18,181 research outputs found

    The genome sequence of the white-shouldered marble, Apotomis turbidana (HĂĽbner, 1825)

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    We present a genome assembly from an individual male Apotomis turbidana (the White-shouldered Marble; Arthropoda; Insecta; Lepidoptera; Tortricidae). The genome sequence is 720.5 megabases in span. Most of the assembly is scaffolded into 28 chromosomal pseudomolecules, including the assembled Z sex chromosome. The mitochondrial genome has also been assembled and is 16.8 kilobases in length. Gene annotation of this assembly on Ensembl identified 22,646 protein coding genes

    A Multi-level Analysis on Implementation of Low-Cost IVF in Sub-Saharan Africa: A Case Study of Uganda.

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    Introduction: Globally, infertility is a major reproductive disease that affects an estimated 186 million people worldwide. In Sub-Saharan Africa, the burden of infertility is considerably high, affecting one in every four couples of reproductive age. Furthermore, infertility in this context has severe psychosocial, emotional, economic and health consequences. Absence of affordable fertility services in Sub-Saharan Africa has been justified by overpopulation and limited resources, resulting in inequitable access to infertility treatment compared to developed countries. Therefore, low-cost IVF (LCIVF) initiatives have been developed to simplify IVF-related treatment, reduce costs, and improve access to treatment for individuals in low-resource contexts. However, there is a gap between the development of LCIVF initiatives and their implementation in Sub-Saharan Africa. Uganda is the first country in East and Central Africa to undergo implementation of LCIVF initiatives within its public health system at Mulago Women’s Hospital. Methods: This was an exploratory, qualitative, single, case study conducted at Mulago Women’s Hospital in Kampala, Uganda. The objective of this study was to explore how LCIVF initiatives have been implemented within the public health system of Uganda at the macro-, meso- and micro-level. Primary qualitative data was collected using semi-structured interviews, hospital observations informal conversations, and document review. Using purposive and snowball sampling, a total of twenty-three key informants were interviewed including government officials, clinicians (doctors, nurses, technicians), hospital management, implementers, patient advocacy representatives, private sector practitioners, international organizational representatives, educational institution, and professional medical associations. Sources of secondary data included government and non-government reports, hospital records, organizational briefs, and press outputs. Using a multi-level data analysis approach, this study undertook a hybrid inductive/deductive thematic analysis, with the deductive analysis guided by the Consolidated Framework for Implementation Research (CFIR). Findings: Factors facilitating implementation included international recognition of infertility as a reproductive disease, strong political advocacy and oversight, patient needs & advocacy, government funding, inter-organizational collaboration, tension to change, competition in the private sector, intervention adaptability & trialability, relative priority, motivation &advocacy of fertility providers and specialist training. While barriers included scarcity of embryologists, intervention complexity, insufficient knowledge, evidence strength & quality of intervention, inadequate leadership engagement & hospital autonomy, poor public knowledge, limited engagement with traditional, cultural, and religious leaders, lack of salary incentives and concerns of revenue loss associated with low-cost options. Research contributions: This study contributes to knowledge of factors salient to implementation of LCIVF initiatives in a Sub-Saharan context. Effective implementation of these initiatives requires (1) sustained political support and favourable policy & legislation, (2) public sensitization and engagement of traditional, cultural, and religious leaders (3) strengthening local innovation and capacity building of fertility health workers, in particular embryologists (4) sustained implementor leadership engagement and inter-organizational collaboration and (5) proven clinical evidence and utilization of LCIVF initiatives in innovator countries. It also adds to the literature on the applicability of the CFIR framework in explaining factors that influence successful implementation in developing countries and offer opportunities for comparisons across studies

    Role of Molecular, Crystal, and Surface Chemistry in Directing the Crystallization of Entacapone Polymorphs on the Au(111) Template Surface

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    The pharmaceutical compound entacapone ((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide) is important in the treatment of Parkinson’s disease, exhibiting interesting polymorphic behavior upon crystallization from solution. It consistently produces its stable form A with a uniform crystal size distribution on the surface of an Au(111) template while concomitantly forming its metastable form D within the same bulk solution. Molecular modeling using empirical atomistic force-fields reveals more complex molecular and intermolecular structures for form D compared to form A, with the crystal chemistry of both polymorphs being dominated by van der Waals and π–π stacking interactions with lower contributions (ca. 20%) from hydrogen bonding and electrostatic interactions. Comparative lattice energies and convergence for the polymorphs are consistent with the observed concomitant polymorphic behavior. Synthon characterization reveals an elongated needle-like morphology for form D crystals in contrast to the more equant form A crystals with the surface chemistry of the latter exposing the molecules’ cyano groups on its {010} and {011} habit faces. Density functional theory modeling of surface adsorption reveals preferential interactions between Au and the synthon GA interactions of form A on the Au surface. Molecular dynamics modeling of the entacapone/gold interface reveals the entacapone molecular structure within the first adsorbed layer to show nearly identical interaction distances, for both the molecules within form A or D with respect to the Au surface, while in the second and third layers when entacapone molecule–molecule interactions overtake the interactions between those of molecule–Au, the intermolecular structures are found to be closer to the form A structure than form D. In these layers, synthon GA (form A) could be reproduced with just two small azimuthal rotations (5° and 15°) whereas the closest alignment to a form D synthon requires larger azimuthal rotations (15° and 40°). The cyano functional group interactions with the Au template dominate interfacial interactions with these groups being aligned parallel to the Au surface and with nearest neighbor distances to Au atoms more closely matching those in form A than form D. The overall polymorph direction pathway thus encompasses consideration of molecular, crystal, and surface chemistry factors

    GenAssist: Making Image Generation Accessible

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    Blind and low vision (BLV) creators use images to communicate with sighted audiences. However, creating or retrieving images is challenging for BLV creators as it is difficult to use authoring tools or assess image search results. Thus, creators limit the types of images they create or recruit sighted collaborators. While text-to-image generation models let creators generate high-fidelity images based on a text description (i.e. prompt), it is difficult to assess the content and quality of generated images. We present GenAssist, a system to make text-to-image generation accessible. Using our interface, creators can verify whether generated image candidates followed the prompt, access additional details in the image not specified in the prompt, and skim a summary of similarities and differences between image candidates. To power the interface, GenAssist uses a large language model to generate visual questions, vision-language models to extract answers, and a large language model to summarize the results. Our study with 12 BLV creators demonstrated that GenAssist enables and simplifies the process of image selection and generation, making visual authoring more accessible to all.Comment: For accessibility tagged pdf, please refer to the ancillary fil

    Segmentation of Pathology Images: A Deep Learning Strategy with Annotated Data

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    Cancer has significantly threatened human life and health for many years. In the clinic, histopathology image segmentation is the golden stand for evaluating the prediction of patient prognosis and treatment outcome. Generally, manually labelling tumour regions in hundreds of high-resolution histopathological images is time-consuming and expensive for pathologists. Recently, the advancements in hardware and computer vision have allowed deep-learning-based methods to become mainstream to segment tumours automatically, significantly reducing the workload of pathologists. However, most current methods rely on large-scale labelled histopathological images. Therefore, this research studies label-effective tumour segmentation methods using deep-learning paradigms to relieve the annotation limitations. Chapter 3 proposes an ensemble framework for fully-supervised tumour segmentation. Usually, the performance of an individual-trained network is limited by significant morphological variances in histopathological images. We propose a fully-supervised learning ensemble fusion model that uses both shallow and deep U-Nets, trained with images of different resolutions and subsets of images, for robust predictions of tumour regions. Noise elimination is achieved with Convolutional Conditional Random Fields. Two open datasets are used to evaluate the proposed method: the ACDC@LungHP challenge at ISBI2019 and the DigestPath challenge at MICCAI2019. With a dice coefficient of 79.7 %, the proposed method takes third place in ACDC@LungHP. In DigestPath 2019, the proposed method achieves a dice coefficient 77.3 %. Well-annotated images are an indispensable part of training fully-supervised segmentation strategies. However, large-scale histopathology images are hardly annotated finely in clinical practice. It is common for labels to be of poor quality or for only a few images to be manually marked by experts. Consequently, fully-supervised methods cannot perform well in these cases. Chapter 4 proposes a self-supervised contrast learning for tumour segmentation. A self-supervised cancer segmentation framework is proposed to reduce label dependency. An innovative contrastive learning scheme is developed to represent tumour features based on unlabelled images. Unlike a normal U-Net, the backbone is a patch-based segmentation network. Additionally, data augmentation and contrastive losses are applied to improve the discriminability of tumour features. A convolutional Conditional Random Field is used to smooth and eliminate noise. Three labelled, and fourteen unlabelled images are collected from a private skin cancer dataset called BSS. Experimental results show that the proposed method achieves better tumour segmentation performance than other popular self-supervised methods. However, by evaluated on the same public dataset as chapter 3, the proposed self-supervised method is hard to handle fine-grained segmentation around tumour boundaries compared to the supervised method we proposed. Chapter 5 proposes a sketch-based weakly-supervised tumour segmentation method. To segment tumour regions precisely with coarse annotations, a sketch-supervised method is proposed, containing a dual CNN-Transformer network and a global normalised class activation map. CNN-Transformer networks simultaneously model global and local tumour features. With the global normalised class activation map, a gradient-based tumour representation can be obtained from the dual network predictions. We invited experts to mark fine and coarse annotations in the private BSS and the public PAIP2019 datasets to facilitate reproducible performance comparisons. Using the BSS dataset, the proposed method achieves 76.686 % IOU and 86.6 % Dice scores, outperforming state-of-the-art methods. Additionally, the proposed method achieves a Dice gain of 8.372 % compared with U-Net on the PAIP2019 dataset. The thesis presents three approaches to segmenting cancers from histology images: fully-supervised, unsupervised, and weakly supervised methods. This research effectively segments tumour regions based on histopathological annotations and well-designed modules. Our studies comprehensively demonstrate label-effective automatic histopathological image segmentation. Experimental results prove that our works achieve state-of-the-art segmentation performances on private and public datasets. In the future, we plan to integrate more tumour feature representation technologies with other medical modalities and apply them to clinical research

    Using knowledge graphs to infer gene expression in plants

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    IntroductionClimate change is already affecting ecosystems around the world and forcing us to adapt to meet societal needs. The speed with which climate change is progressing necessitates a massive scaling up of the number of species with understood genotype-environment-phenotype (GĂ—EĂ—P) dynamics in order to increase ecosystem and agriculture resilience. An important part of predicting phenotype is understanding the complex gene regulatory networks present in organisms. Previous work has demonstrated that knowledge about one species can be applied to another using ontologically-supported knowledge bases that exploit homologous structures and homologous genes. These types of structures that can apply knowledge about one species to another have the potential to enable the massive scaling up that is needed through in silico experimentation.MethodsWe developed one such structure, a knowledge graph (KG) using information from Planteome and the EMBL-EBI Expression Atlas that connects gene expression, molecular interactions, functions, and pathways to homology-based gene annotations. Our preliminary analysis uses data from gene expression studies in Arabidopsis thaliana and Populus trichocarpa plants exposed to drought conditions.ResultsA graph query identified 16 pairs of homologous genes in these two taxa, some of which show opposite patterns of gene expression in response to drought. As expected, analysis of the upstream cis-regulatory region of these genes revealed that homologs with similar expression behavior had conserved cis-regulatory regions and potential interaction with similar trans-elements, unlike homologs that changed their expression in opposite ways.DiscussionThis suggests that even though the homologous pairs share common ancestry and functional roles, predicting expression and phenotype through homology inference needs careful consideration of integrating cis and trans-regulatory components in the curated and inferred knowledge graph

    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
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