4,813 research outputs found

    Graduate Catalog of Studies, 2023-2024

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

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    GeschĂ€tzt mehr als 6.000 Erkrankungen werden durch VerĂ€nderungen 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 begĂŒnstigen. All diese Prozesse mĂŒssen ĂŒberprĂŒft werden, um die zum beschriebenen PhĂ€notyp 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 PathogenitĂ€t. Die Entwicklung eines Varianteneffektmodells erfordert eine Reihe von Schritten: Annotation der Trainingsdaten, Auswahl von Features, Training verschiedener Modelle und Selektion eines Modells. Hier prĂ€sentiere 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 fĂŒr 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 AllelhĂ€ufigkeit 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 verfĂŒgbar.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

    An empirical investigation of the relationship between integration, dynamic capabilities and performance in supply chains

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    This research aimed to develop an empirical understanding of the relationships between integration, dynamic capabilities and performance in the supply chain domain, based on which, two conceptual frameworks were constructed to advance the field. The core motivation for the research was that, at the stage of writing the thesis, the combined relationship between the three concepts had not yet been examined, although their interrelationships have been studied individually. To achieve this aim, deductive and inductive reasoning logics were utilised to guide the qualitative study, which was undertaken via multiple case studies to investigate lines of enquiry that would address the research questions formulated. This is consistent with the author’s philosophical adoption of the ontology of relativism and the epistemology of constructionism, which was considered appropriate to address the research questions. Empirical data and evidence were collected, and various triangulation techniques were employed to ensure their credibility. Some key features of grounded theory coding techniques were drawn upon for data coding and analysis, generating two levels of findings. These revealed that whilst integration and dynamic capabilities were crucial in improving performance, the performance also informed the former. This reflects a cyclical and iterative approach rather than one purely based on linearity. Adopting a holistic approach towards the relationship was key in producing complementary strategies that can deliver sustainable supply chain performance. The research makes theoretical, methodological and practical contributions to the field of supply chain management. The theoretical contribution includes the development of two emerging conceptual frameworks at the micro and macro levels. The former provides greater specificity, as it allows meta-analytic evaluation of the three concepts and their dimensions, providing a detailed insight into their correlations. The latter gives a holistic view of their relationships and how they are connected, reflecting a middle-range theory that bridges theory and practice. The methodological contribution lies in presenting models that address gaps associated with the inconsistent use of terminologies in philosophical assumptions, and lack of rigor in deploying case study research methods. In terms of its practical contribution, this research offers insights that practitioners could adopt to enhance their performance. They can do so without necessarily having to forgo certain desired outcomes using targeted integrative strategies and drawing on their dynamic capabilities

    Resilience and food security in a food systems context

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    This open access book compiles a series of chapters written by internationally recognized experts known for their in-depth but critical views on questions of resilience and food security. The book assesses rigorously and critically the contribution of the concept of resilience in advancing our understanding and ability to design and implement development interventions in relation to food security and humanitarian crises. For this, the book departs from the narrow beaten tracks of agriculture and trade, which have influenced the mainstream debate on food security for nearly 60 years, and adopts instead a wider, more holistic perspective, framed around food systems. The foundation for this new approach is the recognition that in the current post-globalization era, the food and nutritional security of the world’s population no longer depends just on the performance of agriculture and policies on trade, but rather on the capacity of the entire (food) system to produce, process, transport and distribute safe, affordable and nutritious food for all, in ways that remain environmentally sustainable. In that context, adopting a food system perspective provides a more appropriate frame as it incites to broaden the conventional thinking and to acknowledge the systemic nature of the different processes and actors involved. This book is written for a large audience, from academics to policymakers, students to practitioners

    Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism.

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    This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordData availability statement: All non‐clinical data analysed during this study are included in this published article (and its supplementary information files). Clinical and genotype data is available only through collaboration as this can be used to identify individuals and so cannot be made openly available. Requests for collaboration will be considered following an application to the Genetic Beta Cell Research Bank (https://www.diabetesgenes.org/current‐research/genetic‐ beta‐cell‐research‐bank/). Contact by email should be directed to the Corresponding author.Code availability statement: All code and software versions used specified in Methods.Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function1. This silencing is largely controlled by non-coding elements, and their disruption might cause human disease2. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a 'disallowed gene' in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene.Wellcome Trus

    Strain and serovar variants of Salmonella enterica exhibit diverse tolerance to food chain-related stress

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    Non-Typhoidal Salmonella (NTS) continues to be a leading cause of foodborne illness worldwide. Food manufacturers implement hurdle technology by combining more than one approach to control food safety and quality, including preservatives such as organic acids, refrigeration, and heating. We assessed the variation in survival in stresses of genotypically diverse isolates of Salmonella enterica to identify genotypes with potential elevated risk to sub-optimal processing or cooking. Sub-lethal heat treatment, survival in desiccated conditions and growth in the presence of NaCl or organic acids were investigated. S. Gallinarum strain 287/91 was most sensitive to all stress conditions. While none of the strains replicated in a food matrix at 4 °C, S. Infantis strain S1326/28 retained the greatest viability, and six strains exhibited a significantly reduced viability. A S. Kedougou strain exhibited the greatest resistance to incubation at 60 °C in a food matrix that was significantly greater than S. Typhimurium U288, S Heidelberg, S. Kentucky, S. Schwarzengrund and S. Gallinarum strains. Two isolates of monophasic S. Typhimurium, S04698–09 and B54Col9 exhibited the greatest tolerance to desiccation that was significantly more than for the S. Kentucky and S. Typhimurium U288 strains. In general, the presence of 12 mM acetic acid or 14 mM citric acid resulted in a similar pattern of decreased growth in broth, but this was not observed for S. Enteritidis, and S. Typhimurium strains ST4/74 and U288 S01960-05. Acetic acid had a moderately greater effect on growth despite the lower concentration tested. A similar pattern of decreased growth was observed in the presence of 6% NaCl, with the notable exception that S. Typhimurium strain U288 S01960-05 exhibited enhanced growth in elevated NaCl concentrations

    Tradition and Innovation in Construction Project Management

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    This book is a reprint of the Special Issue 'Tradition and Innovation in Construction Project Management' that was published in the journal Buildings

    Local knowledge and practices among Tonga people in Zambia and Zimbabwe: A review

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    There is increasing recognition of the role of Indigenous and local knowledge systems in sustainable land use and conservation practices. However, the evidence base remains fragmented, while local knowledge remains marginalised in many national biodiversity strategies and development plans. This applies to the Tonga people of Zambia and Zimbabwe. Here, we synthesise existing evidence of Tonga knowledge and practices to explore their potential contribution to the implementation of integrated landscape approaches that aim to incorporate multiple stakeholders’ objectives in landscape-scale management. Based on a semi-systematic literature review, we identify how various dimensions of Tonga knowledge contribute to biodiversity, food security, soil conservation, and other well-being dimensions. Research gaps identified include significantly less documented evidence of Tonga knowledge and practices in Zimbabwe and limited attention to the biophysical impact of local practices on land and natural resources. Furthermore, there is limited attention to the historical processes that have led to the erosion of Tonga local knowledge and the political disempowerment of Tonga knowledge holders. The findings contribute to greater recognition and validation of Tonga local knowledge and practices in natural resource governance, particularly how such knowledge can contribute to integrated landscape governance. Finally, the review helps to define a future research agenda based on the knowledge gaps identified

    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

    Sandurot festival as \u3ci\u3emugna\u3c/i\u3e : exploring modernity and belonging through the civic festival

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    Focusing on the Sandurot Festival organized by the City of Dumaguete in the Philippines, my study explores the process of embodying local identity as site to actualize modernity. To highlight this collaborative, creative, and often contentious process, I put forward the concept of mugna (a Cebuano word which means to create) to examine how social actors (such as festival organizers, cultural workers, and artists) configure nodes of belonging to the time and space of the city by engaging with notions of tradition, authenticity, progress, and development. As Cultural Studies stresses the significance of radical contextuality, I examine in this project the problem-spaces of modernity and belonging to investigate how they constitute the conjuncture wherein the performance practice of the civic festival emerges as mugna. In this light, I adapt Diana Taylor’s performance paradigm to approach the festival as a scenario in interrogating how and why local identity is performed. With this approach, I historicize the festival by examining its situatedness within nation-building and city-making policies and institutional directions (discussed mainly in Chapters One and Two). I further probe its embodied practice by analyzing the repeated but reconfigured corporeal forms and exploring the involvement of social actors in the corporeal practices of festivity (examined closely in Chapters Three, Four, and Five). Borrowing from the insights of performance studies and critical ethnography, I aim to show that through this process of mugna, the festival unfolds in a scenario of rediscovery where social actors playfully embody and reinvent the ‘folk’ and the past through networks of creative collaboration to transmit knowledge about Dumaguete. Thus, the festival as mugna, is produced by and produces attachment to the locality through various social actors’ embodiment of their ‘modern desire’ for the city life, in the process that invokes their local identity and associated civic claims to urban space. I conclude that the festival as mugna enhances our understanding on the configurations of modernity, with how social actors fulfill their individual and collective aspirations for the city and their practices of belonging in it, by determining how the city is remembered, lived, and aspired through the Sandurot Festival
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