Understanding compound-induced histopathology in rat liver using gene expression network methods

Current drug discovery is a lengthy and costly pipeline; it takes between twelve and fifteen years and costs $1-2 billion (USD). As such, any compound failures represent a sunk cost – exacerbated if such failures occur later in the pipeline. Compound and drug induced liver injury is a significant cause of failures. Current progress to tackle this is based on systems biology, and so falls within the field of toxicogenomics. As such, the databases in the public domain are crucial to progress. DrugMatrix and Open TG-GATEs were identified as containing large, in vivo transcriptomics data with histopathological observations as endpoints, a proxy for toxicity. Due to the size and chemical variety of the databases, data-driven methods led to the novel creation of histopathology signatures, which accounts for dependence between histopathology observations (Chapter 2). Six toxic groups were determined for DrugMatrix and 13 for Open TG-GATEs, and were analysed with a view to enable classification, namely, what is revealed in the gene expression profiles when the histopathology phenotype was present. This led to determining gene-phenotype associations, both known and novel. An example of a novel association was the match of the histopathology signature of ‘glycogen accumulation, mixed infiltration and lymphocytic inflammatory cell infiltration’ to fructose metabolism, gluconeogenesis, and chemokine response pathways (Chapter 3). Concordance was found between histopathologically related toxicity groups between databases and their co-expression networks. From here, the co-expression network methods were applied to determine the concordance of gene expression across time (one day to four/five days), database (DrugMatrix and Open TG-GATEs), and toxicity group. This found underlying biological terms such as RNA transport, ribosome biogenesis and translation as well as toxicity-specific terms (aminoacyl t-RNA synthesis in metabolic processes for the histopathological observations of glycogen accumulation, cellular infiltrate, hepatocellular necrosis and fatty change in liver. Crucially, this work determined that the toxic group membership plays a more significant role in gene co-expression networks compared to the time point of the gene expression measurement (Chapter 4). In conclusion, data driven clustering was performed to create histopathology signatures. Using these, the usefulness of transcriptomics data was determined both to classify toxic state (gene expression data measured when the phenotype was present) and to determine how consistent it is over time scales. This work provided a framework for the comparison of co-expression networks for the deconvolution of gene expression data with respect to a phenotype.EPSR

DISKNET – A Platform for the Systematic Accumulation of Knowledge in IS Research

The accumulation of knowledge is key for any discipline, IS being no exception. With the number of publications, theoretical constructs, and empirical findings growing, surging demand for structuring and meta-analysis is foreseeable. We introduce DISKNET, an online platform that enables the extraction, exploration, and aggregation of construct’s definitions, semantic relations, and analytical relations. While these aspects exhibit a rather standardized structure in theory, their practical documentation is non-uniform, highly dispersed, and tricky to seize technically. This has impeded the efficiency and effectiveness of review and meta-analytical processes, and resulted in a fragmented theoretical superstructure. We suggest that tool support for systematic knowledge accumulation is a central step to counteract these issues and to build to a consistent body of knowledge within the IS discipline. The current prototype of DISKNET draws on a large sample of SEM-based studies to demonstrate relevant design principles for a platform for systematic accumulation of knowledge

"Copper-in-charcoal" revisited: delineating the nature of the copper species and its role in catalysis

"Copper-in-charcoal" has been shown to be a versatile catalytic source of supported copper for a variety of important synthetic transformations, as well as in other fields such as energy. We herein report the characterization of this material and the implications that its preparation has on catalysis, thus providing a greater understanding of the scope and limitations of this catalyst system. (Chemical Equation Presented)

Genomic diversity of bacteriophages infecting the genus acinetobacter

The number of sequenced Acinetobacter phage genomes in the International Nucleotide Sequence Database Collaboration has increased significantly in recent years, from 37 in 2017 to a total of 139 as of January 2021 with genome sizes ranging from 31 to 378 kb. Here, we explored the genetic diversity of the Acinetobacter phages using comparative genomics approaches that included assessment of nucleotide similarity, shared gene content, single gene phylogeny, and the network-based classification tool vConTACT2. Phages infecting Acinetobacter sp. are genetically diverse and can be grouped into 8 clusters (subfamilies) and 46 sub-clusters (genera), of which 8 represent genomic singletons (additional genera). We propose the creation of five new subfamilies and suggest a reorganisation of the genus Obolenskvirus. These results provide an updated view of the viruses infecting Acinetobacter species, providing insights into their diversity

Taxonomic assignment of uncultivated prokaryotic virus genomes is enabled by gene-sharing networks

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Microbiomes from every environment contain a myriad of uncultivated archaeal and bacterial viruses, but studying these viruses is hampered by the lack of a universal, scalable taxonomic framework. We present vConTACT v.2.0, a network-based application utilizing whole genome gene-sharing profiles for virus taxonomy that integrates distance-based hierarchical clustering and confidence scores for all taxonomic predictions. We report near-identical (96%) replication of existing genus-level viral taxonomy assignments from the International Committee on Taxonomy of Viruses for National Center for Biotechnology Information virus RefSeq. Application of vConTACT v.2.0 to 1,364 previously unclassified viruses deposited in virus RefSeq as reference genomes produced automatic, high-confidence genus assignments for 820 of the 1,364. We applied vConTACT v.2.0 to analyze 15,280 Global Ocean Virome genome fragments and were able to provide taxonomic assignments for 31% of these data, which shows that our algorithm is scalable to very large metagenomic datasets. Our taxonomy tool can be automated and applied to metagenomes from any environment for virus classification

Changes in extremely hot days under stabilized 1.5 °C and 2.0 °c global warming scenarios as simulated by the HAPPI multi-model ensemble

The half a degree additional warming, prognosis and projected impacts (HAPPI) experimental protocol provides a multi-model database to compare the effects of stabilizing anthropogenic global warming of 1.5 °C over preindustrial levels to 2.0 °C over these levels. The HAPPI experiment is based upon large ensembles of global atmospheric models forced by sea surface temperature and sea ice concentrations plausible for these stabilization levels. This paper examines changes in extremes of high temperatures averaged over three consecutive days. Changes in this measure of extreme temperature are also compared to changes in hot season temperatures. We find that over land this measure of extreme high temperature increases from about 0.5 to 1.5 °C over present-day values in the 1.5 °C stabilization scenario, depending on location and model. We further find an additional 0.25 to 1.0 °C increase in extreme high temperatures over land in the 2.0 °C stabilization scenario. Results from the HAPPI models are consistent with similar results from the one available fully coupled climate model. However, a complicating factor in interpreting extreme temperature changes across the HAPPI models is their diversity of aerosol forcing changes

Mortalidad de aves marinas producida por luces artificiales terrestres

Artificial lights at night cause high mortality of seabirds, one of the most endangered groups of birds globally. Fledglings of burrow-nesting seabirds, and to a lesser extent adults, are attracted to and then grounded (i.e., forced to land) by lights when they fly at night. We reviewed the current state of knowledge of seabird attraction to light to identify information gaps and propose measures to address the problem. Although species in families such as Alcidae and Anatidae can be grounded by artificial light, the most affected seabirds are petrels and shearwaters (Procellariiformes). At least 56 species of Procellariiformes, more than one-third of them (24) threatened, are subject to grounding by lights. Seabirds grounded by lights have been found worldwide, mainly on oceanic islands but also at some continental locations. Petrel breeding grounds confined to formerly uninhabited islands are particularly at risk from light pollution due to tourism and urban sprawl. Where it is impractical to ban external lights, rescue programs of grounded birds offer the most immediate and employed mitigation to reduce the rate of light-induced mortality and save thousands of birds every year. These programs also provide useful information for seabird management. However, these data are typically fragmentary, biased, and uncertain and can lead to inaccurate impact estimates and poor understanding of the phenomenon of seabird attraction to lights. We believe the most urgently needed actions to mitigate and understand light-induced mortality of seabirds are estimation of mortality and effects on populations; determination of threshold light levels and safe distances from light sources; documentation of the fate of rescued birds; improvement of rescue campaigns, particularly in terms of increasing recovery rates and level of care; and research on seabird-friendly lights to reduce attraction.RESUMEN: Las luces artificiales nocturnas causan una mortalidad alta de aves marinas, uno de los grupos de aves en mayor peligro de extinción a nivel mundial. Los polluelos de aves marinas que anidan en madrigueras, y en menor medida los adultos, son atraídos y forzados a aterrizar por las luces cuando vuelan de noche. Revisamos el estado actual del conocimiento sobre la atracción de las aves marinas por la luz para identificar vacíos de información y proponer medidas para resolver el problema. Aunque las especies de familias como Alcidae y Anatidae pueden ser forzadas a aterrizar por la luz artificial, las aves marinas más afectadas son los petreles y las pardelas (Procellariiformes). Por lo menos 56 especies de Procellariiformes, más de un tercio (24) de ellas amenazadas, son propensas al aterrizaje atraídas por las luces. Las aves marinas forzadas a aterrizar han sido halladas en todo el mundo, principalmente en islas oceánicas, pero también en algunas localidades continentales. Los sitios de anidación de los petreles confinados anteriormente a islas deshabitadas están particularmente en riesgo de sufrir contaminación lumínica debido al turismo y al crecimiento urbano. En donde no es práctico prohibir las luces externas, los programas de rescate de las aves accidentadas ofrecen la mitigación más inmediata y empleada para reducir la tasa de mortalidad inducida por la luz y salvar a miles de aves cada año. Estos programas también proporcionan información útil para el manejo de aves marinas. Sin embargo, estos datos están típicamente fragmentados, sesgados y son inciertos, y pueden llevar a estimaciones inexactas del impacto y a un entendimiento pobre del fenómeno de la atracción de las aves marinas por la luz. Creemos que las acciones necesarias de mayor urgencia para mitigar y entender la mortalidad de aves marinas producida por la luz son: la estimación de la mortalidad y los efectos sobre la población; la determinación de umbrales de niveles de luz y de distancias seguras a las fuentes de luz; el estudio del destino de las aves rescatadas; la mejora de las campañas de rescate, particularmente en términos de incrementar las tasas de recogida y el nivel de cuidado; y la investigación sobre las características de la luz para reducir la atracción de las aves marinas.This research was supported by a Marie Curie Intra European Fellowship within the 7th European Community Framework Programme (Project ID: 330655 FP7-PEOPLE-2012-IOF)info:eu-repo/semantics/publishedVersio

Normalization of Voltage-Sensitive Dye Signal with Functional Activity Measures

In general, signal amplitude in optical imaging is normalized using the well-established ΔF/F method, where functional activity is divided by the total fluorescent light flux. This measure is used both directly, as a measure of population activity, and indirectly, to quantify spatial and spatiotemporal activity patterns. Despite its ubiquitous use, the stability and accuracy of this measure has not been validated for voltage-sensitive dye imaging of mammalian neocortex in vivo. In this report, we find that this normalization can introduce dynamic biases. In particular, the ΔF/F is influenced by dye staining quality, and the ratio is also unstable over the course of experiments. As methods to record and analyze optical imaging signals become more precise, such biases can have an increasingly pernicious impact on the accuracy of findings, especially in the comparison of cytoarchitechtonic areas, in area-of-activation measurements, and in plasticity or developmental experiments. These dynamic biases of the ΔF/F method may, to an extent, be mitigated by a novel method of normalization, ΔF/ΔFepileptiform. This normalization uses as a reference the measured activity of epileptiform spikes elicited by global disinhibition with bicuculline methiodide. Since this normalization is based on a functional measure, i.e. the signal amplitude of “hypersynchronized” bursts of activity in the cortical network, it is less influenced by staining of non-functional elements. We demonstrate that such a functional measure can better represent the amplitude of population mass action, and discuss alternative functional normalizations based on the amplitude of synchronized spontaneous sleep-like activity. These findings demonstrate that the traditional ΔF/F normalization of voltage-sensitive dye signals can introduce pernicious inaccuracies in the quantification of neural population activity. They further suggest that normalization-independent metrics such as waveform propagation patterns, oscillations in single detectors, and phase relationships between detector pairs may better capture the biological information which is obtained by high-sensitivity imaging