Binary recombinase systems for high-resolution conditional mutagenesis.

Conditional mutagenesis using Cre recombinase expressed from tissue specific promoters facilitates analyses of gene function and cell lineage tracing. Here, we describe two novel dual-promoter-driven conditional mutagenesis systems designed for greater accuracy and optimal efficiency of recombination. Co-Driver employs a recombinase cascade of Dre and Dre-respondent Cre, which processes loxP-flanked alleles only when both recombinases are expressed in a predetermined temporal sequence. This unique property makes Co-Driver ideal for sequential lineage tracing studies aimed at unraveling the relationships between cellular precursors and mature cell types. Co-InCre was designed for highly efficient intersectional conditional transgenesis. It relies on highly active trans-splicing inteins and promoters with simultaneous transcriptional activity to reconstitute Cre recombinase from two inactive precursor fragments. By generating native Cre, Co-InCre attains recombination rates that exceed all other binary SSR systems evaluated in this study. Both Co-Driver and Co-InCre significantly extend the utility of existing Cre-responsive alleles.

Employment rate impacts of charging the Heavy Good Vehicle corridor (Madrid-Sevilla) across Spanish regions: a Random Utility Based Multiregional Input-Output approach

The implementation of a charging policy for heavy goods vehicles in European Union (EU) member countries has been imposed to reflect costs of construction and maintenance of infrastructure as well as externalities such as congestion, accidents and environmental impact. In this context, EU countries approved the Eurovignette directive (1999/62/EC) and its amending directive (2006 /38/EC) which established a legal framework to regulate the system of tolls. Even if that regulation seek s to increase the efficien cy of freight, it will trigger direct and indirect effects on Spain’s regional economies by increasing transport costs. This paper presents the development of a multiregional Input-Output methodology (MRIO) with elastic trade coefficients to predict in terregional trade, using transport attributes integrated in multinomial logit models. This method is highly useful to carry out an ex-ante evaluation of transport policies because it involves road freight transport cost sensitivity, and determine regional distributive and substitution economic effect s of countries like Spain, characterized by socio-demographic and economic attributes, differentiated region by region. It will thus be possible to determine cost-effective strategies, given different policy scenarios. MRIO mode l would then be used to determine the impact on the employment rate of imposing a charge in the Madrid-Sevilla corridor in Spain. This methodology is important for measuring the impact on the employment rate since it is one of the main macroeconomic indicators of Spain’s regional and national economic situation. A previous research developed (DESTINO) using a MRIO method estimated employment impacts of road pricing policy across Spanish regions considering a fuel tax charge (€/liter) in the entire shortest cost path network for freight transport. Actually, it found that the variation in employment is expected to be substantial for some regions, and negligible for others. For example, in this Spanish case study of regional employment has showed reductions between 16.1% (Rioja) and 1.4% (Madrid region). This variation range seems to be related to either the intensity of freight transport in each region or dependency of regions to transport intensive economic sect ors. In fact, regions with freight transport intensive sectors will lose more jobs while regions with a predominantly service economy undergo a fairly insignificant loss of employment. This paper is focused on evaluating a freight transport vehicle-kilometer charge (€/km) in a non-tolled motorway corridor (A-4) between Madrid-Sevilla (517 Km.). The consequences of the road pricing policy implementation show s that the employment reductions are not as high as the diminution stated in the previous research because this corridor does not affect the whole freight transport system of Spain.

Assessing urban mobility through participatory scenario building and combined utility-regret assessment

La planificación de la movilidad sostenible urbana es una tarea compleja que implica un alto grado de incertidumbre debido al horizonte de planificación a largo plazo, la amplia gama de paquetes de políticas posibles, la necesidad de una aplicación efectiva y eficiente, la gran escala geográfica, la necesidad de considerar objetivos económicos, sociales y ambientales, y la respuesta del viajero a los diferentes cursos de acción y su aceptabilidad política (Shiftan et al., 2003). Además, con las tendencias inevitables en motorización y urbanización, la demanda de terrenos y recursos de movilidad en las ciudades está aumentando dramáticamente. Como consecuencia de ello, los problemas de congestión de tráfico, deterioro ambiental, contaminación del aire, consumo de energía, desigualdades en la comunidad, etc. se hacen más y más críticos para la sociedad. Esta situación no es estable a largo plazo. Para enfrentarse a estos desafíos y conseguir un desarrollo sostenible, es necesario considerar una estrategia de planificación urbana a largo plazo, que aborde las necesarias implicaciones potencialmente importantes. Esta tesis contribuye a las herramientas de evaluación a largo plazo de la movilidad urbana estableciendo una metodología innovadora para el análisis y optimización de dos tipos de medidas de gestión de la demanda del transporte (TDM). La metodología nueva realizado se basa en la flexibilización de la toma de decisiones basadas en utilidad, integrando diversos mecanismos de decisión contrariedad‐anticipada y combinados utilidad‐contrariedad en un marco integral de planificación del transporte. La metodología propuesta incluye dos aspectos principales: 1) La construcción de escenarios con una o varias medidas TDM usando el método de encuesta que incorpora la teoría “regret”. La construcción de escenarios para este trabajo se hace para considerar específicamente la implementación de cada medida TDM en el marco temporal y marco espacial. Al final, se construyen 13 escenarios TDM en términos del más deseable, el más posible y el de menor grado de “regret” como resultado de una encuesta en dos rondas a expertos en el tema. 2) A continuación se procede al desarrollo de un marco de evaluación estratégica, basado en un Análisis Multicriterio de Toma de Decisiones (Multicriteria Decision Analysis, MCDA) y en un modelo “regret”. Este marco de evaluación se utiliza para comparar la contribución de los distintos escenarios TDM a la movilidad sostenible y para determinar el mejor escenario utilizando no sólo el valor objetivo de utilidad objetivo obtenido en el análisis orientado a utilidad MCDA, sino también el valor de “regret” que se calcula por medio del modelo “regret” MCDA. La función objetivo del MCDA se integra en un modelo de interacción de uso del suelo y transporte que se usa para optimizar y evaluar los impactos a largo plazo de los escenarios TDM previamente construidos. Un modelo de “regret”, llamado “referencedependent regret model (RDRM)” (modelo de contrariedad dependiente de referencias), se ha adaptado para analizar la contribución de cada escenario TDM desde un punto de vista subjetivo. La validación de la metodología se realiza mediante su aplicación a un caso de estudio en la provincia de Madrid. La metodología propuesta define pues un procedimiento técnico detallado para la evaluación de los impactos estratégicos de la aplicación de medidas de gestión de la demanda en el transporte, que se considera que constituye una herramienta de planificación útil, transparente y flexible, tanto para los planificadores como para los responsables de la gestión del transporte. Planning sustainable urban mobility is a complex task involving a high degree of uncertainty due to the long‐term planning horizon, the wide spectrum of potential policy packages, the need for effective and efficient implementation, the large geographical scale, the necessity to consider economic, social, and environmental goals, and the traveller’s response to the various action courses and their political acceptability (Shiftan et al., 2003). Moreover, with the inevitable trends on motorisation and urbanisation, the demand for land and mobility in cities is growing dramatically. Consequently, the problems of traffic congestion, environmental deterioration, air pollution, energy consumption, and community inequity etc., are becoming more and more critical for the society (EU, 2011). Certainly, this course is not sustainable in the long term. To address this challenge and achieve sustainable development, a long‐term perspective strategic urban plan, with its potentially important implications, should be established. This thesis contributes on assessing long‐term urban mobility by establishing an innovative methodology for optimizing and evaluating two types of transport demand management measures (TDM). The new methodology aims at relaxing the utility‐based decision‐making assumption by embedding anticipated‐regret and combined utilityregret decision mechanisms in an integrated transport planning framework. The proposed methodology includes two major aspects: 1) Construction of policy scenarios within a single measure or combined TDM policy‐packages using the survey method incorporating the regret theory. The purpose of building the TDM scenarios in this work is to address the specific implementation in terms of time frame and geographic scale for each TDM measure. Finally, 13 TDM scenarios are built in terms of the most desirable, the most expected and the least regret choice by means of the two‐round Delphi based survey. 2) Development of the combined utility‐regret analysis framework based on multicriteria decision analysis (MCDA). This assessment framework is used to compare the contribution of the TDM scenario towards sustainable mobility and to determine the best scenario considering not only the objective utility value obtained from the utilitybased MCDA, but also a regret value that is calculated via a regret‐based MCDA. The objective function of the utility‐based MCDA is integrated in a land use and transport interaction model and is used for optimizing and assessing the long term impacts of the constructed TDM scenarios. A regret based model, called referente dependent regret model (RDRM) is adapted to analyse the contribution of each TDM scenario in terms of a subjective point of view. The suggested methodology is implemented and validated in the case of Madrid. It defines a comprehensive technical procedure for assessing strategic effects of transport demand management measures, which can be useful, transparent and flexible planning tool both for planners and decision‐makers.

An Integrated Transport Planning Framework Involving a Combined Utility-Regret Approach

Sustainable transport planning requires an integrated approach involving strategic planning, impact analysis and multi-criteria evaluation. This study aims at relaxing the utility-based decision-making assumption by newly embedding anticipated-regret and combined utility-regret decision mechanisms in an integrated transport planning framework. The framework consists of a two-round Delphi survey, an integrated land-use and transport model for Madrid, and multi-criteria analysis. Results show that (i) regret-based ranking has similar mean but larger variance than utility-based ranking; (ii) the least-regret scenario forms a compromise between the desired and the expected scenarios; (iii) the least-regret scenario can lead to higher user benefits in the short-term and lower user benefits in the long-term; (iv) utility-based, regret-based and combined utility-regret-based multi-criteria analysis result in different rankings of policy packages; and (v) the combined utility-regret ranking is more informative compared with utility-based or regret-based ranking.

Patched 1 conditional null allele in mice

The patched gene (Ptc) is a member of the hedgehog signaling pathway which plays a central role in the development of many invertebrate and vertebrate tissues. In addition, Ptc and a number of other pathway members are mutated in some common human cancers. Patched is the receptor for the hedgehog ligand and in the mouse ablation of the Ptc gene leads to developmental defects and an embryonic lethal phenotype. Here we describe a conditional Ptc allele in mice which will have utility for the temporospatial ablation of Ptc function. genesis 36:158-161, 2003. (C) 2003 Wiley-Liss, Inc.

Supporting decision-making for self-adaptive systems:from goal models to dynamic decision networks

Context/Motivation - Different modeling techniques have been used to model requirements and decision-making of self-adaptive systems (SASs). Specifically, goal models have been prolific in supporting decision-making depending on partial and total fulfilment of functional (goals) and non-functional requirements (softgoals). Different goalrealization strategies can have different effects on softgoals which are specified with weighted contribution-links. The final decision about what strategy to use is based, among other reasons, on a utility function that takes into account the weighted sum of the different effects on softgoals. Questions/Problems - One of the main challenges about decisionmaking in self-adaptive systems is to deal with uncertainty during runtime. New techniques are needed to systematically revise the current model when empirical evidence becomes available from the deployment. Principal ideas/results - In this paper we enrich the decision-making supported by goal models by using Dynamic Decision Networks (DDNs). Goal realization strategies and their impact on softgoals have a correspondence with decision alternatives and conditional probabilities and expected utilities in the DDNs respectively. Our novel approach allows the specification of preferences over the softgoals and supports reasoning about partial satisfaction of softgoals using probabilities. We report results of the application of the approach on two different cases. Our early results suggest the decision-making process of SASs can be improved by using DDNs. © 2013 Springer-Verlag.

Transferable Utility Games with Uncertainty

We introduce the concept of a TUU-game, a transferable utility game with uncertainty. In a TUU-game there is uncertainty regarding the payoffs of coalitions. One out of a finite number of states of nature materializes and conditional on the state, the players are involved in a particular transferable utility game. We consider the case without ex ante commitment possibilities and propose the Weak Sequential Core as a solution concept. We characterize the Weak Sequential Core and show that it is non-empty if all ex post TUgames are convex.

Transferable Utility Games with Uncertainty

We introduce the concept of a TUU-game, a transferableutilitygame with uncertainty. In a TUU-game there is uncertainty regarding the payoffs of coalitions. One out of a finite number of states of nature materializes and conditional on the state, the players are involved in a particular transferableutilitygame. We consider the case without ex ante commitment possibilities and propose the Weak Sequential Core as a solution concept. We characterize the Weak Sequential Core and show that it is non-empty if all ex post TU-games are convex.

An asymptotic test for the Conditional Value-at-Risk

Conditional Value-at-Risk (equivalent to the Expected Shortfall, Tail Value-at-Risk and Tail Conditional Expectation in the case of continuous probability distributions) is an increasingly popular risk measure in the fields of actuarial science, banking and finance, and arguably a more suitable alternative to the currently widespread Value-at-Risk. In my paper, I present a brief literature survey, and propose a statistical test of the location of the CVaR, which may be applied by practising actuaries to test whether CVaR-based capital levels are in line with observed data. Finally, I conclude with numerical experiments and some questions for future research.

Analysis of residuals in contingency tables: another nail in the coffin of conditional approaches to significance testing.

Omnibus tests of significance in contingency tables use statistics of the chi-square type. When the null is rejected, residual analyses are conducted to identify cells in which observed frequencies differ significantly from expected frequencies. Residual analyses are thus conditioned on a significant omnibus test. Conditional approaches have been shown to substantially alter type I error rates in cases involving t tests conditional on the results of a test of equality of variances, or tests of regression coefficients conditional on the results of tests of heteroscedasticity. We show that residual analyses conditional on a significant omnibus test are also affected by this problem, yielding type I error rates that can be up to 6 times larger than nominal rates, depending on the size of the table and the form of the marginal distributions. We explored several unconditional approaches in search for a method that maintains the nominal type I error rate and found out that a bootstrap correction for multiple testing achieved this goal. The validity of this approach is documented for two-way contingency tables in the contexts of tests of independence, tests of homogeneity, and fitting psychometric functions. Computer code in MATLAB and R to conduct these analyses is provided as Supplementary Material.

Conditional moment closure for chemical reactions in laminar chaotic flows

We implement conditional moment closure (CMC) for simulation of chemical reactions in laminar chaotic flows. The CMC approach predicts the expected concentration of reactive species, conditional upon the concentration of a corresponding nonreactive scalar. Closure is obtained by neglecting the difference between the local concentration of the reactive scalar and its conditional average. We first use a Monte Carlo method to calculate the evolution of the moments of a conserved scalar; we then reconstruct the corresponding probability density function and dissipation rate. Finally, the concentrations of the reactive scalars are determined. The results are compared (and show excellent agreement) with full numerical simulations of the reaction processes in a chaotic laminar flow. This is a preprint of an article published in AlChE Journal copyright (2007) American Institute of Chemical Engineers: http://www3.interscience.wiley.com/