Exploring unfrequent events with accelerated molecular dynamics simulations: from photochemistry to drug design

La meva incorporació al grup de recerca del Prof. McCammon (University of California San Diego) en qualitat d’investigador post doctoral amb una beca Beatriu de Pinós, va tenir lloc el passat 1 de desembre de 2010; on vaig dur a terme les meves tasques de recerca fins al darrer 1 d’abril de 2012. El Prof. McCammon és un referent mundial en l’aplicació de simulacions de dinàmica molecular (MD) en sistemes biològics d’interès humà. La contribució més important del Prof. McCammon en la simulació de sistemes biològics és el desenvolupament del mètode de dinàmiques moleculars accelerades (AMD). Les simulacions MD convencionals, les quals estan limitades a l’escala de temps del nanosegon (~10-9s), no son adients per l’estudi de sistemes biològics rellevants a escales de temps mes llargues (μs, ms...). AMD permet explorar fenòmens moleculars poc freqüents però que son clau per l’enteniment de molts sistemes biològics; fenòmens que no podrien ser observats d’un altre manera. Durant la meva estada a la “University of California San Diego”, vaig treballar en diferent aplicacions de les simulacions AMD, incloent fotoquímica i disseny de fàrmacs per ordinador. Concretament, primer vaig desenvolupar amb èxit una combinació dels mètodes AMD i simulacions Car-Parrinello per millorar l’exploració de camins de desactivació (interseccions còniques) en reaccions químiques fotoactivades. En segon lloc, vaig aplicar tècniques estadístiques (Replica Exchange) amb AMD en la descripció d’interaccions proteïna-lligand. Finalment, vaig dur a terme un estudi de disseny de fàrmacs per ordinador en la proteïna-G Rho (involucrada en el desenvolupament de càncer humà) combinant anàlisis estructurals i simulacions AMD. Els projectes en els quals he participat han estat publicats (o estan encara en procés de revisió) en diferents revistes científiques, i han estat presentats en diferents congressos internacionals. La memòria inclosa a continuació conté més detalls de cada projecte esmentat.

Biophysical characterization of tubulin tyrosine ligase-like proteins on microtubule dynamics

Report for the scientific sojourn carried out at the Cell Biology and Biophysics Unit from the National Institutes of Health, from 2010 to 2012.

The role of computational fluid dynamics in the management of unruptured intracranial aneurysms: a clinicians' view

Objective: The importance of hemodynamics in the etiopathogenesis of intracranial aneurysms (IAs) is widely accepted.Computational fluid dynamics (CFD) is being used increasingly for hemodynamic predictions. However, alogn with thecontinuing development and validation of these tools, it is imperative to collect the opinion of the clinicians. Methods: A workshopon CFD was conducted during the European Society of Minimally Invasive Neurological Therapy (ESMINT) Teaching Course,Lisbon, Portugal. 36 delegates, mostly clinicians, performed supervised CFD analysis for an IA, using the @neuFuse softwaredeveloped within the European project @neurIST. Feedback on the workshop was collected and analyzed. The performancewas assessed on a scale of 1 to 4 and, compared with experts’ performance. Results: Current dilemmas in the management ofunruptured IAs remained the most important motivating factor to attend the workshop and majority of participants showedinterest in participating in a multicentric trial. The participants achieved an average score of 2.52 (range 0–4) which was 63% (range 0–100%) of an expert user. Conclusions: Although participants showed a manifest interest in CFD, there was a clear lack ofawareness concerning the role of hemodynamics in the etiopathogenesis of IAs and the use of CFD in this context. More effortstherefore are required to enhance understanding of the clinicians in the subject.

Leveraging explicitly disclosed location information to understand tourist dynamics: a case study

In recent years, the large deployment of mobile devices has led to a massiveincrease in the volume of records of where people have been and when they were there.The analysis of these spatio-temporal data can supply high-level human behaviorinformation valuable to urban planners, local authorities, and designer of location-basedservices. In this paper, we describe our approach to collect and analyze the history ofphysical presence of tourists from the digital footprints they publicly disclose on the web.Our work takes place in the Province of Florence in Italy, where the insights on thevisitors’ flows and on the nationalities of the tourists who do not sleep in town has beenlimited to information from survey-based hotel and museums frequentation. In fact, mostlocal authorities in the world must face this dearth of data on tourist dynamics. In thiscase study, we used a corpus of geographically referenced photos taken in the provinceby 4280 photographers over a period of 2 years. Based on the disclosure of the locationof the photos, we design geovisualizations to reveal the tourist concentration and spatiotemporalflows. Our initial results provide insights on the density of tourists, the points ofinterests they visit as well as the most common trajectories they follow.

Bilinear models for spatio-temporal point distribution analysis: application to extrapolation of left ventricular, biventricular and whole heart cardiac dynamics

In this work we describe the usage of bilinear statistical models as a means of factoring the shape variability into two components attributed to inter-subject variation and to the intrinsic dynamics of the human heart. We show that it is feasible to reconstruct the shape of the heart at discrete points in the cardiac cycle. Provided we are given a small number of shape instances representing the same heart atdifferent points in the same cycle, we can use the bilinearmodel to establish this. Using a temporal and a spatial alignment step in the preprocessing of the shapes, around half of the reconstruction errors were on the order of the axial image resolution of 2 mm, and over 90% was within 3.5 mm. From this, weconclude that the dynamics were indeed separated from theinter-subject variability in our dataset.

Dynamics of diversity within the Mossos d’Esquadra

This chapter offers a case-study of diversity and diversity policies withinthe Mossos d’Esquadra, the police force of the Catalan autonomous communityin Spain. The case is described in a comprehensive way (includingpolicies in all relevant policy areas: recruitment, retention, and promotion)and at the same time analyzed with a new analytical framework (includingthe definition of diversity, the motivation for diversity within the organisation,and the facilitation of diversity within the organisation with policies).The goal of the chapter is twofold. First, offer a deeper understanding ofthe dynamics of diversity within this police force. Second, demonstrate theacademic potential of this new analytical framework.

Financing Constraints, Irreversibility, and Investment Dynamics

We develop a model of an industry with many heterogeneous firms that face both financing constraints and irreversibility constraints. The financing constraint implies that firms cannot borrow unless the debt is secured by collateral; the irreversibility constraint that they can only sell their fixed capital by selling their business. We use this model to examine the cyclical behavior of aggregate fixed investment, variable capital investment, and output in the presence of persistent idiosyncratic and aggregate shocks. Our model yields three main results. First, the effect of the irreversibility constraint on fixed capital investment is reinforced by the financing constraint. Second, the effect of the financing constraint on variable capital investment is reinforced by the irreversibility constraint. Finally, the interaction between the two constraints is key for explaining why input inventories and material deliveries of US manufacturing firms are so volatile and procyclical, and also why they are highly asymmetrical over the business cycle.

Financial Crises and International Portfolio Dynamics

This paper analyzes the behavior of international capital flows by foreigners and domestic agents, especially during financial crises. We show that gross capital flows by foreigners and domestic agents are very large and volatile, especially relative to net capital flows. This is because when foreigners invest in a country domestic agents tend to invest abroad and vice versa. Gross capital flows are also pro-cyclical. During expansions, foreigners tend to bring in more capital and domestic agents tend to invest more abroad. During crises, there is retrenchment, i.e. a reduction in capital inflows by foreigners and an increase in capital inflows by domestic agents. This is especially true during severe crises and during systemic crises. The evidence can shed light on the nature of shocks driving international capital flows. It seems to favor shocks that affect foreigners and domestic agents asymmetrically -e.g. sovereign risk and asymmetric information- over productivity shocks.

The dynamics of US inflation: Can monetary policy explain the changes?

We investigate the relationship between monetary policy and inflation dynamics in theUS using a medium scale structural model. The specification is estimated with Bayesiantechniques and fits the data reasonably well. Policy shocks account for a part of the declinein inflation volatility; they have been less effective in triggering inflation responses overtime and qualitatively account for the rise and fall in the level of inflation. A number ofstructural parameter variations contribute to these patterns.

First impressions matter: Signalling as a source of policy dynamics

We first establish that policymakers on the Bank of England's Monetary PolicyCommittee choose lower interest rates with experience. We then reject increasingconfidence in private information or learning about the structure of the macroeconomy as explanations for this shift. Instead, a model in which voters signal theirhawkishness to observers better fits the data. The motivation for signalling is consistent with wanting to control inflation expectations, but not career concerns orpleasing colleagues. There is also no evidence of capture by industry. The papersuggests that policy-motivated reputation building may be important for explainingdynamics in experts' policy choices.

Two-sided learning in New Keynesian models: Dynamics, (lack of) convergence and the value of information

This paper investigates the role of learning by private agents and the central bank(two-sided learning) in a New Keynesian framework in which both sides of the economyhave asymmetric and imperfect knowledge about the true data generating process. Weassume that all agents employ the data that they observe (which may be distinct fordifferent sets of agents) to form beliefs about unknown aspects of the true model ofthe economy, use their beliefs to decide on actions, and revise these beliefs througha statistical learning algorithm as new information becomes available. We study theshort-run dynamics of our model and derive its policy recommendations, particularlywith respect to central bank communications. We demonstrate that two-sided learningcan generate substantial increases in volatility and persistence, and alter the behaviorof the variables in the model in a significant way. Our simulations do not convergeto a symmetric rational expectations equilibrium and we highlight one source thatinvalidates the convergence results of Marcet and Sargent (1989). Finally, we identifya novel aspect of central bank communication in models of learning: communicationcan be harmful if the central bank's model is substantially mis-specified.

Rules or consequences? The role of ethical mindsets in moral dynamics

Recent research on the dynamics of moral behavior has documented two contrastingphenomena - moral consistency and moral balancing. Moral balancing refers to thephenomenon whereby behaving (un)ethically decreases the likelihood of doing so againat a later time. Moral consistency describes the opposite pattern - engaging in(un)ethical behavior increases the likelihood of doing so later on. Three studies supportthe hypothesis that individuals' ethical mindset (i.e., outcome-based versus rule-based)moderates the impact of an initial (un)ethical act on the likelihood of behaving ethicallyin a subsequent occasion. More specifically, an outcome-based mindset facilitates moralbalancing and a rule-based mindset facilitates moral consistency.