6,503 research outputs found

    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    A Political Theory of Engineered Systems and A Study of Engineering and Justice Workshops

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    Since there are good reasons to think that some engineered systems are socially undesirable—for example, internal combustion engines that cause climate change, algorithms that are racist, and nuclear weapons that can destroy all life—there is a well-established literature that attempts to identify best practices for designing and regulating engineered systems in order to prevent harm and promote justice. Most of this literature, especially the design theory and engineering justice literature meant to help guide engineers, focuses on environmental, physical, social, and mental harms such as ecosystem and bodily poisoning, racial and gender discrimination, and urban alienation. However, the literature that focuses on how engineered systems can produce political harms—harms to how we shape the way we live in community together—is not well established. The first part of this thesis contributes to identifying how particular types of engineered systems can harm a democratic politics. Building on democratic theory, philosophy of collective harms, and design theory, it argues that engineered systems that extend in space and time beyond a certain threshold subvert the knowledge and empowerment necessary for a democratic politics. For example, the systems of global shipping and the internet that fundamentally shape our lives are so large that people cannot attain the knowledge necessary to regulate them well nor the empowerment necessary to shape them. The second part of this thesis is an empirical study of a workshop designed to encourage engineering undergraduates to understand how engineered systems can subvert a democratic politics, with the ultimate goal of supporting students in incorporating that understanding into their work. 32 Dartmouth undergraduate engineering students participated in the study. Half were assigned to participate in a workshop group, half to a control group. The workshop group participants took a pretest; then participated in a 3-hour, semi-structured workshop with 4 participants per session (as well as a discussion leader and note-taker) over lunch or dinner; and then took a posttest. The control group participants took the same pre- and post- tests, but had no suggested activity in the intervening 3 hours. We find that the students who participated in workshops had a statistically significant test-score improvement as compared to the control group (Brunner-Munzel test, p \u3c .001). Using thematic analysis methods, we show the data is consistent with the hypothesis that workshops produced a score improvement because of certain structure (small size, long duration, discussion-based, over homemade food) and content (theoretically rich, challenging). Thematic analysis also reveals workshop failures and areas for improvement (too much content for the duration, not well enough organized). The thesis concludes with a discussion of limitations and suggestions for future theoretical, empirical, and pedagogical research

    UMSL Bulletin 2023-2024

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    The 2023-2024 Bulletin and Course Catalog for the University of Missouri St. Louis.https://irl.umsl.edu/bulletin/1088/thumbnail.jp

    Graduate Catalog of Studies, 2023-2024

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    The Genetic and Neuronal Substrates of Melatonin Signaling in Zebrafish Sleep

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    Sleep is hypothesized to be regulated by two processes: a circadian drive, which communicates time of day to ensure that sleep is timed to the appropriate day/night phase, and a homeostatic drive, by which the propensity for sleep becomes stronger over the course of prolonged wakefulness. While studies suggest that adenosine and serotonin signaling in part mediate the homeostatic sleep drive, factors that act downstream of the circadian clock to promote sleep were unidentified until recently. Previous work in the Prober lab has shown that the nocturnal hormone melatonin acts downstream of the circadian rhythm to promote sleep in zebrafish. The downstream processes by which melatonin promotes sleep is poorly understood across all animal models. This is likely because melatonin research has been primarily conducted using nocturnal laboratory rodent models, in whom melatonin does not seem to play a role in sleep, and because of the widely held view that melatonin informs the circadian clock and does not promote sleep directly. In Chapter 1 of this thesis, I review some of the research conducted over the last 50 years that has informed our current understanding of melatonin and its role in sleep. In Chapter 2, I describe our efforts to use the zebrafish, in which melatonin is both potently sedating and essential for nightly sleep, to uncover some of the mechanisms by which melatonin might promote sleep. We found that melatonin acts through a particular melatonin receptor family called MT1, whereas melatonin receptors belonging to other families were dispensable for sleep. We show that MT1 receptors are expressed broadly throughout the zebrafish brain and are enriched in brain regions involved in sensory processing, particularly in those related to vision. We tested the hypothesis that melatonin promotes sleep, at least in part, by dampening visual responsiveness at night. We show that, separable from sleep, exogenous melatonin suppresses behavioral responses to light stimuli, and loss of endogenous melatonin results in day-like behavioral responses to light stimuli during the night. We are using whole brain imaging in live zebrafish to corroborate our behavioral results with neuronal GCaMP recordings. We hope that the findings presented here contribute to a greater understanding of melatonin’s role in sleep, which may help enhance its value as a natural therapeutic aid

    Technology for Low Resolution Space Based RSO Detection and Characterisation

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    Space Situational Awareness (SSA) refers to all activities to detect, identify and track objects in Earth orbit. SSA is critical to all current and future space activities and protect space assets by providing access control, conjunction warnings, and monitoring status of active satellites. Currently SSA methods and infrastructure are not sufficient to account for the proliferations of space debris. In response to the need for better SSA there has been many different areas of research looking to improve SSA most of the requiring dedicated ground or space-based infrastructure. In this thesis, a novel approach for the characterisation of RSO’s (Resident Space Objects) from passive low-resolution space-based sensors is presented with all the background work performed to enable this novel method. Low resolution space-based sensors are common on current satellites, with many of these sensors being in space using them passively to detect RSO’s can greatly augment SSA with out expensive infrastructure or long lead times. One of the largest hurtles to overcome with research in the area has to do with the lack of publicly available labelled data to test and confirm results with. To overcome this hurtle a simulation software, ORBITALS, was created. To verify and validate the ORBITALS simulator it was compared with the Fast Auroral Imager images, which is one of the only publicly available low-resolution space-based images found with auxiliary data. During the development of the ORBITALS simulator it was found that the generation of these simulated images are computationally intensive when propagating the entire space catalog. To overcome this an upgrade of the currently used propagation method, Specialised General Perturbation Method 4th order (SGP4), was performed to allow the algorithm to run in parallel reducing the computational time required to propagate entire catalogs of RSO’s. From the results it was found that the standard facet model with a particle swarm optimisation performed the best estimating an RSO’s attitude with a 0.66 degree RMSE accuracy across a sequence, and ~1% MAPE accuracy for the optical properties. This accomplished this thesis goal of demonstrating the feasibility of low-resolution passive RSO characterisation from space-based platforms in a simulated environment

    Machine Learning Approaches for the Prioritisation of Cardiovascular Disease Genes Following Genome- wide Association Study

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    Genome-wide association studies (GWAS) have revealed thousands of genetic loci, establishing itself as a valuable method for unravelling the complex biology of many diseases. As GWAS has grown in size and improved in study design to detect effects, identifying real causal signals, disentangling from other highly correlated markers associated by linkage disequilibrium (LD) remains challenging. This has severely limited GWAS findings and brought the method’s value into question. Although thousands of disease susceptibility loci have been reported, causal variants and genes at these loci remain elusive. Post-GWAS analysis aims to dissect the heterogeneity of variant and gene signals. In recent years, machine learning (ML) models have been developed for post-GWAS prioritisation. ML models have ranged from using logistic regression to more complex ensemble models such as random forests and gradient boosting, as well as deep learning models (i.e., neural networks). When combined with functional validation, these methods have shown important translational insights, providing a strong evidence-based approach to direct post-GWAS research. However, ML approaches are in their infancy across biological applications, and as they continue to evolve an evaluation of their robustness for GWAS prioritisation is needed. Here, I investigate the landscape of ML across: selected models, input features, bias risk, and output model performance, with a focus on building a prioritisation framework that is applied to blood pressure GWAS results and tested on re-application to blood lipid traits

    Using machine learning to predict pathogenicity of genomic variants throughout the human genome

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    Geschätzt mehr als 6.000 Erkrankungen werden durch Veränderungen im Genom verursacht. Ursachen gibt es viele: Eine genomische Variante kann die Translation eines Proteins stoppen, die Genregulation stören oder das Spleißen der mRNA in eine andere Isoform begünstigen. All diese Prozesse müssen überprüft werden, um die zum beschriebenen Phänotyp passende Variante zu ermitteln. Eine Automatisierung dieses Prozesses sind Varianteneffektmodelle. Mittels maschinellem Lernen und Annotationen aus verschiedenen Quellen bewerten diese Modelle genomische Varianten hinsichtlich ihrer Pathogenität. Die Entwicklung eines Varianteneffektmodells erfordert eine Reihe von Schritten: Annotation der Trainingsdaten, Auswahl von Features, Training verschiedener Modelle und Selektion eines Modells. Hier präsentiere ich ein allgemeines Workflow dieses Prozesses. Dieses ermöglicht es den Prozess zu konfigurieren, Modellmerkmale zu bearbeiten, und verschiedene Annotationen zu testen. Der Workflow umfasst außerdem die Optimierung von Hyperparametern, Validierung und letztlich die Anwendung des Modells durch genomweites Berechnen von Varianten-Scores. Der Workflow wird in der Entwicklung von Combined Annotation Dependent Depletion (CADD), einem Varianteneffektmodell zur genomweiten Bewertung von SNVs und InDels, verwendet. Durch Etablierung des ersten Varianteneffektmodells für das humane Referenzgenome GRCh38 demonstriere ich die gewonnenen Möglichkeiten Annotationen aufzugreifen und neue Modelle zu trainieren. Außerdem zeige ich, wie Deep-Learning-Scores als Feature in einem CADD-Modell die Vorhersage von RNA-Spleißing verbessern. Außerdem werden Varianteneffektmodelle aufgrund eines neuen, auf Allelhäufigkeit basierten, Trainingsdatensatz entwickelt. Diese Ergebnisse zeigen, dass der entwickelte Workflow eine skalierbare und flexible Möglichkeit ist, um Varianteneffektmodelle zu entwickeln. Alle entstandenen Scores sind unter cadd.gs.washington.edu und cadd.bihealth.org frei verfügbar.More than 6,000 diseases are estimated to be caused by genomic variants. This can happen in many possible ways: a variant may stop the translation of a protein, interfere with gene regulation, or alter splicing of the transcribed mRNA into an unwanted isoform. It is necessary to investigate all of these processes in order to evaluate which variant may be causal for the deleterious phenotype. A great help in this regard are variant effect scores. Implemented as machine learning classifiers, they integrate annotations from different resources to rank genomic variants in terms of pathogenicity. Developing a variant effect score requires multiple steps: annotation of the training data, feature selection, model training, benchmarking, and finally deployment for the model's application. Here, I present a generalized workflow of this process. It makes it simple to configure how information is converted into model features, enabling the rapid exploration of different annotations. The workflow further implements hyperparameter optimization, model validation and ultimately deployment of a selected model via genome-wide scoring of genomic variants. The workflow is applied to train Combined Annotation Dependent Depletion (CADD), a variant effect model that is scoring SNVs and InDels genome-wide. I show that the workflow can be quickly adapted to novel annotations by porting CADD to the genome reference GRCh38. Further, I demonstrate the integration of deep-neural network scores as features into a new CADD model, improving the annotation of RNA splicing events. Finally, I apply the workflow to train multiple variant effect models from training data that is based on variants selected by allele frequency. In conclusion, the developed workflow presents a flexible and scalable method to train variant effect scores. All software and developed scores are freely available from cadd.gs.washington.edu and cadd.bihealth.org

    Advances in Binders for Construction Materials

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    The global binder production for construction materials is approximately 7.5 billion tons per year, contributing ~6% to the global anthropogenic atmospheric CO2 emissions. Reducing this carbon footprint is a key aim of the construction industry, and current research focuses on developing new innovative ways to attain more sustainable binders and concrete/mortars as a real alternative to the current global demand for Portland cement.With this aim, several potential alternative binders are currently being investigated by scientists worldwide, based on calcium aluminate cement, calcium sulfoaluminate cement, alkali-activated binders, calcined clay limestone cements, nanomaterials, or supersulfated cements. This Special Issue presents contributions that address research and practical advances in i) alternative binder manufacturing processes; ii) chemical, microstructural, and structural characterization of unhydrated binders and of hydrated systems; iii) the properties and modelling of concrete and mortars; iv) applications and durability of concrete and mortars; and v) the conservation and repair of historic concrete/mortar structures using alternative binders.We believe this Special Issue will be of high interest in the binder industry and construction community, based upon the novelty and quality of the results and the real potential application of the findings to the practice and industry

    Specificity of the innate immune responses to different classes of non-tuberculous mycobacteria

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    Mycobacterium avium is the most common nontuberculous mycobacterium (NTM) species causing infectious disease. Here, we characterized a M. avium infection model in zebrafish larvae, and compared it to M. marinum infection, a model of tuberculosis. M. avium bacteria are efficiently phagocytosed and frequently induce granuloma-like structures in zebrafish larvae. Although macrophages can respond to both mycobacterial infections, their migration speed is faster in infections caused by M. marinum. Tlr2 is conservatively involved in most aspects of the defense against both mycobacterial infections. However, Tlr2 has a function in the migration speed of macrophages and neutrophils to infection sites with M. marinum that is not observed with M. avium. Using RNAseq analysis, we found a distinct transcriptome response in cytokine-cytokine receptor interaction for M. avium and M. marinum infection. In addition, we found differences in gene expression in metabolic pathways, phagosome formation, matrix remodeling, and apoptosis in response to these mycobacterial infections. In conclusion, we characterized a new M. avium infection model in zebrafish that can be further used in studying pathological mechanisms for NTM-caused diseases
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