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PubMed2005

Crystal structure of quinone reductase 2 in complex with cancer prodrug CB1954.

CB1954 is a cancer pro-drug that can be activated through reduction by Escherichia coli nitro-reductases and quinone reductases. Human quinone reductase 2 is very efficient in the activation of CB1954, approximately 3000 times more efficient than human QR1 in terms of k(cat)/K(m). We have solved the three-dimensional structure of QR2 in complex with CB1954 to a nominal resolution of 1.5A. The complex structure indicates the essentiality of the two nitro groups: one nitro group forms hydrogen bonds with the side-chain of Asn161 of QR2 to hold the other nitro group in position for the reduction. We further conclude that residue 161, an Asn in QR2 and a His in QR1, is critical in differentiating the substrate specificities of these two enzymes. Mutation of Asn161 to His161 in QR2 resulted in the total loss of the enzymatic activity towards activation of CB1954, whereas the rates of reduction towards menadione are not altered.

Antineoplastic Agents↗

PubMed2002

Transcriptional and proteomic analysis of a ferric uptake regulator (fur) mutant of Shewanella oneidensis: possible involvement of fur in energy metabolism, transcriptional regulation, and oxidative stress.

The iron-directed, coordinate regulation of genes depends on the fur (ferric uptake regulator) gene product, which acts as an iron-responsive, transcriptional repressor protein. To investigate the biological function of a fur homolog in the dissimilatory metal-reducing bacterium Shewanella oneidensis MR-1, a fur knockout strain (FUR1) was generated by suicide plasmid integration into this gene and characterized using phenotype assays, DNA microarrays containing 691 arrayed genes, and two-dimensional polyacrylamide gel electrophoresis. Physiological studies indicated that FUR1 was similar to the wild-type strain when they were compared for anaerobic growth and reduction of various electron acceptors. Transcription profiling, however, revealed that genes with predicted functions in electron transport, energy metabolism, transcriptional regulation, and oxidative stress protection were either repressed (ccoNQ, etrA, cytochrome b and c maturation-encoding genes, qor, yiaY, sodB, rpoH, phoB, and chvI) or induced (yggW, pdhC, prpC, aceE, fdhD, and ppc) in the fur mutant. Disruption of fur also resulted in derepression of genes (hxuC, alcC, fhuA, hemR, irgA, and ompW) putatively involved in iron uptake. This agreed with the finding that the fur mutant produced threefold-higher levels of siderophore than the wild-type strain under conditions of sufficient iron. Analysis of a subset of the FUR1 proteome (i.e., primarily soluble cytoplasmic and periplasmic proteins) indicated that 11 major protein species reproducibly showed significant (P < 0.05) differences in abundance relative to the wild type. Protein identification using mass spectrometry indicated that the expression of two of these proteins (SodB and AlcC) correlated with the microarray data. These results suggest a possible regulatory role of S. oneidensis MR-1 Fur in energy metabolism that extends the traditional model of Fur as a negative regulator of iron acquisition systems.

Amino Acid Sequence↗

PubMed2004

Intraoperative 3D imaging of the facial skeleton using the SIREMOBIL Iso-C3D.

OBJECTIVES: With respect to high-contrast structures, cone beam computed tomography (CBCT) offers an alternative imaging modality to computed tomography (CT), requiring less radiation exposure. The C-arm system SIREMOBIL Iso-C3D for three-dimensional (3D) reconstruction has made this modality available for intraoperative use. This paper presents the first intraoperative images of the facial skeleton using the SIREMOBIL Iso-C3D. METHODS: Cases of a zygomaticomaxillary complex fracture, a mandibular angle fracture and a bimaxillary repositioning osteotomy are described to demonstrate the application possibilities of this system in maxillofacial surgery. RESULTS: In addition to the uncomplicated handling of the SIREMOBIL Iso-C3D, generally important was the low level of metal artefacts in its primary and secondary reconstructions, even in close proximity to the material. However, it has to be kept in mind that while soft tissues are visualized using CBCT, information about soft tissue quality cannot be obtained. CONCLUSION: The SIREMOBIL Iso-C3D generates intraoperative data sets suitable for the visualization of the facial bones after open reduction of fractures.

Adolescent↗

PubMed2002

MR image reconstruction algorithms for sparse k-space data: a Java-based integration.

We have worked on multi-dimensional magnetic resonance imaging (MRI) data acquisition and related image reconstruction methods that aim at reducing the MRI scan time. To achieve this scan-time reduction we have combined the approach of 'increasing the speed' of k-space acquisition with that of 'deliberately omitting' acquisition of k-space trajectories (sparse sampling). Today we have a whole range of (sparse) sampling distributions and related reconstruction methods. In the context of a European Union Training and Mobility of Researchers project we have decided to integrate all methods into one coordinating software system. This system meets the requirements that it is highly structured in an object-oriented manner using the Unified Modeling Language and the Java programming environment, that it uses the client-server approach, that it allows multi-client communication sessions with facilities for sharing data and that it is a true distributed computing system with guaranteed reliability using core activities of the Java Jini package.

Algorithms↗

PubMed1997

RNase Activity Decreases following a Heat Shock in Wheat Leaves and Correlates with Its Posttranslational Modification.

Heat shock results in a coordinate loss of translational efficiency and an increase in mRNA stability in plants. The thermally mediated increase in mRNA half-life could be a result of decreased expression and/or regulation of intracellular RNase enzyme activity. We have examined the fate of both acidic and neutral RNases in wheat seedlings that were subjected to a thermal stress. We observed that the activity of all detectable RNases decreased following a heat shock, which was a function of both the temperature and length of the heat shock. In contrast, no reduction in nuclease activity was observed following any heat-shock treatment. Antibodies raised against one of the major RNases was used in western analysis to demonstrate that the RNase protein level did not decrease following a heat shock, and the data suggest that the observed decrease in RNase activity in heat-shocked leaves may be due to modification of the protein. Two-dimensional gel/western analysis of this RNase revealed three isoforms. The most acidic isoform predominated in control leaves, whereas the most basic isoform predominated in leaves following a heat shock and correlated with the heat-shock-induced reduction in RNase activity and increase in mRNA half-life. These data suggest that RNase activity may be regulated posttranslationally following heat shock as a means to reduce RNA turnover until recovery ensues.

Journal Article↗

PubMed2004

Transmural mechanics at left ventricular epicardial pacing site.

Left ventricular (LV) epicardial pacing acutely reduces wall thickening at the pacing site. Because LV epicardial pacing also reduces transverse shear deformation, which is related to myocardial sheet shear, we hypothesized that impaired end-systolic wall thickening at the pacing site is due to reduction in myocardial sheet shear deformation, resulting in a reduced contribution of sheet shear to wall thickening. We also hypothesized that epicardial pacing would reverse the transmural mechanical activation sequence and thereby mitigate normal transmural deformation. To test these hypotheses, we investigated the effects of LV epicardial pacing on transmural fiber-sheet mechanics by determining three-dimensional finite deformation during normal atrioventricular conduction and LV epicardial pacing in the anterior wall of normal dog hearts in vivo. Our measurements indicate that impaired end-systolic wall thickening at the pacing site was not due to selective reduction of sheet shear, but rather resulted from overall depression of fiber-sheet deformation, and relative contributions of sheet strains to wall thickening were maintained. These findings suggest lack of effective end-systolic myocardial deformation at the pacing site, most likely because the pacing site initiates contraction significantly earlier than the rest of the ventricle. Epicardial pacing also induced reversal of the transmural mechanical activation sequence, which depressed sheet extension and wall thickening early in the cardiac cycle, whereas transverse shear and sheet shear deformation were not affected. These findings suggest that normal sheet extension and wall thickening immediately after activation may require normal transmural activation sequence, whereas sheet shear deformation may be determined by local anatomy.

Animals↗

PubMed2002

The function of the [4Fe-4S] clusters and FAD in bacterial and archaeal adenylylsulfate reductases. Evidence for flavin-catalyzed reduction of adenosine 5'-phosphosulfate.

The iron-sulfur flavoenzyme adenylylsulfate (adenosine 5'-phosphosulfate, APS) reductase catalyzes reversibly the 2-electron reduction of APS to sulfite and AMP, a key step in the biological sulfur cycle. APS reductase from one archaea and three different bacteria has been purified, and the molecular and catalytic properties have been characterized. The EPR parameters and redox potentials (-60 and -520 mV versus NHE) have been assigned to the two [4Fe-4S] clusters I and II observed in the three-dimensional structure of the enzyme from Archaeoglobus fulgidus (Fritz, G., Roth, A., Schiffer, A., Büchert, T., Bourenkov, G., Bartunik, H. D., Huber, H., Stetter, K. O., Kroneck, P. M. H., and Ermler, U. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 1836-1841). Sulfite binds to FAD to form a covalent FAD N(5)-sulfite adduct with characteristic UV/visible spectra, in accordance with the three-dimensional structure of crystalline enzyme soaked with APS. UV/visible monitored titrations reveal that the substrates AMP and APS dock closely to the FAD cofactor. These results clearly document that FAD is the site of the 2-electron reduction of APS to sulfite and AMP. Reaction of APS reductase enzyme with sulfite and AMP leads to partial reduction of the [4Fe-4S] centers and formation of the anionic FAD semiquinone. Thus, both [4Fe-4S] clusters function in electron transfer and guide two single electrons from the protein surface to the FAD catalytic site.

Adenosine Phosphosulfate↗

PubMed2002

Preshaped hydroxyapatite tricalcium-phosphate implant using three-dimensional computed tomography in the reconstruction of bone deformities of craniomaxillofacial region.

We prepared solid life-sized models and templates of implants based on three-dimensional computed tomography data in six cases with a bone deformity of the craniomaxillofacial region. After simulation surgery using these models and templates, the preshaped hydroxyapatite-tricalcium phosphate (HAP-TCP) implants were prepared to fill in the facial bone defects, and implantation was performed. Consequently, implants fitted the individual bone defects, and satisfactory facial contouring was obtained in five cases. In one case with severe cutaneous scarring in the grafted site, it was necessary to reduce the volume of the preshaped HAP-TCP implant during surgery. In conclusion, the three-dimensional, solid, life-sized model and template are useful for preoperative detailed simulation, and the use of preshaped HAP-TCP implants based on the template probably contributes to successful reconstruction of complex facial bone deformities and to the reduction of surgical invasion, resulting in achievement of better results.

Adult↗

PubMed1988

Long-term reduction of peripheral resistance with celiprolol and effects on left ventricular mass.

The antihypertensive efficacy of a new beta-blocker, celiprolol, was compared with that of a well established antihypertensive drug, metoprolol. Systemic and forearm haemodynamic effects were investigated using echocardiography and two-dimensional pulsed Doppler flowmetry, respectively. Twenty hypertensive patients completed the double-blind crossover randomized study. Each 6-week active treatment period was both preceded and followed by 2 weeks of placebo treatment such that the total duration of the study was 18 weeks. Despite comparable efficacy in reducing systolic and diastolic blood pressures by approximately 10% of the basal value, the two drugs differed in their systemic and haemodynamic effects. Celiprolol significantly decreased forearm peripheral resistance and total peripheral resistance. Cardiac output remained unchanged and forearm blood flow was increased. Metoprolol reduced cardiac output through a reduction in heart rate, but stroke volume was unaltered. Neither drug significantly modified cardiac performance, as evaluated by left ventricular circumferential fibre shortening and left ventricular ejection fraction. Differences in the systemic and regional haemodynamic effects of the two drugs could account for the different blood pressure response seen in some patients. There was no observable change in left ventricular wall thickness or left ventricular mass. These results confirm previous reports which demonstrate that antihypertensive treatment with beta-blockers does not reduce left ventricular mass in patients with a left ventricle of normal size. It is generally accepted, however, that the ability of beta-blockers to reverse left ventricular hypertrophy is unrelated to the individual pharmacological characteristics of each agent.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Fluxes, first passage times, and the reduction of hill diagrams.

The steady-state flux resulting from the coupling of two multistate systems is considered. The dynamics of these systems are described (a) as diffusion along a continuous one-dimensional free-energy profile specified by a conformational coordinate or (b) in terms of transitions between a discrete but arbitrary number of substates. If these multistate systems are connected in a simple way, it is shown that the steady-state flux can be obtained analytically. For both the continuous and discrete cases, the exact flux is shown to be identical to that calculated from a simple kinetic scheme involving only four states, if the effective rate constants of this reduced scheme are appropriately defined in terms of the mean first passage times for moving between various points along the multistate cycles. These results clarify and quantify the manner in which the internal conformational dynamics of two multistate systems influences the steady-state flux.

Electron Transport↗

PubMed2001

Critical residues for the specificity of cofactors and substrates in human estrogenic 17beta-hydroxysteroid dehydrogenase 1: variants designed from the three-dimensional structure of the enzyme.

Human estrogenic 17beta-hydroxysteroid dehydrogenase is an NADP(H)-preferring enzyme. It possesses 11- and 4-fold higher specificity toward NADP(H) over NAD(H) for oxidation and reduction, respectively, as demonstrated by kinetic studies. To elucidate the roles of the amino acids involved in cofactor specificity, we generated variants by site-directed mutagenesis. The results showed that introducing a positively charged residue, lysine, at the Ser12 position increased the enzyme's preference for NADP(H) more than 20-fold. Substitution of the negatively charged residue, aspartic acid, into the Leu36 position switched the enzyme's cofactor preference from NADPH to NAD with a 220-fold change in the ratio of the specificity toward the two cofactors in the case of oxidation. This variant dramatically abolished the enzyme's reductase function and stimulated its dehydrogenase activity, as shown by enzyme activity in intact cells. The substrate-binding pocket was also studied with four variants: Ser142Gly, Ser142Cys, His221Ala, and Glu282Ala. The Ser142Gly variant abolished most of the enzyme's oxidation and reduction activities. The residual reductase activity in vitro is less than 2% that of the wild-type enzyme. However, the Ser142Cys variant was fully inactive, both as a partially purified protein and in intact cells. This suggests that the bulky sulfhydryl group of cysteine entirely disrupted the catalytic triad and that the Ser142 side chain is important for maintaining the integrity of this triad. His221 variation weakened the apparent affinity for estrone, as demonstrated by a 30-fold increase in Michaelis-Menten constant, supporting its important role in substrate binding. This residue may play an important role in substrate inhibition via the formation of a dead-end complex. The formerly suggested importance of Glu282 could not be confirmed.

17-Hydroxysteroid Dehydrogenases↗

PubMed2006

Oxidation-reduction respiratory chains and ATP synthase complex are localized in detergent-resistant lipid rafts.

In order to detect and identify ubiquitous lipid raft marker proteins, we isolated lipid rafts from different mouse organs, including the liver, lung, large brain, and kidney, and analyzed their proteins via 2-DE. Many protein spots were determined to be ubiquitous in all of the lipid rafts, and were annotated via LC and MS/MS. Twelve proteins were identified as ubiquitous raft proteins, and most of these were determined to be mitochondrial proteins, including mortalin, prohibitin, voltage-dependent anion channel, ATP synthase, NADH dehydrogenase, and ubiquinol-cytochrome c reductase. Via immunoblotting, these proteins were shown to exist in detergent-resistant lipid rafts prepared using different organ tissues. Since these oxidation-reduction respiratory chains and ATP synthase complex were detected in detergent-resistant lipid raft fractions which had been isolated from the plasma membrane but not from the mitochondria, and found in the cell surface when determined by immunofluoresence and immunohistochemistry, we conclude that plasma membrane lipid rafts might contain oxidation-reduction respiratory chains and ATP synthase complex.

ATP Synthetase Complexes↗

PubMed1992

Conservation and characterisation of spatial features in a new method of data compression for body surface potential maps.

Body surface potential maps consist of a huge amount of data represented as a series of three-dimensional maps, which are time consuming to process and expensive to store. In spite of the continuous interest in body surface potential maps, their use has not become common and they are of no practical use in the clinics. This is due to the overwhelming amount of measured data required to generate the maps and the lack of quantitative methods to analyse them. Data compression or reduction may solve these deficiencies. Such a procedure must conserve the fine spatial details of the maps, which are usually extracted from low level surface potentials, as these are reported to be significant in diagnostic electrocardiography. A technique is presented for data reduction, that implements two-level thresholding and conserves the fine significant spatial features of each map. A sequence of annuli thus produced is shown to describe the dynamic nature of the underlying process. This sequence is further processed and characterised by features which quantify its dynamic behaviour: time of annuli sequence appearance, its duration, three-dimensional loci of centres of mass of the annuli, distances between successive centres of mass and cross-correlation coefficients between successive annuli. To test the data reduction procedure and the usefulness of the features, maps from 20 subjects are studied (both normal patients and those with various pathologies). It is found that the use of annuli instead of the whole measured information allows simple storage, display and calculations; the features, which vary in time, represent closely the changes in location of the annuli and their dynamic variations of shape. The features are also found to be grouped together for the maps of the normal patients and for each pathology. Thus, body surface potential maps may become more commonly used in clinics by being represented by a set of features, which conserve their dynamic and spatial nature, and which may serve for classification of cardiac pathologies.

Action Potentials↗

PubMed2003

Three-dimensional conformal radiotherapy in the radical treatment of non-small cell lung cancer.

Patients with locally advanced, inoperable, non-small cell lung cancer (NSCLC) have a poor prognosis mainly due to failure of local control after treatment with radical radiotherapy. This overview addresses the role of three-dimensional conformal radiotherapy (3D CRT) in trying to improve survival and reduce toxicity for patients with NSCLC. Current techniques of 3D CRT are analysed and discussed. They include imaging, target volume definition, optimisation of the delivery of radiotherapy through improvement of set-up inaccuracy and reduction of organ motion, dosimetry and implementation and verification issues; the overview concludes with the clinical results of 3D CRT.

Carcinoma, Non-Small-Cell Lung↗

PubMed1995

Nonreducing two-dimensional polyacrylamide gel electrophoretic analysis of human colonic proteins.

Immunochemical detection of proteins with antigenic determinants that are dependent on the native spatial conformation of the protein can often pose problems with conventional two-dimensional polyacrylamide gel electrophoresis (2-DE). For example, many antigenic determinants are readily destroyed by reducing agents and/or urea, reagents which are critical components of many of the conventional isoelectric focusing and immobilized-pH-gradient (IPG) protocols used in the first electrophoretic dimension. Here we describe the use of commercially available precast 2-DE gels for performing nonreducing/non-urea 2-DE of proteins extracted from the human colon cancer cell line LIM 1215 with 0.3% Triton X-100 that permit the identification of antigens with conformational determinants by immunoblot analysis. Previous, related studies demonstrated the usefulness of peptide-mass fingerprinting for identifying 2-DE resolved proteins. Here we show how partial protein sequence data obtained by rapid peptide mapping, using capillary column liquid chromatography directly coupled with electrospray ionization tandem mass spectrometric methodologies, enhances the usefulness of this approach for identifying incompletely resolved proteins. The nonreducing 2-DE gel images reported in this study, along with our master 2-DE gel protein database for both normal human colonic crypts and several colon-cancer-derived cell lines, and information regarding microtechniques employed in this laboratory for obtaining structural data on 2-DE resolved proteins can be accessed over the Internet using World Wide Web (URL address: http:@www.ludwig.edu.au).

Amino Acid Sequence↗

PubMed2005

A hydroponic rice seedling culture model system for investigating proteome of salt stress in rice leaf.

By using an in vivo hydroponic rice seedling culture system, we investigated the physiological and biochemical responses of a model rice japonica cultivar Nipponbare to salt stress using proteomics and classical biochemical methods. Yoshida's nutrient solution (YS) was used to grow rice seedlings. YS-grown 18-day-old seedlings manifested highly stable and reproducible symptoms, prominently the wilting and browning of the 3rd leaf, reduced photosynthetic activity, inhibition in overall seedling growth, and failure to develop new (5th) leaf, when subjected to salt stress by transferring them to YS containing 130 mM NaCl for 4 days. As leaf response to salt stress is least investigated in rice by proteomics, we used the 3rd leaf as source material. A comparison of 2-DE protein profiles between the untreated control and salt-stressed 3rd leaves revealed 55 differentially expressed CBB-stained spots, where 47 spots were increased over the control. Of these changed spots, the identity of 33 protein spots (27 increased and 5 decreased) was determined by nESI-LC-MS/MS. Most of these identified proteins belonged to major metabolic processes like photosynthetic carbon dioxide assimilation and photorespiration, suggesting a good correlation between salt stress-responsive proteins and leaf morphology. Moreover, 2-DE immunoblot and enzymatic activity analyses of 3rd leaves revealed remarkable changes in the key marker enzymes associated with oxidative damage to salt stress: ascorbate peroxidase and lipid peroxidation were induced, and catalase was suppressed. These results demonstrate that hydroponic culture system is best suited for proteomics of salt stress in rice seedling.

Amino Acid Sequence↗

PubMed2006

Expanding the protein catalogue in the proteome reference map of human breast cancer cells.

In this report we present a catalogue of 162 proteins (including isoforms and variants) identified in a prototype of proteomic map of breast cancer cells. This work represents the prosecution of previous studies describing the protein complement of breast cancer cells of the line 8701-BC, which has been well characterized for several parameters, providing to be a useful model for the study of breast cancer-associated candidate biomarkers. In particular, 110 spots were identified ex novo by PMF, or validated following previous gel matching identification method; 30 were identified by N-terminal microsequencing and the remaining by gel matching with maps available from our former work. As a consequence of the expanded number of proteins, we have updated our previous classification extending the number of protein groups from 4 to 13. In order to facilitate comparative proteome studies of different kinds of breast cancers, in this report we provide the whole complement of proteins so far identified and grouped into the new classification. A consistent number of them were not described before in other proteomic maps of breast cancer cells or tissues, and therefore they represent a valuable contribution for breast cancer protein databases and for future application in basic and clinical researches.

Biomarkers, Tumor↗

PubMed2006

Proteomics as a route to identification of toxicity targets in environmental toxicology.

Ecotoxicology describes a three-way relationship between ecosystems, chemical pollutants and living organisms. It is predicated on the fact that chemical pollution can exert toxic effects on organisms at the individual and population levels. These toxic effects may provide important information to supplement chemical analysis of environmental samples and aid in assessing the environmental quality of specific ecosystems. Traditionally, effects have been detected by means of biomarkers which, of necessity, were often molecules or processes known to be affected by pollutants. Proteomics provides a means of achieving high-throughput analysis of effects on protein populations and sub-populations with the potential to identify novel biomarkers. This review summarises the main approaches currently used in this area and assesses the potential of proteomics for identification of novel toxicity targets.

Chromatography↗