7,802 research outputs found

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

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    Towards A Practical High-Assurance Systems Programming Language

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    Writing correct and performant low-level systems code is a notoriously demanding job, even for experienced developers. To make the matter worse, formally reasoning about their correctness properties introduces yet another level of complexity to the task. It requires considerable expertise in both systems programming and formal verification. The development can be extremely costly due to the sheer complexity of the systems and the nuances in them, if not assisted with appropriate tools that provide abstraction and automation. Cogent is designed to alleviate the burden on developers when writing and verifying systems code. It is a high-level functional language with a certifying compiler, which automatically proves the correctness of the compiled code and also provides a purely functional abstraction of the low-level program to the developer. Equational reasoning techniques can then be used to prove functional correctness properties of the program on top of this abstract semantics, which is notably less laborious than directly verifying the C code. To make Cogent a more approachable and effective tool for developing real-world systems, we further strengthen the framework by extending the core language and its ecosystem. Specifically, we enrich the language to allow users to control the memory representation of algebraic data types, while retaining the automatic proof with a data layout refinement calculus. We repurpose existing tools in a novel way and develop an intuitive foreign function interface, which provides users a seamless experience when using Cogent in conjunction with native C. We augment the Cogent ecosystem with a property-based testing framework, which helps developers better understand the impact formal verification has on their programs and enables a progressive approach to producing high-assurance systems. Finally we explore refinement type systems, which we plan to incorporate into Cogent for more expressiveness and better integration of systems programmers with the verification process

    Investigating neural differentiation capacity in Alzheimer’s disease iPSC-derived neural stem cells

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    Neurodegeneration in Alzheimer’s disease (AD) may be exacerbated by dysregulated hippocampal neurogenesis. Neural stem cells (NSC) maintain adult neurogenesis and depletion of the NSC niche has been associated with age-related cognitive decline and dementia. We hypothesise that familial AD (FAD) mutations bias NSC toward premature neural specification, reducing the stem cell niche over time and accelerating disease progression. Somatic cells derived from patients with FAD (PSEN1 A246E and PSEN1 M146L heterozygous mutations) and healthy controls were reprogrammed to generate induced pluripotent stem cells (iPSC). Pluripotency for patient and control iPSC lines was confirmed, then cells were amplified and cryopreserved as stores. iPSC were subjected to neural specification to rosette-forming SOX2+/nestin+ NSCs for comparative evaluations between FAD and age-matched controls. FAD patient and control NSC were passaged under defined steady state culture conditions to assess stem cell maintenance using quantitative molecular markers (SOX2, nestin, NeuN, MAP2 and βIII-tubulin). We observed trends towards downregulated expression of the nestin coding gene NES (p=0.051) and upregulated expression of MAP2 (p=0.16) in PSEN1 NSC compared with control NSC, indicative of a premature differentiation phenotype induced by presence of the PSEN1 mutation. Cell cycle analysis of PSEN1 NSC showed that compared with controls, a greater number of PSEN1 NSC were retained in G0/G1 phase of the cell cycle (p=0.39), fewer progressed to S-phase (p=0.11) and fewer still reached G2 phase (p=0.23), suggesting cell cycle progression may be impaired in PSEN1 NSC. Nuclear DNA fragmentation was increased (p=0.10) in FAD NSC compared with controls, indicative of elevated cell death/apoptosis. Flow cytometry-based analysis of live, nestin+ NSC and NPC indicated increased apoptosis (p=0.14) in FAD NSC compared with controls, as well as increasing levels of apoptosis (p=0.33) in FAD NSC as they specified to neural progenitor cells. Global RNA sequencing was used to identify transcriptomic changes occurring during both disease and control neural specification. GO analysis of DEGs between PSEN1 and control NSC at P3 revealed significant upregulation (FDR<0.0000259) of 5 biological processes related to transcription and gene expression as well as significant upregulation (FDR<0.000000725) of 12 molecular functions related to DNA binding and transcription factor activity. These data suggest significant changes in gene expression were occurring in PSEN1 NSC at P3 compared with control NSC at the same stage in neural specification. The number of DEGs (p<0.05) between PSEN1 and control NSC at P3 was 9.92-fold higher than the number of DEGs between PSEN1 and control NSC at P2, suggesting transcriptomic differences between PSEN1 and control NSC become more pronounced as cells specify further down the neural lineage. Gene ontology (GO) analysis of differentially expressed genes (DEGs) specific to AD neural differentiation revealed significant dysregulation (FDR p<0.05) of genes related to neurogenesis, apoptosis, cell cycle, transcriptional control, and cell growth/maintenance as PSEN1 NSC matured from P2 to P3. The number of DEGs (p<0.05) in PSEN1 neural differentiation was 4.7-fold higher than the number of DEGs seen in control neural differentiation, indicating more transcriptional changes occurred in PSEN1 NSC than in controls at the same time point in neural specification. Dysregulation of Notch signalling was specific to PSEN1 neural differentiation and Notch related DEGs significantly upregulated (p<0.05) in PSEN1 NSC at P3 compared with P2 included NCOR2, JAG2, CHAC1 and RFNG. qPCR based validation displayed significant upregulation of RFNG (p=0.04) in PSEN1 NSC at P3 compared with PSEN1 NSC at P2, and indicated a trend towards upregulation of JAG2 expression, correlating with RNA sequencing data. Data generated in this study indicate that presence of the PSEN1 mutation significantly increases the number of transcriptional changes occurring during neural differentiation. It is plausible that transcriptional changes to Notch signalling cause dysregulated neural specification and increased apoptosis in PSEN1 NSC, ultimately resulting in depletion of the NSC niche

    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

    Multi-dimensional omics approaches to dissect natural immune control mechanisms associated with RNA virus infections

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    In recent decades, global health has been challenged by emerging and re-emerging viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), human immunodeficiency viruses (HIV-1), and Crimean–Congo hemorrhagic fever virus (CCHFV). Studies have shown dysregulations in the host metabolic processes against SARS-CoV2 and HIV-1 infections, and the research on CCHFV infection is still in the infant stage. Hence, understanding the host metabolic re-programming on the reaction level in infectious disease has therapeutic importance. The thesis uses systems biology methods to investigate the host metabolic alterations in response to SARS-CoV2, HIV-1, and CCHFV infections. The three distinct viruses induce distinct effects on human metabolism that, nevertheless, show some commonalities. We have identified alterations in various immune cell types in patients during the infections of the three viruses. Further, differential expression analysis identified that COVID-19 causes disruptions in pathways related to antiviral response and metabolism (fructose mannose metabolism, oxidative phosphorylation (OXPHOS), and pentose phosphate pathway). Up-regulation of OXPHOS and ROS pathways with most changes in OXPHOS complexes I, III, and IV were identified in people living with HIV on treatment (PLWHART). The acute phase of CCHFV infection is found to be linked with OXPHOS, glycolysis, N-glycan biosynthesis, and NOD-like receptor signaling pathways. The dynamic nature of the metabolic process and adaptive immune response in CCHFV-pathogenesis are also observed. Further, we have identified different metabolic flux in reactions transporting TCA cycle intermediates from the cytosol to mitochondria in COVID-19 patients. Genes such as monocarboxylate transporter (SLC16A6) and nucleoside transporter (SLC29A1) and metabolites such as α-ketoglutarate, succinate, and malate were found to be linked with COVID-19 disease response. Metabolic reactions associated with amino acid, carbohydrate, and energy metabolism pathways and various transporter reactions were observed to be uniquely disrupted in PLWHART along with increased production of αketoglutarate (αKG) and ATP molecules. Changes in essential (leucine and threonine) and non-essential (arginine, alanine, and glutamine) amino acid transport were found to be caused by acute CCHFV infection. The altered flux of reactions involving TCA cycle compounds such as pyruvate, isocitrate, and alpha-ketoglutarate was also observed in CCHFV infection. The research described in the thesis displayed dysregulations in similar metabolic processes against the three viral Infections. But further downstream analysis unveiled unique alterations in several metabolic reactions specific to each virus in the same metabolic pathways showing the importance of increasing the resolution of knowledge about host metabolism in infectious diseases

    AnuraSet: A dataset for benchmarking Neotropical anuran calls identification in passive acoustic monitoring

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    Global change is predicted to induce shifts in anuran acoustic behavior, which can be studied through passive acoustic monitoring (PAM). Understanding changes in calling behavior requires the identification of anuran species, which is challenging due to the particular characteristics of neotropical soundscapes. In this paper, we introduce a large-scale multi-species dataset of anuran amphibians calls recorded by PAM, that comprises 27 hours of expert annotations for 42 different species from two Brazilian biomes. We provide open access to the dataset, including the raw recordings, experimental setup code, and a benchmark with a baseline model of the fine-grained categorization problem. Additionally, we highlight the challenges of the dataset to encourage machine learning researchers to solve the problem of anuran call identification towards conservation policy. All our experiments and resources can be found on our GitHub repository https://github.com/soundclim/anuraset

    Fairness Testing: A Comprehensive Survey and Analysis of Trends

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    Unfair behaviors of Machine Learning (ML) software have garnered increasing attention and concern among software engineers. To tackle this issue, extensive research has been dedicated to conducting fairness testing of ML software, and this paper offers a comprehensive survey of existing studies in this field. We collect 100 papers and organize them based on the testing workflow (i.e., how to test) and testing components (i.e., what to test). Furthermore, we analyze the research focus, trends, and promising directions in the realm of fairness testing. We also identify widely-adopted datasets and open-source tools for fairness testing

    Financial and Economic Review 22.

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    Blending the Material and Digital World for Hybrid Interfaces

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    The development of digital technologies in the 21st century is progressing continuously and new device classes such as tablets, smartphones or smartwatches are finding their way into our everyday lives. However, this development also poses problems, as these prevailing touch and gestural interfaces often lack tangibility, take little account of haptic qualities and therefore require full attention from their users. Compared to traditional tools and analog interfaces, the human skills to experience and manipulate material in its natural environment and context remain unexploited. To combine the best of both, a key question is how it is possible to blend the material world and digital world to design and realize novel hybrid interfaces in a meaningful way. Research on Tangible User Interfaces (TUIs) investigates the coupling between physical objects and virtual data. In contrast, hybrid interfaces, which specifically aim to digitally enrich analog artifacts of everyday work, have not yet been sufficiently researched and systematically discussed. Therefore, this doctoral thesis rethinks how user interfaces can provide useful digital functionality while maintaining their physical properties and familiar patterns of use in the real world. However, the development of such hybrid interfaces raises overarching research questions about the design: Which kind of physical interfaces are worth exploring? What type of digital enhancement will improve existing interfaces? How can hybrid interfaces retain their physical properties while enabling new digital functions? What are suitable methods to explore different design? And how to support technology-enthusiast users in prototyping? For a systematic investigation, the thesis builds on a design-oriented, exploratory and iterative development process using digital fabrication methods and novel materials. As a main contribution, four specific research projects are presented that apply and discuss different visual and interactive augmentation principles along real-world applications. The applications range from digitally-enhanced paper, interactive cords over visual watch strap extensions to novel prototyping tools for smart garments. While almost all of them integrate visual feedback and haptic input, none of them are built on rigid, rectangular pixel screens or use standard input modalities, as they all aim to reveal new design approaches. The dissertation shows how valuable it can be to rethink familiar, analog applications while thoughtfully extending them digitally. Finally, this thesis’ extensive work of engineering versatile research platforms is accompanied by overarching conceptual work, user evaluations and technical experiments, as well as literature reviews.Die Durchdringung digitaler Technologien im 21. Jahrhundert schreitet stetig voran und neue Geräteklassen wie Tablets, Smartphones oder Smartwatches erobern unseren Alltag. Diese Entwicklung birgt aber auch Probleme, denn die vorherrschenden berührungsempfindlichen Oberflächen berücksichtigen kaum haptische Qualitäten und erfordern daher die volle Aufmerksamkeit ihrer Nutzer:innen. Im Vergleich zu traditionellen Werkzeugen und analogen Schnittstellen bleiben die menschlichen Fähigkeiten ungenutzt, die Umwelt mit allen Sinnen zu begreifen und wahrzunehmen. Um das Beste aus beiden Welten zu vereinen, stellt sich daher die Frage, wie neuartige hybride Schnittstellen sinnvoll gestaltet und realisiert werden können, um die materielle und die digitale Welt zu verschmelzen. In der Forschung zu Tangible User Interfaces (TUIs) wird die Verbindung zwischen physischen Objekten und virtuellen Daten untersucht. Noch nicht ausreichend erforscht wurden hingegen hybride Schnittstellen, die speziell darauf abzielen, physische Gegenstände des Alltags digital zu erweitern und anhand geeigneter Designparameter und Entwurfsräume systematisch zu untersuchen. In dieser Dissertation wird daher untersucht, wie Materialität und Digitalität nahtlos ineinander übergehen können. Es soll erforscht werden, wie künftige Benutzungsschnittstellen nützliche digitale Funktionen bereitstellen können, ohne ihre physischen Eigenschaften und vertrauten Nutzungsmuster in der realen Welt zu verlieren. Die Entwicklung solcher hybriden Ansätze wirft jedoch übergreifende Forschungsfragen zum Design auf: Welche Arten von physischen Schnittstellen sind es wert, betrachtet zu werden? Welche Art von digitaler Erweiterung verbessert das Bestehende? Wie können hybride Konzepte ihre physischen Eigenschaften beibehalten und gleichzeitig neue digitale Funktionen ermöglichen? Was sind geeignete Methoden, um verschiedene Designs zu erforschen? Wie kann man Technologiebegeisterte bei der Erstellung von Prototypen unterstützen? Für eine systematische Untersuchung stützt sich die Arbeit auf einen designorientierten, explorativen und iterativen Entwicklungsprozess unter Verwendung digitaler Fabrikationsmethoden und neuartiger Materialien. Im Hauptteil werden vier Forschungsprojekte vorgestellt, die verschiedene visuelle und interaktive Prinzipien entlang realer Anwendungen diskutieren. Die Szenarien reichen von digital angereichertem Papier, interaktiven Kordeln über visuelle Erweiterungen von Uhrarmbändern bis hin zu neuartigen Prototyping-Tools für intelligente Kleidungsstücke. Um neue Designansätze aufzuzeigen, integrieren nahezu alle visuelles Feedback und haptische Eingaben, um Alternativen zu Standard-Eingabemodalitäten auf starren Pixelbildschirmen zu schaffen. Die Dissertation hat gezeigt, wie wertvoll es sein kann, bekannte, analoge Anwendungen zu überdenken und sie dabei gleichzeitig mit Bedacht digital zu erweitern. Dabei umfasst die vorliegende Arbeit sowohl realisierte technische Forschungsplattformen als auch übergreifende konzeptionelle Arbeiten, Nutzerstudien und technische Experimente sowie die Analyse existierender Forschungsarbeiten
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