bluuebunny/crossref_metadata_2025 huggingface dataset:
Properties‐based retrieval and user decision states: User control and behavior modeling
Authors: Benoît Gerald
Published: March 2004

As retrieval set size in information retrieval (IR) becomes larger, users may need greater interactive opportunities to determine for themselves potential relevance of the resources offered by a given collection. A parts‐of‐document approach, coupled with an interactive graphic interface and control panel, permits end users to tailor the information seeking (IS) session. Applying the model described by the author in a previous paper in this journal, this paper explores two issues: whether a group of information seekers in the same research domain will want to use this type of IR interaction, and whether such interaction is more successful than relevancy ranked lists, based on the general vector model. In addition, the paper proposes the use of gradient space as a means of capturing end users' cognitive states—decision‐making points—during a parts‐of‐document‐based IR session. It concludes that, for a group of biomedical researchers, a parts‐of‐document approach is preferred for certain IR situations and that gradient space provides designers of systems with empirical evidence suited for systems analysis.
Bowling alone together: Academic writing as distributed cognition
Authors: Cronin Blaise
Published: March 2004

The twentieth century saw the progressive collectivization of science‐dramatic growth in teamwork in general and large‐scale collaboration in particular. Cognitive partnering in the conduct of research and scholarship has become commonplace, and this trend is reflected in rates of co‐authorship and sub‐authorship collaboration. The effects of these developments on academic writing are discussed and theorized in terms of distributed cognition.
Long‐term influences of interventions in the normal development of science: China and the Cultural Revolution
Authors: Jin Bihui , Li Ling , Rousseau Ronald
Published: March 2004

Intellectual and technological talents and skills are the driving force for scientific and industrial development, especially in our times characterized by a knowledge‐based economy. Major events in society and related political decisions, however, can have a long‐term effect on a country's scientific well‐being. Although the Cultural Revolution took place from 1966 to 1976, its aftermath can still be felt. This is shown by this study of the production and productivity of Chinese scientists as a function of their age. Based on the 1995–2000 data from the Chinese Science Citation database (CSCD), this article investigates the year‐by‐year age distribution of scientific and technological personnel publishing in China. It is shown that the “Talent Fault” originating during the Cultural Revolution still exists, and that a new gap resulting from recent brain drain might be developing. The purpose of this work is to provide necessary information about the current situation and especially the existing problems of the S&T workforce in China.
Evaluation of a contraction flow field on hydrodynamic damage to entomopathogenic nematodes—A biological pest control agent
Authors: Fife Jane P. , Derksen Richard C. , Ozkan H. Erdal , Grewal Parwinder S. , Chalmers Jeffrey J. , Krause Charles R.
Published: March 2004

Mechanized production and delivery of biological pesticides presents challenges because the biological agents must remain viable during these processes. This study evaluates the effect of flow through an abrupt contraction, where flow characteristics similar to that found within bioprocesses and spray equipment are developed, on damage to a benchmark biological pest control agent, entomopathogenic nematodes (EPNs). An opposed‐pistons, contraction flow device generated volumetric flow rates ranging between 8.26 cm3/s and 41.3 cm3/s. Four EPN species were evaluated: Heterorhabditis bacteriophora, Heterorhabditis megidis, Steinernema carpocapsae, and Steinernema glaseri. Damage was quantified by counting living and dead EPNs. Optical and cold field emission scanning electron microscope (CFE‐SEM) images provided qualitative information to describe how the damage occurred. The experimental flow field was completely described using FLUENT, a computational fluid dynamics program. Local flow parameters computed in FLUENT were compared to EPN damage. The type and extent of damage varied between EPN species. Damaged Heterorhabditis spp. generally remained whole with an internal rupture located near the center of the body, while Steinernema spp. most often broke into several pieces. The fast‐transient stress field generated at the entrance to the contraction caused a momentary tensile loading and then relaxation that damaged the EPNs. At high flow rates, the tensile stresses became large enough to cause failure of the EPN structural membrane. The relative elasticity of the EPN structural membrane may explain the differences in damage observed between the species. It is speculated that the internal rupture of the Heterorhabditis spp. occurred during the processes of stretching and relaxing at the contraction entrance. Appreciable damage was observed at lower average energy dissipation rates for H. bacteriophora (1.23E + 8 W/m3), H. megidis (1.72E + 8 W/m3), and S. glaseri (2.89E + 8 W/m3) compared to S. carpocapsae (3.70E + 8 W/m3). Energy dissipation rates within an equipment component should be kept below 1E + 8 W/m3 to avoid hydrodynamic damage to EPNs. The relationship between average energy dissipation and EPN damage provides important information for future simulation efforts of actual spray equipment components. © 2004 Wiley Periodicals, Inc.
Synthetic extracellular matrices for in situ tissue engineering
Authors: Pratt Alison B. , Weber Franz E. , Schmoekel Hugo G. , Müller Ralph , Hubbell Jeffrey A.
Published: March 2004

Cell interactions with the extracellular matrix play important roles in guiding tissue morphogenesis. The matrix stimulates cells to influence such things as differentiation and the cells actively remodel the matrix via local proteolytic activity. We have designed synthetic hydrogel networks that participate in this interplay: They signal cells via bound adhesion and growth factors, and they also respond to the remodeling influence of cell‐associated proteases. Poly(ethylene glycol)‐bis‐vinylsulfone was crosslinked by a Michael‐type addition reaction with a peptide containing three cysteine residues, the peptide sequence being cleavable between each cysteine residue by the cell‐associated protease plasmin. Cells were able to invade gel networks that contained adhesion peptides and were crosslinked by plasmin‐sensitive peptides, while materials lacking either of these two characteristics resisted cell infiltration. Incorporated bone morphogenetic protein‐2 (BMP‐2) induced bone healing in a rat model in materials that were both adhesive and plasmin‐sensitive, while materials lacking plasmin sensitivity resisted formation of bone within the material. Furthermore, when a heparin bridge was incorporated as a BMP‐2 affinity site, mimicking yet another characteristic of the extracellular matrix, statistically improved bone regeneration was observed. © 2004 Wiley Periodicals, Inc.
Oxygen gradients in tissue‐engineered Pegt/Pbt cartilaginous constructs: Measurement and modeling
Authors: Malda J. , Rouwkema J. , Martens D. E. , le Comte E. P. , Kooy F. K. , Tramper J. , van Blitterswijk C. A. , Riesle J.
Published: March 2004

The supply of oxygen within three‐dimensional tissue‐engineered (TE) cartilage polymer constructs is mainly by diffusion. Oxygen consumption by cells results in gradients in the oxygen concentration. The aims of this study were, firstly, to identify the gradients within TE cartilage polymer constructs and, secondly, to predict the profiles during in vitro culture. A glass microelectrode system was adapted and used to penetrate cartilage and TE cartilaginous constructs, yielding reproducible measurements with high spatial resolution. Cartilage polymer constructs were cultured for up to 41 days in vitro. Oxygen concentrations, as low as 2–5%, were measured within the center of these constructs. At the beginning of in vitro culture, the oxygen gradients were steeper in TE constructs in comparison to native tissue. Nevertheless, during the course of culture, oxygen concentrations approached the values measured in native tissue. A mathematical model was developed which yields oxygen profiles within cartilage explants and TE constructs. Model input parameters were assessed, including the diffusion coefficient of cartilage (2.2 × 10−9) + (0.4 × 10−9 m2 s−1), 70% of the diffusion coefficient of water and the diffusion coefficient of constructs (3.8 × 10−10 m2 s−1). The model confirmed that chondrocytes in polymer constructs cultured for 27 days have low oxygen requirements (0.8 × 10−19 mol m−3 s−1), even lower than chondrocytes in native cartilage. The ability to measure and predict local oxygen tensions offers new opportunities to obtain more insight in the relation between oxygen tension and chondrogenesis. © 2004 Wiley Periodicals, Inc.
Solubilization and concentration of carbon dioxide: Novel spray reactors with immobilized carbonic anhydrase
Authors: Bhattacharya Sumana , Nayak Amiya , Schiavone Marc , K. Bhattacharya Sanjoy
Published: March 2004

Novel spray reactors are described that employ immobilized biocatalyst (carbonic anhydrase), enabling concentration and solubilization of emitted CO2 by allowing catalytic contact with water spray. The reactors were fed with simulated emission gas. The performance of the reactors was investigated with respect to operation variable: emission flow rate; gas composition in the emission stream; water flow rate; area‐to‐volume ratio of immobilized reactor core; and the enzyme load within the core. The reactors were also investigated for pressure drop and extractability of CO2 from the emission with single vs. multiple reactors (of combined equal volume). The biotechnological process of solubilization and concentration of CO2 from emission exhausts or streams occurring in the spray reactors could be coupled for further biochemical/chemical conversion of the concentrated CO2. © 2004 Wiley Periodicals, Inc.
τ‐AIMD for asynchronous receiver feedback
Authors: Lahanas Adrian , Tsaoussidis Vassilis
Published: March 2004

In this work we first describe an asynchronous‐feedback model which corresponds to the diverse roundtrip times (RTTs) of competing flows within the same communication channel. We show that even when the feedback of the receivers/network is asynchronous, the duration of a congestion epoch represents ‘common knowledge’ for the competing flows. Based on this property, we propose a diverse linear increase scheme in proportion to the RTT of each flow and we adjust periodically the windows of the competing flows accordingly, in order to enhance fairness of asynchronous‐feedback environments. We name this scheme τ‐AIMD and show that fairness of flows in asynchronous systems is improved since the increase‐rate diversity of long and short RTT flows is largely canceled. We use the max–min notion of fairness to show that τ‐AIMD can constitute the foundation for other window‐based, end‐to‐end algorithms that target a good balance between efficiency and fairness. Copyright © 2004 John Wiley & Sons, Ltd.
Which survey indicators are useful for monitoring consumption? Evidence from European countries
Authors: Nahuis Niek J. , Jansen W. Jos
Published: March 2004

This paper assesses the information content of two survey indicators for consumption developments in the near future for eight European countries in the period 1985–1998. Empirical work on this topic typically focuses on consumer confidence, the perceptions of buyers of consumption goods. This paper examines whether perceptions of sellers of consumption goods, measured by retail trade surveys, may also improve short‐term monitoring of consumption. We find that both consumer confidence and retailer confidence embody valuable information, when analysed in isolation. For France, Italy and Spain we conclude that adding retail confidence does not improve the indicator model once consumer confidence has been included. For the UK the reverse case is obtained. For the remaining four countries we show that combining consumer sentiment and retail trade confidence into a composite indicator leads to optimal results. Our results suggest that incorporating information from retail trade surveys may offer significant benefits for the analysis of short‐term prospects of consumption. Copyright © 2004 John Wiley & Sons, Ltd.
Can out‐of‐sample forecast comparisons help prevent overfitting?
Authors: Clark Todd E.
Published: March 2004

This paper shows that out‐of‐sample forecast comparisons can help prevent data mining‐induced overfitting. The basic results are drawn from simulations of a simple Monte Carlo design and a real data‐based design similar to those used in some previous studies. In each simulation, a general‐to‐specific procedure is used to arrive at a model. If the selected specification includes any of the candidate explanatory variables, forecasts from the model are compared to forecasts from a benchmark model that is nested within the selected model. In particular, the competing forecasts are tested for equal MSE and encompassing. The simulations indicate most of the post‐sample tests are roughly correctly sized. Moreover, the tests have relatively good power, although some are consistently more powerful than others. The paper concludes with an application, modelling quarterly US inflation. Copyright © 2004 John Wiley & Sons, Ltd.
Cambro‐Ordovician trace fossils from the SW‐Norwegian Caledonides
Authors: Knaust Dirk
Published: March 2004

A diverse trace fossil association is described for the first time from low‐grade metamorphic rocks of the SW‐Norwegian Caledonides. The investigated cliff sections with autochthonous to parautochthonous metasediments comprise a coarsening‐ and thickening‐upward succession interpreted as prograding delta deposits. Sedimentary features indicate a tide‐influenced environment. Twenty‐one ichnospecies have been identified and assigned to the Cruziana and Skolithos ichnofacies, including the oldest record of Beaconites capronus and Macaronichnus segregatis. Cruziana ichnostratigraphy (sensu lato), previously rarely used in other palaeocontinents than Gondwana, allows an age determination for these metasediments of Middle Cambrian to Lower Ordovician as indicated by the presence of Cruziana barbata, C. furcifera, C. rugosa, C. semiplicata, Didymaulichnus rouaulti and Rusophycus ramellensis. Baltica was geographically the most isolated from the other three large continents (Gondwana, Laurentia and Siberia) during Cambro‐Ordovician time, and provinciality of faunal assemblages (e.g. brachiopods, conodonts) has been proved and is also supposed for trilobites by some authors. However, although the Cruziana ichnospecies result from a high specialization of their tracemakers, and therefore only a small group of trilobite species is eligible for its origin, the ichnospecies reported from Baltica occur also on other palaeocontinents and do not support the assumption of trilobite provincialism. Copyright © 2004 John Wiley & Sons, Ltd.
Mud volcanoes of Italy
Authors: Martinelli Giovanni , Judd Alan
Published: March 2004

The locations and information about the sizes of 61 mud volcanoes on the Italian mainland and Sicily, plus an area of mud diapirism in the Italian Adriatic Sea, are presented. Data about the emission products are also provided. The majority of these mud volcanoes are found where thick sedimentary sequences occur within a zone of tectonic compression associated with local plate tectonic activity: the movement of the Adriatic microplate between the converging African and Eurasian plates. The principal gas emitted by these mud volcanoes is methane, which probably originates from deep within the sediments. Other mud volcanoes, associated with igneous volcanism, produce mainly carbon dioxide. The mud diapirs in the Adriatic Sea are thought to form as a result of the mobilization of shallow gassy sediments. It has been shown that radon emissions from mud volcanoes are indicators of forthcoming earthquake events. Copyright © 2004 John Wiley & Sons, Ltd.
Mantle‐derived and crustal melts dichotomy in northern Greece: spatiotemporal and geodynamic implications
Authors: Perugini Diego , Poli Giampiero , Christofides George , Eleftheriadis George , Koroneos Antonis , Soldatos Triantafyllos
Published: March 2004

Two distinct groups of subduction‐related (orogenic) granitoid rocks, one Jurassic and the other Tertiary, occur in the area between the Vardar (Axios) Zone and the Rhodope Massif in northern Greece. The two groups of granitoids differ in many respects. The first group shows evolved geochemical characters, it is not associated with mafic facies, and evidence of magmatic interaction between mantle‐ and crustal‐derived melts is lacking. The second group has less evolved geochemical characters, it is associated with larger amount of mafic facies, and magmatic interaction processes between mantle‐derived and crustal melts are ubiquitous as evidenced by mafic microgranular enclaves and synplutonic dykes showing different enrichment in K2O, Ti, and incompatible elements. This kind of magmatism can be attributed to the complex geodynamic evolution of the area. In particular, we suggest that two successive subduction events related to the closure of the Vardar and the Pindos oceans, respectively, occurred in the investigated area from Late Jurassic to Tertiary. We relate the genesis of Jurassic granitoids to the first subduction event, whereas Tertiary granitoids are associated with the second subduction. Fluids released by the two subducted slabs induced metasomatic processes generating a ‘leopard skin’ mantle wedge able to produce mafic melts ranging from typical calc‐alkaline to ultra‐potassic. Such melts interacted in various amounts with crustal calc‐alkaline anatectic melts to generate the wide spectrum of Tertiary granitoids occurring in the study area. Copyright © 2004 John Wiley & Sons, Ltd.
Structural evolution of the southern Rif Cordillera (Morocco): tectonics and synsedimentary fault processes
Authors: Zouhri Lahcen
Published: March 2004

This paper attempts to investigate the tectonics of the southern Rif Cordillera. Hydrogeological and oil well data, together with interpretation of seismic reflection lines help to characterize the architecture of the Rharb–Mamora Basin located in the frontal region of the Gibraltar Arc.

The facies map constructed from the drilling data exhibits four main types of Pliocene facies: (i) conglomerates; (ii) limestones; (iii) sandstones and sands more or less rich with shelly remains; (iv) clays. The lateral variation of deposits is accompanied by thickening, which can reach a few tens of metres. Thickening of layers and lithofacies variation indicate synsedimentary faulting processes. Two major fault zones have been identified: Kenitra–Sidi Slimane Fault Zone (K2SFZ) and Rabat–Kenitra Fault Zone (RKFZ). In the western coastal area, the geometrical configuration suggests a partition into horsts and grabens in the southern part, and a system of three geological units in the northern part.

The analysis and interpretation of the gravity data reveal an important gravity anomaly, referred to as the Kenitra Gravity Anomaly. It corresponds to the Hercynian faults deduced by the seismic reflection line interpretation: K2SFZ and RKFZ. From Larache to El Jadida cities, the Kenitra area represents the hinge between the positive and negative gravity values, with a major negative anomaly in the eastern part of Kenitra. Copyright © 2004 John Wiley & Sons, Ltd.
Implications of dissected drift at Stockdale Head, western Lake District, northern England
Authors: Wilson Peter
Published: March 2004

From mapping and consideration of prominent drift ridges at Stockdale Head, western Lake District, northern England it is inferred that the ridges are the products of dissection of a glacigenic or soliflual drift sheet rather than landforms constructed at the margins of a Loch Lomond Stade (LLS) valley‐head glacier. This proposal has implications for the recognition of LLS glacier limits and, possibly, understanding the dearth of moraine ridges associated with Dimlington ice in Lake District valleys. Copyright © 2004 John Wiley & Sons, Ltd.
Neural substrates of tactile object recognition: An fMRI study
Authors: Reed Catherine L. , Shoham Shy , Halgren Eric
Published: March 2004

A functional magnetic resonance imaging (fMRI) study was conducted during which seven subjects carried out naturalistic tactile object recognition (TOR) of real objects. Activation maps, conjunctions across subjects, were compared between tasks involving TOR of common real objects, palpation of “nonsense” objects, and rest. The tactile tasks involved similar motor and sensory stimulation, allowing higher tactile recognition processes to be isolated. Compared to nonsense object palpation, the most prominent activation evoked by TOR was in secondary somatosensory areas in the parietal operculum (SII) and insula, confirming a modality‐specific path for TOR. Prominent activation was also present in medial and lateral secondary motor cortices, but not in primary motor areas, supporting the high level of sensory and motor integration characteristic of object recognition in the tactile modality. Activation in a lateral occipitotemporal area associated previously with visual object recognition may support cross‐modal collateral activation. Finally, activation in medial temporal and prefrontal areas may reflect a common final pathway of modality‐independent object recognition. This study suggests that TOR involves a complex network including parietal and insular somatosensory association cortices, as well as occipitotemporal visual areas, prefrontal, and medial temporal supramodal areas, and medial and lateral secondary motor cortices. It confirms the involvement of somatosensory association areas in the recognition component of TOR, and the existence of a ventrolateral somatosensory pathway for TOR in intact subjects. It challenges the results of previous studies that emphasize the role of visual cortex rather than somatosensory association cortices in higher‐level somatosensory cognition. Hum. Brain Mapping 21:236–246, 2004. © 2004 Wiley‐Liss, Inc.
Neural correlates of switching set as measured in fast, event‐related functional magnetic resonance imaging
Authors: Smith Anna B. , Taylor Eric , Brammer Mick , Rubia Katya
Published: March 2004

Attentional switching has shown to involve several prefrontal and parietal brain regions. Most cognitive paradigms used to measure cognitive switching such as the Wisconsin Card Sorting Task (WCST) involve additional cognitive processes besides switching, in particular working memory (WM). It is, therefore, questionable whether prefrontal brain regions activated in these conditions, especially dorsolateral prefrontal cortex (DLPFC), are involved in cognitive switching per se, or are related to WM components involved in switching tasks. Functional magnetic resonance imaging (fMRI) was used to examine neural correlates of pure switching using a paradigm purposely designed to minimize WM functions. The switching paradigm required subjects to switch unpredictably between two spatial dimensions, clearly indicated throughout the task before each trial. Fast, event‐related fMRI was used to compare neural activation associated with switch trials to that related to repeat trials in 20 healthy, right‐handed, adult males. A large cluster of activation was observed in the right hemisphere, extending from inferior prefrontal and pre‐ and postcentral gyri to superior temporal and inferior parietal cortices. A smaller and more caudal cluster of homologous activation in the left hemisphere was accompanied by activation of left dorsolateral prefrontal cortex (DLPFC). We conclude that left DLPFC activation is involved directly in cognitive switching, in conjunction with parietal and temporal brain regions. Pre‐ and postcentral gyrus activation may be related to motor components of switching set. Hum. Brain Mapp.21:247–256, 2004. © 2004 Wiley‐Liss, Inc.
Passive perception of odors and semantic circuits
Authors: Savic Ivanka , Berglund Hans
Published: March 2004

The sense of smell has been traditionally assumed to be different from other sensory modalities in that odors are encoded perceptually, without a semantic component. Recent findings of improved odor memory upon encoding with verbal cues question this view. Furthermore, familiar odors are easier to remember and discriminate than are unfamiliar ones, and odor familiarity is reported to predict odor naming. To investigate whether familiar odors are processed by different cerebral structures than those that process unfamiliar odors, 15O H2O‐positron emission tomography (PET) measurements of cerebral blood flow were carried out in 14 healthy men. The task was passive, birhinal, smelling of familiar odors (FAM), unfamiliar odors (uFAM), and odorless air (AIR). Significant activations (P < 0.05) were calculated using the contrasts FAM–AIR, uFAM–AIR, and FAM–uFAM, and deactivations running these contrasts in the opposite direction. In relation to AIR, both FAM and uFAM activated amygdala, piriform cortex, and parts of anterior cingulate cortex. FAM activated, in addition, left frontal cortex (Brodmann's areas 44,45,47), left parietal cortex incorporating precuneus, and right parahippocampus. Clusters covering parahippocampus and precuneus were observed also in FAM–uFAM. The activation of left frontal cortex and right parahippocampus was positively correlated with familiarity ratings. Smelling of familiar but not unfamiliar odorants seems to engage cerebral circuits mediating memory and language functions, in addition to the engagement of olfactory cortex. Already the most elemental form of odor processing, passive perception thus seems to engage semantic circuits. This is achieved by the ability of odorants to immediately elicit associations and judgments of odor characteristics. Hum. Brain Mapping 21:271–278, 2004. © 2004 Wiley‐Liss, Inc.
The effect of training systemic information on the retention of fault‐finding skills in manufacturing industries
Authors: Linou Nadia , Kontogiannis* Tom
Published: March 2004

This study examines how the process of skill retention (including both recall and reconstruction) can benefit from systemic training information that covers several structural, functional, physical (e.g., causal links), and supervisory features (e.g., system control and instrumentation). An experiment was carried out in which a group of participants who received systemic information was compared to a group trained in plant theory and to another three groups trained in heuristics that ranged in terms of high‐ and low‐level diagnostic information. Learning curves revealed that all groups achieved high accuracy scores in diagnosing faults in a distillation plant. Six weeks later, a retention test showed that the systemic group (S) had a better recall score than the groups trained in theory (T) and high‐level heuristics (HH). In addition, the S group had a better reconstruction score than the groups receiving the high‐ and low‐level heuristics (H+) and the low‐level diagnostic information (HL). An interesting finding was that high‐level diagnostic information seemed to support the reconstruction phase of the retention process, whereas low‐level information better supported the recall phase. Overall, it appeared that systemic information enabled trainees to acquire task cues to help recall and reconstruct diagnostic heuristics. © 2004 Wiley Periodicals, Inc. Hum Factors Man 14: 197–217, 2004.
How do employees perceive their organization and job when companies adopt principles of lean production?
Authors: Seppälä Pentti , Klemola Soili
Published: March 2004

The concept of lean production originally emerged in the beginning of the 1990s in the automobile industry, but its principles were adopted in other industries as well. According to the literature, the principles of lean production are controversial from the point of view of human well being. This study examined: 1) the extent to which lean production and related technologies were adopted in four Finnish manufacturing companies; 2) the way different occupational groups experienced their organization and work when principles of lean production had been implemented; and 3) which factors in the organization and change processes were associated with the employees' positive or negative perceptions of production, job satisfaction, and stress. © 2004 Wiley Periodicals, Inc. Hum Factors Man 14: 157–180, 2004.
Pattern recognition strategies for molecular surfaces: III. Binding site prediction with a neural network
Authors: Keil Matthias , Exner Thomas E. , Brickmann Jürgen
Published: March 2004

An algorithm for the identification of possible binding sites of biomolecules, which are represented as regions of the molecular surface, is introduced. The algorithm is based on the segmentation of the molecular surface into overlapping patches as described in the first article of this series.1The properties of these patches (calculated on the basis of physical and chemical properties) are used for the analysis of the molecular surfaces of 7821 proteins and protein complexes. Special attention is drawn to known protein binding sites. A binding site identification algorithm is realized on the basis of the calculated data using a neural network strategy. The neural network is able to classify surface patches as protein–protein, protein–DNA, protein–ligand, or nonbinding sites. To show the capability of the algorithm, results of the surface analysis and the predictions are presented and discussed with representative examples. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 779–789, 2004
Performance of SuSi: A method for generating atomistic models of amorphous polymers based on a random search of energy minima
Authors: Curcó David , Alemán Carlos
Published: March 2004

The performance of a recently developed method to generate representative atomistic models of amorphous polymers has been investigated. This method, which is denoted SuSi, can be defined as a random generator of energy minima. The effects produced by different parameters used to define the size of the system and the characteristics of the generation algorithm have been examined. Calculations have been performed on poly(L,D‐lactic) acid (ρ = 1.25 g/cm3) and nylon 6 (ρ = 1.084 g/cm3), which are important commercial polymers. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 790–798, 2004
Intramolecular interaction energies in model alanine and glycine tetrapeptides. Evaluation of anisotropy, polarization, and correlation effects. A parallel ab initio HF/MP2, DFT, and polarizable molecular mechanics study
Authors: Gresh Nohad , Kafafi Sherif A. , Truchon Jean‐François , Salahub Dennis R.
Published: March 2004

An extension of the SIBFA polarizable molecular mechanics procedure to flexible oligopeptides is reported. The procedure is evaluated by computing the relative conformational energies, δEconf, of the alanine tetrapeptide in 10 representative conformations, which were originally derived by Beachy et al. (J Am Chem Soc 1997, 119, 5908) to benchmark molecular mechanics procedures with respect to ab initio computations. In the present study, a particular emphasis is on the separable nature of the components of the energy and the particular impact of the polarization energy component on δEconf. We perform comparisons with respect to single‐point HF, DFT, LMP2, and MP2 computations done at the SIBFA‐derived energy minima. Such comparisons are made first for the 10 conformers derived from ϕ/ψ torsional angle energy‐minimization (the rigid rotor approach), and, in a second step, after allowing additional relaxation of the Cα centered valence angles. In both series of energy‐minimization, the SIBFA δEconf compared best with the LMP2 results using the 6‐311G** basis set, the rms being 1.3 kcal/mol. In the absence of the polarization component, the rms is 3.5 kcal/mol. In both series of minimizations, the magnitudes of δEconf, computed as differences with respect to the most stable conformer taken as energy zero, decrease along the series: HF > DFT > LMP2 > SIBFA > MP2, indicative of increasing stabilization of the most highly folded conformers. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 823–834, 2004
Development and evaluation of a generic evolutionary method for protein–ligand docking
Authors: Yang Jinn‐Moon
Published: March 2004

We have developed a generic evolutionary method with an empirical scoring function for the protein–ligand docking, which is a problem of paramount importance in structure‐based drug design. This approach, referred to as the GEMDOCK (Generic Evolutionary Method for molecular DOCKing), combines both continuous and discrete search mechanisms. We tested our approach on seven protein–ligand complexes, and the docked lowest energy structures have root‐mean‐square derivations ranging from 0.32 to 0.99 Å with respect to the corresponding crystal ligand structures. In addition, we evaluated GEMDOCK on crossdocking experiments, in which some complexes with an identical protein used for docking all crystallized ligands of these complexes. GEMDOCK yielded 98% docked structures with RMSD below 2.0 Å when the ligands were docked into foreign protein structures. We have reported the validation and analysis of our approach on various search spaces and scoring functions. Experimental results show that our approach is robust, and the empirical scoring function is simple and fast to recognize compounds. We found that if GEMDOCK used the RMSD scoring function, then the prediction accuracy was 100% and the docked structures had RMSD below 0.1 Å for each test system. These results suggest that GEMDOCK is a useful tool, and may systematically improve the forms and parameters of a scoring function, which is one of major bottlenecks for molecular recognition. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 843–857, 2004
Hydrogen bonding and solvent effects on the lowest 1(n, π*) excitations of triazines in water
Authors: Zeng Jun , Xie Daiqian
Published: March 2004

Our method for estimating solvent effects on electronic spectra in media with strong solute–solvent interactions is applied here to calculate the absorption and fluorescence solvatochromatic shifts of dilute triazines in water. First, the ab initio CASSCF method is used to estimate the gas‐phase electronic excitation properties and state charge distributions; second, Monte Carlo simulations are performed to elucidate liquid structures around the ground and excited state solute; finally, the solvent shift is evaluated based on the gas‐phase charge distributions and the explicit solvent structures. For the dilute triazine solutions, simulations predict one linear (different) hydrogen bond attached to each nitrogen atom. Upon the first 1(n, π*)electronic excitation one hydrogen bond is completely broken. For the absorption and fluorescence spectra, our calculations demonstrated that the specific solvent–solute interaction, in any electronic state, plays a critical role in the determination of solvent shifts. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 813–822, 2004
Simultaneous quantification of cyclophosphamide, 4‐hydroxycyclophosphamide, N,N′,N″‐triethylenethiophosphoramide (thiotepa) and N,N′,N″‐triethylenephosphoramide (tepa) in human plasma by high‐performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry
Authors: de Jonge Milly E. , van Dam Selma M. , Hillebrand Michel J. X. , Rosing Hilde , Huitema Alwin D. R. , Rodenhuis Sjoerd , Beijnen Jos H.
Published: March 2004

The alkylating agents cyclophosphamide (CP) and N, N′, N″‐triethylenethiophosphoramide (thiotepa) are often co‐administered in high‐dose chemotherapy regimens. Since these regimens can be complicated by the occurrence of severe and sometimes life‐threatening toxicities, pharmacokinetically guided administration of these compounds, to reduce variability in exposure, may lead to improved tolerability. For rapid dose adaptations during a chemotherapy course, we have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of CP, thiotepa and their respective active metabolites 4‐hydroxycyclophosphamide (4OHCP) and N, N′, N″‐triethylenephosphoramide (tepa) in plasma. Because of the instability of 4OHCP in plasma, the compound is derivatized with semicarbazide (SCZ) immediately after sample collection and quantified as 4OHCP‐SCZ. Sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using 100 µl of plasma. Chromatographic separation was performed on an Zorbax Extend C18 column (150 × 2.1 mm i.d., particle size 5 µm), with a quick gradient using 1 mM ammonia solution and acetonitrile, at a flow‐rate of 0.4 ml min−1. The analytical run time was 10 min. The triple quadrupole mass spectrometer was operating in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 200–40 000 ng ml−1 for CP, 50–5000 ng ml−1 for 4OHCP‐SCZ and 5–2500 ng ml−1 for thiotepa and tepa, using 100 µl of human plasma. These dynamic concentration ranges proved to be relevant in daily practice. Hexamethylphosphoramide was used as an internal standard. The coefficients of variation were <12% for both intra‐day and inter‐day precisions for each compound. Mean accuracies were also between the designated limits (±15%). This robust and rapid LC/MS/MS assay is now successfully applied for routine therapeutic drug monitoring of CP, thiotepa and their metabolites in our hospital. Copyright © 2004 John Wiley & Sons, Ltd.
Electrospray ionization mass spectrometric study of 1,3,4‐oxadiazole–copper complexes
Authors: Frański Rafał
Published: March 2004

The complexes of 2,5‐disubstituted‐1,3,4‐oxadiazoles, namely 2,5‐diphenyl‐1,3,4‐oxadiazole (1), 2,5‐bis(2‐pyridyl)‐1,3,4‐oxadiazole (2) and 2,5‐bis(4‐pyridyl)‐1,3,4‐oxadiazole (3), with copper cation were studied by electrospray ionization mass spectrometry (ESI‐MS). The ability of the compounds studied to form complexes with copper (under the ESI conditions) can be ordered as 2 > 1 > 3. The compounds studied tend to form both 1 : 1 and 2 : 1 chelate complexes with both copper(II) and copper(I). The complexes with copper(I) are formed in the ESI process. The influence of solvent polarity, solution flow‐rate, counter ions (Cl−, NO3−, CH3COO−, SO42−, acetylacetonates) on the type of the ions observed was studied. Copyright © 2004 John Wiley & Sons, Ltd.
Quantitative analysis of the novel anticancer drug ABT‐518, a matrix metalloproteinase inhibitor, plus the screening of six metabolites in human plasma using high‐performance liquid chromatography coupled with electrospray tandem mass spectrometry
Authors: Stokvis E. , Rosing H. , Crul M. , Rieser M. J. , Heck A. J. R. , Schellens J. H. M. , Beijnen J. H.
Published: March 2004

A liquid chromatographic/tandem mass spectrometric (LC/MS/MS) assay for the quantitative analysis of the novel anticancer drug ABT‐518 and the screening of six potential metabolites in human plasma has been developed and validated to support a phase I study with the drug. ABT‐518 is an inhibitor of matrix metalloproteinases, which are associated with tumor growth and development of metastasis. Plasma samples were prepared for analysis using a simple solid‐phase extraction method on phenyl cartridges. LC separation was performed on a Zorbax extend C18 column (150 × 2.1 mm i.d., 5 µm particle size) using a mobile phase of methanol–aqueous 10 mM ammonium hydroxide (80:20, v/v) pumped at a flow‐rate of 0.2 ml min−1. An API2000 triple‐quadrupole mass spectrometer was used for specific and sensitive detection. The best chromatographic speed (total run time 8 min) and peak shapes were obtained by employing an alkaline mobile phase (pH in aqueous phase ∼10). Furthermore, an alkaline eluent was favored in order to obtain a better overall sensitivity for the protonated analytes. The dynamic range was from 10 to 1000 ng ml−1 from 500 µl of plasma for ABT‐518 and the metabolites were detected at levels of the same order of magnitude. Inter‐assay accuracies for ABT‐518 at five concentration levels were between −9.24 and 6.93% and inter‐assay precisions were always <10.7%. Analyte stability was not critical during either storage or processing. This method was successfully applied in a phase I clinical study of ABT‐518. The active drug, ABT‐518, and all of the metabolites included in the assay could be identified in plasma from dosed patients. We believe that the method described in this paper using an alkaline mobile phase in combination with a basic stable analytical column may also be generally useful for the bioanalysis of other basic drugs. Copyright © 2004 John Wiley & Sons, Ltd.
Accurate mass measurement and tandem mass spectrometry of intact globin chains identify the low proportion variant hemoglobin Lepore–Boston–Washington from the blood of a heterozygote
Authors: Rai Dilip K. , Green Brian N. , Landin Britta , Alvelius Gunvor , Griffiths William J.
Published: March 2004

Within a mixture of proteins, minor polymorphic components are difficult to identify using a conventional proteomic approach. Their identification generally requires multi‐dimensional separation steps, before or after proteolytic cleavage, followed by sequence analysis of the proteolytic products. In this study, we investigated the potential of tandem mass spectrometry for protein characterization by identifying the δ–β hybrid human hemoglobin variant Lepore–Boston–Washington using electrospray ionization tandem mass spectrometry. Hemoglobin Lepore–Boston–Washington occurs mainly in heterozygotes, where it comprises ∼10% of the total non‐α‐chains, the dominant non‐α‐chain being the normal β(∼90%). Furthermore, Hemoglobin Lepore–Boston–Washington has an average molecular mass (15 865.23 Da) that is only 2 Da lower than that of the normal β‐chain (15 867.24 Da). Consequently, it cannot be resolved from the normal β‐chain by mass spectrometry. Here we show how Hemoglobin Lepore–Boston–Washington was identified directly from the diluted blood of a heterozygote by analyzing the product ions from the Lepore–Boston–Washington and normal β‐chain ions without prior separation of the individual chains. This study shows the potential of the tandem mass spectrometry for identifying a minor component in an unseparated mixture of proteins. Copyright © 2004 John Wiley & Sons, Ltd.
Collision‐induced dissociation of valdecoxib metabolites: a novel rearrangement involving an isoxazole ring
Authors: Zhang Ji Y. , Xu Fran , Breau Alan P.
Published: March 2004

Valdecoxib is a potent COX‐2 inhibitor. During metabolism studies of valdecoxib by liquid chromatography/tandem mass spectrometry, we observed a novel mass spectral rearrangement involving an isoxazole ring for some of the metabolites in the negative ion mode. Accurate mass measurements were performed with quadrupole time‐of‐flight mass spectrometry to determine the elemental compositions of the fragments. Additionally, two types of stable‐isotope labeled analogues were prepared to assist with the assignments of these fragments and possible mechanistic rearrangements resulting from collision‐induced dissociation (CID). Detailed analyses of the CID mass spectra suggest that the fragmentation process involves a novel two‐step rearrangement. The first step consists of an intramolecular SN2 reaction with a five‐membered ring rearrangement to form an intermediate. The second step involves a four‐membered ring intramolecular rearrangement followed by a cleavage of the N—O bond on the isoxazole ring to form a unique fragment ion at m/z 196. The same phenomenon was observed for a group of structurally related metabolites that also contain a 5‐hydroxymethyl or 5‐carboxylic acid moieties. A mechanism for the novel rearrangement involving an isoxazole ring is proposed. Copyright © 2004 John Wiley & Sons, Ltd.
Characterization of the interglycosidic linkage in di‐, tri‐, tetra‐ and pentaglycosylated flavonoids and differentiation of positional isomers by liquid chromatography/electrospray ionization tandem mass spectrometry
Authors: Ferreres F. , Llorach R. , Gil‐Izquierdo A.
Published: March 2004

The LC/UV‐DAD/ESI‐MSn negative fragmentation mode of 23 O‐glycosylated flavonoids with two, three, four and five hexoses was studied. The results show that it is possible to differentiate the (1 → 2) and (1 → 6) interglucosidic linkages and also to discern between the flavonoid isomers with two glucoses (sophorosides, gentiobiosides and X,Y‐diglucosides), three glucoses (sophorotriosides and X‐sophoroside‐Y‐glucoside) and four glucoses (X‐sophorotriosides‐Y‐glucoside and X‐sophoroside‐Y‐sophoroside). In the characterization of the (1 → 2) and (1 → 6) interglycosidic linkages, the Y1− (−162 u) and Z1− (−180 u) ions play a relevant role. In the first case ions with high relative abundance (13–79%) are found, whereas in the other cases they are in very low abundance or absent. X,Y‐di‐O‐glucoside flavonoids can be differentiated from the O‐diglucoside flavonoids by the presence of Y1− (base peak) and Y0− (∼30%) ions and the absence of Z1− ions. Regarding flavonoids glycosylated with three glucoses, X‐sophoroside‐Y‐glucoside flavonoids show the Y70− (−162 u) ion as the only peak in MS2 events whereas in sophorotrioside flavonoids various ions due to intermediate fragmentations are observed. These ions are characteristic of a (1 → 2) interglucosidic linkage. In MS2 experiments on flavonoids with four glucoses (X‐sophorotrioside‐Y‐glucoside and X‐sophoroside‐Y‐sophoroside), the base peak indicated the total loss of the sugar moieties in position 7. In addition, the characterization of the type of interglycosidic linkage in flavonoids glycosylated with five sugars can be achieved. On the other hand, in tetra‐ and pentaglycosylated flavonoids, the ions that characterize the (1 → 2) interglucosidic linkage formed by intermediate fragmentation of the oligosacharide residues (sophorosides and sophorotriosides) are found in much higher relative abundance in MS3 than in MS2 experiments, where they are almost not detected. Copyright © 2004 John Wiley & Sons, Ltd.