Developing multidimensional metrics for evaluating paediatric neurodevelopmental disorders

Healthy brain functioning depends on efficient communication of information between brain regions, forming complex networks. By quantifying synchronisation between brain regions, a functionally connected brain network can be articulated. In neurodevelopmental disorders, where diagnosis is based on measures of behaviour and tasks, a measure of the underlying biological mechanisms holds promise as a potential clinical tool. Graph theory provides a tool for investigating the neural correlates of neuropsychiatric disorders, where there is disruption of efficient communication within and between brain networks. This research aimed to use recent conceptualisation of graph theory, along with measures of behaviour and cognitive functioning, to increase understanding of the neurobiological risk factors of atypical development. Using magnetoencephalography to investigate frequency-specific temporal dynamics at rest, the research aimed to identify potential biological markers derived from sensor-level whole-brain functional connectivity. Whilst graph theory has proved valuable for insight into network efficiency, its application is hampered by two limitations. First, its measures have hardly been validated in MEG studies, and second, graph measures have been shown to depend on methodological assumptions that restrict direct network comparisons. The first experimental study (Chapter 3) addressed the first limitation by examining the reproducibility of graph-based functional connectivity and network parameters in healthy adult volunteers. Subsequent chapters addressed the second limitation through adapted minimum spanning tree (a network analysis approach that allows for unbiased group comparisons) along with graph network tools that had been shown in Chapter 3 to be highly reproducible. Network topologies were modelled in healthy development (Chapter 4), and atypical neurodevelopment (Chapters 5 and 6). The results provided support to the proposition that measures of network organisation, derived from sensor-space MEG data, offer insights helping to unravel the biological basis of typical brain maturation and neurodevelopmental conditions, with the possibility of future clinical utility.

A Naturalistic Assessment of the Organization of Children’s Memories Predicts Cognitive Functioning and Reading Ability

To explore the relationship between memory and early school performance, we used graph theory to investigate memory reports from 76 children aged 6–8 years. The reports comprised autobiographical memories of events days to years past, and memories of novel images reported immediately after encoding. We also measured intelligence quotient (IQ) and theory of mind (ToM). Reading and Mathematics were assessed before classes began (December 2013), around the time of report collection (June 2014), and at the end of the academic year (December 2014). IQ and ToM correlated positively with word diversity and word-to-word connectivity, and negatively with word recurrence. Connectivity correlated positively with Reading in June 2014 as well as December 2014, even after adjusting for IQ and ToM. To our knowledge, this is the first study demonstrating a link between the structure of children’s memories and their cognitive or academic performance.

A Naturalistic Assessment of the Organization of Children’s Memories Predicts Cognitive Functioning and Reading Ability

To explore the relationship between memory and early school performance, we used graph theory to investigate memory reports from 76 children aged 6–8 years. The reports comprised autobiographical memories of events days to years past, and memories of novel images reported immediately after encoding. We also measured intelligence quotient (IQ) and theory of mind (ToM). Reading and Mathematics were assessed before classes began (December 2013), around the time of report collection (June 2014), and at the end of the academic year (December 2014). IQ and ToM correlated positively with word diversity and word-to-word connectivity, and negatively with word recurrence. Connectivity correlated positively with Reading in June 2014 as well as December 2014, even after adjusting for IQ and ToM. To our knowledge, this is the first study demonstrating a link between the structure of children’s memories and their cognitive or academic performance.

Petri Net Siphon Analysis and Network Centrality Measures for Identifying Combination Therapies in Signaling Pathways

Aberrant behavior of biological signaling pathways has been implicated in diseases such as cancers. Therapies have been developed to target proteins in these networks in the hope of curing the illness or bringing about remission. However, identifying targets for drug inhibition that exhibit good therapeutic index has proven to be challenging since signaling pathways have a large number of components and many interconnections such as feedback, crosstalk, and divergence. Unfortunately, some characteristics of these pathways such as redundancy, feedback, and drug resistance reduce the efficacy of single drug target therapy and necessitate the employment of more than one drug to target multiple nodes in the system. However, choosing multiple targets with high therapeutic index poses more challenges since the combinatorial search space could be huge. To cope with the complexity of these systems, computational tools such as ordinary differential equations have been used to successfully model some of these pathways. Regrettably, for building these models, experimentally-measured initial concentrations of the components and rates of reactions are needed which are difficult to obtain, and in very large networks, they may not be available at the moment. Fortunately, there exist other modeling tools, though not as powerful as ordinary differential equations, which do not need the rates and initial conditions to model signaling pathways. Petri net and graph theory are among these tools. In this thesis, we introduce a methodology based on Petri net siphon analysis and graph network centrality measures for identifying prospective targets for single and multiple drug therapies. In this methodology, first, potential targets are identified in the Petri net model of a signaling pathway using siphon analysis. Then, the graph-theoretic centrality measures are employed to prioritize the candidate targets. Also, an algorithm is developed to check whether the candidate targets are able to disable the intended outputs in the graph model of the system or not. We implement structural and dynamical models of ErbB1-Ras-MAPK pathways and use them to assess and evaluate this methodology. The identified drug-targets, single and multiple, correspond to clinically relevant drugs. Overall, the results suggest that this methodology, using siphons and centrality measures, shows promise in identifying and ranking drugs. Since this methodology only uses the structural information of the signaling pathways and does not need initial conditions and dynamical rates, it can be utilized in larger networks.

A Study of Some Centrality Measures in Graphs

Centrality is in fact one of the fundamental notions in graph theory which has established its close connection with various other areas like Social networks, Flow networks, Facility location problems etc. Even though a plethora of centrality measures have been introduced from time to time, according to the changing demands, the term is not well defined and we can only give some common qualities that a centrality measure is expected to have. Nodes with high centrality scores are often more likely to be very powerful, indispensable, influential, easy propagators of information, significant in maintaining the cohesion of the group and are easily susceptible to anything that disseminate in the network.

Large-scale dynamic hydrofracturing, healing and fracture network characterization

Permeability of a rock is a dynamic property that varies spatially and temporally. Fractures provide the most efficient channels for fluid flow and thus directly contribute to the permeability of the system. Fractures usually form as a result of a combination of tectonic stresses, gravity (i.e. lithostatic pressure) and fluid pressures. High pressure gradients alone can cause fracturing, the process which is termed as hydrofracturing that can determine caprock (seal) stability or reservoir integrity. Fluids also transport mass and heat, and are responsible for the formation of veins by precipitating minerals within open fractures. Veining (healing) thus directly influences the rock’s permeability. Upon deformation these closed factures (veins) can refracture and the cycle starts again. This fracturing-healing-refacturing cycle is a fundamental part in studying the deformation dynamics and permeability evolution of rock systems. This is generally accompanied by fracture network characterization focusing on network topology that determines network connectivity. Fracture characterization allows to acquire quantitative and qualitative data on fractures and forms an important part of reservoir modeling. This thesis highlights the importance of fracture-healing and veins’ mechanical properties on the deformation dynamics. It shows that permeability varies spatially and temporally, and that healed systems (veined rocks) should not be treated as fractured systems (rocks without veins). Field observations also demonstrate the influence of contrasting mechanical properties, in addition to the complexities of vein microstructures that can form in low-porosity and permeability layered sequences. The thesis also presents graph theory as a characterization method to obtain statistical measures on evolving network connectivity. It also proposes what measures a good reservoir should have to exhibit potentially large permeability and robustness against healing. The results presented in the thesis can have applications for hydrocarbon and geothermal reservoir exploration, mining industry, underground waste disposal, CO2 injection or groundwater modeling.

Estudio y optimización de las infraestructuras de los carriles para bicicletas

La necesidad cotidiana de los ciudadanos de desplazarse para realizar diferentes actividades, sea cual fuere su naturaleza, se ha visto afectada en gran medida por los cambios producidos. Las ventajas generadas por la inclusión de la bicicleta como modo de transporte y la proliferación de su uso entre la ciudadanía son innumerables y se extienden tanto en el ámbito de la movilidad urbana como del desarrollo sostenible. En la actualidad, hay multitud de programas para la implantación, fomento o aumento de la participación ciudadana relacionado con la bicicleta en las ciudades. Pero en definitiva, todos y cada uno de estas iniciativas tienen la misma finalidad, crear una malla de vías cicladles eficaz y útil. Capaces de permitir el uso de la bicicleta en vías preferentes con unas garantías de seguridad altas, incorporando la bicicleta en el modelo de intermodalidad del transporte urbano. Con la progresiva implantación del carril bici, muchas personas han empezado a utilizarlas para moverse por la ciudad. Pero todo lo nuevo necesita un periodo de adaptación. Y, la realidad es que la red de viales destinados para estos vehículos está repleta de obstáculos para el ciclista. La actual situación ha llevado a cuestionar qué cantidad de kilómetros de carriles bici son necesarios para abastecer la demanda existente de este modo de transporte y, si las obras ejecutadas y proyectadas son las correctas y suficientes. En este trabajo se presenta una herramienta, basada en un modelo de programación matemática, para el diseño óptimo de una red destinada a los ciclistas. En concreto, el sistema determina una infraestructura para la bicicleta adaptada a las características de la red de carreteras existentes, con base en criterios de teoría de grafos ponderados. Como una aplicación del modelo propuesto, se ofrece el resultado de estos experimentos, obteniéndose un número de conclusiones útiles para la planificación y el diseño de redes de carriles bici desde una perspectiva social. Se realiza una aplicación de la metodología desarrollada para el caso real del municipio de Málaga (España). Por último se produce la validación del modelo de optimización presentado y la repercusión que tiene éste sobre el resultado final y la importancia o el peso del total de variables capaces de condicionar el resultado final de la red ciclista. Se obtiene, por tanto, una herramienta destinada a la mejora de la planificación, diseño y gestión de las diferentes infraestructuras para la bicicleta, con capacidad de interactuar con el modelo de red vial actual y con el resto de los modos de transportes existentes en el entramado urbano de las ciudades.

Detecting phase transitions in community structures using big data analysis of the engineering education research landscape: a European perspective

Comunicação apresentada na 44th SEFI Conference, 12-­15 September 2016, Tampere, Finland

WEAK ISOMETRIES OF HAMMING SPACES

In this thesis we study weak isometries of Hamming spaces. These are permutations of a Hamming space that preserve some but not necessarily all distances. We wish to find conditions under which a weak isometry is in fact an isometry. This type of problem was first posed by Beckman and Quarles for Rn. In chapter 2 we give definitions pertinent to our research. The 3rd chapter focuses on some known results in this area with special emphasis on papers by V. Krasin as well as S. De Winter and M. Korb who solved this problem for the Boolean cube, that is, the binary Hamming space. We attempted to generalize some of their methods to the non-boolean case. The 4th chapter has our new results and is split into two major contributions. Our first contribution shows if n=p or p < n2, then every weak isometry of Hnq that preserves distance p is an isometry. Our second contribution gives a possible method to check if a weak isometry is an isometry using linear algebra and graph theory.

Adaptive edge analytics for distributed networked control of water systems

Over the last decade, there has been a trend where water utility companies aim to make water distribution networks more intelligent in order to improve their quality of service, reduce water waste, minimize maintenance costs etc., by incorporating IoT technologies. Current state of the art solutions use expensive power hungry deployments to monitor and transmit water network states periodically in order to detect anomalous behaviors such as water leakage and bursts. However, more than 97% of water network assets are remote away from power and are often in geographically remote underpopulated areas, facts that make current approaches unsuitable for next generation more dynamic adaptive water networks. Battery-driven wireless sensor/actuator based solutions are theoretically the perfect choice to support next generation water distribution. In this paper, we present an end-to-end water leak localization system, which exploits edge processing and enables the use of battery-driven sensor nodes. Our system combines a lightweight edge anomaly detection algorithm based on compression rates and an efficient localization algorithm based on graph theory. The edge anomaly detection and localization elements of the systems produce a timely and accurate localization result and reduce the communication by 99% compared to the traditional periodic communication. We evaluated our schemes by deploying non-intrusive sensors measuring vibrational data on a real-world water test rig that have had controlled leakage and burst scenarios implemented.

Mathematics and fiber arts

Mathematics can be found all over the world, even in what could be considered an unrelated area, like fiber arts. In knitting, crochet, and counted-thread embroidery, we can find concepts of algebra, graph theory, number theory, geometry of transformations, and symmetry, as well as computer science. For example, many fiber art pieces embody notions related with groups of symmetry. In this work, we focus on two areas of Mathematics associated with knitting, crochet, and cross-stitch works – number theory and geometry of transformations.

A multidisciplinary approach to the study of protein dynamics and signal transmission

Allostery is a phenomenon of fundamental importance in biology, allowing regulation of function and dynamic adaptability of enzymes and proteins. Despite the allosteric effect was first observed more than a century ago allostery remains a biophysical enigma, defined as the “second secret of life”. The challenge is mainly associated to the rather complex nature of the allosteric mechanisms, which manifests itself as the alteration of the biological function of a protein/enzyme (e.g. ligand/substrate binding at the active site) by binding of “other object” (“allos stereos” in Greek) at a site distant (> 1 nanometer) from the active site, namely the effector site. Thus, at the heart of allostery there is signal propagation from the effector to the active site through a dense protein matrix, with a fundamental challenge being represented by the elucidation of the physico-chemical interactions between amino acid residues allowing communicatio n between the two binding sites, i.e. the “allosteric pathways”. Here, we propose a multidisciplinary approach based on a combination of computational chemistry, involving molecular dynamics simulations of protein motions, (bio)physical analysis of allosteric systems, including multiple sequence alignments of known allosteric systems, and mathematical tools based on graph theory and machine learning that can greatly help understanding the complexity of dynamical interactions involved in the different allosteric systems. The project aims at developing robust and fast tools to identify unknown allosteric pathways. The characterization and predictions of such allosteric spots could elucidate and fully exploit the power of allosteric modulation in enzymes and DNA-protein complexes, with great potential applications in enzyme engineering and drug discovery.

Tutte's 5-flow conjecture

The aim of this thesis is to show and put together the results, obtained so far, useful to tackle a conjecture of graph theory proposed in 1954 by William Thomas Tutte. The conjecture in question is Tutte's 5-flow conjecture, which states that every bridgeless graph admits a nowhere-zero 5-flow, namely a flow with non-zero integer values between -4 and 4. We will start by giving some basics on graph theory, useful for the followings, and proving some results about flows on oriented graphs and in particular about the flow polynomial. Next we will treat two cases: graphs embeddable in the plane $\mathbb{R}^2$ and graphs embeddable in the projective plane $\mathbb{P}^2$. In the first case we will see the correlation between flows and colorings and prove a theorem even stronger than Tutte's conjecture, using the 4-color theorem. In the second case we will see how in 1984 Richard Steinberg used Fleischner's Splitting Lemma to show that there can be no minimal counterexample of the conjecture in the case of graphs in the projective plane. In the fourth chapter we will look at the theorems of François Jaeger (1976) and Paul D. Seymour (1981). The former proved that every bridgeless graph admits a nowhere-zero 8-flow, the latter managed to go even further showing that every bridgeless graph admits a nowhere-zero 6-flow. In the fifth and final chapter there will be a short introduction to the Tutte polynomial and it will be shown how it is related to the flow polynomial via the Recipe Theorem. Finally we will see some applications of flows through the study of networks and their properties.

A study of brain functional connectivity and cognitive processes in long COVID-19 patients

In this work, a prospective study conducted at the IRCCS Istituto delle Scienze Neurologiche di Bologna is presented. The aim was to investigate the brain functional connectivity of a cohort of patients (N=23) suffering from persistent olfactory dysfunction after SARS-CoV-2 infection (Post-COVID-19 syndrome), as compared to a matching group of healthy controls (N=26). In particular, starting from individual resting state functional-MRI data, different analytical approaches were adopted in order to find potential alterations in the connectivity patterns of patients’ brains. Analyses were conducted both at a whole-brain level and with a special focus on brain regions involved in the processing of olfactory stimuli (Olfactory Network). Statistical correlations between functional connectivity alterations and the results of olfactory and neuropsychological tests were investigated, to explore the associations with cognitive processes. The three approaches implemented for the analysis were the seed-based correlation analysis, the group-level Independent Component analysis and a graph-theoretical analysis of brain connectivity. Due to the relative novelty of such approaches, many implementation details and methodologies are not standardized yet and represent active research fields. Seed-based and group-ICA analyses’ results showed no statistically significant differences between groups, while relevant alterations emerged from those of the graph-based analysis. In particular, patients’ olfactory sub-graph appeared to have a less pronounced modular structure compared to the control group; locally, a hyper-connectivity of the right thalamus was observed in patients, with significant involvement of the right insula and hippocampus. Results of an exploratory correlation analysis showed a positive correlation between the graphs global modularity and the scores obtained in olfactory tests and negative correlations between the thalamus hyper-connectivity and memory tests scores.

Introducing CHIMeRA: from the development of a comprehensive biomedical database to the analysis of its sub-components.

In this thesis we discuss the expansion of an existing project, called CHIMeRA, which is a comprehensive biomedical network, and the analysis of its sub-components by using graph theory. We describe how it is structured internally, what are the existing databases from which it retrieves information and what machine learning techniques are used in order to produce new knowledge. We also introduce a new technique for graph exploration that is aimed to speed-up the network cover time under the condition that the analyzed graph is stellar; if this condition is satisfied, the improvement in the performance compared to the conventional exploration technique is extremely appealing. We show that the stellar structure is highly recurrent for sub-networks in CHIMeRA generated by queries, which made this technique even more interesting. Finally, we describe the convenience in using the CHIMeRA network for research purposes and what it could become in a very near future.