Computational analysis of transcriptional regulation in metazoans

This HDR thesis presents my work on transcriptional regulation in metazoans (animals). As a computational biologist, my research activities cover both the development of new bioinformatics tools, and contributions to a better understanding of biological questions. The first part focuses on transcription factors, with a study of the evolution of Hox and ParaHox gene families across meta- zoans, for which I developed HoxPred, a bioinformatics tool to automatically classify these genes into their groups of homology. Transcription factors regulate their target genes by binding to short cis-regulatory elements in DNA. The second part of this thesis introduces the prediction of these cis-regulatory elements in genomic sequences, and my contributions to the development of user- friendly computational tools (RSAT software suite and TRAP). The third part covers the detection of these cis-regulatory elements using high-throughput sequencing experiments such as ChIP-seq or ChIP-exo. The bioinformatics developments include reusable pipelines to process these datasets, and novel motif analysis tools adapted to these large datasets (RSAT peak-motifs and ExoProfiler). As all these approaches are generic, I naturally apply them to diverse biological questions, in close collaboration with experimental groups. In particular, this third part presents the studies uncover- ing new DNA sequences that are driving or preventing the binding of the glucocorticoid receptor. Finally, my research perspectives are introduced, especially regarding further developments within the RSAT suite enabling cross-species conservation analyses, and new collaborations with exper- imental teams, notably to tackle the epigenomic remodelling during osteoporosis.Cette thèse d’HDR présente mes travaux concernant la régulation transcriptionelle chez les métazoaires (animaux). En tant que biologiste computationelle, mes activités de recherche portent sur le développement de nouveaux outils bioinformatiques, et contribuent à une meilleure compréhension de questions biologiques. La première partie concerne les facteurs de transcriptions, avec une étude de l’évolution des familles de gènes Hox et ParaHox chez les métazoaires. Pour cela, j’ai développé HoxPred, un outil bioinformatique qui classe automatiquement ces gènes dans leur groupe d’homologie. Les facteurs de transcription régulent leurs gènes cibles en se fixant à l’ADN sur des petites régions cis-régulatrices. La seconde partie de cette thèse introduit la prédiction de ces éléments cis-régulateurs au sein de séquences génomiques, et présente mes contributions au développement d’outils accessibles aux non-spécialistes (la suite RSAT et TRAP). La troisième partie couvre la détection de ces éléments cis-régulateurs grâce aux expériences basées sur le séquençage à haut débit comme le ChIP-seq ou le ChIP-exo. Les développements bioinformatiques incluent des pipelines réutilisables pour analyser ces jeux de données, ainsi que de nouveaux outils d’analyse de motifs adaptés à ces grands jeux de données (RSAT peak-motifs et ExoProfiler). Comme ces approches sont génériques, je les applique naturellement à des questions biologiques diverses, en étroite collaboration avec des groupes expérimentaux. En particulier, cette troisième partie présente les études qui ont permis de mettre en évidence de nouvelles séquences d’ADN qui favorisent ou empêchent la fixation du récepteur aux glucocorticoides. Enfin, mes perspectives de recherche sont présentées, plus particulièrement concernant les nouveaux développements au sein de la suite RSAT pour permettre des analyses basées sur la conservation inter-espèces, mais aussi de nouvelles collaborations avec des équipes expérimentales, notamment pour éudier le remodelage épigénomique au cours de l’ostéoporose

Essays on Applied Public Economics

This thesis consists of three empirical papers on various topics, which are brought together under a broad umbrella of Applied Public Economics. The first paper uncovers causal links between cocaine seizures and cocaine-related hospital admissions in Italian provinces by resorting to instrumental variables approach. and explores spatial interrelations between the variables of interest via the SLX model. According to the results, ignoring endogeneity leads to underestimating the effect of seizures on consumption, while spatial relations between seizures in key entry points and consumption in the rest of the country and between seizures in adjacent provinces and consumption in a home province are found to be significant. The second paper exploits a fertility-incentivizing reform that took place in Russia in 2007 to study its effects on eligible households’ consumption expenditure patterns, treating becoming eligible for the assistance as a positive wealth shock; therefore, the paper is testing several theoretical predictions of the wealth effects literature in a setting of a developing country. Results indicate the presence of liquidity constraints, as well as households consuming from wealth to smoothen consumption trajectories. The third paper investigates causal links between problem drinking and depression by adopting a dynamic bivariate probit model, using Russian individual-level panel data. According to the results, there is evidence of bidirectional causality between the two variables, although there are significant differences along the gender dimension: the impact of depression on alcohol abuse is present only in the female subpopulation. In addition, state dependence of alcohol abuse is higher among males. The study also provides estimates of potential effects of alcohol prices doubling on both depression and alcohol abuse: male alcohol abusers are found to be price-insensitive, whereas depression prevalence among females would decrease as a result of higher alcohol prices due to a lower probability of alcohol abuse

Demographic aspects of abortion in Eastern Europe : a study with special reference to the Czech Republic and Slovakia

During the post-World War II period, widespread resort to induced abortion became a well-known peculiarity of the demographic situation in Eastern European countries. The generally high East European abortion levels resulted from the interplay of several determinants. This study focuses first on population policies and the broader socio-economic and demographic conditions that characterized Eastern Europe during the period 1950-90. It is demonstrated that the emergence of the high-abortion regime coincided demographically with the final stage of secular fertility decline in the region, and politically with the establishment of Soviet-style socialism — a system typified by egalitarian social policies, low material standards of living, limited availability of contraceptives, and policies suppressing personal autonomy and perpetuating inequality between the sexes. Despite the many similarities of the countries under consideration, however, abortion levels differed regionally as well as temporally, reflecting local mores and the effects of country-specific policies related to family and birth control. With this in mind, using data from official registration sources, the study goes onto examine levels, trends, and selected demographic aspects of abortion in the Czech and Slovak populations, applying both period- and cohort-specific modes of analysis. The findings show that the dominant force behind the resort to abortion was the desire to prevent second and higher-order births in families, whereas its use to space childbearing or avoid it altogether was much less typical. Changes in abortion legislation generated some transitory behavioural responses, but had only limited effect on abortion patterns in the long term. There were substantial differences in the resort to abortion between Czech and Slovak women; this indicates that factors such as socio-economic status, religion, respect for certain social norms, and attitudes to contraception were powerful determinants of reproductive and birth-preventing behaviour. Overall fertility levels were not unaffected by changes in abortion legislation, but the net effects were less dramatic than a simple trend analysis would suggest because the observed fertility declines were partly produced by differences in childbearing patterns between cohorts. The study concludes by speculating about the broader institutional and sociopsychological correlates of abortion in the formerly communist-ruled countries of Eastern Europe, and by suggesting an agenda for future research

Essays in public economics and political economy

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Economics, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (p. 157-166).This thesis studies topics in public economics in developed and developing countries, including health insurance regulation, public goods provision and inequality and welfare measurement. The first chapter analyzes the impacts of the managed care backlash in the United States on health care costs in the late 1990s and early 2000s. During the late 1990s, most U.S. states passed a variety of laws in this period that restricted the cost-cutting measures that managed care organizations (HMOs, PPOs and others) could use. I exploit panel variation in the passage of these regulations across states and over time to investigate the effects of the managed care backlash, as proxied by this legislation, on health care cost growth. I find that the backlash had a strong effect on health care costs, and can statistically explain much of the rise in health spending as a share of U.S. GDP between 1993 and 2005 (amounting to 1% - 1.5% of GDP). I also investigate the effects of the managed care backlash on intensity of care, hospital salaries and technology adoption. I conclude that managed care was largely successful in keeping health care costs on a sustainable path relative to the size of the economy. The second chapter attempts to quantify the impact of differences in political factors on economic growth and development, and specifically, assess to what extent variation in public goods provision may be responsible for cross-country differences in income and growth rates. Using a new methodology for the computation of standard errors in a regression discontinuity design with infill asymptotics, I document the existence of discontinuities in the levels and growth of the amount of satellite-recorded light per capita across national borders. Both the amount of lights per capita and its growth rate are shown to increase discontinuously upon crossing a border from a poorer (or lower-growing) into a richer (or higher-growing) country. I argue that these discontinuities form lower bounds for discontinuities in economic activity across borders, which suggest the importance of national-level variables such as institutions and culture relative to local-level variables such as geography for the determination of income and growth. I find that institutions of private property are helpful in explaining differences in growth between two countries at the border, while contracting institutions, local and national levels of public goods, as well as education and cultural variables, are not. The last chapter of my thesis, which I have published in the Journal of Public Economics, investigates the dynamics of the world distribution of income using more robust methods than those in the previous literature. I derive sharp bounds on the Atkinson inequality index for a country's income distribution that are valid for any underlying distribution of income conditional on given fractile shares and Gini coefficient. I apply these bounds to calculate the envelope of possible time paths for global inequality and welfare in the last 40 years. While the bounds are too wide to reject the hypothesis that world inequality may have risen, I show that world welfare rose unambiguously between 1970 and 2006. This conclusion is valid for alternative methods of dealing with countries and years with missing surveys, alternative survey harmonization procedures, alternative GDP series, or if the inequality surveys used systematically underreport the income of the very rich, or suffer from nonresponse bias.by Maxim L. Pinkovskiy.Ph.D

Toward a Restoration Protocol for Mediterranean Red Coral: Incorporating Life History Traits, Genetics, Demography, and Experimental Approaches

In recent decades, the cumulative effect of anthropogenic stressors and climate change has raised particular concern for habitat degradation and biodiversity loss. Globally, there is a growing recognition of the urgent need for interventions to address this environmental deterioration. Current understanding suggests that conservation and management efforts alone are often insufficient to halt or reverse the degradation of threatened ecosystems. Consequently, active ecological restoration has emerged as a crucial strategy to address this challenge. Ecological restoration is particularly relevant when dealing with ecosystem-engineering species, which play a pivotal role in shaping the three-dimensional structure of their environments, providing shelter and trophic resources for a diverse array of associated species. Among marine organisms, corals are outstanding for creating Marine Animal Forests by notably shaping the three-dimensional structure of benthic ecosystems. In this PhD thesis, I investigated key bio-ecological processes of a Mediterranean flagship species, Corallium rubrum, in order to improve their current restoration protocols. When planning restoration actions, it is crucial to aim at reintroducing self-sustaining populations that are demographically stable and genetically resilient, ensuring their long-term viability and adaptability to future environmental changes. To this aim, I focused on two key aspects: (1) demography, trying to decode reproduction mechanisms (Chapter 1), and better describe the ecological trajectory of early life history stages of C. rubrum (Chapter 2); and (2) genetics, trying to highlight the importance of incorporating genetic diversity into restoration efforts (Chapter 3). Thanks to an approach that included in-situ and ex-situ experimentations, I described the fertilization mechanisms of C. rubrum by quantifying the influence of male/female distance on fertilization success. This result shed light on the importance of considering ecological thresholds, such as those linked to the density and distribution of transplanted individuals, which can dramatically influence the output of ecological restoration by impairing fertilization success and, consequently, the reproductive output of the transplanted populations. Beyond transplantation, other restoration techniques have recently gained momentum, such as coral breeding. Here, I present the first attempt at developing a breeding protocol for C. rubrum. I show how rearing corals in captivity may offer a viable ecological shortcut to classical transplantation techniques by broadly enhancing the number of individuals available for restocking. Studying early life history stages allowed us to determine the better settlement and growth conditions for this species by comparing settlement success, and growth and survival performance in-situ or ex-situ. In this context, preserving adequate genetic diversity is crucial for ensuring the long-term viability of restored populations, regardless of the method used for restocking damaged populations—whether through transplantation or coral breeding. Recognizing the pivotal role genetic diversity plays in the resilience and adaptability of coral populations to environmental changes, I aimed to develop guidelines for determining the optimal number of donor colonies required to preserve the genetic variability of wild coral populations during restoration efforts. Overall, this thesis represents a comprehensive approach that integrates life history traits, genetics, demography, and experimental approaches to inform and construct new restoration protocols. These findings demonstrate the necessity of considering bio-ecological processes such as successful reproduction or genetic recombination to ensure long-term successful restoration outputs

A discussion on hidden Markov models for life course data

This is an introduction on discrete-time Hidden Markov models (HMM) for longitudinal data analysis in population and life course studies. In the Markovian perspective, life trajectories are considered as the result of a stochastic process in which the probability of occurrence of a particular state or event depends on the sequence of states observed so far. Markovian models are used to analyze the transition process between successive states. Starting from the traditional formulation of a first-order discrete-time Markov chain where each state is liked to the next one, we present the hidden Markov models where the current response is driven by a latent variable that follows a Markov process. The paper presents also a simple way of handling categorical covariates to capture the effect of external factors on the transition probabilities and existing software are briefly overviewed. Empirical illustrations using data on self reported health demonstrate the relevance of the different extensions for life course analysis

Markovian-based clustering of internet addiction trajectories

A hidden Markov clustering procedure is applied to a sample of n=185 longitudinal Internet Addiction Test trajectories collected in Switzerland. The best solution has 4 groups. This solution is related to the level of emotional wellbeing of the subjects, but no relation is observed with age, gender and BMI

Using dynamic microsimulation to understand professional trajectories of the active Swiss population

Within the social and economic sciences and of particular interest to demographers are life course events. Looking at life sequences we can better understand which states, or life events, precede or are precursors to vulnerability. A tool that has been used for policy evaluation and recently has been gaining ground in life course sequence simulation is dynamic microsimulation. Within this context dynamic microsimulation consists in generating entire life courses from the observation of portions of the trajectories of individuals of different ages. In this work, we aim to use dynamic microsimulation in order to analyse individual professional trajectories with a focus on vulnerability. The primary goal of this analysis is to deepen upon current literature by providing insight from a longitudinal perspective on the signs of work instability and the process of precarity. The secondary goal of this work which is to show how, by using microsimulation, data collected for one purpose can be analysed under a different scope and used in a meaningful way. The data to be used in this analysis are longitudinal and were collected by NCCR-LIVES IP207 under the supervision of Prof. Christian Maggiori and Dr. Gregoire Bollmann. Individuals aged 25 to 55 residing in the German-speaking and French-speaking regions of Switzerland were followed annually for four years. These individuals were questioned regarding, amongst their personal, professional and overall situations and well-being. At the end of the fourth wave, there were 1131 individuals who had participated in all waves. The sample remained representative of the Swiss population with women and the unemployed slightly over represented. Using the information collected from these surveys, we use simulation to construct various longitudinal data modules where each data module represents a specific life domain. We postulate the relationship between these modules and layout a framework of estimation. Within certain data modules a set of equations are created to model the process therein. For every dynamic (time-variant) data module, such as the labour-market module, the transition probabilities between states (ex. labour market status) are estimated using a Markov model and then the possible outcomes are simulated. The benefit of using dynamic microsimulation is that longitudinal sample observations instead of stylised profiles are used to model population dynamics. This is one of the main reasons large-scale dynamic microsimulation models are employed by many developed nations. There has been limited use, however, of such approaches with Swiss data. This work contributes to the analysis of professional trajectories of the active Swiss population by utilising dynamic microsimulation methods

Taking Stock to Look Ahead: Celebrating Forty Years of English Studies in Spain

This volume brings together a diverse but well-balanced selection of the plenary lectures, scholarly papers and round tables presented at the AEDEAN Conference at Huesca. The contents of this e-book are divided into four sections. The volume opens with two thought-provoking essays by writers Anne Karpf (London Metropolitan University) and Tabish Khair (Aahrus University). The next two sections constitute the main body of the volume and comprise over thirty essays on the two wider areas of scholarship within English and North-American studies: literature and cultural studies (Part I) and language and linguistics (Part II). Finally, the last section of this volume includes some of the latest findings of three research projects in the form of round tables, dealing with cutting-edge research topics such as Neo-Victorian studies, musical narratives of the American West and European renditions of the American West. In short, the contributions included in this volume succeed not only in putting forward provocative and innovative research, but also in sampling the wealth and breadth of scholarly interests and approaches that the annual AEDEAN Conference unfailingly gathers