional) sites/locations, (ii) analysis of confidence intervals for each group of measurement, (iii) assessment of the stress state for the Forsmark site accounting for geological/tectonic evolution at the site, (iv) assessment of stress state for selected nearby (regional) sites/locations, and (v) comparison and combined interpretation of similarities and/or differences in stress state from a regional perspective. The combined assessment of the local (site-scale) and regional stress data for Forsmark showed that the major stress is orientated sub-horizontally and trending NW-SE; however, with significant local variation. A thrust faulting ({sigma}H > {sigma}h > {sigma}v) or possibly strike-slip faulting ({sigma}H > {sigma}v > {sigma}h) stress regime is evident at the Forsmark site. The maximum horizontal stress tends to be higher at the site compared to nearby sites and regional conditions. The site and regional data indicate that the vertical stress seems to be solely due to the overburden pressure. The lack of solid core discing for large portions of the boreholes at Forsmark was used to estimate an upper limit of the maximum horizontal stress magnitude. However, such an estimation is highly uncertain due to e.g. partly unknown mechanism for core discing failure, and unknown effects of the simplifying assumptions made in the analysis. The possible effects of shallow-dipping deformation zones on the stress state, could not be verified from the currently available data. However, the possibility of different stress regimes above and below deformation zones must be considered in future work. Slightly lower

Lean Six Sigma in financial services

NARCIS (Netherlands)

de Koning, H.; Does, R.J.M.M.; Bisgaard, S.

2008-01-01

Lean Thinking and Six Sigma are typically considered as separate approaches to process innovation, with complementary strengths. When combined as Lean Six Sigma, this approach provides a unified framework for systematically developing innovations. Lean Six Sigma can also bring about significant

Automatic generation of bioinformatics tools for predicting protein-ligand binding sites.

Science.gov (United States)

Komiyama, Yusuke; Banno, Masaki; Ueki, Kokoro; Saad, Gul; Shimizu, Kentaro

2016-03-15

Predictive tools that model protein-ligand binding on demand are needed to promote ligand research in an innovative drug-design environment. However, it takes considerable time and effort to develop predictive tools that can be applied to individual ligands. An automated production pipeline that can rapidly and efficiently develop user-friendly protein-ligand binding predictive tools would be useful. We developed a system for automatically generating protein-ligand binding predictions. Implementation of this system in a pipeline of Semantic Web technique-based web tools will allow users to specify a ligand and receive the tool within 0.5-1 day. We demonstrated high prediction accuracy for three machine learning algorithms and eight ligands. The source code and web application are freely available for download at http://utprot.net They are implemented in Python and supported on Linux. shimizu@bi.a.u-tokyo.ac.jp Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo

OpenAIRE

Kaushal, Nidhi; Seminerio, Michael J.; Robson, Matthew J.; McCurdy, Christopher R.; Matsumoto, Rae R.

2012-01-01

Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it acts in part as an agonist. SN79 (6-acetyl-3-(4-(4-(4-florophenyl)...

Correlation holography: imaging of atoms when sigma/sub inelastic//sup >>sigma/elastic

International Nuclear Information System (INIS)

Csonka, P.L.

1979-01-01

Atomic-scale resolution of details is possible with this method, even if protons interact with the atoms overwhelmingly inelastically, i.e. when sigma/sub inelastic/ >>sigma/sub elastic/. Observation of small objects is compatible with quantum mechanics even if the disturbance of the object caused by the observation process is arbitrarily small

Design for six sigma: A review

Directory of Open Access Journals (Sweden)

Kouroush Jenab

2018-01-01

Full Text Available Six Sigma is recognized as an essential tool for continuous improvement of quality. A large num-ber of publications by various authors reflect the interest in this technique. Reviews of literature on Six Sigma have been done in the past by a few authors. However, considering the contributions in the recent times, a more comprehensive review is attempted here. The authors have examined vari-ous papers and have proposed a different scheme of classification. In addition, certain gaps that would provide hints for further research in Six Sigma have been identified. As a results the rela-tionship between Six Sigma, Design for Six Sigma (DFSS, and how these two concepts support the quality system for organizational learning and innovation performance have been discussed that would help researchers, academicians and practitioners to take a closer look at the growth, devel-opment and applicability of Six Sigma in Design.

Getting the sigma in the M_BH - sigma relation right

Science.gov (United States)

van der Marel, Roeland

2017-08-01

The relation between the mass of the central supermassive black hole (M_BH) and the velocity dispersion of its host spheroid (sigma) is fundamental for our understanding of galaxy evolution and its relation to their nuclei. Correspondingly many HST orbits have been invested in determining accurate M_BH masses. Surprisingly little has been done on standardizing the other axis, i.e. sigma measurements. These values are often derived from various long-slit datasets at different physical radii of the galaxy and no homogeneous definition has been given. We propose to remedy this situation by using our dataset of MUSE and PPAK kinematic maps out to 1 R_e of galaxies with a secure black hole mass. These data are useful for large scale kinematics, however, obtaining velocity dispersions at small radii is not possible. To measure velocity dispersions at small radii we require high-spatial resolution spectroscopy as provided by HST/STIS. In addtion, high-resolution photometric data is needed to define consistent apertures in each galaxy. We therefore propose to use the unique capabilities of HST and harvest years of efforts to collect archival spectroscopic and imaging data for BH host galaxies. This will allow creating a catalog of sigma values, calculated in various ways and at various radii and to re-calibrate the M_BH - sigma relation.

Barriers of six sigma in healthcare organizations

Directory of Open Access Journals (Sweden)

Serkan Deniz

2018-09-01

Full Text Available Six Sigma approach is based on decreasing defects and variations in the products and processes, and it provides important benefits to healthcare organizations. This study aims to identify managers’ opinions, who work in private healthcare organizations, about the reasons behind not using Six Sigma in their organizations. The research was performed between December 2016 and March 2018 in private healthcare organizations (private hospitals and medical centers operating in Turkey and not using Six Sigma approach. Data were collected from managers, who have knowledge about Six Sigma, through using surveys. In this study, survey methodology was used to collect data. According to the results, the biggest barrier related to not using Six Sigma is based on the lack of knowledge about Six Sigma. The other important barrier about the diffusion of Six Sigma within this organizations is related to the lack of support from top management and leaders. Another finding about the reasons of not applying Six Sigma approach is that there is not a statistically significant difference among managers in terms of their managerial position. In order to overcome the lack of knowledge about Six Sigma, it is advised that managers should take steps in the direction of promoting Six Sigma within their current organization, and provide necessary support and leadership about the process.

One-pot synthesis and sigma receptor binding studies of novel spirocyclic-2,6-diketopiperazine derivatives.

Science.gov (United States)

Ghandi, Mehdi; Sherafat, Fatemeh; Sadeghzadeh, Masoud; Alirezapour, Behrouz

2016-06-01

New spirocyclic-2,6-diketopiperazine derivatives containing benzylpiperidine and cycloalkane moieties were synthesized by a one-pot two-step sequential Ugi/intramolecular N-amidation process in moderate to good yields. The in vitro ligand-binding profile studies performed on the sigma-1 and sigma-2 receptors revealed that the σ1 affinities and subtype selectivities of three spirocyclic piperidine derivatives are generally comparable to those of spirocycloalkane analogues. Compared to the low σ1 affinities obtained for cycloalkyl-substituted spirocyclic-2,6-diketopiperazines with n=2, those with n=1 proved to have optimal fitting with σ2 subtype by exhibiting higher affinities. Moreover, the best binding affinity and subtype selectivity was identified for compound 3c with Kiσ1=5.9±0.5nM and Kiσ2=563±21nM as well as 95-fold σ1/σ2 selectivity ratio, respectively. Copyright © 2016. Published by Elsevier Ltd.

Six Sigma in Education

Science.gov (United States)

LeMahieu, Paul G.; Nordstrum, Lee E.; Cudney, Elizabeth A.

2017-01-01

Purpose: This paper is one of seven in this volume that aims to elaborate different approaches to quality improvement in education. It delineates a methodology called Six Sigma. Design/methodology/approach: The paper presents the origins, theoretical foundations, core principles and a case study demonstrating an application of Six Sigma in a…

Six Sigma: not for the faint of heart.

Science.gov (United States)

Benedetto, Anthony R

2003-01-01

appoint the "cream of the crop" to the project teams. Success is predicated on having the most knowledgeable personnel involved in the project. Without them, the chances of success are reduced. A Six Sigma project's length always exceeds the attention span of the vast majority of its participants. The department director and project manager must anticipate this and devote special efforts to maintaining motivation and momentum after the initial flurry of activity. The complexity of a Six Sigma project will be greatly increased, and all of the pitfalls discussed here will be exacerbated, if your facility has multiple sites. At the simplest, the multiple sites will introduce complications in getting personnel to come to project meetings. The complications will escalate if the sites are under different management, such as a confederated health system. The project manager and the consultant will expend additional time and effort dealing with these issues, which likely will lengthen the project unavoidably. The project manager must spend time with the department's external customers who have significant stakes in the project. At a minimum, this should include relatively formal meetings with other department directors or subordinate managers and key physician and nurse leaders, and attendance at their managerial or staff meetings (you may need to ask to be invited). Although paper or e-mail surveys can be helpful, only sustained personal contact with a stakeholder will truly allow you to understand how they interact with radiology and what their concerns are. As with daily operational management, a performance improvement project requires attention to policies, procedures, processes, physical plant and infrastructure, personnel, and perhaps most importantly, to politics.

Dissecting Orthosteric Contacts for a Reverse-Fragment-Based Ligand Design.

Science.gov (United States)

Chandramohan, Arun; Tulsian, Nikhil K; Anand, Ganesh S

2017-08-01

Orthosteric sites on proteins are formed typically from noncontiguous interacting sites in three-dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the local secondary structure. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD). In this study, we describe an approach of progressive unfolding of a target protein using a gradient of denaturant urea to reveal the individual energetic contributions of various ligand-functional groups to the affinity of the entire ligand. Through calibrated unfolding of two protein-ligand systems: cAMP-bound regulatory subunit of Protein Kinase A (RIα) and IBMX-bound phosphodiesterase8 (PDE8), monitored by amide hydrogen-deuterium exchange mass spectrometry, we show progressive disruption of individual orthosteric contacts in the ligand binding sites, allowing us to rank the energetic contributions of these individual interactions. In the two cAMP-binding sites of RIα, exocyclic phosphate oxygens of cAMP were identified to mediate stronger interactions than ribose 2'-OH in both the RIα-cAMP binding interfaces. Further, we have also ranked the relative contributions of the different functional groups of IBMX based on their interactions with the orthosteric residues of PDE8. This strategy for deconstruction of individual binding sites and identification of the strongest functional group interaction in enzyme orthosteric sites offers a rational starting point for FBDD.

Quantitative application of sigma metrics in medical biochemistry.

Science.gov (United States)

Nanda, Sunil Kumar; Ray, Lopamudra

2013-12-01

Laboratory errors are result of a poorly designed quality system in the laboratory. Six Sigma is an error reduction methodology that has been successfully applied at Motorola and General Electric. Sigma (σ) is the mathematical symbol for standard deviation (SD). Sigma methodology can be applied wherever an outcome of a process has to be measured. A poor outcome is counted as an error or defect. This is quantified as defects per million (DPM). A six sigma process is one in which 99.999666% of the products manufactured are statistically expected to be free of defects. Six sigma concentrates, on regulating a process to 6 SDs, represents 3.4 DPM (defects per million) opportunities. It can be inferred that as sigma increases, the consistency and steadiness of the test improves, thereby reducing the operating costs. We aimed to gauge performance of our laboratory parameters by sigma metrics. Evaluation of sigma metrics in interpretation of parameter performance in clinical biochemistry. The six month internal QC (October 2012 to march 2013) and EQAS (external quality assurance scheme) were extracted for the parameters-Glucose, Urea, Creatinine, Total Bilirubin, Total Protein, Albumin, Uric acid, Total Cholesterol, Triglycerides, Chloride, SGOT, SGPT and ALP. Coefficient of variance (CV) were calculated from internal QC for these parameters. Percentage bias for these parameters was calculated from the EQAS. Total allowable errors were followed as per Clinical Laboratory Improvement Amendments (CLIA) guidelines. Sigma metrics were calculated from CV, percentage bias and total allowable error for the above mentioned parameters. For parameters - Total bilirubin, uric acid, SGOT, SGPT and ALP, the sigma values were found to be more than 6. For parameters - glucose, Creatinine, triglycerides, urea, the sigma values were found to be between 3 to 6. For parameters - total protein, albumin, cholesterol and chloride, the sigma values were found to be less than 3. ALP was the best

The applicability of Lean and Six Sigma techniques to clinical and translational research.

Science.gov (United States)

Schweikhart, Sharon A; Dembe, Allard E

2009-10-01

Lean and Six Sigma are business management strategies commonly used in production industries to improve process efficiency and quality. During the past decade, these process improvement techniques increasingly have been applied outside the manufacturing sector, for example, in health care and in software development. This article concerns the potential use of Lean and Six Sigma in improving the processes involved in clinical and translational research. Improving quality, avoiding delays and errors, and speeding up the time to implementation of biomedical discoveries are prime objectives of the National Institutes of Health (NIH) Roadmap for Medical Research and the NIH's Clinical and Translational Science Award program. This article presents a description of the main principles, practices, and methods used in Lean and Six Sigma. Available literature involving applications of Lean and Six Sigma to health care, laboratory science, and clinical and translational research is reviewed. Specific issues concerning the use of these techniques in different phases of translational research are identified. Examples of Lean and Six Sigma applications that are being planned at a current Clinical and Translational Science Award site are provided, which could potentially be replicated elsewhere. We describe how different process improvement approaches are best adapted for particular translational research phases. Lean and Six Sigma process improvement methods are well suited to help achieve NIH's goal of making clinical and translational research more efficient and cost-effective, enhancing the quality of the research, and facilitating the successful adoption of biomedical research findings into practice.

Sigma-1 receptor and inflammatory pain.

Science.gov (United States)

Gris, Georgia; Cobos, Enrique José; Zamanillo, Daniel; Portillo-Salido, Enrique

2015-06-01

The sigma-1 receptor (Sig-1R) is a unique ligand-regulated molecular chaperone that interacts with several protein targets such as G protein-coupled receptors and ion channels to modulate their activity. Sig-1R is located in areas of the central and peripheral nervous system that are key to pain control. Previous preclinical studies have suggested a potential therapeutic use of Sig-1R antagonists for the management of neuropathic pain. Recent studies using pharmacological and genetic tools have explored the role of Sig-1R in inflammatory pain conditions. Mice lacking the Sig-1R have shown different patterns of phenotypic responses to inflammatory injury. Systemic or peripheral administration of several Sig-1R antagonists, including the selective Sig-1R antagonist S1RA, inhibited both mechanical and thermal hypersensitivity in several preclinical models of inflammatory pain. These recent studies are summarized in the present commentary. Central and peripheral pharmacological blockade of Sig-1R could be an effective option to treat inflammatory pain.

Sigma models on supercosets

Energy Technology Data Exchange (ETDEWEB)

Mitev, Vladimir

2010-08-15

The purpose of this thesis is to deepen our understanding of the fundamental properties and defining features of non-linear sigma models on superspaces. We begin by presenting the major concepts that we have used in our investigation, namely Lie superalgebras and supergroups, non-linear sigma models and two dimensional conformal field theory. We then exhibit a method, called cohomological reduction, that makes use of the target space supersymmetry of non-linear sigma models to compute certain correlation functions. We then show how the target space supersymmetry of Ricci flat Lie supergroups simplifies the perturbation theory of suitable deformed Wess-Zumino-Witten models, making it possible to compute boundary conformal weights to all orders. This is then applied to the OSP (2S+2 vertical stroke 2S) Gross-Neveu Model, leading to a dual description in terms of the sigma model on the supersphere S{sup 2S+1} {sup vertical} {sup stroke} {sup 2S}. With this results in mind, we then turn to the similar, yet more intricate, theory of the non-linear sigma model on the complex projective superspaces CP{sup N-1} {sup vertical} {sup stroke} {sup N}. The cohomological reduction allows us to compute several important quantities non-perturbatively with the help of the system of symplectic fermions. Combining this with partial perturbative results for the whole theory, together with numerical computations, we propose a conjecture for the exact evolution of boundary conformal weights for symmetry preserving boundary conditions. (orig.)

Sigma models on supercosets

International Nuclear Information System (INIS)

Mitev, Vladimir

2010-08-01

The purpose of this thesis is to deepen our understanding of the fundamental properties and defining features of non-linear sigma models on superspaces. We begin by presenting the major concepts that we have used in our investigation, namely Lie superalgebras and supergroups, non-linear sigma models and two dimensional conformal field theory. We then exhibit a method, called cohomological reduction, that makes use of the target space supersymmetry of non-linear sigma models to compute certain correlation functions. We then show how the target space supersymmetry of Ricci flat Lie supergroups simplifies the perturbation theory of suitable deformed Wess-Zumino-Witten models, making it possible to compute boundary conformal weights to all orders. This is then applied to the OSP (2S+2 vertical stroke 2S) Gross-Neveu Model, leading to a dual description in terms of the sigma model on the supersphere S 2S+1 vertical stroke 2S . With this results in mind, we then turn to the similar, yet more intricate, theory of the non-linear sigma model on the complex projective superspaces CP N-1 vertical stroke N . The cohomological reduction allows us to compute several important quantities non-perturbatively with the help of the system of symplectic fermions. Combining this with partial perturbative results for the whole theory, together with numerical computations, we propose a conjecture for the exact evolution of boundary conformal weights for symmetry preserving boundary conditions. (orig.)

Spectra of conformal sigma models

International Nuclear Information System (INIS)

Tlapak, Vaclav

2015-04-01

In this thesis the spectra of conformal sigma models defined on (generalized) symmetric spaces are analysed. The spaces where sigma models are conformal without the addition of a Wess-Zumino term are supermanifolds, in other words spaces that include fermionic directions. After a brief review of the general construction of vertex operators and the background field expansion, we compute the diagonal terms of the one-loop anomalous dimensions of sigma models on semi-symmetric spaces. We find that the results are formally identical to the symmetric case. However, unlike for sigma models on symmetric spaces, off diagonal terms that lead to operator mixing are also present. These are not computed here. We then present a detailed analysis of the one-loop spectrum of the supersphere S 3 vertical stroke 2 sigma model as one of the simplest examples. The analysis illustrates the power and simplicity of the construction. We use this data to revisit a duality with the OSP(4 vertical stroke 2) Gross-Neveu model that was proposed by Candu and Saleur. With the help of a recent all-loop result for the anomalous dimension of (1)/(2)BPS operators of Gross-Neveu models, we are able to recover the entire zero-mode spectrum of the supersphere model. We also argue that the sigma model constraints and its equations of motion are implemented correctly in the Gross-Neveu model, including the one-loop data. The duality is further supported by a new all-loop result for the anomalous dimension of the ground states of the sigma model. However, higher-gradient operators cannot be completely recovered. It is possible that this discrepancy is related to a known instability of the sigma model. The instability of sigma models is due to symmetry preserving high-gradient operators that become relevant at arbitrarily small values of the coupling. This feature has been observed long ago in one-loop calculations of the O(N)-vector model and soon been realized to be a generic property of sigma models

Commutative $C^*$-algebras and $\\sigma$-normal morphisms

OpenAIRE

de Jeu, Marcel

2003-01-01

We prove in an elementary fashion that the image of a commutative monotone $\\sigma$-complete $C^*$-algebra under a $\\sigma$-normal morphism is again monotone $\\sigma$-complete and give an application of this result in spectral theory.

Seasonal variation of Sigma sub(Theta) with wind speed, direction and stability

Digital Repository Service at National Institute of Oceanography (India)

Sadhuram, Y.

For an airport site near Visakhapatnam, India, and based on 10 years of data for the months of January, April, August and October, values of Sigma sub(Theta) are given as a function of wind speed, wind direction and Pasquill diffusion category...

Spectra of coset sigma models

Energy Technology Data Exchange (ETDEWEB)

Candu, Constantin [Institut fuer Theoretische Physik, Zuerich (Switzerland); Mitev, Vladimir [Humboldt-Universitaet, Berlin (Germany). Inst. fuer Mathematik; Humboldt-Universitaet, Berlin (Germany). Inst. fuer Physik; Schomerus, Volker [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group

2013-08-15

We compute the complete 1-loop spectrum of anomalous dimensions for the bulk fields of non-linear sigma models on symmetric coset (super)spaces G/H, both with and without world-sheet supersymmetry. In addition, we provide two new methods for the construction of partition functions in the infinite radius limit and demonstrate their efficiency in the case of (super)sphere sigma models. Our results apply to a large number of target spaces including superspheres and superprojective spaces such as the N=2 sigma model on CP{sup 3} {sup vertical} {sup stroke} {sup 4}.

Spectra of coset sigma models

International Nuclear Information System (INIS)

Candu, Constantin; Mitev, Vladimir; Humboldt-Universitaet, Berlin; Schomerus, Volker

2013-08-01

We compute the complete 1-loop spectrum of anomalous dimensions for the bulk fields of non-linear sigma models on symmetric coset (super)spaces G/H, both with and without world-sheet supersymmetry. In addition, we provide two new methods for the construction of partition functions in the infinite radius limit and demonstrate their efficiency in the case of (super)sphere sigma models. Our results apply to a large number of target spaces including superspheres and superprojective spaces such as the N=2 sigma model on CP 3 vertical stroke 4 .

Lean Six Sigma in financial services

OpenAIRE

de Koning, H.; Does, R.J.M.M.; Bisgaard, S.

2008-01-01

Lean Thinking and Six Sigma are typically considered as separate approaches to process innovation, with complementary strengths. When combined as Lean Six Sigma, this approach provides a unified framework for systematically developing innovations. Lean Six Sigma can also bring about significant results and breakthrough improvements in financial services, as demonstrated with four case studies from Dutch multinational insurance companies. These cases demonstrate the importance of incremental i...

Mucosal vaccination by adenoviruses displaying reovirus sigma 1

Energy Technology Data Exchange (ETDEWEB)

Weaver, Eric A. [Department of Internal Medicine, Division of Infectious Diseases, Translational Immunovirology and Biodefense Program, Mayo Clinic, Rochester, MN 55902 (United States); Camacho, Zenaido T. [Department of Cell Biology, Department of Natural Sciences, Western New Mexico University, Silver City, NM 88062 (United States); Hillestad, Matthew L. [Nephrology Training Program, Mayo Clinic, Rochester, MN 55902 (United States); Crosby, Catherine M.; Turner, Mallory A.; Guenzel, Adam J.; Fadel, Hind J. [Virology and Gene Therapy Graduate Program, Mayo Clinic, Rochester, MN 55902 (United States); Mercier, George T. [Department of Physics, University of Houston, Houston, TX 77004 (United States); Barry, Michael A., E-mail: mab@mayo.edu [Department of Internal Medicine, Division of Infectious Diseases, Translational Immunovirology and Biodefense Program, Mayo Clinic, Rochester, MN 55902 (United States); Department of Immunology and Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902 (United States)

2015-08-15

We developed adenovirus serotype 5 (Ad5) vectors displaying the sigma 1 protein from reovirus as mucosal vaccines. Ad5-sigma retargets to JAM-1 and sialic acid, but has 40-fold reduced gene delivery when compared to Ad5. While weaker at transduction, Ad5-sigma generates stronger T cell responses than Ad5 when used for mucosal immunization. In this work, new Ad5-fiber-sigma vectors were generated by varying the number of fiber β-spiral shaft repeats (R) between the fiber tail and sigma. Increasing chimera length led to decreasing insertion of these proteinsAd5 virions. Ad-R3 and R14 vectors effectively targeted JAM-1 in vitro while R20 did not. When wereused to immunize mice by the intranasal route, Ad5-R3-sigma produced higher serum and vaginal antibody responses than Ad5. These data suggest optimized Ad-sigma vectors may be useful vectors for mucosal vaccination. - Highlights: • Constructed adenoviruses (Ads) displaying different reovirus sigma 1 fusion proteins. • Progressively longer chimeras were more poorly encapsidated onto Ad virions. • Ad5-R3-sigma mediated better systemic and mucosal immune responses than Ad5.

Mucosal vaccination by adenoviruses displaying reovirus sigma 1

International Nuclear Information System (INIS)

Weaver, Eric A.; Camacho, Zenaido T.; Hillestad, Matthew L.; Crosby, Catherine M.; Turner, Mallory A.; Guenzel, Adam J.; Fadel, Hind J.; Mercier, George T.; Barry, Michael A.

2015-01-01

We developed adenovirus serotype 5 (Ad5) vectors displaying the sigma 1 protein from reovirus as mucosal vaccines. Ad5-sigma retargets to JAM-1 and sialic acid, but has 40-fold reduced gene delivery when compared to Ad5. While weaker at transduction, Ad5-sigma generates stronger T cell responses than Ad5 when used for mucosal immunization. In this work, new Ad5-fiber-sigma vectors were generated by varying the number of fiber β-spiral shaft repeats (R) between the fiber tail and sigma. Increasing chimera length led to decreasing insertion of these proteinsAd5 virions. Ad-R3 and R14 vectors effectively targeted JAM-1 in vitro while R20 did not. When wereused to immunize mice by the intranasal route, Ad5-R3-sigma produced higher serum and vaginal antibody responses than Ad5. These data suggest optimized Ad-sigma vectors may be useful vectors for mucosal vaccination. - Highlights: • Constructed adenoviruses (Ads) displaying different reovirus sigma 1 fusion proteins. • Progressively longer chimeras were more poorly encapsidated onto Ad virions. • Ad5-R3-sigma mediated better systemic and mucosal immune responses than Ad5

Sigma1 and dopamine D2 receptor occupancy in the mouse brain after a single administration of haloperidol and two dopamine D2-like receptor ligands

International Nuclear Information System (INIS)

Ishiwata, Kiichi; Kawamura, Kazunori; Kobayashi, Tadayuki; Matsuno, Kiyoshi

2003-01-01

We investigated sigma 1 and dopamine D 2 receptor occupancy in mouse brain after a single injection of haloperidol, nemonapride, or spiperone using [ 11 C]SA4503 and [ 11 C]raclopride, respectively. Co-injection of the three compounds significantly blocked the uptake of each radioligand. Six hours later, only haloperidol blocked [ 11 C]SA4503 uptake, while all three reduced [ 11 C]raclopride uptake. Sigma 1 receptor occupancy by haloperidol was reduced to 19% at day 2 when D 2 receptor occupancy disappeared. [ 11 C]SA4503 would be applicable to the investigation of sigma 1 receptor occupancy of antispychotic drugs using PET

THE LEAN AND SIX SIGMA SINERGY

Directory of Open Access Journals (Sweden)

Mirko Sokovic

2008-12-01

Full Text Available Many organizations, dealing with continuous improvement methods, have realized that Lean and Six Sigma methodologies complement each other. Lean manufacturing focuses on the remova l of waste so that all processes in the total system add value from the customers' perspectives. The main emphasis of Six Sigma is the application of statistical tools in a disciplined manner, which requires data-driven decision-making. The integration of Lean and Six Sigma provides a synergetic effect, a rapid process improvement strategy for attaining organizational goals. When separated, Lean manufacturing cannot bring a process under statistical control, and Six Sigma cannot dramatically improve cycle time or reduce invested capital. Together, synergistic qualities are created to maximize the potential for a process improvement. The paper deals with Lean and Six Sigma principles and approaches used in modern manufacturing for process improvements, and bring forward benefits that are gained when these two methodologies are integrated.

Lean Six Sigma implementation and organizational culture.

Science.gov (United States)

Knapp, Susan

2015-01-01

The purpose of this paper is to examine the relationship between four organizational cultural types defined by the Competing Values Framework and three Lean Six Sigma implementation components - management involvement, use of Lean Six Sigma methods and Lean Six Sigma infrastructure. The study involved surveying 446 human resource and quality managers from 223 hospitals located in Maine, New Hampshire, Vermont, Massachusetts and Rhode Island using the Organizational Culture Assessment Instrument. Findings - In total, 104 completed responses were received and analyzed using multivariate analysis of variance. Follow-up analysis of variances showed management support was significant, F(3, 100)=4.89, p cultures having significant interactions with management support. The relationship between organizational culture and Lean Six Sigma in hospitals provides information on how specific cultural characteristics impact the Lean Six Sigma initiative key components. This information assists hospital staff who are considering implementing quality initiatives by providing an understanding of what cultural values correspond to effective Lean Six Sigma implementation. Managers understanding the quality initiative cultural underpinnings, are attentive to the culture-shared values and norm's influence can utilize strategies to better implement Lean Six Sigma.

New Synthesis and Tritium Labeling of a Selective Ligand for Studying High-Affinity γ-Hydroxybutyrate (GHB) Binding Sites

DEFF Research Database (Denmark)

Vogensen, Stine B.; Marek, Ales; Bay, Tina

2013-01-01

3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [3H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screen...

Identification of sigma and chi phases in duplex stainless steels

Energy Technology Data Exchange (ETDEWEB)

Llorca-Isern, Núria, E-mail: nullorca@ub.edu [Departament de Ciència dels Materials i Enginyeria Metallurgica, Facultat de Química, Universitat de Barcelona, Marti-Franqués 1, 08028 Barcelona (Spain); López-Luque, Héctor, E-mail: hlopezlu7@alumnes.ub.edu [Departament de Ciència dels Materials i Enginyeria Metallurgica, Facultat de Química, Universitat de Barcelona, Marti-Franqués 1, 08028 Barcelona (Spain); López-Jiménez, Isabel, E-mail: ilopezji9@alumnes.ub.edu [Departament de Ciència dels Materials i Enginyeria Metallurgica, Facultat de Química, Universitat de Barcelona, Marti-Franqués 1, 08028 Barcelona (Spain); Biezma, Maria Victoria, E-mail: maria.biezma@unican.es [Department of Earth, Materials Science and Engineering, University of Cantabria - UC, Gamazo, 1, 39004 Santander (Spain)

2016-02-15

The aim of this work is to find out the most suitable method for detecting and analyzing accurately the formation conditions of secondary phases, particularly Sigma-phase (σ-phase) and Chi-phase (χ-phase) in duplex stainless steels (UNS S32205 and UNS S32750). The microstructure was characterized after a solution annealing at 1080 °C followed by an isothermal heating at 830 °C for different time ranges, ranging from 1 min to 9 h, in order to enlighten the controversial point concerning the mechanism of χ-phase nucleation in relation with the σ-phase. Etched samples were observed using optical microscopy (MO), and scanning electron microscopy (FESEM) with a backscattered electron detector (BSE) was used on unetched samples. Compositional microanalysis (EDS) was carried out for identifying the different phases present in the steels. Sigma phase was easily observed using different etching procedures, whereas χ-phase was only clearly detected with FESEM–BSE on unetched samples. The compositional analyses showed that the molybdenum content in χ-phase almost doubles the content of this element in σ-phase, and as a result the kinetics of nucleation and growth were also found to be remarkably faster when the alloy content in the steel is higher. In addition, chromium nitrides and carbides were also observed to precipitate as a result of the heat treatments and, in the case of the chromium nitrides, they act as a favorable site for the nucleation of σ-phase and χ-phase. - Highlights: • Microscopy was used on heat treated duplex steels for microstructure identification. • FESEM–BSE observation on unetched samples provided the best contrast between phases. • Analyses of carbides, nitrides, chi and sigma phases were possible by EDS and WDS. • Chromium nitrides act as favorable site for the nucleation of chi and sigma phases. • Secondary phases nucleation kinetics are faster in superduplex than in duplex steels.

Site Identification by Ligand Competitive Saturation (SILCS) simulations for fragment-based drug design.

Science.gov (United States)

Faller, Christina E; Raman, E Prabhu; MacKerell, Alexander D; Guvench, Olgun

2015-01-01

Fragment-based drug design (FBDD) involves screening low molecular weight molecules ("fragments") that correspond to functional groups found in larger drug-like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind nonoverlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy.The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is "soaked" in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called "FragMaps" can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine "Grid Free Energies (GFEs)," which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank-order the molecules in accordance with binding affinities.

Investigation of the Copper Binding Site And the Role of Histidine As a Ligand in Riboflavin Binding Protein

Energy Technology Data Exchange (ETDEWEB)

Smith, S.R.; Bencze, K.Z.; Russ, K.A.; Wasiukanis, K.; Benore-Parsons, M.; Stemmler, T.L.

2009-05-26

Riboflavin Binding Protein (RBP) binds copper in a 1:1 molar ratio, forming a distinct well-ordered type II site. The nature of this site has been examined using X-ray absorption and pulsed electron paramagnetic resonance (EPR) spectroscopies, revealing a four coordinate oxygen/nitrogen rich environment. On the basis of analysis of the Cambridge Structural Database, the average protein bound copper-ligand bond length of 1.96 {angstrom}, obtained by extended x-ray absorption fine structure (EXAFS), is consistent with four coordinate Cu(I) and Cu(II) models that utilize mixed oxygen and nitrogen ligand distributions. These data suggest a Cu-O{sub 3}N coordination state for copper bound to RBP. While pulsed EPR studies including hyperfine sublevel correlation spectroscopy and electron nuclear double resonance show clear spectroscopic evidence for a histidine bound to the copper, inclusion of a histidine in the EXAFS simulation did not lead to any significant improvement in the fit.

Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules [version 2; referees: 2 approved

Directory of Open Access Journals (Sweden)

Ignacio Boron

2015-07-01

Full Text Available Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O2 and •ŸNO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels interrupted by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify Ÿ•NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, Ÿ•NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations affect both the tunnels accessibility as well as the affinity of distal site water molecules, thus modifying the ligand access to the iron. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site.

In-vivo characteristics of high and low specific activity radioiodinated (+)-2-[4-(4-iodophenyl) piperidino] cyclohexanol [(+)-pIV] for imaging sigma-1 receptor in brain

International Nuclear Information System (INIS)

Akhter, Nasima; Kinuya, Seigo; Nakajima, Kenichi; Shiba, Kazuhiro; Ogawa, Kazuma; Mori, Hirofumi

2007-01-01

Full text: In this study, (+)-enantiomer of radioiodinated 2-[4-(4- iodophenyl)piperidino]cyclohexanol ((+)-[ 125 I]-p- iodovesamicol) [(+)-[ 125 I]pIV], which is reported to bind with high affinity to the sigma-1 receptor both in vitro and in vivo, was tested to compare the in vivo characteristics between high and low specific activity (+)-[ 125 I]pIV to image sigma-1 receptor in the central nervous system. In the biodistribution study, no significant difference was observed between two methods. Accumulation of (+)- [ 125 I]pIV in rat brain was significant (approximately 3% of the injected dose) and its retention was prolonged. In the blocking study, the accumulation of (+)-[ 125 I] pIV in the rat brain was significantly reduced by the co-administration of sigma ligands such as pentazocine, haloperidol or SA4503 in both methods. But the blocking effect was relatively stronger in the study using high specific activity radioiodinated (+)pIV. Though, the distribution of high and low specific activity (+)-[ 125 I] pIV was more or less similar to bind to sigma-1 receptor in the central nervous system in vivo, high specific activity radioiodinated (+) pIV might have a better specificity to bind sigma-1 receptor in brain. (author)

Six sigma quality for fuel manufacturing

International Nuclear Information System (INIS)

Gabbani, M.D.; Onderwater, T.

1997-01-01

It is widely recognized that operational performance in product manufacturing is largely determined by understanding and maintaining process capability. By definition, Six Sigma is a statistical unit of measure reflecting process capability that yields less' than 6.8 defects per million product produced. Statistically, this translates into obtaining a long term manufacturing process capability of ± 4.5 standard deviations about the mean within specification limits. The heart of the Six Sigma program developed by the Six Sigma Academy is what we refer to as the Breakthrough Strategy. This rigorous analytical methodology is the driving force in obtaining world class performance of Six Sigma. The methodology applies statistical and practical tools in resolving a problem or improving a product or process. The application of Six Sigma focuses on attacking process input variables (independent) rather than the output variables. Focusing on these independent variables (temperature, power, force, etc.) and the variation in the end product they create, enables us to get to the root of the problem rather than react to the symptoms of the problem. In this manner we prevent defects from occurring rather than inspecting and monitoring the product. Why the need for such an ambitious program? It is estimated that the cost of failure (rework, scrap, warranties, etc.) can be as high as 15% of sales for companies typically operating at 3-4 sigma. In achieving Six Sigma, costs of failure are typically less than 5%. The thought of reducing business costs while achieving the recognition of being our customer's premier choice provides enormous incentive to reach such status. (author)

(125I)Iodoazidococaine, a photoaffinity label for the haloperidol-sensitive sigma receptor

International Nuclear Information System (INIS)

Kahoun, J.R.; Ruoho, A.E.

1992-01-01

A carrier-free radioiodinated cocaine photoaffinity label, (-)-3-( 125 I)iodo-4-azidococaine [( 125 I)IACoc], has been synthesized and used as a probe for cocaine-binding proteins. Photoaffinity labeling with 0.5 nM ( 125 I)IACoc resulted in selective derivatization of a 26-kDa polypeptide with the pharmacology of a sigma receptor in membranes derived from whole rat brain, rat liver, and human placenta. ( 125 I)IACoc labeling of the 26-kDa polypeptide was also inhibited by 10 μM imipramine, amitriptyline, fluoxetine, benztropine, and tetrabenazine. The size of the ( 125 I)I-ACoc-labeled proteins is consistent with the size of proteins photolabeled in guinea pig brain and liver membranes by using the sigma photolabel azido-[ 3 H]DTG. Kinetic analysis of ( 125 I)IACoc binding to rat liver microsomes revealed two sites with K d values of 19 and 126 pM, respectively. The presence or absence of proteolytic inhibitors during membrane preparation did not alter the size of the photolabeled sigma receptor, indicating that the 26-kDa polypeptide was not derived from a larger protein. In summary, ( 125 I)IACoc is a potent and highly specific photoaffinity label for the haloperidol-sensitive sigma receptor and will be useful for its biochemical and molecular characterization

Active sites of ligand-protected Au25 nanoparticle catalysts for CO2 electroreduction to CO

Science.gov (United States)

Alfonso, Dominic R.; Kauffman, Douglas; Matranga, Christopher

2016-05-01

Recent experimental studies have reported the electrochemical reduction of carbon dioxide (CO2) into CO at atomically precise negatively charged Au25- nanoclusters. The studies showed CO2 conversion at remarkably low overpotentials, but the exact mechanisms and nature of the active sites remain unclear. We used first-principles density functional theory and continuum solvation models to examine the role of the cluster during electrochemical CO2 reduction and analyze the free energies of proposed intermediate species. Contrary to previous assumptions, our results show that the fully ligand protected cluster is not an active CO2 reduction catalyst because formation of the crucial carboxyl intermediate required very high electrochemical potentials. Instead, our calculations suggest that the reduction process likely occurs on a dethiolated gold site, and adsorbed carboxyl intermediate formation was significantly stabilized at dethiolated gold sites. These findings point to the crucial role of exposed metal sites during electrochemical CO2 reduction at gold nanocluster catalysts.

pMD-Membrane: A Method for Ligand Binding Site Identification in Membrane-Bound Proteins.

Directory of Open Access Journals (Sweden)

Priyanka Prakash

2015-10-01

Full Text Available Probe-based or mixed solvent molecular dynamics simulation is a useful approach for the identification and characterization of druggable sites in drug targets. However, thus far the method has been applied only to soluble proteins. A major reason for this is the potential effect of the probe molecules on membrane structure. We have developed a technique to overcome this limitation that entails modification of force field parameters to reduce a few pairwise non-bonded interactions between selected atoms of the probe molecules and bilayer lipids. We used the resulting technique, termed pMD-membrane, to identify allosteric ligand binding sites on the G12D and G13D oncogenic mutants of the K-Ras protein bound to a negatively charged lipid bilayer. In addition, we show that differences in probe occupancy can be used to quantify changes in the accessibility of druggable sites due to conformational changes induced by membrane binding or mutation.

Six sigma for revenue retrieval.

Science.gov (United States)

Plonien, Cynthia

2013-01-01

Deficiencies in revenue retrieval due to failures in obtaining charges have contributed to a negative bottom line for numerous hospitals. Improving documentation practices through a Six Sigma process improvement initiative can minimize opportunities for errors through reviews and instill structure for compliance and consistency. Commitment to the Six Sigma principles with continuous monitoring of outcomes and constant communication of results to departments, management, and payers is a strong approach to reducing the financial impact of denials on an organization's revenues and expenses. Using Six Sigma tools can help improve the organization's financial performance not only for today, but also for health care's uncertain future.

6 Sigma project advance

International Nuclear Information System (INIS)

2002-12-01

This book deals with 6 sigma project advance which introduces 6 sigma project in Changwon special steel, how is failure accepted? CTQ selection which is starting line, definition of performance standard, measurement system check on reliability of measurement data, check of process capacity for current level, establishment of target, optimal design and performance of application, practice of management system for maintain of improved result, CTQ selection, check of measurement system and practice of management system.

Variation in one residue associated with the metal ion-dependent adhesion site regulates αIIbβ3 integrin ligand binding affinity.

Directory of Open Access Journals (Sweden)

Joel Raborn

Full Text Available The Asp of the RGD motif of the ligand coordinates with the β I domain metal ion dependent adhesion site (MIDAS divalent cation, emphasizing the importance of the MIDAS in ligand binding. There appears to be two distinct groups of integrins that differ in their ligand binding affinity and adhesion ability. These differences may be due to a specific residue associated with the MIDAS, particularly the β3 residue Ala(252 and corresponding Ala in the β1 integrin compared to the analogous Asp residue in the β2 and β7 integrins. Interestingly, mutations in the adjacent to MIDAS (ADMIDAS of integrins α4β7 and αLβ2 increased the binding and adhesion abilities compared to the wild-type, while the same mutations in the α2β1, α5β1, αVβ3, and αIIbβ3 integrins demonstrated decreased ligand binding and adhesion. We introduced a mutation in the αIIbβ3 to convert this MIDAS associated Ala(252 to Asp. By combination of this mutant with mutations of one or two ADMIDAS residues, we studied the effects of this residue on ligand binding and adhesion. Then, we performed molecular dynamics simulations on the wild-type and mutant αIIbβ3 integrin β I domains, and investigated the dynamics of metal ion binding sites in different integrin-RGD complexes. We found that the tendency of calculated binding free energies was in excellent agreement with the experimental results, suggesting that the variation in this MIDAS associated residue accounts for the differences in ligand binding and adhesion among different integrins, and it accounts for the conflicting results of ADMIDAS mutations within different integrins. This study sheds more light on the role of the MIDAS associated residue pertaining to ligand binding and adhesion and suggests that this residue may play a pivotal role in integrin-mediated cell rolling and firm adhesion.

Lean sigma--will it work for healthcare?

Science.gov (United States)

Bahensky, James A; Roe, Janet; Bolton, Romy

2005-01-01

The manufacturing industry has been using Lean Sigma for years in pursuit of continuous improvement to obtain a competitive advantage. The objectives of these efforts are to use the Lean techniques for reducing cycle times and the Six Sigma concepts for reducing product defects. The Iowa Business Council with several advocates worked with the University of Iowa Hospital and Clinics (UIHC) and two other Iowa hospitals to determine whether Lean Sigma is adaptable in healthcare. A team of 15 people at UIHC used the Kaizen Breakthrough Methodology over a five-day period in an aggressive identification and elimination of non-value added activities in Radiology CT scanning. The results exceeded the initial project objectives and indicated that Lean Sigma is applicable in healthcare. Overall, the Lean Sigma project increased revenue by approximately $750,000 per year. The Kaizen process proved to be successful and interesting. Within three days, the team installed new work flow processes. This implementation-oriented approach is what differentiates Lean Sigma from other quality improvement processes.

A change of in vivo characteristics depending on specific activity of radioiodinated (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-pIV] as a ligand for sigma receptor imaging

International Nuclear Information System (INIS)

Akhter, Nasima; Shiba, Kazuhiro; Ogawa, Kazuma; Tsuji, Shiro; Kinuya, Seigo; Nakajima, Kenichi; Mori, Hirofumi

2008-01-01

The radioiodinated (+)-p-iodovesamicol [(+)-pIV], which shows a high binding affinity for sigma-1 (σ-1) receptors, is prepared by an exchange reaction. The specific activity (SA) is fairly low and therefore is insufficient for clinical use. In this study, we prepared (+)-[ 125 I]pIV with a high SA from tributylstannyl precursor and compared the in vivo characteristics between high and low SA by imaging σ-1 receptors in the central nervous system. In the biodistribution study, a difference in brain accumulation was observed between the two methods. At 30 min postinjection, the brain accumulation (1.58%ID/g) of low SA [0.6-1.1 TBq/mmol (16-30 Ci/mmol)] (+)-[ 125 I]pIV was higher than that (1.34%ID/g) of high SA [>88.8 TBq/mmol (>2400 Ci/mmol)] (+)-[ 125 I]pIV. In the blocking study, the brain uptake of high SA (+)-[ 125 I]pIV was reduced more significantly by the coadministration of sigma ligands such as pentazocine, haloperidol or SA4503 than that of low SA (+)-[ 125 I]pIV. These results showed that nonspecific binding of high SA (+)-[ 125 I]pIV in the brain was lower than that of low SA (+)-[ 125 I]pIV, and high SA (+)-[ 125 I]pIV bound more specifically to σ-1 receptors in the brain than low SA (+)-[ 125 I]pIV. In contrast, in the blood-binding study, high SA (+)-[ 125 I]pIV (58.4%) bound to blood cells with higher affinity than low SA (+)-[ 125 I]pIV (46.0%). In metabolite studies, blood metabolites of high SA (+)-[ 125 I]pIV (57.3±3.5%) were higher than those of low SA (+)-[ 125 I]pIV (45.5±4.1%) at 30 min postinjection. Higher SA may be apt to bind to blood cells with higher affinity and to be metabolized faster

SigmaCalc recent development and present status of the evaluated cross-sections for IBA

Energy Technology Data Exchange (ETDEWEB)

Gurbich, A.F.

2016-03-15

A new version of the SigmaCalc Internet site ( (http://sigmacalc.iate.obninsk.ru)) intended to provide evaluated differential cross-sections for spectra simulation is presented. Results of the revision of previously evaluated cross-sections and new evaluations including data for PIGE were made available to the IBA community through a simple interface. New SigmaCalc features allow users to compare evaluated differential cross-sections with the available results of the cross-section measurements taken on-the-fly from the IBANDL database and to validate them against benchmarks. The current status of the evaluated cross-sections for IBA is discussed.

Ligand intermediates in metal-catalyzed reactions; Annual technical report, August 1, 1992--August 1, 1993

Energy Technology Data Exchange (ETDEWEB)

Gladysz, J.A.

1993-08-10

Achievements are reported for the following 4 areas: {pi}/{sigma} equillibria in aldehyde and ketone complexes; thermodynamic ligand binding affinities ({alpha},{beta} unsaturated organic carbonyl compounds); (a new form of coordinated carbon) an unsupported C{sub 3} chain that spans two different transition metals; and (a new form of coordinated carbon) an C{sub 3} chain that is anchored by a metal on each end and spanned by a third.

The sigma-1 receptor: roles in neuronal plasticity and disease

Science.gov (United States)

Kourrich, Saïd; Su, Tsung-Ping; Fujimoto, Michiko; Bonci, Antonello

2012-01-01

Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. The Sig-1R is an intracellular chaperone that resides specifically at the endoplasmic reticulum (ER)-mitochondrion interface referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER-mitochondrion Ca2+ signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanism linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating some aspects of neurological and psychiatric diseases. PMID:23102998

The sigma-1 receptor: roles in neuronal plasticity and disease.

Science.gov (United States)

Kourrich, Saïd; Su, Tsung-Ping; Fujimoto, Michiko; Bonci, Antonello

2012-12-01

Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. Sig-1Rs are intracellular chaperones that reside specifically at the endoplasmic reticulum (ER)-mitochondrion interface, referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER-mitochondrion Ca(2+) signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanisms linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating aspects of neurological and psychiatric diseases. Published by Elsevier Ltd.

New Synthesis and Tritium Labeling of a Selective Ligand for Studying High-affinity γ-Hydroxybutyrate (GHB) Binding Sites

Science.gov (United States)

Vogensen, Stine B.; Marek, Aleš; Bay, Tina; Wellendorph, Petrine; Kehler, Jan; Bundgaard, Christoffer; Frølund, Bente; Pedersen, Martin H.F.; Clausen, Rasmus P.

2013-01-01

3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [3H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screening of 1 against different CNS targets establishes a high selectivity and we demonstrate in vivo brain penetration. In vitro characterization of [3H]-1 binding shows high specificity to the high-affinity GHB binding sites. PMID:24053696

Heterotic sigma models and non-linear strings

International Nuclear Information System (INIS)

Hull, C.M.

1986-01-01

The two-dimensional supersymmetric non-linear sigma models are examined with respect to the heterotic string. The paper was presented at the workshop on :Supersymmetry and its applications', Cambridge, United Kingdom, 1985. The non-linear sigma model with Wess-Zumino-type term, the coupling of the fermionic superfields to the sigma model, super-conformal invariance, and the supersymmetric string, are all discussed. (U.K.)

The C-Terminal RpoN Domain of sigma54 Forms an unpredictedHelix-Turn-Helix Motif Similar to domains of sigma70

Energy Technology Data Exchange (ETDEWEB)

Doucleff, Michaeleen; Malak, Lawrence T.; Pelton, Jeffrey G.; Wemmer, David E.

2005-11-01

The ''{delta}'' subunit of prokaryotic RNA-polymerase allows gene-specific transcription initiation. Two {sigma} families have been identified, {sigma}{sup 70} and {sigma}{sup 54}, which use distinct mechanisms to initiate transcription and share no detectable sequence homology. Although the {sigma}{sup 70}-type factors have been well characterized structurally by x-ray crystallography, no high-resolution structural information is available for the {sigma}{sup 54}-type factors. Here we present the NMR derived structure of the C-terminal domain of {sigma}{sup 54} from Aquifex aeolicus. This domain (Thr323 to Gly389), which contains the highly conserved RpoN box sequence, consists of a poorly structured N-terminal tail followed by a three-helix bundle, which is surprisingly similar to domains of the {sigma}{sup 70}-type proteins. Residues of the RpoN box, which have previously been shown to be critical for DNA binding, form the second helix of an unpredicted helix-turn-helix motif. This structure's homology with other DNA binding proteins, combined with previous biochemical data, suggest how the C-terminal domain of {sigma}{sup 54} binds to DNA.

Application of Six Sigma towards improving surgical outcomes.

Science.gov (United States)

Shukla, P J; Barreto, S G; Nadkarni, M S

2008-01-01

Six Sigma is a 'process excellence' tool targeting continuous improvement achieved by providing a methodology for improving key steps of a process. It is ripe for application into health care since almost all health care processes require a near-zero tolerance for mistakes. The aim of this study is to apply the Six Sigma methodology into a clinical surgical process and to assess the improvement (if any) in the outcomes and patient care. The guiding principles of Six Sigma, namely DMAIC (Define, Measure, Analyze, Improve, Control), were used to analyze the impact of double stapling technique (DST) towards improving sphincter preservation rates for rectal cancer. The analysis using the Six Sigma methodology revealed a Sigma score of 2.10 in relation to successful sphincter preservation. This score demonstrates an improvement over the previous technique (73% over previous 54%). This study represents one of the first clinical applications of Six Sigma in the surgical field. By understanding, accepting, and applying the principles of Six Sigma, we have an opportunity to transfer a very successful management philosophy to facilitate the identification of key steps that can improve outcomes and ultimately patient safety and the quality of surgical care provided.

SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [3H]dextromethorphan and σligands to guinea pig brain

International Nuclear Information System (INIS)

Klein, M.; Canoll, P.D.; Musacchio, J.M.

1991-01-01

The DM 1 /σ 1 site binds dextromethorphan (DM) and σ receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [ 3 H]dextromethorphan, [ 3 H]3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine and (+)-[ 3 H]1,3-Di-o-tolyl-guanidine ([ 3 H]DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM K i values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM 1 σ 1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed K i values of 9-13 and 3-4 μM respectively against the three labeled ligands. These results, the broad specificity of the DM 1 /σ 1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor

Evidence for the decay sigma+ --> pmu+ mu-.

Science.gov (United States)

Park, H K; Burnstein, R A; Chakravorty, A; Chen, Y C; Choong, W S; Clark, K; Dukes, E C; Durandet, C; Felix, J; Fu, Y; Gidal, G; Gustafson, H R; Holmstrom, T; Huang, M; James, C; Jenkins, C M; Jones, T; Kaplan, D M; Lederman, L M; Leros, N; Longo, M J; Lopez, F; Lu, L C; Luebke, W; Luk, K B; Nelson, K S; Perroud, J-P; Rajaram, D; Rubin, H A; Volk, J; White, C G; White, S L; Zyla, P

2005-01-21

We report the first evidence for the decay Sigma(+)-->pmu(+)mu(-) from data taken by the HyperCP (E871) experiment at Fermilab. Based on three observed events, the branching ratio is B(Sigma(+)-->pmu(+)mu(-))=[8.6(+6.6)(-5.4)(stat)+/-5.5(syst)]x10(-8). The narrow range of dimuon masses may indicate that the decay proceeds via a neutral intermediate state, Sigma(+)-->pP(0),P0-->mu(+)mu(-) with a P0 mass of 214.3+/-0.5 MeV/c(2) and branching ratio B(Sigma(+)-->pP(0),P0-->mu(+)mu(-))=[3.1(+2.4)(-1.9)(stat)+/-1.5(syst)]x10(-8).

Synthesis and receptor binding studies of novel 4,4-disubstituted arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as a new class of σ1 ligands.

Science.gov (United States)

Sadeghzadeh, Masoud; Sheibani, Shahab; Ghandi, Mehdi; Daha, Fariba Johari; Amanlou, Massoud; Arjmand, Mohammad; Hasani Bozcheloie, Abolfazl

2013-06-01

This study presents the synthesis and biological evaluation of a new series of arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as sigma receptor ligands. It was found that a number of halogen substituted sulfonamides display relatively high and low affinities to σ1 and σ2 receptors, respectively. The σ1 affinities and subtype selectivities of four piperidine derivatives were also found to be generally comparable to those of piperazine analogues. Compared to σ1-Rs compounds with n = 0 and 2, those with n = 1 proved to have optimal length of carbon chain by exhibiting higher affinities. Within this series, the 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine sigma ligand was identified with 96-fold σ1/σ2 selectivity ratio (Kiσ1 = 0.96 ± 0.05 nM and Kiσ2 = 91.8 ± 8.1 nM). Copyright © 2013 Elsevier Masson SAS. All rights reserved.

De praktijk van Lean Six Sigma

NARCIS (Netherlands)

Does, R.J.M.M.; de Koning, H.

2008-01-01

Zowel Lean als Six Sigma zijn benaderingen van kwaliteits- en efficiëntieverbetering die op dit moment sterk in de belangstelling staan van zowel de industrie als de dienstverlening. Lean Six Sigma integreert beide benaderingen. Ze wordt door sommigen gezien als panacee voor alle mogelijke

Lean Six Sigma in a hospital

NARCIS (Netherlands)

van den Heuvel, J.; Does, R.J.M.M.; de Koning, H.

2006-01-01

Abstract Hospitals today face major challenges. Patients demand quality of care to be improved continuously. Health insurance companies demand the lowest possible prices. Lean Six Sigma is a program that can help healthcare providers to achieve these (seemingly) conflicting goals. Lean Six Sigma is

Recording, monitoring and managing the conservation of historic sites: a new application for BGS·SIGMA

Science.gov (United States)

Tracey, Emily; Smith, Nichola; Lawrie, Ken

2017-04-01

The principles behind, and the methods of, digital data capture can be applied across many scientific, and other, disciplines, as can be demonstrated by the use of a custom modified version of the British Geological Survey's System for Integrated Geoscience Mapping, (BGS·SIGMA), for the capture of data for use in the conservation of Scottish built heritage. Historic Environment Scotland (HES), an executive agency of the Scottish Government charged with safeguarding the nation's historic environment, is directly responsible for 345 sites of national significance, most of which are built from stone. In common with many other heritage organisations, HES needs a system that can capture, store and present conservation, maintenance and condition indicator information for single or multiple historic sites; this system would then be used to better target and plan effective programmes of maintenance and repair. To meet this need, the British Geological Survey (BGS) has worked with HES to develop an integrated digital site assessment system that provides a refined survey process for stone-built (and other) historic sites. Based on BGS·SIGMA—an integrated workflow underpinned by a geo-spatial platform for data capture and interpretation—the new system is built on top of ESRI's ArcGIS software, and underpinned by a relational database. Users can, in the field or in the office, populate custom-built data entry forms to record maintenance issues and repair specifications for architectural elements ranging from individual blocks of stone to entire building elevations. Photographs, sketches, and digital documents can be linked to architectural elements to enhance the usability of the data. Predetermined data fields and supporting dictionaries constrain the input parameters, ensuring a high degree of standardisation in the datasets and, therefore, enabling highly consistent data extraction and querying. The GIS presentation of the data provides a powerful and versatile

SIGMA Experimental Facility; Facilidad Experimental SIGMA

Energy Technology Data Exchange (ETDEWEB)

Rivarola, Martin; Florido, Pablo; Gonzalez, Jose; Brasnarof, Daniel; Orellano, Pablo; Bergallo, Juan [Comision Nacional de Energia Atomica, Centro Atomico Bariloche, Grupo de Disenos Avanzados y Evaluacion Economica, Complejo Tecnologico Pilcaniyeu (Argentina)

2000-07-01

The SIGMA ( Separacion Isotopica Gaseosa por Metodos Avanzados) concept is outlined.The old gaseous diffusion process to enrich uranium has been updated to be economically competitive for small production volumes.Major innovations have been introduced in the membrane design and in the integrated design of compressors and diffusers.The use of injectors and gas turbines has been also adopted.The paper describes the demonstration facility installed by the Argentine Atomic Energy Commission.

Six Sigma: blauwdruk voor de kenniseconomie.

NARCIS (Netherlands)

Does, R.J.M.M.; de Mast, J.

2005-01-01

Abstract Six Sigma is zo langzamerhand een niet weg te denken programma voor kwaliteits- en efficiencyverbeteringen. Het heeft met name voor enorme successen gezorgd in productiebedrijven. Six Sigma ligt ook onder vuur: het zou een trend zijn die voorbij gaat. De auteurs van dit artikel zijn het van

Sigma meson in heavy ion collision

International Nuclear Information System (INIS)

Cristian, Ivan; Fuchs, Christian

2004-01-01

We want to present a short theoretical prediction of the behaviour of the sigma meson in heavy ion collisions. It is considered that the sigma meson is a pion-pion correlation, resulting from the decay of the N*(1440) resonance. There will be presented some QMD simulations. (authors)

The six sigma program: an empirical study of brazilian companies.

OpenAIRE

Carvalho, Marly Monteiro de; Ho, Linda Lee; Pinto, Silvia Helena Boarin

2014-01-01

Purpose – The purpose of this paper is to assess the status of Six Sigma's status in Brazilian companies and understand the integration of this program with other quality management approaches. Additionally, the critical success factors (CSFs) for Six Sigma implementation and primary Six Sigma program characteristics were identified. Finally, the results of the used of Six Sigma were analysed. Design/methodology/approach – An extensive literature review illustrates the primary Six Sigma c...

Calreticulin discriminates the proximal region at the N-glycosylation site of Glc1Man9GlcNAc2 ligand

Energy Technology Data Exchange (ETDEWEB)

Hirano, Makoto; Adachi, Yuka [Department of Materials and Life Science, Seikei University, 3-3-1 Kichijoji-kita, Musashino, Tokyo 180-8633 (Japan); Ito, Yukishige [Synthetic Cellular Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); ERATO, Japan Science and Technology Agency, Ito Glycotrilogy Project, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Totani, Kiichiro, E-mail: ktotani@st.seikei.ac.jp [Department of Materials and Life Science, Seikei University, 3-3-1 Kichijoji-kita, Musashino, Tokyo 180-8633 (Japan)

2015-10-23

Calreticulin (CRT) is well known as a lectin-like chaperone that recognizes Glc1Man9GlcNAc2 (G1M9)-glycoproteins in the endoplasmic reticulum (ER). However, whether CRT can directly interact with the aglycone moiety (protein portion) of the glycoprotein remains controversial. To improve our understanding of CRT interactions, structure-defined G1M9-derivatives with different aglycones (–OH, –Gly–NH{sub 2}, and –Gly–Glu–{sup t}Bu) were used as CRT ligands, and their interactions with recombinant CRT were analyzed using thermal shift analysis. The results showed that CRT binds strongly to a G1M9-ligand in the order –Gly–Glu–{sup t}Bu > –Gly–NH{sub 2} > –OH, which is the same as that of the reglucosylation of Man9GlcNAc2 (M9)-derivatives by the folding sensor enzyme UGGT (UDP-glucose: glycoprotein glucosyltransferase). Our results indicate that, similar to UGGT, CRT discriminates the proximal region at the N-glycosylation site, suggesting a similar mechanism mediating the recognition of aglycone moieties in the ER glycoprotein quality control system. - Highlights: • Glc1Man9GlcNAc2 (G1M9) ligands with different aglycones were chemically prepared. • Calreticulin (CRT) discriminates the aglycone of Glc1Man9GlcNAc2 (G1M9) ligand. • CRT binds with G1M9 ligands in a similar manner to folding sensor enzyme.

IDENTIFICATION AND SELECTION OF SIX SIGMA PROJECTS

Directory of Open Access Journals (Sweden)

Abdalhkeim FA. Flifel

2017-04-01

Full Text Available Six Sigma is a well-structured and proven methodology for improving organizational performance. It helps achieving the goals of the organization through the use of project-driven approach. The implementation of Six sigma approach depends on proper identification and selection of projects, moreover, the selection of right Six sigma projects is one of the critical success factors of six sigma efforts. The paper provides the sources for the identification of potential projects, top down and bottom up approaches, the process of selection of projects, guidelines that assist the selection of appropriate projects, selection criteria which must be precisely chosen in accordance with the objectives, needs and capabilities of the organization as well as sophisticated techniques and tools recommended in the literature for the selection of projects.

Mutations that silence constitutive signaling activity in the allosteric ligand-binding site of the thyrotropin receptor.

Science.gov (United States)

Haas, Ann-Karin; Kleinau, Gunnar; Hoyer, Inna; Neumann, Susanne; Furkert, Jens; Rutz, Claudia; Schülein, Ralf; Gershengorn, Marvin C; Krause, Gerd

2011-01-01

The thyrotropin receptor (TSHR) exhibits elevated cAMP signaling in the basal state and becomes fully activated by thyrotropin. Previously we presented evidence that small-molecule ligands act allosterically within the transmembrane region in contrast to the orthosteric extracellular hormone-binding sites. Our goal in this study was to identify positions that surround the allosteric pocket and that are sensitive for inactivation of TSHR. Homology modeling combined with site-directed mutagenesis and functional characterization revealed seven mutants located in the allosteric binding site that led to a decrease of basal cAMP signaling activity. The majority of these silencing mutations, which constrain the TSHR in an inactive conformation, are found in two clusters when mapped onto the 3D structural model. We suggest that the amino acid positions identified herein are indicating locations where small-molecule antagonists, both neutral antagonists and inverse agonists, might interfere with active TSHR conformations.

Supersymmetric sigma models

International Nuclear Information System (INIS)

Bagger, J.A.

1984-09-01

We begin to construct the most general supersymmetric Lagrangians in one, two and four dimensions. We find that the matter couplings have a natural interpretation in the language of the nonlinear sigma model

Supersymmetric sigma models

Energy Technology Data Exchange (ETDEWEB)

Bagger, J.A.

1984-09-01

We begin to construct the most general supersymmetric Lagrangians in one, two and four dimensions. We find that the matter couplings have a natural interpretation in the language of the nonlinear sigma model.

Six sigma critical success factors in manufacturing industries

Science.gov (United States)

Mustafa, Zainol; Jamaluddin, Z.

2017-04-01

The success of Six Sigma implementation is known to depend on a number of contributing factors. The purpose of this paper is to explore Six Sigma critical success factors (CSFs) in the context of Malaysian manufacturing organizations. Although Six Sigma success factors have been abundantly researched in the global context, in this paper, a maiden attempt is made to identify, through an extensive literature review, the CSFs for Six Sigma implementation followed by their validation using primary data collection from Malaysian manufacturing companies. A total of 33 indicators have thus been compiled through an extensive literature review which then been grouped into 6 contributing factors. These contributing success factors are then validated through an empirical research of selected Malaysian manufacturing companies at various stages of implementation of the Six Sigma process improvement methodology. There has been an overemphasis on the role and commitment of the management in the success of a Six Sigma program. Though it is undoubted, certain other factors also play an equally important role in ensuring that the Six Sigma programs are successful. The factor analysis of CSFs of the Malaysian manufacturing organizations selected in this study demonstrates that the top factor is a composite factor showing combination of the ability of the project teams to use the process management on quality initiative and a training using a proper analysis in problem solving. The CSFs extracted through the factor analysis could provide a basis for manufacturing organizations embarking on the Six Sigma journey to look beyond just management involvement. Thus, one can develop an integrated framework of other factors as outlined and give them appropriate priority and focus.

Muscarinic acetylcholine receptors: location of the ligand binding site

International Nuclear Information System (INIS)

Hulme, E.; Wheatley, M.; Curtis, C.; Birdsall, N.

1987-01-01

The key to understanding the pharmacological specificity of muscarinic acetylcholine receptors (mAChR's) is the location within the receptor sequence of the amino acid residues responsible for ligand binding. To approach this problem, they have purified mAChR's from rat brain to homogeneity by sequential ion-exchange chromatography, affinity chromatography and molecular weight fractionation. Following labelling of the binding site with an alkylating affinity label, 3 H-propylbenzilycholine mustard aziridinium ion ( 3 H-PrBCM), the mAChR was digested with a lysine-specific endoproteinase, and a ladder of peptides of increasing molecular weight, each containing the glycosylated N-terminus, isolated by chromatography on wheat-germ agglutinin sepharose. The pattern of labelling showed that a residue in the peptides containing transmembrane helices 2 and/or 3 of the mAChR was alkylated. The linkage was cleaved by 1 M hydroxylamine, showing that 3 H-PrBCM was attached to an acidic residue, whose properties strongly suggested it to be embedded in a hydrophobic intramembrane region of the mAChR. Examination of the cloned sequence of the mAChR reveals several candidate residues, the most likely of which is homologous to an aspartic acid residue thought to protonate the retinal Schiff's base in the congeneric protein rhodopsin

Precipitation Mechanism of Sigma Phase in Super Duplex Stainless Steels

Science.gov (United States)

Nakade, Katsuyuki; Kuroda, Toshio

The influence of alloying elements on the precipitation behavior of sigma (σ) phase was investigated for conventional SAF2205 and SAF2507 super duplex stainless steel. Time-Temperature-Precipitation (T-T-P) diagram of sigma phase of SAF2507 were shifted toward to shorter times compared to SAF2205. The precipitation of sigma phase was accelerated with increasing Cr and Mo concentration. According to the microstructure observation, the sigma phase began to precipitate at ferrite (α) ⁄ austenite (γ) phase boundaries and grew into ferrite for SAF2507 and SAF2205 steel. In the as-received condition, Cr and Mo concentration in ferrite was clearly higher than that in austenite. Especially, it was found that Mo concentration in ferrite of SAF2507 was higher than that in ferrite of SAF2205. The result of EPMA-measurement showed that sigma phase was mainly Fe-Cr-Mo intermetallic compound and Mo was significantly enriched into sigma phase. The difference of Mo concentration in ferrite significantly affected to the sigma phase precipitation. The secondary austenite formation was also induced by sigma phase precipitation. Cr and Mo were ejected to the remained ferrite ⁄ austenite phase boundaries by secondary austenite formation. Consequently, sigma phase precipitation was more accelerated by the reheating.

SIGMA WEB INTERFACE FOR REACTOR DATA APPLICATIONS

Energy Technology Data Exchange (ETDEWEB)

Pritychenko,B.; Sonzogni, A.A.

2010-05-09

We present Sigma Web interface which provides user-friendly access for online analysis and plotting of the evaluated and experimental nuclear reaction data stored in the ENDF-6 and EXFOR formats. The interface includes advanced browsing and search capabilities, interactive plots of cross sections, angular distributions and spectra, nubars, comparisons between evaluated and experimental data, computations for cross section data sets, pre-calculated integral quantities, neutron cross section uncertainties plots and visualization of covariance matrices. Sigma is publicly available at the National Nuclear Data Center website at http://www.nndc.bnl.gov/sigma.

Sigma Web Interface For Reactor Data Applications

International Nuclear Information System (INIS)

Pritychenko, B.; Sonzogni, A.A.

2010-01-01

We present Sigma Web interface which provides user-friendly access for online analysis and plotting of the evaluated and experimental nuclear reaction data stored in the ENDF-6 and EXFOR formats. The interface includes advanced browsing and search capabilities, interactive plots of cross sections, angular distributions and spectra, nubars, comparisons between evaluated and experimental data, computations for cross section data sets, pre-calculated integral quantities, neutron cross section uncertainties plots and visualization of covariance matrices. Sigma is publicly available at the National Nuclear Data Center website at http://www.nndc.bnl.gov/sigma.

Six sigma and lean production adoption in a manufacturing company

Directory of Open Access Journals (Sweden)

Alisson Christian Scheller

2014-11-01

Full Text Available The connection among Lean Production with Six Sigma originated the Lean Six Sigma methodology, focused on processes variation and waste reduction. This methodology was developed on different ways in the companies and there is no consensus over its structure and its implementation. In this context, this paper aims to identify and analyze the main characteristics on the adoption and integration of Lean Six Sigma methodology through a case study conducted in a manufacturing company that adopts lean production and six sigma. The results show two important aspects of the Lean Six Sigma methodology. One of them is the adoption of the value stream mapping as a central tool on Lean Six Sigma. The other is the use of DMAIC for improvements actions. The study indicates that despite the difficulties on Lean Six Sigma implementation, the methodology offers benefits to the company that adopts it in the suitable way.

Functional Analysis of the Alternative Sigma-28 Factor FliA and Its Anti-Sigma Factor FlgM of the Nonflagellated Legionella Species L. oakridgensis.

Science.gov (United States)

Tlapák, Hana; Rydzewski, Kerstin; Schulz, Tino; Weschka, Dennis; Schunder, Eva; Heuner, Klaus

2017-06-01

Legionella oakridgensis causes Legionnaires' disease but is known to be less virulent than Legionella pneumophila L. oakridgensis is one of the Legionella species that is nonflagellated. The genes of the flagellar regulon are absent, except those encoding the alternative sigma-28 factor (FliA) and its anti-sigma-28 factor (FlgM). Similar to L. oakridgensis , Legionella adelaidensis and Legionella londiniensis , located in the same phylogenetic clade, have no flagellar regulon, although both are positive for fliA and flgM Here, we investigated the role and function of both genes to better understand the role of FliA, the positive regulator of flagellin expression, in nonflagellated strains. We demonstrated that the FliA gene of L. oakridgensis encodes a functional sigma-28 factor that enables the transcription start from the sigma-28-dependent promoter site. The investigations have shown that FliA is necessary for full fitness of L. oakridgensis Interestingly, expression of FliA-dependent genes depends on the growth phase and temperature, as already shown for L. pneumophila strains that are flagellated. In addition, we demonstrated that FlgM is a negative regulator of FliA-dependent gene expression. FlgM seems to be degraded in a growth-phase- and temperature-dependent manner, instead of being exported into the medium as reported for most bacteria. The degradation of FlgM leads to an increase of FliA activity. IMPORTANCE A less virulent Legionella species, L. oakridgensis , causes Legionnaires' disease and is known to not have flagella, even though L. oakridgensis has the regulator of flagellin expression (FliA). This protein has been shown to be involved in the expression of virulence factors. Thus, the strain was chosen for use in this investigation to search for FliA target genes and to identify putative virulence factors of L. oakridgensis One of the five major target genes of FliA identified here encodes the anti-FliA sigma factor FlgM. Interestingly, in

Integrating the Many Facets of Six Sigma

NARCIS (Netherlands)

de Mast, J.

2007-01-01

We seek to provide a unified characterization of Six Sigma by studying the phenomenon from the perspectives of business economics, organizational theory, competitive strategy and industrial statistics, and we pinpoint its core methodological principles. We describe Six Sigma as a prescriptive

Ab initio calculation of the electronic structures of the (7)Sigma+ ground and A (7)Pi and a (5)Sigma+ excited states of MnH.

Science.gov (United States)

Tomonari, Mutsumi; Nagashima, Umpei; Hirano, Tsuneo

2009-04-21

Electronic structures and molecular constants of the ground (7)Sigma(+) and low-lying A (7)Pi and a (5)Sigma(+) electronic excited states of the MnH molecule were studied by multireference single and double excitation configuration interaction (MR-SDCI) with Davidson's correction (+Q) calculations under exact C(infinity v) symmetry using Slater-type basis sets. To correctly describe the (7)Sigma(+) electronic ground state, X (7)Sigma(+), at the MR-SDCI+Q calculation, we employed a large number of reference configurations in terms of the state-averaged complete active space self-consistent field (CASSCF) orbitals, taking into account the contribution from the B (7)Sigma(+) excited state. The A (7)Pi and a (5)Sigma(+) states can well be described by the MR-SDCI wave functions based on the CASSCF orbitals obtained for the lowest state only. In the MR-SDCI+Q, calculations of the X (7)Sigma(+), A (7)Pi, and a (5)Sigma(+) states required 16, 7, and 17 reference configurations, respectively. Molecular constants, i.e., r(e) and omega(e) of these states and excitation energy from the X (7)Sigma(+) state, obtained at the MR-SDCI+Q level, showed a good agreement with experimental values. The small remaining differences may be accounted for by taking relativistic effects into account.

SIX SIGMA: A LITERATURE REVIEW

Directory of Open Access Journals (Sweden)

S.A. Oke

2012-01-01

Full Text Available

ENGLISH ABSTRACT: Despite stiff international competition in the global market, world-class manufacturers are increasing their market share and profits through low-cost production, waste reduction in manufacturing, production of high quality products, and exceptional customer service. Six Sigma has been successfully implemented in this regard. In this paper, a selected survey of Six Sigma literature is presented to illustrate the wide scope of the application of the concept. This could be of immense benefit to organizations’ top management who need to understand the critical variables and factors for the successful implementation of Six Sigma programmes, leading to substantial, sustainable long-term improvement in performance results, value for money, and effort. The paper presents motivated pointers – substantiated as far as possible by data and evidence – to key success factors, variables, and their interrelationships.

AFRIKAANSE OPSOMMING: Sterk internasionale mededinging ten spyt verhoog wêreldklasvervaardigers hul markaandeel en winste via laekosteproduksie, skrootvermindering, die produksie van gehalteprodukte en die lewering van primadiens aan klante. Ses Sigma is in hierdie verband as gereedskap suksesvol geïmplimenteer. Die artikel behandel 'n gekeurde oorsig van Ses Sigmaliteratuur om sodoende die toepassingsveldwyde van die konsep te illustreer. Die artikel is nuttig vir organisasiebestuurders uit die oogpunt van veranderlikes en suksesfaktore wat deur die Ses Sigmametode tot substansiële en volhoubare langtermyn verbeterings van 'n onderneming kan lei.

Six Sigma in healthcare delivery.

Science.gov (United States)

Liberatore, Matthew J

2013-01-01

The purpose of this paper is to conduct a comprehensive review and assessment of the extant Six Sigma healthcare literature, focusing on: application, process changes initiated and outcomes, including improvements in process metrics, cost and revenue. Data were obtained from an extensive literature search. Healthcare Six Sigma applications were categorized by functional area and department, key process metric, cost savings and revenue generation (if any) and other key implementation characteristics. Several inpatient care areas have seen most applications, including admission, discharge, medication administration, operating room (OR), cardiac and intensive care. About 42.1 percent of the applications have error rate as their driving metric, with the remainder focusing on process time (38 percent) and productivity (18.9 percent). While 67 percent had initial improvement in the key process metric, only 10 percent reported sustained improvement. Only 28 percent reported cost savings and 8 percent offered revenue enhancement. These results do not favorably assess Six Sigma's overall effectiveness and the value it offers healthcare. Results are based on reported applications. Future research can include directly surveying healthcare organizations to provide additional data for assessment. Future application should emphasize obtaining improvements that lead to significant and sustainable value. Healthcare staff can use the results to target promising areas. This article comprehensively assesses Six Sigma healthcare applications and impact.

Improving laboratory data entry quality using Six Sigma.

Science.gov (United States)

Elbireer, Ali; Le Chasseur, Julie; Jackson, Brooks

2013-01-01

The Uganda Makerere University provides clinical laboratory support to over 70 clients in Uganda. With increased volume, manual data entry errors have steadily increased, prompting laboratory managers to employ the Six Sigma method to evaluate and reduce their problems. The purpose of this paper is to describe how laboratory data entry quality was improved by using Six Sigma. The Six Sigma Quality Improvement (QI) project team followed a sequence of steps, starting with defining project goals, measuring data entry errors to assess current performance, analyzing data and determining data-entry error root causes. Finally the team implemented changes and control measures to address the root causes and to maintain improvements. Establishing the Six Sigma project required considerable resources and maintaining the gains requires additional personnel time and dedicated resources. After initiating the Six Sigma project, there was a 60.5 percent reduction in data entry errors from 423 errors a month (i.e. 4.34 Six Sigma) in the first month, down to an average 166 errors/month (i.e. 4.65 Six Sigma) over 12 months. The team estimated the average cost of identifying and fixing a data entry error to be $16.25 per error. Thus, reducing errors by an average of 257 errors per month over one year has saved the laboratory an estimated $50,115 a year. The Six Sigma QI project provides a replicable framework for Ugandan laboratory staff and other resource-limited organizations to promote quality environment. Laboratory staff can deliver excellent care at a lower cost, by applying QI principles. This innovative QI method of reducing data entry errors in medical laboratories may improve the clinical workflow processes and make cost savings across the health care continuum.

Incorporating Six Sigma Methodology Training into Chemical Engineering Education

Science.gov (United States)

Dai, Lenore L.

2007-01-01

Six Sigma is a buzz term in today's technology and business world and there has been increasing interest to initiate Six Sigma training in college education. We have successfully incorporated Six Sigma methodology training into a traditional chemical engineering course, Engineering Experimentation, at Texas Tech University. The students have…

Lean six sigma application to transportation logistics

Directory of Open Access Journals (Sweden)

Simone Tavares Fernandes

2012-06-01

Full Text Available This work presents the application of Lean Six Sigma in a case study of a metallurgic industry. The Six Sigma and the Lean are two processes used by enterprises in Brazil and worldwide. Currently the integration of these processes is a challenge for these companies, which search a way more efficient to reduce their wastes and to adapt to the needs of their markets. The paper had as purpose to demonstrate the applicability of the Lean Six Sigma in a real logistical problem related to the transportation of goods among units of a metallurgic industry. The stages used for the solution of the problem follow the DMAIC cycle – Define, Measure, Analyze, Improve and Control. The paper presents in details the integrated approach of the improvement processes Lean and Six Sigma, their tools set, as well the excellent results obtained in the case study.

Studi Implementasi Six Sigma dalam Sistem Inventori Galangan Kapal

Directory of Open Access Journals (Sweden)

Elwin Elwin

2012-09-01

Full Text Available Dalam industri galangan kapal terdapat bahan baku, barang dalam proses dan barang jadi yang merupakan macam-macam bentuk dari persediaan dan berhubungan dengan stok, ketika persediaan tidak dikelola dengan benar maka akan terjadi pembengkakkan biaya/pengeluaran biaya yang tidak dibutuhkan. Tugas akhir ini bertujuan untuk mengetahui kondisi inventori di PT. Dok dan Perkapalan Surbaya, untuk mengetahui faktor-faktor yang menjadi penyebab terjadinya variabilitas output six sigma dan mengurangi defect pada sistem inventori dengan menggunakan metode six sigma DMAIC (Define, Measure, Analyze, Improve dan Control,. Berdasarkan perhitungan Material Pipa mengalami defect sebesar 50.98% dengan nilai sigma 1.48, Material Elbow mengalami defect sebesar 89.80% dengan nilai sigma 0.33, Material Flange mengalami defect sebesar 71.99% dengan nilai sigma 0.90, Material Paking mengalami defect sebesar 13.12% dengan nilai sigma 2.74 dan Material Mur mengalami defect sebesar 17.26% dengan nilai sigma 2.57. Sesuai dengan perhitungan reorder point for the inventory untuk masing-masing material, maka dapat diketahui bahwa material Pipa reoder point adalah 58 lonjor, elbow 100 buah, flange 168 buah, paking 24 buah dan mur 946 buah. Nilai sigma yang diperoleh dalam perhitungan tingkat persediaan masih jauh dari nilai yang seharusnya dapat dicapai oleh suatu perusahaan (6σ, sehingga dilakukan tahap Improve dengan metode Failure Mode and Effect Analysis (FMEA, pembuat SOP Pengendalian persediaan material dengan format baru serta galangan perlu melakukan perhitungan reorder point.  

Radiation sensitization by an iodine-labelled DNA ligand

Energy Technology Data Exchange (ETDEWEB)

Martin, R F; Murray, V; D' Cunha, G; Pardee, M; Haigh, A; Hodgson, G S [Peter MacCallum Cancer Inst., Melbourne (Australia); Kampouris, E; Kelly, D P [Melbourne Univ., Parkville (Australia)

1990-05-01

An iodinated DNA ligand, iodoHoechst 33258, which binds in the minor groove of DNA, enhances DNA strand breakage and cell killing by UV-A irradiation. The sites of UV-induced strand breaks reflect the known sequence specificity of the ligand. (author).

Ligand recognition by RAR and RXR receptors: binding and selectivity.

Science.gov (United States)

Sussman, Fredy; de Lera, Angel R

2005-10-06

Fundamental biological functions, most notably embriogenesis, cell growth, cell differentiation, and cell apoptosis, are in part regulated by a complex genomic network that starts with the binding (and activation) of retinoids to their cognate receptors, members of the superfamily of nuclear receptors. We have studied ligand recognition of retinoic receptors (RXRalpha and RARgamma) using a molecular-mechanics-based docking method. The protocol used in this work is able to rank the affinity of pairs of ligands for a single retinoid receptor, the highest values corresponding to those that adapt better to the shape of the binding site and generate the optimal set of electrostatic and apolar interactions with the receptor. Moreover, our studies shed light onto some of the energetic contributions to retinoid receptor ligand selectivity. In this regard we show that there is a difference in polarity between the binding site regions that anchor the carboxylate in RAR and RXR, which translates itself into large differences in the energy of interaction of both receptors with the same ligand. We observe that the latter energy change is canceled off by the solvation energy penalty upon binding. This energy compensation is borne out as well by experiments that address the effect of site-directed mutagenesis on ligand binding to RARgamma. The hypothesis that the difference in binding site polarity might be exploited to build RXR-selective ligands is tested with some compounds having a thiazolidinedione anchoring group.

Understanding delta-sigma data converters

CERN Document Server

Pavan, Shanti; Temes, Gabor C

2017-01-01

This new edition introduces novel analysis and design techniques for delta-sigma (ΔΣ) converters in physical and conceptual terms, and includes new chapters that explore developments in the field over the last decade. This book explains the principles and operation of delta-sigma analog-to-digital converters (ADCs) in physical and conceptual terms in accordance with the most recent developments in the field. The interest of ΔΣ converter designers has shifted significantly over the past decade, due to many new applications for data converters at the far ends of the frequency spectrum. Continuous-time delta-sigma A/D converters with GHz clocks, of both lowpass and bandpass types, are required for wireless applications. At the other extreme, multiplexed ADCs with very narrow (sometimes 10 Hz wide) signal bandwidths, but very high accuracy are needed in the interfaces of biomedical and environmental sensors. To reflect the changing eeds of designers, the second edition includes significant new material on bo...

The SIGMA plants economic behavior

International Nuclear Information System (INIS)

Rivarola, Martin E.; Bergallo, Juan E.

1999-01-01

In this work, the economical behavior of the Uranium Enrichment Plants, built using the Gaseous Isotopic Separation using Advanced Methods (SIGMA) (Separacion Isotopica Gaseosa por Metodos Avanzados) technology is analyzed. The calculations were made using an integrated computer code, where the cost of each main component of the plant is estimated. The program computes the production cost for several configurations of enrichment cascades, each one corresponding to a production rate. The program also includes a numerical optimizer and it seeks the SIGMA optimal configuration for a given set of design parameters. The present work does not contemplate the model and calculation of the auxiliary system costs. The total amortization cost is obtained by using the cascade capital cost and assuming that the auxiliary system represents a fixed part of the total cost.The results obtained show that the SIGMA technology for Enrichment Uranium Plants could achieve economical competition in a much lower production scale than the conventional Gaseous Diffusion Enrichment Plants. (author)

Peningkatan performansi produksi dengan pendekatan lean six sigma

Directory of Open Access Journals (Sweden)

H. Harisupriyanto

2018-01-01

Full Text Available Abstrak Persaingan pasar tidak sekedar menjual produk akan tetapi membutuhkan kualitas produk yang semakin baik. Kondisi tersebut semakin penting bila dihubungkan dengan permintaan produk yang semakin tinggi. Untuk itu diperlukan pengolahan sumber daya yang semakin efisiensi dan effektif. Sering terjadi proses produksi berhenti dan ditaksir kerugian finansial yang tinggi. Terdapat aktifitas yang bersifat non value added. Aktifitas tersebut menyebabkan timbulnyalosses. Diperlukan cara untuk menelusuri penyebab terjadinya waste atau losses pada aktivitas produksi dengan pendekatan lean six sigma. Tools yang dipakai untuk mengidentifikasi permasalahan adalah E-DOWNTIME waste, RCA (root cause Analisys dan FMEA (Failure modes and effect analysis. Diperoleh hasil bahwavalue added activity sebesar 22%, necessary but non value added activity yaitu 44% dan nonvalue added activity sebesar 34%. Diperoleh tiga waste kritis yaitu waiting, defect dan excess processing waste. Nilai sigma awal pada defect waste yaitu sebesar 2.70;nilai sigma ini merupakan permasalahan. Rekomendasi perbaikan adalah pembuatan dan pengawasan SOP dan pengadaan pelatihan guna meningkatkan kemampuan dan keterampilan tenaga kerja. Terjadi kenaikan nilai sigma sampai 3.10 dan terjadi pengurangan biaya sampai 25%. Kata Kunci: Losses, activity, RCA, Lean, six-sigma Abstract The market competition is not just selling a product but needs a better product quality. That condition increasingly important when associated with higher product demand. It required the processing resources more efficient and effective.The production process often stops and estimated financial loss is high. There were indications of activities nonvalue added. These activities cause losses. Need a way to explore the causes of waste or losses in production activities with lean six- sigma approach.Tools used to identify the problem are E-DOWNTIME waste, RCA (root cause Analisys and FMEA (Failure modes and effects

Real-Time Ligand Binding Pocket Database Search Using Local Surface Descriptors

Science.gov (United States)

Chikhi, Rayan; Sael, Lee; Kihara, Daisuke

2010-01-01

Due to the increasing number of structures of unknown function accumulated by ongoing structural genomics projects, there is an urgent need for computational methods for characterizing protein tertiary structures. As functions of many of these proteins are not easily predicted by conventional sequence database searches, a legitimate strategy is to utilize structure information in function characterization. Of a particular interest is prediction of ligand binding to a protein, as ligand molecule recognition is a major part of molecular function of proteins. Predicting whether a ligand molecule binds a protein is a complex problem due to the physical nature of protein-ligand interactions and the flexibility of both binding sites and ligand molecules. However, geometric and physicochemical complementarity is observed between the ligand and its binding site in many cases. Therefore, ligand molecules which bind to a local surface site in a protein can be predicted by finding similar local pockets of known binding ligands in the structure database. Here, we present two representations of ligand binding pockets and utilize them for ligand binding prediction by pocket shape comparison. These representations are based on mapping of surface properties of binding pockets, which are compactly described either by the two dimensional pseudo-Zernike moments or the 3D Zernike descriptors. These compact representations allow a fast real-time pocket searching against a database. Thorough benchmark study employing two different datasets show that our representations are competitive with the other existing methods. Limitations and potentials of the shape-based methods as well as possible improvements are discussed. PMID:20455259

Six Sigma, absorptive capacity and organizational learning orientation

OpenAIRE

Gutiérrez Gutiérrez , Leopoldo J; Bustinza Sánchez , Oscar F; Barrales Molina , Vanesa

2011-01-01

Abstract The importance of the Six Sigma methodology in industry is growing constantly. However, there are few empirical studies that analyze the advantages of this methodology and its positive effects on organizational performance. The purpose of this paper is to extend understanding of the success of Six Sigma quality management initiatives by investigating the effects of Six Sigma teamwork and process management on absorptive capacity. It also seeks to understand the relation be...

A Heteroleptic Ferrous Complex with Mesoionic Bis(1,2,3-triazol-5-ylidene) Ligands: Taming the MLCT Excited State of Iron(II)

DEFF Research Database (Denmark)

Liu, Yizhu; Kjær, Kasper Skov; Fredin, Lisa A.

2015-01-01

based on sequentially furnishing the Fe-II center with the benchmark 2,2-bipyridine (bpy) ligand and the more strongly sigma-donating mesoionic ligand, 4,4-bis(1,2,3-triazol-5-ylidene) (btz). Complex1 was comprehensively characterized by electrochemistry, static and ultrafast spectroscopy, and quantum...... chemical calculations and compared to [Fe(bpy)(3)](PF6)(2) and (TBA)(2)[Fe(bpy)(CN)(4)]. Heteroleptic complex1 extends the absorption spectrum towards longer wavelengths compared to a previously synthesized homoleptic Fe-II NHC complex. The combination of the mesoionic nature of btz and the heteroleptic...

A Versatile Dinucleating Ligand Containing Sulfonamide Groups

DEFF Research Database (Denmark)

Sundberg, Jonas; Witt, Hannes; Cameron, Lisa

2014-01-01

ligand can be prepared in aqueous solutions using only divalent metal ions. Two of the copper(II) complexes, [Cu2(psmp)(OH)] and [Cu2(psmp)(OAc)2]-, demonstrate the anticipated 1:2 ligand/metal stoichiometry and show that the dimetallic binding site created for exogenous ligands possesses high inherent...... of antiferromagnetic coupling. This is corroborated computationally by broken-symmetry density functional theory, which for isotropic modeling of the coupling predicts an antiferromagnetic coupling strength of J = 70.5 cm-1....

Development and utilization of a fluorescence-based receptor-binding assay for the site 5 voltage-sensitive sodium channel ligands brevetoxin and ciguatoxin.

Science.gov (United States)

McCall, Jennifer R; Jacocks, Henry M; Niven, Susan C; Poli, Mark A; Baden, Daniel G; Bourdelais, Andrea J

2014-01-01

Brevetoxins are a family of ladder-frame polyether toxins produced during blooms of the marine dinoflagellate Karenia brevis. Consumption of fish exposed to K. brevis blooms can lead to the development of neurotoxic shellfish poisoning. The toxic effects of brevetoxins are due to activation of voltage-sensitive sodium channels (VSSCs) in cell membranes. Binding of toxins has historically been measured using a radioligand competition assay that is fraught with difficulty. In this study, we developed a novel fluorescence-based binding assay for the brevetoxin receptor. Several fluorophores were conjugated to polyether brevetoxin-2 and used as the labeled ligand. Brevetoxin analogs were able to compete for binding with the fluorescent ligands. This assay was qualified against the standard radioligand receptor assay for the brevetoxin receptor. Furthermore, the fluorescence-based assay was used to determine relative concentrations of toxins in raw extracts of K. brevis culture, and to determine ciguatoxin affinity to site 5 of VSSCs. The fluorescence-based assay was quicker, safer, and far less expensive. As such, this assay can be used to replace the current radioligand assay and will be a vital tool for future experiments examining the binding affinity of various ligands for site 5 on sodium channels.

Some examples of instantons in sigma models

International Nuclear Information System (INIS)

Kogan, Ya.I.; Markushevich, D.G.; Morozov, A.Yu.; Ol'shanetskii, M.A.; Perelomov, A.M.; Roslyi, A.A.

1989-01-01

The paper considers (supersymmetric) sigma models in which the fields are defined on a Riemann surface of genus p and take values on a Kaehlerian manifold. Some mathematical methods for finding instantons and their zero modes in such sigma models are explained. Only holomorphic instantons are considered

Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival.

Science.gov (United States)

Hayashi, Teruo; Su, Tsung-Ping

2007-11-02

Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.

An application of six sigma for SMEs: A case study

Directory of Open Access Journals (Sweden)

Prabhakar Kaushik

2017-03-01

Full Text Available Six Sigma is the concept of improving the quality by reducing process variations, making con-tinuous improvements, reducing defect rates and improving the processes. Initially, the concept of Six Sigma focused on defect reduction, cost reduction and value addition. Fundamentally the basic idea of Six Sigma is to improve the process-capability and making the process more relia-ble along with reducing wastes within industries. Evaluation the implication of applying Six Sigma over the small and medium-sized enterprises is the main purpose of this research work taking a particular case of automobile industries. In the present work, DMAIC methodology of Six Sigma is used to a small seat slider lock nut manufacturing unit to reduce the play issue in K2 seat slider lock in automobile units by reducing defects inherent in the process. After apply-ing Six Sigma methodology, it was found that manufacturing units could earn profits in terms of reducing the wastage as well as improving the quality standard of the product by controlling the play issue in seat slider lock nut mechanism. Result shows that with the application of Six Sig-ma, process, sigma level brought up to 5.53σ from 1.59σ by varying the seat slider lock nut di-mensions/size.

Lattice sigma models with exact supersymmetry

International Nuclear Information System (INIS)

Simon Catterall; Sofiane Ghadab

2004-01-01

We show how to construct lattice sigma models in one, two and four dimensions which exhibit an exact fermionic symmetry. These models are discretized and twisted versions of conventional supersymmetric sigma models with N=2 supersymmetry. The fermionic symmetry corresponds to a scalar BRST charge built from the original supercharges. The lattice theories possess local actions and exhibit no fermion doubling. In the two and four dimensional theories we show that these lattice theories are invariant under additional discrete symmetries. We argue that the presence of these exact symmetries ensures that no fine tuning is required to achieve N=2 supersymmetry in the continuum limit. As a concrete example we show preliminary numerical results from a simulation of the O(3) supersymmetric sigma model in two dimensions. (author)

Comments on Nonlinear Sigma Models Coupled to Supergravity arXiv

CERN Document Server

Ferrara, Sergio

2017-12-10

N=1 , D=4 nonlinear sigma models, parametrized by chiral superfields, usually describe Kählerian geometries, provided that Einstein frame supergravity is used. The sigma model metric is no longer Kähler when local supersymmetry becomes nonlinearly realized through the nilpotency of the supergravity auxiliary fields. In some cases the nonlinear realization eliminates one scalar propagating degree of freedom. This happens when the sigma model conformal-frame metric has co-rank 2. In the geometry of the inflaton, this effect eliminates its scalar superpartner. We show that the sigma model metric remains semidefinite positive in all cases, due the to positivity properties of the conformal-frame sigma model metric.

Six Sigma als blauwdruk voor de kenniseconomie.

NARCIS (Netherlands)

de Mast, J.; Does, R.J.M.M.

2005-01-01

Abstract Six Sigma is zo langzamerhand een niet weg te denken programma voor kwaliteits- en efficiencyverbeteringen. Het heeft met name voor enorme successen gezorgd in productiebedrijven. Six Sigma ligt ook onder vuur: het zou een trend zijn die voorbij gaat. De auteurs van dit artikel zijn het van

Dissipative quantum dynamics and nonlinear sigma-model

International Nuclear Information System (INIS)

Tarasov, V.E.

1992-01-01

Sedov variational principle which is the generalization of the least action principle for the dissipative and irreversible processes and the classical dissipative mechanics in the phase space is considered. Quantum dynamics for the dissipative and irreversible processes is constructed. As an example of the dissipative quantum theory the nonlinear two-dimensional sigma-model is considered. The conformal anomaly of the energy momentum tensor trace for closed bosonic string on the affine-metric manifold is investigated. The two-loop metric beta-function for nonlinear dissipative sigma-model was calculated. The results are compared with the ultraviolet two-loop conterterms for affine-metric sigma model. 71 refs

On D-branes from gauged linear sigma models

International Nuclear Information System (INIS)

Govindarajan, S.; Jayaraman, T.; Sarkar, T.

2001-01-01

We study both A-type and B-type D-branes in the gauged linear sigma model by considering worldsheets with boundary. The boundary conditions on the matter and vector multiplet fields are first considered in the large-volume phase/non-linear sigma model limit of the corresponding Calabi-Yau manifold, where we find that we need to add a contact term on the boundary. These considerations enable to us to derive the boundary conditions in the full gauged linear sigma model, including the addition of the appropriate boundary contact terms, such that these boundary conditions have the correct non-linear sigma model limit. Most of the analysis is for the case of Calabi-Yau manifolds with one Kaehler modulus (including those corresponding to hypersurfaces in weighted projective space), though we comment on possible generalisations

Quality and Competitiveness: A Lean Six Sigma Approach

Directory of Open Access Journals (Sweden)

Irina-Virginia Drăgulănescu

2015-11-01

Full Text Available Originally developed to improve the quality and production efficiency, Lean Six Sigma is now widely adopted in other non-manufacturing sectors such as financial, trade, services, etc. The methodology known as Lean Six Sigma combines the Six Sigma techniques, ‒ which allow companies to reduce manufacturing defects ‒ and the Lean Manufacturing principles, ‒ which help companies benefit from faster processing for lower costs and with superior quality. As a result of the research, the authors observed that, despite growing popularity and impressive outcomes obtained by some companies, the Lean Six Sigma model does not always offer the expected results. However, the research has shown that the analysed company, operating in the field of courier services has managed to boost productivity and competitiveness by implementing measures that generated added value.

A sequence-based dynamic ensemble learning system for protein ligand-binding site prediction

KAUST Repository

Chen, Peng

2015-12-03

Background: Proteins have the fundamental ability to selectively bind to other molecules and perform specific functions through such interactions, such as protein-ligand binding. Accurate prediction of protein residues that physically bind to ligands is important for drug design and protein docking studies. Most of the successful protein-ligand binding predictions were based on known structures. However, structural information is not largely available in practice due to the huge gap between the number of known protein sequences and that of experimentally solved structures

A sequence-based dynamic ensemble learning system for protein ligand-binding site prediction

KAUST Repository

Chen, Peng; Hu, ShanShan; Zhang, Jun; Gao, Xin; Li, Jinyan; Xia, Junfeng; Wang, Bing

2015-01-01

Background: Proteins have the fundamental ability to selectively bind to other molecules and perform specific functions through such interactions, such as protein-ligand binding. Accurate prediction of protein residues that physically bind to ligands is important for drug design and protein docking studies. Most of the successful protein-ligand binding predictions were based on known structures. However, structural information is not largely available in practice due to the huge gap between the number of known protein sequences and that of experimentally solved structures

Production of the $\\Sigma^0_c$ and $\\Sigma^{++}_c$ by High-Energy Neutrons

Energy Technology Data Exchange (ETDEWEB)

Ladbury, Raymond, Jr. [Colorado U.

1988-01-01

We present the first observation of hadroproduction of the $\\Sigma^{++}_C$ and $\\Sigma^0_c$ , decaying into $\\Lambda_{c\\pi}$. The daughter $\\Lambda_c$ is observed in the decay modes $pK \\pi$ and $pK_s\\pi\\pi$. The Experiment was conducted at a broadband neutron beam in the Proton East area of the Fermi National Accelerator Laboratory. A two - magnet multiparticle spectrometer equipped with proportional wire chambers and a high resolution MWPC vertex detector was used to momentum analyze charged particles produced in the interactions of neutrons on targets of beryllium, silicon and tungsten. Particles were identified using three Cerenkov counters. The beam energy for each event was reconstructed using hadronic and electromagnetic calorimetry....

Six Lessons We Learned Applying Six Sigma

Science.gov (United States)

Carroll, Napoleon; Casleton, Christa H.

2005-01-01

As Chief Financial Officer of Kennedy Space Center (KSC), I'm not only responsible for financial planning and accounting but also for building strong partnerships with the CFO customers, who include Space Shuttle and International Space Station operations as well all who manage the KSC Spaceport. My never ending goal is to design, manage and continuously improve our core business processes so that they deliver world class products and services to the CFO's customers. I became interested in Six Sigma as Christa Casleton (KSC's first Six Sigma Black belt) applied Six Sigma tools and methods to our Plan and Account for Travel Costs Process. Her analysis was fresh, innovative and thorough but, even more impressive, was her approach to ensure ongoing, continuous process improvement. Encouraged by the results, I launched two more process improvement initiatives aimed at applying Six Sigma principles to CFO processes that not only touch most of my employees but also have direct customer impact. As many of you know, Six Sigma is a measurement scale that compares the output of a process with customer requirements. That's straight forward, but demands that you not only understand your processes but also know your products and the critical customer requirements. The objective is to isolate and eliminate the causes of process variation so that the customer sees consistently high quality.

Ligand-receptor Interactions by NMR Spectroscopy

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Novak. P.

2008-04-01

Full Text Available Today NMR spectroscopy is a method of choice for elucidation of interactions between biomolecules and the potential ligands. Knowledge on these interactions is an essential prerequisite for the rational drug design. The most important contribution of NMR to drug design a few years ago was the 3D structure determination of proteins. Besides delivering the 3D structures of the free proteins as a raw material for the modeling studies on ligand binding, NMR can directly yield valuable experimental data on the biologically important protein-ligand complexes. In addition to X-ray diffraction, NMR spectroscopy can provide information on the internal protein dynamics ordynamics of intermolecular interactions. Changes in NMR parameters allow us to detect ("SAR by NMR" and quantitatively determine binding affinities (titration, diffusion NMR experiments, etc. of potential ligands. Also, it is possible to determine the binding site and conformations of ligands, receptors and receptor-ligand complexes with the help of NMR methods such as tr-NOESY. Epitopes or functional groups responsible for binding of ligands to the receptor can be identified by employing STD or WaterLOGSY experiments. In this review are described some of the most frequent NMR methods for the characterization of the interactions between biomolecules and ligands, together with their advantages and disadvantages.

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

Science.gov (United States)

Kozakov, Dima; Hall, David R.; Jehle, Stefan; Luo, Lingqi; Ochiana, Stefan O.; Jones, Elizabeth V.; Pollastri, Michael; Allen, Karen N.; Whitty, Adrian; Vajda, Sandor

2015-01-01

Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots—regions of the protein where interactions with a ligand contribute substantial binding free energy—the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand. PMID:25918377

Ligand deconstruction: Why some fragment binding positions are conserved and others are not.

Science.gov (United States)

Kozakov, Dima; Hall, David R; Jehle, Stefan; Jehle, Sefan; Luo, Lingqi; Ochiana, Stefan O; Jones, Elizabeth V; Pollastri, Michael; Allen, Karen N; Whitty, Adrian; Vajda, Sandor

2015-05-19

Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots--regions of the protein where interactions with a ligand contribute substantial binding free energy--the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

Success of manufacturing industries – Role of Six Sigma

Directory of Open Access Journals (Sweden)

Venkatesh N.

2018-01-01

Full Text Available Six Sigma is a phenomenal quality management concepts which has helped many organizations to overcome quality crisis in the recent past. Six Sigma is observed as a very promising quality management tool for any organization to make its presence felt in the corporate world as it emphasizes on obtaining a fruitful solution to improve accuracy, reduce defect thereby reduce the cost and improve profits. The main objective of this investigation is to unearth the extent to which the companies have been benefitted due to Six Sigma implementation. This article presents the results based on the analysis of collective opinion of employees of various Indian manufacturing industries that have implemented Six Sigma. This research also examines interrelationship among various parameters defined in the research. The research revealed that industries are benefitted irrespective of their nature in terms of their growth, financial benefits, productivity and satisfaction of the customer. However, peoples’ equity that deals with the benefits that employees obtain after Six Sigma implementation is not certain. The research also revealed the existence of strong interrelationship among various parameters used to measure the success of Six Sigma.

Six Sigma method

NARCIS (Netherlands)

Does, R.J.M.M.; de Mast, J.; Balakrishnan, N.; Brandimarte, P.; Everitt, B.; Molenberghs, G.; Piegorsch, W.; Ruggeri, F.

2015-01-01

Six Sigma is built on principles and methods that have proven themselves over the twentieth century. It has incorporated the most effective approaches and integrated them into a full program. It offers a management structure for organizing continuous improvement of routine tasks, such as

Development of radiolabeled probes directed against sigma-1 receptors

International Nuclear Information System (INIS)

Ogawa, Kazuma; Masuda, Ryohei; Shiba, Kazuhiro

2017-01-01

It has been reported that sigma-1 receptors regulate the release of signaling substances in the central nervous systems and are related to various diseases, such as schizophrenia, stress disorders, dementia, amyotrophic lateral sclerosis (ALS), and cancer. If the quantification of the sigma-1 receptors is possible, the pathophysiology, the stage, and the early detection of the diseases could be understandable. Molecular imaging using Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) and radioactive probes makes noninvasive quantification of the in vivo metabolism and function possible. Currently, only nuclear medicine diagnosis using PET or SPECT can quantify the sigma-1 receptors. Therefore, there is great expectation for the development of molecular probes to image the sigma-1 receptors specifically. In this paper, we introduce our research on the development of radiohalogen-labeled molecular probes directed against the sigma-1 receptors. (author)

Six Sigma Driven Enterprise Model Transformation

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Raymond Vella

2009-10-01

Full Text Available Enterprise architecture methods provide a structured system to understand enterprise activities. However, existing enterprise modelling methodologies take static views of the enterprise and do not naturally lead to a path of improvement during enterprise model transformation. This paper discusses the need for a methodology to facilitate changes for improvement in an enterprise. The six sigma methodology is proposed as the tool to facilitate progressive and continual Enterprise Model Transformation to allow businesses to adapt to meet increased customer expectation and global competition. An alignment of six sigma with phases of GERAM life cycle is described with inclusion of Critical-To-Satisfaction (CTS requirements. The synergies of combining the two methodologies are presented in an effort to provide a more culturally embedded framework for Enterprise Model Transformation that builds on the success of six sigma.

NHS-Esters As Versatile Reactivity-Based Probes for Mapping Proteome-Wide Ligandable Hotspots.

Science.gov (United States)

Ward, Carl C; Kleinman, Jordan I; Nomura, Daniel K

2017-06-16

Most of the proteome is considered undruggable, oftentimes hindering translational efforts for drug discovery. Identifying previously unknown druggable hotspots in proteins would enable strategies for pharmacologically interrogating these sites with small molecules. Activity-based protein profiling (ABPP) has arisen as a powerful chemoproteomic strategy that uses reactivity-based chemical probes to map reactive, functional, and ligandable hotspots in complex proteomes, which has enabled inhibitor discovery against various therapeutic protein targets. Here, we report an alkyne-functionalized N-hydroxysuccinimide-ester (NHS-ester) as a versatile reactivity-based probe for mapping the reactivity of a wide range of nucleophilic ligandable hotspots, including lysines, serines, threonines, and tyrosines, encompassing active sites, allosteric sites, post-translational modification sites, protein interaction sites, and previously uncharacterized potential binding sites. Surprisingly, we also show that fragment-based NHS-ester ligands can be made to confer selectivity for specific lysine hotspots on specific targets including Dpyd, Aldh2, and Gstt1. We thus put forth NHS-esters as promising reactivity-based probes and chemical scaffolds for covalent ligand discovery.

Projeto Seis Sigma para a implementação de software de programação Six Sigma project for scheduling software implementation

Directory of Open Access Journals (Sweden)

Rogério Cerávolo Calia

2005-12-01

Full Text Available O artigo visa analisar a eficácia organizacional da metodologia Seis Sigma na gestão de projetos para a redução de atrasos e redução de estoques na manufatura, por meio da implementação de um software com algoritmos da Teoria das Restrições. Inicialmente, é apresentada uma revisão bibliográfica sobre a gestão de projetos na perspectiva da gestão da mudança organizacional nos processos de negócios. Em seguida, são revistos os conceitos sobre a metodologia Seis Sigma para a gestão de projetos e sobre os algoritmos da Teoria das Restrições. Então, são descritos os estudos de caso em dois projetos de implementação do software da Teoria das Restrições, sendo que apenas uma das implementações utilizou-se da metodologia Seis Sigma para a gestão do projeto. Na análise dos resultados, busca-se compreender os motivos de o projeto com a metodologia Seis Sigma ter reduzido inventário três vezes mais rápido do que o projeto sem o Seis Sigma.The article aims to analyze the organizational effectiveness of the Six Sigma methodology for project management to reduce delays and to reduce inventory in manufacture, by the implementation of software with Theory of Constraints algorithms. Initially, the article presents a bibliographic revision on project management and its impact on the organizational change management for improving business processes. Then, the article revises the concepts about the Six Sigma methodology for project management and about the Theory of Constraints algorithms. It follows, the case studies descriptions on two implementation projects of the Theory of Constraints software, in which only one of these implementations adopted the Six Sigma methodology in the project management. In the results analyzes, the article discusses the reasons why the project with the Six Sigma methodology was three times faster than the other project.

sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H]SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes

International Nuclear Information System (INIS)

Tam, S.W.; Cook, L.

1984-01-01

The relationship between binding of antipsychotic drugs and sigma psychotomimetic opiates to binding sites for the sigma agonist (+)-[ 3 H]SKF 10,047 (N-allylnormetazocine) and to dopamine D 2 sites was investigated. In guinea pig brain membranes, (+)-[ 3 H]SKF 10,047 bound to single class of sites with a K/sub d/ of 4 x 10 -8 M and a B/sub max/ of 333 fmol/mg of protein. This binding was different from μ, kappa, or delta opiate receptor binding. It was inhibited by opiates that produce psychotomimetic activities but not by opiates that lack such activities. Some antipsychotic drugs inhibited (+)-[ 3 H]SKF 10,047 binding with high to moderate affinities in the following order of potency: haloperidol > perphenazine > fluphenazine > acetophenazine > trifluoperazine > molindone greater than or equal to pimozide greater than or equal to thioridazine greater than or equal to chlorpromazine greater than or equal to triflupromazine. However, there were other antipsychotic drugs such as spiperone and clozapine that showed low affinity for the (+)-[ 3 H]SKF 10,047 binding sites. Affinities of antipsychotic drugs for (+)-[ 3 H]SKF 10,047 binding sites did not correlate with those for [ 3 H]spiperone (dopamine D 2 ) sites. [ 3 H]-Haloperidol binding in whole brain membranes was also inhibited by the sigma opiates pentazocine, cyclazocine, and (+)-[ 3 H]SKF 10,047. In the striatum, about half of the saturable [ 3 H]haloperidol binding was to [ 3 H]spiperone (D 2 ) sites and the other half was to sites similar to (+)-[ 3 H]SKF 10,047 binding sites. 15 references, 4 figures, 1 table

Lean six sigma case studies in the healthcare enterprise

CERN Document Server

Furterer, Sandra L

2014-01-01

This book provides a detailed description of how to apply Lean Six Sigma in the health care industry, with a special emphasis on process improvement and operations management in hospitals.  The book begins with a description of the Enterprise Performance Excellence (EPE) improvement methodology developed by the author that links several methodologies including systems thinking, theory of constraints, Lean and Six Sigma to provide an enterprise-wide prioritization and value-chain view of health care. The EPE methodology helps to improve flow at the macro or value-chain level, and then identifies Lean Six Sigma detailed improvements that can further improve processes within the value-chain.  The book also provides real-world health care applications of the EPE and Lean Six Sigma methodologies that showed significant results on throughput, capacity, operational and financial performance. The Enterprise Performance Excellence methodology is described, and also the Six Sigma DMAIC (Define-Measure-Analyze-Improve...

Precipitation of the sigma-phase in Mo-Re alloys

International Nuclear Information System (INIS)

Freze, N.I.; Levitskij, A.D.; Tyumentsev, A.N.; Korotaev, A.D.

1975-01-01

Disintegration processes in thin foils and replicas of alloys Mo+(52 - 56) wpc Re and Mo+(52 - 56)% Re+(0.05 - 0.10)% Fe wpc were studied by electronic microscopy. Alloying with iron was conducted to determine the effect of iron atom segregations at the grain boundaries on separation of the sigma-phase in these regions. Since the nature of disintegration in all alloys was identical, the experimental data were considered on the example of alloy Mo + 54 wpc Re. The laminated specimens of 1 - 2 mm in thickness subjected to cold rolling with subsequent tempering at T = 1100 deg C for 15 min were characterized by intensive disintegration. As a result finelydispersed laminated sigma-phase uniformly distributed throughout the entire volume of the material was formed. The non-deformed specimens did not show separation of the sigma-phase. As a result of separation of the finely-dispersed sigma-phase plasticity of the alloys was increased. So that a foil of Δh = 0.2 mm in thickness can be produced by cold rolling of the laminated specimens without intermediate annealing. By changing the initial state of the specimens and temperature of annealing dispersity and spatial distribution of the sigma-phase may be substantially modified. It provides for considerably increasing plasticity of the two-phase alloys. During separation of the sigma-phase hardness of the deformed specimens becomes greater. Therefore the low-temperature disintegration accompanied by separation of the sigma-phase may be employed for disperse strengthening of the Mo-Re alloys. The refractory properties of such alloye will not be high, since it is coagulated the finely-dispersed segregations of the sigma-phase even at T > 1100 deg C

β-lactoglobulin's conformational requirements for ligand binding at the calyx and the dimer interphase: a flexible docking study.

Directory of Open Access Journals (Sweden)

Lenin Domínguez-Ramírez

Full Text Available β-lactoglobulin (BLG is an abundant milk protein relevant for industry and biotechnology, due significantly to its ability to bind a wide range of polar and apolar ligands. While hydrophobic ligand sites are known, sites for hydrophilic ligands such as the prevalent milk sugar, lactose, remain undetermined. Through the use of molecular docking we first, analyzed the known fatty acid binding sites in order to dissect their atomistic determinants and second, predicted the interaction sites for lactose with monomeric and dimeric BLG. We validated our approach against BLG structures co-crystallized with ligands and report a computational setup with a reduced number of flexible residues that is able to reproduce experimental results with high precision. Blind dockings with and without flexible side chains on BLG showed that: i 13 experimentally-determined ligands fit the calyx requiring minimal movement of up to 7 residues out of the 23 that constitute this binding site. ii Lactose does not bind the calyx despite conformational flexibility, but binds the dimer interface and an alternate Site C. iii Results point to a probable lactolation site in the BLG dimer interface, at K141, consistent with previous biochemical findings. In contrast, no accessible lysines are found near Site C. iv lactose forms hydrogen bonds with residues from both monomers stabilizing the dimer through a claw-like structure. Overall, these results improve our understanding of BLG's binding sites, importantly narrowing down the calyx residues that control ligand binding. Moreover, our results emphasize the importance of the dimer interface as an insufficiently explored, biologically relevant binding site of particular importance for hydrophilic ligands. Furthermore our analyses suggest that BLG is a robust scaffold for multiple ligand-binding, suitable for protein design, and advance our molecular understanding of its ligand sites to a point that allows manipulation to control

Synthesis and study of new oxazoline-based ligands

OpenAIRE

Tilliet, Mélanie

2008-01-01

This thesis deals with the study of oxazoline-based ligands in metal-catalyzed asymmetric reactions. The first part describes the synthesis of six new bifunctinal pyridine-bis(oxazoline) ligands and their applications in asymmetric metal-catalysis. These ligands, in addition to a Lewis acid coordination site, are equipped with a Lewis basic part in the 4-position of the oxazoline rings. Dual activation by means of this system was probed in cyanide addition to aldehydes. The second part is con...

Enzyme-ligand interactions that drive active site rearrangements in the Helicobacter pylori 5´-methylthioadenosine/S-adenosylhomocysteine nucleosidase

Energy Technology Data Exchange (ETDEWEB)

Ronning, Donald R; Iacopelli, Natalie M; Mishra, Vidhi [Toledo

2012-03-15

The bacterial enzyme 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) plays a central role in three essential metabolic pathways in bacteria: methionine salvage, purine salvage, and polyamine biosynthesis. Recently, its role in the pathway that leads to the production of autoinducer II, an important component in quorum-sensing, has garnered much interest. Because of this variety of roles, MTAN is an attractive target for developing new classes of inhibitors that influence bacterial virulence and biofilm formation. To gain insight toward the development of new classes of MTAN inhibitors, the interactions between the Helicobacter pylori-encoded MTAN and its substrates and substrate analogs were probed using X-ray crystallography. The structures of MTAN, an MTAN-Formycin A complex, and an adenine bound form were solved by molecular replacement and refined to 1.7, 1.8, and 1.6 Å, respectively. The ribose-binding site in the MTAN and MTAN-adenine cocrystal structures contain a tris[hydroxymethyl]aminomethane molecule that stabilizes the closed form of the enzyme and displaces a nucleophilic water molecule necessary for catalysis. This research gives insight to the interactions between MTAN and bound ligands that promote closing of the enzyme active site and highlights the potential for designing new classes of MTAN inhibitors using a link/grow or ligand assembly development strategy based on the described H. pylori MTAN crystal structures.

Towards ligand docking including explicit interface water molecules.

Directory of Open Access Journals (Sweden)

Gordon Lemmon

Full Text Available Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta's ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9:1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation.

Effect of iodination site on binding of radiolabeled ligand by insulin antibodies and insulin autoantibodies

International Nuclear Information System (INIS)

Diaz, J.L.; Wilkin, T.J.

1988-01-01

Four human insulins and four porcine insulins, each monoiodinated to the same specific activity at one of the four tyrosine residues (A14, A19, B16, B26) and purified by reversed-phase liquid chromatography, were tested in a radiobinding assay against a panel of insulin-antibody (IA)-positive sera from 10 insulin-treated diabetics and insulin-autoantibody-positive (IAA) sera from 10 nondiabetics. Of the 10 IAA-positive sera, five were fully cross reactive with both insulin species, and five were specific for human insulin. The rank order of binding of sera with the four ligands from each species was random for IA (mean rank values of 1.9 for A14, 2.0 for A19, 2.5 for B16, and 3.6 for B26 from a possible ranking range of 1 to 4), but more consistent for non-human-insulin-specific IAA (mean rank values 1.3 for A14, 3.8 for A19, 1.7 for B16, and 3.2 for B26 for labeled human insulins; 1.2 for A14, 4.0 for A19, 1.8 for B16, and 3.0 for B26 for labeled porcine insulins). The rank order of binding was virtually uniform for human-insulin-specific IAA (mean values 1.2 for A14, 3.0 for A19, 1.8 for B16, and 4.0 for B26). The influence of iodination site on the binding of labeled insulin appears to be dependent on the proximity of the labeled tyrosine to the antibody binding site and the clonal diversity, or restriction, of insulin-binding antibodies in the test serum. When IA and IAA are measured, the implications of this study regarding the choice of assay ligand may be important

Consensus of sample-balanced classifiers for identifying ligand-binding residue by co-evolutionary physicochemical characteristics of amino acids

KAUST Repository

Chen, Peng

2013-01-01

Protein-ligand binding is an important mechanism for some proteins to perform their functions, and those binding sites are the residues of proteins that physically bind to ligands. So far, the state-of-the-art methods search for similar, known structures of the query and predict the binding sites based on the solved structures. However, such structural information is not commonly available. In this paper, we propose a sequence-based approach to identify protein-ligand binding residues. Due to the highly imbalanced samples between the ligand-binding sites and non ligand-binding sites, we constructed several balanced data sets, for each of which a random forest (RF)-based classifier was trained. The ensemble of these RF classifiers formed a sequence-based protein-ligand binding site predictor. Experimental results on CASP9 targets demonstrated that our method compared favorably with the state-of-the-art. © Springer-Verlag Berlin Heidelberg 2013.

Kinetics of sigma phase formation in a Duplex Stainless Steel

Directory of Open Access Journals (Sweden)

Rodrigo Magnabosco

2009-09-01

Full Text Available This work determines the kinetics of sigma phase formation in UNS S31803 Duplex Stainless Steel (DSS, describing the phase transformations that occur in isothermal aging between 700 and 900 ºC for time periods up to 1032 hours, allowing the determination of the Time-Temperature-Precipitation (TTP diagram for sigma phase and proposing a model to predict the kinetics of sigma phase formation using a Johnson-Mehl-Avrami (JMA type expression. The higher kinetics of sigma phase formation occurs at 850 ºC. However, isothermal aging between 700 and 900 ºC for time periods up to 1032 hours are not sufficient to the establishment of thermodynamic equilibrium. Activation energy for both nucleation and growth of sigma phase is determined (185 kJ.mol-1 and its value is equivalent to the activation energy for Cr diffusion in ferrite, indicating that diffusion of Cr is probably the major thermally activated process involved in sigma phase formation. The determined JMA type expression presents good fit with experimental data between 700 and 850 ºC.

Six Sigma Project Selection Using Fuzzy TOPSIS Decision Making Approach

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Rajeev Rathi

2015-05-01

Full Text Available Six Sigma is considered as a logical business strategy that attempts to identify and eliminate the defects or failures for improving the quality of product and processes. A decision on project selection in Six Sigma is always very critical; it plays a key role in successful implementation of Six Sigma. Selection of a right Six Sigma project is essentially important for an automotive company because it greatly influences the manufacturing costs. This paper discusses an approach for right Six Sigma project selection at an automotive industry using fuzzy logic based TOPSIS method. The fuzzy TOPSIS is a well recognized tool to undertake the fuzziness of the data involved in choosing the right preferences. In this context, evaluation criteria have been designed for selection of best alternative. The weights of evaluation criteria are calculated by using the MDL (modified digital logic method and final ranking is calculated through priority index obtained by using fuzzy TOPSIS method. In the selected case study, this approach has rightly helped to identify the right project for implementing Six Sigma for achieving improvement in productivity.

A Lean Six Sigma program in higher education

KAUST Repository

Svensson, Carsten

2015-01-01

Purpose The objective of this paper is to contribute to the body of Lean Six Sigma knowledge within the field of higher education institutions. The paper will review the initial phase of an implementation and highlight future challenges of applying the Lean Six Sigma method in a complex transactional environment. Design/methodology/approach The observations presented in this paper originate from rolling out a large Lean Six Sigma implementation at a recently established university. The paper is supported with secondary data from literature. Findings The implementation of Lean Six Sigma methodology at King Abdullah University of Science and Technology (KAUST) has resulted in improvements in business processes and efficiency. This has been achieved through project execution and training programs. Approximately 350 staff members have completed awareness training, 50 yellow belts and 150 green belts have been trained, and the first round of seven black belts have completed training of which two have completed certification. Research limitations/implications This paper is based on an empirical study of a single instance and the authors’ experiences as practitioners. Originality/value This paper is the first description of what is believed to be one of the largest implementations of Lean Six Sigma in higher education.

Operational excellence (six sigma) philosophy: Application to software quality assurance

Energy Technology Data Exchange (ETDEWEB)

Lackner, M.

1997-11-01

This report contains viewgraphs on operational excellence philosophy of six sigma applied to software quality assurance. This report outlines the following: goal of six sigma; six sigma tools; manufacturing vs administrative processes; Software quality assurance document inspections; map software quality assurance requirements document; failure mode effects analysis for requirements document; measuring the right response variables; and questions.

Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels.

Directory of Open Access Journals (Sweden)

Xiao-Fei Gao

Full Text Available (+-SKF 10047 (N-allyl-normetazocine is a prototypic and specific sigma-1 receptor agonist that has been used extensively to study the function of sigma-1 receptors. (+-SKF 10047 inhibits K(+, Na(+ and Ca2+ channels via sigma-1 receptor activation. We found that (+-SKF 10047 inhibited Na(V1.2 and Na(V1.4 channels independently of sigma-1 receptor activation. (+-SKF 10047 equally inhibited Na(V1.2/1.4 channel currents in HEK293T cells with abundant sigma-1 receptor expression and in COS-7 cells, which barely express sigma-1 receptors. The sigma-1 receptor antagonists BD 1063,BD 1047 and NE-100 did not block the inhibitory effects of (+-SKF-10047. Blocking of the PKA, PKC and G-protein pathways did not affect (+-SKF 10047 inhibition of Na(V1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM and 1,3-di-o-tolyl-guanidine (DTG also inhibited Na(V1.2 currents through a sigma-1 receptor-independent pathway. The (+-SKF 10047 inhibition of Na(V1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe(1764 and Tyr(1771 in the IV-segment 6 domain of the Na(V1.2 channel and Phe(1579 in the Na(V1.4 channel for (+-SKF 10047 inhibition. In conclusion, our results suggest that sigma-1 receptor agonists directly inhibit Na(V1.2/1.4 channels and that these interactions should be given special attention for future sigma-1 receptor function studies.

Comparing nonmanufacturing with traditional applications of Six Sigma

NARCIS (Netherlands)

Does, R.J.M.M.; Heuvel, van den E.R.; Mast, de J.; Bisgaard, S.

2002-01-01

The Six Sigma approach has in the past been predominantly used to improve manufacturing processes. However, Six Sigma is now increasingly applied to a wide variety of nonmanufacturing operations also. This is an important development—there are potentially more benefits to be achieved in those areas

A construction of observables for AKSZ sigma models

OpenAIRE

Mnev, Pavel

2012-01-01

A construction of gauge-invariant observables is suggested for a class of topological field theories, the AKSZ sigma-models. The observables are associated to extensions of the target Q-manifold of the sigma model to a Q-bundle over it with additional Hamiltonian structure in fibers.

O-fucosylation of the notch ligand mDLL1 by POFUT1 is dispensable for ligand function.

Directory of Open Access Journals (Sweden)

Julia Müller

Full Text Available Fucosylation of Epidermal Growth Factor-like (EGF repeats by protein O-fucosyltransferase 1 (POFUT1 in vertebrates, OFUT1 in Drosophila is pivotal for NOTCH function. In Drosophila OFUT1 also acts as chaperone for Notch independent from its enzymatic activity. NOTCH ligands are also substrates for POFUT1, but in Drosophila OFUT1 is not essential for ligand function. In vertebrates the significance of POFUT1 for ligand function and subcellular localization is unclear. Here, we analyze the importance of O-fucosylation and POFUT1 for the mouse NOTCH ligand Delta-like 1 (DLL1. We show by mass spectral glycoproteomic analyses that DLL1 is O-fucosylated at the consensus motif C²XXXX(S/TC³ (where C² and C³ are the second and third conserved cysteines within the EGF repeats found in EGF repeats 3, 4, 7 and 8. A putative site with only three amino acids between the second cysteine and the hydroxy amino acid within EGF repeat 2 is not modified. DLL1 proteins with mutated O-fucosylation sites reach the cell surface and accumulate intracellularly. Likewise, in presomitic mesoderm cells of POFUT1 deficient embryos DLL1 is present on the cell surface, and in mouse embryonic fibroblasts lacking POFUT1 the same relative amount of overexpressed wild type DLL1 reaches the cell surface as in wild type embryonic fibroblasts. DLL1 expressed in POFUT1 mutant cells can activate NOTCH, indicating that POFUT1 is not required for DLL1 function as a Notch ligand.

Potentialities of a new sigma(+)-sigma(-)laser configuration for radiative cooling and trapping

Energy Technology Data Exchange (ETDEWEB)

Dalibard, J; Reynaud, S; Cohen-Tannoudji, C

1984-11-28

In the process of cooling and trapping neutral atoms, a new laser configuration is investigated which consists of two counterpropagating laser beams with orthogonal sigma(+) and sigma(-)polarizations. It is shown that such a configuration looks more promising than an ordinary standing wave (where the two counterpropagating waves have the same polarization), and this result is explained as being due to angular momentum conservation which prevents any coherent redistribution of photons between the two waves. The present conclusions are based on a quantitative calculation of the various parameters (potential depth, friction coefficient, diffusion coefficient) describing the mean value and the fluctuations of the radiative forces experienced, in such a laser configuration, by an atom with a J 0 ground state and a J 1 excited state. 30 references.

Adoção do Six Sigma pelas 500 Maiores Empresas em PortugalUse of the Six Sigma by the 500 Largent Companies in PortugalAdopción del Six Sigma por las 500 Mayores Empresas de Portugal

Directory of Open Access Journals (Sweden)

CONCEIÇÃO, Ana Cristina Mendes da

2011-09-01

Full Text Available RESUMOO Six Sigma teve sua gênese em empresas industriais de grande porte que o implementaram como uma ferramenta para redução de falhas na área de produção. Seu sucesso inicial estimulou o emprego desta ferramenta em organizações de outros setores em outras áreas além da de produção. O resultado exitoso destas experiências conferiram ao Six Sigma um status de ferramenta de gestão. O objetivo deste estudo é investigar em que medida o Six Sigma está presente nas 500 maiores empresas não-financeiras portuguesas. A coleta de dados deu-se por intermédio de questionário. Os resultados revelam que o êxito na implementação do Six Sigma está condicionado ao envolvimento dos diversos níveis organizacionais. Além disto, os resultados reportam que a implementação do Six Sigma vem acompanhada de ganhos produtividade e, em geral, de uma maior satisfação dos clientes externos. Constatou-se ainda que há pequena expressão nas empresas analisadas embora o interesse pelo mesmo, como ferramenta de gestão, seja apenas suplantado pela ISO 9001 e o Balanced Scorecard.ABSTRACTThe Six Sigma had its genesis in big industrial companies that have implemented it as a tool for reducing defects. The initial success encouraged its application in other areas and we see today successful implementation in other sectors such as services, and within their own organizations in other areas beyond production, setting; this has contributed to Six Sigma being recognized as a new management model. In order to determine the extent to which Six Sigma is present in Portuguese companies, a questionnaire has been designed to target the 500 largest, non-financial companies, operating in Portugal. From the analysis of the results, we can conclude that top management support and the level of involvement of employees in developing and implementing Six Sigma projects are perceived as critical factors in successful implementations. In terms of impact on the

The alternative sigma factor sigma B of Staphylococcus aureus modulates virulence in experimental central venous catheter-related infections.

Science.gov (United States)

Lorenz, Udo; Hüttinger, Christian; Schäfer, Tina; Ziebuhr, Wilma; Thiede, Arnulf; Hacker, Jörg; Engelmann, Susanne; Hecker, Michael; Ohlsen, Knut

2008-03-01

The impact of the alternative sigma factor sigma B (SigB) on pathogenesis of Staphylococcus aureus is not conclusively clarified. In this study, a central venous catheter (CVC) related model of multiorgan infection was used to investigate the role of SigB for the pathogenesis of S. aureus infections and biofilm formation in vivo. Analysis of two SigB-positive wild-type strains and their isogenic mutants revealed uniformly that the wild-type was significantly more virulent than the SigB-deficient mutant. The observed difference in virulence was apparently not linked to the capability of the strains to form biofilms in vivo since wild-type and mutant strains were able to produce biofilm layers inside of the catheter. The data strongly indicate that the alternative sigma factor SigB plays a role in CVC-associated infections caused by S. aureus.

Six Sigma Evaluation of the High Level Waste Tank Farm Corrosion Control Program at the Savannah River Site

International Nuclear Information System (INIS)

Hill, P. J.

2003-01-01

Six Sigma is a disciplined approach to process improvement based on customer requirements and data. The goal is to develop or improve processes with defects that are measured at only a few parts per million. The process includes five phases: Identify, Measure, Analyze, Improve, and Control. This report describes the application of the Six Sigma process to improving the High Level Waste (HLW) Tank Farm Corrosion Control Program. The report documents the work performed and the tools utilized while applying the Six Sigma process from September 28, 2001 to April 1, 2002. During Fiscal Year 2001, the High Level Waste Division spent $5.9 million to analyze samples from the F and H Tank Farms. The largest portion of these analytical costs was $2.45 million that was spent to analyze samples taken to support the Corrosion Control Program. The objective of the Process Improvement Project (PIP) team was to reduce the number of analytical tasks required to support the Corrosion Control Program by 50 percent. Based on the data collected, the corrosion control decision process flowchart, and the use of the X-Y Matrix tool, the team determined that analyses in excess of the requirements of the corrosion control program were being performed. Only two of the seven analytical tasks currently performed are required for the 40 waste tanks governed by the Corrosion Control Program. Two additional analytical tasks are required for a small subset of the waste tanks resulting in an average of 2.7 tasks per sample compared to the current 7 tasks per sample. Forty HLW tanks are sampled periodically as part of the Corrosion Control Program. For each of these tanks, an analysis was performed to evaluate the stability of the chemistry in the tank and then to determine the statistical capability of the tank to meet minimum corrosion inhibitor limits. The analyses proved that most of the tanks were being sampled too frequently. Based on the results of these analyses and th e use of additional

The sigma(54) regulon (sigmulon) of Pseudomonas putida

DEFF Research Database (Denmark)

Cases, I.; Ussery, David; de Lorenzo, V.

2003-01-01

, the sigma(54) regulon has been studied both in Escherichia coli, Salmonella typhimurium and several species of the Rhizobiaceae. Here we present the analysis of the sigma(54) regulon (sigmulon) in the complete genome of Pseudomonas putida KT2440. We have developed an improved method for the prediction...

Establishing a Lean Six Sigma Program in Higher Education

KAUST Repository

Svensson, Carsten; Baessa, Mohamed A.; Bakhsh, Majed M.

2013-01-01

Purpose: The objective of this paper is a contribution to the body of Lean Six Sigma knowledge within the vertical of higher education institutions. The paper will review the initial phase of an implementation and highlight future challenges. Approach: The observations presented in this paper, originates from rolling out a large lean six sigma implementation at a newly established university. The paper is supported with secondary data from literature. Findings: The paper will discuss the challenges of applying the lean six sigma method in a complex transactional environment. Research limitations: This paper is based on an empirical study of a single instance and authors’ experiences as practitioners. Originality: This paper is the first description of what is believed to be one of the largest implementations of Lean Six Sigma in higher education.

Establishing a Lean Six Sigma Program in Higher Education

KAUST Repository

Svensson, Carsten

2013-09-12

Purpose: The objective of this paper is a contribution to the body of Lean Six Sigma knowledge within the vertical of higher education institutions. The paper will review the initial phase of an implementation and highlight future challenges. Approach: The observations presented in this paper, originates from rolling out a large lean six sigma implementation at a newly established university. The paper is supported with secondary data from literature. Findings: The paper will discuss the challenges of applying the lean six sigma method in a complex transactional environment. Research limitations: This paper is based on an empirical study of a single instance and authors’ experiences as practitioners. Originality: This paper is the first description of what is believed to be one of the largest implementations of Lean Six Sigma in higher education.

A ligand peptide motif selected from a cancer patient is a receptor-interacting site within human interleukin-11.

Directory of Open Access Journals (Sweden)

Marina Cardó-Vila

Full Text Available Interleukin-11 (IL-11 is a pleiotropic cytokine approved by the FDA against chemotherapy-induced thrombocytopenia. From a combinatorial selection in a cancer patient, we isolated an IL-11-like peptide mapping to domain I of the IL-11 (sequence CGRRAGGSC. Although this motif has ligand attributes, it is not within the previously characterized interacting sites. Here we design and validate in-tandem binding assays, site-directed mutagenesis and NMR spectroscopy to show (i the peptide mimics a receptor-binding site within IL-11, (ii the binding of CGRRAGGSC to the IL-11R alpha is functionally relevant, (iii Arg4 and Ser8 are the key residues mediating the interaction, and (iv the IL-11-like motif induces cell proliferation through STAT3 activation. These structural and functional results uncover an as yet unrecognized receptor-binding site in human IL-11. Given that IL-11R alpha has been proposed as a target in human cancer, our results provide clues for the rational design of targeted drugs.

Production of n-bar's and Sigma-bar+-'s in e+e- annihilations

International Nuclear Information System (INIS)

Ferguson, T.; Buchanan, C.; Nodulman, L.; Poster, R.; Breidenbach, M.; Morehouse, C.C.; Vannucci, F.

1979-01-01

The production of antineutrons and charged Sigma-bar's in e + e - annihilations has been measured at √s +- production between 4 and 7 GeV is consistent with simple expectations for charmed-baryon production. A search for the decays Lambda-bar - /sub c/ → Sigma-bar +- π -+ π - and Sigma-baratsup asteriskat/sub c//Sigma-bar/sub c/ → Lambda-bar - /sub c/π +- yields no significant peaks. An upper limit, at the 90% confidence level, of sigmaatsub Lambda-baratc-italicB (Lambda-bar/sub c/ → Sigma-bar +- π -+ π - ) < 56 pb is set

sigma model approach to the heterotic string theory

International Nuclear Information System (INIS)

Sen, A.

1985-09-01

Relation between the equations of motion for the massless fields in the heterotic string theory, and the conformal invariance of the sigma model describing the propagation of the heterotic string in arbitrary background massless fields is discussed. It is emphasized that this sigma model contains complete information about the string theory. Finally, we discuss the extension of the Hull-Witten proof of local gauge and Lorentz invariance of the sigma-model to higher order in α', and the modification of the transformation laws of the antisymmetric tensor field under these symmetries. Presence of anomaly in the naive N = 1/2 supersymmetry transformation is also pointed out in this context. 12 refs

Sigma: Web Retrieval Interface for Nuclear Reaction Data

International Nuclear Information System (INIS)

Pritychenko, B.; Sonzogni, A.A.

2008-01-01

The authors present Sigma, a Web-rich application which provides user-friendly access in processing and plotting of the evaluated and experimental nuclear reaction data stored in the ENDF-6 and EXFOR formats. The main interface includes browsing using a periodic table and a directory tree, basic and advanced search capabilities, interactive plots of cross sections, angular distributions and spectra, comparisons between evaluated and experimental data, computations between different cross section sets. Interactive energy-angle, neutron cross section uncertainties plots and visualization of covariance matrices are under development. Sigma is publicly available at the National Nuclear Data Center website at www.nndc.bnl.gov/sigma

Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells.

Directory of Open Access Journals (Sweden)

Attila Szabo

Full Text Available The orphan receptor sigma-1 (sigmar-1 is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT, its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Radioiodinated ligands for dopamine receptors

International Nuclear Information System (INIS)

Kung, H.F.

1994-01-01

The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

A Novel Sigma-Delta Modulator with Fractional-Order Digital Loop Integrator

Directory of Open Access Journals (Sweden)

Chi Xu

2017-01-01

Full Text Available This paper proposes using a fractional-order digital loop integrator to improve the robust stability of Sigma-Delta modulator, thus extending the integer-order Sigma-Delta modulator to a non-integer-order (fractional-order one in the Sigma-Delta ADC design field. The proposed fractional-order Sigma-Delta modulator has reasonable noise characteristics, dynamic range, and bandwidth; moreover the signal-to-noise ratio (SNR is improved remarkably. In particular, a 2nd-order digital loop integrator and a digital PIλDμ controller are combined to work as the fractional-order digital loop integrator, which is realized using FPGA; this will reduce the ASIC analog circuit layout design and chip testing difficulties. The parameters of the proposed fractional-order Sigma-Delta modulator are tuned by using swarm intelligent algorithm, which offers opportunity to simplify the process of tuning parameters and further improve the noise performance. Simulation results are given and they demonstrate the efficiency of the proposed fractional-order Sigma-Delta modulator.

Measurement of $\\sigma_{t\\bar{t}b\\bar{b}}/\\sigma_{t\\bar{t}jj}$ ratio at 13 TeV with the CMS Detector

CERN Document Server

Jo, Young-kwon

2016-01-01

The measurement of the cross section ratio $\\sigma_{t\\bar{t}b\\bar{b}}/\\sigma_{t\\bar{t}jj}$ is presented using a data sample corresponding to an integrated luminosity of 2.3~$\\rm{fb}^{-1}$ collected in pp collisions at \\\\ $\\sqrt{s}$ = 13TeV with the CMS detector at the LHC. Events with two leptons and at least four reconstructed jets, including at least two identified as b quark jets, in the final state are selected. The measured ratio is $0.022 \\pm 0.003$(stat.)$\\pm0.006$(syst.) in the full phase space. The measured cross section $\\sigma_{t\\bar{t}b\\bar{b}}$ is $3.9 \\pm 0.6$(stat.)$\\pm1.3$(syst.) pb and $\\sigma_{t\\bar{t}jj}$ is $176 \\pm 5$(stat.)$ \\pm 33 $(syst.) pb.

High resolution transmission electron microscopy studies of {sigma} phase in Ni-based single crystal superalloys

Energy Technology Data Exchange (ETDEWEB)

Sun Fei [Key Laboratory of Liquid Structure and Heredity of Materials, Ministry of Education, Shandong University, Jinan 250061 (China); Zhang Jianxin, E-mail: jianxin@sdu.edu.cn [Key Laboratory of Liquid Structure and Heredity of Materials, Ministry of Education, Shandong University, Jinan 250061 (China); Liu Pan [Institute of Microstructure and Property of Advanced Materials, Beijing University of Technology, Beijing 100124 (China); Feng Qiang [National Center for Materials Service Safety, University of Science and Technology Beijing, Beijing 100083 (China); State Key Laboratory for Advanced Metals and Materials, University of Science and Technology Beijing, Beijing 100083 (China); Han Xiaodong; Mao Shengcheng [Institute of Microstructure and Property of Advanced Materials, Beijing University of Technology, Beijing 100124 (China)

2012-09-25

Graphical abstract: (a) TEM micrograph of {sigma} phase; (b) HRTEM image of {sigma}/{gamma} interface corresponding to the area of the white frame in (a); (c) an enlarged image of area from the white frame in (b). The combination of {sigma}/{gamma} interface appears very well, and a two-atomic-layer step is shown on the {sigma}/{gamma} interface. In addition, {sigma} phase has the orientation relationship of [0 0 1]{sub {gamma}}//[1 1 2{sup Macron }]{sub {sigma}}, (2{sup Macron} 2 0){sub {gamma}}//(1{sup Macron} 1 0){sub {sigma}}, (2{sup Macron }2{sup Macron} 0){sub {gamma}}//(1 1 1){sub {sigma}}; [0 1 1]{sub {gamma}}//[1 1 0]{sub {sigma}}, (1 1{sup Macron} 1){sub {gamma}}//(0 0 1{sup Macron }){sub {sigma}} with the {gamma} phase. Highlights: Black-Right-Pointing-Pointer Elemental characteristic of {sigma} phase is studied by HAADF techniques and EDS analysis. Black-Right-Pointing-Pointer Interfacial characteristics of {sigma}/{gamma} interface are revealed by HRTEM. Black-Right-Pointing-Pointer An atomic structural {sigma}/{gamma} interface with a two-atomic-layer step has been proposed. - Abstract: By means of high resolution transmission electron microscopy (HRTEM) and high-angle annular dark-field image technique (HAADF), morphological of plate-shaped {sigma} phase and interfacial characteristics between plate-shaped {sigma} phase and {gamma} phase in Ni-based single crystal superalloys have been studied. On the basis of HRTEM observations, an atomic structural interface between {sigma} phase and {gamma} phase with a step has been proposed. {sigma} Phase has the relationship of [0 0 1]{sub {gamma}}//[1 1 2{sup Macron }]{sub {sigma}}, (2{sup Macron} 2 0){sub {gamma}}//(1{sup Macron} 1 0){sub {sigma},} (2{sup Macron }2{sup Macron} 0){sub {gamma}}//(1 1 1){sub {sigma}}; [0 1 1]{sub {gamma}}//[1 1 0]{sub {sigma}}, (1 1{sup Macron} 1){sub {gamma}}//(0 0 1{sup Macron }){sub {sigma}} with the {gamma} phase. The compositional characteristics of the {sigma} phase which

Single-electron transfer in palladium complexes of 1,4-naphthoquinone-containing bis(pyrazol-1-yl)methane ligands.

Science.gov (United States)

Scheuermann, Sebastian; Sarkar, Biprajit; Bolte, Michael; Bats, Jan W; Lerner, Hans-Wolfram; Wagner, Matthias

2009-10-05

A 1,4-naphthoquinone-substituted bis(pyrazol-1-yl)methane ligand (N--N) has been synthesized and transformed into its corresponding Pd(II) chelate complex [(N--N)PdCl(2)]. Both N--N and [(N--N)PdCl(2)] have been fully characterized by NMR spectroscopy, spectro-electrochemistry, and X-ray crystallography. After treatment of [(N--N)PdCl(2)] with NEt(3), the signature of a 1,4-naphthosemiquinonate radical is visible in the UV-vis- and electron paramagnetic resonance (EPR) spectrum of the reaction mixture; the free ligand N--N does not react with NEt(3) under the conditions applied. It is therefore concluded that NEt(3) first reduces the Pd(II)-ion of [(N--N)PdCl(2)] to the zero-valent state and that this reaction is followed by a single-electron transfer from the metal atom to the 1,4-naphthoquinone moiety. The complex has been specifically designed to disfavor any direct Pd-to-naphthoquinone coordination. Electron transfer thus proceeds through space or, less likely, via sigma-bonds of the ligand framework.

Sigma-1 Receptor Plays a Negative Modulation on N-type Calcium Channel

Directory of Open Access Journals (Sweden)

Kang Zhang

2017-05-01

Full Text Available The sigma-1 receptor is a 223 amino acids molecular chaperone with a single transmembrane domain. It is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes. By chaperone-mediated interactions with ion channels, G-protein coupled receptors and cell-signaling molecules, the sigma-1 receptor performs broad physiological and pharmacological functions. Despite sigma-1 receptors have been confirmed to regulate various types of ion channels, the relationship between the sigma-1 receptor and N-type Ca2+ channel is still unclear. Considering both sigma-1 receptors and N-type Ca2+ channels are involved in intracellular calcium homeostasis and neurotransmission, we undertake studies to explore the possible interaction between these two proteins. In the experiment, we confirmed the expression of the sigma-1 receptors and the N-type calcium channels in the cholinergic interneurons (ChIs in rat striatum by using single-cell reverse transcription-polymerase chain reaction (scRT-PCR and immunofluorescence staining. N-type Ca2+ currents recorded from ChIs in the brain slice of rat striatum was depressed when sigma-1 receptor agonists (SKF-10047 and Pre-084 were administrated. The inhibition was completely abolished by sigma-1 receptor antagonist (BD-1063. Co-expression of the sigma-1 receptors and the N-type calcium channels in Xenopus oocytes presented a decrease of N-type Ca2+ current amplitude with an increase of sigma-1 receptor expression. SKF-10047 could further depress N-type Ca2+ currents recorded from oocytes. The fluorescence resonance energy transfer (FRET assays and co-immunoprecipitation (Co-IP demonstrated that sigma-1 receptors and N-type Ca2+ channels formed a protein complex when they were co-expressed in HEK-293T (Human Embryonic Kidney -293T cells. Our results revealed that the sigma-1 receptors played a negative modulation on N-type Ca2+ channels. The mechanism for the inhibition of sigma-1 receptors on

Nonlinear consider covariance analysis using a sigma-point filter formulation

Science.gov (United States)

Lisano, Michael E.

2006-01-01

The research reported here extends the mathematical formulation of nonlinear, sigma-point estimators to enable consider covariance analysis for dynamical systems. This paper presents a novel sigma-point consider filter algorithm, for consider-parameterized nonlinear estimation, following the unscented Kalman filter (UKF) variation on the sigma-point filter formulation, which requires no partial derivatives of dynamics models or measurement models with respect to the parameter list. It is shown that, consistent with the attributes of sigma-point estimators, a consider-parameterized sigma-point estimator can be developed entirely without requiring the derivation of any partial-derivative matrices related to the dynamical system, the measurements, or the considered parameters, which appears to be an advantage over the formulation of a linear-theory sequential consider estimator. It is also demonstrated that a consider covariance analysis performed with this 'partial-derivative-free' formulation yields equivalent results to the linear-theory consider filter, for purely linear problems.

6 Sigma DFSS technique which is easy to use

International Nuclear Information System (INIS)

2002-01-01

This book gives descriptions of 6 sigma DFSS technique. The contents of this book are storm of change, way of problem and solution, importance of customer satisfaction, quality improvement is key of customer satisfaction, quality improvement equals cost cutting, quality aim in perfect level, finding basic cause, data is life, standardization is fundamentals of all activity for improvement, chief, Chang's house, collection of data, setting goal to improve, experiment is the best way, importance of the last step, x control power of 6 sigma and Let's go six-sigma.

Lectures on nonlinear sigma-models in projective superspace

Energy Technology Data Exchange (ETDEWEB)

Kuzenko, Sergei M, E-mail: kuzenko@cyllene.uwa.edu.a [School of Physics M013, University of Western Australia, 35 Stirling Highway, Crawley WA 6009 (Australia)

2010-11-05

N= 2 supersymmetry in four spacetime dimensions is intimately related to hyperkaehler and quaternionic Kaehler geometries. On one hand, the target spaces for rigid supersymmetric sigma-models are necessarily hyperkaehler manifolds. On the other hand, when coupled to N= 2 supergravity, the sigma-model target spaces must be quaternionic Kaehler. It is known that such manifolds of restricted holonomy are difficult to generate explicitly. Projective superspace is a field-theoretic approach to construct general N= 2 supersymmetric nonlinear sigma-models, and hence to generate new hyperkaehler and quaternionic Kaehler metrics. Intended for a mixed audience consisting of both physicists and mathematicians, these lectures provide a pedagogical introduction to the projective-superspace approach. (topical review)

Lectures on nonlinear sigma-models in projective superspace

International Nuclear Information System (INIS)

Kuzenko, Sergei M

2010-01-01

N= 2 supersymmetry in four spacetime dimensions is intimately related to hyperkaehler and quaternionic Kaehler geometries. On one hand, the target spaces for rigid supersymmetric sigma-models are necessarily hyperkaehler manifolds. On the other hand, when coupled to N= 2 supergravity, the sigma-model target spaces must be quaternionic Kaehler. It is known that such manifolds of restricted holonomy are difficult to generate explicitly. Projective superspace is a field-theoretic approach to construct general N= 2 supersymmetric nonlinear sigma-models, and hence to generate new hyperkaehler and quaternionic Kaehler metrics. Intended for a mixed audience consisting of both physicists and mathematicians, these lectures provide a pedagogical introduction to the projective-superspace approach. (topical review)

SU-D-BRC-02: Application of Six Sigma Approach to Improve the Efficiency of Patient-Specific QA in Proton Therapy

International Nuclear Information System (INIS)

LAH, J; Shin, D; Manger, R; Kim, G

2016-01-01

Purpose: To show how the Six Sigma DMAIC (Define-Measure-Analyze-Improve-Control) can be used for improving and optimizing the efficiency of patient-specific QA process by designing site-specific range tolerances. Methods: The Six Sigma tools (process flow diagram, cause and effect, capability analysis, Pareto chart, and control chart) were utilized to determine the steps that need focus for improving the patient-specific QA process. The patient-specific range QA plans were selected according to 7 treatment site groups, a total of 1437 cases. The process capability index, Cpm was used to guide the tolerance design of patient site-specific range. We also analyzed the financial impact of this project. Results: Our results suggested that the patient range measurements were non-capable at the current tolerance level of ±1 mm in clinical proton plans. The optimized tolerances were calculated for treatment sites. Control charts for the patient QA time were constructed to compare QA time before and after the new tolerances were implemented. It is found that overall processing time was decreased by 24.3% after establishing new site-specific range tolerances. The QA failure for whole process in proton therapy would lead up to a 46% increase in total cost. This result can also predict how costs are affected by changes in adopting the tolerance design. Conclusion: We often believe that the quality and performance of proton therapy can easily be improved by merely tightening some or all of its tolerance requirements. This can become costly, however, and it is not necessarily a guarantee of better performance. The tolerance design is not a task to be undertaken without careful thought. The Six Sigma DMAIC can be used to improve the QA process by setting optimized tolerances. When tolerance design is optimized, the quality is reasonably balanced with time and cost demands.

SU-D-BRC-02: Application of Six Sigma Approach to Improve the Efficiency of Patient-Specific QA in Proton Therapy

Energy Technology Data Exchange (ETDEWEB)

LAH, J [Myongji Hospital, Goyang-si (Korea, Republic of); Shin, D [Proton Therapy Center, National Cancer Center, Goyang (Korea, Republic of); Manger, R; Kim, G [University of California, San Diego, La Jolla, CA (United States)

2016-06-15

Purpose: To show how the Six Sigma DMAIC (Define-Measure-Analyze-Improve-Control) can be used for improving and optimizing the efficiency of patient-specific QA process by designing site-specific range tolerances. Methods: The Six Sigma tools (process flow diagram, cause and effect, capability analysis, Pareto chart, and control chart) were utilized to determine the steps that need focus for improving the patient-specific QA process. The patient-specific range QA plans were selected according to 7 treatment site groups, a total of 1437 cases. The process capability index, Cpm was used to guide the tolerance design of patient site-specific range. We also analyzed the financial impact of this project. Results: Our results suggested that the patient range measurements were non-capable at the current tolerance level of ±1 mm in clinical proton plans. The optimized tolerances were calculated for treatment sites. Control charts for the patient QA time were constructed to compare QA time before and after the new tolerances were implemented. It is found that overall processing time was decreased by 24.3% after establishing new site-specific range tolerances. The QA failure for whole process in proton therapy would lead up to a 46% increase in total cost. This result can also predict how costs are affected by changes in adopting the tolerance design. Conclusion: We often believe that the quality and performance of proton therapy can easily be improved by merely tightening some or all of its tolerance requirements. This can become costly, however, and it is not necessarily a guarantee of better performance. The tolerance design is not a task to be undertaken without careful thought. The Six Sigma DMAIC can be used to improve the QA process by setting optimized tolerances. When tolerance design is optimized, the quality is reasonably balanced with time and cost demands.

Six sigma implementation and its effects on configuration management related to metal industry

International Nuclear Information System (INIS)

Tariq, M.M.; Ahmad, S.F.; Mahmoo, A.; Kalsoom, T.

2006-01-01

This paper discusses the implementation of Six Sigma and its effects on Configuration Management (CM) of metal industry. The basic idea behind the Six Sigma philosophy is to continuously reduce product and process variation. Design for Six Sigma (DFSS) methodology generates new processes, products, services, plants, etc., whereas Define, Measure, Analyze, Improve and Control (DMAIC) methodology improves existing processes, products, services, designs, plants, etc. The DFSS project stages are summarized as Identify, Design, Optimize, and Validate (IDOV). Role of CM for DFSS and DMAIC will be discussed. Seven steps for Six Sigma introduction in new management strategy and the other seven steps for Six Sigma improvement implementation shall be discussed indicating possible role of CM. Tasks of Black Belt leader in Six Sigma implementation are very important. The expected outcomes of Six Sigma efforts are: Faster and more robust product development. More efficient and capable manufacturing processes and, more confident overall business performance. The investigation and knowledge of Six Sigma effects produced in metals industry on CM will increase the effectiveness of each other, and it will be a better, reliable and well documented approach towards Six Sigma. (author)

Importance of the pharmacological profile of the bound ligand in enrichment on nuclear receptors: toward the use of experimentally validated decoy ligands.

Science.gov (United States)

Lagarde, Nathalie; Zagury, Jean-François; Montes, Matthieu

2014-10-27

The evaluation of virtual ligand screening methods is of major importance to ensure their reliability. Taking into account the agonist/antagonist pharmacological profile should improve the quality of the benchmarking data sets since ligand binding can induce conformational changes in the nuclear receptor structure and such changes may vary according to the agonist/antagonist ligand profile. We indeed found that splitting the agonist and antagonist ligands into two separate data sets for a given nuclear receptor target significantly enhances the quality of the evaluation. The pharmacological profile of the ligand bound in the binding site of the target structure was also found to be an additional critical parameter. We also illustrate that active compound data sets for a given pharmacological activity can be used as a set of experimentally validated decoy ligands for another pharmacological activity to ensure a reliable and challenging evaluation of virtual screening methods.

Guiding inpatient quality improvement: a systematic review of Lean and Six Sigma.

Science.gov (United States)

Glasgow, Justin M; Scott-Caziewell, Jill R; Kaboli, Peter J

2010-12-01

Two popular quality improvement (QI) approaches in health care are Lean and Six Sigma. Hospitals continue to adopt these QI approaches-or the hybrid Lean Sigma approach-with little knowledge on how well they produce sustainable improvements. A systematic literature review was conducted to determine whether Lean, Six Sigma, or Lean Sigma have been effectively used to create and sustain improvements in the acute care setting. Databases were searched for articles published in the health care, business, and engineering literatures. Study inclusion criteria required identification of a Six Sigma, Lean, or Lean Sigma project; QI efforts focused on hospitalized patients; descriptions of project improvements; and reported results. Depending on the quality of data reported, articles were classified as summary reports, pre-post observational studies, or time-series reports. Database searches identified 539 potential articles. After review of titles, abstracts, and full text, 47 articles met inclusion criteria--10 articles summarized multiple projects, 12 reported Lean projects, 20 reported Six Sigma projects, and 5 reported Lean Sigma projects. Generally, the studies provided limited data, with only 15 articles providing any sort of follow-up data; of the 15, only 3 report a follow-up period greater than two years. Lean, Six Sigma, and Lean Sigma as QI approaches can aid institutions in tackling a wide variety of problems encountered in acute care. However, the true impact of these approaches is difficult to judge, given that the lack of rigorous evaluation or clearly sustained improvements provides little evidence supporting broad adoption. There is still a need for future work that will improve the evidence base for understanding more about QI approaches and how to achieve sustainable improvement.

Six Sigma Process and its Impact on the Organizational Productivity

OpenAIRE

Masoud Hekmatpanah; Mohammad Sadroddin; Saeid Shahbaz; Farhad Mokhtari; Farahnaz Fadavinia

2008-01-01

The six sigma method is a project-driven management approach to improve the organization-s products, services, and processes by continually reducing defects in the organization. Understanding the key features, obstacles, and shortcomings of the six sigma method allows organizations to better support their strategic directions, and increasing needs for coaching, mentoring, and training. It also provides opportunities to better implement six sigma projects. The purpose of this paper is the surv...

Magnetic detection of sigma phase in duplex stainless steel UNS S31803

Energy Technology Data Exchange (ETDEWEB)

Tavares, S.S.M., E-mail: ssmtavares@terra.com.b [Universidade Federal Fluminense, Departamento de Engenharia Mecanica, PGMEC, Rua Passo da Patria, 156, CEP 24210-240, Niteroi (Brazil); Pardal, J.M.; Guerreiro, J.L. [Universidade Federal Fluminense, Departamento de Engenharia Mecanica, PGMEC, Rua Passo da Patria, 156, CEP 24210-240, Niteroi (Brazil); Gomes, A.M. [Universidade Federal do Rio de Janeiro, Instituto de Fisica (Brazil); Silva, M.R. da [Universidade Federal de Itajuba, Instituto de Ciencias (Brazil)

2010-09-15

Duplex stainless steels are high strength and corrosion resistant steels extensively used in the chemical and petrochemical industry. The best mechanical properties and corrosion resistance are obtained with a microstructure composed by equal parts of ferrite and austenite and free from tertiary phases. Sigma phase is one of these deleterious tertiary phases. In the present work different amounts of sigma phase were precipitated by heat treatments in a UNS S31803 stainless steel. Some specimens were cold rolled before sigma phase precipitation in order to evaluate the effect of deformation on the magnetic measurements. The amount of sigma phase was precisely determined by microscopy and image analysis for each heat treatment condition. The effects of sigma phase on the steel properties were investigated, confirming the detrimental effects of very small percentages on corrosion resistance and toughness. Two magnetic methods were used to detect sigma phase: magnetization saturation measurements in a Vibrating Sample Magnetometer and ferritoscope testing. Both methods were found to be sensitive to small percentages of sigma phase in the microstructure.

Interest and limits of the six sigma methodology in medical laboratory.

Science.gov (United States)

Scherrer, Florian; Bouilloux, Jean-Pierre; Calendini, Ors'Anton; Chamard, Didier; Cornu, François

2017-02-01

The mandatory accreditation of clinical laboratories in France provides an incentive to develop real tools to measure performance management methods and to optimize the management of internal quality controls. Six sigma methodology is an approach commonly applied to software quality management and discussed in numerous publications. This paper discusses the primary factors that influence the sigma index (the choice of the total allowable error, the approach used to address bias) and compares the performance of different analyzers on the basis of the sigma index. Six sigma strategy can be applied to the policy management of internal quality control in a laboratory and demonstrates through a comparison of four analyzers that there is no single superior analyzer in clinical chemistry. Similar sigma results are obtained using approaches toward bias based on the EQAS or the IQC. The main difficulty in using the six sigma methodology lies in the absence of official guidelines for the definition of the total error acceptable. Despite this drawback, our comparison study suggests that difficulties with defined analytes do not vary with the analyzer used.

Calculation of site affinity constants and cooperativity coefficients for binding of ligands and/or protons to macromolecules. II. Relationships between chemical model and partition function algorithm.

Science.gov (United States)

Fisicaro, E; Braibanti, A; Lamb, J D; Oscarson, J L

1990-05-01

The relationships between the chemical properties of a system and the partition function algorithm as applied to the description of multiple equilibria in solution are explained. The partition functions ZM, ZA, and ZH are obtained from powers of the binary generating functions Jj = (1 + kappa j gamma j,i[Y])i tau j, where i tau j = p tau j, q tau j, or r tau j represent the maximum number of sites in sites in class j, for Y = M, A, or H, respectively. Each term of the generating function can be considered an element (ij) of a vector Jj and each power of the cooperativity factor gamma ij,i can be considered an element of a diagonal cooperativity matrix gamma j. The vectors Jj are combined in tensor product matrices L tau = (J1) [J2]...[Jj]..., thus representing different receptor-ligand combinations. The partition functions are obtained by summing elements of the tensor matrices. The relationship of the partition functions with the total chemical amounts TM, TA, and TH has been found. The aim is to describe the total chemical amounts TM, TA, and TH as functions of the site affinity constants kappa j and cooperativity coefficients bj. The total amounts are calculated from the sum of elements of tensor matrices Ll. Each set of indices (pj..., qj..., rj...) represents one element of a tensor matrix L tau and defines each term of the summation. Each term corresponds to the concentration of a chemical microspecies. The distinction between microspecies MpjAqjHrj with ligands bound on specific sites and macrospecies MpAqHR corresponding to a chemical stoichiometric composition is shown. The translation of the properties of chemical model schemes into the algorithms for the generation of partition functions is illustrated with reference to a series of examples of gradually increasing complexity. The equilibria examined concern: (1) a unique class of sites; (2) the protonation of a base with two classes of sites; (3) the simultaneous binding of ligand A and proton H to a

LEAN SIX SIGMA – MULTIPLE CASE STUDY

Directory of Open Access Journals (Sweden)

Delvio Venanzi

2017-12-01

Full Text Available Lean Six Sigma é uma gestão focada na qualidade e desempenho produtivo em sistemas operacionais. Este artigo discute os fundamentos desta metodologia através de duas diferentes concepções de gestão, Lean Manufacturing e Six Sigma. Primeiro, o artigo explica o DMAIC (definir, medir, analisar, melhorar e controlar e suas respectivas fases, após a filosofia Lean com o sipoc e técnicas de mapeamento de fluxo de valor. O artigo pretende mostrar a integração destes dois conceitos e seus resultados. A metodologia consistiu em uma teoria baseada em uma pesquisa bibliográfica de pesquisa exploratória que consistiu de três estudos de caso em empresas de diferenças localizadas em Sorocaba, São Paulo. Neste artigo estuda a aplicação de Lean Seis Sigma e seus resultados.

Modelo de referência para estruturar o Seis Sigma nas organizações Reference model to structure the Six Sigma in organizations

Directory of Open Access Journals (Sweden)

Adriana Barbosa Santos

2008-04-01

Full Text Available Este artigo apresenta o modelo de referência para estruturar o Seis Sigma, o qual é resultante da incorporação de teorias que contribuem para aumentar o potencial estratégico do Seis Sigma no sentido de incrementar o desempenho organizacional. Em sua proposta, o modelo de referência engloba um direcionamento sobre certos requisitos primordiais para o sucesso do programa Seis Sigma. A base teórica de sustentação do modelo de referência foi construída a partir de estudos sobre a influência dos seguintes fatores: orientação estratégica e alinhamento estratégico; medição e gerenciamento do desempenho organizacional; uso de estatística (pensamento estatístico; capacitação/especialização de pessoas; implementação e gerenciamento de projetos; e uso de tecnologia de informação. Complementando a proposição do modelo, o artigo traz evidências empíricas acerca da contribuição dos fatores identificados na formulação do modelo de referência, expondo resultados decorrentes de estudos de caso realizados em quatro subsidiárias brasileiras de multinacionais de grande porte. A análise dos dados forneceu evidências positivas de que os fatores mencionados influenciam de forma efetiva o sucesso e a consolidação do Seis Sigma nas empresas estudadas.This paper introduces the reference model to structure Six Sigma. This model is a result of theory incorporation that contributes to increase the strategic power of Six Sigma for improving businesses performance. Reference model proposal points out certain primordial requirements for de Six Sigma program success. The theoretical basis to sustain the reference model was supported in studies about the influence of critical factors such as: strategic orientation and strategic alignment; business performance measurement; statistical approach (statistical thinking; people training; project implementation; and information technology use. Complementing the model proposition, this paper

Architecture effects on multivalent interactions by polypeptide-based multivalent ligands

Science.gov (United States)

Liu, Shuang

Multivalent interactions are characterized by the simultaneous binding between multiple ligands and multiple binding sites, either in solutions or at interfaces. In biological systems, most multivalent interactions occur between protein receptors and carbohydrate ligands through hydrogen-bonding and hydrophobic interactions. Compared with weak affinity binding between one ligand and one binding site, i.e. monovalent interaction, multivalent interactioins provide greater avidity and specificity, and therefore play unique roles in a broad range of biological activities. Moreover, the studies of multivalent interactions are also essential for producing effective inhibitors and effectors of biological processes that could have important therapeutic applications. Synthetic multivalent ligands have been designed to mimic the biological functions of natural multivalent interactions, and various types of scaffolds have been used to display multiple ligands, including small molecules, linear polymers, dendrimers, nanoparticle surfaces, monolayer surfaces and liposomes. Studies have shown that multivalent interactions can be highly affected by various architectural parameters of these multivalent ligands, including ligand identities, valencies, spacing, ligand densities, nature of linker arms, scaffold length and scaffold conformation. Most of these multivalent ligands are chemically synthesized and have limitations of controlling over sequence and conformation, which is a barrier for mimicking ordered and controlled natural biological systems. Therefore, multivalent ligands with precisely controlled architecture are required for improved structure-function relationship studies. Protein engineering methods with subsequent chemical coupling of ligands provide significant advantages of controlling over backbone conformation and functional group placement, and therefore have been used to synthesize recombinant protein-based materials with desired properties similar to natural

Can Six Sigma be the "cure" for our "ailing" NHS?

Science.gov (United States)

Antony, Jiju; Downey-Ennis, Kay; Antony, Frenie; Seow, Chris

2007-01-01

The purpose of this research is to analyse whether Six Sigma business strategy can be used to improve the financial and operational performance of the NHS. The paper will also look at some of the major challenges and barriers in the implementation of this powerful process improvement strategy within the healthcare sector. This paper discusses whether Six Sigma DMAIC methodology can be a useful and disciplined approach to tackle process- and quality-related problems in the NHS. The paper presents some key findings from other researchers in the field, followed by some comments on whether Six Sigma is a useful approach to be considered by the NHS for cost reduction and defect reduction strategies. The paper illustrates the point that Six Sigma is not confined just to manufacturing industry, rather it is equally applicable to service industry, especially the healthcare and financial sectors. The application of Six Sigma in the UK health sector is relatively new and the purpose of the paper is to increase the awareness of this powerful business strategy in healthcare discipline.

An application of Lean Six Sigma in a hospital

NARCIS (Netherlands)

van den Heuvel, J.; Does, R.J.M.M.; de Koning, H.; Anthony, J.; Kumar, M.

2007-01-01

Abstract Healthcare today faces major challenges. Patients demand quality of care to be improved continuously. Insurance companies demand the lowest possible prices. Lean Six Sigma is a tool that can help healthcare providers to achieve these at least partly conflicting goals. Lean Six Sigma is an

CMOS sigma-delta converters practical design guide

CERN Document Server

De la Rosa, Jose M

2013-01-01

A comprehensive overview of Sigma-Delta Analog-to-Digital Converters (ADCs) and a practical guide to their design in nano-scale CMOS for optimal performance. This book presents a systematic and comprehensive compilation of sigma-delta converter operating principles, the new advances in architectures and circuits, design methodologies and practical considerations - going from system-level specifications to silicon integration, packaging and measurements, with emphasis on nanometer CMOS implementation. The book emphasizes practical design issues - from high-level behavioural modelling i

The use of the Six Sigma concept in supply logistics

Directory of Open Access Journals (Sweden)

Agnieszka Szmelter

2012-12-01

Full Text Available This paper aims to present Six Sigma as one of the concepts of business process improvement, including logistics processes. Firstly, the author presents the role of information logistics and controlling to improve the efficiency of supply logistics. Then, she focuses on the characteristics of Six Sigma, including Lean Management philosophy, and identifies the connection between logistics and this methodology. She also presents an example of using the Six Sigma tools in the process of supply in a chosen company.

Continuous time sigma delta ADC design and non-idealities analysis

International Nuclear Information System (INIS)

Yuan Jun; Chen Zhenhai; Yang Yintang; Zhang Zhaofeng; Wu Jun; Wang Chao; Qian Wenrong

2011-01-01

A wide bandwidth continuous time sigma delta ADC is implemented in 130 nm CMOS. A detailed non-idealities analysis (excess loop delay, clock jitter, finite gain and GBW, comparator offset and DAC mismatch) is performed developed in Matlab/Simulink. This design is targeted for wide bandwidth applications such as video or wireless base-stations. Athird-order continuous time sigma delta modulator comprises a third-order RC operational-amplifier-based loop filter and 3-bit internal quantizer operated at 512 MHz clock frequency. The sigma delta ADC achieves 60 dB SNR and 59.3 dB SNDR over a 16-MHz signal band at an OSR of 16. The power consumption of the CT sigma delta modulator is 22 mW from the 1.2-V supply. (semiconductor integrated circuits)

Water oxidation catalyzed by mononuclear ruthenium complexes with a 2,2'-bipyridine-6,6'-dicarboxylate (bda) ligand: how ligand environment influences the catalytic behavior.

Science.gov (United States)

Staehle, Robert; Tong, Lianpeng; Wang, Lei; Duan, Lele; Fischer, Andreas; Ahlquist, Mårten S G; Sun, Licheng; Rau, Sven

2014-02-03

A new water oxidation catalyst [Ru(III)(bda)(mmi)(OH2)](CF3SO3) (2, H2bda = 2,2'-bipyridine-6,6'-dicarboxylic acid; mmi = 1,3-dimethylimidazolium-2-ylidene) containing an axial N-heterocyclic carbene ligand and one aqua ligand was synthesized and fully characterized. The kinetics of catalytic water oxidation by 2 were measured using stopped-flow technique, and key intermediates in the catalytic cycle were probed by density functional theory calculations. While analogous Ru-bda water oxidation catalysts [Ru(bda)L2] (L = pyridyl ligands) are supposed to catalyze water oxidation through a bimolecular coupling pathway, our study points out that 2, surprisingly, undergoes a single-site water nucleophilic attack (acid-base) pathway. The diversion of catalytic mechanisms is mainly ascribed to the different ligand environments, from nonaqua ligands to an aqua ligand. Findings in this work provide some critical proof for our previous hypothesis about how alternation of ancillary ligands of water oxidation catalysts influences their catalytic efficiency.

THE QUALITY IMPROVEMENT OF PRIMER PACKAGING PROCESS USING SIX SIGMA METHODOLOGY

Directory of Open Access Journals (Sweden)

Prima Ditahardiyani

2008-01-01

Full Text Available The implementation of Six Sigma has become a common theme in many organizations. This paper presents the Six Sigma methodology and its implementation in a primer packaging process of Cranberry drink. DMAIC (Define, Measure, Analyze, Improve and Control approach is used to analyze and to improve the primer packaging process, which have high variability and defects output. After the improvement, the results showed that there was an increasing sigma level. However, it is not significantly and has not achieved the world standard quality, yet. Therefore, the implementation of Six Sigma in primer packaging process of Cranberry drink still has a room for doing a further research.

NMR studies of DNA oligomers and their interactions with minor groove binding ligands

Energy Technology Data Exchange (ETDEWEB)

Fagan, Patricia A. [Univ. of California, Berkeley, CA (United States). Dept. of Chemistry

1996-05-01

The cationic peptide ligands distamycin and netropsin bind noncovalently to the minor groove of DNA. The binding site, orientation, stoichiometry, and qualitative affinity of distamycin binding to several short DNA oligomers were investigated by NMR spectroscopy. The oligomers studied contain A,T-rich or I,C-rich binding sites, where I = 2-desaminodeoxyguanosine. I•C base pairs are functional analogs of A•T base pairs in the minor groove. The different behaviors exhibited by distamycin and netropsin binding to various DNA sequences suggested that these ligands are sensitive probes of DNA structure. For sites of five or more base pairs, distamycin can form 1:1 or 2:1 ligand:DNA complexes. Cooperativity in distamycin binding is low in sites such as AAAAA which has narrow minor grooves, and is higher in sites with wider minor grooves such as ATATAT. The distamycin binding and base pair opening lifetimes of I,C-containing DNA oligomers suggest that the I,C minor groove is structurally different from the A,T minor groove. Molecules which direct chemistry to a specific DNA sequence could be used as antiviral compounds, diagnostic probes, or molecular biology tools. The author studied two ligands in which reactive groups were tethered to a distamycin to increase the sequence specificity of the reactive agent.

Consistent two-dimensional visualization of protein-ligand complex series

Directory of Open Access Journals (Sweden)

Stierand Katrin

2011-06-01

Full Text Available Abstract Background The comparative two-dimensional graphical representation of protein-ligand complex series featuring different ligands bound to the same active site offers a quick insight in their binding mode differences. In comparison to arbitrary orientations of the residue molecules in the individual complex depictions a consistent placement improves the legibility and comparability within the series. The automatic generation of such consistent layouts offers the possibility to apply it to large data sets originating from computer-aided drug design methods. Results We developed a new approach, which automatically generates a consistent layout of interacting residues for a given series of complexes. Based on the structural three-dimensional input information, a global two-dimensional layout for all residues of the complex ensemble is computed. The algorithm incorporates the three-dimensional adjacencies of the active site residues in order to find an universally valid circular arrangement of the residues around the ligand. Subsequent to a two-dimensional ligand superimposition step, a global placement for each residue is derived from the set of already placed ligands. The method generates high-quality layouts, showing mostly overlap-free solutions with molecules which are displayed as structure diagrams providing interaction information in atomic detail. Application examples document an improved legibility compared to series of diagrams whose layouts are calculated independently from each other. Conclusions The presented method extends the field of complex series visualizations. A series of molecules binding to the same protein active site is drawn in a graphically consistent way. Compared to existing approaches these drawings substantially simplify the visual analysis of large compound series.

Supersymmetric sigma models and the heterotic string

International Nuclear Information System (INIS)

Hull, C.M.; Witten, E.

1989-01-01

The authors define the (1 + 1)-dimensional supersymmetry algebra of type (p, q) to be that generated by p right-handed Majorana-Weyl supercharges and q left-handed ones. They construct the non-linear sigma models with supersymmetry of type (1, 0) and (2, 0) and discuss their geometry and their relevance to compactifications of the heterotic superstring. The sigma-model anomalies can be canceled by a mechanism closely related to that used by Green and Schwarz to cancel gravitational and Yang-Mills anomalies for the superstring

6 Sigma DFSS technique with easy practice

Energy Technology Data Exchange (ETDEWEB)

NONE

2003-12-15

This book describes 6 Sigma DFSS technique which is easy to use. These are the titles of the contents : new demand, the reason that DFSS needs, when is DFSS used?, DMAIC and DMADV and the bastion for achievement of 6 sigma, new trouble, chief, Chang's new store, plan on kalguksu development propel, customers are holding the key, CTQ refinement, process capability evaluation, setting goal, finding of conception of optimum design, finding of design element, the last gateway, and it's time for a DFSS!.

The ligand-binding profile of HARE: hyaluronan and chondroitin sulfates A, C, and D bind to overlapping sites distinct from the sites for heparin, acetylated low-density lipoprotein, dermatan sulfate, and CS-E.

Science.gov (United States)

Harris, Edward N; Weigel, Paul H

2008-08-01

The hyaluronic acid receptor for endocytosis (HARE)/ Stabilin-2 is the primary systemic scavenger receptor for hyaluronan (HA), the chondroitin sulfates (CS), dermatan sulfate (DS), and nonglycosaminoglycan (GAG) ligands such as acetylated low-density lipoprotein (AcLDL), pro-collagen propeptides, and advanced glycation end products. We recently discovered that HARE is also a systemic scavenger receptor for heparin (Hep) (Harris EN, Weigel JA, Weigel PH. 2008. The human hyaluronan receptor for endocytosis [HARE/Stabilin-2] is a systemic clearance receptor for heparin. J Biol Chem. 283:17341-17350). Our goal was to map the binding sites of eight different ligands within HARE. We used biotinylated GAGs and radio-iodinated streptavidin or AcLDL to assess the binding activities of ligands directly or indirectly (by competition with unlabeled ligands) in endocytosis assays using stable cell lines expressing the 315 or 190 kDa HA receptor for endocytosis (315- or 190-HARE) isoforms, and ELISA-like assays, with purified recombinant soluble 190-HARE ecto-domain. For example, Hep binding to HARE was competed by DS, CS-E, AcLDL, and dextran sulfate, but not by other CS types, HA, dextran, or heparosan. (125)I-AcLDL binding to HARE was partially competed by Hep and dextran sulfate, but not competed by HA. Two ligands, DS and CS-E, competed with both Hep and HA to some degree. Hep and HA binding or endocytosis is mutually inclusive; binding of these two GAGs occurs with functionally separate, noncompetitive, and apparently noninteracting domains. Thus, HARE binds to HA and Hep simultaneously. Although the domain(s) responsible for Hep binding remains unknown, the Link domain was required for HARE binding to HA, CS-A, CS-C, and CS-D. These results enable us to outline, for the first time, a binding activity map for multiple ligands of HARE.

Ligand-controlled, tunable silver-catalyzed C-H amination.

Science.gov (United States)

Alderson, Juliet M; Phelps, Alicia M; Scamp, Ryan J; Dolan, Nicholas S; Schomaker, Jennifer M

2014-12-03

The development of readily tunable and regioselective C-H functionalization reactions that operate solely through catalyst control remains a challenge in modern organic synthesis. Herein, we report that simple silver catalysts supported by common nitrogenated ligands can be used to tune a nitrene transfer reaction between two different types of C-H bonds. The results reported herein represent the first example of ligand-controlled and site-selective silver-promoted C-H amination.

Maass waveforms arising from sigma and related indefinite theta functions

OpenAIRE

Zwegers, Sander

2010-01-01

In this paper we consider an example of a Maass waveform which was constructed by Cohen from a function $\\sigma$, studied by Andrews, Dyson and Hickerson, and it's companion $\\sigma^*$. We put this example in a more general framework.

A diketiminate-bound diiron complex with a bridging carbonate ligand

Science.gov (United States)

Sadique, Azwana R.; Brennessel, William W.; Holland, Patrick L.

2009-01-01

Reduction of carbon dioxide by a diiron(I) complex gives μ-carbonato-κ3 O:O′,O′′-bis­{[2,2,6,6-tetra­methyl-3,5-bis­(2,4,6-triisopropyl­phenyl)heptane-2,5-diiminate(1−)-κ2 N,N′]iron(II)} toluene disolvate, [Fe2(C41H65N)2(CO3)]·2C7H8, a diiron(II) species with a bridging carbonate ligand. The asymmetric unit contains one diiron complex and two cocrystallized toluene solvent mol­ecules that are distributed over three sites, one with atoms in general positions and two in crystallographic sites. Both FeII atoms are η2-coordinated to diketiminate ligands, but η1- and η2-coordinated to the bridging carbonate ligand. Thus, one FeII center is three-coordinate and the other is four-coordinate. The bridging carbonate ligand is nearly perpendicular to the iron–diketiminate plane of the four-coordinate FeII center and parallel to the plane of the three-coordinate FeII center. PMID:19407402

Genome-scale reconstruction of the sigma factor network in Escherichia coli: topology and functional states

DEFF Research Database (Denmark)

Cho, Byung-Kwan; Kim, Donghyuk; Knight, Eric M.

2014-01-01

Background: At the beginning of the transcription process, the RNA polymerase (RNAP) core enzyme requires a sigma-factor to recognize the genomic location at which the process initiates. Although the crucial role of sigma-factors has long been appreciated and characterized for many individual...... to transcription units (TUs), representing an increase of more than 300% over what has been previously reported. The reconstructed network was used to investigate competition between alternative sigma-factors (the sigma(70) and sigma(38) regulons), confirming the competition model of sigma substitution...

A Lean Six Sigma journey in radiology.

Science.gov (United States)

Bucci, Ronald V; Musitano, Anne

2011-01-01

The department of radiology at Akron Children's Hospital embarked on a Lean Six Sigma mission as part of a hospital wide initiative to show increased customer satisfaction, reduce employee dissatisfaction and frustration, and decrease costs. Three processes that were addressed were reducing the MRI scheduling back-log, reconciling discrepancies in billing radiology procedures, and implementing a daily management system. Keys to success is that managers provide opportunities to openly communicate between department sections to break down barriers. Executive leaders must be engaged in Lean Six Sigma for the company to be successful.

A lattice determination of Sigma-Lambda mixing

Energy Technology Data Exchange (ETDEWEB)

Horsley, R. [Edinburgh Univ. (United Kingdom). School of Physics and Astronomy; Najjar, J. [Regensburg Univ. (Germany). Institut fuer Theoretische Physik; Nakamura, Y. [RIKEN Advanced Institute for Computational Science, Kobe (Japan); Perlt, H.; Schiller, A. [Leipzig Univ. (Germany). Inst. fuer Theoretische Physik; Pleiter, D. [Forschungszentrum Juelich (Germany). Juelich Supercomputer Centre; Rakow, P.E.L. [Liverpool Univ. (United Kingdom). Theoretical Physics Division; Schierholz, G. [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Stueben, H. [Hamburg Univ. (Germany). Regionales Rechenzentrum; Zanotti, J.M. [Adelaide Univ. (Australia). CSSM, Dept. of Physics; Collaboration: QCDSF-UKQCD Collaboration

2014-11-15

Isospin breaking effects in baryon octet (and decuplet) masses are due to a combination of up and down quark mass differences and electromagnetic effects and lead to small mass splittings. Between the Sigma and Lambda this mass splitting is much larger, this being mostly due to their different wavefunctions. However when isospin is broken, there is a mixing between between these states. We describe the formalism necessary to determine the QCD mixing matrix and hence find the mixing angle and mass splitting between the Sigma and Lambda particles due to QCD effects.

Amino propynyl benzoic acid building block in rigid spacers of divalent ligands binding to the Syk SH2 domains with equally high affinity as the natural ligand

NARCIS (Netherlands)

Dekker, Frank J; de Mol, Nico J; Fischer, Marcel J E; Liskamp, Rob M J; Dekker, Frank

2003-01-01

The construction of rigid spacers composed of amino propynyl benzoic acid building blocks is described. These spacers were used to link two phosphopeptide ligand sites towards obtaining divalent ligands with a high affinity for Syk tandem SH2 domains, which are important in signal transduction. The

Studi Implementasi Six Sigma pada Tahap Fabrikasi dalam Proses Pembangunan Kapal Baru

Directory of Open Access Journals (Sweden)

Jauhary Tsulastsy Yanuar

2013-03-01

Full Text Available Proses produksi pada tahap fabrikasi dalam proses pembangunan kapal baru masih memiliki masalah defect pada output proses produksi berupa defect dimension yang menyebabkan rework (pekerjaan tambahan. Tugas akhir ini bertujuan untuk menentukan besarnya sigma proses tahap fabrikasi dari sebuah galangan kapal yang menjadi studi kasus, mengidentifikasi penyebab yang mempengaruhi defect, dan menentukan upaya-upaya yang dilakukan untuk meminimasi defect menggunakan metode six sigma DMAIC (Define, Measure, Analyze, Improve dan Control. Berdasarkan perhitungan menggunakan lembar kerja perhitungan sigma yang dikeluarkan oleh pivotal resources, komponen plate mengalami defect dimension sebesar 0,36% untuk hasil marking dan 0,48% untuk hasil proses cutting menghasilkan nilai sigma 2,2074, komponen bracket mengalami defect dimension sebesar 0,28% untuk hasil marking dan 0,40% untuk hasil cutting menghasilkan nilai sigma 2,3429, komponen stiffener mengalami defect dimension sebesar 0,20% untuk hasil marking dan 0,24% untuk hasil cutting menghasilkan nilai sigma 2,6771, dan  komponen clip (collar plate mengalami defect dimension sebesar 0,28% untuk hasil marking dan 0,36% untuk hasil cutting menghasilkan nilai sigma 2,4171. Berdasarkan hasil analisa, nilai sigma tersebut masih jauh dari nilai yang seharusnya dapat dicapai oleh suatu perusahaan (6σ disebabkan oleh faktor antara lain keterampilan SDM yang belum memadai saat ini, PMS (Planned Maintenance System yang berjalan tidak sesuai prosedur, dan tidak dilakukannya pendokumentasian/kontrol pada setiap komponen hasil tahap fabrikasi. Dengan menggunakan metode FMEA (Failure Mode and Effect Analysis yang dikorelasikan dengan berbagai analisa, diperoleh solusi antara lain diperlukannya training/pelatihan untuk meningkatkan skill/kemampuan SDM baru, dijalankannya PMS sesuai prosedur, dan menghidupkan kembali tim QC yang tergabung dalam keorganisasian bengkel fabrikasi. Implementasi six sigma dilakukan secara

Introduction to sigma model anomalies

International Nuclear Information System (INIS)

Nelson, P.

1985-01-01

This paper presents results dealing with the specific case in which a sigma model with fermions arises as a result of dynamical symmetry breakdown from some group G to a subgroup H. H may contain chiral symmetries protecting some fermions in a representation ρ H of H. In this case it may be impossible to quantize the remaining fermions in a way which reproduces the anomalous Ward identities of any underlying strongly-interacting gauge theory. The author concludes that this pattern of symmetry breakdown will not be realized in any such theory. The criterion in this case is local in character, since roughly speaking once the sigma model in question behaves for field configurations close to the vacuum base point in the internal mainfold is known, symmetry can be used to find how it behaves everywhere else

Under the knife: a national survey of six sigma programs in US healthcare organizations.

Science.gov (United States)

Feng, Qianmei; Manuel, Chris M

2008-01-01

Medical and policy literature reports many six sigma applications at specific healthcare organizations. However, there is a lack of studies that investigate the broader status of six sigma in US healthcare systems. The purpose of this paper is to present the results from a national survey of six sigma programs in US healthcare organizations. Through the design, distribution, and analysis of a nationwide survey, this paper assesses the implementation of six sigma in healthcare facilities. Two sets of surveys were designed based on whether an organization has adopted six sigma or not. Findings from this paper indicate the common six sigma projects implemented in healthcare organizations, typical implementation durations, cost benefits, and major barriers in implementation, and so on. This paper is limited by the low-response rate owing to time and budget constraints. Through the dissemination of this paper, it is hoped that more organizations will become interested in this subject and participate in future studies. This work is the first study to investigate the implementation status of six sigma in US healthcare systems. It will share experiences amongst six sigma institutions and promote its application in many institutions. The findings will provide instructive information to six sigma practitioners and researchers, and particularly to health care management.

Characterization and in vivo regulon determination of an ECF sigma factor and its cognate anti-sigma factor in Nostoc punctiforme.

Science.gov (United States)

Bell, Nicole; Lee, Jamie J; Summers, Michael L

2017-04-01

Based on primary sequence comparisons and genomic context, Npun_F4153 (SigG)/Npun_F4154 (SapG) of the cyanobacterium Nostoc punctiforme were hypothesized to encode an ECF sigma factor/anti-sigma factor pair. Transcription of sigG increased in heterocysts and akinetes, and after EDTA treatment. Interaction between SigG and the predicted cytoplasmic domain of SapG was observed in vitro. A SigG-GFP translational fusion protein localized to the periphery of vegetative cells in vivo, but lost this association following heat stress. A sigG mutant was unable to survive envelope damage caused by heat or EDTA, but was able to form functional heterocysts. Akinetes in the mutant strain appeared normal, but these cultures were less resistant to lysozyme and cold treatments than those of the wild-type strain. The SigG in vivo regulon was determined before and during akinete differentiation using DNA microarray analysis, and found to include multiple genes with putative association to the cell envelope. Mapped promoters common to both arrays enabled identification of a SigG promoter-binding motif that was supported in vivo by reporter studies, and in vitro by run-off transcription experiments. These findings support SigG/SapG as a sigma/anti-sigma pair involved in repair of envelope damage resulting from exogenous sources or cellular differentiation. © 2017 John Wiley & Sons Ltd.

In search of Six Sigma in Portuguese SMEs

OpenAIRE

Fonseca, Luis Miguel

2017-01-01

This exploratory research aims to study the reasons for the low implementation level of Six Sigma within Portuguese Small and Medium Enterprises. The results suggest that ISO 9001 certification, and Lean Management, are still regarded as enough for company success. The descriptive analysis and the statistical tests performed led to the conclusion that there are no significant differences for the motivations not to implement Six Sigma between small and medium companies. The qualitative researc...

IBIS UvA: research and consultancy in Lean Six Sigma

NARCIS (Netherlands)

Kemper, B.; de Mast, J.

2008-01-01

Lean Six Sigma is an advanced process improvement methodology. Initially, Six Sigma focused on the reduction of the number of defects in manufacturing. It was introduced at Motorola in 1986, and it incorporates previous methodologies, such as Statistical Process Control, Total Quality Management,

SIGMA Experimental Facility

International Nuclear Information System (INIS)

Rivarola, Martin; Florido, Pablo; Gonzalez, Jose; Brasnarof, Daniel; Orellano, Pablo; Bergallo, Juan

2000-01-01

The SIGMA ( Separacion Isotopica Gaseosa por Metodos Avanzados) concept is outlined.The old gaseous diffusion process to enrich uranium has been updated to be economically competitive for small production volumes.Major innovations have been introduced in the membrane design and in the integrated design of compressors and diffusers.The use of injectors and gas turbines has been also adopted.The paper describes the demonstration facility installed by the Argentine Atomic Energy Commission

Iron and Zinc Complexes of Bulky Bis-Imidazole Ligands : Enzyme Mimicry and Ligand-Centered Redox Activity

NARCIS (Netherlands)

Folkertsma, E.

2016-01-01

The research described in this thesis is directed to the development of cheap and non-toxic iron-based homogeneous catalysts, using enzyme models and redox non-innocent ligands. Inspired by nature, the first approach focuses on the synthesis of structural models of the active site of non-heme iron

Some Practical Issues in the Application of Lean Six Sigma to Service Systems

Directory of Open Access Journals (Sweden)

Goh Thong-Ngee

2014-11-01

Full Text Available Six Sigma as a quality improvement framework has gained considerable popularity in the past two decades. Its extension Lean Six Sigma has also been embraced by many organizations for improvement of quality and business competitiveness. One important factor for the popularity of Six Sigma and Lean Six Sigma is their potential for improving service systems, in contrast to the conventional perceptions that only manufacturing systems can benefit from statistics-based methodologies. There are however a number of issues related to the nature of service systems that must be resolved before the full benefits of Lean Six Sigma can be realized. In this paper, these issues are discussed from a practical point of view from three angles: analytical, organizational, and personal. Awareness of the existence of such issues, if not the answers to all of them, is a pre-requisite to effective adoption of Lean Six Sigma tools.

Identification and characterization of PPARα ligands in the hippocampus.

Science.gov (United States)

Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu; Mishra, Rama K; Yung, Yeni; Luan, Chi-Hao; Gonzalez, Frank J; Pahan, Kalipada

2016-12-01

Peroxisome proliferator-activated receptor-α (PPARα) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently we found that PPARα is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here we report the discovery of three endogenous PPARα ligands-3-hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide-in mouse brain hippocampus. Mass spectrometric detection of these compounds in mouse hippocampal nuclear extracts, in silico interaction studies, time-resolved FRET analyses, and thermal shift assay results clearly indicated that these three compounds served as ligands of PPARα. Site-directed mutagenesis studies further revealed that PPARα Y464 and Y314 are involved in binding these hippocampal ligands. Moreover, these ligands activated PPARα and upregulated the synaptic function of hippocampal neurons. These results highlight the discovery of hippocampal ligands of PPARα capable of modulating synaptic functions.

THE ROLE OF INFORMATION COMUNICATION TECHNOLOGY IN SIX SIGMA APPROACH IMPLEMENTATION

Directory of Open Access Journals (Sweden)

Živko Kondić

2006-06-01

Full Text Available The article discusses Six Sigma Methodology as business philosophy assuring excellent product or service quality and continuous process improving to realise highest customer satisfaction level. There are analysed methodology advantages allowing defects and costs reduction and customer satisfaction improvement. Also, authors discuss methodology successful implementation according to gathering data on business processes regulation indicators values variation, and issued products or services performances. The results of implementation process of the Six Sigma Methodology in business system depend on prompt and correct data needed for statistical analysis, and its accessibility via organisation’ information system. Correlation between implementation of Six Sigma Methodology and information system development is so strong that non-conformances could cause the Six Sigma Methodology implementation fall.

[Reducing patient waiting time for the outpatient phlebotomy service using six sigma].

Science.gov (United States)

Kim, Yu Kyung; Song, Kyung Eun; Lee, Won Kil

2009-04-01

One of the challenging issues of the outpatient phlebotomy services at most hospitals is that patients have a long wait. The outpatient phlebotomy team of Kyungpook National University Hospital applied six sigma breakthrough methodologies to reduce the patient waiting time. The DMAIC (Define, Measure, Analyze, Improve, and Control) model was employed to approach the project. Two hundred patients visiting the outpatient phlebotomy section were asked to answer the questionnaires at inception of the study to ascertain root causes. After correction, we surveyed 285 patients for same questionnaires again to follow-up the effects. A defect was defined as extending patient waiting time so long and at the beginning of the project, the performance level was 2.61 sigma. Using fishbone diagram, all the possible reasons for extending patient waiting time were captured, and among them, 16 causes were proven to be statistically significant. Improvement plans including a new receptionist, automatic specimen transport system, and adding one phlebotomist were put into practice. As a result, the number of patients waited more than 5 min significantly decreased, and the performance level reached 3.0 sigma in December 2007 and finally 3.35 sigma in July 2008. Applying the six sigma, the performance level of waiting times for blood drawing exceeding five minutes were improved from 2.61 sigma to 3.35 sigma.

Thermal isomerizations of ketenimines to nitriles: evaluations of sigma-Dot (sigma(*)) constants for spin-delocalizations

Science.gov (United States)

Kim; Zhu; Lee

2000-05-19

Rate constants (k(Y)) of the isomerizations of 11 diphenyl N-(substituted benzyl) ketenimines were measured at 40, 50, 60, and 70 degrees C. Activation parameters DeltaH()(Y) and DeltaS()(Y) were obtained using the Eyring equation. The relative rates (k(Y)/k(H)) were fitted into Hammett single correlations (log k(Y)/k(H) = rhosigma and log k(Y)/k(H) = rho(*)sigma(*)). The single correlations have been compared with Hammett dual correlations (log k(Y)/k(H) = rhosigma + rho(*)sigma(*) ). Separate treatments of para and meta substituents yielded even better correlations. Para substituents control the rates through spin-delocalizations and inductive effects. The former outweighs the latter when the latter exerts a modest but distinct influence on the rates. On the other hand, inductive effects are the "major" or the sole interactions triggered by meta substituents.

Tripod sigma: results of a pro-active work stress-survey

NARCIS (Netherlands)

Nelemans, R.; Wiezer, N.; Vaas, F.; Gort, J.; Groeneweg, J.

2003-01-01

Work related stress is an important causes of disability and absenteeism. TNO Work and Employment has developed an instrument, called Tripod Sigma, that identifies risks to work stress and provides tools for remedying these risks. The Tripod Sigma model is developed analogous to the Tripod

Sistem Informasi Kinerja Layanan Laboratorium Medis dengan Metode Six Sigma

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Anindita Kusumastuti Dewi

2016-01-01

Full Text Available Medical Laboratory currently holds a very important role in medicine. Evaluation of laboratory quality plays a very important to maintain accurate laboratory results. This study aims to design an information system performance based on the same perception of medical laboratory services from customers using Six Sigma methods and frameworks using ServQual questionnaire. Selection of Six Sigma itself is based on this method can measure the extent to which each process deviates from its purpose as well as to reduce the variation of each of the attributes.  Six Sigma DMAIC namely (Define, Measure, Analyze, Improve, Control preferred because the end result will not yield new products, but only improvements on existing processes. The results of this calculation will be presented in the form of a dashboard for easier management in understanding the results of the evaluation. From the system can be obtained an average value of consumer perceptions terhdap performance today is 2,883, consumer expectations on the performance of 3.3768, the gap between the perceptions and expectations of consumers is -0.4936, customer satisfaction will be the performance of the current 85.37%, the value of 423 360 DPMO and sigma value there at the 2.07664 level.   Keywords: Laboratory Performance; Six Sigma; Servqual; Dashboard

Aplicação da metodologia Lean Six Sigma para melhoria de um processo produtivo

OpenAIRE

Augusto Schaffer

2016-01-01

O Lean Six Sigma é a metodologia originada a partir da integração das metodologias Lean e Six Sigma. O Lean Six Sigma procura eliminar as perdas e reduzir os defeitos, agregando os benefícios de cada uma das duas metodologias que a dão origem. O objetivo deste trabalho é aplicar a metodologia Lean Six Sigma para melhoria de um processo produtivo. Neste trabalho é apresentada uma revisão bibliográfica sobre as metodologias Lean e Six Sigma, buscando a compreensão das origens do Lean Six Sigma,...

Site-specific chemical conjugation of human Fas ligand extracellular domain using trans-cyclooctene - methyltetrazine reactions.

Science.gov (United States)

Muraki, Michiro; Hirota, Kiyonori

2017-07-03

Fas ligand plays a key role in the human immune system as a major cell death inducing protein. The extracellular domain of human Fas ligand (hFasLECD) triggers apoptosis of malignant cells, and therefore is expected to have substantial potentials in medical biotechnology. However, the current application of this protein to clinical medicine is hampered by a shortage of the benefits relative to the drawbacks including the side-effects in systemic administration. Effective procedures for the engineering of the protein by attaching useful additional functions are required to overcome the problem. A procedure for the site-specific chemical conjugation of hFasLECD with a fluorochrome and functional proteins was devised using an inverse-electron-demand Diels-Alder reaction between trans-cyclooctene group and methyltetrazine group. The conjugations in the present study were attained by using much less molar excess amounts of the compounds to be attached as compared with the conventional chemical modification reactions using maleimide derivatives in the previous study. The isolated conjugates of hFasLECD with sulfo-Cy3, avidin and rabbit IgG Fab' domain presented the functional and the structural integrities of the attached molecules without impairing the specific binding activity toward human Fas receptor extracellular domain. The present study provided a new fundamental strategy for the production of the engineered hFasLECDs with additional beneficial functions, which will lead to the developments of the improved diagnostic systems and the effective treatment methods of serious diseases by using this protein as a component of novel molecular tools.

Quasicomplex N=2, d=1 Supersymmetric Sigma Models

Directory of Open Access Journals (Sweden)

Evgeny A. Ivanov

2013-11-01

Full Text Available We derive and discuss a new type of N=2 supersymmetric quantum mechanical sigma models which appear when the superfield action of the (1,2,1 multiplets is modified by adding an imaginary antisymmetric tensor to the target space metric, thus completing the latter to a non-symmetric Hermitian metric. These models are not equivalent to the standard de Rham sigma models, but are related to them through a certain special similarity transformation of the supercharges. On the other hand, they can be obtained by a Hamiltonian reduction from the complex supersymmetric N=2 sigma models built on the multiplets (2,2,0 and describing the Dolbeault complex on the manifolds with proper isometries. We study in detail the extremal two-dimensional case, when the target space metric is defined solely by the antisymmetric tensor, and show that the corresponding quantum systems reveal a hidden N=4 supersymmetry.

Role of sigma-1 receptors in neurodegenerative diseases

Directory of Open Access Journals (Sweden)

Linda Nguyen

2015-01-01

Full Text Available Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

complexes of pyrimidine derived

Indian Academy of Sciences (India)

Administrator

The ligands are prepared by the condensation of 4,6-dimethyl 2-hydrazino pyrimidine with salicylaldehyde ... 6. With the knowledge of approximate coordination sphere of Mo in the metal- loenzymes at hand, several attempts have been made to model the active sites of these enzymes and study ..... [I > 2 sigma(I)]R indices.

Design and synthesis of a tetradentate '3-amine-1-carboxylate' ligand to mimic the metal binding environment at the non-heme iron(II) oxidase active site.

Science.gov (United States)

Dungan, Victoria J; Ortin, Yannick; Mueller-Bunz, Helge; Rutledge, Peter J

2010-04-07

Non-heme iron(II) oxidases (NHIOs) catalyse a diverse array of oxidative chemistry in Nature. As part of ongoing efforts to realize biomimetic, iron-mediated C-H activation, we report the synthesis of a new 'three-amine-one-carboxylate' ligand designed to complex with iron(II) and mimic the NHIO active site. The tetradentate ligand has been prepared as a single enantiomer in nine synthetic steps from N-Cbz-L-alanine, pyridine-2,6-dimethanol and diphenylamine, using Seebach oxazolidinone chemistry to control the stereochemistry. X-Ray crystal structures are reported for two important intermediates, along with variable temperature NMR experiments to probe the hindered interconversion of conformational isomers of several key intermediates, 2,6-disubstituted pyridine derivatives. The target ligand and an N-Cbz-protected precursor were each then complexed with iron(II) and tested for their ability to promote alkene dihydroxylation, using hydrogen peroxide as the oxidant.

Vortices, semi-local vortices in gauged linear sigma model

International Nuclear Information System (INIS)

Kim, Namkwon

1998-11-01

We consider the static (2+1)D gauged linear sigma model. By analyzing the governing system of partial differential equations, we investigate various aspects of the model. We show the existence of energy finite vortices under a partially broken symmetry on R 2 with the necessary condition suggested by Y. Yang. We also introduce generalized semi-local vortices and show the existence of energy finite semi-local vortices under a certain condition. The vacuum manifold for the semi-local vortices turns out to be graded. Besides, with a special choice of a representation, we show that the O(3) sigma model of which target space is nonlinear is a singular limit of the gauged linear sigma model of which target space is linear. (author)

Lean Six Sigma in het ziekenhuis: De beschikbaarheid van infuuspompen

NARCIS (Netherlands)

Does, R.J.M.M.; Kemper, B.P.H.; Koopmans, M.

2011-01-01

In het topklinisch ziekenhuis Medisch Spectrum Twente werd in 2008 een Lean Six Sigma-project gestart. Het doel was vermindering van operationele kosten van infuuspompen. Het is een interessant voorbeeld van Lean Six Sigma in de gezondheidszorg, omdat het laat zien dat kostenbesparing niet hoeft te

Logistics services and Lean Six Sigma implementation: a case study

NARCIS (Netherlands)

Gutierrez Gutierrez, L.; de Leeuw, S.L.J.M.; Dubbers, R.

2016-01-01

Purpose: This paper aims to analyze the application of Lean Six Sigma (LSS) framework for supporting continuous improvement (CI) in logistics services. Both the lean philosophy and the Six Sigma methodology have become two of the most important initiatives for CI in organizations. The combination of

The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases.

Science.gov (United States)

Penke, Botond; Fulop, Livia; Szucs, Maria; Frecska, Ede

2018-01-01

Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. Research articles on Sigma-1 receptor were reviewed. ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins. Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A healthcare Lean Six Sigma System for postanesthesia care unit workflow improvement.

Science.gov (United States)

Kuo, Alex Mu-Hsing; Borycki, Elizabeth; Kushniruk, Andre; Lee, Te-Shu

2011-01-01

The aim of this article is to propose a new model called Healthcare Lean Six Sigma System that integrates Lean and Six Sigma methodologies to improve workflow in a postanesthesia care unit. The methodology of the proposed model is fully described. A postanesthesia care unit case study is also used to demonstrate the benefits of using the Healthcare Lean Six Sigma System model by combining Lean and Six Sigma methodologies together. The new model bridges the service gaps between health care providers and patients, balances the requirements of health care managers, and delivers health care services to patients by taking the benefits of the Lean speed and Six Sigma high-quality principles. The full benefits of the new model will be realized when applied at both strategic and operational levels. For further research, we will examine how the proposed model is used in different real-world case studies.

SIX SIGMA FRAMEWORKS: AN ANALYSIS BASED ON ROGERS’ DIFFUSION OF INNOVATION THEORY

Directory of Open Access Journals (Sweden)

Kifayah Amar

2012-06-01

Full Text Available This paper attempt to analyze frameworks related to Six Sigma and Lean Six Sigma. The basis of analysis the frameworks is the diffusion of innovation theory. Several criteria was used to analyze the frameworks e.g. relative advantage, compatibility, complexity, trialability, observability, communication channels, nature of the social system/culture and extent of change agent. Based on framework analysis, there is only one framework fits to Rogers’ theory on diffusion of innovation. The framework is a Lean Six Sigma framework which consists elements such owner/manager commitment and involvement, employee involvement, training, culture change and external support. Even though the elements have similarity to other Six Sigma frameworks but they put more attention on culture change and external support. Generally speaking, the culture change and external support are the most important elements to the implementation of Six Sigma or other soft approaches particularly for small organizations.

SIX SIGMA FRAMEWORKS: AN ANALYSIS BASED ON ROGERS’ DIFFUSION OF INNOVATION THEORY

Directory of Open Access Journals (Sweden)

Kifayah Amar

2012-06-01

Full Text Available This paper attempt to analyze frameworks related to Six Sigma and Lean Six Sigma. The basis of analysis the frameworks is the diffusion of innovation theory. Several criteria was used to analyze the frameworks e.g. relative advantage, compatibility, complexity, trialability, observability, communication channels, nature of the social system/culture and extent of change agent.    Based on framework analysis, there is only one framework fits to Rogers’ theory on diffusion of innovation. The framework is a Lean Six Sigma framework which consists elements such owner/manager commitment and involvement, employee involvement, training, culture change and external support. Even though the elements have similarity to other Six Sigma frameworks but they put more attention on culture change and external support. Generally speaking, the culture change and external support are the most important elements to the implementation of Six Sigma or other soft approaches particularly for small organizations.

Quality assurance and management in microelectronics companies: ISO 9000 versus Six Sigma

Science.gov (United States)

Lupan, Razvan; Kobi, Abdessamad; Robledo, Christian; Bacivarov, Ioan; Bacivarov, Angelica

2009-01-01

A strategy for the implementation of the Six Sigma method as an improvement solution for the ISO 9000:2000 Quality Standard is proposed. Our approach is focused on integrating the DMAIC cycle of the Six Sigma method with the PDCA process approach, highly recommended by the standard ISO 9000:2000. The Six Sigma steps applied to each part of the PDCA cycle are presented in detail, giving some tools and training examples. Based on this analysis the authors conclude that applying Six Sigma philosophy to the Quality Standard implementation process is the best way to achieve the optimal results in quality progress and therefore in customers satisfaction.

Study of the critical behavior of the O(N) linear and nonlinear sigma models

International Nuclear Information System (INIS)

Graziani, F.R.

1983-01-01

A study of the large N behavior of both the O(N) linear and nonlinear sigma models is presented. The purpose is to investigate the relationship between the disordered (ordered) phase of the linear and nonlinear sigma models. Utilizing operator product expansions and stability analyses, it is shown that for 2 - (lambda/sub R/(M) is the dimensionless renormalized quartic coupling and lambda* is the IR fixed point) limit of the linear sigma model which yields the nonlinear sigma model. It is also shown that stable large N linear sigma models with lambda 0) and nonlinear models are trivial. This result (i.e., triviality) is well known but only for one and two component models. Interestingly enough, the lambda< d = 4 linear sigma model remains nontrivial and tachyonic free

Maturational Patterns of Sigma Frequency Power Across Childhood and Adolescence: A Longitudinal Study

Science.gov (United States)

Campbell, Ian G.; Feinberg, Irwin

2016-01-01

Study Objectives: To further evaluate adolescent brain maturation by determining the longitudinal trajectories of nonrapid eye movement (NREM) sigma (11–15 Hz) power across childhood-adolescence. Methods: The maturational trend for sigma (11–15 Hz) power was evaluated in an accelerated longitudinal study of three overlapping age cohorts (n = 92) covering ages 6 to 18 y. Semiannually, sleep electroencephalography (EEG) was recorded from participants sleeping at home in their normal sleep environment while keeping their current school night schedules. Results: Sigma frequencies became faster with age. The frequency of the 11–15 Hz spectral peak increased linearly. Sigma frequency power (SFP) declined with age, but its trajectory was complex (cubic). Power in a group of low sigma subfrequencies declined with age. Power in a group of high sigma frequencies increased with age. Power in subfrequencies within 11–15 Hz also showed different trends across the night, with lower frequencies increasing across NREM periods and higher frequencies decreasing across NREM periods. The upper and lower boundaries for the sigma frequencies that changed across NREMPs shifted upward with age. Conclusions: We hypothesize that these maturational brain changes result from synaptic elimination which decreases sleep depth and streamlines circuits. SFP displays a maturational trajectory different from both delta and theta power. Theories on the function of sigma must be reconciled with its maturational trajectory. These findings further demonstrate the value of sleep EEG for studying noninvasively the complex developmental brain changes of adolescence. Citation: Campbell IG, Feinberg I. Maturational patterns of sigma frequency power across childhood and adolescence: a longitudinal study. SLEEP 2016;39(1):193–201. PMID:26285004

Cytotoxicity of an 125I-labelled DNA ligand

International Nuclear Information System (INIS)

Karagiannis, T.C.; Lobachevsky, P.N.; Martin, R.F.

2000-01-01

The subcellular distribution and cytotoxicity of a DNA-binding ligand [ 125 I]-Hoechst 33258 following incubation of K562 cells with the drug was investigated. The ability of a radical scavenger, dimethyl sulphoxide, to protect cells from the 125 I-decay induced cell death was also studied. Three different concentrations and specific activities of the drug were used to provide different ligand : DNA binding ratios. The results demonstrated a trend toward improved delivery of the ligand to the nucleus and to chromatin at higher ligand concentrations, with concomitant increased sensitivity to 125 I-decay induced cytotoxicity and decreased protection by dimethyl sulphoxide. This correlation of radiobiological parameters with subcellular drug distribution is consistent with the classical dogma that attributes cytotoxicity to DNA double-stranded breakage in the vicinity of the site of decay, where the high LET nature of the damage confers minimal sensitivity to radical scavenging

The Role of Protein-Ligand Contacts in Allosteric Regulation of the Escherichia coli Catabolite Activator Protein*

Science.gov (United States)

Townsend, Philip D.; Rodgers, Thomas L.; Glover, Laura C.; Korhonen, Heidi J.; Richards, Shane A.; Colwell, Lucy J.; Pohl, Ehmke; Wilson, Mark R.; Hodgson, David R. W.; McLeish, Tom C. B.; Cann, Martin J.

2015-01-01

Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distant site. Both experimental and theoretical evidence demonstrate that allostery can be communicated through altered slow relaxation protein dynamics without conformational change. The catabolite activator protein (CAP) of Escherichia coli is an exemplar for the analysis of such entropically driven allostery. Negative allostery in CAP occurs between identical cAMP binding sites. Changes to the cAMP-binding pocket can therefore impact the allosteric properties of CAP. Here we demonstrate, through a combination of coarse-grained modeling, isothermal calorimetry, and structural analysis, that decreasing the affinity of CAP for cAMP enhances negative cooperativity through an entropic penalty for ligand binding. The use of variant cAMP ligands indicates the data are not explained by structural heterogeneity between protein mutants. We observe computationally that altered interaction strength between CAP and cAMP variously modifies the change in allosteric cooperativity due to second site CAP mutations. As the degree of correlated motion between the cAMP-contacting site and a second site on CAP increases, there is a tendency for computed double mutations at these sites to drive CAP toward noncooperativity. Naturally occurring pairs of covarying residues in CAP do not display this tendency, suggesting a selection pressure to fine tune allostery on changes to the CAP ligand-binding pocket without a drive to a noncooperative state. In general, we hypothesize an evolutionary selection pressure to retain slow relaxation dynamics-induced allostery in proteins in which evolution of the ligand-binding site is occurring. PMID:26187469

Measurement of the $\\Sigma \\pi$ photoproduction line shapes near the $\\Lambda(1405)$

Energy Technology Data Exchange (ETDEWEB)

Moriya, K; Adhikari, K P; Adikaram, D; Aghasyan, M; Anderson, M D; Anefalos Pereira, S; Ball, J; Baltzell, N A; Battaglieri, M; Batourine, V; Bedlinskiy, I; Bellis, M; Biselli, A S; Bono, J; Boiarinov, S; Briscoe, W J; Burkert, V D; Carman, D S; Celentano, A; Chandavar, S; Charles, G; Cole, P L; Collins, P; Crede, V; D& #x27; Angelo, A; Dashyan, N; De Sanctis, E; De Vita, R; Deur, A; Dey, B; Djalali, C; Doughty, R; Dupre, R; Egiyan, H; El Fassi, L; Eugenio, P; Fedotov, G; Fegan, S; Fersch, R; Fleming, J A; Gevorgyan, N; Gilfoyle, G P; Giovanetti, K L; Girod, F X; Goetz, J T; Gohn, W; Golovatch, E; Gothe, R W; Griffioen, K A; Guidal, M; Hafidi, K; Hakobyan, H; Hanretty, C; Harrison, N; Heddle, D; Hicks, K; Ho, D; Holtrop, M; Hyde, C E; Ilieva, Y; Ireland, D G; Ishkhanov, B S; Isupov, E L; Jo, H S; Keller, D; Khandaker, M; Khertarpal, P; Kim, A; Kim, W; Klein, A; Klein, F J; Koirala, S; Kubarovsky, A; Kubarovsky, V; Kuleshov, S V; Kvaltine, N D; Livingston, K; Lu, H Y; MacGregor, I.J. D; Markov, N; Mayer, M; McCracken, M; McKinnon, B; Mestayer, M D; Meyer, C A; Mirazita, M; Mineeva, T; Mokeev, V; Montgomery, R A; Munevar, E; Munoz Camacho, C; Nadel-Turonski, P; Nasseripour, R; Nepali, C S; Niccolai, S; Niculescu, G; Niculescu, I; Osipenko, M; Ostrovidov, A I; Pappalardo, L L; Paremuzyan, R; Park, K; Park, S; Pasyuk, E; Phelps, E; Phillips, J J; Pisano, S; Pivnyuk, N; Pogorelko, O; Pozdniakov, S; Price, J W; Procureur, S; Protopopescu, D; Rimal, D; Ripani, M; Ritchie, B G; Rosner, G; Rossi, P; Sabatio, F; Saini, M S; Salgado, C; Schott, D; Seder, E; Seraydaryan, H; Sharabian, Y G; Smith, E S; Smith, G D; Sober, D I; Stepanyan, S S; Stepanyan, S; Stoler, P; Strakovsky, I I; Strauch, S; Taiuti, M; Tang, W; Taylor, S; Taylor, C E; Tian, Ye; Tkachenko, S; Torayev, B; Ungaro, M; Vernarsky, B; Vlassov, A V; Voskanyan, H; Voutier, E; Walford, N K; Watts, D P

2013-03-01

The reaction {gamma} + p -> K{sup +} + {Sigma} + {p}i was used to determine the invariant mass distributions or "line shapes" of the {Sigma}{sup +} {pi}{sup -}, {Sigma}{sup -} {pi}{sup +} and {Sigma}{sup 0} {pi}{sup 0} final states, from threshold at 1328 MeV/c^2 through the mass range of the {Lambda}(1405) and the {Lambda}(1520). The measurements were made with the CLAS system at Jefferson Lab using tagged real photons, for center-of-mass energies 1.95 < W < 2.85 GeV. The three mass distributions differ strongly in the vicinity of the I=0 {Lambda}(1405), indicating the presence of substantial I=1 strength in the reaction. Background contributions to the data from the {Sigma}{sup 0}(1385) and from K* {Sigma} production were studied and shown to have negligible influence. To separate the isospin amplitudes, Breit-Wigner model fits were made that included channel-coupling distortions due to the Nkbar threshold. A best fit to all the data was obtained after including a phenomenological I=1, J{sup P} = 1/2{sup -} amplitude with a centroid at 1394\\pm20 MeV/c^2 and a second I=1 amplitude at 1413\\pm10 MeV/c^2. The centroid of the I=0 {Lambda}(1405) strength was found at the {Sigma} {pi} threshold, with the observed shape determined largely by channel-coupling, leading to an apparent overall peak near 1405 MeV/c^2.

Using chemical shift perturbation to characterise ligand binding.

Science.gov (United States)

Williamson, Mike P

2013-08-01

Chemical shift perturbation (CSP, chemical shift mapping or complexation-induced changes in chemical shift, CIS) follows changes in the chemical shifts of a protein when a ligand is added, and uses these to determine the location of the binding site, the affinity of the ligand, and/or possibly the structure of the complex. A key factor in determining the appearance of spectra during a titration is the exchange rate between free and bound, or more specifically the off-rate koff. When koff is greater than the chemical shift difference between free and bound, which typically equates to an affinity Kd weaker than about 3μM, then exchange is fast on the chemical shift timescale. Under these circumstances, the observed shift is the population-weighted average of free and bound, which allows Kd to be determined from measurement of peak positions, provided the measurements are made appropriately. (1)H shifts are influenced to a large extent by through-space interactions, whereas (13)Cα and (13)Cβ shifts are influenced more by through-bond effects. (15)N and (13)C' shifts are influenced both by through-bond and by through-space (hydrogen bonding) interactions. For determining the location of a bound ligand on the basis of shift change, the most appropriate method is therefore usually to measure (15)N HSQC spectra, calculate the geometrical distance moved by the peak, weighting (15)N shifts by a factor of about 0.14 compared to (1)H shifts, and select those residues for which the weighted shift change is larger than the standard deviation of the shift for all residues. Other methods are discussed, in particular the measurement of (13)CH3 signals. Slow to intermediate exchange rates lead to line broadening, and make Kd values very difficult to obtain. There is no good way to distinguish changes in chemical shift due to direct binding of the ligand from changes in chemical shift due to allosteric change. Ligand binding at multiple sites can often be characterised, by

Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

Science.gov (United States)

Lipinski, Christopher A

2016-06-01

The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier. Copyright © 2016 Elsevier B.V. All rights reserved.

Landau-Lifshitz sigma-models, fermions and the AdS/CFT correspondence

OpenAIRE

Stefanski Jr, B.

2007-01-01

We define Landau-Lifshitz sigma models on general coset space $G/H$, with $H$ a maximal stability sub-group of $G$. These are non-relativistic models that have $G$-valued N\\"other charges, local $H$ invariance and are classically integrable. Using this definition, we construct the $PSU(2,2|4)/PS(U(2|2)^2)$ Landau-Lifshitz sigma-model. This sigma model describes the thermodynamic limit of the spin-chain Hamiltonian obtained from the complete one-loop dilatation operator of the N=4 super Yang-M...

A Geographical Information System for Malaria in Colombia (SIGMA)

International Nuclear Information System (INIS)

Poveda, German; Hernandez, Olver; Urquijo, Lenis; Padilla Julio Cesar

2005-01-01

A Geographical Information System for Malaria in Colombia (SIGMA) is introduced and its capabilities and modules are described. It allows the interactive visualization of the Colombian Ministry of Social Protection database at national, regional and municipal levels and the analysis of relationships with different environmental and climatic variables. SIGMA is a powerful decision support system for human health intervention and management programs in Colombia

Sigma beta decay

International Nuclear Information System (INIS)

Newman, D.E.

1975-01-01

Describes an experiment to measure beta decays of the sigma particle. Sigmas produced by stopping a K - beam in a liquid hydrogen target decayed in the following reactions: Kp → Σπ; Σ → Neν. The electron and pion were detected by wire spark chambers in a magnetic spectrometer and by plastic scintillators, and were differentiated by a threshold gas Cherenkov counter. The neutron was detected by liquid scintillation counters. The data (n = 3) shell electrons or the highly excited electrons decay first. Instead, it is suggested that when there are two to five electrons in highly excited states immediately after a heavy ion--atom collision the first transitions to occur will be among highly excited Rydberg states in a cascade down to the 4s, 4p, and 3d-subshells. If one of the long lived states becomes occupied by electrons promoted during the collision or by electrons falling from higher levels, it will not decay until after the valence shell decays. LMM rates calculated to test the methods used are compared to previous works. The mixing coefficients are given in terms of the states 4s4p, 45sp+-, and 5s5p. The applicability of Cooper, Fano, and Prats' discussion of the energies and transition rates of doubly excited states is considered

Environmental Professional’s Guide to Lean and Six Sigma: Executive Summary

Science.gov (United States)

Introduction to the guide that describes how Lean and Six Sigma relate to the environment and provides guidance on how environmental professionals can connect with Lean and Six Sigma activities to generate better environmental and operational results.

An exploratory analysis for Lean and Six Sigma implementation in hospitals: Together is better?

Science.gov (United States)

Lee, Jung Young; McFadden, Kathleen L; Gowen, Charles R

2016-12-22

Despite the increasing interest for Lean and Six Sigma implementations in hospitals, there has been little empirical evidence that goes beyond descriptive case studies to address the current status and the effectiveness of the implementations. The aim of this study was to explore existing patterns of Lean and Six Sigma implementation in U.S. hospitals and compare the performance of the different patterns. We collected data from 215 U.S. hospitals via a survey that includes measurement items developed from related literature. Using the cross-sectional data, we conducted a cluster analysis, followed by t tests, chi-square tests, and regression analyses for cluster verification. The cluster analysis identifies two clusters, a Moderate Six Sigma group and a Lean Six Sigma group. Results show that the Lean Six Sigma group outperforms the Moderate Six Sigma group across many performance dimensions: responsiveness capability, patient safety, and possibly cost saving. In addition, the Lean Six Sigma group tends to be composed of larger, private teaching hospitals located in more urban areas, and they employ more resources for quality improvement. Our research contributes to the quality management literature by supporting the possible complementary relationship between Lean and Six Sigma in hospitals. Our study encourages practitioners and managers to pay more attention to Lean implementation. Although Lean seems to be conducted in a limited fashion in many hospitals, it should be expanded and combined with Six Sigma for better results.

Squashed Toric Sigma Models and Mock Modular Forms

Science.gov (United States)

Gupta, Rajesh Kumar; Murthy, Sameer

2018-05-01

We study a class of two-dimensional N}=(2,2)} sigma models called squashed toric sigma models, using their Gauged Linear Sigma Models (GLSM) description. These models are obtained by gauging the global {U(1)} symmetries of toric GLSMs and introducing a set of corresponding compensator superfields. The geometry of the resulting vacuum manifold is a deformation of the corresponding toric manifold in which the torus fibration maintains a constant size in the interior of the manifold, thus producing a neck-like region. We compute the elliptic genus of these models, using localization, in the case when the unsquashed vacuum manifolds obey the Calabi-Yau condition. The elliptic genera have a non-holomorphic dependence on the modular parameter {τ} coming from the continuum produced by the neck. In the simplest case corresponding to squashed {C / Z_{2 the elliptic genus is a mixed mock Jacobi form which coincides with the elliptic genus of the {N=(2,2)} {SL(2,R) / U(1)} cigar coset.

Effects of electrostatic interactions on ligand dissociation kinetics

Science.gov (United States)

Erbaş, Aykut; de la Cruz, Monica Olvera; Marko, John F.

2018-02-01

We study unbinding of multivalent cationic ligands from oppositely charged polymeric binding sites sparsely grafted on a flat neutral substrate. Our molecular dynamics simulations are suggested by single-molecule studies of protein-DNA interactions. We consider univalent salt concentrations spanning roughly a 1000-fold range, together with various concentrations of excess ligands in solution. To reveal the ionic effects on unbinding kinetics of spontaneous and facilitated dissociation mechanisms, we treat electrostatic interactions both at a Debye-Hückel (DH) (or implicit ions, i.e., use of an electrostatic potential with a prescribed decay length) level and by the more precise approach of considering all ionic species explicitly in the simulations. We find that the DH approach systematically overestimates unbinding rates, relative to the calculations where all ion pairs are present explicitly in solution, although many aspects of the two types of calculation are qualitatively similar. For facilitated dissociation (FD) (acceleration of unbinding by free ligands in solution) explicit-ion simulations lead to unbinding at lower free-ligand concentrations. Our simulations predict a variety of FD regimes as a function of free-ligand and ion concentrations; a particularly interesting regime is at intermediate concentrations of ligands where nonelectrostatic binding strength controls FD. We conclude that explicit-ion electrostatic modeling is an essential component to quantitatively tackle problems in molecular ligand dissociation, including nucleic-acid-binding proteins.

Non destructive method to follow the phase sigma in a duplex stainless steel; Metodologia nao destrutiva para acompanhamento da fase sigma, em um aco inoxidavel duplex

Energy Technology Data Exchange (ETDEWEB)

Silva, E.M.; Andrade, A.L.S. Souza; Fialho, W.M.L.; Araujo, B.R., E-mail: edgard@ifpb.edu.br [Instituto Federal de Educacao Ciencia e Tecnologia da Paraiba (IFPB), Joao Pessoa, PB (Brazil); Silva, J.H.R.; Leite, Josinaldo P.; Silva, Eloy M. [Instituto Federal de Educacao Ciencia e Tecnologia do Ceara (IFCE), CE (Brazil); Leite, Joao P. [Universidade Federal da Paraiba (UFPB), PB (Brazil)

2014-07-01

Duplex stainless steels are subject to embrittlement due to the formation of sigma phase, which is one with the greatest effect of weakening because they are rich in chromium and deplete the matrix of this element. In this paper, a non-destructive methodology based on measurements of Hall voltage, is presented for monitoring the formation of sigma phase at temperatures of 800 deg C and 900 deg C. Different field intensities are generated by an electromagnet and the flow of field lines is detected by a Hall effect sensor. Hall voltage measurements are proportional to the formation of sigma phase generated by different times of aging methods. The results are correlated with results of microscopic, hardness and X-ray diffraction. It was showed that exist a correlation between the Hall voltage and the amount of sigma phase. The formation of this phase influences the signal voltage by reducing the voltage. (author)

APLIKASI SIX SIGMA PADA PRODUK CLEAR FILE DI PERUSAHAAN STATIONARY

Directory of Open Access Journals (Sweden)

Desy Emilasari

2007-01-01

Full Text Available This paper describes the application of the Six Sigma methods is used in order to improve quality in manufacturing company that produce stationary product. DMAIC approach is utilized to analyze and improve 'Pocket Clear File' product since this product has more variability and defects. Quality improvement also monitor the process that influenced pocket defect in Bag Making, Kami-ire, Karidome, and Pocket after Karidome Inspections section. Determining of Six Sigma project is based in process and defect type in each section. FMEA also gave the recommendation for quality improvement we need to evaluate the final result of the improvement since some of them were not working properly. Abstract in Bahasa Indonesia : Paper ini menggambarkan bagaimana aplikasi metode Six Sigma digunakan untuk melakukan perbaikan kualitas pada perusahaan manufaktur yang memproduksi produk stationary. Pendekatan DMAIC dipakai untuk menganalisa dan melakukan perbaikan produk 'Pocket Clear File' karena tingginya variabilitas dan cacat dibanding produk lain. Perbaikan kualitas juga memperhatikan proses yang mempengaruhi terjadinya cacat pocket pada section Bag Making, Kami-ire, Karidome, dan Pocket after Karidome Inspection. Penentuan proyek Six Sigma didasarkan atas proses dan jenis cacat pada setiap section. Pendekatan FMEA mampu memberi rekomendasi perbaikan kualitas. Evaluasi dari hasil perbaikan penting untuk dilakukan karena beberapa implementasi perbaikan kualitas tidak berjalan sesuai dengan rencana. kata kunci: six sigma, DMAIC, perusahaan stationary.

IMPROVING PERFORMANCE OF BISCUIT PRODUCTION PROCESS THROUGH LEAN SIX-SIGMA AT PT XYZ

Directory of Open Access Journals (Sweden)

Ahmad Mukti Almansur

2017-05-01

Full Text Available This research aims to analyze waste or loss using the 7-waste approach and value added/non value added activities in the production process at PT. XYZ. This research also aims to evaluate the production process capability and sigma values at PT. XYZ and used DMAIC technique (Define, Measure, Analysis, Improvement, and Control from Lean Six-sigma with an analysis using Failure Mode and Effect Analysis (FMEA. The results of the research obtained the values of Process Cycle Efficiency (PCE of 47.29%, CTQ (Critical to Quality and process capability value in the form of Cpm (Capability Index for each process stage and yield. Line-5 has DPMO (Defects per Million Opportunities value of 29,632,607 with a Sigma Score 3.39, and FMEA (Failure Mode and Effect Analysis analysis resulted in recommendations for improvement at each process stage.Keywords: process cycle efficiency, biscuit, lean six-sigma, CTQ, CpmABSTRAKPenelitian ini bertujuan melakukan analisis tingkat pemborosan (waste/loss dengan menggunakan pendekatan 7 waste dan value added/non value added activity dalam proses produksi di PT. XYZ. Selanjutnya, melakukan evaluasi terhadap nilai kapabilitas proses produksi dan nilai sigma di PT. XYZ. Penelitian ini menggunakan teknik DMAIC (Define, Measure, Analysis, Improvement, and Control dari Lean Six Sigma dengan Analisis menggunakan menggunakan alat Failure Mode and Effect Analysis (FMEA. Hasil Penelitian mendapati nilai Process Cycle Efficiency (PCE 47.29%, CTQ (Critical to Quality dan nilai kapabilitas proses berupa Cpm (Capability Index setiap tahapan proses dan Yield. Line-5 memiliki DPMO (Defects Per Million Opportunities sebesar 29632.607 dengan Sigma Score 3.39 Sigma, analisis FMEA(Failure Mode and Effect Analysis menghasilkan rekomendasi perbaikan di setiap tahapan proses.Kata kunci: process cycle efficiency, biskuit, lean six sigma, CTQ, Cpm

THE SUBSTELLAR POPULATION OF {sigma} ORIONIS: A DEEP WIDE SURVEY

Energy Technology Data Exchange (ETDEWEB)

Bejar, V. J. S.; Rebolo, R. [Instituto de Astrofisica de Canarias, E-38205 La Laguna, Tenerife (Spain); Zapatero Osorio, M. R.; Martin, E. L. [Centro de Astrobiologia (INTA-CSIC), Crta. Ajalvir km 4, E-28850 Torrejon de Ardoz, Madrid (Spain); Caballero, J. A.; Barrado, D. [Centro de Astrobiologia (INTA-CSIC), ESAC campus, P.O. Box 78, E-28691 Villanueva de la Canada, Madrid (Spain); Mundt, R.; Bailer-Jones, C. A. L., E-mail: vbejar@iac.es, E-mail: mosorio@cab.inta-csic.es, E-mail: ege@cab.inta-csic.es, E-mail: rrl@iac.es, E-mail: caballero@cab.inta-csic.es, E-mail: barrado@cab.inta-csic.es, E-mail: mundt@mpia.de, E-mail: calj@mpia.de [Max-Planck-Institut fuer Astronomie, Koenigstuhl 17, D-69117 Heidelberg (Germany)

2011-12-10

We present a deep I, Z photometric survey covering a total area of 1.12 deg{sup 2} of the {sigma} Orionis cluster and reaching completeness magnitudes of I = 22 and Z = 21.5 mag. From I, I - Z color-magnitude diagrams we have selected 153 candidates that fit the previously known sequence of the cluster. They have magnitudes in the range I = 16-23 mag, which corresponds to a mass interval from 0.1 down to 0.008 M{sub Sun} at the most probable age of {sigma} Orionis (2-4 Myr). Using J-band photometry, we find that 124 of the 151 candidates within the completeness of the optical survey (82%) follow the previously known infrared photometric sequence of the cluster and are probably members. We have studied the spatial distribution of the very low mass stars and brown dwarf population of the cluster and found that there are objects located at distances greater than 30 arcmin to the north and west of {sigma} Orionis that probably belong to different populations of the Orion's Belt. For the 102 bona fide {sigma} Orionis cluster member candidates, we find that the radial surface density can be represented by a decreasing exponential function ({sigma}={sigma}{sub 0}e{sup -r/r{sub 0}}) with a central density of {sigma}{sub 0} = 0.23 {+-} 0.03 objects arcmin{sup -2} and a characteristic radius of r{sub 0} = 9.5 {+-} 0.7 arcmin. From a statistical comparison with Monte Carlo simulations, we conclude that the spatial distribution of the objects located at the same distance from the center of the cluster is compatible with a Poissonian distribution and, hence, that very low mass stars and brown dwarfs are not mainly forming aggregations or sub-clustering. Using near-infrared JHK-band data from Two Micron All Sky Survey and UKIRT Deep Infrared Sky Survey and mid-infrared data from Infrared Array Camera/Spitzer, we find that about 5%-9% of the brown dwarf candidates in the {sigma} Orionis cluster have K-band excesses and 30% {+-} 7% of them show mid-infrared excesses at

Superconducting bandpass delta-sigma modulator

International Nuclear Information System (INIS)

Bulzacchelli, J.F.; Lee, H.-S.; Misewich, J.A.; Ketchen, M.B.

1999-01-01

Bandpass delta-sigma modulators digitize narrowband signals with high dynamic range and linearity. The required sampling rate is only a few times higher than the centre frequency of the input. This paper presents a superconducting bandpass delta-sigma modulator for direct analogue-to-digital conversion of RF signals in the GHz range. The input signal is capacitively coupled to one end of a microstrip transmission line, and a single flux quantum balanced comparator quantizes the current flowing out of the other end. Quantization noise is suppressed at the quarter-wave resonance of the transmission line (about 2 GHz in our design). Circuit performance at a 20 GHz sampling rate has been studied with several long JSIM simulations. Full-scale (FS) input sensitivity is 20 mV (rms), and in-band noise is -53 dBFS and -57 dBFS over bandwidths of 39 MHz and 19.5 MHz, respectively. In-band intermodulation distortion is better than -69 dBFS. (author)

Integration of Value Stream Map and Healthcare Failure Mode and Effect Analysis into Six Sigma Methodology to Improve Process of Surgical Specimen Handling.

Science.gov (United States)

Hung, Sheng-Hui; Wang, Pa-Chun; Lin, Hung-Chun; Chen, Hung-Ying; Su, Chao-Ton

2015-01-01

Specimen handling is a critical patient safety issue. Problematic handling process, such as misidentification (of patients, surgical site, and specimen counts), specimen loss, or improper specimen preparation can lead to serious patient harms and lawsuits. Value stream map (VSM) is a tool used to find out non-value-added works, enhance the quality, and reduce the cost of the studied process. On the other hand, healthcare failure mode and effect analysis (HFMEA) is now frequently employed to avoid possible medication errors in healthcare process. Both of them have a goal similar to Six Sigma methodology for process improvement. This study proposes a model that integrates VSM and HFMEA into the framework, which mainly consists of define, measure, analyze, improve, and control (DMAIC), of Six Sigma. A Six Sigma project for improving the process of surgical specimen handling in a hospital was conducted to demonstrate the effectiveness of the proposed model.

Sigma and beta convergence in regional mortality: A case study of the Netherlands

Directory of Open Access Journals (Sweden)

Fanny Janssen

2016-07-01

Full Text Available Background: For allocation of health budgets it is important to know whether regional mortality differences tend to decline or to increase. Sigma convergence tests can measure whether the dispersion of the regional distribution of mortality has declined. Beta convergence tests can examine whether regions with a low level of life expectancy have experienced a stronger increase than regions with a high level. In demographic research, however, sigma and beta convergence have not been formally assessed simultaneously. Objective: We demonstrate the application of both sigma and beta convergence tests to the study of trends in regional mortality differences for the Netherlands. Methods: Using all-cause mortality and population data for 40 Dutch NUTS-3 regions, by year (1988‒2009, age group, and sex, we assess both sigma and beta convergence, and ist significance. Results: Beta convergence proved statistically significant. The regions with the lowest life expectancy in 1988 generally exhibited the highest increase from 1988 to 2009, and vice versa. However, dispersion measures displayed no statistically significant sigma convergence. Conclusions: Whereas the absence of sigma convergence shows that regional mortality differences have not declined, beta convergence indicates that the disadvantage of regions with low life expectancy is not persistent. Contribution: We demonstrated the added value of simultaneously studying sigma convergence, beta convergence, and trajectories of regions in the tails of the distribution. Where absence of sigma convergence does not imply that disadvantaged regions did not improve, beta convergence does not always indicate complete convergence due to structural differences across regions.

Definition of the sigma(W) Regulon of Bacillus subtilis in the Absence of Stress

NARCIS (Netherlands)

Zweers, Jessica C.; Nicolas, Pierre; Wiegert, Thomas; van Dijl, Jan Maarten; Denham, Emma L.

2012-01-01

Bacteria employ extracytoplasmic function (ECF) sigma factors for their responses to environmental stresses. Despite intensive research, the molecular dissection of ECF sigma factor regulons has remained a major challenge due to overlaps in the ECF sigma factor-regulated genes and the stimuli that

Assessing precision, bias and sigma-metrics of 53 measurands of the Alinity ci system.

Science.gov (United States)

Westgard, Sten; Petrides, Victoria; Schneider, Sharon; Berman, Marvin; Herzogenrath, Jörg; Orzechowski, Anthony

2017-12-01

Assay performance is dependent on the accuracy and precision of a given method. These attributes can be combined into an analytical Sigma-metric, providing a simple value for laboratorians to use in evaluating a test method's capability to meet its analytical quality requirements. Sigma-metrics were determined for 37 clinical chemistry assays, 13 immunoassays, and 3 ICT methods on the Alinity ci system. Analytical Performance Specifications were defined for the assays, following a rationale of using CLIA goals first, then Ricos Desirable goals when CLIA did not regulate the method, and then other sources if the Ricos Desirable goal was unrealistic. A precision study was conducted at Abbott on each assay using the Alinity ci system following the CLSI EP05-A2 protocol. Bias was estimated following the CLSI EP09-A3 protocol using samples with concentrations spanning the assay's measuring interval tested in duplicate on the Alinity ci system and ARCHITECT c8000 and i2000 SR systems, where testing was also performed at Abbott. Using the regression model, the %bias was estimated at an important medical decisions point. Then the Sigma-metric was estimated for each assay and was plotted on a method decision chart. The Sigma-metric was calculated using the equation: Sigma-metric=(%TEa-|%bias|)/%CV. The Sigma-metrics and Normalized Method Decision charts demonstrate that a majority of the Alinity assays perform at least at five Sigma or higher, at or near critical medical decision levels. More than 90% of the assays performed at Five and Six Sigma. None performed below Three Sigma. Sigma-metrics plotted on Normalized Method Decision charts provide useful evaluations of performance. The majority of Alinity ci system assays had sigma values >5 and thus laboratories can expect excellent or world class performance. Laboratorians can use these tools as aids in choosing high-quality products, further contributing to the delivery of excellent quality healthcare for patients

Evaluation of Preanalytical Quality Indicators by Six Sigma and Pareto`s Principle.

Science.gov (United States)

Kulkarni, Sweta; Ramesh, R; Srinivasan, A R; Silvia, C R Wilma Delphine

2018-01-01

Preanalytical steps are the major sources of error in clinical laboratory. The analytical errors can be corrected by quality control procedures but there is a need for stringent quality checks in preanalytical area as these processes are done outside the laboratory. Sigma value depicts the performance of laboratory and its quality measures. Hence in the present study six sigma and Pareto principle was applied to preanalytical quality indicators to evaluate the clinical biochemistry laboratory performance. This observational study was carried out for a period of 1 year from November 2015-2016. A total of 1,44,208 samples and 54,265 test requisition forms were screened for preanalytical errors like missing patient information, sample collection details in forms and hemolysed, lipemic, inappropriate, insufficient samples and total number of errors were calculated and converted into defects per million and sigma scale. Pareto`s chart was drawn using total number of errors and cumulative percentage. In 75% test requisition forms diagnosis was not mentioned and sigma value of 0.9 was obtained and for other errors like sample receiving time, stat and type of sample sigma values were 2.9, 2.6, and 2.8 respectively. For insufficient sample and improper ratio of blood to anticoagulant sigma value was 4.3. Pareto`s chart depicts out of 80% of errors in requisition forms, 20% is contributed by missing information like diagnosis. The development of quality indicators, application of six sigma and Pareto`s principle are quality measures by which not only preanalytical, the total testing process can be improved.

Seis Sigma: Fatores Críticos de Sucesso para sua Implantação

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Antonio Cesar Amaru Maximiano

2009-10-01

Full Text Available This article describes an investigation of critical success factors to implement Six Sigma in organizations operating in the Brazilian market place. Besides that, a secondary objective was to investigate the relationship between aspects like success perception among those companies which implemented Six Sigma, company size, company nationality, time of Six Sigma of implementation, continuous training, communication level between professionals, full-time and part-time Black Belts, project completion, project duration and project savings. Data were collected through an Internet questionnaire, distributed by email and sent to discussion groups involving Six Sigma professionals. Questionnaire development included a literature review and interviews with experienced Six Sigma professionals. The results indicated eight critical success factors for Six Sigma implementation: (a Leadership, (b Projects, (c Training, (d Communication and Review, (e Managerial Process, (f Black Belts Profile, (g Project Teams and (h Previous Quality Initiatives.

A modular approach to neutral P,N-ligands: synthesis and coordination chemistry

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Vladislav Vasilenko

2016-04-01

Full Text Available We report the modular synthesis of three different types of neutral κ2-P,N-ligands comprising an imine and a phosphine binding site. These ligands were reacted with rhodium, iridium and palladium metal precursors and the structures of the resulting complexes were elucidated by means of X-ray crystallography. We observed that subtle changes of the ligand backbone have a significant influence on the binding geometry und coordination properties of these bidentate P,N-donors.

Six sigma management and its application in nuclear power plant

International Nuclear Information System (INIS)

Liu Weihua; Tong Lili

2007-01-01

Six sigma management mode is presented. The feasibility, necessity and the steps to extend six sigma in nuclear power plant are addressed. Nuclear power plant can eliminate or decrease human errors through importing six management concept, the 'zero disfigurement' quality and operation can achieved, decreasing accident risk and realizing safety operation. (authors)

Detection of site-specific binding and co-binding of ligands to macromolecules using 19F NMR

International Nuclear Information System (INIS)

Jenkins, B.G.

1991-01-01

Study of ligand-macromolecular interactions by 19 F nuclear magnetic resonance (NMR) spectroscopy affords many opportunities for obtaining molecular biochemical and pharmaceutical information. This is due to the absence of a background fluorine signal, as well as the relatively high sensitivity of 19 F NMR. Use of fluorine-labeled ligands enables one to probe not only binding and co-binding phenomena to macromolecules, but also can provide data on binding constants, stoichiometries, kinetics, and conformational properties of these complexes. Under conditions of slow exchange and macromolecule-induced chemical shifts, multiple 19 F NMR resonances can be observed for free and bound ligands. These shifted resonances are a direct correlate of the concentration of ligand bound in a specific state rather than the global concentrations of bound or free ligand which are usually determined using other techniques such as absorption spectroscopy or equilibrium dialysis. Examples of these interactions are demonstrated both from the literature and from interactions of 5-fluorotryptophan, 5-fluorosalicylic acid, flurbiprofen, and sulindac sulfide with human serum albumin. Other applications of 19 F NMR to study of these interactions in vivo, as well for receptor binding and metabolic tracing of fluorinated drugs and proteins are discussed

Soliton surfaces associated with sigma models: differential and algebraic aspects

International Nuclear Information System (INIS)

Goldstein, P P; Grundland, A M; Post, S

2012-01-01

In this paper, we consider both differential and algebraic properties of surfaces associated with sigma models. It is shown that surfaces defined by the generalized Weierstrass formula for immersion for solutions of the CP N-1 sigma model with finite action, defined in the Riemann sphere, are themselves solutions of the Euler–Lagrange equations for sigma models. On the other hand, we show that the Euler–Lagrange equations for surfaces immersed in the Lie algebra su(N), with conformal coordinates, that are extremals of the area functional, subject to a fixed polynomial identity, are exactly the Euler–Lagrange equations for sigma models. In addition to these differential constraints, the algebraic constraints, in the form of eigenvalues of the immersion functions, are systematically treated. The spectrum of the immersion functions, for different dimensions of the model, as well as its symmetry properties and its transformation under the action of the ladder operators are discussed. Another approach to the dynamics is given, i.e. description in terms of the unitary matrix which diagonalizes both the immersion functions and the projectors constituting the model. (paper)

The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

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Bryan L Roth

Full Text Available In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS-2-(ethylamino-2-(3-methoxyphenylcyclohexanone and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenylcyclohexanamine and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenylcyclohexyl]piperidine and 1-[1-(4-methoxyphenylcyclohexyl]piperidine, were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

The thermodynamic signature of ligand binding to histone deacetylase-like amidohydrolases is most sensitive to the flexibility in the L2-loop lining the active site pocket.

Science.gov (United States)

Meyners, Christian; Krämer, Andreas; Yildiz, Özkan; Meyer-Almes, Franz-Josef

2017-07-01

The analysis of the thermodynamic driving forces of ligand-protein binding has been suggested to be a key component for the selection and optimization of active compounds into drug candidates. The binding enthalpy as deduced from isothermal titration calorimetry (ITC) is usually interpreted assuming single-step binding of a ligand to one conformation of the target protein. Although successful in many cases, these assumptions are oversimplified approximations of the reality with flexible proteins and complicated binding mechanism in many if not most cases. The relationship between protein flexibility and thermodynamic signature of ligand binding is largely understudied. Directed mutagenesis, X-ray crystallography, enzyme kinetics and ITC methods were combined to dissect the influence of loop flexibility on the thermodynamics and mechanism of ligand binding to histone deacetylase (HDAC)-like amidohydrolases. The general ligand-protein binding mechanism comprises an energetically demanding gate opening step followed by physical binding. Increased flexibility of the L2-loop in HDAC-like amidohydrolases facilitates access of ligands to the binding pocket resulting in predominantly enthalpy-driven complex formation. The study provides evidence for the great importance of flexibility adjacent to the active site channel for the mechanism and observed thermodynamic driving forces of molecular recognition in HDAC like enzymes. The flexibility or malleability in regions adjacent to binding pockets should be given more attention when designing better drug candidates. The presented case study also suggests that the observed binding enthalpy of protein-ligand systems should be interpreted with caution, since more complicated binding mechanisms may obscure the significance regarding potential drug likeness. Copyright © 2017 Elsevier B.V. All rights reserved.

[Supercomputer investigation of the protein-ligand system low-energy minima].

Science.gov (United States)

Oferkin, I V; Sulimov, A V; Katkova, E V; Kutov, D K; Grigoriev, F V; Kondakova, O A; Sulimov, V B

2015-01-01

The accuracy of the protein-ligand binding energy calculations and ligand positioning is strongly influenced by the choice of the docking target function. This work demonstrates the evaluation of the five different target functions used in docking: functions based on MMFF94 force field and functions based on PM7 quantum-chemical method accounting or without accounting the implicit solvent model (PCM, COSMO or SGB). For these purposes the ligand positions corresponding to the minima of the target function and the experimentally known ligand positions in the protein active site (crystal ligand positions) were compared. Each function was examined on the same test-set of 16 protein-ligand complexes. The new parallelized docking program FLM based on Monte Carlo search algorithm was developed to perform the comprehensive low-energy minima search and to calculate the protein-ligand binding energy. This study demonstrates that the docking target function based on the MMFF94 force field can be used to detect the crystal or near crystal positions of the ligand by the finding the low-energy local minima spectrum of the target function. The importance of solvent accounting in the docking process for the accurate ligand positioning is also shown. The accuracy of the ligand positioning as well as the correlation between the calculated and experimentally determined protein-ligand binding energies are improved when the MMFF94 force field is substituted by the new PM7 method with implicit solvent accounting.

DESIGN FOR SIX SIGMA

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Liem Ferryanto

2007-01-01

Full Text Available This article provides a step by step process of executing analytical or computer based Design for Six Sigma using a Sliding Door project as an example. It comprises of identification of Voice Of the Customer (VOC, transformation of VOC to what it is called Critical To Quality characteristics (CTQs, modeling of system transfers function, optimal and robust solutions, and tolerance design approach

Usulan Perbaikan Kualitas Penggulungan Benang Nilon Dengan Menggunakan Metode Six Sigma di PT. XYZ

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I Wayan Sukania

2016-07-01

Full Text Available Abstrak: PT. XYZ merupakan perusahaan yang bergerak dibidang textil yang memproduksi benang jahit. Perusahaan selalu berusaha meningkatkan kualitas produknya dalam penanganan produk yang cacat yang terjadi pada proses produksi karena jumlah cacat yang timbul cukup banyak. Untuk itu perlu dilakukan tindakan perbaikan dalam menurunkan tingkat cacat yang terjadi. Pada penelitian ini, penulis menggunakan metode six sigma dengan model perbaikian Define-Measure-Analyze-Improve-Control (DMAIC dan Failure Mode and Effect Analysis (FMEA untuk menganalisis kinerja proses dan produk yang dihasilkan. Penerapan metode tersebut diharapakan mampu meningkatkan kualitas perusahaan yang sekarang pada level sigma 3,8 menuju tingkat kinerja kualitas 6 Sigma. Kata kunci: Six Sigma, FMEA Abstract: PT. XYZ is a company engaged in textile-producing sewing thread. The company is always trying to improve the quality of products due to quite a lot of products defects occur in the production process. It is necessary for corrective action in reducing the level of defects that occur. In this research, the six sigma with Define-Measure Analyze-Improve-Control (DMAIC and Failure Mode and Effect Analysis (FMEA models were used to analyze the performance of processes and products. Application of those methods are expected to be able to improve the quality of company that are now at the level of sigma 3,8 to 6 sigma level of quality performance . Keywords: Six Sigma, FMEA

Impact of Six Sigma in a developing economy: analysis on benefits drawn by Indian industries

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Darshak A. Desai

2009-12-01

Full Text Available  Overall operational excellence is the key requirement of any business to have global competence and sustained growth. Indian industries are not the exception to this. Six Sigma has emerged as one of the most effective business improvement strategies world wide.  Nothing much has been published so far illustrating an overall experience of Indian industries with Six Sigma. This paper presents an analysis of the impact of Six Sigma on developing economy like India.  The paper provides an insight into what kind of benefits Indian industries are gaining from Six Sigma as a whole. The study further highlights similarity and differences of benefit gained by different scales and sectors of Indian industries through Six Sigma. This exhaustive analysis of the benefits drawn by Indian industries through Six Sigma can assist other industries in India as well as those in other developing countries, who have yet not experimented with Six Sigma, to become more focused regarding their expectations from this improvement drive. 

Design Principles of A Sigma-delta Flux-gate Magnetometer

Science.gov (United States)

Magnes, W.; Valavanoglou, A.; Pierce, D.; Frank, A.; Schwingenschuh, K.

A state-of-the-art flux-gate magnetometer is characterised by magnetic field resolution of several pT in a wide frequency range, low power consumption, low weight and high robustness. Therefore, flux-gate magnetometers are frequently used for ground-based Earth's field observation as well as for measurements aboard scientific space missions. But both traditional analogue and recently developed digital flux-gate magnetometers need low power and high-resolution analogue-to-digital converters for signal quan- tization. The disadvantage of such converters is the low radiation hardness. This fact has led to the idea of combining a traditional analogue flux-gate regulation circuit with that of a discretely realized sigma-delta converter in order to get a radiation hard and further miniaturized magnetometer. The name sigma-delta converter is derived from putting an integrator in front of a 1-bit delta modulator which forms the sigma-delta loop. It is followed by a digital decimation filter realized in a field-programmable gate array (FPGA). The flux-gate regulation and the sigma-delta loop are quite similar in the way of realizing the integrator and feedback circuit, which makes it easy to com- bine these two systems. The presented talk deals with the design principles and the results of a first bread board model.

The Role of Protein-Ligand Contacts in Allosteric Regulation of the Escherichia coli Catabolite Activator Protein.

Science.gov (United States)

Townsend, Philip D; Rodgers, Thomas L; Glover, Laura C; Korhonen, Heidi J; Richards, Shane A; Colwell, Lucy J; Pohl, Ehmke; Wilson, Mark R; Hodgson, David R W; McLeish, Tom C B; Cann, Martin J

2015-09-04

Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distant site. Both experimental and theoretical evidence demonstrate that allostery can be communicated through altered slow relaxation protein dynamics without conformational change. The catabolite activator protein (CAP) of Escherichia coli is an exemplar for the analysis of such entropically driven allostery. Negative allostery in CAP occurs between identical cAMP binding sites. Changes to the cAMP-binding pocket can therefore impact the allosteric properties of CAP. Here we demonstrate, through a combination of coarse-grained modeling, isothermal calorimetry, and structural analysis, that decreasing the affinity of CAP for cAMP enhances negative cooperativity through an entropic penalty for ligand binding. The use of variant cAMP ligands indicates the data are not explained by structural heterogeneity between protein mutants. We observe computationally that altered interaction strength between CAP and cAMP variously modifies the change in allosteric cooperativity due to second site CAP mutations. As the degree of correlated motion between the cAMP-contacting site and a second site on CAP increases, there is a tendency for computed double mutations at these sites to drive CAP toward noncooperativity. Naturally occurring pairs of covarying residues in CAP do not display this tendency, suggesting a selection pressure to fine tune allostery on changes to the CAP ligand-binding pocket without a drive to a noncooperative state. In general, we hypothesize an evolutionary selection pressure to retain slow relaxation dynamics-induced allostery in proteins in which evolution of the ligand-binding site is occurring. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The Statistical point of view of Quality: the Lean Six Sigma methodology.

Science.gov (United States)

Bertolaccini, Luca; Viti, Andrea; Terzi, Alberto

2015-04-01

Six Sigma and Lean are two quality improvement methodologies. The Lean Six Sigma methodology is applicable to repetitive procedures. Therefore, the use of this methodology in the health-care arena has focused mainly on areas of business operations, throughput, and case management and has focused on efficiency outcomes. After the revision of methodology, the paper presents a brief clinical example of the use of Lean Six Sigma as a quality improvement method in the reduction of the complications during and after lobectomies. Using Lean Six Sigma methodology, the multidisciplinary teams could identify multiple modifiable points across the surgical process. These process improvements could be applied to different surgical specialties and could result in a measurement, from statistical point of view, of the surgical quality.

THE IMPROVEMENT OF PROCESSES’ QUALITY IN ORGANISATIONS USING THE SIX SIGMA CONCEPT

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MĂDĂLINA BRUTU

2010-01-01

Full Text Available Six Sigma is a problem-solving methodology. In fact, it’s the most effective problem-solving methodology available for improving business and organizational performance. Bill Smith from Motorola first developed in 1986 the specific elements of Six Sigma. At the beginning, it was a set of practices which have been used in the manufacturing processes in order to eliminate the defects but, as time passed, the concept has been extended so as to be used in other types of businesses, too. The 6th Sigma level corresponds to a 99,9997% performance, respectively 3,4 defects per a million of occasions. A Six Sigma process is a redesigned business process and has three basic elements: Process Improvement; Designing/redesigning the process; The Process Management.

Facilitating Teamwork with Lean Six Sigma and Web-Based Technology

Science.gov (United States)

Krause, Tim

2009-01-01

In this article, the author outlines a variety of ways of defining, making explicit, and supporting effective team-based projects through the basic tenets of Lean Six Sigma and the use of Web-based technologies. A combination of Lean Six Sigma and a handful of project management technologies not only help in fostering the communication central to…

Inspanning om Lean Six Sigma op kaart te zetten beloond

NARCIS (Netherlands)

Does, R.J.M.M.

2008-01-01

Prof.dr. R.J.M.M. Does is al jarenlang een fervent voorvechter voor het gebruik van statistiek. En meer recent is hij zo’n beetje de belichaming van (Lean) Six Sigma in Europa. Tal van grote organisaties hebben hem te hulp geroepen bij de invoering van (Lean) Six Sigma. Het is dan ook niet meer dan

Statistical Profiling of One Promiscuous Protein Binding Site: Illustrated by Urokinase Catalytic Domain.

Science.gov (United States)

Cerisier, Natacha; Regad, Leslie; Triki, Dhoha; Petitjean, Michel; Flatters, Delphine; Camproux, Anne-Claude

2017-10-01

While recent literature focuses on drug promiscuity, the characterization of promiscuous binding sites (ability to bind several ligands) remains to be explored. Here, we present a proteochemometric modeling approach to analyze diverse ligands and corresponding multiple binding sub-pockets associated with one promiscuous binding site to characterize protein-ligand recognition. We analyze both geometrical and physicochemical profile correspondences. This approach was applied to examine the well-studied druggable urokinase catalytic domain inhibitor binding site, which results in a large number of complex structures bound to various ligands. This approach emphasizes the importance of jointly characterizing pocket and ligand spaces to explore the impact of ligand diversity on sub-pocket properties and to establish their main profile correspondences. This work supports an interest in mining available 3D holo structures associated with a promiscuous binding site to explore its main protein-ligand recognition tendency. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Robust sigma delta converters : and their application in low-power highly-digitized flexible receivers

NARCIS (Netherlands)

Veldhoven, van R.H.M.; Roermund, van A.H.M.

2011-01-01

Sigma Delta converters are a very popular choice for the A/D converter in multi-standard, mobile and cellular receivers. Key A/D converter specifications are high dynamic range, robustness, scalability, low-power and low EMI. Robust Sigma Delta Converters presents a requirement derivation of a Sigma

Mutual control of axial and equatorial ligands: model studies with [Ni]-bacteriochlorophyll-a.

Science.gov (United States)

Yerushalmi, Roie; Noy, Dror; Baldridge, Kim K; Scherz, Avigdor

2002-07-17

) computationally, we found that a reduction of [Ni]-BChl*imidazole results in a weaker metal-axial ligand bond. Yet, it remains weakly bound in the gas phase. The experimentally observed ligand dissociation is accounted for computationally when solvation is considered. On the basis of the experimental observations and QM calculations, we propose a mechanism whereby alterations in the equatorial pi system and modulation of sigma bonding between the axial ligands and the metal core are mutually correlated. Such a mechanism highlights the dynamic role of axial ligands in regulating the activity of metal centers such as factor F430 (F430), a nickel-based coenzyme that is essential in methanogenic archea.

Production quality improvement analysis of grey cambric using Six Sigma Method

Directory of Open Access Journals (Sweden)

Shafira Yosa Permata

2018-01-01

Full Text Available Quality has an important role in business. A good quality means it is able to meet the required standards. The concept of quality must be comprehensive, whether the quality of the product or its process. PT Textile Yogyakarta is still having a high rate of defect products. The Waste Assessment Model (WAM was used to identify the wastes that frequently occur by scoring each type of waste. The results show the waste rank are defect 26.12%, inventory 20.36%, motion 15.26%, transportation 14.51%, over production 12.91%, waiting 7.17%, and process 3.67%. While using the Six Sigma from the 4 CTQ process, the result of sigma level is 3.3. It means that the sigma level of PT Textile Yogyakarta is still under the average sigma level in Japan which is 5 Sigma. As for the improvement part, FMEA AHP was used and the results show that the first rank is the uncleaned woof residue, the second rank is the uncut thread which has an RPN value of 8.04 that was caused when the operator did not clean the machine from the woof residue, and the third rank is the malfunctioned machine which has an RPN value of 7.32 that was caused by broken kleting.

Doubly graded sigma model with torsion

International Nuclear Information System (INIS)

Kowalski-Glikman, J.

1986-08-01

Using the Hull-Witten construction we show how to introduce torsion to the doubly graded sigma model. This construction enables us to find a link between this model and the ten-dimensional supergravity theory in superspace. (Auth.)

Virtual screening applications: a study of ligand-based methods and different structure representations in four different scenarios.

Science.gov (United States)

Hristozov, Dimitar P; Oprea, Tudor I; Gasteiger, Johann

2007-01-01

Four different ligand-based virtual screening scenarios are studied: (1) prioritizing compounds for subsequent high-throughput screening (HTS); (2) selecting a predefined (small) number of potentially active compounds from a large chemical database; (3) assessing the probability that a given structure will exhibit a given activity; (4) selecting the most active structure(s) for a biological assay. Each of the four scenarios is exemplified by performing retrospective ligand-based virtual screening for eight different biological targets using two large databases--MDDR and WOMBAT. A comparison between the chemical spaces covered by these two databases is presented. The performance of two techniques for ligand--based virtual screening--similarity search with subsequent data fusion (SSDF) and novelty detection with Self-Organizing Maps (ndSOM) is investigated. Three different structure representations--2,048-dimensional Daylight fingerprints, topological autocorrelation weighted by atomic physicochemical properties (sigma electronegativity, polarizability, partial charge, and identity) and radial distribution functions weighted by the same atomic physicochemical properties--are compared. Both methods were found applicable in scenario one. The similarity search was found to perform slightly better in scenario two while the SOM novelty detection is preferred in scenario three. No method/descriptor combination achieved significant success in scenario four.

Six Sigma Quality Management System and Design of Risk-based Statistical Quality Control.

Science.gov (United States)

Westgard, James O; Westgard, Sten A

2017-03-01

Six sigma concepts provide a quality management system (QMS) with many useful tools for managing quality in medical laboratories. This Six Sigma QMS is driven by the quality required for the intended use of a test. The most useful form for this quality requirement is the allowable total error. Calculation of a sigma-metric provides the best predictor of risk for an analytical examination process, as well as a design parameter for selecting the statistical quality control (SQC) procedure necessary to detect medically important errors. Simple point estimates of sigma at medical decision concentrations are sufficient for laboratory applications. Copyright © 2016 Elsevier Inc. All rights reserved.

Use of the Six Sigma by the 500 Largent Companies in Portugal

OpenAIRE

Mendes da Conceição, Ana Cristina; Martins Ferreira Major, Maria João

2011-01-01

The Six Sigma had its genesis in big industrial companies that have implemented it as a tool for reducing defects. The initial success encouraged its application in other areas and we see today successful implementation in other sectors such as services, and within their own organizations in other areas beyond production, setting; this has contributed to Six Sigma being recognized as a new management model. In order to determine the extent to which Six Sigma is present in Portuguese companies...

Plastic Injection Quality Controlling Using the Lean Six Sigma and FMEA Method

Science.gov (United States)

Mansur, A.; Mu'alim; Sunaryo

2016-01-01

PT. Yogya Presisi Teknikatama Industri (PT. YPTI) is a mold, precision part, and plastic injection maker company. One of the obstacles faced by the company is the high level of nonconformity on its production results. The waste on production process can be identified and classified into four types, i.e.: a). during the process of injection molding machines, b). finishing and cutting processes, c). quality control process and d). the packaging process. The objectives of this research are minimizing the defective goods and reducing the waste using Lean Six Sigma and FMEA approaches, especially for Bush product. From the analysis result, defective types on Bush product can be classified into bubble, speckle, short shoot, sunken, sink mark, over-cut, flashing, and discolor. Based on the attributes data on Bush product, the DPMO score is 988.42 or the sigma level is 4.6, While the DPMO score on the variable data on each dimension i.e.: a). Slit width on the bottom side has DPMO score of 30119 (sigma level 3.37), b). Diameter of the circle on the top side has DPMO score of 392294 (sigma level 1.77), c). Product thickness on the top side has DPMO score of 70474 (sigma level 2.97), d). Product height has DPMO score of 82107 (sigma level 2.89), product thickness on the bottom side has DPMO score of 24448 (sigma level 3.47), and f). Diameter of the circle on the bottom side has DPMO score of 24448 (sigma level 3.47). The highest RPN score on the dominant types of product defects which needs improvement are the defective goods of bubble type has RPN score of 729, flashing and the molten material out on the heating channel has RPN score of 384, over cutting has RPN score of 324 and sink mark has RPN score of 270. The recommendations for improvement that can be given from this research are making checklist for maintenance and production monitoring, enhancing work supervision and inspection, as well as improving the environment and work stations.

Interaction of cadmium with atrial natriuretic factor receptors: Ligand binding and cellular processing

International Nuclear Information System (INIS)

Giridhar, J.; Rathinavelu, A.; Isom, G.E.

1990-01-01

ANF is a peptide hormone secreted by the heart and produces potent diuresis and vascular smooth muscle relaxation. It is well known that Cd produces cardiovascular toxicity and is implicated in the pathogenesis of hypertension. Hence the effects of Cd on ANF receptor dynamics and ligand binding were studied in PC12 cells. Receptor internalization using 125 I-ANF as the ligand at 37 degree C displayed a decrease in endocytic rate constants (ERC) when either preincubated with Cd (500 μM for 30 min, ERC = 0.183/min) or coincubated with Cd (500 μM, ERC = 0.196) when compared to control value (ERC = 0.259/min). Ligand binding ( 125 I-ANF) was changed by Cd as reflected by a decrease in the number of binding sites/cell in both Cd preincubated (Kd = 3.81 x 10 -10 M, B max = 1 x 10 -10 M, binding sites/cell = 9333) and coincubated cells (Kd = 1.76 x 10 -10 M, B max = 3.92 x 10 -11 M, binding sites/cell = 5960) from control (Kd = 3.87 x 10 -10 M, B max = 9.58 x 10 -11 M, binding sites/cell = 12141). Photoaffinity labelling with 125 I-ANF as the ligand was used to measure receptor subtype binding. Coincubation of cells with Cd (500 μM) and ligand decreased both high and low mol. wt. receptor binding, whereas preincubation with Cd (500μM) for 60 min produced a slight decrease in binding of both receptor subtypes. These results indicate that the cardiovascular toxicity of Cd may be partially mediated by altered ANF receptor function

Measuring emittances and sigma matrices

International Nuclear Information System (INIS)

Rees, J.; Rivkin, L.

1984-03-01

The method used for measuring emittance at the SLAC Linac and the linear collider damping ring is described. The basis of the method is derived using one two-by-two matrix to specify the state of the input beam (sigma matrix) and another to describe the lens-drift transport system (R-matrix)

Multiple ligand-binding modes in bacterial R67 dihydrofolate reductase

Science.gov (United States)

Alonso, Hernán; Gillies, Malcolm B.; Cummins, Peter L.; Bliznyuk, Andrey A.; Gready, Jill E.

2005-03-01

R67 dihydrofolate reductase (DHFR), a bacterial plasmid-encoded enzyme associated with resistance to the drug trimethoprim, shows neither sequence nor structural homology with the chromosomal DHFR. It presents a highly symmetrical toroidal structure, where four identical monomers contribute to the unique central active-site pore. Two reactants (dihydrofolate, DHF), two cofactors (NADPH) or one of each (R67•DHF•NADPH) can be found simultaneously within the active site, the last one being the reactive ternary complex. As the positioning of the ligands has proven elusive to empirical determination, we addressed the problem from a theoretical perspective. Several potential structures of the ternary complex were generated using the docking programs AutoDock and FlexX. The variability among the final poses, many of which conformed to experimental data, prompted us to perform a comparative scoring analysis and molecular dynamics simulations to assess the stability of the complexes. Analysis of ligand-ligand and ligand-protein interactions along the 4 ns trajectories of eight different structures allowed us to identify important inter-ligand contacts and key protein residues. Our results, combined with published empirical data, clearly suggest that multipe binding modes of the ligands are possible within R67 DHFR. While the pterin ring of DHF and the nicotinamide ring of NADPH assume a stacked endo-conformation at the centre of the pore, probably assisted by V66, Q67 and I68, the tails of the molecules extend towards opposite ends of the cavity, adopting multiple configurations in a solvent rich-environment where hydrogen-bond interactions with K32 and Y69 may play important roles.

Integration of Value Stream Map and Healthcare Failure Mode and Effect Analysis into Six Sigma Methodology to Improve Process of Surgical Specimen Handling

Directory of Open Access Journals (Sweden)

Sheng-Hui Hung

2015-01-01

Full Text Available Specimen handling is a critical patient safety issue. Problematic handling process, such as misidentification (of patients, surgical site, and specimen counts, specimen loss, or improper specimen preparation can lead to serious patient harms and lawsuits. Value stream map (VSM is a tool used to find out non-value-added works, enhance the quality, and reduce the cost of the studied process. On the other hand, healthcare failure mode and effect analysis (HFMEA is now frequently employed to avoid possible medication errors in healthcare process. Both of them have a goal similar to Six Sigma methodology for process improvement. This study proposes a model that integrates VSM and HFMEA into the framework, which mainly consists of define, measure, analyze, improve, and control (DMAIC, of Six Sigma. A Six Sigma project for improving the process of surgical specimen handling in a hospital was conducted to demonstrate the effectiveness of the proposed model.

The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

International Nuclear Information System (INIS)

Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.; Anderson, Redmond-Craig; Zeng, Chenbo; Xu, Kuiying; Hou, Catherine; McDonald, Elizabeth S.; Pryma, Daniel A.; Mach, Robert H.

2015-01-01

Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods: Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. - Highlights: • TNBC cells are sensitive to sigma-2 receptor targeted drug conjugate SW IV-134. • MDA-MB-231 displayed the highest amount of sigma-2 receptors and corresponded well with

The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

Energy Technology Data Exchange (ETDEWEB)

Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.; Anderson, Redmond-Craig; Zeng, Chenbo; Xu, Kuiying; Hou, Catherine; McDonald, Elizabeth S.; Pryma, Daniel A.; Mach, Robert H., E-mail: rmach@mail.med.upenn.edu

2015-11-27

Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods: Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. - Highlights: • TNBC cells are sensitive to sigma-2 receptor targeted drug conjugate SW IV-134. • MDA-MB-231 displayed the highest amount of sigma-2 receptors and corresponded well with

Carbon monoxide and cyanide as intrinsic ligands to iron in the active site of [NiFe]-hydrogenases. NiFe(CN)2CO, biology's way to activate H2

NARCIS (Netherlands)

Pierik, A.J.; Roseboom, W.; Happe, R.P.; Bagley, K.A.; Albracht, S.P.J.

1999-01-01

Infrared-spectroscopic studies on the [NiFe]-hydrogenase of Chromatium vinosum-enriched in 15N or 13C, as well as chemical analyses, show that this enzyme contains three non-exchangeable, intrinsic, diatomic molecules as ligands to the active site, one carbon monoxide molecule and two cyanide

Lean Six Sigma in health care and the challenge of implementation of Six Sigma methodologies at a Veterans Affairs Medical Center.

Science.gov (United States)

Pocha, Christine

2010-01-01

Six Sigma and Lean Thinking are quality initiatives initially deployed in industry to improve operational efficiency leading to better quality and subsequent cost savings. The financial rationale for embarking on this quality journey is clear; applying it to today's health care remains challenging. The cost of medical care is increasing at an alarming rate; most of these cost increases are attributed to an aging population and technological advances; therefore, largely beyond control. Furthermore, health care cost increases are caused by unnecessary operational inefficiency associated with the direct medical service delivery process. This article describes the challenging journey of implementing Six Sigma methodology at a tertiary care medical center. Many lessons were learned; however, of utmost importance were team approach, "buy in" of the stakeholders, and the willingness of team members to change daily practice and to adapt new and innovative ways how health care can be delivered. Six Sigma incorporated as part of the "company's or hospital's culture" would be most desirable but the learning curve will be steep.

C[sub 10]-O[sub eq]-N-(4-azido-5-[sup 125]iodo salicyloyl)-[beta]-alanyl-[beta] alanyl ryanodine (Az-[beta]AR), a novel photo-affinity ligand for the ryanodine binding site

Energy Technology Data Exchange (ETDEWEB)

Bidasee, K.R.; Besch, H.R. Jr.; Kwon, Sangyeol; Emmick, J.T.; Besch, K.T.; Gerzon, Koert; Humerickhouse, R.A. (Indiana Univ., Indianapolis, IN (United States). School of Medicine)

1994-01-01

A high affinity, photoactivatable, radio-iodinated ligand for the ryanodine binding site(s) of the sarcoplasmic reticulum calcium-release channel, C[sub 10]-O[sub e]-N-(4-azido-5-[sup 125]iodo salicyloyl)-[beta]-alanyl-[beta]-alanyl ryanodine (Az-[beta]AR), was synthesized at a specific activity of 1400mCi/mmol. (Author).

Application of Six Sigma methodology to a cataract surgery unit.

Science.gov (United States)

Taner, Mehmet Tolga

2013-01-01

The article's aim is to focus on the application of Six Sigma to minimise intraoperative and post-operative complications rates in a Turkish public hospital cataract surgery unit. Implementing define-measure-analyse-improve and control (DMAIC) involves process mapping, fishbone diagrams and rigorous data-collection. Failure mode and effect analysis (FMEA), pareto diagrams, control charts and process capability analysis are applied to redress cataract surgery failure root causes. Inefficient skills of assistant surgeons and technicians, low quality of IOLs used, wrong IOL placement, unsystematic sterilisation of surgery rooms and devices, and the unprioritising network system are found to be the critical drivers of intraoperative-operative and post-operative complications. Sigma level was increased from 2.60 to 3.75 subsequent to extensive training of assistant surgeons, ophthalmologists and technicians, better quality IOLs, systematic sterilisation and air-filtering, and the implementation of a more sophisticated network system. This article shows that Six Sigma measurement and process improvement can become the impetus for cataract unit staff to rethink their process and reduce malpractices. Measuring, recording and reporting data regularly helps them to continuously monitor their overall process and deliver safer treatments. This is the first Six Sigma ophthalmology study in Turkey.

Lean Six Sigma: Stap voor stap

NARCIS (Netherlands)

Does, R.J.M.M.; de Koning, H.; de Mast, J.

2008-01-01

Lean Six Sigma is de culminatie van ontwikkelingen in kwaliteitsverbetering in de 20ste eeuw. Het combineert belangrijke principes en technieken in een goed gestructureerde en geïntegreerde benadering. Het belichaamt wetenschappelijke inzichten over onderzoeksmethodologie, management en economie. In

IceBridge Sigma Space Lidar L0 Raw Time-of-Flight Data

Data.gov (United States)

National Aeronautics and Space Administration — The NASA IceBridge Sigma Space Lidar L0 Raw Time-of-Flight Data (ILSIG0) contain raw time-of-flight values for Antarctica and Greenland using the Sigma Space Lidar....

Juego de rol Lean Six Sigma para empresas

OpenAIRE

Moldon Garrido, David; Porqueras Vila, Olga

2015-01-01

El objetivo del presente trabajo es la creación de un juego de rol que sirva a las empresas como formación. El fin de este juego es concienciar y formar a los trabajadores en la metodología Lean Six Sigma. Lean Six Sigma es una metodología centrada en la mejora continua para reducir los costes de la no calidad. Estos costes son aquellos generados por la producción de material o servicios que no cumplen los requerimientos del cliente. Creamos un juego de rol en el que los participantes form...

Lean Six Sigma en las administraciones públicas

OpenAIRE

Chiaburu, Gheorghe

2014-01-01

RESUMEN: El objetivo principal de este trabajo es realizar un estudio sobre la metodología Six Sigma y la metodología Lean, evaluando su posible implementación en las Administraciones públicas. Como se muestra más adelante la unión de estas dos metodologías es más que un sistema de calidad, es una filosofía de trabajo que busca la perfección continua de los procesos. La implementación de la Six Sigma se ha realizado principalmente en industrias manufactureras y de producción y de mane...

Performance specifications and six sigma theory: Clinical chemistry and industry compared.

Science.gov (United States)

Oosterhuis, W P; Severens, M J M J

2018-04-11

Analytical performance specifications are crucial in test development and quality control. Although consensus has been reached on the use of biological variation to derive these specifications, no consensus has been reached which model should be preferred. The Six Sigma concept is widely applied in industry for quality specifications of products and can well be compared with Six Sigma models in clinical chemistry. However, the models for measurement specifications differ considerably between both fields: where the sigma metric is used in clinical chemistry, in industry the Number of Distinct Categories is used instead. In this study the models in both fields are compared and discussed. Copyright © 2018. Published by Elsevier Inc.

Integration of six sigma with lean production: an analysis through multiple cases

Directory of Open Access Journals (Sweden)

Thiago Henrique Pinheiro

2013-08-01

Full Text Available The intense competition between markets has taken companies, regardless of their size, to implement one or more quality improvement programs. One of the main purposes of these programs is the enhancement of company effectiveness and efficiency. There is today a growing interested in a proposal named Lean Six Sigma. Their objective is to apply six sigma concepts integrated with Lean Production. A model named Lean Six Sigma has raised interest, once its objective is to apply the concepts of the Six Sigma program integrating them with the principles of Lean Production. Six Sigma contributes with methods for problem identification, measurement and analysis, and the Lean Production offers techniques and procedures applied to reduce waste in the production. In this context, this paper aims at demonstrating the results of a field research, from which purpose was to identify relevant factors for Six Sigma implementation combined with Lean Production. To meet these objectives, three organizations from different industrial sectors were investigated. It was verified that in two of those companies, the programs were successfully implemented. Based on data analysis, it is possible to identify that one of the major difficulties encountered by the program leaders is related to the company’s human resources infra-structure. It is necessary to take into account that the conclusions are limited to a small sample of three units of analysis. However, this work offers the possibility of an analytical generalization.

Reduction in Chemotherapy Mixing Errors Using Six Sigma: Illinois CancerCare Experience.

Science.gov (United States)

Heard, Bridgette; Miller, Laura; Kumar, Pankaj

2012-03-01

Chemotherapy mixing errors (CTMRs), although rare, have serious consequences. Illinois CancerCare is a large practice with multiple satellite offices. The goal of this study was to reduce the number of CTMRs using Six Sigma methods. A Six Sigma team consisting of five participants (registered nurses and pharmacy technicians [PTs]) was formed. The team had 10 hours of Six Sigma training in the DMAIC (ie, Define, Measure, Analyze, Improve, Control) process. Measurement of errors started from the time the CT order was verified by the PT to the time of CT administration by the nurse. Data collection included retrospective error tracking software, system audits, and staff surveys. Root causes of CTMRs included inadequate knowledge of CT mixing protocol, inconsistencies in checking methods, and frequent changes in staffing of clinics. Initial CTMRs (n = 33,259) constituted 0.050%, with 77% of these errors affecting patients. The action plan included checklists, education, and competency testing. The postimplementation error rate (n = 33,376, annualized) over a 3-month period was reduced to 0.019%, with only 15% of errors affecting patients. Initial Sigma was calculated at 4.2; this process resulted in the improvement of Sigma to 5.2, representing a 100-fold reduction. Financial analysis demonstrated a reduction in annualized loss of revenue (administration charges and drug wastage) from $11,537.95 (Medicare Average Sales Price) before the start of the project to $1,262.40. The Six Sigma process is a powerful technique in the reduction of CTMRs.

Four dimensional sigma model coupled to the metric tensor field

International Nuclear Information System (INIS)

Ghika, G.; Visinescu, M.

1980-02-01

We discuss the four dimensional nonlinear sigma model with an internal O(n) invariance coupled to the metric tensor field satisfying Einstein equations. We derive a bound on the coupling constant between the sigma field and the metric tensor using the theory of harmonic maps. A special attention is paid to Einstein spaces and some new explicit solutions of the model are constructed. (author)

Dilaton gravity, Poisson sigma models and loop quantum gravity