6,621 research outputs found

    TANDEM: taming failures in next-generation datacenters with emerging memory

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    The explosive growth of online services, leading to unforeseen scales, has made modern datacenters highly prone to failures. Taming these failures hinges on fast and correct recovery, minimizing service interruptions. Applications, owing to recovery, entail additional measures to maintain a recoverable state of data and computation logic during their failure-free execution. However, these precautionary measures have severe implications on performance, correctness, and programmability, making recovery incredibly challenging to realize in practice. Emerging memory, particularly non-volatile memory (NVM) and disaggregated memory (DM), offers a promising opportunity to achieve fast recovery with maximum performance. However, incorporating these technologies into datacenter architecture presents significant challenges; Their distinct architectural attributes, differing significantly from traditional memory devices, introduce new semantic challenges for implementing recovery, complicating correctness and programmability. Can emerging memory enable fast, performant, and correct recovery in the datacenter? This thesis aims to answer this question while addressing the associated challenges. When architecting datacenters with emerging memory, system architects face four key challenges: (1) how to guarantee correct semantics; (2) how to efficiently enforce correctness with optimal performance; (3) how to validate end-to-end correctness including recovery; and (4) how to preserve programmer productivity (Programmability). This thesis aims to address these challenges through the following approaches: (a) defining precise consistency models that formally specify correct end-to-end semantics in the presence of failures (consistency models also play a crucial role in programmability); (b) developing new low-level mechanisms to efficiently enforce the prescribed models given the capabilities of emerging memory; and (c) creating robust testing frameworks to validate end-to-end correctness and recovery. We start our exploration with non-volatile memory (NVM), which offers fast persistence capabilities directly accessible through the processor’s load-store (memory) interface. Notably, these capabilities can be leveraged to enable fast recovery for Log-Free Data Structures (LFDs) while maximizing performance. However, due to the complexity of modern cache hierarchies, data hardly persist in any specific order, jeop- ardizing recovery and correctness. Therefore, recovery needs primitives that explicitly control the order of updates to NVM (known as persistency models). We outline the precise specification of a novel persistency model – Release Persistency (RP) – that provides a consistency guarantee for LFDs on what remains in non-volatile memory upon failure. To efficiently enforce RP, we propose a novel microarchitecture mechanism, lazy release persistence (LRP). Using standard LFDs benchmarks, we show that LRP achieves fast recovery while incurring minimal overhead on performance. We continue our discussion with memory disaggregation which decouples memory from traditional monolithic servers, offering a promising pathway for achieving very high availability in replicated in-memory data stores. Achieving such availability hinges on transaction protocols that can efficiently handle recovery in this setting, where compute and memory are independent. However, there is a challenge: disaggregated memory (DM) fails to work with RPC-style protocols, mandating one-sided transaction protocols. Exacerbating the problem, one-sided transactions expose critical low-level ordering to architects, posing a threat to correctness. We present a highly available transaction protocol, Pandora, that is specifically designed to achieve fast recovery in disaggregated key-value stores (DKVSes). Pandora is the first one-sided transactional protocol that ensures correct, non-blocking, and fast recovery in DKVS. Our experimental implementation artifacts demonstrate that Pandora achieves fast recovery and high availability while causing minimal disruption to services. Finally, we introduce a novel target litmus-testing framework – DART – to validate the end-to-end correctness of transactional protocols with recovery. Using DART’s target testing capabilities, we have found several critical bugs in Pandora, highlighting the need for robust end-to-end testing methods in the design loop to iteratively fix correctness bugs. Crucially, DART is lightweight and black-box, thereby eliminating any intervention from the programmers

    The telecoupled sustainability impacts of global agricultural value chains:Assessing the cross-scale sustainability impacts of the cocoa sector

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    Agriculture is a major contributor to the global environmental crisis. Natural ecosystems are being replaced by agricultural land, which leads to the extinction of species and the release of tons of carbon emissions. Global agricultural value chains (GVCs) have grown due to the intensification of international trade. While GVCs have undeniably created economic opportunities for the agriculture sector, they have also led to the escalation of local environmental issues. Several initiatives have been implemented to reduce the negative impacts of agriculture, including government regulations, sustainability certification labels, and voluntary sustainability commitments. However, the effectiveness of these initiatives has been questioned due to several reasons, including the mismatches between the scale of the problem and the solution, the lack of monitoring and verification of sustainability actions, and their weak enforcement. Sustainability initiatives are informed by studies assessing the impacts of agriculture that often only focus on local impacts, while disregarding larger-scale – telecoupled– dynamics that can trigger impacts across geographic and temporal scales. This thesis aims to help bridge these knowledge gaps by examining the impacts of agricultural GVCs across scales, studying the role of GVC’s configuration in modulating these impacts and investigating the role of GVC actors in mitigating sustainability risks across scales. The global cocoa value chain is used as a case study. Chapter 2 examines various impact assessment methods and their ability to capture the effects caused by telecoupled dynamics across different scales. The study concludes that no single method is sufficient to capture all telecoupled cross-scale dynamics and that the integration of different methods is necessary to bridge gaps between methods and complement their scope. Chapter 3 implements the recommendations outlined in Chapter 2 by analyzing the impacts caused by cocoa agroforestry and cocoa full-sun production in Ghana. Impacts on carbon, biodiversity stocks, and environmental pollution were analyzed within and beyond the farm-level. This chapter reveals that findings drawn from farm-level assessments can contradict those from landscape-level assessments. Decision-makers focused should be wary of extrapolating farm-level assessment results to larger scales. Chapter 4 expands the scope to the global scale by examining the role of the cocoa GVC configuration on the capacity of the sector to address sustainability challenges across scales. The chapter identifies different types of cocoa traders, their market dominance, and sustainability commitments. The chapter highlights that to address the telecoupled impacts of the cocoa GVC, coordinated action between traders is required, along with government interventions to balance power asymmetries. Chapter 5 measured the degree to which cocoa traders, as identified in Chapter 4, are exposed to deforestation and climate change. This chapter highlights that sustainability challenges in agricultural value chains cannot be resolved in isolation as farming systems are constantly interacting with other farming systems and land competing sectors. To avoid displacing negative impacts across scales, it is necessary to have a coordinated and collaborative effort from stakeholders and sectors involved in making decisions related to land use. This thesis shows that addressing the telecoupled impacts caused by agricultural value chains needs a good understanding of the cause-effect dynamics at play. This requires the quantification of impacts caused by agriculture across scales and the characterization of the GVC network of actors modulating these impacts. Interdisciplinary methods need to be leveraged and integrated to generate actionable insights. The findings of this thesis can assist decision-makers and private actors in devising customized sustainability strategies, prioritizing action, and addressing the most vulnerable hotspots while being mindful of global teleconnections and avoiding spillovers

    MOVEing Microorganisms:The effect of the built environment of the hospital and screening strategies on microbial safety

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    In this dissertation the results of the MOVE study are described, which determined if the transition to solely single-occupancy rooms in the new hospital building of the Erasmus MC contributed to a microbial safer hospital. Additionally, the effect of screenings methods for MDRO at admission of patients was evaluated

    Displacement and the Humanities: Manifestos from the Ancient to the Present

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    This is the final version. Available on open access from MDPI via the DOI in this recordThis is a reprint of articles from the Special Issue published online in the open access journal Humanities (ISSN 2076-0787) (available at: https://www.mdpi.com/journal/humanities/special_issues/Manifestos Ancient Present)This volume brings together the work of practitioners, communities, artists and other researchers from multiple disciplines. Seeking to provoke a discourse around displacement within and beyond the field of Humanities, it positions historical cases and debates, some reaching into the ancient past, within diverse geo-chronological contexts and current world urgencies. In adopting an innovative dialogic structure, between practitioners on the ground - from architects and urban planners to artists - and academics working across subject areas, the volume is a proposition to: remap priorities for current research agendas; open up disciplines, critically analysing their approaches; address the socio-political responsibilities that we have as scholars and practitioners; and provide an alternative site of discourse for contemporary concerns about displacement. Ultimately, this volume aims to provoke future work and collaborations - hence, manifestos - not only in the historical and literary fields, but wider research concerned with human mobility and the challenges confronting people who are out of place of rights, protection and belonging

    Safe passage for attachment systems:Can attachment security at international schools be measured, and is it at risk?

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    Relocations challenge attachment networks. Regardless of whether a person moves or is moved away from, relocation produces separation and loss. When such losses are repeatedly experienced without being adequately processed, a defensive shutting down of the attachment system could result, particularly when such experiences occur during or across the developmental years. At schools with substantial turnover, this possibility could be shaping youth in ways that compromise attachment security and young people’s willingness or ability to develop and maintain deep long-term relationships. Given the well-documented associations between attachment security, social support, and long-term physical and mental health, the hypothesis that mobility could erode attachment and relational health warrants exploration. International schools are logical settings to test such a hypothesis, given their frequently high turnover without confounding factors (e.g. war trauma or refugee experiences). In addition, repeated experiences of separation and loss in international school settings would seem likely to create mental associations for the young people involved regarding how they and others tend to respond to such situations in such settings, raising the possibility that people at such schools, or even the school itself, could collectively be represented as an attachment figure. Questions like these have received scant attention in the literature. They warrant consideration because of their potential to shape young people’s most general convictions regarding attachment, which could, in turn, have implications for young people’s ability to experience meaning in their lives

    Investigation of the metabolism of rare nucleotides in plants

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    Nucleotides are metabolites involved in primary metabolism, and specialized metabolism and have a regulatory role in various biochemical reactions in all forms of life. While in other organisms, the nucleotide metabolome was characterized extensively, comparatively little is known about the cellular concentrations of nucleotides in plants. The aim of this dissertation was to investigate the nucleotide metabolome and enzymes influencing the composition and quantities of nucleotides in plants. For this purpose, a method for the analysis of nucleotides and nucleosides in plants and algae was developed (Chapter 2.1), which comprises efficient quenching of enzymatic activity, liquid-liquid extraction and solid phase extraction employing a weak-anionexchange resin. This method allowed the analysis of the nucleotide metabolome of plants in great depth including the quantification of low abundant deoxyribonucleotides and deoxyribonucleosides. The details of the method were summarized in an article, serving as a laboratory protocol (Chapter 2.2). Furthermore, we contributed a review article (Chapter 2.3) that summarizes the literature about nucleotide analysis and recent technological advances with a focus on plants and factors influencing and hindering the analysis of nucleotides in plants, i.e., a complex metabolic matrix, highly stable phosphatases and physicochemical properties of nucleotides. To analyze the sub-cellular concentrations of metabolites, a protocol for the rapid isolation of highly pure mitochondria utilizing affinity chromatography was developed (Chapter 2.4). The method for the purification of nucleotides furthermore contributed to the comprehensive analysis of the nucleotide metabolome in germinating seeds and in establishing seedlings of A. thaliana, with a focus on genes involved in the synthesis of thymidilates (Chapter 2.5) and the characterization of a novel enzyme of purine nucleotide degradation, the XANTHOSINE MONOPHOSPHATE PHOSPHATASE (Chapter 2.6). Protein homology analysis comparing A. thaliana, S. cerevisiae, and H. sapiens led to the identification and characterization of an enzyme involved in the metabolite damage repair system of plants, the INOSINE TRIPHOSPHATE PYROPHOSPHATASE (Chapter 2.7). It was shown that this enzyme dephosphorylates deaminated purine nucleotide triphosphates and thus prevents their incorporation into nucleic acids. Lossof-function mutants senesce early and have a constitutively increased content of salicylic acid. Also, the source of deaminated purine nucleotides in plants was investigated and it was shown that abiotic factors contribute to nucleotide damage.Nukleotide sind Metaboliten, die am Primärstoffwechsel und an spezialisierten Stoffwechselvorgängen beteiligt sind und eine regulierende Rolle bei verschiedenen biochemischen Reaktionen in allen Lebensformen spielen. Während bei anderen Organismen das Nukleotidmetabolom umfassend charakterisiert wurde, ist in Pflanzen vergleichsweise wenig über die zellulären Konzentrationen von Nukleotiden bekannt. Ziel dieser Dissertation war es, das Nukleotidmetabolom und die Enzyme zu untersuchen, die die Zusammensetzung und Menge der Nukleotide in Pflanzen beeinflussen. Zu diesem Zweck wurde eine Methode zur Analyse von Nukleotiden und Nukleosiden in Pflanzen und Algen entwickelt (Kapitel 2.1), die ein effizientes Stoppen enzymatischer Aktivität, eine Flüssig-Flüssig-Extraktion und eine Festphasenextraktion unter Verwendung eines schwachen Ionenaustauschers umfasst. Mit dieser Methode konnte das Nukleotidmetabolom von Pflanzen eingehend analysiert werden, einschließlich der Quantifizierung von Desoxyribonukleotiden und Desoxyribonukleosiden mit geringer Abundanz. Die Einzelheiten der Methode wurden in einem Artikel zusammengefasst, der als Laborprotokoll dient (Kapitel 2.2). Darüber hinaus wurde ein Übersichtsartikel (Kapitel 2.3) verfasst, der die Literatur über die Analyse von Nukleotiden und die jüngsten technologischen Fortschritte zusammenfasst. Der Schwerpunkt lag hierbei auf Pflanzen und Faktoren, die die Analyse von Nukleotiden in Pflanzen beeinflussen oder behindern, d. h. eine komplexe Matrix, hochstabile Phosphatasen und physikalisch-chemische Eigenschaften von Nukleotiden. Um die subzellulären Konzentrationen von Metaboliten zu analysieren, wurde ein Protokoll für die schnelle Isolierung hochreiner Mitochondrien unter Verwendung einer Affinitätschromatographie entwickelt (Kapitel 2.4). Die Methode zur Analyse von Nukleotiden trug außerdem zu einer umfassenden Analyse des Nukleotidmetaboloms in keimenden Samen und in sich etablierenden Keimlingen von A. thaliana bei, wobei der Schwerpunkt auf Genen lag, die an der Synthese von Thymidilaten beteiligt sind (Kapitel 2.5), sowie zu der Charakterisierung eines neuen Enzyms des Purinnukleotidabbaus, der XANTHOSINE MONOPHOSPHATE PHOSPHATASE (Kapitel 2.6). Eine Proteinhomologieanalyse, die A. thaliana, S. cerevisiae und H. sapiens miteinander verglich führte zur Identifizierung und Charakterisierung eines Enzyms, das an der Reparatur von geschädigten Metaboliten in Pflanzen beteiligt ist, der INOSINE TRIPHOSPHATE PYROPHOSPHATASE (Kapitel 2.7). Es konnte gezeigt werden, dass dieses Enzym desaminierte Purinnukleotidtriphosphate dephosphoryliert und so deren Einbau in Nukleinsäuren verhindert. Funktionsverlustmutanten altern früh und weisen einen konstitutiv erhöhten Gehalt an Salicylsäure auf. Außerdem wurde die Quelle der desaminierten Purinnukleotide in Pflanzen untersucht, und es wurde gezeigt, dass abiotische Faktoren zur Nukleotidschädigung beitragen

    Synthesis of multifunctional glyco-pseudodendrimers and glyco-dendrimers and their investigation as anti-Alzheimer agents

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    As the world population is aging, the cases of Alzheimer’s Disease (AD) are increasing. AD is a disorder of the brain which is characterized by the aggregation of amyloid beta (Aβ) plaques. This leads to the death of numerous brain cells thus affecting the cognitive and motor functions of the individual. Till date, no cure for the disease is available. Aβ are peptides with 40/42 amino acid residues but, their exact mechanism(s) of action in AD is under debate. Having different amino acid residues makes them susceptible to form hydrogen bonds. Dendrimers with sugar units are often referred to as glycopolymers and have been shown to have potential anti-amyloidogenic activity. However, they also have drawbacks, the synthesis involves multiple tedious steps, and dendrimers themselves offer only a limited number of functional units. Pseudodendrimers are another class of branched polymers based on hyperbranched polymers. Unlike the dendrimers, they are easy to synthesize with a dense shell of functional units on the surface. One of the main goals in this dissertation is the synthesis and characterization of pseudodendrimers and dendrimers based on 2,2-bis(hydroxymethyl)-propionic acid (bis-MPA), an aliphatic polyester scaffold, as it offers biocompatibility and easy degradability. Furthermore, they are decorated with mannose units on the surface using a ‘click’ reaction forming glyco-pseudodendrimers and glyco-dendrimers. A detailed characterization of their structures and physical properties was undertaken using techniques such as size exclusion chromatography, asymmetric flow field flow fractionation (AF4), and dynamic light scattering. The second main focus of this work has been to investigate the interaction of synthesized glyco-pseudodendrimers and glyco-dendrimers with Aβ 40 peptides. For this task, five different concentrations of the synthesized glycopolymers were tested with Aβ 40 using the Thioflavin T assay. The results of the synthesized polymers which produced the best results of showing maximum anti-aggregation behavior against Aβ 40 were confirmed with circular dichroism spectroscopy. AF4 was also used to investigate Aβ 40-glycopolymer aggregates, which has never been done before and constitutes the highlight of this dissertation. Atomic force microscopy was used to image Aβ 40-glycopseudodenrimer aggregates. A basic but important step in the development of drug delivery platforms is to evaluate the toxicity of the drugs synthesized. In this work, preliminary studies of the cytotoxicity of glyco-pseudodendrimers were performed in two different cell lines. Thus, this study comprises a preliminary investigation of the anti-amyloidogenic activity of glyco-pseudodendrimers synthesized on an aliphatic polyester backbone.:Abstract List of Tables List of Figures Abbreviations 1 Introduction 1.1 Objectives of the work 1.2 Thesis overview 2 Fundamentals and Literature 2.1 Alzheimer’s Disease and its impact 2.1.1 Neurological diagnosis of AD 2.1.2 Histopathology of AD 2.1.3 Amyloid precursor protein (APP) and its role in AD 2.2. Amyloid Beta (Aβ) peptide 2.2.1 Aβ peptide 2.2.2. Location and function 2.2.3 Amyloid hypothesis 2.2.4 The mechanism of Aβ aggregation 2.2.5 Amyloid fibrils 2.2.6 Toxicity of Aβ 2.3 Research methods to study Aβ aggregates 2.3.1 Models to study the mode of action of aggregates 2.3.2 Endogenous Aβ aggregates and synthetic aggregates 2.3.3 Strategies to alter aggregation of amyloids 2.4 Treatment and therapeutics 2.4.1 Current therapeutics 2.4.2 Current therapeutic research 2.4.2.1 Reduction of Aβ production 2.4.2.2 Reduction of Aβ plaque accumulation 2.4.2.2.1 Anti-amyloid aggregation agents 2.4.2.2.2 Metals 2.4.2.2.3 Immunotherapy 2.4.2.2.4 Dendrimers as potential anti-amyloidogenic agent 2.6 Dendrimers 2.6.1 Definition 2.6.2 Structure Table of Contents 2.6.3 Synthesis 2.6.4 Properties 2.7 Pseudodendrimers - a sub-class of hyperbranched polymer 2.7.1 Definition 2.7.2 Structure 2.7.3 Synthesis 3 Analytical Techniques 3.1 Size Exclusion Chromatography Coupled to Light Scattering (SEC-MALS) 3.2 Asymmetric Flow Field Flow Fractionation (AF4) 3.3 Dynamic Light Scattering 3.4 Molecular Dynamics Simulation 3.5 Nuclear Magnetic Resonance Spectroscopy 3.6 Thioflavin T fluorescence 3.6.1 Kinetic analysis 3.7 Circular Dichroism Spectroscopy 3.8 Atomic Force Microscopy 3.9 Cytotoxic assay 3.9.1 MTT assay 3.9.2 Determining the level of reactive oxygen species 3.9.3 Changes in mitochondrial transmembrane potential 3.9.4 Flow cytometric detection of phosphatidyl serine exposure 4 Experimental Details and Methodology 4.1 Details of chemicals/components used 4.1.1 Other materials 4.1.2 Peptide preparation 4.1.3 Buffer preparation 4.1.4 Fibril growth conditions 4.2 Synthesis and characterization of polymers 4.2.1 Synthesis and characterization of pseudodendrimers and dendrimers 4.2.1.1 Synthesis of hyperbranched polymer (1) 4.2.1.2 Synthesis of protected monomer 4.2.1.2.1 bis-MPA acetonide (2) 4.2.1.2.2 bis-MPA-acetonide anhydride (3) 4.2.1.3 Synthesis of protected pseudodendrimers (4, 6 and 8) and protected dendrimers (10, 12, and 14) 4.2.1.4 Deprotection of pseudodendrimers (5,7, and 9) and dendrimers (11,13 and 15) 4.2.2 Synthesis of glyco-pseudodendrimers and glyco-dendrimers 4.2.2.1 Pentynoic anhydride (16) 4.2.2.2 Synthesis of pentinate modified pseudodendrimers (17, 18 and 19) and dendrimers (20, 21 and 22) 4.2.2.3 3-Azido-1-propanol (23) 4.2.2.4 Mannose propyl azide tetraacetate (24) Table of Contents 4.2.2.5 Mannosepropylazide (25) 4.2.2.6 Glyco-pseudodendrimers (Gl-P) (26, 27 and 28) and glyco- dendrimers (Gl-D) (29, 30 and 31) 4.3 Analytical techniques and their general details 4.3.1 SEC-MALS - Instrumentation, software and analysis 4.3.2 AF4 - Instrumentation, software and analysis 4.3.2.1 Sample preparation 4.3.2.2 Method development for analysis of Gl-P and Gl-D 4.3.2.3 Method development for analysis of Aβ 40 and its interaction with Gl-P and Gl-D 4.3.3 Batch DLS - Instrumentation, software and analysis 4.3.3.1 Sample preparation 4.3.4 Theoretical calculations and molecular dynamics simulations 4.3.4.1 Ab-initio calculations 4.3.4.2 Modelling of the polymer structures 4.3.4.2.1 Pseudodendrimers 4.3.4.2.2 Dendrimers 4.3.4.2.3 Modification of the polymers with special end groups 4.3.4.2.4 Preparing of the THF solvent box 4.3.4.2.5 Solvation of the polymer structures 4.3.4.3 Molecular dynamics simulations 4.3.4.3.1 Evaluation of the simulation trajectories 4.4 Investigation of interaction of Gl-P and Gl-D with amyloid beta (Aβ 40) 4.4.1 ThT Assay - Instrumentation and software 4.4.1.1 Sample preparation 4.4.1.2 Kinetics based on ThT assay- software and data analysis 4.4.2 CD spectroscopy - Instrumentation and software 4.4.2.1 Sample preparation 4.4.3 AFM - Instrumentation and software 4.4.3.1 Substrate and sample preparation 4.4.3.2 Height determination and counting procedures 4.4.3.3 Topography and diameter 4.5 Cytotoxicity 4.5.1 Zeta potential 4.5.2 Cell culturing 4.5.3 Sample preparation 4.5.4 MTT assay 4.5.5 Changes in mitochondrial transmembrane potential (JC-1 method) 4.5.6 Flow cytometric detection of phosphatidyl serine exposure (Annexin V and PI method) 5 Results and Discussion 5.1 Synthesis and characterization of glyco-pseudodendrimers and glyco- dendrimers 5.1.1 Synthesis and characterization of hyperbranched polyester Table of Contents 5.1.2 Synthesis and characterization of pseudodendrimers P-G1-OH, P-G2-OH and P-G3-OH 5.1.3 Synthesis and characterization of dendrimers D-G4-OH, D-G5-OH and D-G6-OH 5.1.4 Synthesis and characterization of Gl-P and Gl-D 5.1.4.1 Molecular size determination of Gl-P and Gl-D using SEC 5.1.4.2 Particle size determination using batch DLS 5.1.4.3 Apparent densities 5.1.4.4 Molecular size determination of Gl-P and Gl-D using AF4 ..... 5.1.5 Molecular dynamics simulation 5.2 Investigation of interaction of Gl-P and Gl-D with amyloid beta (Aβ 40) ...... 5.2.1 ThT Assay 5.2.1.1 Kinetics based on ThT assay 5.2.2 CD spectroscopy 5.2.3 Time dependent AF4 5.3.2.1 Separation of Aβ 40 by AF4 5.3.2.2 Aβ 40 amyloid aggregation in the presence of Gl-P and Gl-D 5.2.4 AFM 5.2.4.1 Height 5.2.4.2 Topography and diameter 5.2.4.3 Length 5.2.4.4 Morphology 5.2.5 Cytotoxicity 5.2.5.1 MTT assay 5.2.5.2 Changes in mitochondrial transmembrane potential 5.2.5.3 Flow cytometric detection of phosphatidyl serine exposure 6 Conclusions and Outlook 7 Bibliography Appendix Acknowledgement

    Fictocritical Cyberfeminism: A Paralogical Model for Post-Internet Communication

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    This dissertation positions the understudied and experimental writing practice of fictocriticism as an analog for the convergent and indeterminate nature of “post-Internet” communication as well a cyberfeminist technology for interfering and in-tervening in metanarratives of technoscience and technocapitalism that structure contemporary media. Significant theoretical valences are established between twen-tieth century literary works of fictocriticism and the hybrid and ephemeral modes of writing endemic to emergent, twenty-first century forms of networked communica-tion such as social media. Through a critical theoretical understanding of paralogy, or that countercultural logic of deploying language outside legitimate discourses, in-volving various tactics of multivocity, mimesis and metagraphy, fictocriticism is ex-plored as a self-referencing linguistic machine which exists intentionally to occupy those liminal territories “somewhere in among/between criticism, autobiography and fiction” (Hunter qtd. in Kerr 1996). Additionally, as a writing practice that orig-inated in Canada and yet remains marginal to national and international literary scholarship, this dissertation elevates the origins and ongoing relevance of fictocriti-cism by mapping its shared aims and concerns onto proximal discourses of post-structuralism, cyberfeminism, network ecology, media art, the avant-garde, glitch feminism, and radical self-authorship in online environments. Theorized in such a matrix, I argue that fictocriticism represents a capacious framework for writing and reading media that embodies the self-reflexive politics of second-order cybernetic theory while disrupting the rhetoric of technoscientific and neoliberal economic forc-es with speech acts of calculated incoherence. Additionally, through the inclusion of my own fictocritical writing as works of research-creation that interpolate the more traditional chapters and subchapters, I theorize and demonstrate praxis of this dis-tinctively indeterminate form of criticism to empirically and meaningfully juxtapose different modes of knowing and speaking about entangled matters of language, bod-ies, and technologies. In its conclusion, this dissertation contends that the “creative paranoia” engendered by fictocritical cyberfeminism in both print and digital media environments offers a pathway towards a more paralogical media literacy that can transform the terms and expectations of our future media ecology

    ENGINEERING HIGH-RESOLUTION EXPERIMENTAL AND COMPUTATIONAL PIPELINES TO CHARACTERIZE HUMAN GASTROINTESTINAL TISSUES IN HEALTH AND DISEASE

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    In recent decades, new high-resolution technologies have transformed how scientists study complex cellular processes and the mechanisms responsible for maintaining homeostasis and the emergence and progression of gastrointestinal (GI) disease. These advances have paved the way for the use of primary human cells in experimental models which together can mimic specific aspects of the GI tract such as compartmentalized stem-cell zones, gradients of growth factors, and shear stress from fluid flow. The work presented in this dissertation has focused on integrating high-resolution bioinformatics with novel experimental models of the GI epithelium systems to describe the complexity of human pathophysiology of the human small intestines, colon, and stomach in homeostasis and disease. Here, I used three novel microphysiological systems and developed four computational pipelines to describe comprehensive gene expression patterns of the GI epithelium in various states of health and disease. First, I used single cell RNAseq (scRNAseq) to establish the transcriptomic landscape of the entire epithelium of the small intestine and colon from three human donors, describing cell-type specific gene expression patterns in high resolution. Second, I used single cell and bulk RNAseq to model intestinal absorption of fatty acids and show that fatty acid oxidation is a critical regulator of the flux of long- and medium-chain fatty acids across the epithelium. Third, I use bulk RNAseq and a machine learning model to describe how inflammatory cytokines can regulate proliferation of intestinal stem cells in an experimental model of inflammatory hypoxia. Finally, I developed a high throughput platform that can associate phenotype to gene expression in clonal organoids, providing unprecedented resolution into the relationship between comprehensive gene expression patterns and their accompanying phenotypic effects. Through these studies, I have demonstrated how the integration of computational and experimental approaches can measurably advance our understanding of human GI physiology.Doctor of Philosoph
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