bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of incorporating the 2C5 crystal structure into comparative models of cytochrome P450 2D6
Authors: Kirton Stewart B. , Kemp Carol A. , Tomkinson Nicholas P. , St.‐Gallay Steven , Sutcliffe Michael J. 
Published: October 2002

AbstractCytochrome P450 2D6 (CYP2D6) metabolizes approximately one third of the drugs in current clinical use. To gain insight into its structure and function, we have produced four different sets of comparative models of 2D6: one based on the structures of P450s from four different microorganisms (P450 terp, P450 eryF, P450 cam, and P450 BM3), another on the only mammalian P450 (2C5) structure available, and the other two based on alternative amino acid sequence alignments of 2D6 with all five of these structures. Principal component analysis suggests that inclusion of the 2C5 crystal structure has a profound effect on the modeling process, altering the general topology of the active site, and that the models produced differ significantly from all of the templates. The four models of 2D6 were also used in conjunction with molecular docking to produce complexes with the substrates codeine and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP); this identified Glu 216 [in the F‐helix; substrate recognition site (SRS) 2] as a key determinant in the binding of the basic moiety of the substrate. Our studies suggest that both Asp 301 and Glu 216 are required for metabolism of basic substrates. Furthermore, they suggest that Asp 301 (I‐helix, SRS‐4), a residue thought from mutagenesis studies to bind directly to the basic moiety of substrates, may play a key role in positioning the B′‐C loop (SRS‐1) and that the loss of activity on mutating Asp 301 may therefore be the result of an indirect effect (movement of the B′‐C loop) on replacing this residue. Proteins 2002;49:216–231. © 2002 Wiley‐Liss, Inc.
Generic serial and parallel on‐line direct‐injection using turbulent flow liquid chromatography/tandem mass spectrometry
Authors: Grant Russell P. , Cameron Cheryl , Mackenzie‐McMurter Shelley 
Published: October 2002

AbstractThe development of turbulent flow chromatography (TFC) has enabled considerable growth in the utility of on‐line direct‐injection technologies. TFC has now become established in a large number of varied analytical environments, particularly drug discovery/pharmacokinetics, metabolite profiling, combinatorial library purification, pre‐clinical and clinical GLP applications. The utility of turbulent flow technology for in‐house pre‐clinical and clinical quantitative applications has necessitated extensive valve‐cleaning procedures, and consequently lengthy cycle‐times, to effectively remove the system carry‐over. In‐house requirements for assay validation require carry‐over less than 20% of the lowest level of quantification (LLOQ), corresponding to 0.02% carry‐over for a linear calibration range incorporating 3 orders. A generic turbulent flow chromatography protocol has been developed for drug discovery that incorporates polymeric turbulent flow extraction (cyclone) with C18‐based reverse‐phase chromatography. Further, multiple wash steps are incorporated within the methodology to meet in‐house requirements for carry‐over. Selection of novel switching‐valve materials based on polyarylethyl ketone (PAEK) and Hastelloy/Valcon E autosampler injection hardware has enabled us to significantly impact the cycle‐time required to reduce carry‐over. Consequently, optimal usage of switching valves has enabled parallel operation for a generic on‐line direct‐injection methodology to successfully reduce the total cycle‐time. Overall reductions from 4 min per sample to 90 s per sample are shown with comparable data quality using a proprietary target molecule from 0.1–100 ng/mL. This paper describes the hardware configuration and methodologies utilized to perform generic serial and parallel on‐line direct‐injection using a Turboflow HTLC 2300 system. Copyright © 2002 John Wiley & Sons, Ltd.
Direct determination of alkyl phosphates in human urine by liquid chromatography/electrospray tandem mass spectrometry
Authors: Hernández Félix , Sancho Juan V. , Pozo Oscar J. 
Published: October 2002

AbstractA novel and rapid procedure based on liquid chromatography/tandem mass spectrometry (LC/MS/MS) for the determination of dialkyl phosphates (metabolites of organophosphorus pesticides) in human urine has been developed. After addition of 40 mM tetrabutylammonium acetate, 10 µL of urine sample were directly injected into the LC/MS/MS system. The method was validated yielding calibration curves with correlation coefficients greater than 0.997 and repeatability coefficient of variation (CV) lower than 9%. The accuracy and precision were evaluated by direct injection of spiked samples at 10 and 100 µg/L obtaining recoveries between 78 and 119% with coefficients of variation below 12%. Limits of detection of 1 µg/L for diethyl phosphate (DEP), diethylthiophosphate (DETP) and diethyldithiophosphate (DEDTP) and 2 µg/L for dimethyldithiophosphate (DMDTP) were achieved, all the analytes being detected in negative ion mode. The fragmentation pathway of dialkyl phosphates allowed us the use of an additional transition for confirmation in order to improve their identification in real‐world samples. The applicability of the LC/MS/MS method was demonstrated by applying it to the analysis of urine samples of farmers exposed to the organophosphorus pesticide chlorpyrifos. Good correlation between application of the product in the field (citrus orchards), concentration levels of dialkyl phosphates and levels of the chlorpyrifos‐specific metabolite (1,3,5‐trichloro‐2‐pyridinol) was obtained. Copyright © 2002 John Wiley & Sons, Ltd.
Alphavirus vectors and vaccination
Authors: Rayner Jonathan O. , Dryga Sergey A. , Kamrud Kurt I. 
Published: October 2002

AbstractAlphaviruses are positive‐stranded RNA viruses that have a broad host range and therefore are capable of replicating in many vertebrate and invertebrate cells. The single‐stranded alphavirus genome is divided into two ORFs. The first ORF encodes the nonstructural proteins that are translated upon entry of the virus into the cytoplasm and are responsible for transcription and replication of viral RNA. The second ORF is under the control of a subgenomic promoter and normally encodes the structural proteins, which are responsible for encapsidation of viral RNA and final assembly into enveloped particles. Expression vectors have been engineered from at least three alphaviruses in which the structural protein gene region has been replaced by heterologous genes and have been shown to express high levels of the heterologous protein in cultured cells. These RNA vectors, known as replicons, are capable of replicating on their own but are not packaged into virus‐like particles unless the structural proteins are provided in trans. Thus, replicons are single cycle vectors incapable of spreading from infected to noninfected cells. Because of these features, alphavirus replicon vectors are being developed as a platform vaccine technology for numerous viral, bacterial, protozoan and tumour antigens where they have been shown to be efficient inducers of both humoral and T cell responses. In addition, as the alphavirus structural proteins are not expressed in vaccine recipients, antivector immune responses are generally minimal, allowing for multiple effective immunisations of the same individual. Copyright © 2002 John Wiley & Sons, Ltd.
An introduction to the use of neural networks in control systems
Authors: Hagan Martin T. , Demuth Howard B. , Jesús Orlando De 
Published: October 2002

AbstractThe purpose of this paper is to provide a quick overview of neural networks and to explain how they can be used in control systems. We introduce the multilayer perceptron neural network and describe how it can be used for function approximation. The backpropagation algorithm (including its variations) is the principal procedure for training multilayer perceptrons; it is briefly described here. Care must be taken, when training perceptron networks, to ensure that they do not overfit the training data and then fail to generalize well in new situations. Several techniques for improving generalization are discussed. The paper also presents three control architectures: model reference adaptive control, model predictive control, and feedback linearization control. These controllers demonstrate the variety of ways in which multilayer perceptron neural networks can be used as basic building blocks. We demonstrate the practical implementation of these controllers on three applications: a continuous stirred tank reactor, a robot arm, and a magnetic levitation system. Copyright © 2002 John Wiley & Sons, Ltd.
A review of hydroecological results of the Northern River Basins Study, Canada. Part 2. Peace–Athabasca Delta
Authors: Prowse T. D. , Conly F. M. 
Published: October 2002

AbstractThe Peace–Athabasca Delta (PAD) in northern Canada is one of the world's largest freshwater deltas. Concern developed over the ecological health of this system in the early 1970s following regulation of its main headwater tributary, the Peace River. Continued drying of the delta into the 1990s resulted in the initiation of two major science programs, the Northern River Basins Study and the Peace–Athabasca Delta Technical Studies. Recognizing the importance of water to restoring and maintaining biological productivity and diversity of the PAD, a series of studies was initiated to explain the reasons for the protracted drying and to design methods to restore flooding. These studies demonstrated that open‐water floods from the Peace River were unlikely to flood the ecologically sensitive perched basins within the PAD. Moreover they discovered that most large‐scale overbank flooding resulted from ice‐jams formed during spring break‐up. Increases in freeze‐up ice levels due to enhanced winter flows from the reservoir and a decrease in spring snowmelt runoff from downstream tributaries were suggested as being responsible for a decline in the frequency and severity of ice‐jam floods. Based on results from numerical modelling studies of ice‐jams, a flow augmentation strategy was designed to aid the formation of ice‐jams near the PAD. Results of a test trial based on this strategy are presented. An update is also provided about ecological studies conducted since the delta was recharged by floodwaters in 1996. Copyright © 2002 Environment Canada. Published by John Wiley & Sons, Ltd.
Classification of adsorbed protein static ToF‐SIMS spectra by principal component analysis and neural networks
Authors: Sanni O. D. , Wagner M. S. , Briggs D. , Castner D. G. , Vickerman J. C. 
Published: October 2002

AbstractAnalysis of the static time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS) spectra of adsorbed protein films is reported using principal component analysis (PCA) and a novel artificial neural network (ANN) approach,NeuroSpectraNet, to classify chemically the spectra of the protein films. The ease of application and the efficiency with which each approach classified positive ion spectra from adsorbed films of 13 different proteins is reported and assessed. The ToF‐SIMS spectra of adsorbed protein films are especially difficult to analyze owing to the absence of unique peaks in the spectra of different proteins. Although PCA was able to differentiate successfully ToF‐SIMS spectra of adsorbed protein films using the ions generated from the fragmentation of the amino acids, differentiation of the spectra using the entire spectrum was unsuccessful. Outliers in several of the protein groups make classification of unknown spectra difficult, despite the use of only amino‐acid‐specific ions. However,NeuroSpectraNetsuccessfully classified the spectra from 11 of the protein films using the whole positive ion spectra after a vector analysis enhancement had been incorporated into the neural network. Full classification of all 13 proteins was achieved by using the combined positive and negative ion spectra. However, as with PCA, ANN classification was enhanced when the input patterns only contained amino‐acid‐specific ions. The complex and multivariate nature of static SIMS spectra is a domain well suited to the application of neural networks for pattern recognition and classification. Copyright © 2002 John Wiley & Sons, Ltd.
Intensive short courses in biostatistics for fellows and physicians
Authors: Ambrosius Walter T. , Manatunga Amita K. 
Published: October 2002

AbstractAt both of our universities we teach (with colleagues) introductory courses in statistics for fellows and physicians. We do not expect that those taking these courses will be able to do their own statistical work, but rather the intention is for them to ‘learn the language’ and to facilitate future collaboration. Basic principles of study design are introduced in the courses, as well as some of the most common statistical procedures. We will discuss the factors (what works and what does not) that may contribute to a successful course, a comparison to other courses, and our self‐evaluation strategy. Finally, we will cover the financial arrangements that we have made when teaching these courses. Copyright © 2002 John Wiley & Sons, Ltd.
Virtual‐machine‐based heterogeneous checkpointing
Authors: Agbaria Adnan , Friedman Roy 
Published: October 2002

AbstractCheckpointingan application is the act of saving the application's state during its execution on stable storage, so that if the application fails it can berestartedfrom the last saved state, thereby avoiding loss of the work that was already done. Aheterogeneous checkpoint/restartmechanism allows one to restart an application on a possibly different hardware architecture and/or operating system than those in which the application was saved. This paper explores how to construct such a mechanism at the virtual machine level. That is, rather than dumping the entire state of the application process, the mechanism reported here dumps the state of the application as maintained by a virtual machine. During restart, the saved state is loaded into a new copy of the virtual machine, which continues running from there. The heterogeneous checkpoint/restart mechanism reported here was developed for the OCaml variant of ML. The paper reports on the main issues encountered in building such a mechanism and the design choices made, presents performance evaluations, and discusses some lessons and ideas for extending the work to native code OCaml and Java. Copyright © 2002 John Wiley & Sons, Ltd.
Influence of aging and social isolation on changes in brain monoamine turnover and biosynthesis of rats elicited by novelty stress
Authors: Miura Hideki , Qiao Hong , Ohta Tatsuro 
Published: October 2002

AbstractAging is a risk factor of human depression. Middle‐aged or older men are vulnerable to adverse life events and an absence of social contact and easily become depressed. In the present study, we investigated the influence of aging on responses to life events in socially isolated conditions. We applied isolation‐rearing (4 W) to two age groups, older (18 M) and younger (11 W), of male F344 rats that had been reared in a group and then examined responses to novelty stress (20 min). Changes in brain monoamines and their metabolites such as dopamine (DA), serotonin (5‐HT), dihydroxyphenylacetic acid (DOPAC), homovanilic acid (HVA), and 5‐hydroxyindoleacetic acid (5‐HIAA) were measured in six regions: the prefrontal cortex, nucleus accumbens, hippocampus, amygdala, midbrain, and raphe nuclei. MANOVA was carried out for rearing condition, age, and novelty stress. Isolation significantly changed monoamines and their metabolites, except in amygdala and raphe nuclei. Aging significantly altered them in all regions, although novelty stress did not. In the amygdala and midbrain, isolation significantly changed monoamine biosynthesis, with monoamine turnover remaining unchanged. In the prefrontal cortex and nucleus accumbens, aging significantly altered turnover, while biosynthesis remained unchanged. Novelty stress significantly varied only the turnover in the prefrontal cortex. The interaction between isolation and aging indicated that aging influences changes in turnover and biosynthesis elicited by isolation primarily at the center of the mesolymbic DA system, the midbrain, and in raphe nuclei of the 5‐HT system. In peripheral regions of the mesolymbic system, aging primarily affects changes in turnover induced by isolation. Synapse 46:116–124, 2002. © 2002 Wiley‐Liss, Inc.
Brain DA D2 receptors predict reinforcing effects of stimulants in humans: Replication study
Authors: Volkow Nora D. , Wang Gene‐Jack , Fowler Joanna S. , Thanos Pether , Logan Jean , Gatley Samuel J. , Gifford Andrew , Ding Yu‐Shin , Wong Chris , Pappas Naomi 
Published: October 2002

AbstractWe had shown that striatal DA D2 receptors levels predicted the reinforcing responses to the psychostimulant drug methylphenidate in nondrug‐abusing subjects. Here, we assessed the replicability of this finding. We measured D2 receptors with PET and [11C]raclopride (twice to determine stability) in seven nondrug‐abusing subjects to assess if they predicted the self‐reports of “drug‐liking” to intravenous methylphenidate (0.5 mg/kg). DA D2 measures were significantly correlated with “drug‐liking” in both evaluations (r = 0.82 and r = 0.78); subjects with the lowest levels reported the higher ratings of “drug‐liking” and vice versa. These results replicate our previous findings and provide further evidence that striatal DA D2 receptors modulate reinforcing responses to stimulants in humans and may underlie predisposition for drug self‐administration. Synapse 46:79–82, 2002. © 2002 Wiley‐Liss, Inc.
Chemotactic response of unicellular tetrahymena to a leukocyte attractant peptide and its repellent derivate: evolutionary conclusions.
Authors: Kõhidai László , Kovács Péter , Csaba György 
Published: October 2002

ABSTRACTChemotactic properties of the leukocyte chemoattractant N‐formyl‐Norleucine‐Leucine‐Phenylalanine (NLP) and its antagonist N‐t‐BOC‐Norleucine‐Leucine‐Phenylalanine (BOC‐NLP) were investigated in unicellular Tetrahymena pyriformis cells. NLP express its attractant character in a two‐peak profile of concentration course (maximum at 10−8‐10−7 M and 10−11 M) while BOC‐NLP has a constant repellent character (maximum at 10−12 M). The observed homology of action concurs with our theory about the wide evolutionary background of signal molecules and receptors.
New Species of Lichenized and Non-Lichenized Ascomycetes from a Rainforest Canopy in Southern Venezuela
Authors: Komposch Harald , Aptroot André , Hafellner Josef 
Published: October 2002

AbstractFour species of corticolous lichenized and non-lichenized ascomycetes are described from a tropical lowland rainforest in southern Venezuela: Mycomicrothelia xanthonica Komposch, Aptroot & Hafellner along with the closely related M. macrocarpa Komposch, Aptroot & Hafellner (Arthopyreniaceae), Pseudopyrenula cryptotheca Komposch, Aptroot & Hafellner (Trypetheliaceae), and Ancistrosporella psoromica Komposch, Aptroot & Hafellner (Opegraphaceae). Descriptions and illustrations are presented and the relationships of the taxa discussed. In addition, the following new combination is proposed: Ancistrosporella curvata (Aptroot) Komposch (Opegrapha curvata Aptroot). Ancistroporella G.Thor is regarded as typographical error and corrected to Ancistrosporella.
Nutritive Value of Terricolous Lichens for Reindeer in Winter
Authors: Storeheier Pål Vegar , Mathiesen Svein D. , Tyler Nicholas J. C. , Olsen Monica A. 
Published: October 2002

AbstractIn contrast to virtually all other species of ruminants, reindeer (Rangifer arandus) eat substantial amounts of lichens in winter. Several different species of lichens are eaten and most are highly palatable. The chemical composition and the in vitro digestibility of six species of terricolous lichens commonly eaten by reindeer were measured. Ruminal inoculum was obtained in winter from six free-ranging reindeer that had been grazing on natural pastures in northern Norway. Analysis of the plant parts recovered from their rumens confirmed that the animals had been eating a mixed diet that included both lichens and vascular plants. The chemical composition and the in vitro digestibility of the different species of lichens varied considerably between species and genera. Cetraria islandica, C. nivalis and Cladonia arbuscula were highly digestible [69-77% dry matter (DM)], Stereocaulon paschale was poorly digestible (43% DM), whereas Cladonia stellaris and C. gradlis had an intermediate digestibility (56-57% DM). Mixing ladonia stellaris with vascular plants (50:50) had no effect on the in vitro digestibility of the combined substrates. The in vitro digestibility of Cladonia stellaris in inoculum from two captive reindeer which had had no access to lichens was very low (10% DM). This shows that the source of inoculum used for digestibility trials has a major effect on the apparent digestibility of the substrates. Evidently, the extent to which reindeer are able to utilize lichens depends on the species that are selected and on what the animals have been eating recently.
Risk factors and infant outcomes associated with umbilical cord prolapse
Authors: Uygur D , Kiş S , Tuncer R , Özcan F.S , Erkaya S 
Published: October 2002

AbstractObjectives: Our goal was to identify risk factors associated with umbilical cord prolapse and to review the perinatal outcome of cases of cord prolapse. Methods: During the study years 77 cases were identified retrospectively. Associations between cord prolapse and potential risk factors were evaluated by means of the odds ratio. Results: Of the 77 fetuses with umbilical cord prolapse 9.1% had a fetal weight of <2500 g as compared with 9.4% for fetuses in control group (P>0.05). The umbilical cord prolapse occurred in association with vertex presentation 66 times (85.7%), breech presentation nine times (11.7%) and transverse presentation two times (2.6%). The occurrence of breech presentation among the control cases was 2.6%, and that of transverse lie was 1.7% (P<0.01). Case mothers were 1.6 times more likely to be multiparas compared with the control group (P<0.01). The perinatal mortality rate was 39/1000. Conclusions: Our study showed that abnormal fetal presentation and multiparity are associated with an increased risk of umbilical cord prolapse. The association of risk of cord prolapse with low birth weight was statistically insignificant (P>0.05). We suggest that the cesarean delivery decreased the risk of perinatal mortality among cases of cord prolapse.
Spanning the continuum between marketing and operations
Authors: Malhotra Manoj K. , Sharma Subhash 
Published: October 2002

AbstractWe discuss here the importance of the marketing operations interface and our motivations in creating this special issue. We also evaluate and summarize the papers presented in this special issue, and present our observations on how the study of this interface has methodologically evolved over the course of years. Some of the dominant common themes emphasized in the six papers contained in this special issue were communication between operations and marketing, as well as the value of trust and harmony between these functional areas in improving firm performance. Based on these observations and extant literature in both disciplines, a simple framework that delineates broad areas of mutual interest and integration between these two functional areas is proposed. We finally outline a limited set of future research projects that lie at the interface of marketing and operations, and which can potentially be pursued by researchers in this domain in order to promote a better understanding of the interface.