6,231 research outputs found

    Machine learning in solar physics

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    The application of machine learning in solar physics has the potential to greatly enhance our understanding of the complex processes that take place in the atmosphere of the Sun. By using techniques such as deep learning, we are now in the position to analyze large amounts of data from solar observations and identify patterns and trends that may not have been apparent using traditional methods. This can help us improve our understanding of explosive events like solar flares, which can have a strong effect on the Earth environment. Predicting hazardous events on Earth becomes crucial for our technological society. Machine learning can also improve our understanding of the inner workings of the sun itself by allowing us to go deeper into the data and to propose more complex models to explain them. Additionally, the use of machine learning can help to automate the analysis of solar data, reducing the need for manual labor and increasing the efficiency of research in this field.Comment: 100 pages, 13 figures, 286 references, accepted for publication as a Living Review in Solar Physics (LRSP

    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

    Beam scanning by liquid-crystal biasing in a modified SIW structure

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    A fixed-frequency beam-scanning 1D antenna based on Liquid Crystals (LCs) is designed for application in 2D scanning with lateral alignment. The 2D array environment imposes full decoupling of adjacent 1D antennas, which often conflicts with the LC requirement of DC biasing: the proposed design accommodates both. The LC medium is placed inside a Substrate Integrated Waveguide (SIW) modified to work as a Groove Gap Waveguide, with radiating slots etched on the upper broad wall, that radiates as a Leaky-Wave Antenna (LWA). This allows effective application of the DC bias voltage needed for tuning the LCs. At the same time, the RF field remains laterally confined, enabling the possibility to lay several antennas in parallel and achieve 2D beam scanning. The design is validated by simulation employing the actual properties of a commercial LC medium

    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

    Studies on genetic and epigenetic regulation of gene expression dynamics

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    The information required to build an organism is contained in its genome and the first biochemical process that activates the genetic information stored in DNA is transcription. Cell type specific gene expression shapes cellular functional diversity and dysregulation of transcription is a central tenet of human disease. Therefore, understanding transcriptional regulation is central to understanding biology in health and disease. Transcription is a dynamic process, occurring in discrete bursts of activity that can be characterized by two kinetic parameters; burst frequency describing how often genes burst and burst size describing how many transcripts are generated in each burst. Genes are under strict regulatory control by distinct sequences in the genome as well as epigenetic modifications. To properly study how genetic and epigenetic factors affect transcription, it needs to be treated as the dynamic cellular process it is. In this thesis, I present the development of methods that allow identification of newly induced gene expression over short timescales, as well as inference of kinetic parameters describing how frequently genes burst and how many transcripts each burst give rise to. The work is presented through four papers: In paper I, I describe the development of a novel method for profiling newly transcribed RNA molecules. We use this method to show that therapeutic compounds affecting different epigenetic enzymes elicit distinct, compound specific responses mediated by different sets of transcription factors already after one hour of treatment that can only be detected when measuring newly transcribed RNA. The goal of paper II is to determine how genetic variation shapes transcriptional bursting. To this end, we infer transcriptome-wide burst kinetics parameters from genetically distinct donors and find variation that selectively affects burst sizes and frequencies. Paper III describes a method for inferring transcriptional kinetics transcriptome-wide using single-cell RNA-sequencing. We use this method to describe how the regulation of transcriptional bursting is encoded in the genome. Our findings show that gene specific burst sizes are dependent on core promoter architecture and that enhancers affect burst frequencies. Furthermore, cell type specific differential gene expression is regulated by cell type specific burst frequencies. Lastly, Paper IV shows how transcription shapes cell types. We collect data on cellular morphologies, electrophysiological characteristics, and measure gene expression in the same neurons collected from the mouse motor cortex. Our findings show that cells belonging to the same, distinct transcriptomic families have distinct and non-overlapping morpho-electric characteristics. Within families, there is continuous and correlated variation in all modalities, challenging the notion of cell types as discrete entities

    Endogenous measures for contextualising large-scale social phenomena: a corpus-based method for mediated public discourse

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    This work presents an interdisciplinary methodology for developing endogenous measures of group membership through analysis of pervasive linguistic patterns in public discourse. Focusing on political discourse, this work critiques the conventional approach to the study of political participation, which is premised on decontextualised, exogenous measures to characterise groups. Considering the theoretical and empirical weaknesses of decontextualised approaches to large-scale social phenomena, this work suggests that contextualisation using endogenous measures might provide a complementary perspective to mitigate such weaknesses. This work develops a sociomaterial perspective on political participation in mediated discourse as affiliatory action performed through language. While the affiliatory function of language is often performed consciously (such as statements of identity), this work is concerned with unconscious features (such as patterns in lexis and grammar). This work argues that pervasive patterns in such features that emerge through socialisation are resistant to change and manipulation, and thus might serve as endogenous measures of sociopolitical contexts, and thus of groups. In terms of method, the work takes a corpus-based approach to the analysis of data from the Twitter messaging service whereby patterns in users’ speech are examined statistically in order to trace potential community membership. The method is applied in the US state of Michigan during the second half of 2018—6 November having been the date of midterm (i.e. non-Presidential) elections in the United States. The corpus is assembled from the original posts of 5,889 users, who are nominally geolocalised to 417 municipalities. These users are clustered according to pervasive language features. Comparing the linguistic clusters according to the municipalities they represent finds that there are regular sociodemographic differentials across clusters. This is understood as an indication of social structure, suggesting that endogenous measures derived from pervasive patterns in language may indeed offer a complementary, contextualised perspective on large-scale social phenomena

    The development and applications of ceragenins and bone-binding antimicrobials to prevent osteomyelitis in orthopaedic patients

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    Bone infection remains a high-burden disease in orthopaedic and trauma patients with fractures and implantations. Osteomyelitis is difficult to cure in clinical settings, especially if antimicrobial resistance or biofilm is involved, which may prolong the treatments with antibiotics and require multiple surgeries, severely affecting the patients' quality of life and mobility. Osteomyelitis can lead to osteonecrosis, septicaemia, amputation, multi-organ dysfunction, and death in severe cases. Preclinical models are essential for efficacy testing to develop new prophylactic and therapeutic interventions. Previously bone infection models in rats involved fractures and implantations, making it complicated to perform. In this study, we have developed and optimised murine models with a tibial drilled hole (TDH) and needle insertion surgery (NIS) that are reliable, reproducible, and cost-effective for studying implant- related and biofilm bone infections and efficacy testing. Ceragenins (CSAs) are a novel class of broad-spectrum antimicrobials that mimic the activities of antimicrobial peptides. They are effective against bacterial, viral, fungal, and parasitic infections with low minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs). CSAs can also penetrate biofilm and kill antimicrobial-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). In recent years, CSA-131 has been approved by the FDA for endotracheal tube coating to prevent infection in intubated and critical patients. In our study, we applied CSA-90 (which belongs to the same family as CSA-131) to implant coating and prevented osteomyelitis in a mouse model and demonstrated the osteogenic properties of CSA- 90, which promotes bone healing and reunion of the bone defects. CSA-90 has been classified as a potential drug to prevent and treat osteomyelitis. However, conventional methods of antibiotic delivery to the bone are inefficient. To increase the bone-binding property of CSA-90, we invented a new molecule by attaching alendronate (bisphosphonate) to CSA-90 and named it bone-binding antimicrobial-1 (BBA-1). In vitro, we determined the bone-binding properties of BBA-1 and confirmed its antimicrobial activities against S. aureus. Later, we conducted a preclinical trial to test the in vivo efficacy of BBA-1 and showed that BBA-1 could prevent osteomyelitis in mice and has low cytotoxicity. Multiple myeloma (MM) is an aggressive cancer of plasma cells. Although chemotherapy, corticosteroids, and radiation therapy manage multiple myeloma, MM has no cure. Most MM patients (>90%) suffer myeloma-skeletal disease, including local osteolytic lesions and osteomyelitis. Thus, we dedicate the clinical application of BBA-1 to MM patients. To pursue clinical trials, preclinical trials must be conducted. In our attempts, we proposed a feasible murine model that can induce bone infections in MM mice and elucidated how MM patients will benefit from BBA-1

    The determinants of value addition: a crtitical analysis of global software engineering industry in Sri Lanka

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    It was evident through the literature that the perceived value delivery of the global software engineering industry is low due to various facts. Therefore, this research concerns global software product companies in Sri Lanka to explore the software engineering methods and practices in increasing the value addition. The overall aim of the study is to identify the key determinants for value addition in the global software engineering industry and critically evaluate the impact of them for the software product companies to help maximise the value addition to ultimately assure the sustainability of the industry. An exploratory research approach was used initially since findings would emerge while the study unfolds. Mixed method was employed as the literature itself was inadequate to investigate the problem effectively to formulate the research framework. Twenty-three face-to-face online interviews were conducted with the subject matter experts covering all the disciplines from the targeted organisations which was combined with the literature findings as well as the outcomes of the market research outcomes conducted by both government and nongovernment institutes. Data from the interviews were analysed using NVivo 12. The findings of the existing literature were verified through the exploratory study and the outcomes were used to formulate the questionnaire for the public survey. 371 responses were considered after cleansing the total responses received for the data analysis through SPSS 21 with alpha level 0.05. Internal consistency test was done before the descriptive analysis. After assuring the reliability of the dataset, the correlation test, multiple regression test and analysis of variance (ANOVA) test were carried out to fulfil the requirements of meeting the research objectives. Five determinants for value addition were identified along with the key themes for each area. They are staffing, delivery process, use of tools, governance, and technology infrastructure. The cross-functional and self-organised teams built around the value streams, employing a properly interconnected software delivery process with the right governance in the delivery pipelines, selection of tools and providing the right infrastructure increases the value delivery. Moreover, the constraints for value addition are poor interconnection in the internal processes, rigid functional hierarchies, inaccurate selections and uses of tools, inflexible team arrangements and inadequate focus for the technology infrastructure. The findings add to the existing body of knowledge on increasing the value addition by employing effective processes, practices and tools and the impacts of inaccurate applications the same in the global software engineering industry
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