699 research outputs found

    Personal Identity as a Hypothesis

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    I propose that the notions of personhood and personal identity are most accurately understood as merely negative hypotheses in the brains of us humans. Understanding the notions of personhood and personal identity in this way will also explain why the disagreements about the nature of personhood and personal identity have been intractable so far in the philosophical literature. And it also predicts that settling these disagreements through the analytic dialectic is unlikely

    Researching animal research: What the humanities and social sciences can contribute to laboratory animal science and welfare

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    Every year around 80 million scientific procedures are carried out on animals globally. These experiments have the potential to generate new understandings of biology and clinical treatments. They also give rise to ongoing societal debate.This book demonstrates how the humanities and social sciences can contribute to understanding what is created through animal procedures - including constitutional forms of research governance, different institutional cultures of care, the professional careers of scientists and veterinarians, collaborations with patients and publics, and research animals, specially bred for experiments or surplus to requirements.Developing the idea of the animal research nexus, this book explores how connections and disconnections are made between these different elements, how these have reshaped each other historically, and how they configure the current practice and policy of UK animal research

    Information actors beyond modernity and coloniality in times of climate change:A comparative design ethnography on the making of monitors for sustainable futures in Curaçao and Amsterdam, between 2019-2022

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    In his dissertation, Mr. Goilo developed a cutting-edge theoretical framework for an Anthropology of Information. This study compares information in the context of modernity in Amsterdam and coloniality in Curaçao through the making process of monitors and develops five ways to understand how information can act towards sustainable futures. The research also discusses how the two contexts, that is modernity and coloniality, have been in informational symbiosis for centuries which is producing negative informational side effects within the age of the Anthropocene. By exploring the modernity-coloniality symbiosis of information, the author explains how scholars, policymakers, and data-analysts can act through historical and structural roots of contemporary global inequities related to the production and distribution of information. Ultimately, the five theses propose conditions towards the collective production of knowledge towards a more sustainable planet

    Epigenetic regulation of enhancer activity in the mammalian genome

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    Cell types are defined by their spatiotemporal gene expression patterns and their differential activity of promoters and enhancers. Enhancers are cis-regulatory elements in the DNA critical for the acquisition and maintenance of cellular identities by regulating the expression of key genes. Enhancers serve as landing pads for transcription factors (TFs) which are DNA-binding proteins that interpret the genomic code and enhance gene expression upon their binding. However, the underlying DNA sequence does not solely convey binding specificity, and therefore it is still largely elusive what additional factors regulate TF binding. An important regulatory layer in gene expression are dynamic and reversible epigenetic modifications of chromatin including DNA and histone proteins. To date, dozens of histone modifications have been identified that are associated with different genomic contexts and transcriptional states. For instance, histone H3 lysine acetylation has been generally associated with active chromatin as active enhancers and promoters, while histone H3 tri-methylation at lysine 23 (H3K27me3) is coupled to transcription repression. Yet, the causal contribution of such histone modifications to the regulation of enhancer activity and TF binding is still large unknown. To address this question, I developed a technical approach to analyse TF binding at DNA molecules where a certain histone modification of interest is present. For this, I combined a genomic enrichment technique with a single molecule footprinting (SMF) approach that allows to detect TF binding at single DNA molecule resolution. However, this experimental set-up paired with different optimization approaches did not produce high enough enrichments of DNA molecules harboring certain histone modifications to suffice the required statistical power. Therefore, the focus was laid on investigating the causal role of DNA methylation. DNA methylation in CpG context is the most common epigenetic modification in the mammalian genome that covers 70-80% of all CpG dinucleotides. Despite its prevalence, DNA methylation can be highly dynamic, especially at enhancer elements that exhibit reduced methylation levels during their activation. Previous studies have identified that the binding of TFs to enhancers is correlated with the partial loss in DNA methylation and it has been suggested that DNA methylation regulates enhancer activity. This hypothesis has remained elusive up to date, which has multiple reasons. First, the relationship between TFs and DNA methylation is bidirectional. Previous studies have identified many methyl-sensitive TFs in vitro whose binding is reduced upon methylation of their DNA binding motif. Some of those have been confirmed by in vivo studies, which showed that DNA methylation prevents the spurious binding of those TFs in the genome. Opposingly, TFs have also been identified to be directly responsible for the demethylation of enhancers. In consequence, the bidirectional regulation between DNA methylation and TF binding has prevented the establishment of a causal relationship between them. Second, the cell-to-cell epigenetic variability observed as intermediate methylation at enhancers elements makes common bulk-cell genomics approaches ineffective to identify a direct correlation between DNA methylation and TF binding and to determine whether DNA methylation generally contributes to the regulation of enhancer activity. In the here presented PhD project, I overcame these issues and limitation by advancing the single molecule footprinting (SMF) approach to resolve chromatin accessibility, TF binding, and simultaneously quantify the presence of DNA methylation on the same DNA molecules. By applying this technology across the murine genome, I demonstrate that TFs can bind most (>90%) enhancers irrespective of the underlying DNA methylation, suggesting that presence of DNA methylation does not generally impede enhancer activity. Yet, for stem cells and three somatic cell types, I identified active enhancers where TF occupancy is directly repressed by DNA methylation, including enhancers involved in the control of key cell identity genes. Using global perturbation assays and orthogonal enhancer activity measurements, I was able to show that at these active sites, DNA methylation directly controls the occupancy levels of TFs such as Max-Myc, that play a key role in the control of stem cell identity and proliferation. In the end, my data suggest a model where the function of DNA methylation extends beyond protecting the genome from spurious TF binding, by directly regulating the activation of cell-type specific enhancers. This detailed analysis is an important addition to our general knowledge on gene regulation and suggest that while epigenetic factors may have largely redundant functions, their individual contributions can play important and instructive roles in tuning the quantitative expression of key cell- specific genes. Understanding the regulation of such genes involved in cell identity will have important implications in the comprehension of development and disease

    The power of organized fandoms in the age of Web 2.0:the Snyder Cut

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    Abstract. The internet has given many individuals the chance to connect with each other in a virtual manner and engage in discussions concerning topics they are interested in a new and modern fashion. Fandoms can be described as a designated culture of emotion, aiming to encourage individuals to experience culture with a heightened sense of enthusiasm, emotional involvement, and strong attachments. This thesis seeks to investigate the different impacts that fandoms can have on the internet, via an analysis of the subreddit r/DC_Cinematic, which is one of the various communities on the internet where fans demanded for director’s Zack Snyder’s Justice League film to be released, after allegations of his vision being replaced by the theatrical release directed by Joss Whedon. In this subreddit, different posts were examined, along with its comments. The dataset was retrieved using RStudio, with the data extraction toolkit known as RedditExtractoR. The dataset was organized to allow for analysis, and the results were summarized for the thesis. The results were discussed based on previous literature, and implications for research and practice are identified. It was found that individuals became motivated to join the Snyder Cut movement because they wanted to share their emotions, expectations, shared experiences, and increase their sense of belonging surrounding the movement. Moreover, individuals were twice as likely to encounter positive than negative engagement, with the most frequent signs of positivity being support, guidance, encouragement, respect and expressing or developing a sense of community. On the other hand, the most frequent signs of negativity involved facing or expressing negative and extremist thoughts and behaviours, as well as facing or finding toxic behaviours from those that support or not the Snyder Cut. The factors that were believed to have contributed to the success and release of the Snyder Cut were the support for the cut, the desire to see Snyder’s vision, and the theory of Warner Brothers using the Snyder Cut to market their then yet-to-be-released new streaming platform HBO Max

    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

    Using Formal Epistemology to Model Epistemic Injustice Against Neurodivergent People

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    Neurodivergent people experience epistemic injustice, injustices that harm them in their capacity as knowers, but so far the epistemic injustice literature has mostly ignored this. This dissertation addresses this gap in knowledge in a novel way, using tools of formal epistemology. Bayesian network learning models that include modeled bias, communication style gaps, exclusion, and difference between people, are used to investigate testimonial injustice. Novel simultaneous Lewis-Skyrms signal games that include modeled bias, focus on success, gaps in way of thinking, exclusion, and difference in material interests are used to investigate hermeneutical injustice, the subset of epistemic injustice that involves concepts important to an identity group being obscured both in and out of that identity group, due to the model\u27s ability to track formation of meaning over time. The model results indicate that improvement first requires neurodivergent people be integrated into social networks with mixed neurotypes, but that this must be done with care to not isolate neurodivergent people among neurotypical people, and without tokenizing. Additionally, the models give evidence of social evolutionary forces that would contribute towards the presence of ableism in norms of communication, so it is recommended that action to combat ableism should include actions that create countervailing cultural evolutionary pressure, and aim to benefit anyone whom the action hopes to win over

    To the Last Drop: Affective Economies of Extraction and Sentimentality

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    The romance of extraction underlies and partly defines Western modernity and our cultural imaginaries. Combining affect studies and environmental humanities, this volume analyzes societies' devotion to extraction and fossil resources. This devotion is shaped by a nostalgic view on settler colonialism as well as by contemporary "affective economies" (Sara Ahmed). The contributors examine the links between forms of extractivism and gendered discourses of sentimentality and the ways in which cultural narratives and practices deploy the sentimental mode (in plots of attachment, sacrifice, and suffering) to promote or challenge extractivism

    Structural optimization in steel structures, algorithms and applications

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    L'abstract è presente nell'allegato / the abstract is in the attachmen
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