Fast and accurate semantic annotation of bioassays exploiting a hybrid of machine learning and user confirmation

Bioinformatics and computer aided drug design rely on the curation of a large number of protocols for biological assays that measure the ability of potential drugs to achieve a therapeutic effect. These assay protocols are generally published by scientists in the form of plain text, which needs to be more precisely annotated in order to be useful to software methods. We have developed a pragmatic approach to describing assays according to the semantic definitions of the BioAssay Ontology (BAO) project, using a hybrid of machine learning based on natural language processing, and a simplified user interface designed to help scientists curate their data with minimum effort. We have carried out this work based on the premise that pure machine learning is insufficiently accurate, and that expecting scientists to find the time to annotate their protocols manually is unrealistic. By combining these approaches, we have created an effective prototype for which annotation of bioassay text within the domain of the training set can be accomplished very quickly. Well-trained annotations require single-click user approval, while annotations from outside the training set domain can be identified using the search feature of a well-designed user interface, and subsequently used to improve the underlying models. By drastically reducing the time required for scientists to annotate their assays, we can realistically advocate for semantic annotation to become a standard part of the publication process. Once even a small proportion of the public body of bioassay data is marked up, bioinformatics researchers can begin to construct sophisticated and useful searching and analysis algorithms that will provide a diverse and powerful set of tools for drug discovery researchers

BioAssay Ontology (BAO): a semantic description of bioassays and high-throughput screening results

<p>Abstract</p> <p>Background</p> <p>High-throughput screening (HTS) is one of the main strategies to identify novel entry points for the development of small molecule chemical probes and drugs and is now commonly accessible to public sector research. Large amounts of data generated in HTS campaigns are submitted to public repositories such as PubChem, which is growing at an exponential rate. The diversity and quantity of available HTS assays and screening results pose enormous challenges to organizing, standardizing, integrating, and analyzing the datasets and thus to maximize the scientific and ultimately the public health impact of the huge investments made to implement public sector HTS capabilities. Novel approaches to organize, standardize and access HTS data are required to address these challenges.</p> <p>Results</p> <p>We developed the first ontology to describe HTS experiments and screening results using expressive description logic. The BioAssay Ontology (BAO) serves as a foundation for the standardization of HTS assays and data and as a semantic knowledge model. In this paper we show important examples of formalizing HTS domain knowledge and we point out the advantages of this approach. The ontology is available online at the NCBO bioportal <url>http://bioportal.bioontology.org/ontologies/44531</url>.</p> <p>Conclusions</p> <p>After a large manual curation effort, we loaded BAO-mapped data triples into a RDF database store and used a reasoner in several case studies to demonstrate the benefits of formalized domain knowledge representation in BAO. The examples illustrate semantic querying capabilities where BAO enables the retrieval of inferred search results that are relevant to a given query, but are not explicitly defined. BAO thus opens new functionality for annotating, querying, and analyzing HTS datasets and the potential for discovering new knowledge by means of inference.</p

Ontological representation, integration, and analysis of LINCS cell line cells and their cellular responses

Abstract Background Aiming to understand cellular responses to different perturbations, the NIH Common Fund Library of Integrated Network-based Cellular Signatures (LINCS) program involves many institutes and laboratories working on over a thousand cell lines. The community-based Cell Line Ontology (CLO) is selected as the default ontology for LINCS cell line representation and integration. Results CLO has consistently represented all 1097 LINCS cell lines and included information extracted from the LINCS Data Portal and ChEMBL. Using MCF 10A cell line cells as an example, we demonstrated how to ontologically model LINCS cellular signatures such as their non-tumorigenic epithelial cell type, three-dimensional growth, latrunculin-A-induced actin depolymerization and apoptosis, and cell line transfection. A CLO subset view of LINCS cell lines, named LINCS-CLOview, was generated to support systematic LINCS cell line analysis and queries. In summary, LINCS cell lines are currently associated with 43 cell types, 131 tissues and organs, and 121 cancer types. The LINCS-CLO view information can be queried using SPARQL scripts. Conclusions CLO was used to support ontological representation, integration, and analysis of over a thousand LINCS cell line cells and their cellular responses.https://deepblue.lib.umich.edu/bitstream/2027.42/140390/1/12859_2017_Article_1981.pd

“A very orderly retreat”: Democratic transition in East Germany, 1989-90

East Germany's 1989-90 democratisation is among the best known of East European transitions, but does not lend itself to comparative analysis, due to the singular way in which political reform and democratic consolidation were subsumed by Germany's unification process. Yet aspects of East Germany's democratisation have proved amenable to comparative approaches. This article reviews the comparative literature that refers to East Germany, and finds a schism between those who designate East Germany's transition “regime collapse” and others who contend that it exemplifies “transition through extrication”. It inquires into the merits of each position and finds in favour of the latter. Drawing on primary and secondary literature, as well as archival and interview sources, it portrays a communist elite that was, to a large extent, prepared to adapt to changing circumstances and capable of learning from “reference states” such as Poland. Although East Germany was the Soviet state in which the positions of existing elites were most threatened by democratic transition, here too a surprising number succeeded in maintaining their position while filing across the bridge to market society. A concluding section outlines the alchemy through which their bureaucratic power was transmuted into property and influence in the “new Germany”

CLO: The cell line ontology

Abstract Background Cell lines have been widely used in biomedical research. The community-based Cell Line Ontology (CLO) is a member of the OBO Foundry library that covers the domain of cell lines. Since its publication two years ago, significant updates have been made, including new groups joining the CLO consortium, new cell line cells, upper level alignment with the Cell Ontology (CL) and the Ontology for Biomedical Investigation, and logical extensions. Construction and content Collaboration among the CLO, CL, and OBI has established consensus definitions of cell line-specific terms such as ‘cell line’, ‘cell line cell’, ‘cell line culturing’, and ‘mortal’ vs. ‘immortal cell line cell’. A cell line is a genetically stable cultured cell population that contains individual cell line cells. The hierarchical structure of the CLO is built based on the hierarchy of the in vivo cell types defined in CL and tissue types (from which cell line cells are derived) defined in the UBERON cross-species anatomy ontology. The new hierarchical structure makes it easier to browse, query, and perform automated classification. We have recently added classes representing more than 2,000 cell line cells from the RIKEN BRC Cell Bank to CLO. Overall, the CLO now contains ~38,000 classes of specific cell line cells derived from over 200 in vivo cell types from various organisms. Utility and discussion The CLO has been applied to different biomedical research studies. Example case studies include annotation and analysis of EBI ArrayExpress data, bioassays, and host-vaccine/pathogen interaction. CLO’s utility goes beyond a catalogue of cell line types. The alignment of the CLO with related ontologies combined with the use of ontological reasoners will support sophisticated inferencing to advance translational informatics development.http://deepblue.lib.umich.edu/bitstream/2027.42/109554/1/13326_2013_Article_185.pd

OSCI: standardized stem cell ontology representation and use cases for stem cell investigation

Abstract Background Stem cells and stem cell lines are widely used in biomedical research. The Cell Ontology (CL) and Cell Line Ontology (CLO) are two community-based OBO Foundry ontologies in the domains of in vivo cells and in vitro cell line cells, respectively. Results To support standardized stem cell investigations, we have developed an Ontology for Stem Cell Investigations (OSCI). OSCI imports stem cell and cell line terms from CL and CLO, and investigation-related terms from existing ontologies. A novel focus of OSCI is its application in representing metadata types associated with various stem cell investigations. We also applied OSCI to systematically categorize experimental variables in an induced pluripotent stem cell line cell study related to bipolar disorder. In addition, we used a semi-automated literature mining approach to identify over 200 stem cell gene markers. The relations between these genes and stem cells are modeled and represented in OSCI. Conclusions OSCI standardizes stem cells found in vivo and in vitro and in various stem cell investigation processes and entities. The presented use cases demonstrate the utility of OSCI in iPSC studies and literature mining related to bipolar disorder.https://deepblue.lib.umich.edu/bitstream/2027.42/148822/1/12859_2019_Article_2723.pd

Contributions to the development of Olefin metathesis

In der organischen Chemie und insbesondere durch die Etablierung der kombinatorischen Chemie innerhalb der letzten zehn Jahre besteht ein hoher Bedarf an neuen effizienten Synthesemethoden zur Erzeugung von Strukturvielfalt. In der vorliegenden Arbeit werden neue flexible Methoden zur modularen Synthese hochsubstituierter 6-Ring-Carbo- und Heterocyclen aus einfachen Bausteinen beschrieben. Die entwickelte Methodologie beruht auf atomökonomischen Synthesesequenzen aus einer neuen rutheniumkatalysierten In-En-Kreuzmetathese und Diels-Alder-Reaktionen nichtaktivierter 1,3-Diene. Dabei wurde das Synthesepotential der In-En-Kreuzmetathese stark erweitert und bisher nicht durchführbare Diels-Alder-Reaktionen entwickelt. Zahlreiche in guten Ausbeuten synthetisierte Derivate, die aus unterschiedlichen löslichen bzw. immobilisierten Alkinen und Alkenen sowie verschiedenen Dienophilen aufgebaut wurden, demonstrieren die Effizienz des Synthesekonzeptes in Lösung sowie auch an fester Phase. Im Verlauf dieser Arbeiten wurde eine neue Synthese für Tetrahydropyridine entwickelt. Durch Verknüpfung verschiedener Zuckerbausteine in der In-En-Metathese gefolgt von Diels-Alder-Transformation unter Verwendung unterschiedlicher Dienophile gelang der Aufbau flexibel funktionalisierter Pseudooligosaccharide. Dem großen Bedarf an neuen Methoden für Festphasensynthesen folgend, wurde ein Linker entwickelt, bei dem die Immobilisierungs- und Abspaltungsschritte übergangsmetallkatalysiert verlaufen und zur Derivatisierung des Substrates genutzt werden können. Zahlreiche verschiedenartig funktionalisierte Produkte wurden in guten Gesamtausbeuten synthetisiert und belegen die Anwendbarkeit dieses neuen Linkerkonzeptes. Durch eine Sequenz von In-En-Kreuzmetathese, Diels-Alder-Reaktion und reduktiver Aminierung gelang die kombinatorische Festphasensynthese substituierter Oktahydrobenzazepinone, die unter Verwendung eines geeigneten Linkers durch eine cyclisierende Abspaltung in sehr hoher Reinheit erhalten wurden. In den letzten Jahren wurden zahlreiche neue auf Ruthenium basierende Metathesekatalysatoren entwickelt. In Kooperation mit der Arbeitsgruppe von Prof. Dr. h. c. W. A. Herrmann (TU München) wurden asymmetrische Metathesereaktionen durch Ruthenium-Alkyliden-Katalysatoren, die chirale N-heterocyclische Carbenliganden tragen, untersucht. Dabei wurde eine neue chirale Isomerisierungsreaktion eines Vinyldihydrofurans und eine asymmetrische rutheniumkatalysierte Ringschlußmetathese gefunden. Für die Weiterentwicklung von Ruthenium-Metathesekatalysatoren wurden neue lösliche und immobilisierte Ligandenvorstufen synthetisiert und auf ihre Eignung zur Darstellung neuer Katalysatoren untersucht. So konnten in der oben genannten Kooperation bisher unbekannte lösliche und polymergebundene Rhodium-Benzimidazolcarbenkomplexe, die Aktivität in der Hydrosilylierung zeigen, durch in-situ-Synthese aus den entsprechenden Benzimidazoliumsalzen hergestellt werden. Zur Synthese immobilisierter Ruthenium-Metathesekatalysatoren, die insbesondere für kombinatorische Anwendungen interessant sein können, wurde neben einem immobilisierten Benzimidazoliumsalz auch ein festphasengebundenes 3,4-Dihydroimidazoliumsalz synthetisiert und in einen aktiven Metathesekatalysator überführt