Sequence and Structural Determinants of Specificity Differences between Paralogous Transcription Factors

Transcription factors (TFs) control the temporal and spatial expression of target genes by interacting with DNA in a sequence-specific manner. Recent advances in high throughput experiments that measure TF-DNA interactions in vitro and in vivo have facilitated the identification of DNA binding sites for thousands of TFs. However, it remains unclear how each individual TF achieves its specificity, especially in the case of paralogous TFs that recognize distinct target genomic sites despite sharing very similar DNA binding motifs. In my work, I used a combination of high throughput in vitro protein-DNA binding assays and machine-learning algorithms to characterize and model the binding specificity of 11 paralogous TFs from 4 distinct structural families. My work proves that even very closely related paralogous TFs, with indistinguishable DNA binding motifs, oftentimes exhibit differential binding specificity for their genomic target sites, especially for sites with moderate binding affinity. Importantly, the differences I identify in vitro and through computational modeling help explain, at least in part, the differential in vivo genomic targeting by paralogous TFs. Future work will focus on in vivo factors that might also be important for specificity differences between paralogous TFs, such as DNA methylation, interactions with protein cofactors, or the chromatin environment. In this larger context, my work emphasizes the importance of intrinsic DNA binding specificity in targeting of paralogous TFs to the genome.

Structural and agentic analysis of supply-chains: a social network analysis approach

This research adds to a body of work exploring the role of Social Network Analysis (SNA) in the study of both relational and structural characteristics of supply chain networks. Two contrasting network cases (food enterprises and digital-based enterprises) are chosen in order to elicit structural differences in business networks subject to divergences in local embeddedness and the relative materiality of the goods and services produced. Our analysis and findings draw out differences in network structure as evidenced by metrics of network centralization and cohesion, the presence of components and other sub-groupings, and the position of central actors. We relate these structural features both to the nature of the networks and to the (qualitative) experiences of the actors themselves. We find, in particular, the role of customers as co-creators of knowledge (for the Food network), the central role of infrastructure and services (for the Digital network), the importance of ICT as a source of codified knowledge inputs, along with the continuing importance of geographical proximity for the development and transfer of tacit knowledge and for incremental learning.

The potential contributions of concept maps for learning website to assessment for learning practices

The purpose of this paper is to examine the promising contributions of the Concept Maps for Learning (CMfL) website to assessment for learning practices. The CMfL website generates concept maps from relatedness degree of concepts pairs through the Pathfinder Scaling Algorithm. This website also confirms the established principles of effective assessment for learning, for it is capable of automatically assessing students' higher order knowledge, simultaneously identifying strengths and weaknesses, immediately providing useful feedback and being user-friendly. According to the default assessment plan, students first create concept maps on a particular subject and then they are given individualized visual feedback followed by associated instructional material (e.g., videos, website links, examples, problems, etc.) based on a comparison of their concept map and a subject matter expert's map. After studying the feedback and instructional material, teachers can monitor their students' progress by having them create revised concept maps. Therefore, we claim that the CMfL website may reduce the workload of teachers as well as provide immediate and delayed feedback on the weaknesses of students in different forms such as graphical and multimedia. For the following study, we will examine whether these promising contributions to assessment for learning are valid in a variety of subjects.

Convex Optimization Algorithms and Statistical Bounds for Learning Structured Models

Thesis (Ph.D.)--University of Washington, 2016-08

Adapting prospective structural analysis to strengthen sustainable management and capacity building in community-based natural resource management contexts

Local communities collectively managing common pool resources can play an important role in sustainable management, but they often lack the skills and context-specific tools required for such management. The complex dynamics of social-ecological systems (SES), the need for management capacities, and communities’ limited empowerment and participation skills present challenges for community-based natural resource management (CBNRM) strategies. We analyzed the applicability of prospective structural analysis (PSA), a strategic foresight tool, to support decision making and to foster sustainable management and capacity building in CBNRM contexts and the modifications necessary to use the tool in such contexts. By testing PSA in three SES in Colombia, Mexico, and Argentina, we gathered information regarding the potential of this tool and its adaptation requirements. The results suggest that the tool can be adapted to these contexts and contribute to fostering sustainable management and capacity building. It helped identify the systems’ dynamics, thus increasing the communities’ knowledge about their SES and informing the decision-making process. Additionally, it drove a learning process that both fostered empowerment and built participation skills. The process demanded both time and effort, and required external monitoring and facilitation, but community members could be trained to master it. Thus, we suggest that the PSA technique has the potential to strengthen CBNRM and that other initiatives could use it, but they must be aware of these requirements.

A satisfação e a intenção de continuidade de uso em servços de e-learning:validação empírica de um modelo aplicado no serviço público

The present study aims to investigate the constructs of Technological Readiness Index (TRI) and the Expectancy Disconfirmation Theory (EDT) as determinants of satisfaction and continuance intention use in e-learning services. Is proposed a theoretical model that seeks to measure the phenomenon suited to the needs of public organizations that offer distance learning course with the use of virtual platforms for employees. The research was conducted from a quantitative analytical approach, via online survey in a sample of 343 employees of 2 public organizations in RN who have had e-learning experience. The strategy of data analysis used multivariate analysis techniques, including structural equation modeling (SEM), operationalized by AMOS© software. The results showed that quality, quality disconfirmation, value and value disconfirmation positively impact on satisfaction, as well as disconfirmation usability, innovativeness and optimism. Likewise, satisfaction proved to be decisive for the purpose of continuance intention use. In addition, technological readiness and performance are strongly related. Based on the structural model found by the study, public organizations can implement e-learning services for employees focusing on improving learning and improving skills practiced in the organizational environment

Structure learning of context-specific graphical models

Abstract The ultimate problem considered in this thesis is modeling a high-dimensional joint distribution over a set of discrete variables. For this purpose, we consider classes of context-specific graphical models and the main emphasis is on learning the structure of such models from data. Traditional graphical models compactly represent a joint distribution through a factorization justi ed by statements of conditional independence which are encoded by a graph structure. Context-speci c independence is a natural generalization of conditional independence that only holds in a certain context, speci ed by the conditioning variables. We introduce context-speci c generalizations of both Bayesian networks and Markov networks by including statements of context-specific independence which can be encoded as a part of the model structures. For the purpose of learning context-speci c model structures from data, we derive score functions, based on results from Bayesian statistics, by which the plausibility of a structure is assessed. To identify high-scoring structures, we construct stochastic and deterministic search algorithms designed to exploit the structural decomposition of our score functions. Numerical experiments on synthetic and real-world data show that the increased exibility of context-specific structures can more accurately emulate the dependence structure among the variables and thereby improve the predictive accuracy of the models.

To Integrate Or Not: A Comparison of the English Skills of Finnish Students in Mainstream Education and Content and Language Integrated Learning

The objective of the thesis was to study the possible linguistic differences of English of Finnish mainstream students and Finnish students following content and language integrated learning (CLIL), in terms of the given language test. The difference of test results between the test groups was further analyzed in more detail. The research was carried out by comparing the 9th grade students of the Finnish comprehensive school (the mainstream group) and CLIL students of the 9th grade of the Finnish comprehensive school (the CLIL group). The comparison was based on the national language test for the 9th grade students of the Finnish comprehensive school 2006 (A-English), produced by Sukol-Palvelu, owned by the Federation of Foreign Language Teachers in Finland SUKOL. The mainstream group of the present study consisted of 30 students, whereas the CLIL group included 27 students. Testing was carried out in spring 2007. The test results of the mainstream group (average of 64.1% out of the maximum score) were consistent with the results of the national average (63.9%). The average score of the CLIL students for the present study was 83.3% out of the maximum score. The results of the two groups in question were rather similar in the tasks measuring the skill of listening comprehension, in addition to one of the reading comprehension tasks. Moreover, a particular task with requirements of cultural and reactional skills produced results rather similar between the test groups. The differences between the results of the mainstream group and the CLIL group were most evident in three particular tasks. In general, the CLIL group performed clearly better than the mainstream group in the task measuring the knowledge of the polite conversational manners of the English-speaking world and in the tasks with requirements of lexical and structural knowledge of English. However, the writing task resulted in the most evident difference of results between the groups. In other words, the CLIL students of the present study were clearly more capable of producing English language with more varied vocabulary and more complex structures than the mainstream students. Thus, it might be argued whether the CLIL programme is to enhance the students´ performance in the productive skill of writing in particular. As a result, it might be useful to consider the possibilities of the CLIL programme in developing certain linguistic skills of the mainstream students of English as well.

A satisfação e a intenção de continuidade de uso em servços de e-learning:validação empírica de um modelo aplicado no serviço público

The present study aims to investigate the constructs of Technological Readiness Index (TRI) and the Expectancy Disconfirmation Theory (EDT) as determinants of satisfaction and continuance intention use in e-learning services. Is proposed a theoretical model that seeks to measure the phenomenon suited to the needs of public organizations that offer distance learning course with the use of virtual platforms for employees. The research was conducted from a quantitative analytical approach, via online survey in a sample of 343 employees of 2 public organizations in RN who have had e-learning experience. The strategy of data analysis used multivariate analysis techniques, including structural equation modeling (SEM), operationalized by AMOS© software. The results showed that quality, quality disconfirmation, value and value disconfirmation positively impact on satisfaction, as well as disconfirmation usability, innovativeness and optimism. Likewise, satisfaction proved to be decisive for the purpose of continuance intention use. In addition, technological readiness and performance are strongly related. Based on the structural model found by the study, public organizations can implement e-learning services for employees focusing on improving learning and improving skills practiced in the organizational environment

Motivation and relationship of the student with the school as factors involved in the perceived learning

Motivation should be seen as a very important factor in the learning process. The motivated student has the inner strength to learn, to discover and capitalize on capabilities, to improve academic performance and to adapt to the demands of the school context. Contextual factors like the psychological sense of school membership may be also especially important to students’ classroom engagement, their motivation and learning success. So with this study we intend to examine how the sense of school belonging and intrinsic motivation influences perceived learning.A structural model reveals that the negative sense of school belonging has a negative impact on intrinsic motivation and on perceived learning. In turn, intrinsic motivation positively and significantly influences perceived learning in the course.

Structural brain connectivity and cognitive ability differences: A multivariate distance matrix regression analysis

Neuroimaging research involves analyses of huge amounts of biological data that might or might not be related with cognition. This relationship is usually approached using univariate methods, and, therefore, correction methods are mandatory for reducing false positives. Nevertheless, the probability of false negatives is also increased. Multivariate frameworks have been proposed for helping to alleviate this balance. Here we apply multivariate distance matrix regression for the simultaneous analysis of biological and cognitive data, namely, structural connections among 82 brain regions and several latent factors estimating cognitive performance. We tested whether cognitive differences predict distances among individuals regarding their connectivity pattern. Beginning with 3,321 connections among regions, the 36 edges better predicted by the individuals' cognitive scores were selected. Cognitive scores were related to connectivity distances in both the full (3,321) and reduced (36) connectivity patterns. The selected edges connect regions distributed across the entire brain and the network defined by these edges supports high-order cognitive processes such as (a) (fluid) executive control, (b) (crystallized) recognition, learning, and language processing, and (c) visuospatial processing. This multivariate study suggests that one widespread, but limited number, of regions in the human brain, supports high-level cognitive ability differences. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

Deep Learning Architectures for time of arrival detection in Acoustic Emissions Monitoring

Acoustic Emission (AE) monitoring can be used to detect the presence of damage as well as determine its location in Structural Health Monitoring (SHM) applications. Information on the time difference of the signal generated by the damage event arriving at different sensors is essential in performing localization. This makes the time of arrival (ToA) an important piece of information to retrieve from the AE signal. Generally, this is determined using statistical methods such as the Akaike Information Criterion (AIC) which is particularly prone to errors in the presence of noise. And given that the structures of interest are surrounded with harsh environments, a way to accurately estimate the arrival time in such noisy scenarios is of particular interest. In this work, two new methods are presented to estimate the arrival times of AE signals which are based on Machine Learning. Inspired by great results in the field, two models are presented which are Deep Learning models - a subset of machine learning. They are based on Convolutional Neural Network (CNN) and Capsule Neural Network (CapsNet). The primary advantage of such models is that they do not require the user to pre-define selected features but only require raw data to be given and the models establish non-linear relationships between the inputs and outputs. The performance of the models is evaluated using AE signals generated by a custom ray-tracing algorithm by propagating them on an aluminium plate and compared to AIC. It was found that the relative error in estimation on the test set was < 5% for the models compared to around 45% of AIC. The testing process was further continued by preparing an experimental setup and acquiring real AE signals to test on. Similar performances were observed where the two models not only outperform AIC by more than a magnitude in their average errors but also they were shown to be a lot more robust as compared to AIC which fails in the presence of noise.

Exploiting the environment for structural health monitoring: Strategies, algorithms, and technologies

A densely built environment is a complex system of infrastructure, nature, and people closely interconnected and interacting. Vehicles, public transport, weather action, and sports activities constitute a manifold set of excitation and degradation sources for civil structures. In this context, operators should consider different factors in a holistic approach for assessing the structural health state. Vibration-based structural health monitoring (SHM) has demonstrated great potential as a decision-supporting tool to schedule maintenance interventions. However, most excitation sources are considered an issue for practical SHM applications since traditional methods are typically based on strict assumptions on input stationarity. Last-generation low-cost sensors present limitations related to a modest sensitivity and high noise floor compared to traditional instrumentation. If these devices are used for SHM in urban scenarios, short vibration recordings collected during high-intensity events and vehicle passage may be the only available datasets with a sufficient signal-to-noise ratio. While researchers have spent efforts to mitigate the effects of short-term phenomena in vibration-based SHM, the ultimate goal of this thesis is to exploit them and obtain valuable information on the structural health state. First, this thesis proposes strategies and algorithms for smart sensors operating individually or in a distributed computing framework to identify damage-sensitive features based on instantaneous modal parameters and influence lines. Ordinary traffic and people activities become essential sources of excitation, while human-powered vehicles, instrumented with smartphones, take the role of roving sensors in crowdsourced monitoring strategies. The technical and computational apparatus is optimized using in-memory computing technologies. Moreover, identifying additional local features can be particularly useful to support the damage assessment of complex structures. Thereby, smart coatings are studied to enable the self-sensing properties of ordinary structural elements. In this context, a machine-learning-aided tomography method is proposed to interpret the data provided by a nanocomposite paint interrogated electrically.

Development and characterization of deep learning techniques for neuroimaging data

Deep learning methods are extremely promising machine learning tools to analyze neuroimaging data. However, their potential use in clinical settings is limited because of the existing challenges of applying these methods to neuroimaging data. In this study, first a data leakage type caused by slice-level data split that is introduced during training and validation of a 2D CNN is surveyed and a quantitative assessment of the model’s performance overestimation is presented. Second, an interpretable, leakage-fee deep learning software written in a python language with a wide range of options has been developed to conduct both classification and regression analysis. The software was applied to the study of mild cognitive impairment (MCI) in patients with small vessel disease (SVD) using multi-parametric MRI data where the cognitive performance of 58 patients measured by five neuropsychological tests is predicted using a multi-input CNN model taking brain image and demographic data. Each of the cognitive test scores was predicted using different MRI-derived features. As MCI due to SVD has been hypothesized to be the effect of white matter damage, DTI-derived features MD and FA produced the best prediction outcome of the TMT-A score which is consistent with the existing literature. In a second study, an interpretable deep learning system aimed at 1) classifying Alzheimer disease and healthy subjects 2) examining the neural correlates of the disease that causes a cognitive decline in AD patients using CNN visualization tools and 3) highlighting the potential of interpretability techniques to capture a biased deep learning model is developed. Structural magnetic resonance imaging (MRI) data of 200 subjects was used by the proposed CNN model which was trained using a transfer learning-based approach producing a balanced accuracy of 71.6%. Brain regions in the frontal and parietal lobe showing the cerebral cortex atrophy were highlighted by the visualization tools.

Deep learning and embeddings for problems of computational biology

The development of Next Generation Sequencing promotes Biology in the Big Data era. The ever-increasing gap between proteins with known sequences and those with a complete functional annotation requires computational methods for automatic structure and functional annotation. My research has been focusing on proteins and led so far to the development of three novel tools, DeepREx, E-SNPs&GO and ISPRED-SEQ, based on Machine and Deep Learning approaches. DeepREx computes the solvent exposure of residues in a protein chain. This problem is relevant for the definition of structural constraints regarding the possible folding of the protein. DeepREx exploits Long Short-Term Memory layers to capture residue-level interactions between positions distant in the sequence, achieving state-of-the-art performances. With DeepRex, I conducted a large-scale analysis investigating the relationship between solvent exposure of a residue and its probability to be pathogenic upon mutation. E-SNPs&GO predicts the pathogenicity of a Single Residue Variation. Variations occurring on a protein sequence can have different effects, possibly leading to the onset of diseases. E-SNPs&GO exploits protein embeddings generated by two novel Protein Language Models (PLMs), as well as a new way of representing functional information coming from the Gene Ontology. The method achieves state-of-the-art performances and is extremely time-efficient when compared to traditional approaches. ISPRED-SEQ predicts the presence of Protein-Protein Interaction sites in a protein sequence. Knowing how a protein interacts with other molecules is crucial for accurate functional characterization. ISPRED-SEQ exploits a convolutional layer to parse local context after embedding the protein sequence with two novel PLMs, greatly surpassing the current state-of-the-art. All methods are published in international journals and are available as user-friendly web servers. They have been developed keeping in mind standard guidelines for FAIRness (FAIR: Findable, Accessible, Interoperable, Reusable) and are integrated into the public collection of tools provided by ELIXIR, the European infrastructure for Bioinformatics.