bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability of macromolecular complexes
Authors: Brooijmans Natasja , Sharp Kim A. , Kuntz Irwin D.
Published: October 2002

Macromolecular interactions are crucial in numerous biologic processes, yet few general principles are available that establish firm expectations for the strength of these interactions or the expected contribution of specific forces. The simplest principle would be a monotonic increase in interactions as the size of the interface grows. The exact relationship might be linear or nonlinear depending on the nature of the forces involved. Simple “linear–free energy” relationships based on atomic properties have been well documented, for example, additivity for the interaction of small molecules with solvent, and, recently, have been explored for ligand–receptor interactions. Horton and Lewis propose such additivity based on buried surface area for protein–protein complexes. We investigated macromolecular interactions and found that the highest‐affinity complexes do not fulfill this simple expectation. Instead, binding free energies of the tightest macromolecular complexes are roughly constant, independent of interface size, with the notable exception of DNA duplexes. By comparing these results to an earlier study of protein–ligand interactions we find that: (1) The maximum affinity is approximately 1.5 kcal/mol per nonhydrogen atom or 120 cal/mol Å2 of buried surface area, comparable to results of our earlier work; (2) the lack of an increase in affinity with interface size is likely due to nonthermodynamic factors, such as functional and evolutionary constraints rather than some fundamental physical limitation. The implication of these results have some importance for molecular design because they suggest that: (1) The stability of any given complex can be increased significantly if desired; (2) small molecule inhibitors of macromolecular interactions are feasible; and (3) different functional classes of protein–protein complexes exhibit differences in maximal stability, perhaps in response to differing evolutionary pressures. These results are consistent with the widespread observation that proteins have not evolved to maximize thermodynamic stability, but are only marginally stable. Proteins 2002;48:645–653. © 2002 Wiley‐Liss, Inc.
Monte Carlo simulations of the peptide recognition at the consensus binding site of the constant fragment of human immunoglobulin G: The energy landscape analysis of a hot spot at the intermolecular interface
Authors: Verkhivker Gennady M. , Bouzida Djamal , Gehlhaar Daniel K. , Rejto Paul A. , Freer Stephan T. , Rose Peter W.
Published: October 2002

Monte Carlo simulations of molecular recognition at the consensus binding site of the constant fragment (Fc) of human immunoglobulin G (Ig) protein have been performed to analyze structural and thermodynamic aspects of binding for the 13‐residue cyclic peptide DCAWHLGELVWCT. The energy landscape analysis of a hot spot at the intermolecular interface using alanine scanning and equilibrium‐simulated tempering dynamics with the simplified, knowledge‐based energy function has enabled the role of the protein hot spot residues in providing the thermodynamic stability of the native structure to be determined. We have found that hydrophobic interactions between the peptide and the Met‐252, Ile‐253, His‐433, and His‐435 protein residues are critical to guarantee the thermodynamic stability of the crystallographic binding mode of the complex. Binding free energy calculations, using a molecular mechanics force field and a solvation energy model, combined with alanine scanning have been conducted to determine the energetic contribution of the protein hot spot residues in binding affinity. The conserved Asn‐434, Ser‐254, and Tyr‐436 protein residues contribute significantly to the binding affinity of the peptide–protein complex, serving as an energetic hot spot at the intermolecular interface. The results suggest that evolutionary conserved hot spot protein residues at the intermolecular interface may be partitioned in fulfilling thermodynamic stability of the native binding mode and contributing to the binding affinity of the complex. Proteins 2002;48:539–557. © 2002 Wiley‐Liss, Inc.
Design and folding of dimeric proteins
Authors: Tiana Guido , Broglia Ricardo A.
Published: October 2002

In a similar way in which the folding of single‐domain proteins provides an important test in the study of self‐organization, the folding of homodimers constitutes a basic challenge in the quest for the mechanisms that are the basis of biological recognition. Dimerization is studied by following the evolution of two identical 20‐letter amino acid chains within the framework of a lattice model and using Monte Carlo simulations. It is found that when design (evolution pressure) selects few, strongly interacting (conserved) amino acids to control the process, a three‐state folding scenario follows, where the monomers first fold forming the halves of the eventual dimeric interface independently of each other, and then dimerize (“lock and key” kind of association). On the other hand, if design distributes the control of the folding process on a large number of (conserved) amino acids, a two‐state folding scenario ensues, where dimerization takes place at the beginning of the process, resulting in an “induced type” of association. Making use of conservation patterns of families of analogous dimers, it is possible to compare the model predictions with the behavior of real proteins. It is found that theory provides an overall account of the experimental findings. Proteins 2002;49:82–94. © 2002 Wiley‐Liss, Inc.
Herbicide loss following application to a roadside
Authors: Ramwell Carmel T , Heather Andrew I J , Shepherd Anthony J
Published: October 2002

Risk assessments for herbicides applied to roads are limited by the lack of knowledge on the fate and behaviour of the compounds in the urban environment. This study was designed to address this deficiency by quantifying the percentage loss of six herbicides following application to a roadside. Herbicides were applied on two occasions to a 16‐m length of roadside and kerb edge. An automatic water sampler was used to collect run‐off, draining to a single gulley pot, until 25 mm of rain had fallen. Samples were analysed for glyphosate, atrazine, diuron, oxadiazon and oryzalin, and peak concentrations were 650, 2210, 1810, 390 and 70 µg litre−1 respectively. Isoxaben was also applied, but concentrations in run‐off were below the limit of detection (10 µg litre−1). Herbicide concentrations all followed a similar pattern of rapid decline throughout the first rain event following application, with the majority of loss occurring within the first 10 mm of accumulated rainfall, but compounds of high solubility and low Koc produced the highest peak concentrations. For those compounds of relatively low solubility and moderate Koc, application rate may be an influential factor in determining herbicide loss for these compounds. The percentage loss of the active substances applied differed between compounds, ranging from <10% to 73%. The ecotoxicological significance of the results is discussed.

© 2002 Society of Chemical Industry
The strobilurin fungicides
Authors: Bartlett Dave W , Clough John M , Godwin Jeremy R , Hall Alison A , Hamer Mick , Parr‐Dobrzanski Bob
Published: October 2002

Strobilurins are one of the most important classes of agricultural fungicide. Their invention was inspired by a group of fungicidally active natural products. The outstanding benefits they deliver are currently being utilised in a wide range of crops throughout the world. First launched in 1996, the strobilurins now include the world's biggest selling fungicide, azoxystrobin. By 2002 there will be six strobilurin active ingredients commercially available for agricultural use. This review describes in detail the properties of these active ingredients – their synthesis, biochemical mode of action, biokinetics, fungicidal activity, yield and quality benefits, resistance risk and human and environmental safety. It also describes the clear technical differences that exist between these active ingredients, particularly in the areas of fungicidal activity and biokinetics.

© 2002 Society of Chemical Industry
Effects of Melilotus officinalis on acute inflammation
Authors: Pleşca‐Manea Luminiţa , Pârvu Alina Elena , Pârvu M. , Taaˇmaş M. , Buia R. , Puia M.
Published: October 2002

Our study investigated the effects of Melilotus officinalis L. extract, containing 0.25% coumarin, on acute inflammation induced with oil of turpentine in male rabbits. The results were compared with those from a group treated with hydrocortisone sodium hemisuccinate and one injected with coumarin before inflammation was induced. The effects were evaluated by measuring serum citrulline, a test of in vitro phagocytosis, total leukocyte count and differential leukocyte count expressed as a percentage. M. officinalis had antiinflammatory effects because it reduced the activation of circulating phagocytes and lowered citrulline production. These properties were similar to those of hydrocortisone sodium hemisuccinate and coumarin. In the bone marrow acute phase response, M. officinalis had an inhibitory action that was lower than that of hydrocortisone sodium hemisuccinate and similar to coumarin. Copyright © 2002 John Wiley & Sons, Ltd.
Effect of saikosaponin‐A, a triterpenoid glycoside, isolated from Bupleurum falcatum on experimental allergic asthma
Authors: Park Kwan Ha , Park Jongmin , Koh Dongsoo , Lim Yoongho
Published: October 2002

The separation and isolation of an extract of Bupleurum falcatum were performed based on antiallergic activities in preliminary studies with higher plants. The final active compound was identified as saikosaponin‐A (SSA), a triterpenoid glycoside. SSA at more than 1 mg/kg (i.v.) significantly inhibited the passive cutaneous anaphylaxis reaction in rats in a dose‐dependent manner, attaining a maximum inhibition of approximately 60% with 10 mg/kg. SSA at 3 and 10 mg/kg also suppressed asthmatic bronchoconstriction in sensitized guinea‐pigs. SSA possesses a weak inhibitory activity on histamine‐induced tracheal contraction in guinea‐pigs and on histamine release induced by A‐23187 in rat mast cells. These results indicate that SSA has an inhibitory activity against allergic asthma. This activity seems to derive from both antagonism of the histamine action and inhibition of allergic mediators. Additional mechanisms may also be involved. Copyright © 2002 John Wiley & Sons, Ltd.
Globularia alypum L. extracts reduced histamine and serotonin contraction in vitro
Authors: Bello Regina , Moreno Lucrecia , Primo‐Yúfera Eduardo , Esplugues Juan
Published: October 2002

The present study analyses in in vitro models the pharmacological activity of methanol and dichloromethane extracts (1, 10 and 100 μg/mL) obtained from the leaves and stems of Globularia alypum L. Preincubation of the guinea‐pig ileum and rat uterus with both extracts produced a dose dependent abolition of the contractile effects of histamine and serotonin, respectively. At the same doses, neither methanol nor dichloromethane extract reduced the contractile effects of acetylcholine on rat duodenum or noradrenaline on rat vas deferens. Copyright © 2002 John Wiley & Sons, Ltd.
Inhibition of cholesterol biosynthesis in HepG2 cells by artichoke extracts is reinforced by glucosidase pretreatment
Authors: Gebhardt Rolf
Published: October 2002

High‐dose aqueous extracts from artichoke leaves were found to inhibit cholesterol biosynthesis from 14C‐acetate rather moderately in HepG2 cells in contrast to primary cultured rat hepatocytes in which the inhibition was stronger. Preincubation of the extracts with several glycohydrolases revealed that pretreatment with β‐glucosidase considerably reinforced the inhibition. A significant reduction of acetate incorporation was found above extract concentrations of 0.01 mg/mL and at 0.2 mg/mL almost 60% inhibition was observed. Cytotoxic effects detected by the MTT‐assay were restricted to higher concentrations of the extracts with and without β‐glucosidase pretreatment. Since cynaroside represents a major glucoside in artichoke extracts, both cynaroside and its aglycone luteolin were tested. It could be demonstrated that cynaroside is indeed one of the targets of β‐glucosidase and that the liberated luteolin is responsible for the inhibitory effect. Direct measurements of β‐glucosidase activity in rat hepatocytes and HepG2 cells revealed that endogenous enzyme activity in hepatocytes may be sufficient to convert cynaroside to its aglycone, while in HepG2 cells this may not be the case. These findings emphasize the importance of β‐glucosidase‐dependent liberation of luteolin for the ability of artichoke extracts to inhibit hepatic cholesterol biosynthesis. Copyright © 2002 John Wiley & Sons, Ltd.
Influence of co‐monomer structure on properties of co‐polyamide packaging films
Authors: Scarfato P. , Di Maio L. , Incarnato L. , Acierno D. , Mariano A.
Published: October 2002

In this work a series of co‐polyamides were prepared by random polymerization of ϵ‐caprolactam in presence of four different co‐monomers at a percentage of 5% w/w, with the aim of verifying their suitability as film‐forming materials. The effects of structural changes induced in the ϵ‐caprolactam homopolymer by co‐monomers were evaluated in both molten and solid states. Rheological tests in shear and elongational flow were performed to evaluate the processability of co‐polyamides. Cast films were obtained and their thermal, mechanical and transport properties were evaluated to establish the performances of the co‐polyamides in view of packaging applications. The results indicate that co‐polyamide films having a partially aromatic structure display the best mechanical performances and show a significant improvement in barrier properties to gases compared to the homopolymer. Copyright © 2002 John Wiley & Sons, Ltd.
Comparison of flat film to total package water vapour transmission rates for several commercial food wraps
Authors: Steven Matthew D. , Hotchkiss Joseph H.
Published: October 2002

The barrier properties of a package are the sum of material and seal permeations. Although addressed for hermetically sealed and modified atmosphere packages, little consideration of total package permeation has been given to commercial food wraps. Standard protocols were used to compare the water vapour transmission rates (WVTRs) of materials and packages for seven commercial food wraps: aluminum foil; poly(vinylidene chloride) (PVdC) film; three poly(ethylene) (PE) films; an adhesive‐modified PE film; and plasticized poly(vinyl chloride) (PVC) film. Water ingress for a complete package was compared to calculated material permeation based on film WVTRs. Film‐to‐glass adhesion strength was also measured. Model systems (desiccant) were compared to foods at ambient and refrigeration temperatures. Aluminum foil had the lowest material WVTR (0.10 g/h/m2), closely followed by PVdC (0.13 g/h/m2). These WVTRs were approximately five‐fold lower than the PEs (∼0.65 g/h/m2), which were nearly 10‐fold lower than PVC (4.9 g/h/m2). The adhesive‐modified PE film had the lowest difference between material and package transmission rates (0.7 E‐03 g/h), approximately half that of the PVdC film (1.1 E‐03 g/h), which was significantly lower than the remaining films (2.3 E‐03 –3.9 E‐03 g/h). The adhesive PE film had the strongest film–glass adhesion. Ambient food product test results were similar to model system (desiccant) results, but refrigerated trials showed significantly different relative package transmission rates. This was attributed to the reduced adhesion of most wraps at refrigeration temperatures. Copyright © 2002 John Wiley & Sons, Ltd.
Theoretical quantum chemical study of benzoic acid: Geometrical parameters and vibrational wavenumbers
Authors: Palafox M. Alcolea , Núñez J. L. , Gil M.
Published: October 2002

The structure of benzoic acid as monomer was studied by semiempirical, ab initio, and density functional methods using several basis sets. The performance of these methods in calculating and describing the vibrational frequencies of benzoic acid and several derivatives was determined. The cyclic dimer form of benzoic acid was also reproduced. Two new procedures of scaling the frequencies were presented. For the ring modes, specific scale equations and scale factors were used from benzene molecule. For the carboxylic group, scaling equations and specific scale factors at different levels were also determined to be used in benzoic acid derivatives. A reassignment of several bands was done. A comparison of the cost/effective method and procedure of scaling was carried out. A significant reduction of the error in the predicted frequencies was obtained over the one‐factor standard scaling procedure. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002
When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?
Authors: Hoffmann Marcin , Rychlewski Jacek
Published: October 2002

In this article, we deal with the question of whether a fluorine atom can substitute a hydroxyl group in such a way that will lead to a compound showing a desired biologic activity, that is, a potential new drug. It is obvious that a fluorine atom differs from a hydroxyl group, as it cannot donate hydrogen bonds. However, it can accept them. Moreover, both fluorine and oxygen are of similar size and are the most electronegative elements. Therefore, a fluorine atom is thought to be a good substitute for a hydroxyl group. However, it was shown that for conformationally labile aliphatic compounds a replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorine‐containing aliphatic molecules are present in equilibrium at room temperature as a mixture of several different conformers. In contrast, for cyclic compounds the substitution of an OH group by an F atom does not much change shape and electrostatic potential around corresponding conformers. Moreover, these compounds are present in equilibrium at room temperature in aqueous solution as a mixture of the same most favored structures. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002
Study of phenothiazine and N‐methyl phenothiazine by infrared, raman, 1H‐, and 13C‐NMR spectroscopies
Authors: Alcolea Palafox M. , Gil M. , Núñez J. L. , Tardajos G.
Published: October 2002

A complete vibrational analysis of the Fourier transform (FT) infrared (IR) and FT‐Raman spectra of both molecules was carried out using quantum chemical calculations. The structure of phenothiazine (PTZ) and N‐methylphenothiazine (N‐MePTZ) were studied by semiempirical, and ab initio methods. Different basis sets and two new procedures for scaling the frequencies of the ring modes were used. Vibrational data of the methyl group in N‐MePTZ were interpreted in terms of the different molecular conformations in the solid state. The 1H‐ and 13C–nuclear magnetic resonance (NMR) data were interpreted in terms of the electron densities on the atoms and the stacking solute–solute association in dimethyl sulfoxide solution. Chemical shifts were related to the Merz‐Kollman atomic charges. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002
On‐line high‐performance liquid chromatography/mass spectrometric characterization of native oligosaccharides from glycoproteins
Authors: Barroso Begona , Dijkstra Rene , Geerts Marlieke , Lagerwerf Fija , Veelen Peter van , Ru Arnoud de
Published: October 2002

An on‐line high‐performance liquid chromatography/mass spectrometry (HPLC/MS) method is described for the rapid characterization of any type of oligosaccharide released from glycoproteins. The procedure can be applied without further manipulation to fractions collected from a high‐performance anion‐exchange chromatography‐pulse amperometric detection (HPAEC‐PAD) system commonly used for glycosylation mapping of glycoproteins, or to a pool of oligosaccharides directly released from glycoproteins. The system consists of a porous graphitized high‐performance chromatography column (Hypercarb) coupled to a quadrupole time‐of‐flight (TOF) mass spectrometer. Oligosaccharides are eluted from the column with a gradient of ammonium acetate/acetonitrile and directly identified following in‐source fragmentation. Some applications of the method are presented, as well as information about the spectra and fragmentation behavior observed for N‐ and O‐linked oligosaccharides released from some recombinant glycoproteins. Low femtomole limits of detection are achieved using proper miniaturization. Copyright © 2002 John Wiley & Sons, Ltd.
Identification of 1‐hydroxypyrene glucuronide in tissue of marine polychaete Nereis diversicolor by liquid chromatography/ion trap multiple mass spectrometry
Authors: Giessing Anders M. B. , Lund Torben
Published: October 2002

1‐Hydroxypyrene glucuronide is identified as the single major aqueous metabolite of the tetracyclic aromatic hydrocarbon pyrene, in tissue from a deposit‐feeding marine polychaete, Nereis diversicolor. Identification was performed using an ion trap mass spectrometer fitted with an atmospheric pressure chemical ionization (APCI) probe and connected to a high‐performance liquid chromatography/diode array detector (HPLC/DAD) system. Besides 1‐hydroxypyrene, the 339‐nm UV trace of tissue samples from pyrene‐exposed worms showed only one dominant peak that could be related to pyrene metabolism. Negative APCI‐MS of this supposed 1‐ hydroxypyrene conjugate gave a characteristic signal at m/z 429 corresponding to the molecular ion of 1‐hydroxypyrene glucuronide plus eluent adducts ([M − H + 2H2O]−). Fragmentation pathways were studied by isolating the abundant ion at m/z 429 in the ion trap and performing multiple mass spectrometric experiments (MSn). The fragmentations observed were consistent with the proposed identification. Two low intensity LC peaks that could be related to pyrene metabolism by their DAD absorption spectra were also present in the 339‐nm UV chromatogram of tissue samples. However, these peaks could not be identified by their mass spectra in negative ion mode due to ion suppression by very abundant co‐eluting impurities. The present method shows that LC/MSn is a fast and useful analytical tool for identification of aqueous polycyclic aromatic hydrocarbon biotransformation products in samples from relatively small marine invertebrates with limited sample preparation. Copyright © 2002 John Wiley & Sons, Ltd.
Identification of the main by‐products of the developing agent N‐hydroxyethyl‐N‐ethyl‐3‐methyl‐p‐phenylenediamine in photographic effluents by liquid chromatography/mass spectrometry
Authors: Lunar Loreto , Rubio Soledad , Pérez‐Bendito Dolores , Jiménez César
Published: October 2002

N‐Hydroxyethyl‐N‐ethyl‐3‐methyl‐p‐phenylenediamine (CD4) is commonly used as a developing agent in color photographic processes. The main by‐products formed in developer baths used in the process were separated and identified by liquid chromatography/electron ionization mass spectrometry (LC/EI‐MS) and liquid chromatography/atmospheric pressure ionization mass spectrometry (LC/API‐MS). A number of side reactions, in addition to the main reactions involved in the developing process, were found to occur. Such side reactions involved in the formation of CD4 by‐products included oxidation, hydroxylation, sulfonation and the formation of coupling products. A reaction pathway for the degradation of CD4 based on the nature of the by‐products identified is proposed and discussed. Copyright © 2002 John Wiley & Sons, Ltd.
SITE Demonstration of Enhanced In‐Situ Bioremediation of Chlorinated and Nonchlorinated Organic Compounds in Fractured Bedrock
Authors: Gallardo Vicente J. , Beckman Scott W. , Tillman Joseph W.
Published: October 2002

A field demonstration of an enhanced in‐situ bioremediation technology was conducted between March 1998
and August 1999 at the ITT Industries Night Vision (ITTNV) Division plant in Roanoke, Virginia. The
bioremediation process was evaluated for its effectiveness in treating both chlorinated and nonchlorinated
volatile organic compounds (VOCs) in groundwater located in fractured bedrock. Chlorinated compounds,
such as trichloroethene (TCE), in fractured bedrock pose a challenging remediation problem. Not only are
chlorinated compounds resistant to normal biological degradation, but the fractured bedrock presents difficulties
to traditional techniques used for recovery of contaminants and for delivery of amendments or reagents for
in‐situ remediation.

The demonstration was conducted under the U.S. Environmental Protection Agency's Superfund Innovative
Technology Evaluation (SITE) program. The SITE program was established to promote the development,
demonstration, and use of innovative treatment technologies for the cleanup of Superfund and other hazardous waste
sites. This article presents selected results of the demonstration and focuses on understanding the data in light
of the fractured bedrock formation. © 2002 Wiley Periodicals, Inc.
Changes in fish communities of the Shoalhaven River 20 years after construction of Tallowa Dam, Australia
Authors: Gehrke P. C. , Gilligan D. M. , Barwick M.
Published: October 2002

This study was undertaken as part of a long‐term investigation of the ability of high‐level fishways to rehabilitate fish communities upstream of high dams. Effects of Tallowa Dam on fish of the Shoalhaven River system were studied by comparing species abundances, population size‐structures and the structure of fish communities above and below the dam. Fish were sampled twice yearly for two years at 12 sites throughout the catchment. Species richness was greater downstream of the dam, with 21 species, compared to 16 species upstream of the dam. Ten diadromous species are believed to be extinct above the dam because of obstructed fish passage. Another four migratory species capable of climbing the wall have reduced abundances upstream. Accumulations of fish, particularly juveniles, directly below the dam were evident for nine species. Fish communities upstream and downstream of the dam differed significantly, identifying the dam as a significant discontinuity in the available fish habitats within the system. Historical evidence suggests that before the dam was built, fish communities from the tidal limit to at least 130 m elevation were largely continuous. This study has demonstrated that Tallowa Dam is a major barrier to fish migration and has had adverse effects on the biodiversity of the system. The creation of Lake Yarrunga by Tallowa Dam has resulted in distinctive fish communities in riverine and lacustrine habitats. Populations of five species that occur both upstream and downstream of the dam have developed differences in their size structures. The fish community downstream of the dam also differs from its historical condition because of the virtual disappearance of Australian grayling (Prototroctes maraena) and the establishment of non‐native species.

A high‐level fishway is now being designed for the dam to restore fish passage. Data from this study will serve as a baseline against which to assess the effectiveness of the fishway in rehabilitating fish communities of the river system. Copyright © 2002 John Wiley & Sons, Ltd.
Meaningful learning: The essential factor for conceptual change in limited or inappropriate propositional hierarchies leading to empowerment of learners
Authors: Novak Joseph D.
Published: October 2002

The construction and reconstruction of meanings by learners requires that they actively seek to integrate new knowledge with knowledge already in their cognitive structure. Ausubel's assimilation theory of cognitive learning has been shown to be effective in guiding research and instructional design to facilitate meaningful learning (Ausubel, The psychology of meaningful verbal learning, New York: Grune and Stratton, 1963; Educational psychology: A cognitive view, New York: Holt, Rinehart and Winston, 1968; The acquisition and retention of knowledge, Dordrecht: Kluwer, 2000). Gowin's Vee heuristic has been employed effectively to aid teachers and students in understanding the constructed nature of knowledge (Gowin, Educating, Ithaca, NY: Cornell University Press, 1981). “Situated learning” occurs when learning is by rote or at a lower level of meaningful learning. Concept mapping has been used effectively to aid meaningful learning with resulting modification of student's knowledge structures. When these knowledge structures are limited or faulty in some way, they may be referred to as Limited or Inappropriate Propositional Hierarchies (LIPH's). Conceptual change, or more accurately conceptual reconstrution, requires meaningful learning to modify LIPH's. Collaborative group learning facilitates meaningful learning and new knowledge construction. World‐wide economic changes are forcing major changes in business and industry placing a premium on the power and value of knowledge and new knowledge production. These changes require changes in school and university education that centers on the nature and power of meaningful learning. New computer tools are available to facilitate teaching activities targeted at modifying LIPH's, and aiding meaningful learning in general. © 2002 Wiley Periodicals, Inc. Sci Ed 86:548–571, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/sce.10032
Diagnostics for conformity of paired quantitative measurements
Authors: Hawkins Douglas M.
Published: October 2002

Matched pairs data arise in many contexts – in case‐control clinical trials, for example, and from cross‐over designs. They also arise in experiments to verify the equivalence of quantitative assays. This latter use (which is the main focus of this paper) raises difficulties not always seen in other matched pairs applications. Since the designs deliberately vary the analyte levels over a wide range, issues of variance dependent on mean, calibrations of differing slopes, and curvature all need to be added to the usual model assumptions such as normality. Violations in any of these assumptions invalidate the conventional matched pairs analysis. A graphical method, due to Bland and Altman, of looking at the relationship between the average and the difference of the members of the pairs is shown to correspond to a formal testable regression model. Using standard regression diagnostics, one may detect and diagnose departures from the model assumptions and remedy them – for example using variable transformations. Examples of different common scenarios and possible approaches to handling them are shown. Copyright © 2002 John Wiley & Sons, Ltd.
A solution to the problem of separation in logistic regression
Authors: Heinze Georg , Schemper Michael
Published: October 2002

The phenomenon of separation or monotone likelihood is observed in the fitting process of a logistic model if the likelihood converges while at least one parameter estimate diverges to ± infinity. Separation primarily occurs in small samples with several unbalanced and highly predictive risk factors. A procedure by Firth originally developed to reduce the bias of maximum likelihood estimates is shown to provide an ideal solution to separation. It produces finite parameter estimates by means of penalized maximum likelihood estimation. Corresponding Wald tests and confidence intervals are available but it is shown that penalized likelihood ratio tests and profile penalized likelihood confidence intervals are often preferable. The clear advantage of the procedure over previous options of analysis is impressively demonstrated by the statistical analysis of two cancer studies. Copyright © 2002 John Wiley & Sons, Ltd.
Estimating the causal effect of zidovudine on CD4 count with a marginal structural model for repeated measures
Authors: Hernán Miguel A. , Brumback Babette A. , Robins James M.
Published: October 2002

Even in the absence of unmeasured confounding factors or model misspecification, standard methods for estimating the causal effect of a time‐varying treatment on the mean of a repeated measures outcome (for example, GEE regression) may be biased when there are time‐dependent variables that are simultaneously confounders of the effect of interest and are predicted by previous treatment. In contrast, the recently developed marginal structural models (MSMs) can provide consistent estimates of causal effects when unmeasured confounding and model misspecification are absent. We describe an MSM for repeated measures that parameterizes the marginal means of counterfactual outcomes corresponding to prespecified treatment regimes. The parameters of MSMs are estimated using a new class of estimators – inverse‐probability of treatment weighted estimators. We used an MSM to estimate the effect of zidovudine therapy on mean CD4 count among HIV‐infected men in the Multicenter AIDS Cohort Study. We estimated a potential expected increase of 5.4 (95 per cent confidence interval ‐1.8,12.7) CD4 lymphocytes/l per additional study visit while on zidovudine therapy. We also explain the theory and implementation of MSMs for repeated measures data and draw upon a simple example to illustrate the basic ideas. Copyright © 2002 John Wiley & Sons, Ltd.
Analysis of mutational spectra: locating hotspots and clusters of mutations using recursive segmentation
Authors: Fijal Bonnie A. , Idury Ramana M. , Witte John S.
Published: October 2002

Mutations within different regions of disease‐causing genes can vary in their impact on disease initiation and progression. Determining how individual mutations within such genes affect disease risk and progression can improve the accuracy of prognoses and help guide treatment selection. Estimates of mutation‐specific risks can be poor, however, when genes have a large number of distinct mutations, and data for any given mutation is sparse. To address this problem, we present here a method of analysing the spectrum of mutations observed across a gene that pools together mutations that appear to have similar effects on disease. One of the assumptions underlying the analysis of mutational spectra created in this manner is that the frequency of the mutation in the sample reflects the degree of its effect on disease development. Additionally, mutations that disrupt the same functionally important region of the gene are expected to have a similar impact on disease development. These mutations tend to form a cluster within the spectrum. Therefore, we developed an algorithm that segments a spectrum into regions containing sites with similar mutational frequencies, and have derived by simulation equations that allow one to evaluate whether segmentation is needed. We used this approach to investigate the spectrum of mutations observed in the p53 tumour suppressor gene in colorectal cancer tumours. Here, recursive segmentation identified the boundaries of apparent clusters better than did other methods, and this approach could identify clusters of mutations which corresponded to biologically important regions of the p53 protein. Copyright © 2002 John Wiley & Sons, Ltd.
Meta‐analysis combining parallel and cross‐over clinical trials. I: Continuous outcomes
Authors: Curtin François , Altman Douglas G. , Elbourne Diana
Published: October 2002

Among clinical trials assessing a given treatment, often parallel and cross‐over designs are used together. In the first paper of a series of three, we explore two methods to pool continuous outcomes in a meta‐analysis combining parallel and cross‐over trial designs: the weighted mean difference (WMD) and the standardized weighted mean difference (SWMD). The combined design meta‐analytic formulae are based on a weighted average of the two design treatment estimates. A random effects model can be implemented. Both WMD and SWMD can be used, the choice of the method is determined by the type of outcomes obtained in the trials. Compared to the number of included subjects, the relative weight of the cross‐over design is large in combined‐design meta‐analysis. Differences in the weight estimation between WMD and SWMD can also accentuate the relative weight of cross‐over trials, which must be considered a case of design‐specific bias. Copyright © 2002 John Wiley & Sons, Ltd.
Edith Penrose's contribution to the resource‐based view of strategic management
Authors: Rugman Alan M. , Verbeke Alain
Published: October 2002

Edith Penrose's (1959) book,The Theory of the Growth of the Firm, is considered by many scholars in the strategy field to be the seminal work that provided the intellectual foundations for the modern, resource‐based theory of the firm. However, the present paper suggests that Penrose's direct or intended contribution to resource‐based thinking has been misinterpreted. Penrose never aimed to provide useful strategy prescriptions for managers to create a sustainable stream of rents; rather, she tried to rigorously describe the processes through which firms grow. In her theory, rents were generally assumed not to occur. If they arose this reflected an inefficient macro‐level outcome of an otherwise efficient micro‐level growth process. Nevertheless, her ideas have undoubtedly stimulated ‘good conversation’ within the strategy field in the spirit of Mahoney and Pandian (1992); their emerging use by some scholars as building blocks in models that show how sustainable competitive advantage and rents can be achieved is undeniable, although such use was never intended by Edith Penrose herself. Copyright © 2002 John Wiley & Sons, Ltd.
Competitive advantages exist: a critique of Powell
Authors: Durand Rodolphe
Published: October 2002

This response is a plea for considering cautiously the use of formal logic and philosophy in strategic management. In a recent article, logical and philosophical considerations on the relationship between competitive advantage and superior returns led to a pragmatic view of competitive advantage. First, we propose a different logical analysis of the links between competitive advantage and superior performance. Using the same premises, this analysis leads to different conclusions. Second, our commentaries suggest that philosophy should be employed for opening discussions and perspectives rather than as an instrument for conviction. Copyright © 2002 John Wiley & Sons, Ltd.
Managing change in student affairs leadership roles
Authors: Dalton Jon C. , Imanuel Gardner Diana
Published: October 2002

Managing change is one of the most complex skills of leadership. This chapter examines some of the most difficult changes confronted by student affairs leaders and the practical wisdom they have gained from these encounters.
The moral domain of student affairs leadership
Authors: Thomas William
Published: October 2002

Student affairs leaders describe why ethical considerations are so critical for making tough decisions and resolving complex problems in everyday work.
Nuggets of practical wisdom
Authors: Dalton Jon C. , Trexler Alicia
Published: October 2002

The authors offer a compilation of maxims, advice, and anecdotes that convey some essential truths they have learned about professional leadership in student affairs.
Region‐specific targeting of dopamine D2‐receptors and somatodendritic vesicular monoamine transporter 2 (VMAT2) within ventral tegmental area subdivisions
Authors: Pickel Virginia M. , Chan June , Nirenberg Melissa J.
Published: October 2002

Throughout the ventral tegmental area (VTA), dopamine is packaged within subcellular organelles by the vesicular monoamine transporter‐2 (VMAT2). Somatodendritically released dopamine in this region binds to the D2 receptor (D2R) to modulate ongoing neurotransmission. Although autoregulation of mesocortical dopaminergic neurons in the parabrachial VTA (PB‐VTA) is known to be less efficacious than that of mesolimbic dopaminergic neurons in the paranigral (PN‐VTA), the cellular basis for this regional heterogeneity is not known. For this reason, we used electron microscopic immunocytochemistry to determine the subcellular localization of the dopamine storage vesicles (identified by the presence of VMAT2) in relation to the D2R in these VTA subdivisions. In both regions, D2R immunoreactivity was principally located on extrasynaptic dendritic plasma membranes near excitatory‐type synapses. Equivalent percentages (72 and 74%) of the D2R‐labeled dendrites in each region contained VMAT2‐immunoreactive tubulovesicles. Of the total VMAT2‐labeled dendrites, however, a significantly lower percentage in the PB‐VTA (26%) than in the PN‐VTA (38%) contained D2R labeling. In contrast, a significantly higher number of VMAT2 immunogold‐silver deposits was seen within individual dendrites in the PB‐VTA than in PN‐VTA. In both regions, D2R immunoreactivity was also detected in VMAT2‐negative axon terminals that formed synapses on dendrites containing VMAT2. Our results are the first to demonstrate that within VTA neurons and their afferents the D2R is strategically positioned for activation by dopamine released from dendritic storage vesicles. These findings also suggest that the potential for D2R activation may affect the expression levels of VMAT2 in VTA dendrites. Synapse 45:113–124, 2002. © 2002 Wiley‐Liss, Inc.
Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization
Authors: Miró Xavier , Pérez‐Torres Silvia , Puigdomènech Pere , Palacios José M. , Mengod Guadalupe
Published: October 2002

cAMP plays an important role as a second‐messenger molecule controlling multiple cellular processes. Its hydrolysis provides an important mechanism by which cAMP levels are regulated. This is performed by a large multigene family of cyclic nucleotide phosphodiesterases (PDEs). Members of the PDE4 enzyme family are selectively inhibited by rolipram. Five different mRNA splice forms for PDE4D have been isolated. Here, we analyzed the regional distribution of the mRNAs coding for the splice variants PDE4D1, PDE4D2, PDE4D3, PDE4D4, and PDE4D5 in the rat brain by in situ hybridization histochemistry using specific radiolabeled oligonucleotides. We found that all five splice variants showed a distinct distribution pattern and, in some cases, in association with specific brain pathways. The most relevant differences were in hippocampal formation, medial habenula, basal ganglia, and area postrema, at both the regional and cellular level. The dorsal and median raphe nuclei exclusively contained PDE4D2 mRNA transcripts, probably located on serotonergic cells. PDE4D1 mRNA was expressed in some white matter cells. PDE4D1 and PDE4D2 mRNA splice forms presented a similar distribution in the area postrema, whereas for PDE4D4 and PDE4D5 the cellular distribution presented a complementary pattern. The differential expression of PDE4D mRNA splice variants in the area postrema is consistent with their possible involvement in emesis control and suggests new molecular targets for a more selective drug design. Synapse 45:259–269, 2002. © 2002 Wiley‐Liss, Inc.
Fear‐like biochemical and behavioral responses in rats to the predator odor, TMT, are dependent on the exposure environment
Authors: Morrow Bret A. , Elsworth John D. , Roth Robert H.
Published: October 2002

Several laboratories have reported that exposure to predator odor can result in stress‐like effects in rodents. While some laboratories have reported fear‐like alterations in behavior, other laboratories, including our own, have failed to consistently observe fearful behaviors in rats exposed to the predator odor TMT. One potential contributing factor to this discrepancy is the handling of the rat and its test environment. In the current report, we examine biochemical, endocrinological, and behavioral effects of TMT in two distinct open fields: one small, familiar, and dimly lit, while the other was large, novel, and brightly lit. Only exposure to TMT in the large, novel open field resulted in fearful behavior; however, no increase in dopamine turnover was noted compared to no odor and control odor rats. As expected, the different open fields resulted in some biochemical and behavioral differences, including more horizontal locomotion and less grooming, higher serum corticosterone, and increased dopamine turnover in the ventral prefrontal cortex in the large open field. Finally, compared to the same open field controls, TMT exposure elevated rat serum corticosterone levels in both open fields and dopamine turnover in the dorsal and ventral medial prefrontal cortex and amygdala of rats only in the small, familiar open field. These results indicate that the TMT‐induced biochemical activation of may occur without detectable fearful behaviors and may indicate a mechanism that prepares the animal for the expression of a fearful response if additional provocative stimuli are present. Synapse 46:11–18, 2002. © 2002 Wiley‐Liss, Inc.
High‐Throughput Approaches for the Discovery and Optimization of New Olefin Polymerization Catalysts
Authors: Murphy Vince , Bei Xiaohong , Boussie Thomas R. , Brümmer Oliver , Diamond Gary M. , Goh Christopher , Hall Keith A. , Lapointe Anne M. , Leclerc Margarete , Longmire James M. , Shoemaker James A.W. , Turner Howard , Weinberg W. Henry
Published: October 2002

The discovery of new olefin polymerization catalysts is currently a time‐intensive trial‐and‐error process with no guarantee of success. A fully integrated high‐throughput screening workflow for the discovery of new catalysts for polyolefin production has been implemented at Symyx Technologies. The workflow includes the design of the metal–ligand libraries using custom–made computer software, automated delivery of metal precursors and ligands into the reactors using a liquid‐handling robot, and a rapid primary screen that serves to assess the potential of each metalligand‐activator combination as an olefin polymerization catalyst. “Hits” from the primary screen are subjected to secondary screens using a 48‐cell parallel polymerization reactor. Individual polymerization reactions are monitored in real time under conditions that provide meaningful information about the performance capabilities of each catalyst. Rapid polymer characterization techniques support the primary and secondary screens. We have discovered many new and interesting catalyst classes using this technology. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc., Chem Rec 2: 278–289; 2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10025
Molecular Sieving and Sensing with Gold Nanotube Membranes
Authors: Wirtz Marc , Parker Matthew , Kobayashi Yoshio , Martin Charles R.
Published: October 2002

We have developed a new class of synthetic membranes that consist of a porous polymeric support that contains an ensemble of gold nanotubes that span the thickness of the support membrane. The support is a commercially available microporous polycarbonate filter with cylindrical nanoscopic pores. The gold nanotubes are prepared via electroless deposition of Au onto the pore walls; i.e., the pores act as templates for the nanotubes. We have shown that by controlling the Au deposition time, Au nanotubes that have effective inside diameters of molecular dimensions (<1 nm) can be prepared. These nanotube membranes can be used to cleanly separate small molecules on the basis of molecular size. Furthermore, use of these membranes as a novel electrochemical sensor is also discussed. This new sensing scheme involves applying a constant potential across the Au nanotube membrane and measuring the drop in the transmembrane current upon the addition of the analyte. This paper reviews our recent progress on size‐based transport selectivity and sensor applications in this new class of membranes. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2:259–267, 2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10027