9,343 research outputs found

    Annals [...].

    Get PDF
    Pedometrics: innovation in tropics; Legacy data: how turn it useful?; Advances in soil sensing; Pedometric guidelines to systematic soil surveys.Evento online. Coordenado por: Waldir de Carvalho Junior, Helena Saraiva Koenow Pinheiro, Ricardo SimĂŁo Diniz Dalmolin

    Development of in-vitro in-silico technologies for modelling and analysis of haematological malignancies

    Get PDF
    Worldwide, haematological malignancies are responsible for roughly 6% of all the cancer-related deaths. Leukaemias are one of the most severe types of cancer, as only about 40% of the patients have an overall survival of 10 years or more. Myelodysplastic Syndrome (MDS), a pre-leukaemic condition, is a blood disorder characterized by the presence of dysplastic, irregular, immature cells, or blasts, in the peripheral blood (PB) and in the bone marrow (BM), as well as multi-lineage cytopenias. We have created a detailed, lineage-specific, high-fidelity in-silico erythroid model that incorporates known biological stimuli (cytokines and hormones) and a competing diseased haematopoietic population, correctly capturing crucial biological checkpoints (EPO-dependent CFU-E differentiation) and replicating the in-vivo erythroid differentiation dynamics. In parallel, we have also proposed a long-term, cytokine-free 3D cell culture system for primary MDS cells, which was firstly optimized using easily-accessible healthy controls. This system enabled long-term (24-day) maintenance in culture with high (>75%) cell viability, promoting spontaneous expansion of erythroid phenotypes (CD71+/CD235a+) without the addition of any exogenous cytokines. Lastly, we have proposed a novel in-vitro in-silico framework using GC-MS metabolomics for the metabolic profiling of BM and PB plasma, aiming not only to discretize between haematological conditions but also to sub-classify MDS patients, potentially based on candidate biomarkers. Unsupervised multivariate statistical analysis showed clear intra- and inter-disease separation of samples of 5 distinct haematological malignancies, demonstrating the potential of this approach for disease characterization. The work herein presented paves the way for the development of in-vitro in-silico technologies to better, characterize, diagnose, model and target haematological malignancies such as MDS and AML.Open Acces

    Socio-endocrinology revisited: New tools to tackle old questions

    Get PDF
    Animals’ social environments impact their health and survival, but the proximate links between sociality and fitness are still not fully understood. In this thesis, I develop and apply new approaches to address an outstanding question within this sociality-fitness link: does grooming (a widely studied, positive social interaction) directly affect glucocorticoid concentrations (GCs; a group of steroid hormones indicating physiological stress) in a wild primate? To date, negative, long-term correlations between grooming and GCs have been found, but the logistical difficulties of studying proximate mechanisms in the wild leave knowledge gaps regarding the short-term, causal mechanisms that underpin this relationship. New technologies, such as collar-mounted tri-axial accelerometers, can provide the continuous behavioural data required to match grooming to non-invasive GC measures (Chapter 1). Using Chacma baboons (Papio ursinus) living on the Cape Peninsula, South Africa as a model system, I identify giving and receiving grooming using tri-axial accelerometers and supervised machine learning methods, with high overall accuracy (~80%) (Chapter 2). I then test what socio-ecological variables predict variation in faecal and urinary GCs (fGCs and uGCs) (Chapter 3). Shorter and rainy days are associated with higher fGCs and uGCs, respectively, suggesting that environmental conditions may impose stressors in the form of temporal bottlenecks. Indeed, I find that short days and days with more rain-hours are associated with reduced giving grooming (Chapter 4), and that this reduction is characterised by fewer and shorter grooming bouts. Finally, I test whether grooming predicts GCs, and find that while there is a long-term negative correlation between grooming and GCs, grooming in the short-term, in particular giving grooming, is associated with higher fGCs and uGCs (Chapter 5). I end with a discussion on how the new tools I applied have enabled me to advance our understanding of sociality and stress in primate social systems (Chapter 6)

    Machine learning for managing structured and semi-structured data

    Get PDF
    As the digitalization of private, commercial, and public sectors advances rapidly, an increasing amount of data is becoming available. In order to gain insights or knowledge from these enormous amounts of raw data, a deep analysis is essential. The immense volume requires highly automated processes with minimal manual interaction. In recent years, machine learning methods have taken on a central role in this task. In addition to the individual data points, their interrelationships often play a decisive role, e.g. whether two patients are related to each other or whether they are treated by the same physician. Hence, relational learning is an important branch of research, which studies how to harness this explicitly available structural information between different data points. Recently, graph neural networks have gained importance. These can be considered an extension of convolutional neural networks from regular grids to general (irregular) graphs. Knowledge graphs play an essential role in representing facts about entities in a machine-readable way. While great efforts are made to store as many facts as possible in these graphs, they often remain incomplete, i.e., true facts are missing. Manual verification and expansion of the graphs is becoming increasingly difficult due to the large volume of data and must therefore be assisted or substituted by automated procedures which predict missing facts. The field of knowledge graph completion can be roughly divided into two categories: Link Prediction and Entity Alignment. In Link Prediction, machine learning models are trained to predict unknown facts between entities based on the known facts. Entity Alignment aims at identifying shared entities between graphs in order to link several such knowledge graphs based on some provided seed alignment pairs. In this thesis, we present important advances in the field of knowledge graph completion. For Entity Alignment, we show how to reduce the number of required seed alignments while maintaining performance by novel active learning techniques. We also discuss the power of textual features and show that graph-neural-network-based methods have difficulties with noisy alignment data. For Link Prediction, we demonstrate how to improve the prediction for unknown entities at training time by exploiting additional metadata on individual statements, often available in modern graphs. Supported with results from a large-scale experimental study, we present an analysis of the effect of individual components of machine learning models, e.g., the interaction function or loss criterion, on the task of link prediction. We also introduce a software library that simplifies the implementation and study of such components and makes them accessible to a wide research community, ranging from relational learning researchers to applied fields, such as life sciences. Finally, we propose a novel metric for evaluating ranking results, as used for both completion tasks. It allows for easier interpretation and comparison, especially in cases with different numbers of ranking candidates, as encountered in the de-facto standard evaluation protocols for both tasks.Mit der rasant fortschreitenden Digitalisierung des privaten, kommerziellen und öffentlichen Sektors werden immer größere Datenmengen verfügbar. Um aus diesen enormen Mengen an Rohdaten Erkenntnisse oder Wissen zu gewinnen, ist eine tiefgehende Analyse unerlässlich. Das immense Volumen erfordert hochautomatisierte Prozesse mit minimaler manueller Interaktion. In den letzten Jahren haben Methoden des maschinellen Lernens eine zentrale Rolle bei dieser Aufgabe eingenommen. Neben den einzelnen Datenpunkten spielen oft auch deren Zusammenhänge eine entscheidende Rolle, z.B. ob zwei Patienten miteinander verwandt sind oder ob sie vom selben Arzt behandelt werden. Daher ist das relationale Lernen ein wichtiger Forschungszweig, der untersucht, wie diese explizit verfügbaren strukturellen Informationen zwischen verschiedenen Datenpunkten nutzbar gemacht werden können. In letzter Zeit haben Graph Neural Networks an Bedeutung gewonnen. Diese können als eine Erweiterung von CNNs von regelmäßigen Gittern auf allgemeine (unregelmäßige) Graphen betrachtet werden. Wissensgraphen spielen eine wesentliche Rolle bei der Darstellung von Fakten über Entitäten in maschinenlesbaren Form. Obwohl große Anstrengungen unternommen werden, so viele Fakten wie möglich in diesen Graphen zu speichern, bleiben sie oft unvollständig, d. h. es fehlen Fakten. Die manuelle Überprüfung und Erweiterung der Graphen wird aufgrund der großen Datenmengen immer schwieriger und muss daher durch automatisierte Verfahren unterstützt oder ersetzt werden, die fehlende Fakten vorhersagen. Das Gebiet der Wissensgraphenvervollständigung lässt sich grob in zwei Kategorien einteilen: Link Prediction und Entity Alignment. Bei der Link Prediction werden maschinelle Lernmodelle trainiert, um unbekannte Fakten zwischen Entitäten auf der Grundlage der bekannten Fakten vorherzusagen. Entity Alignment zielt darauf ab, gemeinsame Entitäten zwischen Graphen zu identifizieren, um mehrere solcher Wissensgraphen auf der Grundlage einiger vorgegebener Paare zu verknüpfen. In dieser Arbeit stellen wir wichtige Fortschritte auf dem Gebiet der Vervollständigung von Wissensgraphen vor. Für das Entity Alignment zeigen wir, wie die Anzahl der benötigten Paare reduziert werden kann, während die Leistung durch neuartige aktive Lerntechniken erhalten bleibt. Wir erörtern auch die Leistungsfähigkeit von Textmerkmalen und zeigen, dass auf Graph-Neural-Networks basierende Methoden Schwierigkeiten mit verrauschten Paar-Daten haben. Für die Link Prediction demonstrieren wir, wie die Vorhersage für unbekannte Entitäten zur Trainingszeit verbessert werden kann, indem zusätzliche Metadaten zu einzelnen Aussagen genutzt werden, die oft in modernen Graphen verfügbar sind. Gestützt auf Ergebnisse einer groß angelegten experimentellen Studie präsentieren wir eine Analyse der Auswirkungen einzelner Komponenten von Modellen des maschinellen Lernens, z. B. der Interaktionsfunktion oder des Verlustkriteriums, auf die Aufgabe der Link Prediction. Außerdem stellen wir eine Softwarebibliothek vor, die die Implementierung und Untersuchung solcher Komponenten vereinfacht und sie einer breiten Forschungsgemeinschaft zugänglich macht, die von Forschern im Bereich des relationalen Lernens bis hin zu angewandten Bereichen wie den Biowissenschaften reicht. Schließlich schlagen wir eine neuartige Metrik für die Bewertung von Ranking-Ergebnissen vor, wie sie für beide Aufgaben verwendet wird. Sie ermöglicht eine einfachere Interpretation und einen leichteren Vergleich, insbesondere in Fällen mit einer unterschiedlichen Anzahl von Kandidaten, wie sie in den de-facto Standardbewertungsprotokollen für beide Aufgaben vorkommen

    Industry 4.0: product digital twins for remanufacturing decision-making

    Get PDF
    Currently there is a desire to reduce natural resource consumption and expand circular business principles whilst Industry 4.0 (I4.0) is regarded as the evolutionary and potentially disruptive movement of technology, automation, digitalisation, and data manipulation into the industrial sector. The remanufacturing industry is recognised as being vital to the circular economy (CE) as it extends the in-use life of products, but its synergy with I4.0 has had little attention thus far. This thesis documents the first investigating into I4.0 in remanufacturing for a CE contributing a design and demonstration of a model that optimises remanufacturing planning using data from different instances in a product’s life cycle. The initial aim of this work was to identify the I4.0 technology that would enhance the stability in remanufacturing with a view to reducing resource consumption. As the project progressed it narrowed to focus on the development of a product digital twin (DT) model to support data-driven decision making for operations planning. The model’s architecture was derived using a bottom-up approach where requirements were extracted from the identified complications in production planning and control that differentiate remanufacturing from manufacturing. Simultaneously, the benefits of enabling visibility of an asset’s through-life health were obtained using a DT as the modus operandi. A product simulator and DT prototype was designed to use Internet of Things (IoT) components, a neural network for remaining life estimations and a search algorithm for operational planning optimisation. The DT was iteratively developed using case studies to validate and examine the real opportunities that exist in deploying a business model that harnesses, and commodifies, early life product data for end-of-life processing optimisation. Findings suggest that using intelligent programming networks and algorithms, a DT can enhance decision-making if it has visibility of the product and access to reliable remanufacturing process information, whilst existing IoT components provide rudimentary “smart” capabilities, but their integration is complex, and the durability of the systems over extended product life cycles needs to be further explored

    The Neural Mechanisms of Value Construction

    Get PDF
    Research in decision neuroscience has characterized how the brain makes decisions by assessing the expected utility of each option in an abstract value space that affords the ability to compare dissimilar options. Experiments at multiple levels of analysis in multiple species have localized the ventromedial prefrontal cortex (vmPFC) and nearby orbitofrontal cortex (OFC) as the main nexus where this abstract value space is represented. However, much less is known about how this value code is constructed by the brain in the first place. By using a combination of behavioral modeling and cutting edge tools to analyze functional magnetic resonance imaging (fMRI) data, the work of this thesis proposes that the brain decomposes stimuli into their constituent attributes and integrates across them to construct value. These stimulus features embody appetitive or aversive properties that are either learned from experience or evaluated online by comparing them to previously experienced stimuli with similar features. Stimulus features are processed by cortical areas specialized for the perception of a particular stimulus type and then integrated into a value signal in vmPFC/OFC. The project presented in Chapter 2 examines how food items are evaluated by their constituent attributes, namely their nutrient makeup. A linear attribute integration model succinctly captures how subjective values can be computed from a weighted combination of the constituent nutritive attributes of the food. Multivariate analysis methods revealed that these nutrient attributes are represented in the lateral OFC, while food value is encoded both in medial and lateral OFC. Connectivity between lateral and medial OFC allows this nutrient attribute information to be integrated into a value representation in medial OFC. In Chapter 3, I show that this value construction process can operate over higher-level abstractions when the context requires bundles of items to be valued, rather than isolated items. When valuing bundles of items, the constituent items themselves become the features, and their values are integrated with a subadditive function to construct the value of the bundle. Multiple subregions of PFC including but not limited to vmPFC compute the value of a bundle with the same value code used to evaluate individual items, suggesting that these general value regions contextually adapt within this hierarchy. When valuing bundles and single items in interleaved trials, the value code rapidly switches between levels in this hierarchy by normalizing to the distribution of values in the current context rather than representing all options on an absolute scale. Although the attribute integration model of value construction characterizes human behavior on simple decision-making tasks, it is unclear how it can scale up to environments of real-world complexity. Taking inspiration from modern advances in artificial intelligence, and deep reinforcement learning in particular, in Chapter 4 I outline how connectionist models generalize the attribute integration model to naturalistic tasks by decomposing sensory input into a high dimensional set of nonlinear features that are encoded with hierarchical and distributed processing. Participants freely played Atari video games during fMRI scanning, and a deep reinforcement learning algorithm trained on the games was used as an end-to-end model for how humans evaluate actions in these high-dimensional tasks. The features represented in the intermediate layers of the artificial neural network were found to also be encoded in a distributed fashion throughout the cortex, specifically in the dorsal visual stream and posterior parietal cortex. These features emerge from nonlinear transformations of the sensory input that connect perception to action and reward. In contrast to the stimulus attributes used to evaluate the stimuli presented in the preceding chapters, these features become highly complex and inscrutable as they are driven by the statistical properties of high-dimensional data. However, they do not solely reflect a set of features that can be identified by applying common dimensionality reduction techniques to the input, as task-irrelevant sensory features are stripped away and task-relevant high-level features are magnified.</p

    Principles of Massively Parallel Sequencing for Engineering and Characterizing Gene Delivery

    Get PDF
    The advent of massively parallel sequencing and synthesis technologies have ushered in a new paradigm of biology, where high throughput screening of billions of nucleid acid molecules and production of libraries of millions of genetic mutants are now routine in labs and clinics. During my Ph.D., I worked to develop data analysis and experimental methods that take advantage of the scale of this data, while making the minimal assumptions necessary for deriving value from their application. My Ph.D. work began with the development of software and principles for analyzing deep mutational scanning data of libraries of engineered AAV capsids. By looking at not only the top variant in a round of directed evolution, but instead a broad distribution of the variants and their phenotypes, we were able to identify AAV variants with enhanced ability to transduce specific cells in the brain after intravenous injection. I then shifted to better understand the phenotypic profile of these engineered variants. To that end, I turned to single-cell RNA sequencing to seek to identify, with high resolution, the delivery profile of these variants in all cell types present in the cortex of a mouse brain. I began by developing infrastructure and tools for dealing with the data analysis demands of these experiments. Then, by delivering an engineered variant to the animal, I was able to use the single-cell RNA sequencing profile, coupled with a sequencing readout of the delivered genetic cargo present in each cell type, to define the variant’s tropism across the full spectrum of cell types in a single step. To increase the throughput of this experimental paradigm, I then worked to develop a multiplexing strategy for delivering up to 7 engineered variants in a single animal, and obtain the same high resolution readout for each variant in a single experiment. Finally, to take a step towards translation to human diagnostics, I leveraged the tools I built for scaling single-cell RNA sequencing studies and worked to develop a protocol for obtaining single-cell immune profiles of low volumes of self-collected blood. This study enabled repeat sampling in a short period of time, and revealed an incredible richness in individual variability and time-of-day dependence of human immune gene expression. Together, my Ph.D. work provides strategies for employing massively parallel sequencing and synthesis for new biological applications, and builds towards a future paradigm where personalized, high-resolution sequencing might be coupled with modular, customized gene therapy delivery.</p
    • …
    corecore