Allergies and asthma result from immune responses to common environmental antigens. Despite the fact that both diseases have been described as having a strong genetic background, influences by environmental factors are not negligible. In fact, direct exposure to environmental pollutants (e.g tobacco smoke or chemicals) has already been associated with the development of such diseases and pieces of evidence pile up that early life exposure to these substances is critical. The group of chemicals called 'phthalates' are classified among the incriminated substances. Long non-coding RNAs (lncRNAs) are part of the cellular elements that can be influenced by such exposure. They have been extensively studied over the last decade, highlighting potential roles in both normal and pathological cell functions, and have been associated with various diseases including some immune-related ones such as allergic reactions. Nevertheless, the role they play in environmental health still requires to be clarified. Maternal exposure to benzyl butyl phthalate (BzBP), a chemical from the phthalate family present in daily-life products (e.g. vinyl flooring, adhesives), has been associated with allergies and asthma development in cohort studies. The underlying cellular mechanisms remain nonetheless mostly unknown. Because the immune cells T helper (TH) and B cells are key actors in such pathologies, we hypothesized that maternal exposure to BzBP may have an impact on asthma and allergy development by affecting these cells. The present study therefore focused on the effect of maternal exposure to BzBP on TH and B cells, with a particular interest in BzBP-induced changes in lncRNAs expression, motivated by their cellular functions and their putative responsiveness to chemicals. Using a murine model and RNA-sequencing, we observed that perinatal (during pregnancy and breastfeeding) and prenatal (pregnancy only) exposure to BzBP led to differential expression in TH cells, including for lncRNAs. With the aim of identifying putative roles of BzBP-regulated lncRNAs, weighted correlation network analysis was performed. The results suggest that some of the non-coding transcripts regulated by prenatal exposure to BzBP may be involved in TH cell-related functions such as cell activation, TH2-cytokines expression and regulation of the inflammatory response. Differential expression of lncRNAs due to prenatal exposure to BzBP was also observed in mouse B cells. Recently published RNA-sequencing data for B cell development and activation (Brazao et al., 2016) were integrated with our own data for correlation network analysis. The results revealed that some of the BzBP-regulated lncRNAs were correlated with genes involved in B cell-related functions. In particular, we hypothesized that two of these lncRNAs may play a role in germinal center B cell functions. Several non-coding transcripts that are regulated by prenatal exposure to BzBP and that may be involved in TH cell-related processes and in germinal center B cell functions were therefore identified. Due to the association of the concerned processes and of this B cell sub-population with the development of allergies and asthma, we suspect these genes to also be actors in such phenomenons after prenatal exposure to BzBP. We propose models of how these genes are involved in immune-related functions and how their regulation by BzBP may be critical. Taken together, these data thus provide a whole new layer of information of the toxicological effect of prenatal exposure to BzBP and of how this exposure might be associated with allergies and asthma development by providing an insight of underlying cellular mechanisms. Moreover, our study also contributes to filling the gaps in the knowledge concerning the roles of lncRNAs in environmental health by showing that BzBP influences non-coding transcripts that may be involved in pathologies.

Die Unterteilung der Arzneimittelversorgung in einen ambulanten und stationären Sektor führt zu vermeidbaren arzneimittelbezogenen Problemen an den Versorgungsschnittstellen. Medikationspläne werden häufig zum Schließen von Informationslücken bei Krankenhausaufnahme genutzt. Diese wurden bisher noch nicht unter Routinebedingungen in einem multizentrischen Setting auf ihren Nutzen hin untersucht. Des Weiteren wird die Nachhaltigkeit der Informationsweitergabe bei Krankenhausentlassung wissenschaftlich kontrovers diskutiert. Von besonderer Relevanz für den Patienten sind stationäre Medikationsänderungen, die zur Aufhebung eines arzneimittelbezogenen Problems geführt haben. Für die Untersuchung dieser beiden Aspekte ist eine sektorenübergreifende Datenbasis notwendig, die ressourceneffektiv und möglichst frei von systematischen Bias ist. Das Ziel dieser Dissertation war daher unter Nutzung eines innovativen Datenlinkage aus Primär- und Sekundärdaten der gesetzlichen Krankenversicherung, den Einfluss von Medikationsplänen auf die Arzneimittelkontinuität an den Versorgungsschnittstellen und die Nachhaltigkeit pharmazeutischer Interventionen in einem multizentrischen Setting zu bestimmen. Für die Untersuchung des Einflusses von Medikationsplänen wurden Medikationsprofile von 279 Studienteilnehmern ausgewertet. Dabei zeigte sich, dass Arzneimittel von Patienten mit Medikationsplan zur Krankenhausaufnahme stationär häufiger weiterverordnet wurden. Neben diesem Nutzen des Medikationsplans wurde auch Optimierungsbedarf aufgezeigt, da sich beispielsweise in Bezug auf den Ersteller sowie einzelner Arzneimittelgruppen kein Benefit eines Medikationsplanes darstellen ließ. Neu war ebenfalls die Beobachtung, dass sich beide Arzneimittelversorgungsschnittstellen hinsichtlich der Weiterverordnung von Arzneimittel statistisch signifikant voneinander unterscheiden. Folglich sind unterschiedliche Herangehensweisen für die Reduktion von arzneimittelbezogenen Problemen notwendig. Im Rahmen einer prospektiven, randomisierten, kontrollierten Interventionsstudie an 532 Patienten wurde die Informationsweitergabe zu arzneimittelbezogenen Problemen nach Krankenhausentlassung analysiert. Pharmazeutische Empfehlungen allein konnten dabei die Prävalenz von arzneimittelbezogenen Problemen nicht reduzieren. Kommunikationsbarrieren und sektorenspezifische Arzneimitteltherapien haben wahrscheinlich die Nachhaltigkeit reduziert. Die publizierten multizentrischen Studien zeigen zusammen die Probleme der sektorenübergreifenden Arzneimittelverordnung und die Limitationen bisheriger Lösungsstrategien auf. Durch diese Erkenntnisse ist es möglich, weiterführende Strategien zur Erhöhung der Arzneimitteltherapiesicherheit zu entwickeln und flächendeckend zu implementieren.:1. Zusammenfassung 1 2. Abstract 8 3. Einleitende Kapitel 14 3.1. Arzneimittelversorgung im deutschen Gesundheitssystem 14 3.2. Schließen von Informationslücken an Versorgungsschnittstellen durch Medikationspläne 15 3.3. Nachhaltige Lösung von arzneimittelbezogenen Problemen an Versorgungsschnittstellen 17 3.4. Anforderungen an die Datenerhebung an Versorgungsschnittstellen 20 3.5. Fragestellungen 22 4. Originalarbeit 1: Medikationspläne bei Krankenhausaufnahme – eine multizentrische Analyse unter Nutzung von Routinedaten einer gesetzlichen Krankenversicherung 24 5. Originalarbeit 2: Verwendung von Routinedaten der gesetzlichen Krankenkasse in einer Pilotstudie zur Evaluation pharmazeutischer Interventionen im Krankenhaus 34 6. Diskussion 44 6.1. Machbarkeit und Vorteile des Datenlinkage 46 6.2. Bedeutung des Medikationsplans für die Arzneimittelkontinuität 50 6.3. Unterschiede in der Weiterverordnung von Arzneimitteln bei Krankenhausaufnahme und -enlassung 55 6.4. Nachhaltigkeit pharmazeutischer Empfehlungen 57 7. Fazit und Ausblick 61 Literaturverzeichnis 62 Abkürzungsverzeichnis 67 Wissenschaftlicher Werdegang 68 Publikationsverzeichnis 69

The thesis investigated objective neuroimaging biomarkers in parkinsonian syndromes, which could be applied to increase diagnostic accuracy. To find convergence of the literature concerning disease-specific patterns in Parkinson’s disease and progressive supranuclear palsy, we conducted meta-analyses. In Parkinson’s disease glucose hypometabolism was re- vealed in bilateral inferior parietal cortex and left caudate nucleus and focal gray matter atrophy in the middle occipital gyrus. In progressive supranu- clear palsy we identified gray matter atrophy in the midbrain and white mat- ter atrophy in the cerebral/cerebellar pedunculi and midbrain. In sum, in Parkinson’s disease hypometabolism outperforms atrophy and in progres- sive supranuclear palsy we validated pathognomonic markers as disease- specific. Our studies create a novel framework to investigate disease- specific regional alterations for use in clinical routine. Further, we inves- tigated neural correlates by voxel-based morphometry and discriminated disease and clinical syndrome by multivariate pattern recognition in sin- gle patients with corticobasal syndrome and corticobasal syndrome with a unique syndrome - alien/ anarchic limb phenomenon. We found gray matter volume differences between patients and controls in asymmetric frontotem- poral/ occipital regions, motor areas, and insulae. The frontoparietal gyrus including the supplementary motor area contralateral to the side of the af- fected limb was specific for alien/ anarchic limb phenomenon. The predic- tion of the disease among controls was 79.0% accurate. The prediction of the specific syndrome within a disease reached an accuracy of 81.3%. In conclusion, we reliably classified patients and controls by objective pattern recognition. Moreover, we were able to predict a specific clinical syndrome within a disease, paving the way to individualized disease prediction.:SELBSTSTÄNDIGKEITSERKLÄRUNG I ACKNOWLEDGMENTS II SUMMARY III ZUSAMMENFASSUNG VIII BIBLIOGRAPHISCHE DARSTELLUNG XIV CONTENTS XVI 1 GENERAL INTRODUCTION 1 1.1 ParkinsonianSyndromes .................... 2 1.2 Parkinson’sDisease ....................... 2 1.2.1 DiagnosticCriteria .................... 3 1.3 ProgressiveSupranuclearPalsy ................ 4 1.3.1 DiagnosticCriteria .................... 5 1.4 CorticobasalDegeneration ................... 5 1.4.1 DiagnosticCriteria .................... 7 1.5 ImagingBiomarkers ....................... 7 1.6 CurrentThesis .......................... 9 1.6.1 MotivationandFramework ............... 9 1.6.2 ResearchQuestions................... 9 2 GENERAL MATERIALS AND METHODS 12 2.1 MagneticResonanceImaging.................. 12 2.2 AnalyticalMethods........................ 13 2.2.1 Meta-Analysis ...................... 13 2.2.2 Voxel-BasedMorphometry ............... 14 2.2.3 Support-Vector Machine Classification . . . . . . . . . 15 2.3 Multi-CentricData ........................ 16 2.4 ClinicalAssessment ....................... 17 3 Study 1 4 Study 2 5 Study 3 6 Study 4 7 Study 5 8 DISCUSSION 73 8.1 MainFindings........................... 73 8.2 Statistical Approaches to Find Imaging Biomarker . . . . . . 76 8.3 Brain Alterations and their Utility as Imaging Biomarker . . . . 77 8.4 Limitations ............................ 78 8.5 Contributions of the Current Thesis and Future Directions . . 79 9 REFERENCES APPENDIX XVIII LIST OF AUTHORSHIP XXVII CURRICULUM VITÆ XXXVIII

No description available.

FTIR spectroscopy as molecular fingerprint has been used to assess macromolecular and ele-mental stoichiometry as well as growth rates of phytoplankton cells. Chemometric models have been developed to extract quantitative information from FTIR spectra to reveal macro-molecular composition (of proteins, carbohydrates and lipids), C:N ratio, and growth potential. In this study, we tested these chemometric models based on lab-cultured algal species in mon-itoring changes of phytoplankton community structure in a hypertrophic lake (Lake Auensee, Leipzig, Germany), where a seasonal succession of spring green algal bloom followed by cya-nobacterial dominance in summer can be commonly observed. Our results demonstrated that green algae reacted to environmental changes such as nitrogen limitation (due to imbalanced nitrogen and phosphorus supply) with restricted growth by changing carbon allocation from protein synthesis to storage carbohydrates and/or lipids, and increased C:N ratio. By contrast, cyanobacteria proliferated under nitrogen limiting conditions. Furthermore, the FTIR-based growth potential of green alga matched well with the population biomass determined by the Chl-a concentration. However, the predicted growth potential based on FTIR spectroscopy cannot describe the realistic growth development of cyanobacteria in this lake. These results revealed that green algae and cyanobacteria have different strategies of C-allocation stoichi-ometry and growth patterns in response to environmental changes. These taxon-specific re-sponses may explain at a molecular level why green algae bloomed in the spring under condi-tions with sufficient nutrient, lower pH and lower water temperature; while cyanobacteria overgrew green algae and dominated in the summer under conditions with limited nutrient availability, higher pH and higher water temperature. In addition, the applicability of these chemometric models for predicting field cyanobacterial growth is of limited value. This may be attributed to other special adaptation properties of cyanobacterial species under stress growth conditions. We used flow cytometry to isolate functional algal groups from the water samples. Despite some drawbacks of the flow cytometry combined FTIR spectroscopy tech-nique, this method provides prospects of monitoring water quality and early warning of harmful algal blooms.

Increasing anthropogenic alterations propelled by a growing human population paired with ecological perturbations and climate change has amplified rates of disease transmission at the human-wildlife interface. While attention has focused primarily on diseases that cause high rates of morbidity and mortality, there is a dearth of research on more common, non-lethal “mild” infections. However, despite less obvious and immediate consequences, these infections still have long-term effects on both public health and the conservation of wildlife. Currently, disease research is primarily cross-sectional, with a lack of longitudinal studies, leading to an undervaluation of the dynamic nature of disease systems. In addition to pathogen monitoring, concurrently being able to measure immune system activation will help to clarify the effects of non-lethal diseases on host health and to provide further insights into life-history trade-offs. Here, I investigated malaria parasite (Plasmodium spp.) infections, a “mild” disease, in wild habituated chimpanzees (Pan troglodytes verus) residing in Taï National Park (TNP), Côte d'Ivoire. I used historical biological samples collected from non-human primates (including chimpanzees) and humans, as well as collected mosquitoes within their habitat. First, I identified longitudinal patterns of malaria parasite prevalence detected in chimpanzee faeces; next, I validated a biomarker of immune system activation, urinary neopterin, in wild chimpanzees; and lastly, within a larger ecological framework, I examined the interface of malaria parasite transmission between humans and non-human primates sharing a habitat. With a longitudinal study design, I found substantial intra- and inter-annual fluctuations in the faecal detection of malaria parasites across four non-consecutive sampling periods between 2004 and 2015. Peaks were observed during wet seasons—suggesting that environmental factors relating to vector abundance determine infection patterns. A higher prevalence was also detected in younger individuals, suggesting that the availability of susceptible hosts plays a role. With variations in parasite detection, similar trends should also be observed in health status. Urinary neopterin, an early inflammation marker of the non-specific immune response, increases during malaria parasite infections in humans and has been validated as a marker of immune system activation in laboratory and captive non-human primates. However, it was unclear whether it would be sensitive enough to provide a clear signal in mild diseases against the back-drop of co-infections commonly seen in wildlife. Therefore, we first needed to validate urinary neopterin as a biomarker of immune system activation during severe disease in wild animals. I measured urinary neopterin before, during, and after a severe respiratory outbreak and showed that levels corresponded to respiratory symptoms and predicted mortality. While urinary neopterin is sensitive enough to detect changes in immune system activation during severe disease, future research should still aim to validate its use in mild diseases, such as malaria. Finally, human-to-animal disease transmission is known to occur in TNP, with direct declines in chimpanzee populations observed that resulted from several outbreaks caused by human respiratory diseases. Given the zoonotic origin of malaria parasites in humans, I examined the genetic diversity of malaria parasites infecting humans and non-human primates sharing a habitat. Mosquitoes were also captured to identify potential vectors that may bridge transmission between host species. Only P. malariae was found in both humans and chimpanzees—however, the directionality of cross-species transmission would require a larger sample size to correctly assess. Additionally, no anopheline mosquitoes, the only known vector of mammalian malaria parasites, or mosquitoes positive for human- or great ape-specific malaria parasites were captured—suggesting that transmission events may be rare due to the sparsity of vectors in this region. This thesis shows that malaria epidemiology is a temporally and spatially diverse system that requires the use of longitudinal datasets and diverse sampling schemes. This thesis provides a baseline of data on which future malaria parasite research can build. Additionally, the validation of urinary neopterin will allow researchers to pursue questions on how mild diseases affect host health and to investigate questions relating to strategies and variations in life history trade-offs. This thesis is relevant for research on wildlife disease ecology, eco-immunology, and in the creation of pathogen and health surveillance programs.

The biological process of the carbon cycle in the Antarctic Ocean is controlled by the photosynthetic activity of the primary producers. The amount of fixed carbon does not only depend on the photosynthetic activity but also on the carbon losses due to respiration. Thus, the ratio photosynthesis to respiration (rP/R) is an important parameter to predict the effect of climate change on the Antarctic ecosystem. Indeed, the ongoing changes in climate change are influencing the dynamics of environmental conditions, which has tremendous effects on the phytoplankton community. Therefore, two ecologically relevant species from the Southern Ocean were here investigated: the diatom Chaetoceros sp. and the prymnesiophyte Phaeocystis antarctica, studying the changes in the rP/R under global climate change conditions. Three main parameters were examined i.e temperature, salinity and iron limitation. The P/R ratio was significantly affected by temperature, while salinity had only a secondary importance, although with species-specific differences. More specifically, the values were ranging from 12.3 to 7.5 for Chaetoceros sp. and from 12.4 to 2.5 for P. antarctica. The changes in this ratio were principally due to variations in respiration, rather than in photosynthesis. Chaetoceros sp. appears to be less flexible in the regulation of the extent of photoprotective mechanisms (non-photochemical quenching and alternative electrons), but its photoprotective level was generally higher than in P. antarctica. Regarding iron limitation, data were successfully collected only for Chaetoceros sp.. The P/R ratio, equal to 2.8, did not change under iron limitation, with iron limited cells showing a very efficient acclimation to the lowered assimilatory metabolism by decreasing their respiratory losses.

Fehlregulationen von nichtkodierenden RNAs können Einfluss auf die Tumorgenese, Proliferation und Invasion verschiedenster Tumortypen, unter anderen auch auf das Glioblastom, nehmen. Das Glioblastom stellt nicht nur den häufigsten, sondern mit einer mittleren Überlebensrate von lediglich 14 Monaten auch den tödlichsten Hirntumor dar. Ein tieferes Verständnis der molekularen Grundlagen, die hinter dem hochinvasiven Verhalten dieses aggressiven Tumors liegen, ist folglich von großer Bedeutung, um neue gezielte Therapieansätze entwickeln zu können. In der vorliegenden Arbeit wurde die lange nichtkodierende RNA STAiR18 als möglicher Regulator der zellulären Funktionen von Glioblastomzellen strukturell und funktionell charakterisiert. STAiR18 zeigt eine ubiquitäre Expression in allen untersuchten humanen Geweben, wobei es durch zelltypspezifische, alternative Spleißvorgänge zu einer hohen Anzahl verschiedener Transkriptvarianten kommt, deren Expressionslevel einer strikten Regulation unterliegen. Die für dasGlioblastom spezifische Transkriptstruktur von STAiR18 wurde mit Hilfe der neuartigen MinIONTM Sequenzierung aufgeschlüsselt und ausgewählte Transkriptvarianten mittels in situ Hybridisierung visualisiert. Die erhöhten Expressionslevel von STAiR18 in jedem untersuchten Tumortyp im Vergleich zum Normalgewebe könnten auf eine umfassende Rolle von STAiR18 während der Tumorgenese hindeuten. Zur Analyse der physiologischen Funktion wurde STAiR18 mittels RNAi in Glioblastomzellen ausgeschaltet, was sich auf die Adhärenz sowie das Migrations- und Invasionsverhalten der Zellen auswirkte. Im Rahmen globaler Transkriptomanalysen konnte eine Vielzahl von infolge des STAiR18-Knockdowns unterdrückten oder induzierten Zielgenen identifiziert werden, wobei die einzelnen Transkriptvarianten von STAiR18 unterschiedliche Gensets zu regulieren scheinen. Durch weiterführende Interaktionsstudien konnten direkte Bindungspartner von STAiR18 detektiert und die zentrale Rolle von STAiR18 bei der Regulation der Zellmigration untersucht werden. Die erhobenen Daten sollen damit Einblicke in die komplexen Regulationsnetzwerke des Glioblastoms gewähren und Zusammenhänge zwischen langen nichtkodierenden RNAs und Tumorerkrankungen aufschlüsseln.

In der vorliegenden Dissertation wurde der Einfluss der Baumdiversität auf die Bodenpilzgemeinschaft in Chinesischen subtropischen experimentellen Waldflächen untersucht.

No description available.