bluuebunny/crossref_metadata_2025 huggingface dataset:
Intermediate cells in normal and malignant prostate epithelium express c‐MET: Implications for prostate cancer invasion
Authors: van Leenders Geert , van Balken Bianca , Aalders Tilly , Hulsbergen‐van de Kaa Christina , Ruiter Dirk , Schalken Jack
Published: August 2002

BACKGROUND

Analysis of keratin (K) expression discriminates luminal (K18) and intermediate (K5/18) cells in prostate carcinoma, while basal (K5/14) cells are absent. Intermediate cells have been proposed as targets of malignant transformation in prostate cancer and precursors of androgen‐independent tumor progression. We demonstrate localization of hepatocyte growth factor (HGF) receptor c‐MET in intermediate cells in both normal and malignant prostate epithelium.

METHODS

Receptor localization was analyzed using triple staining for c‐MET, K5, K14, and K18. The percentage of strongly c‐MET positive cells was determined in 15 prostate cancer patients undergoing androgen‐deprivation and 14 patients without neo‐adjuvant treatment. Effects of HGF were investigated on prostate cancer cell line DU145.

RESULTS

c‐MET expression in non‐malignant epithelium was strong in intermediate cells absent in differentiated cells, and heterogeneous in basal cells. In prostate cancer, intermediate cells displayed high c‐MET levels coupled with mild expression in differentiated cells. During androgen‐deprivation, 7.6% of tumor cells revealed high c‐MET expression compared to 1.7% without treatment (P = 0.02). Matrigel penetration of DU145 was 8.2 ± 1.7 mm2 after HGF stimulation compared to 3.6 ± 2.4 mm2 in controls (P < 0.02).

CONCLUSIONS

Intermediate cells in normal and malignant prostate epithelium express high c‐MET levels, indicating that they are prone to stromal invasion in prostate carcinoma. Prostate 51: 98–107, 2002. © 2002 Wiley‐Liss, Inc.
PEAZ‐1: A new human prostate neoplastic epithelial cell line
Authors: Schmelz Monika , Cress Anne E. , Barrera Jean , McDaniel Kathy M. , Davis Tracy L. , Fuchs Laura , Dalkin Bruce L. , Nagle Raymond B.
Published: August 2002

BACKGROUND

The generation of prostatic cell lines provides in vitro models for experimental studies of the pathogenesis of prostate carcinoma. Therefore, we established and characterized a new human prostate epithelial cell line, PEAZ‐1 (prostate epithelial Arizona‐1).

METHODS

The PEAZ‐1 cells were grown from a primary human prostate carcinoma specimen obtained from radical prostatectomy. The isolated cells were characterized by immunobiochemistry, immunohistochemistry, and tumorigenicity studies.

RESULTS

PEAZ‐1 cells are near diploid, tumorigenic, and androgen independent for cell growth. PEAZ‐1 cells express N‐cadherin, α‐ and β‐catenins, and p120 at cell–cell contacts, cytoplasmic laminin 5, vinculin, paxillin, and phosphotyrosine at focal adhesions, vimentin, and cytokeratins 8 and 18. They do not express plakoglobin, E‐cadherin, and PSA, and do not form desmosomes and hemidesomomes. PEAZ‐1 respond to ocadaic acid, a pro‐apoptotic agent, by expression of p53.

CONCLUSIONS

PEAZ‐1 cells is a human prostate cancer cell line that has a number of mesenchymal characteristics. Prostate 48:79–92, 2001. © 2001 Wiley‐Liss, Inc.
Classification of proteins based on the properties of the ligand‐binding site: The case of adenine‐binding proteins
Authors: Cappello Valentina , Tramontano Anna , Koch Uwe
Published: August 2002

Comparative analysis of protein binding sites for similar ligands yields information about conserved interactions, relevant for ligand affinity, and variable interactions, which are important for specificity. The pattern of variability can indicate new targets for a pharmacologically validated class of compounds binding to a similar site. A particularly vast group of therapeutically interesting proteins using the same or similar substrates are those that bind adenine‐containing ligands. Drug development is focusing on compounds occupying the adenine‐binding site and their specificity is an issue of paramount importance. We use a simple scheme to characterize and classify the adenine‐binding sites in terms of their intermolecular interactions, and show that this classification does not necessarily correspond to protein classifications based on either sequence or structural similarity. We find that only a limited number of the different hydrogen bond patterns possible for adenine‐binding is used, which can be utilized as an effective classification scheme. Closely related protein families usually share similar hydrogen patterns, whereas non‐polar interactions are less well conserved. Our classification scheme can be used to select groups of proteins with a similar ligand‐binding site, thus facilitating the definition of the properties that can be exploited to design specific inhibitors. Proteins 2002;47:106–115. © 2002 Wiley‐Liss, Inc.
Population analyses of kinetic partitioning in protein folding
Authors: Nakamura Hironori K. , Sasai Masaki
Published: August 2002

A simple lattice model of protein folding is studied in order to analyze the kinetic partitioning phenomena in the energy landscape perspective. By restricting the area of conformational space, it becomes possible to follow many Monte Carlo trajectories until they reach equilibrium. Alteration of population of trajectories is monitored and the relations between the energy landscape and kinetics are examined. Kinetic partitioning phenomena are categorized into different types in terms of characteristic time constants and partitioning ratio. In a specific partitioning process, refolding proceeds along the parallel pathways; the time constants have a temperature dependence similar to that observed in hen lysozyme. High‐energy conformations are classified into groups according to the probability that the trajectories starting from those conformations will reach each energy valley. The partitioning ratio is determined by the way in which the conformational space is organized into these groups. Proteins 2001;43:280–291. © 2001 Wiley‐Liss, Inc.
Structural implications of drug‐resistant mutants of HIV‐1 protease: High‐resolution crystal structures of the mutant protease/substrate analogue complexes
Authors: Mahalingam Bhuvaneshwari , Louis John M. , Hung Jason , Harrison Robert W. , Weber Irene T.
Published: August 2002

Emergence of drug‐resistant mutants of HIV‐1 protease is an ongoing problem in the fight against AIDS. The mechanisms governing resistance are both complex and varied. We have determined crystal structures of HIV‐1 protease mutants, D30N, K45I, N88D, and L90M complexed with peptide inhibitor analogues of CA–p2 and p2–NC cleavage sites in the Gag–pol precursor in order to study the structural mechanisms underlying resistance. The structures were determined at 1.55–1.9‐Å resolution and compared with the wild‐type structure. The conformational disorder seen for most of the hydrophobic side‐chains around the inhibitor binding site indicates flexibility of binding. Eight water molecules are conserved in all 9 structures; their location suggests that they are important for catalysis as well as structural stability. Structural differences among the mutants were analyzed in relation to the observed changes in protease activity and stability. Mutant L90M shows steric contacts with the catalytic Asp25 that could destabilize the catalytic loop at the dimer interface, leading to its observed decreased dimer stability and activity. Mutant K45I reduces the mobility of the flap and the inhibitor and contributes to an enhancement in structural stability and activity. The side‐chain variations at residue 30 relative to wild‐type are the largest in D30N and the changes are consistent with the altered activity observed with peptide substrates. Polar interactions in D30N are maintained, in agreement with the observed urea sensitivity. The side‐chains of D30N and N88D are linked through a water molecule suggesting correlated changes at the two sites, as seen with clinical inhibitors. Structural changes seen in N88D are small; however, water molecules that mediate interactions between Asn88 and Thr74/Thr31/Asp30 in other complexes are missing in N88D. Proteins 2001;43:455–464. © 2001 Wiley‐Liss, Inc.
Differential effects of isomeric incorporation of fluorophenylalanines into PvuII endonuclease
Authors: Dominguez Miguel A. , Thornton Kevin C. , Melendez Maria G. , Dupureur Cynthia M.
Published: August 2002

Incorporation of fluorine into proteins has long served as a means of probing structure and function, yet there are few studies that examine the impact of fluorine substitution, particularly at locations distant from the active sites of enzymes. The flexibility of isomeric fluorine incorporation at Phe is used to explore subtle substitution effects on enzyme activity and conformation. The unnatural amino acids o‐, m‐, and p‐fluorophenylalanines were incorporated biosynthetically into the representative PvuII restriction endonuclease. Interestingly, m‐fluoro‐Phe‐PvuII endonuclease exhibits very similar conformational stability to that of the native enzyme, but it exhibits a reproducible, 2‐fold higher average specific activity. Given the level of incorporation and the distribution of species, the species of modified enzyme responsible for this increase in specific activity is most likely even faster. Further, moving the fluorine atom from the meta‐ to the para‐position of Phe results in a 4‐fold decrease in specific activity and a decrease in conformational stability of 1.5 kcal/mol. Since none of the Phe residues in PvuII endonuclease lies near the DNA recognition or catalytic sites, this differential behavior alludes to the impact of subtle changes in enzyme conformation on endonuclease activity and suggests novel ways to influence catalytic behavior. Proteins 2001;45:55–61. © 2001 Wiley‐Liss, Inc.
Filling a cavity dramatically increases pressure stability of the c‐Myb R2 subdomain
Authors: Lassalle Michael W. , Yamada Hiroaki , Morii Hisayuki , Ogata Kazuhiro , Sarai Akinori , Akasaka Kazuyuki
Published: August 2002

Cavities or packing defects in proteins may generally be related with the dynamics and function of a protein. In the c‐Myb R2 subdomain, its single cavity has been shown to be crucial for its DNA recognition. Cavities are also considered important in determining the pressure stability of a protein. In the present work, high‐pressure proton nuclear magnetic resonance (1H NMR) spectroscopy at 750 MHz is used to study the effect of a cavity‐filling mutation (V103L) on the stability of the c‐Myb R2 subdomain in the pressure range between 1 and 3,700 bar at 5°C. A dramatic increase in the pressure stability of the c‐Myb R2 subdomain is attained, from which we estimate the cavity size to be 35.3 Å3, in good agreement with literature values. We also evaluated the increase in thermodynamic stability ΔGfrom 5.35 kJ/mol to 7.34 kJ/mol by the mutation, giving a clear example of the effect of a cavity on the global stability of a globular protein. Proteins 2001;45:96–101. © 2001 Wiley‐Liss, Inc.
Degradation of herbicides in shallow Danish aquifers: an integrated laboratory and field study
Authors: Albrechtsen Hans‐Jørgen , Mills Margaret S , Aamand Jens , Bjerg Poul L
Published: August 2002

Degradation of pesticides in aquifers has been evaluated based on a number of co‐ordinated field and laboratory studies carried out in Danish aquifers. These studies included investigations of vertical and horizontal variability in degradation rates from the vadose zone to an aquifer, the effects of aerobic versus anaerobic conditions, and the importance of concentration on degradation kinetics for a selected range of herbicides. The studies were based on different experimental approaches ranging from simple batch experiments to column studies to field injection experiments and, where appropriate, results were compared. Some herbicides were degraded under aerobic conditions (some phenoxy acids, DNOC and glyphosate) and others under aerobic conditions (other phenoxy acids, DNOC; there was some indication of atrazine transformation). Certain pesticides were not degraded in any investigations (dichlobenil, the dichlobenil metabolite 2,6‐dichlorobenzamide (BAM), bentazone, isoproturon, metamitron and metsulfuron‐methyl). The spatial variability was substantial, since hardly any of the investigated pesticides were degraded in all comparable samples. This means that it is very difficult to claim that a given pesticide is readily degradable in aquifers. However, the experimental approaches used (with incubations lasting more than a year) may not be sensitive enough to verify the low degradation rates that may be significant as a result of the long retention time of groundwaters.

© 2001 Society of Chemical Industry
Prediction of pesticide concentrations found in rivers in the UK
Authors: Brown Colin D , Bellamy Pat H , Dubus Igor G
Published: August 2002

SWATCATCH is a distributed model combined with databases within a GIS as the POPPIE system to predict pesticide concentrations in rivers at the catchment outlet. The model was evaluated against a dataset of pesticide concentrations in rivers of England and Wales. More than 2000 individual analyses in each of the years 1995 and 1997 covered approximately 150 catchment–pesticide combinations drawn from 29 catchments and 16 pesticides, themselves selected to represent a range of characteristics and properties. SWATCATCH was better able to simulate maximum pesticide concentrations at any time during the year than the proportion of samples containing residues of a particular pesticide above the limit of quantification. The model simulated maximum pesticide concentrations in surface waters which were within a factor of 10 of those observed for 66–74% of catchment–pesticide–year combinations. Simulated and observed frequency of detection could not be differentiated using a χ2 test for 54–67% of simulations. Time series analysis for seven of the 29 catchment–pesticide combinations indicated that measured and detected series of concentrations generally followed similar patterns. The evaluation supports the intended use of the model in assisting the construction of pesticide monitoring programmes.

© 2002 Society of Chemical Industry
Antioxidant and hepatoprotective effects of punicalagin and punicalin on acetaminophen‐induced liver damage in rats
Authors: Lin Chun‐Ching , Hsu Yu‐Fang , Lin Ta‐Chen , Hsu Hsue‐Yin
Published: August 2002

Punicalagin and punicalin were isolated from the leaves of Terminalia catappa L., a Combretaceous plant distributed throughout tropical and subtropical beaches, which is used for the treatment of dermatitis and hepatitis. Our previous studies showed that both of these compounds exert antioxidative activity. In this study, the antihepatotoxic activity of punicalagin and punicalin on acetaminophen‐induced toxicity in the rat liver was evaluated. After evaluating the changes of several biochemical functions in serum, the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased by acetaminophen administration and reduced by punicalagin and punicalin. Histological changes around the hepatic central vein and oxidative damage induced by acetaminophen were also recovered by both compounds. The data show that both punicalagin and punicalin exert antihepatotoxic activity, but treatment with larger doses enhanced liver damage. These results suggest that even if punicalagin and punicalin have antioxidant activity at small doses, treatment with larger doses will possibly induce some cell toxicities. Copyright © 2001 John Wiley & Sons, Ltd.
Heteropteris aphrodisiaca O. Machado : effects of Extract BST 0298 on the oxidative stress of young and old rat brains
Authors: Mattei Rita , Paz Barros Marcelo , Pereira Galvão Suzana Maria , Bechara Etelvino José Henriques , de Araujo Carlini Elisaldo Luiz
Published: August 2002

The plant Heteropteris aphrodisiaca O. Machado is widely employed in Brazilian popular medicine as a stimulant, a tonic and a remedy for nervous debility. Several other plant products with similar therapeutic applications may have such effects based on the antioxidant content of polyphenols (gallates, cathecols, etc.) and flavonoids. The aim of this work was to investigate the effects of Heteropteris aphrodisiaca O. Machado extracts on the antioxidant defences and oxidative stress of young and old rat brains. Tests of lipoperoxidation in vitro, comparing H. aphrodisiaca extracts with butylhydroxytoluene (BHT), a classic antioxidant, showed an efficient inhibition of lipoperoxidation (Q1/2 = 3.3 μg/mL). Chronic treatment of young and old rats with 50 mg plant extract/kg body weight resulted in a significant increase in superoxide dismutase (SOD) activities (40%) in the brain of old rats, but no changes in catalase and glutathione peroxidase (GPX). No significant variations in antioxidant enzyme activities were observed in the brains of young rats. However, significantly lower levels of lipoperoxidation (30%) were detected in the brain of young rats upon plant extract administration, suggesting that H. aphrodisiaca extracts reduced the oxidative stress to brain lipids. Copyright © 2001 John Wiley & Sons, Ltd.
Ab initio calculation of the Young's modulus of α‐polyamides
Authors: Peeters Anik , Van Alsenoy C. , Bartha F. , Bogár F. , Zhang M.‐L. , Van Doren V. E.
Published: August 2002

In earlier works the supermolecule model has been applied to the calculation of the Young's modulus of crystalline polyethylene and polyamide‐6. In the supermolecule model a crystalline polymer is represented as a single finite chain divided into a head, body, and tail part. The body contains a number of monomer units and is representative for a polymer chain. In this article, this model has been used to study the geometric properties and the elastic moduli of the α form of other polyamides: polyamide‐2 (or polyglycine), polyamide‐3, polyamide‐4, polyamide‐11, and polyamide‐6,6. All calculations have been performed with a linearly constrained body. The results have been compared to other theoretical and experimental results if available. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/qua.2002;10121
Computed molecular surface electrostatic potentials of two groups of reverse transcriptase inhibitors: Relationships to anti‐HIV‐1 activities
Authors: Galvez Gonzalez Oscar , Murray Jane S. , Peralta‐Inga Zenaida , Politzer Peter
Published: August 2002

We have used the GIPF approach (general interaction properties function) to develop analytical representations for the anti‐HIV‐1 potencies of two groups of reverse transcriptase inhibitors. Their activities are expressed in terms of certain statistical properties of their molecular surface electrostatic potentials, computed at the HF/STO‐5G*//HF/STO‐3G* level. The results provide insight into some of the factors that promote inhibition. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 83: 115–121, 2001
Models for protein–zinc ion binding sites. II. The catalytic sites*
Authors: Deerfield David W. , Carter Charles W. , Pedersen Lee G.
Published: August 2002

The first and selected members of the second coordination shells for four model protein–Zn(II) ion catalytic sites have been studied using ab initio computational methodology. The influence of deprotonation on the structure and relative energetics of model complexes was examined. Significant lengthening of the Zn(II)–S, Zn(II)–O, and Zn(II)–N ionic distance is observed as the negative charge about the Zn(II) ion increases. In a model Escheridia coli cytidine deaminase site, we find a substantial lengthening of the Zn–SH2 ionic distance in the active site, which corresponds to the lengthening found for transition state analogs in X‐ray crystal structures. The lowest energy complex of a sulfur‐containing ligand was found to be singly deprotonated, with the complex having an overall charge of +1. The deprotonation of any ligand in a model complex for thermolysin, on the other hand, was found to be endothermic. The influence of other ligands of the metal ion, along with second‐shell ligands, on the energy requirement for deprotonation was also examined for other model systems. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 83: 150–165, 2001
Electrostatic models of inhibitory activity
Authors: Grembecka J. , Kȩdzierski P. , Sokalski W. A. , Leszczyński J.
Published: August 2002

Various models of electrostatic interactions have been applied and tested for several leucine aminopeptidase (LAP) inhibitors interacting with the enzyme active site. Our results indicate that atomic multipoles up to quadrupole moment as well as potential derived Merz–Kollman and RESP charges reproduce reasonably the ab initio electrostatic interaction energies and the expectation values of the molecular electrostatic potential. These electrostatic models together with CHELP atomic point charges, yield the satisfactory correlation of the electrostatic interaction energy with the experimental activities of the inhibitors, in contrast to the results obtained from atomic monopoles (Mulliken charges) and atomic dipoles. Reasonable correlation has been also obtained for the simple electrostatic “key‐lock” model proposed by Náray‐Szabó, in which the LAP active site is represented by set of point charges (“lock”) interacting with the molecular electrostatic potential of each inhibitor (“key”). © 2001 John Wiley & Sons, Inc. Int J Quant Chem 83: 180–192, 2001
An analysis of the topology of the electron charge density and the reactant–product electronic structure variation along the intrinsic reaction coordinate
Authors: Rincón Luis , Almeida Rafael
Published: August 2002

In this work the topology of the electron charge density and the variations in the reactant and product electronic structures are analyzed along the Fukui intrinsic reaction coordinate (IRC). The systems studied are the ionic and the MenschutkinSN2 reactions. This study is performed at ab initio RHF and MP2 levels, and density functional level, employing the B3LYP functional. The basis set in all cases is of split valence type and includes diffuse and polarization functions in nonhydrogen atoms 6‐31+G*. As a measure of the variations of reactant and product electronic structures, we calculate at the RHF level, the overlap integral between the total wavefunction and the wavefunction based on the reactant (or product) localized fragment orbitals. This integral can be interpreted, in Hilbert space, as the cosine of the angle between the vector representing the electronic structure of the molecule in each point of the IRC and that of reactant (or product) electronic structure. The calculated molecular properties were analyzed in light of the valence bond approach, and qualitative differences were noted depending on the property studied. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem, 2001
High‐performance liquid chromatography/tandem mass spectrometry for the quantitative analysis of a novel taxane derivative (BAY59‐8862) in biological samples and characterisation of its metabolic profile in rat bile samples
Authors: Sottani Cristina , Colombo Tina , Zucchetti Massimo , Fruscio Robert , D'Incalci Maurizio , Minoia Claudio
Published: August 2002

A sensitive, specific, accurate and reproducible high‐performance liquid chromatography (HPLC) analytical method was developed and validated for the quantification of the novel oral taxane analogue BAY59‐8862 in mouse plasma and tissue samples. A fully automated solid‐phase extraction procedure was applied to the plasma after internal standard (IS) addition, with only 0.2 mL volume of the sample loaded on a CN‐Sep‐pak cartridge. In the case of the tissues a very simple acetonitrile extraction was used to recover BAY59‐8862 and its internal standard from liver. The procedure for the quantification of BAY59‐8862 and its IS (IDN5127) is based on high‐performance liquid chromatography/ion spray‐tandem mass spectrometry, operating in selected ion monitoring mode. The retention times of BAY and IS were 7.21 and 10.36 min, respectively. In both plasma and tissue specimens the assay was linear in the range 50–5000 ng/mL (ng/g). The overall precision and accuracy were assessed on three different days. The results for plasma were within 6.1% (precision) and between 99 and 112% (accuracy), and for the liver samples within 7.3% and between 104 and 118%, respectively. The LOD was 5 ng/mL and 20 ng/g in the plasma and liver, respectively. In addition, the biliary excretion of the compound in rats was studied. The study showed that an oxidative chemical reaction was the preferred metabolic pathway for biliary excretion, and two sets of mono‐ and dihydroxylated metabolites were detected by LC/ISP‐MS/MS experiments. With this method, BAY59‐8862 pharmacokinetic was determined in mice. The combined results demonstrate that the methodology can be considered a valid approach to conduct pharmacokinetic and metabolic studies during preclinical and clinical investigations. Copyright © 2001 John7 Wiley & Sons, Ltd.
The Effectiveness of Environmental Dredging: A Study of Three Sites
Authors: Thibodeaux Louis J. , Duckworth Karl T.
Published: August 2002

This manuscript is the result of a research project on the effectiveness of environmental dredging. The
project consisted of technical evaluations of dredging performed at sites in Louisiana, New York, and Michigan.
Models and measurements were used to examine increased water concentrations, post‐dredging sediment
concentrations, effects on biota (primarily fish), contaminant losses, etc., for dredging primarily,
but including the natural‐recovery and capping remediation options. The effectiveness was evaluated by
quantifying 1) enhanced contaminant release during dredging, 2) short‐term on the aquatic
environment and 3) long‐term impacts on the aquatic environment.

It was found that existing technologies provide the means to extract large volumes of contaminated
bed‐sediment. Targeted removals of greater than 95 percent are achievable. However, 100 percent removal
was impossible, so that significant contaminants remained. The surficial‐sediment concentrations remained
high, with reduction in the 50 to 75 percent range being typical. The impact on fish in the short term was
nearly always negative. During dredging, significant contaminants enter the water column in both soluble and
particulate form. The long‐term impact of dredging was indeterminate because of the limited observational
database. Complete chemical and biota data sets necessary to quantify the efficiency of the dredge and residual
losses were generally absent at all three sites. 2001 © John Wiley & Sons, Inc.
An Updated Cost Study for Enhanced Sludge Washing of Radioactive Waste
Authors: DeMuth Scott F. , Thayer Gary R.
Published: August 2002

This article updates previous cost savings studies conducted to evaluate the use of enhanced sludge washing
(ESW) of high‐level radioactive waste at the United States Department of Energy Hanford Site.
The cost savings estimate was updated using stochastic analysis based on new information from the
Independent Review of Hanford High Level Waste Volume and the more recent Tank Waste
Remediation System Operation and Utilization Plan. It is estimated that implementation of ESW in the
tank waste remediation system (TWRS) at the Hanford Site can save approximately $4.8 billion
compared to the use of an alternative, simpler water wash. The simpler water wash dissolution was found to be
85 percent as effective as the ESW dissolution. Further, the updated remediation cost estimate of $4.8
billion savings is uncertain only within ±$1.6 billion at the 95 percent confidence interval.
© 2002 Wiley Periodicals, Inc.
Silencing of gene expression: implications for design of retrovirus vectors
Authors: Pannell Dylan , Ellis James
Published: August 2002

Transcriptional silencing of retroviruses poses a major obstacle to their use as gene therapy vectors. Silencing is most pronounced in stem cells which are desirable targets for therapeutic gene delivery. Many vector designs combat silencing through cis‐modifications of retroviral vector sequences. These designs include mutations of known retroviral silencer elements, addition of positive regulatory elements and insulator elements to protect the transgene from negative position effects. Similar strategies are being applied to lentiviral vectors that readily infect non‐dividing quiescent stem cells. Collectively these cis‐modifications have significantly improved vector design but optimal expression may require additional intervention to escape completely the trans‐factors that scan for foreign DNA, establish silencing in stem cells and maintain silencing in their progeny. Cytosine methylation of CpG sites was proposed to cause retroviral silencing over 20 years ago. However, several studies provide evidence that retrovirus silencing acts through methylase‐independent mechanisms. We propose an alternative silencing mechanism initiated by a speculative stem cell‐specific ‘somno‐complex’. Further understanding of retroviral silencing mechanisms will facilitate better gene therapy vector design and raise new strategies to block transcriptional silencing in transduced stem cells. Copyright © 2001 John Wiley & Sons, Ltd.
Historical patterns of river stage and fish communities as criteria for operations of dams on the Illinois river
Authors: Koel Todd M. , Sparks Richard E.
Published: August 2002

The hydrologic regime of the Illinois River has been altered over the past 100 years. Locks and dams regulate water surface elevations and flow, enabling commercial navigation to continue year round. This study relates changes in water surface elevation to fish abundance in the river, and establishes target criteria for operating locks and dams. Using long‐term records of daily river stage, we identified ecologically meaningful hydrological parameters for eight gage locations along the Illinois River. Inter‐annual variability of a long‐term fisheries dataset beginning in 1957 was related to variability in stage, flood and recession duration, frequency, timing, and rate of change of water levels. Reversals in water surface elevation, maximum stage levels, and length of the spring flood were the most important parameters influencing abundance of age‐zero fishes in annual collections. Smallmouth buffalo (Ictiobus bubalus), black crappie (Pomoxis nigromaculatus), freshwater drum (Aplodinotus grunneins), and white bass (Morone chrysops) were most abundant in samples during years that approximated the natural water level regime. Of the 33 hydrologic parameters evaluated for the entire water year from an Illinois River gage site on La Grange Reach, all except average stage in January and Julian date (JD) of maximum stage had moderate or high hydrologic alteration based on the historical range of variation (RVA). The highest degree of hydrologic alteration was for minimum stage levels (1‐day, 3‐day, and 7‐day), rate‐of‐rise, and rate‐of‐fall. Other parameters that have been severely altered were 30‐day minimum stage, 90‐day maximum stage, and the annual number of water level reversals. Operations of the La Grange and Peoria locks and dams could be modified so water level variability would approximate that of the late 1800s, when fish and wildlife resources were abundant. The water regime could be regulated to maintain navigation and improve conditions for native plants and animals without increasing flood damages. Copyright © 2002 John Wiley & Sons, Ltd.
The infamous upper tail
Authors: Janson Svante , Ruciński Andrzej
Published: August 2002

Let Γ be a finite index set and k ≥ 1 a given integer. Let further 𝒮 ⊆ [Γ]≤k be an arbitrary family of k element subsets of Γ. Consider a (binomial) random subset Γp of Γ, where p = (pi : i ∈ Γ) and a random variable X counting the elements of 𝒮 that are contained in this random subset. In this paper we survey techniques of obtaining upper bounds on the upper tail probabilities ℙ(X ≥ λ + t) for t > 0. Seven techniques, ranging from Azuma's inequality to the purely combinatorial deletion method, are described, illustrated, and compared against each other for a couple of typical applications. As one application, we obtain essentially optimal bounds for the upper tails for the numbers of subgraphs isomorphic to K4 or C4 in a random graph G(n, p), for certain ranges of p. © 2002 Wiley Periodicals, Inc. Random Struct. Alg., 20:317–342 2002
Small worlds
Authors: Barbour A. D. , Reinert Gesine
Published: August 2002

Small world models are networks consisting of many local links and fewer long range ‘shortcuts’. In this paper, we consider some particular instances, and rigorously investigate the distribution of their inter‐point network distances. Our results are framed in terms of approximations, whose accuracy increases with the size of the network. We also give some insight into how the reduction in typical inter‐point distances occasioned by the presence of shortcuts is related to the dimension of the underlying space. © 2001 John Wiley & Sons, Inc. Random Struct. Alg., 19, 54–74, 2001
Student goal orientation in learning inquiry skills with modifiable software advisors
Authors: Shimoda Todd A. , White Barbara Y. , Frederiksen John R.
Published: August 2002

A computer support environment (SCI‐WISE) for learning and doing science inquiry projects was designed. SCI‐WISE incorporates software advisors that give general advice about a skill such as hypothesizing. By giving general advice (rather than step‐by‐step procedures), the system is intended to help students conduct experiments that are more epistemologically authentic. Also, students using SCI‐WISE can select the type of advice the advisors give and when they give advice, as well as modify the advisors' knowledge bases. The system is based partly on a theoretical framework of levels of agency and goal orientation. This framework assumes that giving students higher levels of agency facilitates higher‐level goal orientations (such as mastery or knowledge building as opposed to task completion) that in turn produce higher levels of competence. A study of sixth grade science students was conducted. Students took a pretest questionnaire that measured their goal orientations for science projects and their inquiry skills. The students worked in pairs on an open‐ended inquiry project that requires complex reasoning about human memory. The students used one of two versions of SCI‐WISE—one that was modifiable and one that was not. After finishing the project, the students took a posttest questionnaire similar to the pretest, and evaluated the version of the system they used. The main results showed that (a) there was no correlation of goal orientation with grade point average, (b) knowledge‐oriented students using the modifiable version tended to rate SCI‐WISE more helpful than task‐oriented students, and (c) knowledge‐oriented pairs using the nonmodifiable version tended to have higher posttest inquiry skills scores than other pair types. © 2002 Wiley Periodicals, Inc.Sci Ed86:244–263, 2002; DOI 10.1002/sce.10003
Gaining legitimacy? Sustainable development in business school curricula
Authors: Springett Delyse , Kearins Kate
Published: August 2002

Exploring reasons why sustainable development remains largely at the margins of business school curricula and seeking to develop courses of action to embed its ethos more firmly in the institutions in which they work, the authors review international evidence and reflect on their experiences.

A number of related factors appear to contribute to the marginalization of sustainable development in business school curricula. There is the tendency for the tertiary sector to follow the corporate world in market‐driven values and goals, with concomitant reluctance on the part of many business school academics to step outside mainstream orthodoxy. A degree of resistance to interdisciplinary and non‐traditional pedagogical approaches and evaluative methods required by sustainable development is also manifest within many business schools. Encouraging signs are seen, however, in a burgeoning academic literature and growing opportunities for collegial support internationally.

Means by which business studies curricula can incorporate the concept of sustainable development are considered in conjunction with their implications for traditional conceptions of organizational theory, and for tertiary institutions more generally. A modus operandi for a national programme for environmental responsibility in New Zealand tertiary institutions is outlined as an example of a possible way forward. Copyright © 2001 John Wiley & Sons, Ltd. and ERP Environment
Institutional sustainability indicators: an analysis of the institutions in Agenda 21 and a draft set of indicators for monitoring their effectivity
Authors: Spangenberg Joachim H.
Published: August 2002

Objectives of sustainable development are defined for the economic, social and environmental dimension, but for effective compliance as well as for sustainability characteristics such as justice or participation they must be complemented by core institutional objectives. The CSD's set of sustainability indicators was the first one to explicitly take into account the institutional dimension of sustainability, and other organizations such as the World Bank and the OECD have followed. Like most pioneers, the indicators suggested offer significant room for improvement.

In order to measure the effectiveness of the relevant institutions, Agenda 21 has been analysed regarding its institutional content (organizations, mechanisms, orientations). From this basis, the purposes of the institutions have been determined in a stepwise approach and indicators developed that permit us to measure the progress achieved against the purposes of the respective institution.

The methodology developed can be applied to other international agreements, providing the basis for an integrated reporting system. Copyright © 2002 John Wiley & Sons, Ltd. and ERP Environment.
Grain boundary segregation and fracture resistance of engineering steels
Authors: Misra R. D. K.
Published: August 2002

The developments in surface analytical techniques and experimental measurements have made it possible to understand grain boundary segregation processes and related fracture mechanisms. This article shows how experimental contributions have led to the concept of grain boundary segregation isotherms for a complete understanding of grain boundary segregation behavior, and its effect on material properties in terms of the kinetics of segregation, the interaction processes amongst trace and solute elements and the influence of solute elements, heat treatment practice and applied tensile stress on grain boundary segregation processes. The determining role of grain boundary chemistry in obtaining a marked improvement in toughness of engineering steels at the specified levels of strength is elucidated here. Copyright © 2001 John Wiley & Sons, Ltd.
High‐resolution analytical electron microscopy characterization of corrosion and cracking at buried interfaces
Authors: Bruemmer S. M. , Thomas L. E.
Published: August 2002

Recent results are presented demonstrating the application of cross‐sectional analytical transmission electron microscopy (ATEM) to corrosion and cracking in high‐temperature water environments. Microstructural, chemical and crystallographic characterization of buried interfaces at near‐atomic resolutions is shown to reveal evidence for unexpected local environments, corrosion reactions and material transformations. Information obtained by a wide variety of high‐resolution imaging and analysis methods indicates the processes occurring during crack advance and provides insights into the mechanisms controlling environmental degradation. Examples of intergranular attack and cracking in type 316 austenitic stainless steel and Ni‐based alloy 600 are presented to illustrate the potential for this approach. The presence of deeply attacked grain boundaries off the main cracks, revealed by TEM, is believed to indicate a major role of active corrosion in the stress corrosion cracking (SCC) process. Corroded boundaries were filled with oxides to the leading edges of attack. Analyses of the oxide films and impurities in the narrow intergranular penetrations and crack tips with widths of 10 nm or less indicate influences of the grain boundary characteristics and water chemistry. Boundary and precipitate corrosion structures can be used to identify the local electrochemistry promoting degradation in complex service environments. Solution impurities such as lead are found in high concentrations at nanometer‐wide reaction zones in samples from secondary water environments, indicating water access at leading edges of the attack and the influence of these impurities on the corrosion processes. Results for specific samples are used to demonstrate the ability of cross‐sectional ATEM to reveal new details of buried corrosion structures that cannot be detected by other methods. Copyright © 2001 John Wiley & Sons, Ltd.
Simplified equations for correction parameters for elastic scattering effects in AES and XPS for Q, β and attenuation lengths
Authors: Seah M. P. , Gilmore I. S.
Published: August 2002

In this work we develop simple equations, suitable for the analyst, based on the Monte Carlo calculations of Jablonski, for the corrections arising from elastic scattering. These concern modification of the angular anisotropy in XPS and the absolute intensities in both Auger electron spectroscopy (AES) and x‐ray photoelectron spectroscopy (XPS) as a function of the atomic number Z. We also derive more accurate equations for these parameters and the ratio of the attenuation length, L, to the inelastic mean free path (IMFP) based on a knowledge of ω, where ω is the ratio of the IMFP to the sum of the transport mean free path (TrMFP) and the IMFP.

The first equations give the corrections to the anisotropy, βeff(α)/β, and the total emission, Q(α), from Jablonski's work in terms of a total of four equations and a total of 19 coefficients to replace Jablonski's two equations with a total of 2376 coefficients. The present equations describe the dependencies of βeff(α)/β and Q(α) on the angle of electron emission α, the electron energy E and the atomic number of the matrix in the ranges 0° < α < 70°, 300 < E < 1500 eV and 6 < Z < 83. The standard deviation of the scatter with regard to Jablonski's calculations are 4.6% for βeff(α)/β and 1.35% for Q(α), giving an overall uncertainty for quantification, relative to the Monte Carlo calculations, of better than 2%. The equations allow values of βeff(α) to be calculated for revised values of β and for elements other than the 27 studied by Jablonski. They also allow Q(α) to be calculated for other elements and for energies appropriate to Auger electrons within the above ranges.

More complex equations, derived from a slight modification to the transport equations, allow βeff(0)/β, Q(0) and the ratio L/IMFP to be derived from a knowledge of ω. These equations exhibit a standard deviation of scatter of 2.8%, 0.3% and 1.1%, respectively, compared with the Monte Carlo calculations of Jablonski and of Cumpson and Seah, leading to uncertainties in quantification of the order of 1%. These equations are more complex for the analyst to use than the simple equations as a function of Z, but have superior accuracies and accuracies that are probably limited by the precision of the Monte Carlo calculations. © Crown Copyright 2001. Reproduced by permission of the Controller of HMSO. Published by John Wiley & Sons, Ltd.
Yield enhancement effect of low‐energy O2+ ion bombardment in Ga focused ion beam SIMS
Authors: Kikuma Jun , Imai Hideaki
Published: August 2002

The effect of low‐energy oxygen ion irradiation during Ga focused ion beam (FIB) SIMS analyses has been investigated. The positive secondary ion yield in Ga FIB‐SIMS analysis was increased dramatically due to the bombardment of O2+ ions. The degree of yield enhancement increased with increased oxygen doses until it became constant above 1.5 × 1016 atoms cm−2, indicating saturation of the oxygen concentration at the analysis depth. Secondary ion images of a line‐and‐space pattern of boron in the silicon matrix have been obtained with 3 keV and 0.7 keV O2+ ions. It was revealed that the enhancement effect of irradiation with 0.7 keV O2+ ions is of the same degree as that with the 3 keV O2+ ions. From the perspective of sensitivity, however, a lower energy beam is more effective because the sputtering of the sample surface by the O2+ irradiation is reduced, resulting in a greater volume for analysis by the Ga+ beam. A secondary ion image of 0.6 at.% boron from the 0.5 µm line width with an analysis depth of 6 nm has been obtained readily by irradiation of the 0.7 keV O2+ beam. Copyright © 2001 John Wiley & Sons, Ltd.
A refined method for the meta‐analysis of controlled clinical trials with binary outcome
Authors: Hartung Joachim , Knapp Guido
Published: August 2002

For the meta‐analysis of controlled clinical trials with binary outcome a test statistic for testing an overall treatment effect is proposed, which is based on a refined estimator for the variance of the treatment effect estimator usually used in the random‐effects model of meta‐analysis. In simulation studies it is shown that the proposed test keeps the prescribed significance level much better than the commonly used tests in the fixed‐effects and random‐effects model, respectively. Moreover, when using the test it is not necessary to choose between fixed effects and random effects approaches in advance. The proposed method applies in the same way to the analysis of a controlled multi‐centre study with binary outcome, including a possible interaction between drugs and centres. Copyright © 2001 John Wiley & Sons, Ltd.
Recruitment strategies in a cluster randomized trial – cost implications
Authors: Flynn Terry N. , Whitley Elise , Peters Tim J.
Published: August 2002

The presence of a non‐zero intracluster correlation coefficient in cluster randomized trial data has well‐known statistical implications for trial design, in particular, inflating the required sample size for given specifications. However, problems in recruitment are common in such trials and there may be different costs of recruitment resulting from different recruitment strategies. Examples of how such differences arise are taken from cluster randomized trials and more intuitive methods of describing clustering are summarized which, in conjunction with such cost issues, may provide a framework that enables triallists to consider explicitly the trade‐off between power and cost that is often inherent in such trials. Copyright © 2002 John Wiley & Sons, Ltd.
Exploring sources of heterogeneity in systematic reviews of diagnostic tests
Authors: Lijmer Jeroen G. , Bossuyt Patrick M. M. , Heisterkamp Siem H.
Published: August 2002

It is indispensable for any meta‐analysis that potential sources of heterogeneity are examined, before one considers pooling the results of primary studies into summary estimates with enhanced precision. In reviews of studies on the diagnostic accuracy of tests, variability beyond chance can be attributed to between‐study differences in the selected cutpoint for positivity, in patient selection and clinical setting, in the type of test used, in the type of reference standard, or any combination of these factors. In addition, heterogeneity in study results can also be caused by flaws in study design. This paper critically examines some of the potential reasons for heterogeneity and the methods to explore them. Empirical support for the existence of different sources of variation is reviewed. Incorporation of sources of variability explicitly into systematic reviews on diagnostic accuracy is demonstrated with data from a recent review. Application of regression techniques in meta‐analysis of diagnostic tests can provide relevant additional information. Results of such analyses will help understand problems with the transferability of diagnostic tests and to point out flaws in primary studies. As such, they can guide the design of future studies. Copyright © 2002 John Wiley & Sons, Ltd.