94 research outputs found
Identification of robotic manipulators' inverse dynamics coefficients via model-based adaptive networks
The values of a given manipulator's dynamics coefficients need to be accurately
identified in order to employ model-based algorithms in the control of its motion. This
thesis details the development of a novel form of adaptive network which is capable of
accurately learning the coefficients of systems, such as manipulator inverse dynamics,
where the algebraic form is known but the coefficients' values are not. Empirical motion
data from a pair of PUMA 560s has been processed by the Context-Sensitive Linear
Combiner (CSLC) network developed, and the coefficients of their inverse dynamics
identified. The resultant precision of control is shown to be superior to that achieved from
employing dynamics coefficients derived from direct measurement.
As part of the development of the CSLC network, the process of network learning is
examined. This analysis reveals that current network architectures for processing analogue
output systems with high input order are highly unlikely to produce solutions that are
good estimates throughout the entire problem space. In contrast, the CSLC network is
shown to generalise intrinsically as a result of its structure, whilst its training is greatly
simplified by the presence of only one minima in the network's error hypersurface.
Furthermore, a fine-tuning algorithm for network training is presented which takes
advantage of the CSLC network's single adaptive layer structure and does not rely upon
gradient descent of the network error hypersurface, which commonly slows the later
stages of network training
De novo prediction of RNA-protein interactions with graph neural networks
RNA-binding proteins (RBPs) are key co- and post-transcriptional regulators of gene expression, playing a crucial role in many biological processes. Experimental methods like CLIP-seq have enabled the identification of transcriptome-wide RNA-protein interactions for select proteins; however, the time- and resource-intensive nature of these technologies call for the development of computational methods to complement their predictions. Here, we leverage recent, large-scale CLIP-seq experiments to construct a de novo predictor of RNA-protein interactions based on graph neural networks (GNN). We show that the GNN method allows us not only to predict missing links in an RNA-protein network, but to predict the entire complement of targets of previously unassayed proteins, and even to reconstruct the entire network of RNA-protein interactions in different conditions based on minimal information. Our results demonstrate the potential of modern machine learning methods to extract useful information on post-transcriptional regulation from large data sets
Mathematical Problems in Rock Mechanics and Rock Engineering
With increasing requirements for energy, resources and space, rock engineering projects are being constructed more often and are operated in large-scale environments with complex geology. Meanwhile, rock failures and rock instabilities occur more frequently, and severely threaten the safety and stability of rock engineering projects. It is well-recognized that rock has multi-scale structures and involves multi-scale fracture processes. Meanwhile, rocks are commonly subjected simultaneously to complex static stress and strong dynamic disturbance, providing a hotbed for the occurrence of rock failures. In addition, there are many multi-physics coupling processes in a rock mass. It is still difficult to understand these rock mechanics and characterize rock behavior during complex stress conditions, multi-physics processes, and multi-scale changes. Therefore, our understanding of rock mechanics and the prevention and control of failure and instability in rock engineering needs to be furthered. The primary aim of this Special Issue “Mathematical Problems in Rock Mechanics and Rock Engineering” is to bring together original research discussing innovative efforts regarding in situ observations, laboratory experiments and theoretical, numerical, and big-data-based methods to overcome the mathematical problems related to rock mechanics and rock engineering. It includes 12 manuscripts that illustrate the valuable efforts for addressing mathematical problems in rock mechanics and rock engineering
Previsão e análise da estrutura e dinâmica de redes biológicas
Increasing knowledge about the biological processes that govern the
dynamics of living organisms has fostered a better understanding of the
origin of many diseases as well as the identification of potential therapeutic
targets. Biological systems can be modeled through biological networks,
allowing to apply and explore methods of graph theory in their investigation
and characterization. This work had as main motivation the inference of
patterns and rules that underlie the organization of biological networks.
Through the integration of different types of data, such as gene expression,
interaction between proteins and other biomedical concepts, computational
methods have been developed so that they can be used to predict and study
diseases.
The first contribution, was the characterization a subsystem of the human
protein interactome through the topological properties of the networks that
model it. As a second contribution, an unsupervised method using biological
criteria and network topology was used to improve the understanding of
the genetic mechanisms and risk factors of a disease through co-expression
networks. As a third contribution, a methodology was developed to remove
noise (denoise) in protein networks, to obtain more accurate models, using
the network topology. As a fourth contribution, a supervised methodology
was proposed to model the protein interactome dynamics, using exclusively
the topology of protein interactions networks that are part of the dynamic
model of the system.
The proposed methodologies contribute to the creation of more precise,
static and dynamic biological models through the identification and use of
topological patterns of protein interaction networks, which can be used to
predict and study diseases.O conhecimento crescente sobre os processos biológicos que regem a
dinâmica dos organismos vivos tem potenciado uma melhor compreensão da
origem de muitas doenças, assim como a identificação de potenciais alvos
terapêuticos. Os sistemas biológicos podem ser modelados através de redes
biológicas, permitindo aplicar e explorar métodos da teoria de grafos na sua
investigação e caracterização. Este trabalho teve como principal motivação
a inferência de padrões e de regras que estão subjacentes à organização de
redes biológicas.
Através da integração de diferentes tipos de dados, como a expressão
de genes, interação entre proteínas e outros conceitos biomédicos, foram
desenvolvidos métodos computacionais, para que possam ser usados na
previsão e no estudo de doenças.
Como primeira contribuição, foi proposto um método de caracterização de
um subsistema do interactoma de proteínas humano através das propriedades
topológicas das redes que o modelam. Como segunda contribuição, foi
utilizado um método não supervisionado que utiliza critérios biológicos e
topologia de redes para, através de redes de co-expressão, melhorar a
compreensão dos mecanismos genéticos e dos fatores de risco de uma
doença. Como terceira contribuição, foi desenvolvida uma metodologia
para remover ruído (denoise) em redes de proteínas, para obter modelos
mais precisos, utilizando a topologia das redes. Como quarta contribuição,
propôs-se uma metodologia supervisionada para modelar a dinâmica do
interactoma de proteínas, usando exclusivamente a topologia das redes de
interação de proteínas que fazem parte do modelo dinâmico do sistema.
As metodologias propostas contribuem para a criação de modelos biológicos,
estáticos e dinâmicos, mais precisos, através da identificação e uso de
padrões topológicos das redes de interação de proteínas, que podem ser
usados na previsão e no estudo doenças.Programa Doutoral em Engenharia Informátic
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Analysis of the understudied parts of the phospho-signalome using machine learning methods
Abstract
Analysis of the understudied parts of the phospho-signalome using machine learning methods
Borgthor Petursson
In order to make decisions and respond appropriately to external stimuli, cells rely on an intricate signalling system. One of the most important and best studied components of this signalling system is the phospho-signalling network. Phosphorylation relays information through adding phosphoryl groups onto substrates such as lipids or proteins, which in turn leads to changes in substrate function. Crucial components of this system include kinases, which phosphorylate on the substrate molecule and phosphatases that remove the phosphoryl group from the substrate.
To date, even though >100K phosphoproteins have been identified through high throughput experiments, the vast majority of phosphosites are of unknown function, while over a third of kinases have no known substrate (Needham et al., 2019). Furthermore, there is a large study bias in our current knowledge, demonstrated by a disproportionate number of interactions between highly cited kinases and substrates Invergo and Beltrao, 2018. The vast understudied signalling space combined with this study bias make it difficult to understand the general principles underpinning cell signalling regulation and stresses the need to research the phosphoproteomic signalling system in an unbiased manner.
In this thesis the central aim is to use data-driven and unbiased approaches to study the human phosphoproteomic signalling network. The first chapter describes a project where I co-developed a machine learning model to predict signed kinase-kinase regulatory circuits based on kinase specificities and high throughput phosphoproteomics and transcriptomic data. The network was validated using independent high throughput data and used to identify novel kinase-kinase regulatory interactions. This project was done in collaboration with Brandon Invergo, a postdoc in Pedro Beltrao’s research group.
In the second chapter I expand upon work done in the first chapter. I used various predictors such as: Co-expression, kinase specificities and different variables characterising kinase-substrate potential target phosphosites to predict kinase-substrate relationships and their signs. I then used independent experimental kinase-substrate predictions to validate the predictions and identify high confidence kinase-substrate relationships. I then combined the kinase-substrate predictions with the kinase-kinase regulatory circuits to identify condition-specific signalling networks. To enable easy use of my method and networks and analyses of phosphoproteomics data by non-expert users I also developed the SELPHI2 server, where the user can extract biological insight from their datasets. SELPHI2 presents a substantial improvement upon the SELPHI server, which was developed in 2015 by my supervisor, Evangelia Petsalaki.
Thirdly, to study the architecture of human cell signalling networks at a whole-cell level and address the limited predictive power of the current models of cell signalling such as pathways found in KEGG (Kanehisa, 2019), Reactome (Jassal et al., 2020) and WikiPathways (Slenter et al., 2018), the third chapter aims to identify signalling modules from phosphoproteomic data. These data-extracted modules were found to have a greater predictive power for independent data sets in terms of number of significant enrichments. Furthermore, we sought to predict the probability of module co-membership from predictors such as membership within data-driven modules, co-phosphorylation and co-expression.
In summary, the work presented here seeks to explore the understudied phospho-signalling systems through system-wide prediction of kinase-substrate regulation and the identification of phospho-signalling modules through data-driven means
5HTTLPR Polymorphism, stressful events, neuropsychological performance and brain connectivity in eating disorders
Abstract Introduction. Low functioning variants of 5HTTLPR have been associated to an increased risk of depression in subjects who experienced stressful events, to altered cognitive functioning and decisional processes, and functional and structural neural patterns. Contrasting evidence is available up to now in Eating Disorders (ED), and no study has evaluated the polymorphism effect on brain connectivity according to graph theory in Anorexia Nervosa (AN). Methods. We recruited up to 735 patients with life-time history of AN or bulimia nervosa (BN) according to DSM-IV criteria and up to 241 healthy controls (HC) for the assessment of the association between 5HTTLPR polymorphism and ED. We merged our Biobank data from BIO.Ve.D.A. and meta-analyzed 22 former studies. Patients underwent a structured diagnostic interview for present or life-time ED, an interview for presence and severity of stressful events, Edinburgh Handedness Inventory, Wisconsin Card Sorting Test, Trail A making test, Trail B making test, Iowa Gambling Task, Cognitive Bias Task, psychopathology rating scales for ED and general symptoms. Finally patients with AN and HCs underwent a Magnetic Resonance; their brains’ connectivity integration and segregation measures were then measured with Graph Analysis Toolbox, according to 5HTTLPR polymorpshim. Results. Our results from a meta-analysis including data from BIO.Ve.D.A. and 22 previous studies, suggest that 5HTTLPR polymorphism does not have a role per se in determing ED onset. However it may moderate the effect of SEs in increasing the risk of ED onset, and the influence of SEs on ED severity, anxious, depressive and obsessive symptoms. When we tested both a multiplicative and an additive model, which is considered to be more representative of a real-world gene by environment interaction, such a 5HTTLPR by SE interaction was not confirmed instead. S allele was associated with worse performance at Cognitive Bias Task and Trail Making B, and with increased ED psychopathology, general psychopathology, anxious, depressive, and obsessive symptoms. Finally S allele was associated with decreased segregation measures at brain connectivity analysis according to graph theory compared with L allele in AN; this was an opposite association compared with healthy controls who had higher modularity associated with S allele instead. Conclusions. 5HTTLPR polymorphism does not seem to be a causal factor of ED per se, but it seems to play a role in moderating the role of stressful events in increasing ED risk. Such a moderation however did not reflect a gene by environment interaction according to either a multiplicative or additive model. S allele was associated with higher psychopathology scores, and worse neuropsychological functions in AN, and with a disrupted segregation measures of brain signal connectivity compared to HCs
Neurobiological markers for remission and persistence of childhood attention-deficit/hyperactivity disorder
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in children. Symptoms of childhood ADHD persist into adulthood in around 65% of patients, which elevates the risk for a number of adverse outcomes, resulting in substantial individual and societal burden. A neurodevelopmental double dissociation model is proposed based on existing studies in which the early onset of childhood ADHD is suggested to associate with dysfunctional subcortical structures that remain static throughout the lifetime; while diminution of symptoms over development could link to optimal development of prefrontal cortex. Current existing studies only assess basic measures including regional brain activation and connectivity, which have limited capacity to characterize the functional brain as a high performance parallel information processing system, the field lacks systems-level investigations of the structural and functional patterns that significantly contribute to the symptom remission and persistence in adults with childhood ADHD. Furthermore, traditional statistical methods estimate group differences only within a voxel or region of interest (ROI) at a time without having the capacity to explore how ROIs interact in linear and/or non-linear ways, as they quickly become overburdened when attempting to combine predictors and their interactions from high-dimensional imaging data set.
This dissertation is the first study to apply ensemble learning techniques (ELT) in multimodal neuroimaging features from a sample of adults with childhood ADHD and controls, who have been clinically followed up since childhood. A total of 36 adult probands who were diagnosed with ADHD combined-type during childhood and 36 matched normal controls (NCs) are involved in this dissertation research. Thirty-six adult probands are further split into 18 remitters (ADHD-R) and 18 persisters (ADHD-P) based on the symptoms in their adulthood from DSM-IV ADHD criteria. Cued attention task-based fMRI, structural MRI, and diffusion tensor imaging data from each individual are analyzed. The high-dimensional neuroimaging features, including pair-wise regional connectivity and global/nodal topological properties of the functional brain network for cue-evoked attention process, regional cortical thickness and surface area, subcortical volume, volume and fractional anisotropy of major white matter fiber tract for each subject are calculated. In addition, all the currently available optimization strategies for ensemble learning techniques (i.e., voting, bagging, boosting and stacking techniques) are tested in a pool of semi-final classification results generated by seven basic classifiers, including K-Nearest Neighbors, support vector machine (SVM), logistic regression, Naïve Bayes, linear discriminant analysis, random forest, and multilayer perceptron.
As hypothesized, results indicate that the features of nodal efficiency in right inferior frontal gyrus, right middle frontal (MFG)-inferior parietal (IPL) functional connectivity, and right amygdala volume significantly contributed to accurate discrimination between ADHD probands and controls; higher nodal efficiency of right MFG greatly contributed to inattentive and hyperactive/impulsive symptom remission, while higher right MFG-IPL functional connectivity strongly linked to symptom persistence in adults with childhood ADHD. The utilization of ELTs indicates that the bagging-based ELT with the base model of SVM achieves the best results, with the most significant improvement of the area under the receiver of operating characteristic curve (0.89 for ADHD probands vs. NCs, and 0.9 for ADHD-P vs. ADHD-R). The outcomes of this dissertation research have considerable value for the development of novel interventions that target mechanisms associated with recovery
Understanding factors that influence energy saving campaigns using theory and agent based modelling.
Utilising data from a sample of UK HEI students, this study investigates factors that influence informational interventions for energy saving. It makes an original
contribution by developing an original method for testing theory and explaining how known persuasion and behavioural variables can interact to influence
behavioural outcomes. It achieves this by integrating two empirically established theories—the Theory of Planned Behaviour and the Elaboration Likelihood Model—and using these, develops an agent-based model based for explaining behavioural response to an energy saving intervention. In a first phase, questionnaire surveys based on the stated theories are used to elicit essential information relating to energy use among students. Findings demonstrate that both theories can be used successfully as a framework for understanding how information-based interventions influence energy use. The second phase involving agent-based modelling demonstrated that although the adoption of energy saving behaviour is time-dependent, it is neither proportional to population size nor to time. Further findings show that subjective norms such as the opinions of important others, significantly influence students’ intentions to save energy; and maximum levels of peripheral cues, personal relevance and cognitive ability are individual factors which determine the highest levels of aggregate energy saving. Interrelationships observed among variables indicate that the degree to which cognitive, social, environmental, and situational factors etc. interact in the face of persuasive information, may be more instrumental to achieving desirable energy behaviours than the communication of useful information or even, the information itself. Ideas and findings from the study will be useful for informing the design of behavioural interventions. Further research to investigate the affective tendencies of subjective norms and any effects on attitude and the intention-behaviour gap will be useful for gaining more insight which may help extend the Theory of Planned Behaviour.PhD in Energy and Powe
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