1,765 research outputs found

    The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

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    Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch\u27s APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch\u27s data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch\u27s analytic tools by developing a customized plugin for OpenAI\u27s ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app

    Investigating the Innate Immune Systems of Bats and Their Roles as Zoonotic Viral Reservoirs

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    The zoonotic spillover of viral pathogens from wild animal reservoirs into human populations remains the leading cause of emerging and re-emerging infectious diseases globally. Bats represent important viral reservoirs, notorious for the diversity and richness of the viruses they host, several of which are highly pathogenic when transmitted to humans. Remarkably, bats appear to host an abundance of these viruses without exhibiting any clinical signs of disease. A dominant hypothesis for this ability suggests that bats can control viral replication early in the innate immune response, which acts as the first line of defence against infection. However, bat immunology remains fundamentally understudied, largely due to their high species diversity and the lack of accessible reagents required for bat research. Therefore, in this work we explored and characterised key components of bat innate immunity to gain a better understanding of bats as viral reservoirs and contribute to the currently limited literature. Here, we demonstrated the in vitro transcriptomic response of the bat model species, Pteropus alecto (P.alecto) upon stimulation with the bat henipavirus Cedar virus and also with a type III bat interferon (paIFNĪ»). These investigations highlighted key transcripts, some of which were immune-related, in the response of bats to the separate stimuli and presents a foundation for further research into significant genes concerned in bat viral infection. Building from genome-wide transcriptomics, three distinctive bat innate immune genes representative of different stages of interferon signalling were selected for comparative genomics and functional characterisation. Our work demonstrated the conservation of genes between bats and humans, including IRF7, IFIT5 and IFI35. Specific findings for IRF7 included its successful translocation to the cell nucleus upon stimulation. IFIT5 and IFI35 were specifically selected for exploration due to previous research demonstrating the respective antiviral and conflicting anti- or pro-viral roles of these genes in humans. Significantly, our research demonstrated the direct antiviral action of P.alecto IFIT5 against negative-sense RNA viruses. Collectively, our findings offer valuable contributions to the field of bat antiviral immunity and provide the framework for future investigative studies into the role and function of the bat innate immune system and bat viral tolerance mechanisms

    AI Lifecycle Zero-Touch Orchestration within the Edge-to-Cloud Continuum for Industry 5.0

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    The advancements in human-centered artificial intelligence (HCAI) systems for Industry 5.0 is a new phase of industrialization that places the worker at the center of the production process and uses new technologies to increase prosperity beyond jobs and growth. HCAI presents new objectives that were unreachable by either humans or machines alone, but this also comes with a new set of challenges. Our proposed method accomplishes this through the knowlEdge architecture, which enables human operators to implement AI solutions using a zero-touch framework. It relies on containerized AI model training and execution, supported by a robust data pipeline and rounded off with human feedback and evaluation interfaces. The result is a platform built from a number of components, spanning all major areas of the AI lifecycle. We outline both the architectural concepts and implementation guidelines and explain how they advance HCAI systems and Industry 5.0. In this article, we address the problems we encountered while implementing the ideas within the edge-to-cloud continuum. Further improvements to our approach may enhance the use of AI in Industry 5.0 and strengthen trust in AI systems

    Re-envisioning access for the digital preservation community: challenges, opportunities and recommendations

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    Digital material is not new and has been preserved for a couple of decades now. With a growing digital preservation community, and a growing number of practitioners identifying as doing something digital, there is an understanding that this material is here to stay. More and more institutions are publishing digital strategies or creating networks focusing on digital material. However, when looking at this in practice there seems to be a disconnect between what is being stated within these networks and strategies and what is being made accessible to the public. This thesis will explore this disconnect by first understanding how the digital preservation community has been providing access to this material and how they are envisioning it in the future. This exploration surfaces both a) how digital material can no longer be seen as separate from the infrastructure that ensures its materiality and b) how the provision of access is not just a technological question, but also a social, legal and ethical one. This thesis will also seek to explore the ways in which those who identify as digital preservation practitioners articulate their role and responsibilities. It will do so by drawing on relevant literature and gaining perspectives from practitioners and other relevant participants through in-depth interviews. Building from this exploration, this thesis will offer recommendations for how this practice can move forward in negotiating the provision of access to digital material in the online public space of the internet. This research is part of a collaborative project with The National Archives, UK where a number of the ideas encountered during this work were explored in practice. Some of these results have helped shape the recommendations given in the final chapters of this thesis

    Handbook Transdisciplinary Learning

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    What is transdisciplinarity - and what are its methods? How does a living lab work? What is the purpose of citizen science, student-organized teaching and cooperative education? This handbook unpacks key terms and concepts to describe the range of transdisciplinary learning in the context of academic education. Transdisciplinary learning turns out to be a comprehensive innovation process in response to the major global challenges such as climate change, urbanization or migration. A reference work for students, lecturers, scientists, and anyone wanting to understand the profound changes in higher education

    The Influence of APOE Genotype on Lipid Droplet Dynamics

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    Excess lipid droplet (LD) accumulation is associated with several pathological states, including neurodegenerative disorders such as Alzheimerā€™s disease (AD). However, the mechanism(s) by which changes in LD composition and dynamics may contribute to the pathophysiology of AD remains unclear. Apolipoprotein E (ApoE) is a droplet-related protein with a common variant (ApoE4) that confers the largest increase in genetic risk for late-onset AD. Interestingly, ApoE4 is associated with both increased neuroinflammation and excess LD accumulation. This dissertation work seeks to quantitatively profile the lipid and protein composition of LDs between the ā€˜neutralā€™ ApoE3 and ā€˜riskā€™ ApoE4 isoforms, in order to gain insight into potential LD-driven contributions to AD pathogenesis. Targeted replacement mice expressing human ApoE3 or ApoE4 were injected with saline (control) or LPS (inflammatory stimulus) and after 24 hours, hepatic lipid droplets were isolated and droplet proteomes and lipidomes were analyzed. Quantitative proteomics showed that LD fractions from E4 mice are enriched for proteins involved in innate immunity, while E3 LDs are enriched for proteins involved in lipid Ɵ-oxidation. Lipidomics revealed a shift in the distribution of glycerophospholipids in E4 LDs with an increase in multiple phosphatidylcholine (PC) species. There was also substantial overlap between LD proteins and AD-proteomes of human whole brain tissue. To translate these findings to the brain, primary microglia from the same strain of mice were exposed to exogenous lipid, inflammatory stimulation, necroptotic N2A cells (nN2A), or a combination of treatments to evaluate lipid droplet accumulation and impact on cell function. Microglia from ApoE4 mice accumulated more LDs at baseline, with exogenous OA, LPS stimulation, and nN2As as a percentage of E3 control across multiple experiments. E4 microglia also secreted significantly more cytokines (TNF, IL-1Ī², IL-10) than E3 microglia in the control, oleic acid, and nN2A treatment conditions. Interestingly, droplet inhibitors for ACAT and DGAT both decreased droplet accumulation in cells, but did not ameliorate the cytokine response. Finally, we have established a biobank of APOE genotyped peripheral blood mononuclear cells (PBMCs) from research participants. These easily accessible immune cells will serve as a highly translational model to understand LD dynamics as it relates to ApoE and AD risk. In summary, E4 cells accumulate more LDs compared to E3 under all conditions tested, while the proteomic profile of E4 LDs support the hypothesis that E4 expression increases inflammation under basal conditions. This increased LD formation in non-aged, non-diseased E4 cells may suggest preclinical dysfunction associated with the highest risk APOE genotype, and a better understanding of LD dynamics within these cells and their functional implications may provide novel targets to improve E4-related outcomes
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