Knowledge management for systems biology a general and visually driven framework applied to translational medicine

Background: To enhance our understanding of complex biological systems like diseases we need to put all of the available data into context and use this to detect relations, pattern and rules which allow predictive hypotheses to be defined. Life science has become a data rich science with information about the behaviour of millions of entities like genes, chemical compounds, diseases, cell types and organs, which are organised in many different databases and/or spread throughout the literature. Existing knowledge such as genotype - phenotype relations or signal transduction pathways must be semantically integrated and dynamically organised into structured networks that are connected with clinical and experimental data. Different approaches to this challenge exist but so far none has proven entirely satisfactory. Results: To address this challenge we previously developed a generic knowledge management framework, BioXM™, which allows the dynamic, graphic generation of domain specific knowledge representation models based on specific objects and their relations supporting annotations and ontologies. Here we demonstrate the utility of BioXM for knowledge management in systems biology as part of the EU FP6 BioBridge project on translational approaches to chronic diseases. From clinical and experimental data, text-mining results and public databases we generate a chronic obstructive pulmonary disease (COPD) knowledge base and demonstrate its use by mining specific molecular networks together with integrated clinical and experimental data. Conclusions: We generate the first semantically integrated COPD specific public knowledge base and find that for the integration of clinical and experimental data with pre-existing knowledge the configuration based set-up enabled by BioXM reduced implementation time and effort for the knowledge base compared to similar systems implemented as classical software development projects. The knowledgebase enables the retrieval of sub-networks including protein-protein interaction, pathway, gene - disease and gene - compound data which are used for subsequent data analysis, modelling and simulation. Pre-structured queries and reports enhance usability; establishing their use in everyday clinical settings requires further simplification with a browser based interface which is currently under development.

A general definition and nomenclature for alternative splicing events

Understanding the molecular mechanisms responsible for the regulation of the transcriptome present in eukaryotic cells isone of the most challenging tasks in the postgenomic era. In this regard, alternative splicing (AS) is a key phenomenoncontributing to the production of different mature transcripts from the same primary RNA sequence. As a plethora ofdifferent transcript forms is available in databases, a first step to uncover the biology that drives AS is to identify thedifferent types of reflected splicing variation. In this work, we present a general definition of the AS event along with anotation system that involves the relative positions of the splice sites. This nomenclature univocally and dynamically assignsa specific ‘‘AS code’’ to every possible pattern of splicing variation. On the basis of this definition and the correspondingcodes, we have developed a computational tool (AStalavista) that automatically characterizes the complete landscape of ASevents in a given transcript annotation of a genome, thus providing a platform to investigate the transcriptome diversityacross genes, chromosomes, and species. Our analysis reveals that a substantial part—in human more than a quarter—ofthe observed splicing variations are ignored in common classification pipelines. We have used AStalavista to investigate andto compare the AS landscape of different reference annotation sets in human and in other metazoan species and found thatproportions of AS events change substantially depending on the annotation protocol, species-specific attributes, andcoding constraints acting on the transcripts. The AStalavista system therefore provides a general framework to conductspecific studies investigating the occurrence, impact, and regulation of AS.

"Attès los dits diputats no eran sinó procuradors...": relacions entre els braços i la diputació del general durant la celebració de les Corts Catalanes de 1599

La nostra comunicació s'emmarca en la Catalunya deIs inicis del regnat de Felip II (III de Castella). Té per objecte la complexa situació que es produeix quan, amb motiu d'una convocatoria de Corts, la Diputació del General es troba frec a frec amb els tres braços als quals està legalment subordinada. La convivència forçada d'ambdues institucions en el mateix quadre polític, ni que sigui durant lapses de temps relativament curts, esdevé cada cop més problematica a mesura que avança el segle XVI.

El jurament i el seu significat jurídic al principat segons els dret general de Catalunya (segles XIII-XVIII): edició de la "Forma i pràctica de celebrar els juraments i les eleccions a la ciutat de Barcelona en el segle XV"

Aquesta obra estudia els juraments pronunciats pels reis, pels oficials municipals i pels oficials reials en el municipi de Barcelona des del segle XIII fins el Decret de Nova Planta.

The role of moral values in the economic analysis of crime: A general equilibrium approach

In this paper, we develop a general equilibrium model of crime and show thatlaw enforcement has different roles depending on the equilibrium characterization and the value of social norms. When an economy has a unique stable equilibrium where a fraction of the population is productive and the remaining predates, the government can choose an optimal law enforcement policy to maximize a welfare function evaluated at the steady state. If such steady state is not unique, law enforcement is still relevant but in a completely different way because the steady state that prevails depends on the initial proportions of productive and predator individuals in the economy. The relative importance of these proportions can be changed through law enforcement policy.

Associationism and electoral participation: A multilevel study of 2000 Spanish general election

This work presents an application of the multilevel analysis techniques tothe study of the abstention in the 2000 Spanish general election. Theinterest of the study is both, substantive and methodological. From thesubstantive point of view the article intends to explain the causes ofabstention and analyze the impact of associationism on it. From themethodological point of view it is intended to analyze the interaction betweenindividual and context with a modelisation that takes into account thehierarchical structure of data. The multilevel study of this paper validatesthe one level results obtained in previous analysis of the abstention andshows that only a fraction of the differences in abstention are explained bythe individual characteristics of the electors. Another important fraction ofthese differences is due to the political and social characteristics of thecontext. Relating to associationism, the data suggest that individualparticipation in associations decrease the probability of abstention. However,better indicators are needed in order to catch more properly the effect ofassociationism in electoral behaviour.

Credit constraints in general equilibrium: Experimental results

Our work attempts to investigate the influence of credit tightness orexpansion on activity and relative prices in a multimarket set-up. We report on somedouble- auction, two-market experiments where subjects had to satisfy an inequalityinvolving the use of credit. The experiments display two regimes, characterizedby high and low credit availability. The critical value of credit at the commonboundary of the two regimes has a compelling interpretation as the maximal credituse at the Arrow-Debreu equilibrium of the abstract economy naturally associatedto our experimental environment. Our main results are that changes in theavailability of credit: (a): have minor and unsystematic effects on quantitiesand relative prices in the high-credit regime, (b): have substantial effects, bothon quantities and relative prices, in the low-credit regime.

A general class of adaptative strategies

We exhibit and characterize an entire class of simple adaptive strategies,in the repeated play of a game, having the Hannan-consistency property: In the long-run, the player is guaranteed an average payoff as large as the best-reply payoff to the empirical distribution of play of the otherplayers; i.e., there is no "regret." Smooth fictitious play (Fudenberg and Levine [1995]) and regret-matching (Hart and Mas-Colell [1998]) areparticular cases. The motivation and application of this work come from the study of procedures whose empirical distribution of play is, in thelong-run, (almost) a correlated equilibrium. The basic tool for the analysis is a generalization of Blackwell's [1956a] approachability strategy for games with vector payoffs.

A general decomposition formula for derivative prices in stochastic volatility models

We see that the price of an european call option in a stochastic volatilityframework can be decomposed in the sum of four terms, which identifythe main features of the market that affect to option prices: the expectedfuture volatility, the correlation between the volatility and the noisedriving the stock prices, the market price of volatility risk and thedifference of the expected future volatility at different times. We alsostudy some applications of this decomposition.

General preferences for consumption goods in the random matching model of commodity money

This paper generalizes the original random matching model of money byKiyotaki and Wright (1989) (KW) in two aspects: first, the economy ischaracterized by an arbitrary distribution of agents who specialize in producing aparticular consumption good; and second, these agents have preferences suchthat they want to consume any good with some probability. The resultsdepend crucially on the size of the fraction of producers of each goodand the probability with which different agents want to consume eachgood. KW and other related models are shown to be parameterizations ofthis more general one.

Revenue management under general discrete choice model of consumer behavior

Customer choice behavior, such as 'buy-up' and 'buy-down', is an importantphe-nomenon in a wide range of industries. Yet there are few models ormethodologies available to exploit this phenomenon within yield managementsystems. We make some progress on filling this void. Specifically, wedevelop a model of yield management in which the buyers' behavior ismodeled explicitly using a multi-nomial logit model of demand. Thecontrol problem is to decide which subset of fare classes to offer ateach point in time. The set of open fare classes then affects the purchaseprobabilities for each class. We formulate a dynamic program todetermine the optimal control policy and show that it reduces to a dynamicnested allocation policy. Thus, the optimal choice-based policy caneasily be implemented in reservation systems that use nested allocationcontrols. We also develop an estimation procedure for our model based onthe expectation-maximization (EM) method that jointly estimates arrivalrates and choice model parameters when no-purchase outcomes areunobservable. Numerical results show that this combined optimization-estimation approach may significantly improve revenue performancerelative to traditional leg-based models that do not account for choicebehavior.

Testing calibrated general equilibrium models

This paper illustrates the philosophy which forms the basis of calibrationexercises in general equilibrium macroeconomic models and the details of theprocedure, the advantages and the disadvantages of the approach, with particularreference to the issue of testing ``false'' economic models. We provide anoverview of the most recent simulation--based approaches to the testing problemand compare them to standard econometric methods used to test the fit of non--lineardynamic general equilibrium models. We illustrate how simulation--based techniques can be used to formally evaluate the fit of a calibrated modelto the data and obtain ideas on how to improve the model design using a standardproblem in the international real business cycle literature, i.e. whether amodel with complete financial markets and no restrictions to capital mobility is able to reproduce the second order properties of aggregate savingand aggregate investment in an open economy.

A Hull and White formula for a general stochastic volatility jump-diffusion model with applications to the study of the short-time behavior of the implied volatility

In this paper, generalizing results in Alòs, León and Vives (2007b), we see that the dependence of jumps in the volatility under a jump-diffusion stochastic volatility model, has no effect on the short-time behaviour of the at-the-money implied volatility skew, although the corresponding Hull and White formula depends on the jumps. Towards this end, we use Malliavin calculus techniques for Lévy processes based on Løkka (2004), Petrou (2006), and Solé, Utzet and Vives (2007).

Location of multiple server common service centers or public facilities for minimizing general congestion and travel cost functions

We propose a model and solution methods, for locating a fixed number ofmultiple-server, congestible common service centers or congestible publicfacilities. Locations are chosen so to minimize consumers congestion (orqueuing) and travel costs, considering that all the demand must be served.Customers choose the facilities to which they travel in order to receiveservice at minimum travel and congestion cost. As a proxy for thiscriterion, total travel and waiting costs are minimized. The travel costis a general function of the origin and destination of the demand, whilethe congestion cost is a general function of the number of customers inqueue at the facilities.