Commercial Repositories Research Articles

Integration of questionnaire-based risk factors improves polygenic risk scores for human coronary heart disease and type 2 diabetes

Large-scale biobank initiatives and commercial repositories store genomic data collected from millions of individuals, and tools to leverage the rapidly growing pool of health and genomic data in disease prevention are needed. Here, we describe the derivation and validation of genomics-enhanced risk tools for two common cardiometabolic diseases, coronary heart disease and type 2 diabetes. Data used for our analyses include the FinnGen study (N = 309,154) and the UK Biobank project (N = 343,672). The risk tools integrate contemporary genome-wide polygenic risk scores with simple questionnaire-based risk factors, including demographic, lifestyle, medication, and comorbidity data, enabling risk calculation across resources where genome data is available. Compared to routinely used clinical risk scores for coronary heart disease and type 2 diabetes prevention, the risk tools show at least equivalent risk discrimination, improved risk reclassification (overall net reclassification improvements ranging from 3.7 [95% CI 2.8–4.6] up to 6.2 [4.6–7.8]), and capacity to be improved even further with standard lipid and blood pressure measurements. Without the need for blood tests or evaluation by a health professional, the risk tools provide a powerful yet simple method for preliminary cardiometabolic risk assessment for individuals with genome data available.

‘When you realise your dad is Cristiano Ronaldo’: celebrity sharenting and children’s digital identities

ABSTRACT Sharenting, or the practice of sharing one’s parenting or information about one’s children on social media, occurs in an increasingly platformized digital culture, where visual formats are central across participatory and commercial repositories. This paper investigates the articulation between sharenting as performed by celebrities and the wider construction of children’s digital identities. Through qualitative content analysis, this research looks at how Cristiano Ronaldo, the most-followed individual on Instagram since 2018, his partner, and his mother shared information about his children on that social media platform between 2018 and 2020. Through manual exploration, we searched for Ronaldo’s children across a variety of digital spaces. Our analysis reveals that sharenting on Instagram engages audiences through the portrayal of children as the parents’ extended self. Content from Instagram and news media is appropriated in vernacular and commercial digital spaces for conflicting affects: the cute father-son dyad, and the son as extension of the uber-famous, vain father. This extreme case shows how the digital identities of children of celebrities are widely public, formed by the everyday, intimate content of the family’s life, which is persistent and collectively recreated by news media, vernacular culture, and commercial platforms.

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds' Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening.

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach in early drug discovery. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compounds’ databases. This approach can be combined with physico-chemical parameter and diversity filtering, bioisosteric replacements, and fragment-based approaches for performing a first round biological screening. Our objectives were to investigate the combination of 2D similarity search with various 3D ligand and structure-based methods for hit expansion and validation, in order to increase the hit rate and novelty. In the present account, six case studies are described and the efficiency of mixing is evaluated. While sequentially combined 2D/3D similarity approach increases the hit rate significantly, sequential combination of 2D similarity with pharmacophore model or 3D docking enriched the resulting focused library with novel chemotypes. Parallel integrated approaches allowed the comparison of the various 2D and 3D methods and revealed that 2D similarity-based and 3D ligand and structure-based techniques are often complementary, and their combinations represent a powerful synergy. Finally, the lessons we learnt including the advantages and pitfalls of the described approaches are discussed.

Survey of 3D digital heritage repositories and platforms

<p class="VARAbstract">Despite the increasing number of three-dimensional (3D) model portals and online repositories catering for digital heritage scholars, students and interested members of the general public, there are very few recent academic publications that offer a critical analysis when reviewing the relative potential of these portals and online repositories. Solid reviews of the features and functions they offer are insufficient; there is also a lack of explanations as to how these assets and their related functionality can further the digital heritage (and virtual heritage) field, and help in the preservation, maintenance, and promotion of real-world 3D heritage sites and assets. What features do they offer? How could their feature list better cater for the needs of the GLAM (galleries, libraries, archives and museums) sector? This article’s priority is to examine the useful features of 8 institutional and 11 commercial repositories designed specifically to host 3D digital models. The available features of their associated 3D viewers, where applicable, are also analysed, connecting recommendations for future-proofing with the need to address current gaps and weaknesses in the scholarly field of 3D digital heritage. Many projects do not address the requirements stipulated by charters, such as access, reusability, and preservation. The lack of preservation strategies and examples highlights the oxymoronic nature of virtual heritage (oxymoronic in the sense that the virtual heritage projects themselves are seldom preserved). To study these concerns, six criteria for gauging the usefulness of the 3D repositories to host 3D digital models and related digital assets are suggested. The authors also provide 13 features that would be useful additions for their 3D viewers.</p><p>Highlights:</p><ul><li><p>A survey of relevant features from eight institutional and eleven commercial online 3D repositories in the scholarly fieldof 3D digital heritage.</p></li><li><p>Presents a critical review of their hosting services and 3D model viewer features.</p></li><li><p>Proposes six features to enhance services of 3D repositories to support the GLAM sector, heritage scholars andheritage communities.</p></li></ul>

Design and Development of Open Educational Resources (OERs) in Higher Education

Library and information services have dramatically changed over the last couple of years. Now access to information is not limited to what is physically available in a particular library. Information is accessible free of charge from a wide variety of globally distributed commercial repositories such as open access (OA) journals, OA archives and open courseware and others. Now libraries can provide worldwide access to a never-ending supply of distributed information and knowledge in electronic form that is constantly available and updated. This article provides information about resources like e-journals, e-books, directories/gateways, theses and other OA resources in pure sciences, social sciences and management. The Maris Stella Virtual Library provides links not only for the above resources but also links for Open Course Ware and Massive Open Online Courses

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories.

Rapid in silico selection of target-focused libraries from commercial repositories is an attractive and cost-effective approach. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compound databases, but the generated library requires further focusing. We report here a combination of the 2D approach with pharmacophore matching which was used for selecting 5-HT6 antagonists. In the first screening round, 12 compounds showed >85% antagonist efficacy of the 91 screened. For the second-round (hit validation) screening phase, pharmacophore models were built, applied, and compared with the routine 2D similarity search. Three pharmacophore models were created based on the structure of the reference compounds and the first-round hit compounds. The pharmacophore search resulted in a high hit rate (40%) and led to novel chemotypes, while 2D similarity search had slightly better hit rate (51%), but lacking the novelty. To demonstrate the power of the virtual screening cascade, ligand efficiency indices were also calculated and their steady improvement was confirmed.

Integrating Microarray Data and GRNs.

With the completion of the Human Genome Project and the emergence of high-throughput technologies, a vast amount of molecular and biological data are being produced. Two of the most important and significant data sources come from microarray gene-expression experiments and respective databanks (e,g., Gene Expression Omnibus-GEO (http://www.ncbi.nlm.nih.gov/geo)), and from molecular pathways and Gene Regulatory Networks (GRNs) stored and curated in public (e.g., Kyoto Encyclopedia of Genes and Genomes-KEGG (http://www.genome.jp/kegg/pathway.html), Reactome (http://www.reactome.org/ReactomeGWT/entrypoint.html)) as well as in commercial repositories (e.g., Ingenuity IPA (http://www.ingenuity.com/products/ipa)). The association of these two sources aims to give new insight in disease understanding and reveal new molecular targets in the treatment of specific phenotypes.Three major research lines and respective efforts that try to utilize and combine data from both of these sources could be identified, namely: (1) de novo reconstruction of GRNs, (2) identification of Gene-signatures, and (3) identification of differentially expressed GRN functional paths (i.e., sub-GRN paths that distinguish between different phenotypes). In this chapter, we give an overview of the existing methods that support the different types of gene-expression and GRN integration with a focus on methodologies that aim to identify phenotype-discriminant GRNs or subnetworks, and we also present our methodology.

Combination of 2D/3D ligand-based similarity search in rapid virtual screening from multimillion compound repositories. Selection and biological evaluation of potential PDE4 and PDE5 inhibitors.

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities.

1205Lu Human Metastatic Melanoma Cells, not Human!

Malignant melanoma is a devastating disease with an increase of incidence year by year despite of the scientific innovations. Understanding the basic biology and signaling pathways that operates in melanoma are inevitable to develop targeted therapeutics and personalized therapies against this disease. Even though emerging preclinical models of melanoma in different organisms has vastly contributed to the recent developments in the melanoma therapy, cell lines and cell culture models presented the initial and valuable insights regarding the basic understanding of the cellular mechanisms that operates in different types of melanomas based on their mutation status. Many human melanoma cell lines has been derived to study the role different gene mutations, 1205Lu cells, is one among them which harbor BRAFV600E and CDK4 mutations [1]. This cell line has been widely used by melanoma researchers around the globe for addressing their research questions [2,3]. In a recent issue of Nature Medicine, Gembarska et al. [2], have demonstrated that MDM4 is a key therapeutic target in cutaneous melanoma including1205Lu cells. Our laboratory experiments with 1205Lu WC00058 cells (Coriell Institute of Medical Research, Camden, NJ) has confirmed that this is not a human cell line since there is a major contamination (70-80%) of mouse chromosomes in it. It is apparent that metastatic melanomas classically show evidence of complex karyotypes with numerous structural and numerical aberrations and a high degree of aneuploidy [4]. It is crucial to use well characterized cell lines for biomedical research since these discoveries may lead to the development of novel molecular pathways and discovery of inhibitors that can target these signaling pathways in human melanomas [5]. Human cells contaminated with mouse chromosomes may not recapitulate to answer the questions in translational research or show desired activity in clinical trials. Based on our laboratory investigation, our recommendation to investigators is that to use only cytogenetically analyzed cells from the commercial repositories. Chromosome analysis of 1205Lu cells showed presence of about 80% mouse metaphases and about 20% human metaphases. A representative karyotype from a mouse metaphase has shown in the Figure1. The chromosome number in the mouse cells ranged from 6266 with the model chromosome number of 64. Three clonal markers were present in these cells. The tentative identification of the markers are M1=tandem t (4q:11q), M2=tandem t(10q:11q) and M3=tandem t(5q:16q). Although we have demonstrated here only one melanoma cell line 1205Lu, it might be an invaluable resource for the melanoma community since authenticated cell lines are unique tool for melanoma basic research, preclinical testing and translational research.

O039 The interferonscape: Systems biology of interferon stimulated pathways and networks

Introduction The Interferons (IFNs) are a family of pleiotropic cytokines that mediate anti-microbial, anti-proliferative, anti-tumour, immuno-modulatory and homoeostatic host defence functions. Differential regulation of Interferon Stimulated Genes (ISGs) by IFNs, via multiple signalling pathways and the combinatorial effects of IFN-induced transcription factors, co-regulators, ncRNA and epigenetic modifications underlie these diverse biological functions. Methods We have built InterferonScape – a software platform for data-integration, mining and visualization to study IFN mediated ISG regulation at a systems level. This is a centralized systems-immunology resource that integrates ISG datasets into a data warehouse with a multidimensional data analysis capability. Statistical and computational data-mining methods combined with easy to use graphical user interfaces are included to provide custom-built data-visualization capability. This resource is provided as a web 2.0 rich internet application with novel embedded data-mining, search and semantic web technologies. Results Using integrative data-mining approaches we previously identified approximately 1800 ISGs in the human genome [1] . Very few of these ISGs have been studied systematically, and information on ISG pathways is virtually absent from both public and commercial pathway repositories. We have utilised computational pathway modelling approaches, coupled to natural language text mining and expert manual curation to build a reliable collection of ISG pathways and networks. By integrating both in-house generated and publicly-available gene expression, regulatory genomic and epigenetic datasets in different cell and tissue types and in both normal and disease conditions, we have identified the regulatory elements and promoter modules involved in the regulation of ISG networks. Conclusion Using integrative genomic and computational biology approaches we will demonstrate the evolutionary conservation, information flow, connectivity, network topology and regulatory interactions underlying these ISG networks. Understanding the propagation of ISG networks in different conditions will provide a greater insight into IFN biology in health and disease.

Combining 2D and 3D in silico methods for rapid selection of potential PDE5 inhibitors from multimillion compounds’ repositories: biological evaluation

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach when starting new drug discovery projects. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compounds' databases. This in silico approach can be combined with physico-chemical parameter filtering based on the property space of the active compounds and 3D virtual screening if the structure of the target protein is available. A multi-step virtual screening procedure was developed and applied to select potential phosphodiesterase 5 (PDE5) inhibitors in real time. The combined 2D/3D in silico method resulted in the identification of 14 novel PDE5 inhibitors with <1 μMIC(50) values and the hit rate in the second in silico selection and in vitro screening round exceeded the 20%.

The use of intuitionistic fuzzy cube and operators in treating imprecision in data repositories

Traditional data repositories introduced for the needs of business pro-cessing, typically focus on the storage and querying of crisp domains of data. As a result, current commercial data repositories have no facilities for either storing or querying imprecise/ approximate data.No significant attempt has been made for a generic and application- independent representation of value imprecision mainly as a property of axes of analysis and also as part of dynamic environment, where poten-tial users may wish to define their “own” axes of analysis for querying either precise or imprecise facts. In such cases, measured values and facts are characterised by descriptive values drawn from a number of dimen-sions, whereas values of a dimension are organised as hierarchical levels.In this paper, an extended multidimensional model named IF-Cube is put forward, which allows the representation of imprecision in facts and dimensions and answering of queries based on imprecise hierarchical preferences.

Commercial Tissue Repositories: HIPAA Raises Sponsors' Fears

beyond their original research use. Rather than being destroyed or discarded, these specimens can be stored in repositories for future applications (for example, cell lines, genotyping, and other biotechnologies). These repositories are especially attractive to commercial sponsors, because with little additional capital, a repository can increase the potential return on research and development dollars already spent. Not surprisingly, then, commercial sponsors have amassed huge repositories over the years. Any cloud on the legal right to use these specimens could be catastrophic for the commercial sponsors and could chill important, future discoveries. The threat of just such a situation has emerged. The patient privacy regulations issued under the Health Insurance Portability and Accountability Act of 1996 (HIPAA)' have rekindled legal questions which were raised well over a decade ago, but which still remain unresolved. Generally, commercial repositories have been built quietly, without the specific knowledge of research participants. HIPAA has fundamentally changed the visibility of these commercial repositories. Now, when a health care provider proposes to conduct research on a patient, all research uses and disclosures, including the retention of specimens2 in a repository, must be described on a HIPAA-compliant written authorization form. The patient must sign this form before research activities can begin. Sponsors seem to be uncomfortable directing attention to an area of legal uncertainty. When specimens result in commercially important discoveries, who owns the profits derived from them? The patient? The researcher? The commercial sponsor? Important legal concepts, including property rights, informed consent, and the general fiduciary duty owed by a physician to a patient are implicated. In 199o, the Supreme Court of California addressed these questions in the case of Moore v. Regents of the University of California.3 Mr. Moore suffered from hairy-cell leukemia, and for therapeutic reasons, his physicians recommended that his spleen be removed. Mr. Moore alleged that after surgery, his blood, blood serum, skin, bone marrow aspirate, sperm, and material from his spleen were used to develop a valuable cell line.4 Mr. Moore further alleged that his physicians did not disclose these research activities to him or obtain his

Selecting components in large COTS repositories

The growing availability of COTS (commercial-off-the-shelf) components in the software market has concretized the possibility of building whole systems based on components. In this multitude, a recurrent problem is the location and selection of the components that best fit the requirements. Commercial repositories that offer search mechanisms have reduced these difficulties: system integrators can rely on a wider variety of components and can focus better on the composition of systems. The size of the repository can be an initial obstacle but iterative approaches allow integrators to familiarize with the repository's structure and to formulate effective queries. This paper discusses the search techniques in CLARiFi, a component broker project that supports integrators in the selection of components for systems.