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GST Primary GST Primary Best Strategies for Health Care Quality Im... Best Strategies for Health Care Quality Improvement - Diabetes Quality Improvement Strategies for Antibio... Kathryn McDonald, Stanford-UCSF Evidence-b... Systematic review assessing the effect of ... Quality Improvement Strategies for Antibiotics Management Kathryn McDonald, Stanford-UCSF Evidence-based Practice Center, 117 Encina Commons, Stanford, CA 94305-6019, Kathy.mcdonald@stanford.edu Systematic review assessing the effect of quality improvement strategies on appropriate prescribing of antibiotics and appropriate choice of antibiotics. Adherence Adherence Assistive Devices Assistive Devices Childhood Burn Hanson MacMillan Childhood Burn Hanson MacMillan CLSA_9 CLSA_9 Cyberabuse Cyberabuse Cognitive Behavioural Therapy for Violent ... This review included randomized trials abo... Cognitive Behavioural Therapy for Violent Men who Batter Their Partners This review included randomized trials about the effects of cognitive behavioral therapy on domestic violence. The intervention included programs based on the Duluth Model. The violence had to be committed by a male toward his female partner. The violence also had to be physical. The primary outcomes were new arrests and convictions, and new reports of violence. CABG vs PCI CABG vs PCI Quality Improvement Strategies for Prevent... Quality Improvement Strategies for Preventing Nosocomial Infections (Created 17-Feb-06) Quality Improvement Strategies for Asthma ... Quality Improvement Strategies for Asthma Control Erectile Dysfunction (Created 30-Jan-06) Erectile Dysfunction (Created 30-Jan-06) Inequality - Smoking Cessation to Reduce S... This review was the first part of a projec... Inequality - Smoking Cessation to Reduce Socio-Economic Differences This review was the first part of a project about inequality. It included randomized trials about the effect of smoking cessation interventions on reducing socio-economic differences. The studies had to report data either on persons with low socio-economic groups status or, preferably, on both low and high socio-economic groups. Diet and Physical Activity to Reduce Socio... This review was the second part in a proje... Diet and Physical Activity to Reduce Socio-Economic Differences This review was the second part in a project about inequality. It included randomized trials about the effect of interventions on reducing socio-economic differences in diet and physical activity. The studies had to report data either on persons with low socio-economic groups status or, preferably, on both low and high socio-economic groups. Workfare The data in SRS are not identical to the d... Workfare The data in SRS are not identical to the data in the published report. We used SRS only for an updated search. The review included randomized trials about the effect of welfare-to-work programs. Participants were welfare recipients. There were basically two types of programs. The educational type tried to build knowledge and skills in order to help the welfare recipients acquire jobs that could support them economically. The "work first" approach was more aimed at getting the participants quickly into a job. Exercise interventions for the management ... The objective of this systematic review wa... Exercise interventions for the management of frailty The objective of this systematic review was to examine the effectiveness of current exercise interventions on the management of frailty. A comprehensive search of Medline, Embase, Psycinfo, Cinahl, Scopus, Ageline, Eric, and SportDiscus databases was conducted and produced 1808 citations. So far we have completed 2 levels of “title and abstract” screening and we ended up with 262 articles. We have just started the full text screening. Eligibility criteria included original studies whose participants were identified as frail or prefrail with specific criteria and in which structured physical activity was included as at least one component of the intervention. Create a free account, build a dictionary with saved terms to re-use later! Public Domestic Violence - Using Cognitive Behavior Therapy Smoking Cessation to Reduce Socio-Economic Differences Diet and Physical Activity to Reduce Socio-Economic Differences Workfare Exercise Interventions for the Management of Frailty Search     Simple Advanced Refine (4 coded questions)  Any of these:   Exact Phrase: All of these: None of these: Author: Periodical: Projects: No restrictions   Libraries: Public   Select SRS Projects Show Saved Terms Select Library Show articles that do not have abstracts  Humans or Animals Humans Animals Ages All Infant: birth-23 months All Child: 0-18 years All Adult: 19+ years Newborn: birth-1 month Infant: 1-23 months Preschool Child: 2-5 years Child: 6-12 years Adolescent: 13-18 years Adult: 19-44 years Middle Aged: 45-64 years Middle Aged + Aged: 45+ years Aged: 65+ years 80 and over: 80+ years Undetermined Type of Article Clinical Trial Editorial Letter Meta-Analysis Practice Guideline Randomized Controlled Trial Review Addresses Bibliography Biography Case Reports Classical Article Clinical Conference Clinical Trial, Phase I Clinical Trial, Phase II Clinical Trial, Phase III Clinical Trial, Phase IV Comment Comparative Study Consensus Development Conference Consensus Development Conference, NIH Controlled Clinical Trial Corrected and Republished Article Dictionary Directory Duplicate Publication English Abstract Evaluation Studies Festschrift Government Publications Guideline Historical Article Interview In Vitro Journal Article Lectures Legal Cases Legislation Multicenter Study News Newspaper Article Overall Patient Education Handout Periodical Index Published Erratum Retracted Publication Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 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Retraction of Publication Scientific Integrity Review Support of Research Technical Report Twin Study Validation Studies Not a Primary Study or Review Unknown Primary Study Case Series Case Control Cohort Study Observational Study Qualitative Research CBA or ITS Registry Double Blind Controlled before after study Quasi-randomized trial Simple before after study Cluster-RCT Non-Randomized Study Report Book Book chapter Dissertation Conference procedings Secondary Research Not RCT Language English French German Italian Japanese Russian Spanish Afrikaans Albanian Unknown Arabic Armenian Azerbaijani Bosnian Bulgarian Catalan Chinese Croatian Czech Danish Dutch Esperanto Estonian Finnish Georgian Greek, Modern Hebrew Hindi Hungarian Icelandic Indonesian Kinyarwanda Korean Latin Latvian Lithuanian Macedonian Malay Malayalam Maori Multiple Languages Norwegian Persian Polish Portuguese Pushto Romanian Sanskrit Scottish gaelic Serbian Slovak Slovenian Swedish Thai Turkish Ukrainian Vietnamese Not English Not French Results(1-25 of 4,200) Sort By: Publication Date Relevance Took: 2.509 seconds to search 17,750,454  Action: Copy Results to new Clipboard Build Search Link Page 1 of 168 1 2 3 4 > Last >> (4200 articles found) Comparison of a novel vaginal ring delivering estradiol acetate versus oral estradiol for relief of vasomotor menopausal symptoms. Jun 2003 F Al-Azzawi,H M Buckler,United Kingdom Vaginal Ring Investigator Group OBJECTIVE: To compare a novel vaginal ring releasing estradiol acetate (Menoring; Galen Holdings) with oral estradiol for relief of moderate to severe vasomotor symptoms in healthy postmenopausal women. DESIGN: This was a prospective, double-blind, multicenter, randomized, parallel-group study. MET... ( view more )HOD: Women (n = 159) aged < 65 years experiencing >or= 20 hot flushes/night sweats per week received either a vaginal ring releasing estradiol acetate at a rate equivalent to 50 microg/day estradiol plus placebo tablets or oral estradiol 1 mg/day plus a placebo vaginal ring for 24 weeks. For patients with inadequate control of symptoms, the dosage was doubled at 12 weeks. A 24-week, open-label extension of the vaginal ring treatment followed double-blind treatment. RESULTS: The frequency of hot flushes/night sweats was significantly reduced (p < 0.001) in both groups at 12 and 24 weeks from baseline, by 84% and 94% for the vaginal ring group and by 73% and 83% for the oral group, respectively. The mean intensity of urogenital symptoms decreased from screening to the end of treatment in both groups. The incidence of adverse events was similar for both groups. No clinically relevant local effects of the vaginal ring were observed. CONCLUSIONS: The vaginal ring relieved both systemic and urogenital symptoms and was well tolerated and accepted. Overall, the efficacy, safety and acceptability of the vaginal ring were comparable with those of oral estradiol therapy. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Role of the divalent metal ion in sugar binding, ring opening, and isomerization by D-xylose isomerase: replacement of a catalytic metal by an amino acid. Feb 15, 1994 K N Allen,A Lavie,A Glasfeld,T N Tanada,D P Gerrity,S C Carlson,G K Farber,G A Petsko,D Ringe The distinct roles of the two magnesium ions essential to the activity of D-xylose isomerase from Streptomyces olivochromogenes were examined. The enzyme-magnesium complex was isolated, and the stoichiometry of cation binding determined by neutron activation analysis to be 2 mol of magnesium per mo... ( view more )le of enzyme. A plot of Mg2+ added versus Mg2+ bound to enzyme is consistent with apparent KD values of < or = 0.5-1.0 mM for one Mg2+ and < or = 2-5 mM for the second. A site-directed mutant of D-xylose isomerase was designed to remove the tighter, tetracoordinated magnesium binding site (site 1, Mg-1); Glu180 was replaced with Lys180. The stoichiometry of metal binding to this mutant, E180K, is 1 mol of magnesium per mole of enzyme. Ring-opening assays with 1-thioglucose (H2S released upon ring opening) show E180K catalyzes the opening of the sugar ring at 20% the rate of the wild-type, but E180K does not catalyze isomerization of glucose to fructose. Thus, the magnesium bound to Glu180 is essential for isomerization but not essential for ring opening. The X-ray crystallographic structures of E180K in the absence of magnesium and in the presence and absence of 250 mM glucose were obtained to 1.8-A resolution and refined to R factors of 17.7% and 19.7%, respectively. The wild-type and both E180K structures show no significant structural differences, except the epsilon-amino group of Lys180, which occupies the position usually occupied by the Mg-1.(ABSTRACT TRUNCATED AT 250 WORDS) ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The Ring total knee replacement. 1988 N Reissis,G Dendrinos,E Reissis,P A Ring A prospective study of the Ring Total Knee Replacement is presented. The senior author (P.A. Ring) designed this prosthesis and began to apply it clinically in 1974. The Ring prosthesis is a resurfacing, unconstrained type of knee prosthesis and is designed for use without cement. It comprises two ... ( view more )components, femoral and tibial, both made of titanium. A polyethylene liner is attached to the tibial component. The method was used for treatment of osteoarthritis and rheumatoid arthritis of the knee on 149 patients (178 knees) in the period from 1974 to 1985. Seventeen patients were lost to follow-up, leaving 132 patients (161 knees) for review. During the last review, 75.2% of the knees were pain free and 72% had full correction of the deformity. The average follow-up period was 5.1 years and the survival rate of the prosthesis during the same period was 94.4%. To evaluate the method we used computer analysis of preoperative and postoperative assessment cards with 153 observations. The result was excellent in 92 (57.2%) knees, good in 38 (23.6%) knees, and poor in 31 (19.2%) knees. Loosening of the components occurred in 3.7% knees, and the total revision rate was 5%. One knee was arthrodesed. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Inflammatory bowel disease and hospital treatment in Italy: the RING multi-centre study. Jan 1, 2004 M Soncini,O Triossi,P Leo,G Magni,RING Study Group AIM: To explore the management of chronic inflammatory bowel disease, specifically Crohn's disease and ulcerative colitis, in Italian gastroenterology units. METHODS: The RING (Ricerca Informatizzata in Gastroenterologia) project is an observational study collecting hospital discharge forms from 56... ( view more ) centres. Factors associated with the length of hospital stay were studied using multivariate logistic regression. RESULTS: In 24 months starting from August 2000, out of 29,376 hospital discharge forms, 2131 (7.3%) were collected for inflammatory bowel disease (1163 for Crohn's disease and 968 for ulcerative colitis). The Crohn's disease and ulcerative colitis groups were compared according to demographic characteristics, diagnoses, procedures and hospital stay. In Crohn's disease, computed tomography/magnetic resonance imaging, x-rays/barium enema, number of procedures and number of diagnoses were significantly associated with a hospital stay longer than 10 days. In ulcerative colitis, this association was found for parenteral nutrition, malnutrition, computed tomography/magnetic resonance imaging and number of procedures. CONCLUSIONS: Crohn's disease was confirmed as a disabling disorder requiring more frequent hospital treatment than ulcerative colitis. For the latter, parenteral nutrition and malnutrition were related to a longer hospital stay. The number of procedures, especially abdominal computed tomography/magnetic resonance imaging, was a major item for both pathologies. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The Ring total knee replacement--a comparison of survivorship. Apr 1992 M J Curtis,J M Bland,P A Ring Long term results of joint replacement are frequently expressed as survivorship; it therefore becomes increasingly important to have the ability to make valid comparisons between survivorship tables in order to determine accurately the statistical significance of published differences. We present a... ( view more ) statistical method for direct comparison of survivorship tables. We have applied this technique to evaluate the survivorship of the unconstrained, uncemented Ring total knee replacement first implanted in 1975 and compare this to contemporaneous constrained prostheses. There is a significant improvement in survival, which suggests a beneficial long-term effect on the bone/implant interface of this changing design concept. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Blood loss associated with Ring uncemented total knee replacement: comparison between continuous and intermittent suction drainage. Jul 1984 F W Wittmann,P A Ring In a retrospective comparison of blood loss following uncemented total knee replacement, in which either continuous or intermittent suction drainage was used, measured blood loss was significantly greater with continuous drainage. However, a method of calculating actual blood loss demonstrated no s... ( view more )ignificant difference. With intermittent drainage, more blood remains undetected around the knee joint; this technique should therefore be abandoned in favour of continuous suction drainage. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Ring UPM total hip arthroplasty. Jun 1983 P A Ring It is apparent that failure at the cement-bone interface is an increasing problem with total hip arthroplasty. This failure may be difficult or impossible to rectify. The risk of infection at the cement-bone interface and the difficulty of revisional surgery in the cemented articulation appear to j... ( view more )ustify fully an attempt to develop a reliable, uncemented total hip prosthesis. During the period from 1980 to 1982, 471 uncemented metal-on-plastic total hip arthroplasties have been performed. The results were compared with those for earlier metal-on-metal articulations and a comparable group of cemented metal-on-plastic joints. The short-term results for this procedure appear better than those obtained with the uncemented metal-on-metal articulation and comparable with those of the cemented joint, while retaining the relative freedom from complications of the uncemented articulation. The implant relies on the axial location of the pelvic component, and it is designed to be revised with ease, should revision prove necessary. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Galactose mutarotase: pH dependence of enzymatic mutarotation. Apr 22, 2003 Jane A Beebe,Abolfazl Arabshahi,James G Clifton,Dagmar Ringe,Gregory A Petsko,Perry A Frey Here we report pH dependence of kinetic parameters for the mutarotation of alpha-D-glucose catalyzed by galactose mutarotase (GalM) from Escherichia coli. The values of k(cat) and k(cat)/K(m) for the mutarotation of alpha-D-galactose were found to be 1.84 x 10(4) s(-1) and 4.6 x 10(6) M(-1) s(-1), ... ( view more )respectively, at pH 7.0 and 27 degrees C. The corresponding values for alpha-D-glucose were 1.9 x 10(4) s(-1) and 5.0 x 10(5) M(-1) s(-1). Inasmuch as the value of k(cat)/K(m) for the reaction of alpha-D-galactose is 10 times that for alpha-D-glucose, and the diffusional rate constants should be essentially the same for the two sugars, the mutarotation of alpha-D-glucose should not be diffusion controlled. Therefore, pH-rate profiles should not be distorted by diffusion. The k(cat) for the mutarotation of alpha-D-glucose is independent of pH. Therefore, either the enzyme-substrate complexes do not undergo ionization of catalytic groups, or the rate-limiting step is neither mutarotation nor diffusion. The profile of log k(cat)/K(m) versus pH is a distorted bell-shaped curve, with slopes of +1 on the acid side and -2 on the alkaline side. The values of pK(a) are 6.0 and 7.5, and mutarotation depends on the ionization states of three functional groups in the free enzyme, one unprotonated and two protonated. On the acid side, ring opening of alpha-D-glucose limits the rate, and on the alkaline side, ring closure of the open-chain sugar limits the rate. A mutarotation mechanism is presented in which one of the catalytic groups shuttles a proton to and from the endocyclic oxygen and the other two shuttle protons to the anomeric oxygen atoms. In this mechanism, three catalytic groups overcome the problem of nonstereospecificity in mutarotation. The groups are postulated to be His 104, His 175, and Glu 309. Mutations of these residues grossly impair catalytic activity. Variants H104Q- and E309Q-GalM display sufficient activity to allow profiles of log k(cat)/K(m) versus pH to be constructed. Both profiles show breaks on the acid side corresponding to pK(a) values of 5.8 for H104Q and 6.3 for E309Q. Apparently, ring opening of alpha-D-glucose limits the rate at low pHs, but ring closure does not become rate limiting at pHs up to 8.5 in reactions of these variants. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Substrate inhibition of D-amino acid transaminase and protection by salts and by reduced nicotinamide adenine dinucleotide: isolation and initial characterization of a pyridoxo intermediate related to inactivation. Mar 3, 1998 P W van Ophem,S D Erickson,A Martinez del Pozo,I Haller,B T Chait,T Yoshimura,K Soda,D Ringe,G Petsko,J M Manning D-Amino acid transaminase, a pyridoxal phosphate (PLP) enzyme, is inactivated by its natural substrate, D-alanine, concomitant with its alpha-decarboxylation [Martinez del Pozo, A., Yoshimura, T., Bhatia, M. B., Futaki, S., Manning, J. M., Ringe, D., and Soda, K. (1992) Biochemistry 31, 6018-6023; ... ( view more )Bhatia, M. B., Martinez del Pozo, A., Ringe, D., Yoshimura, T., Soda, K., and Manning, J. M. (1993) J. Biol. Chem. 268, 17687-17694]. beta-Decarboxylation of d-aspartate to d-alanine leads also to this inactivation [Jones, W. M., van Ophem, P. W., Pospischil, M. A., Ringe, D., Petsko, G., Soda, K., and Manning, J. M. (1996) Protein Sci. 5, 2545-2551]. Using a high-performance liquid chromatography-based method for the determination of pyridoxo cofactors, we detected a new intermediate closely related to the inactivation by d-alanine; its formation occurred at the same rate as the inactivation and upon reactivation it reverted to PLP. Conditions were found under which it was characterized by ultraviolet-visible spectral analysis and mass spectroscopy; it is a pyridoxamine phosphate-like compound with a C2 fragment derived from the substrate attached to the C'-4 of the pyridinium ring and it has a molecular mass of 306 consistent with this structure. In the presence of d-serine, slow accumulation of a quinonoid intermediate is also related to inactivation. The inactivation can be prevented by salts, which possibly stabilize the protonated aldimine coenzyme complex. The reduced cofactor, nicotinamide adenine dinucleotide, prevents D-aspartate-induced inactivation. Both of these events also are related to formation of the novel intermediate. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Xylose isomerase in substrate and inhibitor michaelis states: atomic resolution studies of a metal-mediated hydride shift. Jun 1, 2004 Timothy D Fenn,Dagmar Ringe,Gregory A Petsko Xylose isomerase (E.C. 5.3.1.5) catalyzes the interconversion of aldose and ketose sugars and has an absolute requirement for two divalent cations at its active site to drive the hydride transfer rates of sugar isomerization. Evidence suggests some degree of metal movement at the second metal site,... ( view more ) although how this movement may affect catalysis is unknown. The 0.95 A resolution structure of the xylitol-inhibited enzyme presented here suggests three alternative positions for the second metal ion, only one of which appears positioned in a catalytically competent manner. To complete the reaction, an active site hydroxyl species appears appropriately positioned for hydrogen transfer, as evidenced by precise bonding distances. Conversely, the 0.98 A resolution structure of the enzyme with glucose bound in the alpha-pyranose state only shows one of the metal ion conformations at the second metal ion binding site, suggesting that the linear form of the sugar is required to promote the second and third metal ion conformations. The two structures suggest a strong degree of conformational flexibility at the active site, which seems required for catalysis and may explain the poor rate of turnover for this enzyme. Further, the pyranose structure implies that His53 may act as the initial acid responsible for ring opening of the sugar to the aldose form, an observation that has been difficult to establish in previous studies. The glucose ring also appears to display significant segmented disorder in a manner suggestive of ring opening, perhaps lending insight into means of enzyme destabilization of the ground state to promote catalysis. On the basis of these results, we propose a modified version of the bridged bimetallic mechanism for hydride transfer in the case of Streptomyces olivochromogenes xylose isomerase. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. May 3, 1999 T L Burgess,Y Qian,S Kaufman,B D Ring,G Van,C Capparelli,M Kelley,H Hsu,W J Boyle,C R Dunstan,S Hu,D L Lacey Osteoprotegerin (OPG) and OPG-ligand (OPGL) potently inhibit and stimulate, respectively, osteoclast differentiation (Simonet, W.S., D.L. Lacey, C.R. Dunstan, M. Kelley, M.-S. Chang, R. Luethy, H.Q. Nguyen, S. Wooden, L. Bennett, T. Boone, et al. 1997. Cell. 89:309-319; Lacey, D.L., E. Timms, H.-L.... ( view more ) Tan, M.J. Kelley, C.R. Dunstan, T. Burgess, R. Elliott, A. Colombero, G. Elliott, S. Scully, et al. 1998. Cell. 93: 165-176), but their effects on mature osteoclasts are not well understood. Using primary cultures of rat osteoclasts on bone slices, we find that OPGL causes approximately sevenfold increase in total bone surface erosion. By scanning electron microscopy, OPGL-treated osteoclasts generate more clusters of lacunae on bone suggesting that multiple, spatially associated cycles of resorption have occurred. However, the size of individual resorption events are unchanged by OPGL treatment. Mechanistically, OPGL binds specifically to mature OCs and rapidly (within 30 min) induces actin ring formation; a marked cytoskeletal rearrangement that necessarily precedes bone resorption. Furthermore, we show that antibodies raised against the OPGL receptor, RANK, also induce actin ring formation. OPGL-treated mice exhibit increases in blood ionized Ca++ within 1 h after injections, consistent with immediate OC activation in vivo. Finally, we find that OPG blocks OPGL's effects on both actin ring formation and bone resorption. Together, these findings indicate that, in addition to their effects on OC precursors, OPGL and OPG have profound and direct effects on mature OCs and indicate that the OC receptor, RANK, mediates OPGL's effects. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles 1H/2H NMR studies of geometric H/D isotope effects on the coupled hydrogen bonds in porphycene derivatives. Jan 17, 2007 Mariusz Pietrzak,Mohamed F Shibl,Martin Bröring,Oliver Kühn,Hans-Heinrich Limbach The 1H and 2H NMR spectra of porphycene (1), 2,3,6,7,12,13,16,17-octaethylporphycene (2), 2,7,12,17-tetra-n-propylporphycene (3), and 2,7,12,17-tetra-(tert-butyl)-3,6-13,16-dibenzo[cde;mno]porphycene (4) partially deuterated in the mobile proton sites are reported. These compounds exhibit two intra... ( view more )molecular NHN hydrogen bonds of increasing strength representing models of the concerted HH transfer in the parent compound, porphycene. The 1H chemical shifts of the mobile protons are correlated with the difference of the energies of the amino- and imino-N1s orbitals reported by Ghosh A.; Moulder J.; Bröring M.; Vogel E. Angew. Chem., Int. Ed. 2001, 113, 445-448. The chemical shifts of 4 indicate a reduced contribution of the aromatic ring current as compared to the other compounds which is associated to the nonplanarity of this molecule. The primary H/D isotope effects on the chemical shifts give information about the primary, secondary, and vicinal geometric isotope effects of the two inner hydrogen bonds of porphycenes. The vicinal effects indicate a cooperative coupling of the two hydrogen bonds which may favor a concerted double proton-transfer mechanism. ( view less ) View Full Abstract View Article Details   Related Articles Interaction of pyridoxal 5'-phosphate with tryptophan-139 at the subunit interface of dimeric D-amino acid transaminase. Feb 20, 1996 A Martinez del Pozo,P W van Ophem,D Ringe,G Petsko,K Soda,J M Manning The crystal structure of dimeric bacterial D-amino acid transaminase shows that the indole rings of the two Trp-139 side chains face each other in the subunit interface about 10 angstroms from the coenzyme, pyridoxal 5'-phosphate. To determine whether it has a role in the catalytic efficiency of th... ( view more )e enzyme or interacts with the coenzyme, Trp-139 has been substituted by several different types of amino acids, and the properties of these recombinant mutant enzymes have been compared to the wild-type enzyme. In the native wild-type holoenzyme, the fluorescence of one of the three Trp residues per monomer is almost completely quenched, probably due to its interaction with PLP since in the native wild-type apoenzyme devoid of PLP, tryptophan fluorescence is not quenched. Upon reconstitution of this apoenzyme with PLP, the tryptophan fluorescence is quenched to about the same extent as it is in the native wild-type enzyme. The site of fluorescence quenching is Trp-139 since the W139F mutant in which Trp-139 is replaced by Phe has about the same amount of fluorescence as the wild-type enzyme. The circular dichroism spectra of the holo and the apo forms of both the wild-type and the W139F enzymes in the far-ultraviolet show about the same degree of ellipticity, consistent with the absence of extensive global changes in protein structure. Furthermore, comparison of the circular dichroism spectrum of the W139F enzyme at 280 nm with the corresponding spectral region of the wild-type enzyme suggests a restricted microenvironment for Trp-139 in the latter enzyme. The functional importance of Trp-139 is also demonstrated by the finding that its replacement by Phe, His, Pro, or Ala gives mutant enzymes that are optimally active at temperatures below that of the wild-type enzyme and undergo the E-PLP --> E-PMP transition as a function of D-Ala concentration with reduced efficiency. The results suggest that a fully functional dimeric interface with the two juxtaposed indole rings of Trp-139 is important for optimal catalytic function and maximum thermostability of the enzyme and, furthermore, that there might be energy transfer between Trp-139 and coenzyme PLP. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Structural analysis of the active site of porcine pancreatic elastase based on the X-ray crystal structures of complexes with trifluoroacetyl-dipeptide-anilide inhibitors. Mar 14, 1995 C Mattos,D A Giammona,G A Petsko,D Ringe The X-ray crystal structures of two new (trifluoroacetyl)dipeptide p-(trifluoromethyl)anilide (TFA-dipeptide-TFM) inhibitors complexed to porcine pancreatic elastase are presented. TFA-Val-Ala-TFM and TFA-Phe-Ala-TFM both bind to elastase with the TFA group in the S1 subsite, Val or Phe in the S2 s... ( view more )ubsite, Ala in the S3 subsite, and the TFM group in the S4 subsite. Five other TFA-dipeptide-anilide/elastase crystal structures are available (two TFA-X-Ala-p-(trifluoromethyl)anilide, X = Lys, Leu, and three TFA-Lys-X-p-isopropylanilide, X = Pro, Leu, Phe). The four inhibitors with the trifluoromethyl substituent on the anilide ring bind in a single mode to elastase, whereas superposition of the three inhibitors with the isopropyl substituent on the anilide ring show three different modes of binding to the protein [Mattos, C., et al. (1994) Nature Struct. Biol. 1, 55-58]. The seven structures are taken together in a detailed analysis of the active site of porcine pancreatic elastase. The inhibition constants for the inhibitors are used in combination with the crystal structures to understand the specificity of the different elastase subsites. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Three-dimensional structure of chymotrypsin inactivated with (2S)-N-acetyl-L-alanyl-L-phenylalanyl alpha-chloroethane: implications for the mechanism of inactivation of serine proteases by chloroketones. Nov 22, 1994 K Kreutter,A C Steinmetz,T C Liang,M Prorok,R H Abeles,D Ringe The reaction of enantiomerically pure (2S)-N-acetyl-L-alanyl-L-phenylalanyl alpha-chloroethane with gamma-chymotrypsin was studied as a probe of the mechanism of inactivation of serine proteases by peptidyl chloroalkanes. It was determined crystallographically that the peptidyl chloroethane alkylat... ( view more )es His57 with retention of configuration at the chiral center, indicating a double displacement mechanism. We think it likely that a Ser195-epoxy ether adduct is an intermediate on the inactivation pathway, although other possibilities have not been disproven. Kinetic data reported by others [Angliker et al. (1988) Biochem. J. 256, 481-486] indicate that the epoxy ether intermediate is not an irreversibly inactivated form of enzyme [a conclusion confirmed experimentally (Prorok et al. (1994) Biochemistry 33, 9784-9790)] and that both ring closure of the tetrahedral intermediate to form the epoxy ether and ring opening by His57 partially limit the first-order rate constant for inactivation, ki. The peptidyl chloroethyl derivative adopts a very different active site conformation from that assumed by serine proteases inactivated by peptidyl chloromethanes. Positioning the chloroethyl derivative into the conformation adopted by chloromethyl derivatives would cause the extra methyl group to make a bad van der Waals contact with the inactivator P2 carbonyl carbon, thereby preventing the formation of the invariant hydrogen bond between the inactivator P1 amide nitrogen and the carbonyl group of Ser214. We conclude that the unusual conformation displayed by the chloroethyl derivative is caused by steric hindrance between the extra methyl group and the rest of the inactivator chain. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Isotopic exchange plus substrate and inhibition kinetics of D-xylose isomerase do not support a proton-transfer mechanism. Feb 15, 1994 K N Allen,A Lavie,G K Farber,A Glasfeld,G A Petsko,D Ringe The D-xylose isomerase of Streptomyces olivochromogenes is a Mg2+- or Mn(2+)-dependent enzyme that catalyzes the aldose-ketose isomerization of xylose to xylulose or of glucose to fructose. Proton exchange into water during enzyme-catalyzed isomerization of C-2 tritiated glucose at 15, 25 and 55 de... ( view more )grees C shows < 0.6% exchange (the loss of one proton in every billion turnovers). High concentrations of guanidine hydrochloride and extremes of pH had no effect on the amount of exchange detected. Such a low percentage of exchange is inconsistent with a proton-transfer mechanism as the main kinetic pathway for isomerization. 19F NMR experiments showed no release of fluoride after incubation of the enzyme for 4 weeks with 800 mM 3-deoxy-3-fluoroglucose or 3-deoxy-3-fluoroallose (both are competitive inhibitors with Ki values of 600 mM). This result is also inconsistent with a proton-transfer mechanism. A hydride-shift mechanism following ring opening has been proposed for the isomerization. Enzyme-catalyzed ring opening was directly measured by demonstrating H2S release upon reaction of xylose isomerase with 1-thioglucose. D-Xylose isomerase-catalyzed interconversion of glucose to fructose exhibited linear Arrhenius behavior with an activation energy of 14 kcal/mol from 0 to 50 degrees C. No change in rate-determining step occurs over this temperature range. 13C NMR experiments with glucose show that enzyme-bound magnesium or manganese does not interact specifically with any one site on the sugar. These results are consistent with nonproductive binding modes for the substrate glucose in addition to productive binding. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Localization of the incorporation of 3H-galactose and 3H-sialic acid into thyroglobulin in relation to the block of intracellular transport induced by monensin. Studies with isolated porcine thyroid follicles. Oct 1987 P Ring,U Björkman,R Ekholm The Na+/K+ ionophore monensin is known to arrest the intracellular transport of newly synthesized proteins in the Golgi complex. In the present investigation the effect of monensin on the secretion of 3H-galactose-labeled and 3H-sialic acid-labeled thyroglobulin was studied in open thyroid follicle... ( view more )s isolated from porcine thyroid tissue. Follicles were incubated with 3H-galactose at 20 degrees C for 1 h; at this temperature the labeled thyroglobulin remains in the labeling compartment (Ring et al. 1987a). The follicles were then chased at 37 degrees C for 1 h in the absence or presence of 1 microM monensin. Without monensin substantial amounts of labeled thyroglobulin were secreted into the medium, whereas in the presence of the ionophore secretion was inhibited by 80%. Since we have previously shown (Ring et al. 1987b) that monensin does not inhibit secretion of thyroglobulin present on the distal side of the monensin block we conclude that galactose is incorporated into thyroglobulin on the proximal side of this block. Secretion was also measured in follicles continuously incubated with 3H-galactose for 1 h at 37 degrees C in the absence or presence of monensin. In these experiments secretion of labeled thyroglobulin was inhibited by about 85% in the presence of monensin. Identically designed experiments with 3H-N-acetylmannosamine, a precursor of sialic acid, gave similar results, i.e., almost complete inhibition of secretion of labeled thyroglobulin in the presence of monensin. The agreement between the results of the galactose and sialic acid experiments indicates that sialic acid, like galactose, is incorporated into thyroglobulin on the proximal side of the monensin block.(ABSTRACT TRUNCATED AT 250 WORDS) ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Inactivation of chymotrypsin by 5-benzyl-6-chloro-2-pyrone: 13C NMR and X-ray diffraction analyses of the inactivator-enzyme complex. Jan 1, 1985 D Ringe,B A Seaton,M H Gelb,R H Abeles The inactivation of chymotrypsin by 5-benzyl-6-chloro-2-pyrone has been studied. Chloride analysis of the inactivated enzyme suggests that chlorine is no longer present in the complex. 13C NMR spectroscopy of chymotrypsin inactivated with 5-benzyl-6-chloro-2-pyrone-2,6-13 C2 shows the presence of t... ( view more )wo new resonances from the protein-bound inactivator. The chemical shift values of these resonances are consistent with an intact pyrone ring on the enzyme as well as the replacement of the C-6 chlorine by a different heteroatom. X-ray diffraction analysis at 1.5-A resolution of the inactivator-enzyme complex demonstrates that the gamma-oxygen of the active site serine residue (serine 195) is covalently attached to C-6 of the inactivator and that the pyrone ring is intact. The 5-benzyl group of the inactivator is bound to the enzyme in the hydrophobic specificity pocket. The conformational changes that occur in the protein as a result of complexation with the inactivator are discussed. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Gene expression patterns within cell lines are predictive of chemosensitivity. 2008 Brian Z Ring,Stella Chang,L Winston Ring,Robert S Seitz,Douglas T Ross BACKGROUND: The NCI has undertaken a twenty-year project to characterize compound sensitivity patterns in a selected set of sixty tumor derived cell lines. Previous studies have explored the relationship between compound sensitivity patterns to gene expression, protein expression, and DNA copy numb... ( view more )er for these same cell lines. A strong correlation between the pattern of expression of a biomarker and sensitivity to a compound could suggest a clinically interesting biological relationship between the two. RESULTS: We isolated RNA's and measured expression of 40000 genes using cDNA microarrays from the fifty-nine publicly available cell lines. Analysis of this data set in comparison with published gene expression data sets demonstrates a high degree of reproducibility in expression level measurements even using completely independent RNA preparations and array technologies. Using the fifty-nine cell lines for discovery and an additional seven cell lines for which extensive compound sensitivity data were available as a test set, we determined that gene-compound pairs with a correlation coefficient above 0.6 had a false discovery rate of approximately 5%. Large scale features of the gene expression and chemosensitivity data, such as tissue of origin and other physiological factors, did not seem to explain the majority of correlations between gene and compound patterns. CONCLUSION: A comparison of gene expression and compound sensitivity in panels of cell lines was demonstrated to have a relatively high validation and low false discovery rate supporting the use of this approach and datasets for identifying candidate biomarkers and targeted biologically active compounds. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Synthesis and characterization of well-defined aluminum-containing heterobimetallic selenides. Aug 20, 2007 Zhi Yang,Xiaoli Ma,Herbert W Roesky,Ying Yang,Jörg Magull,Arne Ringe A series of novel aluminum heterobimetallic selenides were reported. The reaction of LAl(SeH)2 (1) with LiN(SiMe3)2 resulted in the formation of [LAl(SeLi)2(THF)2] (2) (L = HC(CMeNAr)2, Ar = 2,6-iPr2C6H3). Compound 2 reacted with Me2GeCl2, Ph2GeCl2, Cp2TiCl2, and Cp2ZrCl2, respectively, to produce ... ( view more )LAl(mu-Se)2GeMe2 (3), LAl(mu-Se)2GePh2 (4), LAl(mu-Se)2TiCp2 (5), and LAl(mu-Se)2ZrCp2 (6) in moderate yields. Compounds 2-6 were characterized by elemental analysis, NMR, and electron impact-MS. The X-ray single-crystal structure of 3 is reported and confirms the spirocyclic arrangement of the aluminum atom within the six-membered AlN2C3 and four-membered AlSe2Ge rings. ( view less ) View Full Abstract View Article Details   Related Articles Association of prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism with type 2 diabetes in two German study populations. Aug 2007 Inke Nitz,Eva Fisher,Harald Grallert,Yun Li,Christian Gieger,Diana Rubin,Heiner Boeing,Joachim Spranger,Inka Lindner,Stefan Schreiber,Wolfgang Rathmann,Henning Gohlke,Angela Döring,H-Erich Wichmann,Jürgen Schrezenmeir,Frank Döring,Thomas Illig CONTEXT: On the basis of its chromosomal localization and its role in the synthesis of the antilipolytic compound prostaglandin E(2), the prostaglandin E synthase 2 (PTGES2) is a candidate gene for type 2 diabetes. OBJECTIVE: The aim of the present study was to investigate whether genetic variants ... ( view more )in the PTGES2 gene are associated with type 2 diabetes. RESULTS: Sequencing of the PTGES2 gene revealed one nonsynonymous coding single-nucleotide polymorphism (SNP) (Arg298His, rs13283456) and a previously unknown promoter SNP g.-417G>T. Both SNPs and additional haplotype tagging SNPs (rs884115, rs10987883, rs4837240) were genotyped in a nested case-control study of 192 incident type 2 diabetes subjects and 384 controls (European Prospective Investigation into Cancer and Nutrition-Potsdam). Carriers of the minor allele of Arg298His had a lower risk to develop the disease [odds ratio (OR) 0.63, 95% confidence interval (CI) 0.41-0.97, P = 0.04], compared with homozygous individuals with the common allele. The PTGES2 Arg298His polymorphism was reinvestigated in a population-based cross-sectional study (Cooperative Health Research in the Augsburg Region) consisting of 239 individuals with impaired glucose tolerance, 226 with type 2 diabetes, and 863 normoglycemic controls. In this study population, the Arg298His polymorphism was significantly associated with impaired glucose tolerance (OR 0.68, 95% CI 0.50-0.93, P = 0.007) and type 2 diabetes (OR 0.61, 95% CI 0.43-0.86, P = 0.004). A pooled analysis of data from both study populations revealed reduced risk of type 2 diabetes (OR 0.62, 95% CI 0.47-0.81, P = 0.0005) in PTGES2 298His allele carriers. CONCLUSION: We obtained evidence from two Caucasian study populations that the His298-allele of PTGES2 Arg298His confers to reduced risk of type 2 diabetes. ( view less ) View Full Abstract View Article Details   Related Articles Inhibition of chymotrypsin by a complex of ortho-vanadate and benzohydroxamic acid: structure of the inert complex and its mechanistic interpretation. May 22, 2007 Aaron Moulin,Jason H Bell,R F Pratt,Dagmar Ringe Serine proteases, like serine beta-lactamases, are rapidly and covalently inhibited by suitably designed phosph(on)ates. The active sites of these enzymes must, therefore, be able to stabilize the pentacoordinated transition states of phosphyl transfer reactions as well as the tetrahedral transitio... ( view more )n states of acyl transfers. It follows that these enzymes should also be inhibited by molecules capable of generating inert pentacoordinated species. We (J.H.B. and R.F.P.) have previously shown that these enzymes are, in fact, rapidly and reversibly inhibited by 1:1 complexes of vanadate and hydroxamic acids. In this paper, we present the first crystal structure of an acyl transferase inhibited by vanadate. The complex of vanadate and benzohydroxamic acid is a competitive inhibitor of alpha-chymotrypsin with a KI value of 16 muM. In the structure, obtained at a resolution of 1.5 A, the protein is conformationally little different from the apoenzyme. The vanadium, in a distorted octahedral ligand field, is covalently bound to the active site serine oxygen group. One oxgen ligand, presumably anionic, is located in the oxyanion hole. Another is directed roughly in the direction of the acyl transfer leaving group, and a third in the direction of the S2 site. The hydroxamate is bound to vanadium through the hydroxyl oxygen and also, more weakly, through the carbonyl group, to form a five-membered chelate ring. The effect of this chelation is to place the phenyl group of the inhibitor into the important S1 specificity site. The hydroxamate oxygen is directed in line away from the Ser195 Ogamma, approximating the direction of departure of a leaving group in phosphyl transfer. The entire complex can be seen as a reasonable mimic of a phosphyl transfer transition state where the leaving group is extended into the S1 site. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Single-file diffusion near channel boundaries. Jun 20, 2006 Sergey Vasenkov,Andreas Schüring,Siegfried Fritzsche Molecular transport under the conditions of single-file diffusion was investigated near the channel boundaries by using dynamic Monte Carlo and molecular dynamics simulations of tracer exchange between single-file channels and their surroundings. The boundary effect reported in our recent papers (V... ( view more )asenkov S.; Kärger, J. Phys. Rev. E 2002, 66, 052601. Schüring, A.; Vasenkov S.; Fritzsche, S. J. Phys. Chem. B 2005, 109, 16711) was studied in detail. This boundary effect is characterized by deviations of the intrachannel concentration profiles of tracer molecules observed in the case of single-file diffusion near the channel boundaries from the corresponding profiles typical for normal diffusion. It has been shown in our previous studies that these deviations occur under the conditions when the potential-energy difference inside and outside of single-file channels was both comparable and much larger than the activation energy of intrachannel diffusion. Here, we report a quantitative model describing the boundary effect. According to this model, an occurrence of the boundary effect is related to a complex character of diffusion in finite single-file systems. Such diffusion can be described by the following two types of movements occurring in parallel: (i) correlated displacements of all molecules in any particular channel and (ii) fast displacements of single molecules, which are uncorrelated with the displacements of all other molecules in the same channel. The latter displacements are restricted to a certain length interval that depends on the channel length and the channel occupancy. This length interval is shown to determine the extensions of the channel margins where the boundary effect is observed. ( view less ) View Full Abstract View Article Details   Related Articles Viral diversity in hot springs of Pozzuoli, Italy, and characterization of a unique archaeal virus, Acidianus bottle-shaped virus, from a new family, the Ampullaviridae. Aug 2005 Monika Häring,Reinhard Rachel,Xu Peng,Roger A Garrett,David Prangishvili Virus-like particles with five different morphotypes were observed in an enriched environmental sample from a hot, acidic spring (87 to 93 degrees C, pH 1.5) in Pozzuoli, Italy. The morphotypes included rigid rods, flexible filaments, and novel, exceptional forms. Particles of each type were isolat... ( view more )ed, and they were shown to represent viable virions of five novel viruses which infect members of the hyperthermophilic archaeal genus Acidianus. One of these, named the Acidianus bottle-shaped virus, ABV, exhibits a previously unreported morphotype. The bottle-shaped virion carries an envelope which encases a funnel-shaped core. The pointed end of the virion is likely to be involved in adsorption and channeling of viral DNA into host cells. The broad end exhibits 20 (+/- 2) thin filaments which appear to be inserted into a disk, or ring, and are interconnected at their bases. These filaments are apparently not involved in adsorption. ABV virions contain six proteins in the size range 15 to 80 kDa and a 23.9-kb linear, double-stranded DNA genome. Virus replication does not cause lysis of host cells. On the basis of its unique morphotype and structure, we propose to assign ABV to a new viral family, the Ampullaviridae. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Effect of a Y265F mutant on the transamination-based cycloserine inactivation of alanine racemase. Apr 12, 2005 Timothy D Fenn,Todd Holyoak,Geoffrey F Stamper,Dagmar Ringe The requirement for d-alanine in the peptidoglycan layer of bacterial cell walls is fulfilled in part by alanine racemase (EC 5.1.1.1), a pyridoxal 5'-phosphate (PLP)-assisted enzyme. The enzyme utilizes two antiparallel bases focused at the C(alpha) position and oriented perpendicular to the PLP r... ( view more )ing to facilitate the equilibration of alanine enantiomers. Understanding how this two-base system is utilized and controlled to yield reaction specificity is therefore a potential means for designing antibiotics. Cycloserine is a known alanine racemase suicide substrate, although its mechanism of inactivation is based on transaminase chemistry. Here we characterize the effects of a Y265F mutant (Tyr265 acts as the catalytic base in the l-isomer case) of Bacillus stearothermophilus alanine racemase on cycloserine inactivation. The Y265F mutant reduces racemization activity 1600-fold [Watanabe, A., Yoshimura, T., Mikami, B., and Esaki, N. (1999) J. Biochem. 126, 781-786] and only leads to formation of the isoxazole end product (the result of the transaminase pathway) in the case of d-cycloserine, in contrast to results obtained using the wild-type enzyme. l-Cycloserine, on the other hand, utilizes a number of alternative pathways in the absence of Y265, emphasizing the importance of Y265 in both the inactivation and racemization pathway. In combination with the kinetics of inactivation, these results suggest roles for each of the two catalytic bases in racemization and inactivation, as well as the importance of Y265 in "steering" the chemistry to favor one pathway over another. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Page 1 of 168 1 2 3 4 > Last >> (4200 articles found)

      
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