327 research outputs found

    ACARORUM CATALOGUS IX. Acariformes, Acaridida, Schizoglyphoidea (Schizoglyphidae), Histiostomatoidea (Histiostomatidae, Guanolichidae), Canestrinioidea (Canestriniidae, Chetochelacaridae, Lophonotacaridae, Heterocoptidae), Hemisarcoptoidea (Chaetodactylidae, Hyadesiidae, Algophagidae, Hemisarcoptidae, Carpoglyphidae, Winterschmidtiidae)

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    The 9th volume of the series Acarorum Catalogus contains lists of mites of 13 families, 225 genera and 1268 species of the superfamilies Schizoglyphoidea, Histiostomatoidea, Canestrinioidea and Hemisarcoptoidea. Most of these mites live on insects or other animals (as parasites, phoretic or commensals), some inhabit rotten plant material, dung or fungi. Mites of the families Chetochelacaridae and Lophonotacaridae are specialised to live with Myriapods (Diplopoda). The peculiar aquatic or intertidal mites of the families Hyadesidae and Algophagidae are also included.Publishe

    Computational comparative genomics in cyanobacteria

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    Cyanobacteria are an ancient clade of photosynthetic prokaryotes, varying in morphology, physiology, biochemistry and habitat. They evolve by typical prokaryotic mechanisms including horizontal gene transfer (HGT). Some species produce toxins (cyanotoxins) that present health hazards to humans and animals, with potential harm to local economies. The biosynthetic pathways and roles of some cyanotoxins are unclear. The rapid increase in high quality publicly available genomes presents opportunities for discovery from comparative genomics in cyanobacteria. The work presented here focuses on three topics in cyanobacteria, using bioinformatics analyses of 130 cyanobacterial genomes. Firstly, I consider hypotheses for the biosynthesis and physiology of the non-encoded neurotoxin 2,4-diaminobutanoic acid (2,4-DAB). Secondly, I consider hypotheses for the biosynthesis and potential roles of its structural analogue, β-N-methylaminoalanine (BMAA). These topics use similar methodology: pairwise and multiple sequence alignment, profile hidden Markov models, substrate specificity and active site identification, and the reconstruction of gene phylogenies. We show that some species have genes involved in known biochemical pathways to 2,4-DAB – genes coding for proteins in the aspartate 4-phosphate pathway (including the diaminobutanoate-2-oxo-glutarate transaminase, the downstream decarboxylase, diaminobutanoate decarboxylase, and ectoine synthase) – and BMAA (homologs of the Staphylococcus aureus genes sbnA and sbnB). We highlight the possible involvement of 2,4-DAB and BMAA in the production of siderophores. We show that the biosynthesis of 2,4-DAB and BMAA is likely to be confined to a limited number of species, or to occur via different, unknown, pathways. Thirdly, I investigate hypotheses concerning the association of HGT events with environmental context. I test existing hypotheses claiming that genetic exchanges are more frequent in extreme habitats (versus mesophilic) and in terrestrial habitats (versus aquatic). My results, based on reconciliation of gene trees with the species tree, do not suggest a link between the prevalence of HGT and extreme or terrestrial environments. I highlight the need for complete descriptions of the isolation source and culture type (axenic, non-axenic monocyanobacterial culture, environmental sample), the need for accurate and robust methods for HGT inference, and for more objective and detailed criteria for environmental classification and of cyanobacterial species. This work contributes to research into cyanobacterial neurotoxins and provides insights into the prevalence and distribution of HGT in cyanobacteria

    Specificity of the innate immune responses to different classes of non-tuberculous mycobacteria

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    Mycobacterium avium is the most common nontuberculous mycobacterium (NTM) species causing infectious disease. Here, we characterized a M. avium infection model in zebrafish larvae, and compared it to M. marinum infection, a model of tuberculosis. M. avium bacteria are efficiently phagocytosed and frequently induce granuloma-like structures in zebrafish larvae. Although macrophages can respond to both mycobacterial infections, their migration speed is faster in infections caused by M. marinum. Tlr2 is conservatively involved in most aspects of the defense against both mycobacterial infections. However, Tlr2 has a function in the migration speed of macrophages and neutrophils to infection sites with M. marinum that is not observed with M. avium. Using RNAseq analysis, we found a distinct transcriptome response in cytokine-cytokine receptor interaction for M. avium and M. marinum infection. In addition, we found differences in gene expression in metabolic pathways, phagosome formation, matrix remodeling, and apoptosis in response to these mycobacterial infections. In conclusion, we characterized a new M. avium infection model in zebrafish that can be further used in studying pathological mechanisms for NTM-caused diseases

    Ancestral Sequence Reconstructions of Stator Proteins of the Bacterial Flagellar Motor

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    The bacterial flagellar motor (BFM) is a bidirectional nanomachine that confers motility to several bacteria. The BFM is powered by ion transfer across the cell membrane through its stator. The stator consists of two membrane proteins: MotA and MotB in proton (H+)-powered motors or PomA and PomB in sodium (Na+)-powered motors. Over the years, several parts of the BFM have been resolved using numerous mutagenesis studies and different microscopic techniques. However, the entire structure of the BFM, its ion selection mechanism, the functional roles of each structural residue, and how its complexity evolves and adapts over time are not completely known. In this thesis, we used ancestral sequence reconstruction (ASR) to study the evolutionary history and roles of the key structural residues of the stator complex of the BFM. First, we reconstructed and synthesised thirteen combined transmembrane (TM) and plug domains of ancestral MotBs (MotB-ASRs) to test previously hypothesised critical motifs for the ion-selectivity of BFM. The results showed that all resurrected MotB-ASRs were functional and restored motility with the contemporary E. coli MotA in a stator-deleted strain. In addition, all MotB-ASRs exhibited Na+-independent motility in different ionic conditions, suggesting that the synthesised MotB-ASRs were more likely to be proton-powered. Secondly, we reconstructed and synthesised ten complete ancient MotAs (MotA-ASRs) to study the role of the key structural residues of MotA in BFM function. We identified that four of the ten MotA-ASRs were functional and restored motility in combination with contemporary E. coli MotB and several previously synthesised MotB-ASRs. The functional MotA-ASRs also showed Na+-independent motility in different ionic conditions, like our MotB-ASRs. Additionally, the resurrected MotA-ASRs provided evidence of several variable regions of MotA and revealed 30 conserved residues that were essential for flagellar function. Lastly, we screened two novel motility inhibitors, HM2-16F and BB2-50F, and characterised their anti-motility activity on multiple strains and stator types. We also optimised and developed new high-resolution assays for the phenotypic study of stator function to verify the targets of the motility inhibitors. Our results confirmed that these compounds inhibited bacterial swimming but did not target the stator. In summary, this thesis shows the use of ASR as a tool to study the stator proteins of the BFM

    Modelling the genomic structure, and antiviral susceptibility of Human Cytomegalovirus

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    Human Cytomegalovirus (HCMV) is found ubiquitously in humans worldwide, and once acquired, the infection persists within the host throughout their life. Although Immunocompetent people rarely are affected by HCMV infections, their related diseases pose a major health problem worldwide for those with compromised or suppressed immune systems such as transplant recipients. Additionally, congenital transmission of HCMV is the most common infectious cause of birth defects globally and is associated with a substantial economic burden. This thesis explores the application of statistical modelling and genomics to unpick three key areas of interest in HCMV research. First, a comparative genomics analysis of global HCMV strains was undertaken to delineate the molecular population structure of this highly variable virus. By including in-house sequenced viruses of African origin and by developing a statistical framework to deconvolute highly variable regions of the genome, novel and important insights into the co-evolution of HCMV with its host were uncovered. Second, a rich database relating mutations to drug sensitivity was curated for all the antiviral treated herpesviruses. This structured information along with the development of a mutation annotation pipeline, allowed the further development of statistical models that predict the phenotype of a virus from its sequence. The predictive power of these models was validated for HSV1 by using external unseen mutation data provided in collaboration with the UK Health Security Agency. Finally, a nonlinear mixed effects model, expanded to account for Ganciclovir pharmacokinetics and pharmacodynamics, was developed by making use of rich temporal HCMV viral load data. This model allowed the estimation of the impact of immune-clearance versus antiviral inhibition in controlling HCMV lytic replication in already established infections post-haematopoietic stem cell transplant

    Data journeys in the sciences

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    This is the final version. Available from Springer via the DOI in this record. This groundbreaking, open access volume analyses and compares data practices across several fields through the analysis of specific cases of data journeys. It brings together leading scholars in the philosophy, history and social studies of science to achieve two goals: tracking the travel of data across different spaces, times and domains of research practice; and documenting how such journeys affect the use of data as evidence and the knowledge being produced. The volume captures the opportunities, challenges and concerns involved in making data move from the sites in which they are originally produced to sites where they can be integrated with other data, analysed and re-used for a variety of purposes. The in-depth study of data journeys provides the necessary ground to examine disciplinary, geographical and historical differences and similarities in data management, processing and interpretation, thus identifying the key conditions of possibility for the widespread data sharing associated with Big and Open Data. The chapters are ordered in sections that broadly correspond to different stages of the journeys of data, from their generation to the legitimisation of their use for specific purposes. Additionally, the preface to the volume provides a variety of alternative “roadmaps” aimed to serve the different interests and entry points of readers; and the introduction provides a substantive overview of what data journeys can teach about the methods and epistemology of research.European CommissionAustralian Research CouncilAlan Turing Institut

    Differential evolution of non-coding DNA across eukaryotes and its close relationship with complex multicellularity on Earth

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    Here, I elaborate on the hypothesis that complex multicellularity (CM, sensu Knoll) is a major evolutionary transition (sensu Szathmary), which has convergently evolved a few times in Eukarya only: within red and brown algae, plants, animals, and fungi. Paradoxically, CM seems to correlate with the expansion of non-coding DNA (ncDNA) in the genome rather than with genome size or the total number of genes. Thus, I investigated the correlation between genome and organismal complexities across 461 eukaryotes under a phylogenetically controlled framework. To that end, I introduce the first formal definitions and criteria to distinguish ‘unicellularity’, ‘simple’ (SM) and ‘complex’ multicellularity. Rather than using the limited available estimations of unique cell types, the 461 species were classified according to our criteria by reviewing their life cycle and body plan development from literature. Then, I investigated the evolutionary association between genome size and 35 genome-wide features (introns and exons from protein-coding genes, repeats and intergenic regions) describing the coding and ncDNA complexities of the 461 genomes. To that end, I developed ‘GenomeContent’, a program that systematically retrieves massive multidimensional datasets from gene annotations and calculates over 100 genome-wide statistics. R-scripts coupled to parallel computing were created to calculate >260,000 phylogenetic controlled pairwise correlations. As previously reported, both repetitive and non-repetitive DNA are found to be scaling strongly and positively with genome size across most eukaryotic lineages. Contrasting previous studies, I demonstrate that changes in the length and repeat composition of introns are only weakly or moderately associated with changes in genome size at the global phylogenetic scale, while changes in intron abundance (within and across genes) are either not or only very weakly associated with changes in genome size. Our evolutionary correlations are robust to: different phylogenetic regression methods, uncertainties in the tree of eukaryotes, variations in genome size estimates, and randomly reduced datasets. Then, I investigated the correlation between the 35 genome-wide features and the cellular complexity of the 461 eukaryotes with phylogenetic Principal Component Analyses. Our results endorse a genetic distinction between SM and CM in Archaeplastida and Metazoa, but not so clearly in Fungi. Remarkably, complex multicellular organisms and their closest ancestral relatives are characterized by high intron-richness, regardless of genome size. Finally, I argue why and how a vast expansion of non-coding RNA (ncRNA) regulators rather than of novel protein regulators can promote the emergence of CM in Eukarya. As a proof of concept, I co-developed a novel ‘ceRNA-motif pipeline’ for the prediction of “competing endogenous” ncRNAs (ceRNAs) that regulate microRNAs in plants. We identified three candidate ceRNAs motifs: MIM166, MIM171 and MIM159/319, which were found to be conserved across land plants and be potentially involved in diverse developmental processes and stress responses. Collectively, the findings of this dissertation support our hypothesis that CM on Earth is a major evolutionary transition promoted by the expansion of two major ncDNA classes, introns and regulatory ncRNAs, which might have boosted the irreversible commitment of cell types in certain lineages by canalizing the timing and kinetics of the eukaryotic transcriptome.:Cover page Abstract Acknowledgements Index 1. The structure of this thesis 1.1. Structure of this PhD dissertation 1.2. Publications of this PhD dissertation 1.3. Computational infrastructure and resources 1.4. Disclosure of financial support and information use 1.5. Acknowledgements 1.6. Author contributions and use of impersonal and personal pronouns 2. Biological background 2.1. The complexity of the eukaryotic genome 2.2. The problem of counting and defining “genes” in eukaryotes 2.3. The “function” concept for genes and “dark matter” 2.4. Increases of organismal complexity on Earth through multicellularity 2.5. Multicellularity is a “fitness transition” in individuality 2.6. The complexity of cell differentiation in multicellularity 3. Technical background 3.1. The Phylogenetic Comparative Method (PCM) 3.2. RNA secondary structure prediction 3.3. Some standards for genome and gene annotation 4. What is in a eukaryotic genome? GenomeContent provides a good answer 4.1. Background 4.2. Motivation: an interoperable tool for data retrieval of gene annotations 4.3. Methods 4.4. Results 4.5. Discussion 5. The evolutionary correlation between genome size and ncDNA 5.1. Background 5.2. Motivation: estimating the relationship between genome size and ncDNA 5.3. Methods 5.4. Results 5.5. Discussion 6. The relationship between non-coding DNA and Complex Multicellularity 6.1. Background 6.2. Motivation: How to define and measure complex multicellularity across eukaryotes? 6.3. Methods 6.4. Results 6.5. Discussion 7. The ceRNA motif pipeline: regulation of microRNAs by target mimics 7.1. Background 7.2. A revisited protocol for the computational analysis of Target Mimics 7.3. Motivation: a novel pipeline for ceRNA motif discovery 7.4. Methods 7.5. Results 7.6. Discussion 8. Conclusions and outlook 8.1. Contributions and lessons for the bioinformatics of large-scale comparative analyses 8.2. Intron features are evolutionarily decoupled among themselves and from genome size throughout Eukarya 8.3. “Complex multicellularity” is a major evolutionary transition 8.4. Role of RNA throughout the evolution of life and complex multicellularity on Earth 9. Supplementary Data Bibliography Curriculum Scientiae Selbständigkeitserklärung (declaration of authorship

    Technology, Science and Culture: A Global Vision, Volume IV

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    A systems biology understanding of protein constraints in the metabolism of budding yeasts

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    Fermentation technologies, such as bread making and production of alcoholic beverages, have been crucial for development of humanity throughout history. Saccharomyces cerevisiae provides a natural platform for this, due to its capability to transform sugars into ethanol. This, and other yeasts, are now used for production of pharmaceuticals, including insulin and artemisinic acid, flavors, fragrances, nutraceuticals, and fuel precursors. In this thesis, different systems biology methods were developed to study interactions between metabolism, enzymatic capabilities, and regulation of gene expression in budding yeasts. In paper I, a study of three different yeast species (S. cerevisiae, Yarrowia lipolytica and Kluyveromyces marxianus), exposed to multiple conditions, was carried out to understand their adaptation to environmental stress. Paper II revises the use of genome-scale metabolic models (GEMs) for the study and directed engineering of diverse yeast species. Additionally, 45 GEMs for different yeasts were collected, analyzed, and tested. In paper III, GECKO 2.0, a toolbox for integration of enzymatic constraints and proteomics data into GEMs, was developed and used for reconstruction of enzyme-constrained models (ecGEMs) for three yeast species and model organisms. Proteomics data and ecGEMs were used to further characterize the impact of environmental stress over metabolism of budding yeasts. On paper IV, gene engineering targets for increased accumulation of heme in S. cerevisiae cells were predicted with an ecGEM. Predictions were experimentally validated, yielding a 70-fold increase in intracellular heme. The prediction method was systematized and applied to the production of 102 chemicals in S. cerevisiae (Paper V). Results highlighted general principles for systems metabolic engineering and enabled understanding of the role of protein limitations in bio-based chemical production. Paper VI presents a hybrid model integrating an enzyme-constrained metabolic network, coupled to a gene regulatory model of nutrient-sensing mechanisms in S. cerevisiae. This model improves prediction of protein expression patterns while providing a rational connection between metabolism and the use of nutrients from the environment.This thesis demonstrates that integration of multiple systems biology approaches is valuable for understanding the connection of cell physiology at different levels, and provides tools for directed engineering of cells for the benefit of society
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