807 research outputs found

    Comparative genomics of recent adaptation in Candida pathogens

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    [eng] Fungal infections pose a serious health threat, affecting >1,000 million people and causing ~1.5 million deaths each year. The problem is growing due to insufficient diagnostic and therapeutic options, increased number of susceptible patients, expansion of pathogens partly linked to climate change and the rise of antifungal drug resistance. Among other fungal pathogens, Candida species are a major cause of severe hospital-acquired infections, with high mortality in immunocompromised patients. Various Candida pathogens constitute a public health issue, which require further efforts to develop new drugs, optimize currently available treatments and improve diagnostics. Given the high dynamism of Candida genomes, a promising strategy to improve current therapies and diagnostics is to understand the evolutionary mechanisms of adaptation to antifungal drugs and to the human host. Previous work using in vitro evolution, population genomics, selection inferences and Genome Wide Association Studies (GWAS) have partially clarified such recent adaptation, but various open questions remain. In the three research articles that conform this PhD thesis we addressed some of these gaps from the perspective of comparative genomics. First, we addressed methodological issues regarding the analysis of Candida genomes. Studying recent adaptation in these pathogens requires adequate bioinformatic tools for variant calling, filtering and functional annotation. Among other reasons, current methods are suboptimal due to limited accuracy to identify structural variants from short read sequencing data. In addition, there is a need for easy-to-use, reproducible variant calling pipelines. To address these gaps we developed the “personalized Structural Variation detection” pipeline (perSVade), a framework to call, filter and annotate several variant types, including structural variants, directly from reads. PerSVade enables accurate identification of structural variants in any species of interest, such as Candida pathogens. In addition, our tool automatically predicts the structural variant calling accuracy on simulated genomes, which informs about the reliability of the calling process. Furthermore, perSVade can be used to analyze single nucleotide polymorphisms and copy number-variants, so that it facilitates multi-variant, reproducible genomic studies. This tool will likely boost variant analyses in Candida pathogens and beyond. Second, we addressed open questions about recent adaptation in Candida, using perSVade for variant identification. On the one hand, we investigated the evolutionary mechanisms of drug resistance in Candida glabrata. For this, we used a large-scale in vitro evolution experiment to study adaptation to two commonly-used antifungals: fluconazole and anidulafungin. Our results show rapid adaptation to one or both drugs, with moderate fitness costs and through few mutations in a narrow set of genes. In addition, we characterize a novel role of ERG3 mutations in cross-resistance towards fluconazole in anidulafungin-adapted strains. These findings illuminate the mutational paths leading to drug resistance and cross-resistance in Candida pathogens. On the other hand, we reanalyzed ~2,000 public genomes and phenotypes to understand the signs of recent selection and drug resistance in six major Candida species: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis. We found hundreds of genes under recent selection, suggesting that clinical adaptation is diverse and complex. These involve species-specific but also convergently affected processes, such as cell adhesion, which could underlie conserved adaptive mechanisms. In addition, using GWAS we predicted known drivers of antifungal resistance alongside potentially novel players. Furthermore, our analyses reveal an important role of generally-overlooked structural variants, and suggest an unexpected involvement of (para)sexual recombination in the spread of resistance. Taken together, our findings provide novel insights on how Candida pathogens adapt to human-related environments and suggest candidate genes that deserve future attention. In summary, the results of this thesis improve our knowledge about the mechanisms of recent adaptation in Candida pathogens, which may enable improved therapeutic and diagnostic applications.[cat] Les infeccions fúngiques representen una greu amenaça per a la salut, afectant a més de 1.000 milions de persones i causant aproximadament 1,5 milions de morts cada any. El problema està augmentant a causa d’unes opcions terapèutiques i diagnòstiques insuficients, l'increment del nombre de pacients susceptibles, l'expansió dels patògens parcialment vinculada al canvi climàtic i l'augment de la resistència als fàrmacs antifúngics. D’entre diversos fongs patògens, els llevats del gènere Candida són una causa important d'infeccions nosocomials, amb una alta mortalitat en pacients immunodeprimits. Diverses espècies de Candida constitueixen un problema de salut pública, cosa que requereix més esforços per a desenvolupar nous medicaments, optimitzar els tractaments disponibles i millorar els diagnòstics. Tenint en compte el dinamisme genòmic d’aquests patògens, una estratègia prometedora per millorar les teràpies i diagnòstics actuals és comprendre els mecanismes evolutius d'adaptació als fàrmacs antifúngics i a l’hoste humà. Treballs anteriors utilitzant l'evolució in vitro, la genòmica de poblacions, les inferències de selecció i els estudis d'associació de genoma complet (GWAS, per les sigles en anglès) han aclarit parcialment aquesta adaptació recent, però encara hi ha diverses preguntes obertes. En els tres articles que conformen aquesta tesi doctoral, hem abordat algunes d'aquestes preguntes des de la perspectiva de la genòmica comparativa. En primer lloc, hem abordat qüestions metodològiques relatives a l'anàlisi dels genomes de les espècies Candida. L'estudi de l'adaptació recent en aquests patògens requereix eines bioinformàtiques adequades per a la detecció, filtratge i anotació funcional de variants genètiques. Entre altres raons, els mètodes actuals són subòptims a causa de la limitada precisió per identificar variants estructurals a partir de dades de seqüenciació amb lectures curtes. A més, hi ha una necessitat d’eines computacionals per a la detecció de variants que siguin senzilles d'utilitzar i reproduibles. Per abordar aquestes mancances, hem desenvolupat el mètode bioinformàtic "personalized Structural Variation detection" (perSVade), una eina que permet la detecció, filtratge i anotació de diversos tipus de variants, incloent-hi les variants estructurals, directament des de les lectures. PerSVade permet la identificació precisa de les variants estructurals en qualsevol espècie d'interès, com ara els patògens Candida. A més, la nostra eina prediu automàticament la precisió de la detecció d’aquestes variants en genomes simulats, la qual cosa informa sobre la fiabilitat del procés. Finalment, perSVade es pot utilitzar per analitzar altres tipus de variants, com els polimorfismes de nucleòtid únic o els canvis en el nombre de còpies, facilitant així estudis genòmics integrals i reproduibles. Aquesta eina probablement impulsarà les anàlisis genòmiques en els patògens Candida i també en altres espècies. En segon lloc, hem abordat algunes de les preguntes obertes sobre l'adaptació recent en els llevats Candida, utilitzant perSVade per a la identificació de variants. D'una banda, hem investigat els mecanismes evolutius de resistència als fàrmacs antifúngics en Candida glabrata. Per a això, hem utilitzat un experiment d'evolució in vitro a gran escala per estudiar l'adaptació a dos antifúngics comuns: el fluconazol i l’anidulafungina. Els nostres resultats mostren una adaptació ràpida a un o ambdós fàrmacs, amb un cost per al creixement moderat i a través de poques mutacions en un nombre reduït de gens. A més, hem caracteritzat un paper nou de les mutacions en ERG3 en la resistència creuada al fluconazol en soques adaptades a anidulafungina. Aquests descobriments aclareixen els processos mutacionals que condueixen a la resistència als fàrmacs i a la resistència creuada en els patògens Candida. D'altra banda, hem re-analitzat aproximadament 2.000 genomes i fenotips disponibles en repositoris públics per a comprendre els senyals genòmics de selecció recent i de resistència a fàrmacs antifúngics, en sis espècies rellevants de Candida: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis i C. orthopsilosis. Hem trobat centenars de gens sota selecció recent, suggerint que l'adaptació clínica és diversa i complexa. Aquests gens estan relacionats amb funcions específiques de cada espècie, però també trobem processos alterats de manera similar en diferents patògens, com per exemple l’adhesió cel·lular, cosa que indica fenòmens d’adaptació conservats. A part, utilitzant GWAS hem predit mecanismes esperats de resistència a antifúngics i també possibles nous factors. A més, les nostres anàlisis revelen un paper important de les variants estructurals, generalment poc estudiades, i suggereixen una implicació inesperada de la recombinació (para)sexual en la propagació de la resistència. En conjunt, els nostres descobriments proporcionen noves perspectives sobre com els patògens Candida s'adapten als entorns humans, i suggereixen gens candidats que mereixen investigacions futures. En resum, els resultats d’aquesta tesi milloren el nostre coneixement sobre els mecanismes d'adaptació recent en els patògens Candida, cosa que pot permetre el disseny de noves teràpies i diagnòstics

    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

    Augmented Behavioral Annotation Tools, with Application to Multimodal Datasets and Models: A Systematic Review

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    Annotation tools are an essential component in the creation of datasets for machine learning purposes. Annotation tools have evolved greatly since the turn of the century, and now commonly include collaborative features to divide labor efficiently, as well as automation employed to amplify human efforts. Recent developments in machine learning models, such as Transformers, allow for training upon very large and sophisticated multimodal datasets and enable generalization across domains of knowledge. These models also herald an increasing emphasis on prompt engineering to provide qualitative fine-tuning upon the model itself, adding a novel emerging layer of direct machine learning annotation. These capabilities enable machine intelligence to recognize, predict, and emulate human behavior with much greater accuracy and nuance, a noted shortfall of which have contributed to algorithmic injustice in previous techniques. However, the scale and complexity of training data required for multimodal models presents engineering challenges. Best practices for conducting annotation for large multimodal models in the most safe and ethical, yet efficient, manner have not been established. This paper presents a systematic literature review of crowd and machine learning augmented behavioral annotation methods to distill practices that may have value in multimodal implementations, cross-correlated across disciplines. Research questions were defined to provide an overview of the evolution of augmented behavioral annotation tools in the past, in relation to the present state of the art. (Contains five figures and four tables)

    Molecular mechanisms of environmental signal reception in mouth-form and dauer polyphenism in Pristionchus pacificus

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    Entwicklungsplastizität beschreibt die Fähigkeit eines Genoms, unterschiedliche Phänotypen in unterschiedlichen Umgebungen auszubilden. Obwohl das Phänomen oft in der Natur vorkommt sind die genetischen Mechanismen sowie die Gewebe, die dafür verantwortlich sind, Signal aus der Umwelt in den Entwicklungsprozess zu integrieren, noch nicht genügend erforscht. Diskrete Fälle von Entwicklungsplastizität, auch Polyphänismen genannt, eignen sich aufgrund der klaren Beziehung zwischen Umweltsginal und ausgebildetem Phänotyp sowie der einfachen Identifizierung des Phänotypen besonders gut für die Erforschung der molekularen Steuerung von Entwicklungsplastizität. Das am umfassendsten beschriebene Regulationsnetzwerk eines Polyphänismus unterliegt der Bildung von Dauerlarven im Modellorganismus Caenorhabditis elegans. Um die allgemeinen Prinzipien polyphäner Regulation zu verstehen, bedarf es jedoch eines vergleichenden Ansatzes. Auch bei Pristionchus pacificus, einer Spezies von Fadenwürmern aus der Familie der Diplogastridae, tritt der Polyphänismus der Dauerlarven auf; zudem verfügt die Spezies über einen weiteren Polyphänismus der Mundform (fleischfressende und bakterienfressende Morphe). Das Netzwerk an genetischen Schaltpunkten dieses Polyphänismus wurde bereits gut untersucht, doch eine detaillierte Beschreibung der molekularen Prozesse an den für Sinnesreize verantwortlichen Zilien blieb bislang noch aus. In dieser Arbeit untersuche ich die rezeptiven Mechanismen, die der Integration von Signalen aus der Umweltbei der Entwicklung der Polyphänismen in P. pacificus zugrundeliegen. Das erste Projekt untersuchte die Entwicklung und Rolle der primären Zilien in P. pacificus mithilfe eines Kandidatengen Ansatzes. Obwohl die Entwicklung primärer Zilien in P. pacificus und C. elegans größtenteils konserviert ist, konnten wir beschreiben, wie P. pacificus’ Dauerlarven in kontrastierender Weise durch rezeptive molekularen Pfade reguliert werden, die in den sensorischen Zilien ausgedrückt werden.Damit werden frühere Befunde untermauert, die die Divergenz der Chemotaxis-Präferenzen zwischen C. elegans und P. pacificus Dauerlarven und die Entdeckung des Käfer-Sex-Pheromon-Rezeptors OBI-1 in P. pacificus zeigten. Unsere Studie konkretisiert damit frühere Spekulationen über die schnelle Entwicklung molekularer Signalwege von Polyphänismen zwischen verschiedenen Arten. Die Entdeckung des Mundform-Phänotyps bei Mutanten, denen die sensorischen Flimmerhärchen völlig fehlen, motivierte das Screening auf den Mundform-Phänotyp bei zuvor erzeugten Mutanten der Komponenten der sensorischen Flimmerhärchen. Dies führte zur Entdeckung unterschiedlicher Rollen einzelner Komponenten bei der Regulierung des Mundform-Polyphänismus, wobei der anterograde Transport vermutlich die Hauptrolle bei der Bildung des fleischfressenden Morphs spielt. Das zweite große Projekt verwendete eine EMS-Mutagenese, um die rezeptiven Wege zu untersuchen, die Umgebungstemperatur in die Ausbildung des Mundform-Dimorphismus integrieren, was zur Entdeckung des sensorischen Zilien-assoziierten-cGMP-Signalweges führte, dessen Rolle zuvor in C. elegans’ Dauerlarven beschrieben wurde. Interessanterweise weisen Mutanten dieses Signalweges, wie auch im Fall des vollständigen Verlustes der Zilien, eine gegensätzliche Rolle bei der Dauerpolyphenese in C. elegans und P. pacificus auf. Beide Projekte zeigen, dass verschiedene Umweltreize, die die Mundform beeinflussen, weit upstream durch pleiotrope rezeptive Moleküle integriert werden. Diese Arbeit liefert eine umfassende vergleichende Beschreibung der molekularen Signalwege oberhalb der genetischen Schalter, die den Mundform-Polyphenismus bei P. pacificus regulieren.Developmental plasticity is the ability of a genome to change its phenotype across heterogeneous environments. Although it is a common phenomenon in nature, the receptive molecular pathways and sensory tissues which integrate environmental signals into development are not well investigated yet. Discrete cases of phenotypic plasticity, commonly known as polyphenisms, are particularly useful for the investigation of molecular regulation of developmentally plastic traits due to the clear relationship between environmental signals and phenotypes as well as due to easy identification of distinct phenotypes. The most comprehensive network of polyphenism regulation is found in dauer polyphenism in the model organism Caenorhabditis elegans. Primary cilia of sensory neurons have a major role in the perception of the environmental stimuli which regulate dauer formation in C. elegans. However, a comparative approach is necessary to explore general principles. The diplogastrid nematode Pristionchus pacificus shares a dauer polyphenism with C. elegans, and has an additional polyphenism of mouth-structures (carnivorous and bacteriovorus morph). While the switch network of mouth-form polyphenism is well investigated, the molecular machinery of sensory cilia has not been investigated so far. This thesis addresses the role of far upstream molecular pathways, which integrate aspects of the environment into development. The first major project included an investigation of the development and role of primary sensory cilia in P. pacificus through a candidate approach. Results showed that, while the development of sensory cilia is highly conserved between C. elegans and P. pacificus, dauers in P. pacificus are regulated in a contrasting manner by the receptive molecular pathways expressed in the sensory cilia in P. pacificus and C. elegans. These results, advance previous findings, which showed the divergence in chemotaxis preferences between the two species’ respective dauers and the discovery of the beetle sex pheromone receptor OBI-1 in P. pacificus. Our study fleshes out previous speculations that the receptive molecular pathways of polyphenism evolve fast between different species. The discovery of mouth-form phenotype in mutants completely lacking sensory cilia motivated the screen for mouth-form phenotype across previously generated mutants of the components of sensory cilia, which led to discovery of contrasting roles of individual components in mouth-form polyphenism regulation, with anterograde transport presumably having the strongest role in the formation of the carnivorous morph. The second major project used an unbiased approach via EMS mutagenesis to investigate the receptive pathways which integrate temperature into mouth-form dimorphism which resulted in the discovery of sensory cilia associated-cGMP signalling pathway, a role similar to what has previously been described in the dauer polyphenism in C. elegans. Interestingly, as in the case of complete loss of cilia, mutants of this pathway have a contrasting role in dauer formation between C. elegans and P. pacificus. Both projects showed that different environmental stimuli relevant for determining the mouth-form are integrated far upstream through pleiotropic receptive molecules. This thesis provides a comprehensive comparative description of molecular pathways that regulate mouth-form polyphenism in P. pacificus

    Engineering Proteins by Domain Insertion

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    Protein domains are structural and functional subunits of proteins. The recombination of existing domains is a source of evolutionary innovation, as it can result in new protein features and functions. Inspired by nature, protein engineering commonly uses domain recombination in order to create artificial proteins with tailor-made properties. Customized control over protein activity, for instance, can be achieved by harnessing switchable domains and functionally linking them to effector domains. Many natural protein domains exhibit conformational changes in response to exogenous triggers. The insertion of light-switchable receptor domains into an effector protein of choice, for instance, allows the control of effector activity with light. The resulting optogenetic proteins represent powerful tools for the investigation of dynamic cellular processes with high precision in time and space. On top, optogenetic proteins enable manifold biotechnological applications and they are even considered potential candidates for future therapeutics. In this study, we first focused on CRISPR-Cas9 genome editing and applied a domain insertion strategy to genetically encoded inhibitors of the CRISPR nuclease from Neisseria meningitidis (NmeCas9), which due to its small size and high DNA sequence-specificity is of great interest for CRISPR genome editing applications. Fusing stabilizing domains to the NmeCas9 inhibitory protein AcrIIC1 allowed us to boost its inhibitory effect, thereby yielding a potent gene editing off-switch. Furthermore, the insertion of the light-responsive LOV2 domain from Avena sativa into AcrIIC3, the most potent inhibitor of NmeCas9, enabled the optogenetic control of gene editing via light-dependent NmeCas9 inhibition. Further investigation of the engineered inhibitors revealed the potential these proteins could have with respect to safe-guarding of the CRISPR technology by selectively reducing off-target editing. The laborious optimization of the engineered CRISPR inhibitors necessary by the time motivated us to more systematically investigate possibilities and constraints of protein engineering by domain insertion using an unbiased insertion approach. Previously, single protein domains were usually introduced only at a few rationally selected sites into target proteins. Here, we inserted up to five structurally and functionally unrelated domains into several different candidate effector proteins at all possible positions. The resulting libraries of protein hybrids were screened for activity by fluorescence-activated cell sorting (FACS) and subsequent next-generation sequencing (Flow-seq). Training machine learning models on the resulting, comprehensive datasets allowed us to dissect parameters that affect domain insertion tolerance and revealed that sequence conservation statistics are the most powerful predictors for domain insertion success. Finally, extending our experimental Flow-seq pipeline towards the screening of engineered, switchable effector variants yielded two potent optogenetic derivatives of the E. coli transcription factor AraC. These novel hybrids will enable the co-regulation of bacterial gene expression by light and chemicals. Taken together, our study showcases the design of functionally diverse protein switches for the control of gene editing and gene expression in mammalian cells and E. coli, respectively. In addition, the generation of a large domain insertion datasets enabled - for the first time - the unbiased investigation of domain insertion tolerance in several evolutionary unrelated proteins. Our study showcases the manifold opportunities and remaining challenges behind the engineering of proteins with new properties and functionalities by domain recombination

    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

    ATHENA Research Book, Volume 2

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    ATHENA European University is an association of nine higher education institutions with the mission of promoting excellence in research and innovation by enabling international cooperation. The acronym ATHENA stands for Association of Advanced Technologies in Higher Education. Partner institutions are from France, Germany, Greece, Italy, Lithuania, Portugal and Slovenia: University of Orléans, University of Siegen, Hellenic Mediterranean University, Niccolò Cusano University, Vilnius Gediminas Technical University, Polytechnic Institute of Porto and University of Maribor. In 2022, two institutions joined the alliance: the Maria Curie-Skłodowska University from Poland and the University of Vigo from Spain. Also in 2022, an institution from Austria joined the alliance as an associate member: Carinthia University of Applied Sciences. This research book presents a selection of the research activities of ATHENA University's partners. It contains an overview of the research activities of individual members, a selection of the most important bibliographic works of members, peer-reviewed student theses, a descriptive list of ATHENA lectures and reports from individual working sections of the ATHENA project. The ATHENA Research Book provides a platform that encourages collaborative and interdisciplinary research projects by advanced and early career researchers
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