Analysis of Molecular Dynamics Simulations of Protein Folding

Microsecond long Molecular Dynamics (MD) trajectories of biomolecular processes are now possible due to advances in computer technology. Soon, trajectories long enough to probe dynamics over many milliseconds will become available. Since these timescales match the physiological timescales over which many small proteins fold, all atom MD simulations of protein folding are now becoming popular. To distill features of such large folding trajectories, we must develop methods that can both compress trajectory data to enable visualization, and that can yield themselves to further analysis, such as the finding of collective coordinates and reduction of the dynamics. Conventionally, clustering has been the most popular MD trajectory analysis technique, followed by principal component analysis (PCA). Simple clustering used in MD trajectory analysis suffers from various serious drawbacks, namely, (i) it is not data driven, (ii) it is unstable to noise and change in cutoff parameters, and (iii) since it does not take into account interrelationships amongst data points, the separation of data into clusters can often be artificial. Usually, partitions generated by clustering techniques are validated visually, but such validation is not possible for MD trajectories of protein folding, as the underlying structural transitions are not well understood. Rigorous cluster validation techniques may be adapted, but it is more crucial to reduce the dimensions in which MD trajectories reside, while still preserving their salient features. PCA has often been used for dimension reduction and while it is computationally inexpensive, being a linear method, it does not achieve good data compression. In this thesis, I propose a different method, a nonmetric multidimensional scaling (nMDS) technique, which achieves superior data compression by virtue of being nonlinear, and also provides a clear insight into the structural processes underlying MD trajectories. I illustrate the capabilities of nMDS by analyzing three complete villin headpiece folding and six norleucine mutant (NLE) folding trajectories simulated by Freddolino and Schulten [1]. Using these trajectories, I make comparisons between nMDS, PCA and clustering to demonstrate the superiority of nMDS. The three villin headpiece trajectories showed great structural heterogeneity. Apart from a few trivial features like early formation of secondary structure, no commonalities between trajectories were found. There were no units of residues or atoms found moving in concert across the trajectories. A flipping transition, corresponding to the flipping of helix 1 relative to the plane formed by helices 2 and 3 was observed towards the end of the folding process in all trajectories, when nearly all native contacts had been formed. However, the transition occurred through a different series of steps in all trajectories, indicating that it may not be a common transition in villin folding. The trajectories showed competition between local structure formation/hydrophobic collapse and global structure formation in all trajectories. Our analysis on the NLE trajectories confirms the notion that a tight hydrophobic core inhibits correct 3-D rearrangement. Only one of the six NLE trajectories folded, and it showed no flipping transition. All the other trajectories get trapped in hydrophobically collapsed states. The NLE residues were found to be buried deeply into the core, compared to the corresponding lysines in the villin headpiece, thereby making the core tighter and harder to undo for 3-D rearrangement. Our results suggest that the NLE may not be a fast folder as experiments suggest. The tightness of the hydrophobic core may be a very important factor in the folding of larger proteins. It is likely that chaperones like GroEL act to undo the tight hydrophobic core of proteins, after most secondary structure elements have been formed, so that global rearrangement is easier. I conclude by presenting facts about chaperone-protein complexes and propose further directions for the study of protein folding.

The MUSE Machine -- an Architecture for Structured Data Flow Computation

Computers employing some degree of data flow organisation are now well established as providing a possible vehicle for concurrent computation. Although data-driven computation frees the architecture from the constraints of the single program counter, processor and global memory, inherent in the classic von Neumann computer, there can still be problems with the unconstrained generation of fresh result tokens if a pure data flow approach is adopted. The advantages of allowing serial processing for those parts of a program which are inherently serial, and of permitting a demand-driven, as well as data-driven, mode of operation are identified and described. The MUSE machine described here is a structured architecture supporting both serial and parallel processing which allows the abstract structure of a program to be mapped onto the machine in a logical way.

Collecting valuable consumer data: Motivating consumers to disclose personal information

Collecting and analyzing consumer data is essential in today’s data-driven business environment. However, consumers are becoming more aware of the value of the information they can provide to companies, thereby being more reluctant to share it for free. Therefore, companies need to find ways to motivate consumers to disclose personal information. The main research question of the study was formed as “How can companies motivate consumers to disclose personal information?” and it was further divided into two subquestions: 1) What types of benefits motivate consumers to disclose personal information? 2) How does the disclosure context affect the consumers’ information disclosure behavior? The conceptual framework consisted of a classification of extrinsic and intrinsic benefits, and moderating factors, which were recognized on the basis of prior research in the field. The study was conducted by using qualitative research methods. The primary data was collected by interviewing ten representatives from eight companies. The data was analyzed and reported according to predetermined themes. The findings of the study confirm that consumers can be motivated to disclose personal information by offering different types of extrinsic (monetary saving, time saving, self-enhancement, and social adjustment) and intrinsic (novelty, pleasure, and altruism) benefits. However, not all the benefits are equally useful ways to convince the customer to disclose information. Moreover, different factors in the disclosure context can either alleviate or increase the effectiveness of the benefits and the consumers’ motivation to disclose personal information. Such factors include the consumer’s privacy concerns, perceived trust towards the company, the relevancy of the requested information, personalization, website elements (especially security, usability, and aesthetics of a website), and the consumer’s shopping motivation. This study has several contributions. It is essential that companies recognize the most attractive benefits regarding their business and their customers, and that they understand how the disclosure context affects the consumer’s information disclosure behavior. The likelihood of information disclosure can be increased, for example, by offering benefits that meet the consumers’ needs and preferences, improving the relevancy of the asked information, stating the reasons for data collection, creating and maintaining a trustworthy image of the company, and enhancing the quality of the company’s website.

Using interaction data for improving the offline and online evaluation of search engines

This thesis investigates how web search evaluation can be improved using historical interaction data. Modern search engines combine offline and online evaluation approaches in a sequence of steps that a tested change needs to pass through to be accepted as an improvement and subsequently deployed. We refer to such a sequence of steps as an evaluation pipeline. In this thesis, we consider the evaluation pipeline to contain three sequential steps: an offline evaluation step, an online evaluation scheduling step, and an online evaluation step. In this thesis we show that historical user interaction data can aid in improving the accuracy or efficiency of each of the steps of the web search evaluation pipeline. As a result of these improvements, the overall efficiency of the entire evaluation pipeline is increased. Firstly, we investigate how user interaction data can be used to build accurate offline evaluation methods for query auto-completion mechanisms. We propose a family of offline evaluation metrics for query auto-completion that represents the effort the user has to spend in order to submit their query. The parameters of our proposed metrics are trained against a set of user interactions recorded in the search engine’s query logs. From our experimental study, we observe that our proposed metrics are significantly more correlated with an online user satisfaction indicator than the metrics proposed in the existing literature. Hence, fewer changes will pass the offline evaluation step to be rejected after the online evaluation step. As a result, this would allow us to achieve a higher efficiency of the entire evaluation pipeline. Secondly, we state the problem of the optimised scheduling of online experiments. We tackle this problem by considering a greedy scheduler that prioritises the evaluation queue according to the predicted likelihood of success of a particular experiment. This predictor is trained on a set of online experiments, and uses a diverse set of features to represent an online experiment. Our study demonstrates that a higher number of successful experiments per unit of time can be achieved by deploying such a scheduler on the second step of the evaluation pipeline. Consequently, we argue that the efficiency of the evaluation pipeline can be increased. Next, to improve the efficiency of the online evaluation step, we propose the Generalised Team Draft interleaving framework. Generalised Team Draft considers both the interleaving policy (how often a particular combination of results is shown) and click scoring (how important each click is) as parameters in a data-driven optimisation of the interleaving sensitivity. Further, Generalised Team Draft is applicable beyond domains with a list-based representation of results, i.e. in domains with a grid-based representation, such as image search. Our study using datasets of interleaving experiments performed both in document and image search domains demonstrates that Generalised Team Draft achieves the highest sensitivity. A higher sensitivity indicates that the interleaving experiments can be deployed for a shorter period of time or use a smaller sample of users. Importantly, Generalised Team Draft optimises the interleaving parameters w.r.t. historical interaction data recorded in the interleaving experiments. Finally, we propose to apply the sequential testing methods to reduce the mean deployment time for the interleaving experiments. We adapt two sequential tests for the interleaving experimentation. We demonstrate that one can achieve a significant decrease in experiment duration by using such sequential testing methods. The highest efficiency is achieved by the sequential tests that adjust their stopping thresholds using historical interaction data recorded in diagnostic experiments. Our further experimental study demonstrates that cumulative gains in the online experimentation efficiency can be achieved by combining the interleaving sensitivity optimisation approaches, including Generalised Team Draft, and the sequential testing approaches. Overall, the central contributions of this thesis are the proposed approaches to improve the accuracy or efficiency of the steps of the evaluation pipeline: the offline evaluation frameworks for the query auto-completion, an approach for the optimised scheduling of online experiments, a general framework for the efficient online interleaving evaluation, and a sequential testing approach for the online search evaluation. The experiments in this thesis are based on massive real-life datasets obtained from Yandex, a leading commercial search engine. These experiments demonstrate the potential of the proposed approaches to improve the efficiency of the evaluation pipeline.

Capability Matrix for Open Data

Part 14: Interoperability and Integration

WordPress as a framework for automated data capture, filtering and structuring processes

The Exhibitium Project , awarded by the BBVA Foundation, is a data-driven project developed by an international consortium of research groups . One of its main objectives is to build a prototype that will serve as a base to produce a platform for the recording and exploitation of data about art-exhibitions available on the Internet . Therefore, our proposal aims to expose the methods, procedures and decision-making processes that have governed the technological implementation of this prototype, especially with regard to the reuse of WordPress (WP) as development framework.

Multivalent reuse of web data about temporary art exhibitions: The Exhibitium Project

Our proposal aims to display the analysis techniques, methodologies as well as the most relevant results expected within the Exhibitium project framework (http://www.exhibitium.com). Awarded by the BBVA Foundation, the Exhibitium project is being developed by an international consortium of several research groups . Its main purpose is to build a comprehensive and structured data repository about temporary art exhibitions, captured from the web, to make them useful and reusable in various domains through open and interoperable data systems.

Business Process Management and Process Mining within a Real Business Environment: An Empirical Analysis of Event Logs Data in a Consulting Project

Il presente elaborato esplora l’attitudine delle organizzazioni nei confronti dei processi di business che le sostengono: dalla semi-assenza di struttura, all’organizzazione funzionale, fino all’avvento del Business Process Reengineering e del Business Process Management, nato come superamento dei limiti e delle problematiche del modello precedente. All’interno del ciclo di vita del BPM, trova spazio la metodologia del process mining, che permette un livello di analisi dei processi a partire dagli event data log, ossia dai dati di registrazione degli eventi, che fanno riferimento a tutte quelle attività supportate da un sistema informativo aziendale. Il process mining può essere visto come naturale ponte che collega le discipline del management basate sui processi (ma non data-driven) e i nuovi sviluppi della business intelligence, capaci di gestire e manipolare l’enorme mole di dati a disposizione delle aziende (ma che non sono process-driven). Nella tesi, i requisiti e le tecnologie che abilitano l’utilizzo della disciplina sono descritti, cosi come le tre tecniche che questa abilita: process discovery, conformance checking e process enhancement. Il process mining è stato utilizzato come strumento principale in un progetto di consulenza da HSPI S.p.A. per conto di un importante cliente italiano, fornitore di piattaforme e di soluzioni IT. Il progetto a cui ho preso parte, descritto all’interno dell’elaborato, ha come scopo quello di sostenere l’organizzazione nel suo piano di improvement delle prestazioni interne e ha permesso di verificare l’applicabilità e i limiti delle tecniche di process mining. Infine, nell’appendice finale, è presente un paper da me realizzato, che raccoglie tutte le applicazioni della disciplina in un contesto di business reale, traendo dati e informazioni da working papers, casi aziendali e da canali diretti. Per la sua validità e completezza, questo documento è stata pubblicato nel sito dell'IEEE Task Force on Process Mining.

Network Construction and Graph Theoretical Analysis of Functional Language Networks in Pediatric Epilepsy

This dissertation introduces a new approach for assessing the effects of pediatric epilepsy on the language connectome. Two novel data-driven network construction approaches are presented. These methods rely on connecting different brain regions using either extent or intensity of language related activations as identified by independent component analysis of fMRI data. An auditory description decision task (ADDT) paradigm was used to activate the language network for 29 patients and 30 controls recruited from three major pediatric hospitals. Empirical evaluations illustrated that pediatric epilepsy can cause, or is associated with, a network efficiency reduction. Patients showed a propensity to inefficiently employ the whole brain network to perform the ADDT language task; on the contrary, controls seemed to efficiently use smaller segregated network components to achieve the same task. To explain the causes of the decreased efficiency, graph theoretical analysis was carried out. The analysis revealed no substantial global network feature differences between the patient and control groups. It also showed that for both subject groups the language network exhibited small-world characteristics; however, the patient’s extent of activation network showed a tendency towards more random networks. It was also shown that the intensity of activation network displayed ipsilateral hub reorganization on the local level. The left hemispheric hubs displayed greater centrality values for patients, whereas the right hemispheric hubs displayed greater centrality values for controls. This hub hemispheric disparity was not correlated with a right atypical language laterality found in six patients. Finally it was shown that a multi-level unsupervised clustering scheme based on self-organizing maps, a type of artificial neural network, and k-means was able to fairly and blindly separate the subjects into their respective patient or control groups. The clustering was initiated using the local nodal centrality measurements only. Compared to the extent of activation network, the intensity of activation network clustering demonstrated better precision. This outcome supports the assertion that the local centrality differences presented by the intensity of activation network can be associated with focal epilepsy.

Análisis de las barreras para la unificación de una Historia Clínica Electrónica -HCE- en Colombia

Objetivo: Identificar las barreras para la unificación de una Historia Clínica Electrónica –HCE- en Colombia. Materiales y Métodos: Se realizó un estudio cualitativo. Se realizaron entrevistas semiestructuradas a profesionales y expertos de 22 instituciones del sector salud, de Bogotá y de los departamentos de Cundinamarca, Santander, Antioquia, Caldas, Huila, Valle del Cauca. Resultados: Colombia se encuentra en una estructuración para la implementación de la Historia Clínica Electrónica Unificada -HCEU-. Actualmente, se encuentra en unificación en 42 IPSs públicas en el departamento de Cundinamarca, el desarrollo de la HCEU en el país es privado y de desarrollo propio debido a las necesidades particulares de cada IPS. Conclusiones: Se identificaron barreras humanas, financieras, legales, organizacionales, técnicas y profesionales en los departamentos entrevistados. Se identificó que la unificación de la HCE depende del acuerdo de voluntades entre las IPSs del sector público, privado, EPSs, y el Gobierno Nacional.

Abusing data dominance in the digital market. The application of merger control and article 102 TFEU to data-related conducts.

The internet and digital technologies revolutionized the economy. Regulating the digital market has become a priority for the European Union. While promoting innovation and development, EU institutions must assure that the digital market maintains a competitive structure. Among the numerous elements characterizing the digital sector, users’ data are particularly important. Digital services are centered around personal data, the accumulation of which contributed to the centralization of market power in the hands of a few large providers. As a result, data-driven mergers and data-related abuses gained a central role for the purposes of EU antitrust enforcement. In light of these considerations, this work aims at assessing whether EU competition law is well-suited to address data-driven mergers and data-related abuses of dominance. These conducts are of crucial importance to the maintenance of competition in the digital sector, insofar as the accumulation of users’ data constitutes a fundamental competitive advantage. To begin with, part 1 addresses the specific features of the digital market and their impact on the definition of the relevant market and the assessment of dominance by antitrust authorities. Secondly, part 2 analyzes the EU’s case law on data-driven mergers to verify if merger control is well-suited to address these concentrations. Thirdly, part 3 discusses abuses of dominance in the phase of data collection and the legal frameworks applicable to these conducts. Fourthly, part 4 focuses on access to “essential” datasets and the indirect effects of anticompetitive conducts on rivals’ ability to access users’ information. Finally, Part 5 discusses differential pricing practices implemented online and based on personal data. As it will be assessed, the combination of an efficient competition law enforcement and the auspicial adoption of a specific regulation seems to be the best solution to face the challenges raised by “data-related dominance”.

Interpretable Convolutional Neural Networks for Decoding and Analyzing Neural Time Series Data

Machine learning is widely adopted to decode multi-variate neural time series, including electroencephalographic (EEG) and single-cell recordings. Recent solutions based on deep learning (DL) outperformed traditional decoders by automatically extracting relevant discriminative features from raw or minimally pre-processed signals. Convolutional Neural Networks (CNNs) have been successfully applied to EEG and are the most common DL-based EEG decoders in the state-of-the-art (SOA). However, the current research is affected by some limitations. SOA CNNs for EEG decoding usually exploit deep and heavy structures with the risk of overfitting small datasets, and architectures are often defined empirically. Furthermore, CNNs are mainly validated by designing within-subject decoders. Crucially, the automatically learned features mainly remain unexplored; conversely, interpreting these features may be of great value to use decoders also as analysis tools, highlighting neural signatures underlying the different decoded brain or behavioral states in a data-driven way. Lastly, SOA DL-based algorithms used to decode single-cell recordings rely on more complex, slower to train and less interpretable networks than CNNs, and the use of CNNs with these signals has not been investigated. This PhD research addresses the previous limitations, with reference to P300 and motor decoding from EEG, and motor decoding from single-neuron activity. CNNs were designed light, compact, and interpretable. Moreover, multiple training strategies were adopted, including transfer learning, which could reduce training times promoting the application of CNNs in practice. Furthermore, CNN-based EEG analyses were proposed to study neural features in the spatial, temporal and frequency domains, and proved to better highlight and enhance relevant neural features related to P300 and motor states than canonical EEG analyses. Remarkably, these analyses could be used, in perspective, to design novel EEG biomarkers for neurological or neurodevelopmental disorders. Lastly, CNNs were developed to decode single-neuron activity, providing a better compromise between performance and model complexity.

Advanced statistical models for the segregation, identification and measurement of coexisting sound sources

Long-term monitoring of acoustical environments is gaining popularity thanks to the relevant amount of scientific and engineering insights that it provides. The increasing interest is due to the constant growth of storage capacity and computational power to process large amounts of data. In this perspective, machine learning (ML) provides a broad family of data-driven statistical techniques to deal with large databases. Nowadays, the conventional praxis of sound level meter measurements limits the global description of a sound scene to an energetic point of view. The equivalent continuous level Leq represents the main metric to define an acoustic environment, indeed. Finer analyses involve the use of statistical levels. However, acoustic percentiles are based on temporal assumptions, which are not always reliable. A statistical approach, based on the study of the occurrences of sound pressure levels, would bring a different perspective to the analysis of long-term monitoring. Depicting a sound scene through the most probable sound pressure level, rather than portions of energy, brought more specific information about the activity carried out during the measurements. The statistical mode of the occurrences can capture typical behaviors of specific kinds of sound sources. The present work aims to propose an ML-based method to identify, separate and measure coexisting sound sources in real-world scenarios. It is based on long-term monitoring and is addressed to acousticians focused on the analysis of environmental noise in manifold contexts. The presented method is based on clustering analysis. Two algorithms, Gaussian Mixture Model and K-means clustering, represent the main core of a process to investigate different active spaces monitored through sound level meters. The procedure has been applied in two different contexts: university lecture halls and offices. The proposed method shows robust and reliable results in describing the acoustic scenario and it could represent an important analytical tool for acousticians.

Integrare gli approcci all'innovazione Data Science e Design Thinking: analisi teorica e applicazione al caso della sanità parmense

Nel panorama aziendale odierno, risulta essere di fondamentale importanza la capacità, da parte di un’azienda o di una società di servizi, di orientare in modo programmatico la propria innovazione in modo tale da poter essere competitivi sul mercato. In molti casi, questo e significa investire una cospicua somma di denaro in progetti che andranno a migliorare aspetti essenziali del prodotto o del servizio e che avranno un importante impatto sulla trasformazione digitale dell’azienda. Lo studio che viene proposto riguarda in particolar modo due approcci che sono tipicamente in antitesi tra loro proprio per il fatto che si basano su due tipologie di dati differenti, i Big Data e i Thick Data. I due approcci sono rispettivamente il Data Science e il Design Thinking. Nel corso dei seguenti capitoli, dopo aver definito gli approcci di Design Thinking e Data Science, verrà definito il concetto di blending e la problematica che ruota attorno all’intersezione dei due metodi di innovazione. Per mettere in evidenza i diversi aspetti che riguardano la tematica, verranno riportati anche casi di aziende che hanno integrato i due approcci nei loro processi di innovazione, ottenendo importanti risultati. In particolar modo verrà riportato il lavoro di ricerca svolto dall’autore riguardo l'esame, la classificazione e l'analisi della letteratura esistente all'intersezione dell'innovazione guidata dai dati e dal pensiero progettuale. Infine viene riportato un caso aziendale che è stato condotto presso la realtà ospedaliero-sanitaria di Parma in cui, a fronte di una problematica relativa al rapporto tra clinici dell’ospedale e clinici del territorio, si è progettato un sistema innovativo attraverso l’utilizzo del Design Thinking. Inoltre, si cercherà di sviluppare un’analisi critica di tipo “what-if” al fine di elaborare un possibile scenario di integrazione di metodi o tecniche provenienti anche dal mondo del Data Science e applicarlo al caso studio in oggetto.

Comparison of friction models applied to a control valve

Eight different models to represent the effect of friction in control valves are presented: four models based on physical principles and four empirical ones. The physical models, both static and dynamic, have the same structure. The models are implemented in Simulink/Matlab (R) and compared, using different friction coefficients and input signals. Three of the models were able to reproduce the stick-slip phenomenon and passed all the tests, which were applied following ISA standards. (C) 2008 Elsevier Ltd. All rights reserved.