miRTrail - a comprehensive webserver for analyzing gene and miRNA patterns to enhance the understanding of regulatory mechanisms in diseases

<p>Abstract</p> <p>Background</p> <p>Expression profiling provides new insights into regulatory and metabolic processes and in particular into pathogenic mechanisms associated with diseases. Besides genes, non-coding transcripts as microRNAs (miRNAs) gained increasing relevance in the last decade. To understand the regulatory processes of miRNAs on genes, integrative computer-aided approaches are essential, especially in the light of complex human diseases as cancer.</p> <p>Results</p> <p>Here, we present miRTrail, an integrative tool that allows for performing comprehensive analyses of interactions of genes and miRNAs based on expression profiles. The integrated analysis of mRNA and miRNA data should generate more robust and reliable results on deregulated pathogenic processes and may also offer novel insights into the regulatory interactions between miRNAs and genes. Our web-server excels in carrying out gene sets analysis, analysis of miRNA sets as well as the combination of both in a systems biology approach. To this end, miRTrail integrates information on 20.000 genes, almost 1.000 miRNAs, and roughly 280.000 putative interactions, for Homo sapiens and accordingly for Mus musculus and Danio rerio. The well-established, classical Chi-squared test is one of the central techniques of our tool for the joint consideration of miRNAs and their targets. For interactively visualizing obtained results, it relies on the network analyzers and viewers BiNA or Cytoscape-web, also enabling direct access to relevant literature. We demonstrated the potential of miRTrail by applying our tool to mRNA and miRNA data of malignant melanoma. MiRTrail identified several deregulated miRNAs that target deregulated mRNAs including miRNAs hsa-miR-23b and hsa-miR-223, which target the highest numbers of deregulated mRNAs and regulate the pathway "basal cell carcinoma". In addition, both miRNAs target genes like PTCH1 and RASA1 that are involved in many oncogenic processes.</p> <p>Conclusions</p> <p>The application on melanoma samples demonstrates that the miRTrail platform may open avenues for investigating the regulatory interactions between genes and miRNAs for a wide range of human diseases. Moreover, miRTrail cannot only be applied to microarray based expression profiles, but also to NGS-based transcriptomic data. The program is freely available as web-server at mirtrail.bioinf.uni-sb.de.</p

Autoantibody Signature Differentiates Wilms Tumor Patients from Neuroblastoma Patients

Several studies report autoantibody signatures in cancer. The majority of these studies analyzed adult tumors and compared the seroreactivity pattern of tumor patients with the pattern in healthy controls. Here, we compared the autoimmune response in patients with neuroblastoma and patients with Wilms tumor representing two different childhood tumors. We were able to differentiate untreated neuroblastoma patients from untreated Wilms tumor patients with an accuracy of 86.8%, a sensitivity of 87.0% and a specificity of 86.7%. The separation of treated neuroblastoma patients from treated Wilms tumor patients' yielded comparable results with an accuracy of 83.8%. We furthermore identified the antigens that contribute most to the differentiation between both tumor types. The analysis of these antigens revealed that neuroblastoma was considerably more immunogenic than Wilms tumor. The reported antigens have not been found to be relevant for comparative analyses between other tumors and controls. In summary, neuroblastoma appears as a highly immunogenic tumor as demonstrated by the extended number of antigens that separate this tumor from Wilms tumor

Einflüsse genomischer und ökologischer Arteigenschaften auf die Biodiversität von Inseln - Erkenntnisse aus individuenbasierten Modellen

Life on oceanic islands provides a playground and comparably easy\-/studied basis for the understanding of biodiversity in general. Island biota feature many fascinating patterns: endemic species, species radiations and species with peculiar trait syndromes. However, classic and current island biogeography theory does not yet consider all the factors necessary to explain many of these patterns. In response to this, there is currently a shift in island biogeography research to systematically consider species traits and thus gain a more functional perspective. Despite this recent development, a set of species characteristics remains largely ignored in island biogeography, namely genomic traits. Evidence suggests that genomic factors could explain many of the speciation and adaptation patterns found in nature and thus may be highly informative to explain the fascinating and iconic phenomena known for oceanic islands, including species radiations and susceptibility to biotic invasions. Unfortunately, the current lack of comprehensive meaningful data makes studying these factors challenging. Even with paleontological data and space-for-time rationales, data is bound to be incomplete due to the very environmental processes taking place on oceanic islands, such as land slides and volcanism, and lacks causal information due to the focus on correlative approaches. As promising alternative, integrative mechanistic models can explicitly consider essential underlying eco\-/evolutionary mechanisms. In fact, these models have shown to be applicable to a variety of different systems and study questions. In this thesis, I therefore examined present mechanistic island models to identify how they might be used to address some of the current open questions in island biodiversity research. Since none of the models simultaneously considered speciation and adaptation at a genomic level, I developed a new genome- and niche-explicit, individual-based model. I used this model to address three different phenomena of island biodiversity: environmental variation, insular species radiations and species invasions. Using only a single model I could show that small-bodied species with flexible genomes are successful under environmental variation, that a complex combination of dispersal abilities, reproductive strategies and genomic traits affect the occurrence of species radiations and that invasions are primarily driven by the intensity of introductions and the trait characteristics of invasive species. This highlights how the consideration of functional traits can promote the understanding of some of the understudied phenomena in island biodiversity. The results presented in this thesis exemplify the generality of integrative models which are built on first principles. Thus, by applying such models to various complex study questions, they are able to unveil multiple biodiversity dynamics and patterns. The combination of several models such as the one I developed to an eco\-/evolutionary model ensemble could further help to identify fundamental eco\-/evolutionary principles. I conclude the thesis with an outlook on how to use and extend my developed model to investigate geomorphological dynamics in archipelagos and to allow dynamic genomes, which would further increase the model's generality.Inseln sind nützliche Modellsysteme für das Verständnis von Biodiversität im Allgemeinen. Dies wird verstärkt durch den Umstand, dass Flora und Fauna auf Inseln eine Vielzahl einzigartiger Phänomene aufweisen: von endemischen Arten über Artenradiationen bis hin zu außergewöhnlichen Arteigenschaften. Bisherige Theorien der Inselbiogeographie berücksichtigen jedoch nicht alle Faktoren, die nötig wären, um solche Phänomene zu erklären. Derzeitige Bemühungen zielen daher darauf ab, Arteigenschaften systematisch mit bestehenden Theorien zu vereinen. Trotz dieser Entwicklung werden genomische Arteigenschaften bislang in solch einer funktionalen Inselbiogeographie weitestgehend ignoriert, obwohl es Hinweise darauf gibt, dass genomische Faktoren einige der faszinierenden Diversifizierungsmuster einschließlich Artenradiationen erklären könnten. Die Erforschung dieser Faktoren gestaltet sich aufgrund des Mangels an umfangreichen, aussagekräftigen Daten jedoch als schwierig. Selbst unter Zuhilfenahme von paläontologischen Daten und substituierten Daten aus vergleichbaren Systemen lassen sich Unvollständigkeiten in den Daten und das Problem fehlender Kausalzusammenhänge schwer überwinden. Eine vielversprechende Alternative stellen mechanistische Modelle dar, von denen einige bereits für eine Vielzahl von Systemen und Forschungsprojekten eingesetzt wurden. In dieser Dissertation wurden daher mechanistische Inselmodelle untersucht, um herauszufinden, inwiefern sich diese für derzeitige offene Fragen in der Inselbiogeographie eignen würden. Da keines der untersuchten Modelle gleichzeitig Artbildung and Anpassung unter Berücksichtigung von genomischen Faktoren abbildet, wurde ein neues genom- und nischenexplizites, individuenbasiertes Modell entwickelt. Dieses wurde benutzt, um drei verschiedene Phänomene im Kontext der Inselbiogeographie zu untersuchen: die Anpassung an Umweltvariation, Artenradiationen und Invasionen durch exotische Arten. Mit diesem neuentwickeltem Modell konnte gezeigt werden, dass kleinere Arten mit flexiblen Genomen unter variablen Umwelteigenschaften erfolgreicher sind, dass eine komplexe Kombination aus Ausbreitungsfähigkeiten, Fortpflanzungsstrategien und genomischen Arteigenschaften das Entstehen von Artenradiationen beeinflussen und dass Invasionen vor allem von der Einführungsintensität und den Arteigenschaften exotischer Arten getrieben sind. Diese Ergebnisse demonstrieren, wie die Berücksichtigung funktionaler Arteigenschaften dabei helfen kann, einige bislang wenig untersuchte Phänomene der Inselbiogeographie zu verstehen. Die Ergebnisse dieser Dissertation stehen beispielhaft für die Allgemeingültigkeit integrativer, auf Grundzusammenhängen aufbauender Modelle. Dies wird durch die Aufdeckung diverser Biodiversitätsmuster und -dynamiken im Rahmen der Bearbeitung verschiedener komplexer Fragestellungen hervorgehoben. Weitere Modelle, wie das hier beschriebene, könnten sogar in einem Modellensemble kombiniert werden, um öko-evolutionare Grundprinzipien zu identifizieren. Abschließend wird ein Ausblick auf die Möglichkeit gewährt, das Modell weiterzunutzen und zu erweitern, um beispielsweise geomorphologische Archipeldynamiken oder dynamische Genome abzubilden, und damit die Allgemeingültigkeit des Modells noch zu erweitern

Biodiversity Dynamics on Islands: Explicitly Accounting for Causality in Mechanistic Models

Island biogeography remains a popular topic in ecology and has gained renewed interest due to recent theoretical development. As experimental investigation of the theory is difficult to carry out, mechanistic simulation models provide useful alternatives. Several eco-evolutionary mechanisms have been identified to affect island biodiversity, but integrating more than a few of these processes into models remains a challenge. To get an overview of what processes mechanistic island models have integrated so far and what conclusions they came to, we conducted an exhaustive literature review of studies featuring island-specific mechanistic models. This was done using an extensive systematic literature search with subsequent manual filtering. We obtained a list of 28 studies containing mechanistic island models, out of 647 total hits. Mechanistic island models differ greatly in their integrated processes and computational structure. Their individual findings range from theoretical (such as humped-shaped extinction rates for oceanic islands) to system-specific dynamics (e.g., equilibrium and non-equilibrium dynamics for Galápagos’ birds). However, most models so far only integrate theories and processes pair-wise, while focusing on hypothetical systems. Trophic interactions and explicit micro-evolution are largely underrepresented in models. We expect future models to continue integrating processes, thus promoting the full appraisal of biodiversity dynamics

Temporal environmental variation may impose differential selection on both genomic and ecological traits

The response of populations and species to changing conditions determines how community composition will change functionally, including via trait shifts. Selection from standing variation has been suggested to be more efficient than acquiring new mutations. Yet, studies on community trait composition and trait selection largely focus on phenotypic variation in ecological traits, whereas the underlying genomic traits remain understudied. Using a genome‐explicit, niche‐ and individual‐based model, we address the potential interactions between genomic and ecological traits shaping communities under an environmental selective forcing, namely temporal positively autocorrelated environmental fluctuation. In this model, all ecological traits are explicitly coded by the genome. For our experiments, we initialized 90 replicate communities, each with ca 350 initial species, characterized by random genomic and ecological trait combinations, on a 2D spatially explicit landscape with two orthogonal gradients (temperature and resource use). We exposed each community to two contrasting scenarios: without (i.e. static environments) and with temporal variation. We then analyzed emerging compositions of both genomic and ecological traits at the community, population and genomic levels. Communities in variable environments were species poorer than in static environments, and populations more abundant, whereas genomes had lower genetic linkage, mean genetic variation and a non‐significant tendency towards higher numbers of genes. The surviving genomes (i.e. those selected by variable environments) coded for enhanced environmental tolerance and smaller biomass, which resulted in faster life cycles and thus also in increased potential for evolutionary rescue. Under temporal environmental variation, larger, less linked genomes retained more variation in mean dispersal ability at the population level than at genomic level, whereas the opposite trend emerged for biomass. Our results provide clues to how sexually‐reproducing diploid plant communities might react to variable environments and highlights the importance of genomic traits and their interaction with ecological traits for eco‐evolutionary responses to changing climates

Propagule pressure and an invasion syndrome determine invasion success in a plant community model

The success of species invasions depends on multiple factors, including propagule pressure, disturbance, productivity, and the traits of native and non-native species. While the importance of many of these determinants has already been investigated in relative isolation, they are rarely studied in combination. Here, we address this shortcoming by exploring the effect of the above-listed factors on the success of invasions using an individual-based mechanistic model. This approach enables us to explicitly control environmental factors (temperature as surrogate for productivity, disturbance, and propagule pressure) as well as to monitor whole-community trait distributions of environmental adaptation, mass, and dispersal abilities. We simulated introductions of plant individuals to an oceanic island to assess which factors and species traits contribute to invasion success. We found that the most influential factors were higher propagule pressure and a particular set of traits. This invasion trait syndrome was characterized by a relative similarity in functional traits of invasive to native species, while invasive species had on average higher environmental adaptation, higher body mass, and increased dispersal distances, that is, had greater competitive and dispersive abilities. Our results highlight the importance in management practice of reducing the import of alien species, especially those that display this trait syndrome and come from similar habitats as those being managed

Anaplasma phagocytophilum infection in a dog: identifying the causative agent using PCR

A diagnosis of Anaplasma phagocytophilum infection was confirmed in a two-year-old male golden retriever displaying few clinical and haematological abnormalities. This was achieved by demonstrating ehrlichial organisms in circulating neutrophils, by indirect immunofluorescence assay using A phagocytophilum as an antigen, and by detecting DNA specific for the 16S rRNA gene of granulocytic Anaplasma by PCR. After treatment with doxycycline for 10 days the dog showed improvement and the laboratory values returned to normal