bluuebunny/crossref_metadata_2025 huggingface dataset:
A strategy for metabolite identification using triple‐quadrupole mass spectrometry with enhanced resolution and accurate mass capability
Authors: Jemal Mohammed , Ouyang Zheng , Zhao Weiping , Zhu Mingshe , Wu Wells W.
Published: December 2003

Using a single platform of a triple‐quadrupole mass spectrometer equipped with enhanced resolution and accurate mass capabilities, a strategy for metabolite identification of a drug in a biological matrix has been demonstrated. The strategy is based on first screening for metabolites via neutral loss and precursor ion scan schemes, devised as the result of the product ion spectrum of a matrix‐free standard of the drug. The accurate masses of the precursor ions identified via the two scan schemes plus the precursor ions of structurally likely metabolites are then determined by enhanced resolution, accurate mass (AM) selected ion monitoring (SIM). The identities of the metabolites are further established by determining the accurate masses of the product ions via enhanced resolution AM selected reaction monitoring (SRM). The feasibility of the strategy was demonstrated using a liver microsome incubation sample of nefazodone, an antidepressant drug. The neutral loss and precursor ion screening runs were able to identify most of the metabolites of nefazodone. The subsequent SIM and SRM experiments gave mass accuracy of better than ±0.003 u for the masses of the precursor and product ions of nefazodone and all the metabolites. The ability to perform metabolite screening by using the scan features followed by accurate mass determinations on the same instrument is an attractive feature of using a triple‐quadrupole mass spectrometer with enhanced resolution and accurate mass capability. Copyright © 2003 John Wiley & Sons, Ltd.
Mass spectrometric studies of cisplatin‐induced changes of hemoglobin
Authors: Mandal Rupasri , Kalke Robyn , Li Xing‐Fang
Published: December 2003

This study reports on structural changes of hemoglobin (Hb) that were induced by cisplatin binding. Two techniques, nanoelectrospray quadrupole time‐of‐flight mass spectrometry (nanoES‐MS) and high‐performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC/ICPMS), were developed to facilitate this study. Nanospray MS analyses of cisplatin and Hb reaction mixtures demonstrated that the ion at m/z 616.5, the heme group, increased with an increase of cisplatin concentration, indicating the loss of heme groups from the intact protein. This conclusion was also supported by the increase of cisplatin‐α or ‐β complex formation. The change of the Hb‐bound Fe was further investigated by monitoring Fe signals using size‐exclusion HPLC/ICPMS. After incubation with cisplatin at clinically relevant concentrations, under physiological conditions, the amount of Fe bound to Hb was reduced while formation of cisplatin–Hb complexes increased. Flow‐injection ICPMS analysis of the Fe contents in the low molecular weight fraction (<3000 Da) of the reaction mixtures after size fractionation further demonstrated a corresponding increase of Fe with the increase of cisplatin concentrations. HPLC/ICPMS detected three Hb–cisplatin complexes, one of which eluted at the same retention time as Hb while the other two complexes eluted later than Hb. With clinically relevant concentrations of cisplatin (0.05–1.0 μM) and 10 μM of Hb, the concentrations of the Hb–cisplatin complexes were determined in the range 0.1–64 nM. These results, obtained from nanoES‐MS, HPLC/ICPMS, and FIA‐ICPMS, demonstrate that cisplatin binding to Hb resulted in the dissociation of the heme group from the intact protein. Copyright © 2003 John Wiley & Sons, Ltd.
Kinetics of gas‐phase hydrogen/deuterium exchange and gas‐phase structure of protonated phenylalanine, proline, tyrosine and tryptophan
Authors: Rožman Marko , Kazazić Saša , Klasinc Leo , Srzić Dunja
Published: December 2003

Site‐specific rate constants for the gas‐phase hydrogen/deuterium (H/D) exchange of four, three, five and five hydrogen atoms in protonated phenylalanine (Phe), proline (Pro), tyrosine (Tyr) and tryptophan (Trp), respectively, were determined from matrix‐assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI‐FTICRMS) experiments with D2O, D2S, and CH3OD as deuterating agents. No H/D exchange was observed with D2S. For exchange with both CD3OD and D2O, which is about ten times slower in the latter, results indicate for all compounds protonation of the α‐amino group in agreement with theoretical results. Also, with both reagents, all compounds exchange at the COOH site more than ten times faster than at the protonation site, with OH and NH sites of Tyr and Trp, respectively, exchanging slowest. The observation of H/D exchange despite the high differences in proton affinities between the amino acids and deuterating agent exceeding 200 kJ mol−1 is in agreement with lowering of the barrier for proton transfer through hydrogen bonding proposed by Lebrilla and coworkers. Copyright © 2003 John Wiley & Sons, Ltd.
Automated discrimination of polymerase chain reaction products with closely related sequences by software‐based detection of characteristic peaks in product ion spectra
Authors: Muhammad Warees T. , Tabb David L. , Fox Karen F. , Fox Alvin
Published: December 2003

A computer‐based method is described for automated detection of peaks in product ion spectra that allows discrimination of structurally related polymerase chain reaction (PCR) products. PCR products of K‐ras mutants having single nucleotide substitutions and isomeric sequence changes in positions 1 and 2 of codon 12 (e.g. TGT and GTT) were used as a model system. SpecDiff, a tool for differentiating pairs of mass spectra by identifying peaks that either differ in relative intensity between spectra or only appear in one of a pair of spectra, was created to help automate detection. This program was demonstrated to have great utility in detection of mutations and could also be useful as a general tool for differentiating other molecules of closely related structure. Copyright © 2003 John Wiley & Sons, Ltd.
Development of a liquid chromatographic time‐of‐flight mass spectrometric method for the determination of unlabelled and deuterium‐labelled α‐tocopherol in blood components
Authors: Hall Wendy L. , Jeanes Yvonne M. , Pugh Jonathan , Lodge John K.
Published: December 2003

A method is described for the analysis of deuterated and undeuterated α‐tocopherol in blood components using liquid chromatography coupled to an orthogonal acceleration time‐of‐flight (TOF) mass spectrometer. Optimal ionisation conditions for undeuterated (d0) and tri‐ and hexadeuterated (d3 or d6) α‐tocopherol standards were found with negative ion mode electrospray ionisation. Each species produced an isotopically resolved single ion of exact mass. Calibration curves of pure standards were linear in the range tested (0–1.5 μM, 0–15 pmol injected). For quantification of d0 and d6 in blood components following a standard solvent extraction, a stable‐isotope‐labelled internal standard (d3‐α‐tocopherol) was employed. To counter matrix ion suppression effects, standard response curves were generated following identical solvent extraction procedures to those of the samples. Within‐day and between‐day precision were determined for quantification of d0‐ and d6‐labelled α‐tocopherol in each blood component and both averaged 3–10%. Accuracy was assessed by comparison with a standard high‐performance liquid chromatography (HPLC) method, achieving good correlation (r2 = 0.94), and by spiking with known concentrations of α‐tocopherol (98% accuracy). Limits of detection and quantification were determined to be 5 and 50 fmol injected, respectively. The assay was used to measure the appearance and disappearance of deuterium‐labelled α‐tocopherol in human blood components following deuterium‐labelled (d6) RRR‐α‐tocopheryl acetate ingestion. The new LC/TOFMS method was found to be sensitive, required small sample volumes, was reproducible and robust, and was capable of high throughput when large numbers of samples were generated. Copyright © 2003 John Wiley & Sons, Ltd.
High‐precision measurements of 17O/16O and 18O/16O of O2 and O2/Ar ratio in air
Authors: Barkan Eugeni , Luz Boaz
Published: December 2003

A method for high‐precision and high‐accuracy mass spectometric measurements of the ratios among the three oxygen isotopes, and of the O2/Ar ratio, is presented. It involves separation of the O2‐Ar mixture from air and includes a fully automated system that ensures highly reliable sample processing. Repeated measurements of atmospheric oxygen yield the repeatability (±SE × t, standard error of the mean (n = 12) multiplied by Student's t‐factor for a 95% confidence limit) of 0.004, 0.003 and 0.2‰ for δ18O, δ17O and δO2/Ar, respectively. Copyright © 2003 John Wiley & Sons, Ltd.
A comparison of accurate mass techniques for the structural elucidation of fluconazole
Authors: Thompson Christine M. , Richards Donald S. , Fancy Sally‐Ann , Perkins George L. , Pullen Frank S. , Thom Catriona
Published: December 2003

Mass spectrometry plays a major role in the structural elucidation and characterisation of drug candidates and related substances. Accurate mass data allow the mathematical prediction of molecular formula of both precursor and fragment ions. In this paper, a comparison of the accurate mass data obtained for the fragmentation of fluconazole, an antifungal drug, by three different methods is made: electron ionisation (EI) using a magnetic sector instrument; electrospray ionisation (ES) using a Fourier transform ion cyclotron mass spectrometer (FTICRMS); and ES using a quadrupole—time‐of‐flight mass spectrometer (Q‐ToF). It is clear from the data obtained that mass accuracy is not simply a function of instrument resolution. The subtle differences observed between collisionally activated dissociation (CAD) and sustained off‐resonance collisionally activated dissociation (SORI‐CAD) spectra are explained as a consequence of the excitation process. The advantages and disadvantages of the three techniques are discussed within the context of structural elucidation. Copyright © 2003 John Wiley & Sons, Ltd.
Stable‐isotope dilution analysis of galactose metabolites in human erythrocytes
Authors: Schadewaldt Peter , Kamalanathan Loganathan , Hammen Hans‐Werner , Wendel Udo
Published: December 2003

An established gas chromatography/mass spectrometry (GC/MS) method, devised for stable‐isotope dilution analysis of plasma galactose, was developed to allow determination of erythrocyte (red blood cell, RBC) concentrations of galactose‐1‐phosphate and other primary metabolites relevant in galactosaemia. Galactose‐1‐phosphate was enzymatically converted to galactose, and the aldononitrile pentaacetate derivative was separated by gas chromatography and determined by mass spectrometry using chemical ionisation and selected ion monitoring of the [MH–60]+ ion. U‐13C‐Labelled standard was used for quantification. Comparative measurements were conducted using established fluorimetric and radiometric enzymatic methods. The GC/MS analysis for galactose‐1‐phosphate was linear (range examined 0–600 μmol/LRBC, packed cells), of acceptable repeatability at low and high concentrations (within and between run CVs <15%), with a limit of quantification of 0.01 μmol/LRBC. With samples from patients with classical galactosaemia there was a linear correlation with conventional enzymatic assays (r2 > 0.927). In erythrocytes from post‐absorptive patients under treatment, Q188R‐heterozygous parents, and healthy subjects, galactose‐1‐phosphate concentrations (mean ± SD) were found to be 142 ± 38 (n = 41), 1.4 ± 0.2 (n = 8), and 1.9 ± 0.5 (n = 33) μmol/LRBC, respectively. In comparison, free galactose concentrations were 3.8 ± 1.7, 0.49 ± 0.19, and 0.43 ± 0.20 mol/LRBC, respectively. The procedure allowed simultaneous galactitol analysis and proved to be useful to trace incorporation of 13C‐label into erythrocyte galactose metabolites in a D‐[1‐13C]galactose in vivo turnover study. Copyright © 2003 John Wiley & Sons, Ltd.
Acid‐induced denaturation of cellular retinol‐binding proteins types I and II studied by electrospray mass spectrometry
Authors: Careri Maria , Elviri Lisa , Zagnoni Ingrid , Cavazzini Davide , Rossi Gian Luigi
Published: December 2003

The acid‐induced denaturation of cellular retinol‐binding proteins types I and II (CRBP I and II), in the presence and in the absence of the ligand, was studied by electrospray ionization mass spectrometry (ESI‐MS) in the pH range 6.9–2.4. To avoid artifacts generated by the ESI process, suitable interface parameters were selected. Different charge‐state distributions were observed in the ESI‐MS spectra, reflecting the pH‐dependent equilibria among protein conformations in solution. In the absence of retinol, CRBP II appeared to be more resistant than CRBP I to acid denaturation. The bound ligand stabilized both carriers, with a markedly higher effect on CRBP I. Retinol release from the ligand‐bound carriers and protein denaturation occurred concomitantly. This finding suggests that the lowering of pH, reported to occur in proximity to a biomembrane, might contribute to the conformational transitions required to promote dissociation of the otherwise very stable retinal–carrier complexes and thus permit targeted delivery of vitamin A to the enzymes involved in its metabolism. Copyright © 2003 John Wiley & Sons, Ltd.
The heritability of cause‐specific mortality: a correlated gamma‐frailty model applied to mortality due to respiratory diseases in Danish twins born 1870–1930
Authors: Wienke Andreas , Holm Niels V. , Christensen Kaare , Skytthe Axel , Vaupel James W. , Yashin Anatoli I.
Published: December 2003

The genetic influence on susceptibility to diseases of the respiratory system and all‐cause mortality was studied using data for identical (MZ) and fraternal (DZ) twins. Data from the Danish Twin Register include 1344 MZ and 2411 DZ male twin pairs and 1470 MZ and 2730 DZ female twin pairs born between 1870 and 1930, where both individuals were alive on 1 011943. We used the correlated gamma‐frailty model. Proportions of variance in frailty attributable to genetic and environmental factors were assessed using the structural equation model approach. For all‐cause mortality the correlation coefficients of frailty for MZ twins tend to be higher than for DZ twins. For mortality with respect to respiratory diseases this effect was only seen in females, whereas males showed the opposite effect. Five standard biometric models are fitted to the data to evaluate the magnitude and nature of genetic and environmental factors on mortality. Using the best fitting biometric model heritability for cause of death was found to be 0.58 (0.07) for all‐cause mortality (AE‐model) and zero for diseases of the respiratory system for males. Heritability was 0.63 (0.11) for all‐cause mortality (DE‐model) and 0.18 (0.09) for diseases ofthe respiratory system (DE‐model) for females. The analysis confirms the presence of a strong genetic influence on individual frailty associated with all‐cause mortality. For respiratory diseases, no genetic influence was found in males and only weak genetic influence in females. The nature of genetic influences on frailty with respect to all‐cause mortality is probably additive in males and dominant in females, whereas for frailty with respect to deaths caused by respiratory diseases in females, there are genetic factors present which are caused by dominance. Environmental influences are non‐shared with exception of frailty with respect to respiratory diseases in males, where the shared environment plays an important role. Copyright © 2003 John Wiley & Sons, Ltd.
Evaluation of Cox's model and logistic regression for matched case‐control data with time‐dependent covariates: a simulation study
Authors: Leffondré Karen , Abrahamowicz Michal , Siemiatycki Jack
Published: December 2003

Case‐control studies are typically analysed using the conventional logistic model, which does not directly account for changes in the covariate values over time. Yet, many exposures may vary over time. The most natural alternative to handle such exposures would be to use the Cox model with time‐dependent covariates. However, its application to case‐control data opens the question of how to manipulate the risk sets. Through asimulation study, we investigate how the accuracy of the estimates of Cox's model depends on the operational definition of risk sets and/or on some aspects of the time‐varying exposure. We also assess the estimates obtained from conventional logistic regression. The lifetime experience of a hypothetical population is first generated, and a matched case‐control study is then simulated from this population. We control the frequency, the age at initiation, and the total duration of exposure, as well as the strengths of their effects. All models considered include a fixed‐in‐time covariate and one or two time‐dependent covariate(s): the indicator of current exposure and/or the exposure duration. Simulation results show that none of the models always performs well. The discrepancies between the odds ratios yielded by logistic regression and the ‘true’ hazard ratio depend on both the type of the covariate and the strength of its effect. In addition, it seems that logistic regression has difficulty separating the effects of inter‐correlated time‐dependent covariates. By contrast, each ofthe two versions of Cox's model systematically induces either a serious under‐estimation or a moderate over‐estimation bias. The magnitude of the latter bias is proportional to the true effect, suggesting that an improved manipulation of the risk sets may eliminate, or at least reduce, the bias. Copyright © 2003 JohnWiley & Sons, Ltd.
Construction of a global score quantifying allelic imbalance among biallelic SIDP markers in bladder cancer
Authors: Panhard Xavière , Dominique Sébastien , Gaub Marie‐Pierre , Ravery Vincent , Grandchamp Bernard , Mentré France
Published: December 2003

The purpose of this paper is the construction of an adapted statistical test for urinary detection of bladder cancer basedon the assessment of allelic imbalance using biallelic Short Insertion/Deletion Polymorphism DNA markers. This test is based on the comparison of several of these markers, analysed from urinary DNA, to the distribution of their analogues in blood, which is taken as reference. A reproductibility study is first performed in blood in order to make a selection among the 23 available markers and 18 are retained. A global score based on the χ2 distribution is then built to test for allelic imbalance among all informative markers for each patient. It avoids the count of DNA abnormalities marker by marker and allows to take into account the degree of abnormality of each marker. That method is preliminarily evaluated on a sample of 53 patients and 27 controls. The estimated specificity (96.3%) on that reduced sample is satisfactory, whereas sensitivity (60.4%) could be improved by an augmentation of the number of tested markers. Several issues regarding the validity of the method are discussed. Copyright © 2003 John Wiley & Sons, Ltd.
The analysis of asthma control under a Markov assumption with use of covariates
Authors: Saint‐Pierre P. , Combescure C. , Daurès JP. , Godard P.
Published: December 2003

In studies of disease states and their relation to evolution, data on the state are usually obtained at in frequent time points during follow‐up. Moreover in many applications, there are measured covariates on each individual under study and interest centres on the relationship between these covariates and the disease evolution. We developed a continuous‐time Markov model with use of time‐dependent covariates and a Markov model with piecewise constant intensities to model asthma evolution. Methods to estimate the effect of covariates on transition intensities, to test the assumption of time homogeneity and to assess goodness‐of‐fit are proposed. We apply these methods to asthma control. We consider a three‐state model and we discuss in detail the analysis of asthma control evolution. Copyright © 2003 John Wiley & Sons, Ltd.
Structural Refinement of Systems Specified in Object-Z and CSP
Authors: Derrick John , Smith Graeme
Published: December 2003

This paper is concerned with methods for refinement of specifications written using a combination of Object-Z and CSP. Such a combination has proved to be a suitable vehicle for specifying complex systems which involve state and behaviour, and several proposals exist for integrating these two languages. The basis of the integration in this paper is a semantics of Object-Z classes identical to CSP processes. This allows classes specified in Object-Z to be combined using CSP operators. It has been shown that this semantic model allows state-based refinement relations to be used on the Object-Z components in an integrated Object-Z/CSP specification. However, the current refinement methodology does not allow the structure of a specification to be changed in a refinement, whereas a full methodology would, for example, allow concurrency to be introduced during the development life-cycle. In this paper, we tackle these concerns and discuss refinements of specifications written using Object-Z and CSP where we change the structure of the specification when performing the refinement. In particular, we develop a set of structural simulation rules which allow single components to be refined to more complex specifications involving CSP operators. The soundness of these rules is verified against the common semantic model and they are illustrated via a number of examples.
ArcAngel: a Tactic Language for Refinement
Authors: Oliveira Marcel , Cavalcanti Ana , Woodcock Jim
Published: December 2003

Morgan's refinement calculus is a successful technique for developing software in a precise and consistent way. This technique, however, can be hard to use, as developments may be long and repetitive. Many authors have pointed out that a lot can be gained by identifying commonly used development strategies, documenting them as tactics, and using them as single transformation rules. Also, it is useful to have a notation for describing derivations, so that they can be analysed and modified. In this paper, we present ArcAngel, a language for defining such refinement tactics; we present the language, its semantics, and some of its algebraic laws. Apart from Angel, a general-purpose tactic language that we are extending, no other tactic language has a denotational semantics and proof theory of its own.
Combining Component Specifications in Object-Z and CSP
Authors: Derrick John , Boiten Eerke
Published: December 2003

This paper discusses the separation of components from the contexts in which they are used, and how this separation can be supported whilst using different specification languages. There are a number of ways in which this might be possible and here we show how the technique of promotion in Object-Z can be used to combine components which are specified using process algebras. We outline two approaches. The first is to separate out a single specification into a number of distinct
viewpoints
(i.e., partial specifications), each possibly written in a different notation. These viewpoints can be developed separately, but combined if necessary by a process of translation and unification. The alternative approach we discuss is to use a single hybrid language which is composed of a combination of notations, which we illustrate here by combining CSP and Object-Z. We illustrate both approaches with a simple example, and also consider how such component-based descriptions can be refined, which involves addressing the question of compositionality.
An Introduction to Real-Time Object-Z
Authors: Smith Graeme , Hayes Ian
Published: December 2003

This paper presents Real-Time Object-Z: an integration of the object-oriented, state-based specification language Object-Z with the timed trace notation of the timed refinement calculus. This integration provides a method of formally specifying and refining systems involving continuous variables and real-time constraints. The basis of the integration is a mapping of the existing Object-Z history semantics to timed traces.
Compositional Comparison of Formal Software Specifications Using Transformation Systems
Authors: Große-Rhode Martin
Published: December 2003

In a model-based software systems development formal specifications of the components of the system are developed. Thereby different specifications are used to represent the different aspects or views of the components, possibly following different paradigms. These heterogeneous viewpoint specifications have to be integrated in order to obtain a consistent global specification of the whole system. In this paper transformation systems are introduced as a common semantic domain where specifications written in different languages can be interpreted and formally compared. A transformation system is a transition system where the transitions are labelled by sets of actions and the states are labelled by algebras representing the data states. Development relations and composition operations for transformation systems are investigated, and it is shown that compatible local developments of components induce a global development of their composition. As an application two specifications of the alternating bit protocol are formally compared component-wise, one given in the process calculus CCS, the other one in the parallel programming language UNITY.
A Collection of Papers and Memoirs Celebrating the Contribution of Rod Burstall to Advances in Computer Science
Authors: RYDEHEARD DAVID E. , SANNELLA DONALD T.
Published: December 2003

Formal Aspects of Computing

are dedicated to Professor Rod Burstall, and, as a collection of papers, memoirs and incidental pieces, form a Festschrift for Rod. The contributions are made by some of the many who know Rod and have been in uenced by him. The research papers included here represent some of the areas in which Rod has been active, and the editors thank their colleagues for agreeing to contribute to this Festschrift.
Should ML be Object-Oriented?
Authors: MacQueen David
Published: December 2003

At a fundamental level, functional and object-oriented programming languages are all ‘higher-order’, in the sense that they support computing with values that are themselves pieces of program code encapsulated with a local environment. In functional languages these ‘active’ values are functions, while in object-oriented languages they are objects. Both styles of higher-order language claim to provide good support for writing adaptable programs, but functional and object-oriented languages achieve this adaptability in different ways: functional programs rely on parameterisation at the value, type and module level, while object-oriented languages rely primarily on subtyping and implementation inheritance. Here we compare these two approaches, mainly in terms of the features and properties of their type systems, and consider the benefits and disadvantages of unifying (or merging) the two paradigms by adding object-oriented features to ML as a base language. We argue that while some of the simpler aspects of object-oriented languages are compatible with ML, adding a full- edged class-based object system to ML leads to an excessively complex type system and relatively little expressive gain, especially if we aim to preserve that mostly functional style of programming that is a major advantage of ML.
The List Introduction Strategy for the Derivation of Logic Programs
Authors: Pettorossi Alberto , Proietti Maurizio
Published: December 2003

We present a new program transformation strategy based on the introduction of lists. This strategy is an extension of the tupling strategy which is based on the introduction of tuples of fixed length. The list introduction strategy overcomes some of the limitations of the tupling strategy and, in particular, it makes it possible to transform general recursive programs into linear recursive ones also in cases when this transformation cannot be performed by the tupling strategy. The linear recursive programs we derive by applying the list introduction strategy have in most cases very good time and space performance because they avoid repeated evaluations of goals and unnecessary constructions of data structures.
Dependently Typed Records in Type Theory
Authors: Pollack Robert
Published: December 2003

The languagePebbleof Burstall and Lampson proposed dependent types as the underlying principle in a unified framework to explain facilities for programming in the large, such asmodulesandsignatures, as well as for programming in the small. This proposal soon extended to large scale formal proof development as well. In fact, the functional approach to modularity has turned out to be a hard problem, which is still far from a fully satisfactory solution. This paper discusses aspects of this approach, including representations of records, informative signatures, sharing, and subtyping. My main contribution in this paper is to show that structures with dependent types and manifest fields (roughly ML style modules) are internally definable in a type theoretic framework extended with inductive-recursive definition. This shows that powerful modules follow from general principles without module-specific assumptions.
Proofs-as-Programs as a Framework for the Design of an Analogy-Based ML Editor
Authors: Whittle Jon , Bundy Alan , Boulton Richard
Published: December 2003

C

Y

NTHIA
is a transformation-based editor for a functional subset of ML that lies somewhere between a structure editor and a framework for formal program development. Users construct programs from existing code by applying editing commands that make a semantic analysis of the program's behaviour, e.g., whether it is terminating. All analysis is done using the
Oyster
system, which is an implementation of proofs-as-programs. We concentrate on identifying analyses that can be done fully automatically (e.g., using a decision procedure) and hence can be hidden from the user. As a result,
C

Y

NTHIA
represents progress towards a goal of program editors that make an intelligent analysis of their code, but in a way that requires no extra input from the programmer.
The Ancient Theory of Mind
Authors: Barendregt Henk
Published: December 2003

Happiness and suffering are both the result of two factors combined: the situation in which one is placed and our consciousness of it. Happiness is not only of personal importance, it is also a necessary factor for ensuring peace in society. Therefore it is important to know the two possible ways for the pursuit of happiness: applied science, which focuses on how situations can be controlled, and spirituality, which focuses on developing the various types of consciousness one can have. The notion of purified consciousness is formulated in terms of psychology, neurophysiology, logic and meditative practice.
On Verification of Parallel Message-Passing Processes
Authors: Krogdahl Stein , Lysne Olav
Published: December 2003

One way to reason about parallel processes is to assume that the execution of each process is subdivided into ‘small enough’ steps, and that these are executed in an interleaved fashion, thus obtaining a sequential program. The steps should be so small that for any parallel execution there will, in a suitable sense, exist a corresponding interleaved execution ending in the same state. The usual way to ensure this is to require that each step should contain at most one global access. However, if the global entities are communication channels, then larger steps may in some cases be allowed, and this may make reasoning about the programs easier. This paper explores these cases, and discusses consequences or verification and deadlock avoidance.
On the Use of Data Refinement in the Development of Secure Communications Systems
Authors: Butler Michael
Published: December 2003

We report on experiences gained from the application of data refinement techniques to the development of examples of secure communications systems. The aim was to the carry the development from initial abstract specification of security services through to detailed designs. The development approach was based on action systems, with B and CSP being used as concrete notations. The security services in question are a confidential communications service and an authenticated transaction service. Refinements include explicit representations of intruder behaviour. The paper makes several interrelated contributions. It demonstrates the feasibility of applying a refinement approach to this type of problem, including an effective way of combining B and CSP in refinements. It introduces a more systematic approach to the development of abstraction invariants and refinement checking. Finally, it illustrates the limitation, when modelling security protocols, of a formalism that does not deal with probability.
Local Invariance
Authors: Pitt David H. , Shields Michael
Published: December 2003

A local invariant is a set of states of a transition system with the property that every action possible from each of its states takes the system back into the local invariant, unless it is an ‘exit’ action, each of which is accessible from every state in the set via a sequence of non-‘exit’ actions. This idea supports a form of abstraction construction, abstracting away from behaviour internal to the local invariants themselves, that involving their non-‘exit’ actions. In this way, for example, it is possible to construct from a system one which exhibits precisely the externally visible behaviour. This abstraction is reminiscent of hiding in process algebra, and we compare the notion of abstraction with that of observational equivalence in process calculus.
Dynamical Quantities in Net Systems
Authors: Genrich Hartmann J.
Published: December 2003

The paper presents some known material of higher-level Petri nets in analogy to the dynamics of physical systems. Its aim is to widen the view on the role of the incidence matrix in the analysis of net systems. Rather than focusing on constant state quantities (S-invariants) and cyclic actions (T-invariants), i.e. on solutions of the homogeneous equation systems based on the incidence matrix, it studies dynamical quantities of net systems in general.
Editorial
Authors: COOKE JOHN , MAHARAJ SAVI , ROMIJN JUDI , SHANKLAND CARRON
Published: December 2003

This issue of Formal Aspects of Computing contains nine papers, all related to the formal specification and the analysis of the ‘Tree Identify’ protocol of the IEEE 1394 High Performance Serial Bus.

In March 2001 a workshop on this topic was held in association with the FME conference in Berlin. All but the first paper in this issue are derived from presentations given at that workshop. The mechanisms for invitations to submit papers for this issue and their subsequent refereeing etc. are detailed in the first paper which also introduces the task that was undertaken.
IEEE 1394 Tree Identify Protocol: Introduction to the Case Study
Authors: Maharaj Savi , Romijn Judi , Shankland Carron
Published: December 2003

We introduce a comparative case study on the application of formal methods and techniques to the Tree Identify Protocol of the IEEE standard 1394 serial multimedia bus. The Tree Identify Protocol makes an ideal subject for this purpose because it is small yet complex, and may be modelled in a variety of ways. We provide an informal explanation of the protocol, describe how the case study was conducted, and give an overview of the results.
Specification and Verification of the Tree Identify Protocol of IEEE 1394 in Rewriting Logic
Authors: Verdejo Alberto , Pita Isabel , Martí-Oliet Narciso
Published: December 2003

We present three descriptions, at different abstract levels, of the tree identify protocol from the IEEE 1394 serial multimedia bus standard. The descriptions are given using the language Maude based on rewriting logic. Particularly, the time aspects of the protocol are studied. We prove the correctness of the protocol in two steps. First, the descriptions are validated by an exhaustive exploration of all the possible states reachable from an initial configuration of a network, checking that always only one leader is chosen. Then, we give a formal proof showing that the desirable properties of the protocol are always fulfilled by any network, provided that the network is connected and acyclic.
Using SPIN to Analyse the Tree Identification Phase of the IEEE 1394 High-Performance Serial Bus (FireWire) Protocol
Authors: Calder M. , Miller A.
Published: December 2003

We describe how the tree identification phase of the IEEE 1394 high-performance serial bus (FireWire) protocol is modelled in Promela and verified using SPIN. The verification of arbitrary system configurations is discussed.
Verifying the IEEE 1394 FireWire Tree Identify Protocol with SMV
Authors: Schuppan Viktor , Biere Armin
Published: December 2003

This case study contains a formal verification of the IEEE 1394 FireWire tree identify protocol. Crucial properties of finite models of the protocol have been validated with state-of-the-art symbolic model checkers. Various optimisation techniques were applied to verify concrete and generic configurations.
But What if I Don't Want to Wait Forever?
Authors: Fidge Colin , Shankland Carron
Published: December 2003

We present an abstract model of the leader election protocol used in the IEEE 1394 High Performance Serial Bus standard. The model is expressed in the
probabilistic Guarded Command Language
. By formal reasoning based on this description, we establish the probability of the root contention part of the protocol successfully terminating in terms of the number of attempts to do so. Some simple calculations then allow us to establish an upper bound on the time taken for those attempts.
Probabilistic Model Checking of Deadline Properties in the IEEE 1394 FireWire Root Contention Protocol
Authors: Kwiatkowska Marta , Norman Gethin , Sproston Jeremy
Published: December 2003

The interplay of real time and probability is crucial to the correctness of the IEEE 1394 FireWire root contention protocol. We present a formal verification of the protocol using probabilistic model checking. Rather than analyse the functional aspects of the protocol, by asking such questions as ‘Will a leader be elected?’, we focus on the protocol's performance, by asking the question ‘How certain are we that a leader will be elected sufficiently quickly?’ Probabilistic timed automata are used to formally model and verify the protocol against properties which require that a leader is elected before a deadline with a certain probability. We use techniques such as abstraction, reachability analysis and integer-time semantics to aid the model-checking process, and the efficacy of these techniques is compared.
Fun with FireWire: A Comparative Study of Formal Verification Methods Applied to the IEEE 1394 Root Contention Protocol
Authors: Stoelinga Mariëlle
Published: December 2003

The IEEE 1394 Root Contention Protocol is an industrial leader election algorithm for two processes in which probability, real time and parameters play an important role. This protocol has been analysed in various case studies, using a variety of verification and analysis methods. In this paper, we survey and compare several of these case studies.
Algebraic loop groups and moduli spaces of bundles
Authors: Faltings Gerd
Published: December 2003

We study algebraic loop groups and affine Grassmannians in positive characteristic. The main results are normality of Schubert-varieties, the construction of line-bundles on the affine Grassmannian, and the proof that they induce line-bundles on the moduli-stack of torsors.
Structure of entropy solutions to the eikonal equation
Authors: De Lellis Camillo , Otto Felix
Published: December 2003

In this paper, we establish rectifiability of the jump set of an

\mathbf{S}^1

–valued conservation law in two space–dimensions. This conservation law is a reformulation of the eikonal equation and is motivated by the singular limit of a class of variational problems. The only assumption on the weak solutions is that the entropy productions are (signed) Radon measures, an assumption which is justified by the variational origin. The methods are a combination of Geometric Measure Theory and elementary geometric arguments used to classify blow–ups.

The merit of our approach is that we obtain the structure as if the solutions were in BV, without using the BV–control, which is not available in these variationally motivated problems.
Random walks on finite rank solvable groups
Authors: Pittet Christophe , Saloff-Coste Laurent
Published: December 2003

We establish the lower bound p2t(e,e)scapexp(-t1/3), for the large times asymptotic behaviours of the probabilities p2t(e,e) of return to the origin at even times 2t, for random walks associated with finite symmetric generating sets of solvable groups of finite Prüfer rank. (A group has finite Prüfer rank if there is an integer r, such that any of its finitely generated subgroup admits a generating set of cardinality less or equal to r.)
The asymptotic behavior of fragmentation processes
Authors: Bertoin Jean
Published: December 2003

The fragmentation processes considered in this work are self-similar Markov processes which are meant to describe the evolution of a mass that falls apart randomly as time passes. We investigate their pathwise asymptotic behavior as t foes to infinity. In the so-called homogeneous case, we first point at a law of large numbers and a central limit theorem for (a modified version of) the empirical distribution of the fragments at time t. These results are reminiscent of those of Asmussen and Kaplan [3] and Biggins [12] for branching random walks. Next, in the same vein as Biggins [10], we also investigate some natural martingales, which open the way to an almost sure large deviation principle by an application of the Gärtner-Ellis theorem. Finally, some asymptotic results in the general self-similar case are derived by time-change from the previous ones. Properties of size-biased picked fragments provide key tools for the study.
Dynamic programming for stochastic target problems and geometric flows
Authors: Soner H. Mete , Touzi Nizar
Published: December 2003

Given a controlled stochastic process, the reachability set is the collection of all initial data from which the state process can be driven into a target set at a specified time. Differential properties of these sets are studied by the dynamic programming principle which is proved by the Jankov-von Neumann measurable selection theorem. This principle implies that the reachability sets satisfy a geometric partial differential equation, which is the analogue of the Hamilton-Jacobi-Bellman equation for this problem. By appropriately choosing the controlled process, this connection provides a stochastic representation for mean curvature type geometric flows. Another application is the super-replication problem in financial mathematics. Several applications in this direction are also discussed.
Playing violent electronic games, hostile attributional style, and aggression‐related norms in German adolescents
Authors: Krahé Barbara , Möller Ingrid
Published: December 2003

The relationship was examined between exposure to and preference for violent electronic games and aggressive norms as well as hostile attributional style. Following a pilot study to sample widely used electronic games varying in violent content, 231 eighth‐grade adolescents in Germany reported their use of and attraction to violent electronic games. They also completed measures of hostile attributional style and endorsement of aggressive norms. There were significant gender differences in usage and attraction to violent electronic games, with boys scoring higher than girls. Significant relationships were found between attraction to violent electronic games and the acceptance of norms condoning physical aggression. Violent electronic games were linked indirectly to hostile attributional style through aggressive norms. The findings are discussed with respect to North American research on the aggression‐enhancing effect of violent electronic games.
Rabbit model for in vivo study of anthracycline‐induced heart failure and for the evaluation of protective agents
Authors: Šimůnek Tomáš , Klimtová Ivona , Kaplanová Jana , Mazurová Yvona , Adamcová Michaela , Štěrba Martin , Hrdina Radomír , Geršl Vladimír
Published: December 2003

Background:

Cardiac toxicity associated with chronic administration of anthracycline (ANT) antibiotics represents a serious complication of their use in anticancer chemotherapy, but can also serve as a useful experimental model of cardiomyopathy and congestive heart failure.

Aims:

In this study, a model of chronic ANT cardiotoxicity induced by repeated i.v. daunorubicin (DAU) administration to rabbits was tested.

Methods:

Three groups of animals were used: (1) control group—10 animals received i.v. saline; (2) 11 animals received DAU (3 mg/kg, i.v.); (3) 5 animals received the model cardioprotective agent dexrazoxane (DEX, 60 mg/kg, i.p.), 30 min prior to DAU. All substances were administered once weekly, for 10 weeks. The DAU‐induced heart damage and protective action of DEX were determined and quantitated with the use of histopathology, invasive haemodynamic measurements (e.g. left ventricular pressure changes—dP/dtmax, dP/dtmin), non‐invasive systolic function examinations (left ventricular ejection fraction, PEP/LVET index) and biochemical analysis of cardiac troponin T plasma concentrations.

Results:

All the employed methods showed unambiguously pronounced heart impairment in the DAU group, with the development of both systolic and diastolic heart failure, as well as significant reduction of DAU‐cardiotoxicity in DEX‐pretreated animals. Other toxicities were acceptable.

Conclusion:

The presented model has been approved to be consistent and reliable and it can serve as a basis for future determinations and comparisons of chronic cardiotoxic effects of various drugs, as well as for the evaluation of potential cardioprotectants.
High and low affinity receptors mediate growth effects of gastrin and gastrin‐Gly on DLD‐1 human colonic carcinoma cells
Authors: Ahmed Shawn , Budai Barna , Herédi-Szabó Krisztina , Farkas Judit , Tóth Géza , Murphy Richard F , Lovas Sándor
Published: December 2003

Gastrin (G17) and N‐carboxymethylgastrin (G17‐Gly) have been shown to stimulate the growth of colon cancer cells both in vivo and in vitro. The identity of the receptor mediating these effects is controversial. A recent study demonstrated the presence of a low affinity binding site for G17 and G17‐Gly on the DLD‐1 human colon cancer cell line. The goal of the current study was to further investigate the role of this receptor in mediating the growth‐promoting effects of gastrin peptides. Binding of [Leu15]G17 and [Leu15]G17‐Gly to DLD‐1 cell membranes in competition with [3H]G17‐Gly was examined. Binding of [3H]cholecystokinin‐8 (CCK8) to DLD‐1 cell membranes was also assessed. Whole cell binding experiments were carried out using [125I‐Tyr12,Leu15]G17‐Gly. In addition, the ability of [Leu15]G17 and [Leu15]G17‐Gly to stimulate cell growth, as determined by cell counting, was tested. [Leu15]G17 and [Leu15]G17‐Gly competed with [3H]G17‐Gly at both a high and a low affinity site on DLD‐1 membranes. The IC50 values for [Leu15]G17 were 6.0×10−8 M and 6.9×10−6 M while those for [Leu15]G17‐Gly were 3.2×10−9 M and 4.9×10−6 M. [3H]CCK8 did not bind to either site. [Leu15]G17‐Gly also competed with [125I‐Tyr12,Leu15]G17‐Gly at both a high and a low affinity site on DLD‐1 cells with similar affinities as observed with membranes. [Leu15]G17 and [Leu15]G17‐Gly significantly stimulated the growth of DLD‐1 cells in a dose‐dependent and biphasic manner. The binding profiles of the peptides tested suggest that these sites are different from previously identified wild‐type and mutant CCK1 or CCK2 receptors.