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Institute
- Graduate School of Life Sciences (999) (remove)
Sonstige beteiligte Institutionen
- Helmholtz Institute for RNA-based Infection Research (HIRI) (5)
- Universitätsklinikum Münster (3)
- Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg (2)
- Zentrum für Infektionsforschung (ZINF) Würzburg (2)
- Bio-Imaging Center Würzburg (1)
- Biomedical Center Munich, Department of Physiological Chemistry, Ludwig-Maximilians-Universität München (1)
- CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - the development agency of the Brazilian Federal Government (1)
- CBIO, University of Cape Town, South Africa (1)
- Carl-Ludwig-Institut für Physiologie, Universität Leipzig (1)
- Chair of Experimental Biomedicine I (1)
Gazes are of central relevance for people. They are crucial for navigating the world and communicating with others. Nevertheless, research in recent years shows that many findings from experimental research on gaze behavior cannot be transferred from the laboratory to everyday behavior. For example, the frequency with which conspecifics are looked at is considerably higher in experimental contexts than what can be observed in daily behavior. In short: findings from laboratories cannot be generalized into general statements. This thesis is dedicated to this matter. The dissertation describes and documents the current state of research on social attention through a literature review, including a meta-analysis on the /gaze cueing/ paradigm and an empirical study on the robustness of gaze following behavior. In addition, virtual reality was used in one of the first studies in this research field. Virtual reality has the potential to significantly improve the transferability of experimental laboratory studies to everyday behavior. This is because the technology enables a high degree of experimental control in naturalistic research designs. As such, it has the potential to transform empirical research in the same way that the introduction of computers to psychological research did some 50 years ago. The general literature review on social attention is extended to the classic /gaze cueing/ paradigm through a systematic review of publications and a meta-analytic evaluation (Study 1). The cumulative evidence supported the findings of primary studies: Covert spatial attention is directed by faces. However, the experimental factors included do not explain the surprisingly large variance in the published results. Thus, there seem to be further, not well-understood variables influencing these social processes. Moreover, classic /gaze cueing/ studies have limited ecological validity. This is discussed as a central reason for the lack of generalisability. Ecological validity describes the correspondence between experimental factors and realistic situations. A stimulus or an experimental design can have high and low ecological validity on different dimensions and have different influences on behavior. Empirical research on gaze following behavior showed that the /gaze cueing/ effect also occurs with contextually embedded stimuli (Study 2). The contextual integration of the directional cue contrasted classical /gaze cueing/ studies, which usually show heads in isolation. The research results can thus be transferred /within/ laboratory studies to higher ecologically valid research paradigms. However, research shows that the lack of ecological validity in experimental designs significantly limits the transferability of experimental findings to complex situations /outside/ the laboratory. This seems to be particularly the case when social interactions and norms are investigated. However, ecological validity is also often limited in these studies for other factors, such as contextual embedding /of participants/, free exploration behavior (and, thus, attentional control), or multimodality. In a first study, such high ecological validity was achieved for these factors with virtual reality, which could not be achieved in the laboratory so far (Study 3). Notably, the observed fixation patterns showed differences even under /most similar/ conditions in the laboratory and natural environments. Interestingly, these were similar to findings also derived from comparisons of eye movement in the laboratory and field investigations. These findings, which previously came from hardly comparable groups, were thus confirmed by the present Study 3 (which did not have this limitation). Overall, /virtual reality/ is a new technical approach to contemporary social attention research that pushes the boundaries of previous experimental research. The traditional trade-off between ecological validity and experimental control thus becomes obsolete, and laboratory studies can closely inherit an excellent approximation of reality. Finally, the present work describes and discusses the possibilities of this technology and its practical implementation. Within this context, the extent to which this development can still guarantee a constructive classification of different laboratory tests in the future is examined.
TTFields sind eine Therapieoption des GBM, welche als alternierende elektrische Felder den Aufbau des mitotischen Spindelapparates stören. Gleichzeitig überwacht der SAC, mit seiner Schlüsselkomponente der Kinase MPS1, eine korrekte Anheftung der Spindelfasern an die Kinetochore der Chromosomen. Eine Inhibition des SAC durch den Inhibitor MPS1-IN-3 in Kombination mit Vincristin führt zu einem synergistischen Effekt auf das Tumorwachstum in vitro und in vivo. Aus diesen Erkenntnissen folgerten wir die Hypothese, dass eine SAC-Inhibition die Wirkung von TTFields verstärken könnte. Um dies zu testen, wurden Zellen der Zelllinien U87 und GaMG über 72h mit TTFields, MPS1-IN-3 oder einer Kombination aus den beiden behandelt. Anschließend wurden die Zellen gezählt, es wurde eine Analyse des Zellzyklus vorgenommen und apoptotische Zellen wurden via TUNEL-Assay detektiert. Die Kombinationsbehandlung aus TTFields und MPS1-IN-3 führte zu einer Reduktion der Zellzahl (U87: -54,3% vs. TTFields, p=0,0046; -52,9% vs. MPS1-IN-3, p=0,0026; GaMG: -74,3% vs. TTFields, p=0,0373; -84% vs. MPS1-IN-3, p<0,00001). Nur 28,1% mehr Zellen als ausgesät waren bei der Zelllinie U87 zu finden (TTFields: 179,1%; MPS1-IN-3: 168,3%), während es bei GaMG-Zellen sogar 62% weniger Zellen als ausgesät waren. Im Zellzyklus zeigte sich eine Abnahme der Zellen von der G1-Phase (U87: -59,9% vs. TTFields, p=0,0007; -42,1% vs. IN-3, p=0,0426; GaMG: -45,1% vs. TTFields, p=0,0276; -51,6% vs. IN-3, p=0,0020), während es zu einem massiven Anstieg von toten Zellen kam (U87: 2,9fach vs. TTFields, p=0,0022; 2,2fach vs. IN-3, p=0,0046; GaMG: 5,6fach vs. TTFields, p=0,0078; 7,8fach vs. IN-3, p=0,0005). Diese Zellen ließen sich im TUNEL-Assay als durch Apoptose zu Grunde gegangene Zellen weiter identifizieren (U87: 5,4fach vs. TTFields, p=0,0489; 6,2fach vs. IN-3, p=0,0278; GaMG: 8,9fach vs. IN-3, p=0,0110). Diese Ergebnisse sind erste und wichtige Hinweise für eine Verstärkung der Wirkung von TTFields durch eine Inhibition des SAC und liefern eine gute Grundlage für weitere Forschung zur Verbesserung der Therapie des GBM.
Für die Diagnose und Therapie von Brustkrebs existiert die nationale evidenz- und konsensbasierte S3-Leitlinie. Die klinischen Krebsregister stellen sektor- und facharztübergreifende Diagnose- und Therapiedaten zur Qualitätssicherung bereit. Bislang fehlen jedoch Daten bezüglich patient-reported outcome measures (PROMs). Aufgrund des demographischen Wandels werden Brustkrebserkrankungen vor allem in ländlichen Regionen weiter zunehmen, weshalb Versorgungsstrukturen für alle Patientinnen erreichbar sein sollten. Es wurde ein patientenorientiertes Registerkonzept (Breast Cancer Care for patients with metastatic disease (BRE-4-MED)) für den metastasierten Brustkrebs entwickelt und hinsichtlich vordefinierter Machbarkeitskriterien pilotiert. An der BRE-4-MED-Pilotstudie nahmen 31 Patientinnen (96.8% weiblich) teil. Die bayernweite Erreichbarkeit zu brustkrebsspezifischen Versorgungsstrukturen wurde mithilfe einer Geographic Information System (GIS)-Analyse untersucht. Anhand von Leitlinienempfehlungen und Ergebnissen der BRE-4-MED-Pilotstudie wurden relevante Versorgungsstrukturen identifiziert. Die Ergebnisse der Pilotstudie zeigen, dass die Integration von Primär- und Sekundärdaten aus verschiedenen Quellen in ein zentrales Studienregister machbar ist und die erforderlichen organisatorischen Prozesse (z. B. data linkage mit Krebsregister) funktionieren. Die Ergebnisse der Erreichbarkeitsanalyse verdeutlichen, dass es keine bayernweite Erreichbarkeit zu brustkrebsspezifischen Versorgungsstrukturen gibt. Am stärksten war dieser Zusammenhang in grenznahen Regionen ausgeprägt. Die vorliegende Arbeit zeigt Chancen für eine patientenorientierte, qualitätsgesicherte Brustkrebsversorgung unabhängig vom Wohnort auf.
Bei der Behandlung solider Tumoren spielen systemisch verabreichte Chemotherapeutika eine wich- tige Rolle. Allerdings akkumulieren diese Therapeutika besser in normalem Gewebe als in Tumoren. Als Ursache für diesen unzureichenden Transport von Medikamenten in den Tumor wurde bisher vor allem die dysfunktionale Tumorvaskulatur diskutiert. Diese befindet sich in einem chaotischen und unreifen Zustand ohne ausreichende Bedeckung der Gefäße mit stabilisierenden Perizyten. Aus dem Zustand der Vaskulatur resultierend erreichen Medikamente den Tumor nur in geringem Ausmaß und werden dort heterogen verteilt. Als Grund für den Zustand der Vaskulatur wur- de ein großer Überschuss an pro-angiogenetischen Faktoren im Tumor ausgemacht. Durch eine anti-angiogenetische Behandlung konnte in präklinischen Modellen für einen gewissen Zeitraum die Tumorvaskulatur „normalisiert“ werden. Dies zeichnete sich vor allem durch Veränderung von zwei wichtigen Parametern für die Medikamenteneinbringung aus: zum Einen kommt es zu einer Reduktion der Gefäßdichte. Zum Anderen zu einer Reifung der Blutgefäße. In einem Teil von Pati- enten scheint dabei der Effekt der Gefäßverbesserung zu überwiegen und es kann eine verbesserte Perfusion detektiert werden. Mutmaßlich führt dies auch zu einer verbesserten Einbringung von Therapeutika in den Tumor und so zu einer erhöhten Effizienz der Therapie. In einem weiteren Teil der Patienten scheint jedoch der Effekt der Gefäßreduktion zu überwiegen und die detektierte Perfusion im Tumor wird durch die Behandlung verringert.
Das in dieser Arbeit verwendete MT6-Fibrosarkom-Modell reagierte auf eine anti-angiogenetische Therapie nicht mit einer sonst in murinen Modellen beobachteten Wachstumsreduktion. Die- se ermöglichte eine so bisher nicht mögliche Untersuchung der sekundären Effekte einer anti- angiogenetischen Therapie wie die Medikamenteneinbringung in den Tumor. Die Vaskulatur in MT6-Tumoren zeigte dabei nach einer anti-angiogenetischen Vorbehandlung, die erwarteten Merk-male einer „normalisierten“ Vaskulatur wie eine Reduktion der Gefäßdichte bei gleichzeitiger Rei- fung der verbleibenden Gefäße. Dies führte jedoch nicht zu einer verbesserten Effizienz einer subsequenten Chemotherapie. Durch Vergleich mit einem weiteren Tumor-Modell, dem 4T1-Modell für ein metastasierendes Mammakarzinom, konnten signifikante Unterschiede im Gefäßbild beider Modelle ausgeschlossen werden. Durch mikroskopische Methoden konnte dabei beobachtet werden, dass die Diffusion von Medikamenten aus den Blutgefäßen des MT6-Modells im Vergleich zum 4T1-Modell verringert war. Weitere Untersuchungen deuten auf eine Differenz in der Qualität der extrazellulären Matrix der verwendeten Tumor-Modelle. Durch mRNA-Expressionsanalysen konnte die Enzymfamilie der Lysyloxidasen als mögliche Ursache für diesen Diffusionsunterschied identi- fiziert werden. Lysyloxidasen katalysieren vor allem die Quervernetzung von Proteinen der Extra- zellulärmatrix. Im Weiteren konnte gezeigt werden, dass die Quervernetzung von Matrixproteinen durch Lysyloxidasen ursächlich für die Diffusions-Inhibierung kleiner Moleküle wie das Chemo- therapeutikum Doxorubicin sein kann. Durch spezifische Inhibition der Lysyloxidasen mittels des Inhibitors βAPN konnte diese Diffusions-Inhibition sowohl in vitro als auch im MT6-Tumor-Modell nahezu vollständig verhindert werden. Die hohe Aktivität von Lysyloxidasen im MT6-Modell stell- te allerdings kein Alleinstellungsmerkmal dieses Modells dar. In weiteren Untersuchungen konnte gezeigt werden, dass Lysyloxidasen in einer Vielzahl von murinen und humanen Tumorzelllinien überexprimiert wird. Die Inhibition von Lysyloxidasen durch βAPN konnte dabei in allen unter- suchten Modellen die Einbringung von Medikamenten in den Tumor erhöhen und könnte so eine sinnvolle adjuvante Maßnahme zur Verbesserung bestehender Chemotherapien darstellen.
Malignant melanoma (MM) is the most dangerous type of skin cancer with rising incidences worldwide. Melanoma skin models can help to elucidate its causes and formation or to develop new treatment strategies. However, most of the current skin models lack a vasculature, limiting their functionality and applicability. MM relies on the vascular system for its own supply and for its dissemination to distant body sites via lymphatic and blood vessels. Thus, to accurately study MM progression, a functional vasculature is indispensable. To date, there are no vascularized skin models to study melanoma metastasis in vitro, which is why such studies still rely on animal experimentation.
In the present thesis, two different approaches for the vascularization of skin models are employed with the aim to establish a vascularized 3D in vitro full-thickness skin equivalent (FTSE) that can serve as a test system for the investigation of the progression of MM.
Initially, endothelial cells were incorporated in the dermal part of FTSEs. The optimal seeding density, a spheroid conformation of the cells and the cell culture medium were tested. A high cell density resulted in the formation of lumen-forming shapes distributed in the dermal part of the model. These capillary-like structures were proven to be of endothelial origin by staining for the endothelial cell marker CD31. The established vascularized FTSE (vFTSE) was characterized histologically after 4 weeks of culture, revealing an architecture similar to human skin in vivo with a stratified epidermis, separated from the dermal equivalent by a basement membrane indicated by collagen type IV. However, this random capillary-like network is not functional as it cannot be perfused.
Therefore, the second vascularization approach focused on the generation of a perfusable tissue construct. A channel was molded within a collagen hydrogel and seeded with endothelial cells to mimic a central, perfusable vessel. The generation and the perfusion culture of the collagen hydrogel was enabled by the use of two custom-made, 3D printed bioreactors. Histological assessment of the hydrogels revealed the lining of the channel with a monolayer of endothelial cells, expressing the cell specific marker CD31.
For the investigation of MM progression in vitro, a 3D melanoma skin equivalent was established. Melanoma cells were incorporated in the epidermal part of FTSEs, representing the native microenvironment of the tumor. Melanoma nests grew at the dermo-epidermal junction within the well stratified epidermis and were characterized by the expression of common melanoma markers. First experiments were conducted showing the feasibility of combining the melanoma model with the vFTSE, resulting in skin models with tumors at the dermo-epidermal junction and lumen-like structures in the dermis.
Taken together, the models presented in this thesis provide further steps towards the establishment of a vascularized, perfusable melanoma model to study melanoma progression and metastasis.
Acceleration is a central aim of clinical and technical research in magnetic resonance imaging (MRI) today, with the potential to increase robustness, accessibility and patient comfort, reduce cost, and enable entirely new kinds of examinations. A key component in this endeavor is image reconstruction, as most modern approaches build on advanced signal and image processing. Here, deep learning (DL)-based methods have recently shown considerable potential, with numerous publications demonstrating benefits for MRI reconstruction. However, these methods often come at the cost of an increased risk for subtle yet critical errors. Therefore, the aim of this thesis is to advance DL-based MRI reconstruction, while ensuring high quality and fidelity with measured data. A network architecture specifically suited for this purpose is the variational network (VN). To investigate the benefits these can bring to non-Cartesian cardiac imaging, the first part presents an application of VNs, which were specifically adapted to the reconstruction of accelerated spiral acquisitions. The proposed method is compared to a segmented exam, a U-Net and a compressed sensing (CS) model using qualitative and quantitative measures. While the U-Net performed poorly, the VN as well as the CS reconstruction showed good output quality. In functional cardiac imaging, the proposed real-time method with VN reconstruction substantially accelerates examinations over the gold-standard, from over 10 to just 1 minute. Clinical parameters agreed on average.
Generally in MRI reconstruction, the assessment of image quality is complex, in particular for modern non-linear methods. Therefore, advanced techniques for precise evaluation of quality were subsequently demonstrated.
With two distinct methods, resolution and amplification or suppression of noise are quantified locally in each pixel of a reconstruction. Using these, local maps of resolution and noise in parallel imaging (GRAPPA), CS, U-Net and VN reconstructions were determined for MR images of the brain. In the tested images, GRAPPA delivers uniform and ideal resolution, but amplifies noise noticeably. The other methods adapt their behavior to image structure, where different levels of local blurring were observed at edges compared to homogeneous areas, and noise was suppressed except at edges. Overall, VNs were found to combine a number of advantageous properties, including a good trade-off between resolution and noise, fast reconstruction times, and high overall image quality and fidelity of the produced output. Therefore, this network architecture seems highly promising for MRI reconstruction.
∆Np63 is a master regulator of squamous cell identity and regulates several signaling pathways that crucially
contribute to the development of squamous cell carcinoma (SCC) tumors. Its contribution to coordinating the
expression of genes involved in oncogenesis, epithelial identity, DNA repair, and genome stability has been
extensively studied and characterized. For SCC, the expression of ∆Np63 is an essential requirement to
maintain the malignant phenotype. Additionally, ∆Np63 functionally contributes to the development of cancer
resistance toward therapies inducing DNA damage.
SCC patients are currently treated with the same conventional Cisplatin therapy as they would have been
treated 30 years ago. In contrast to patients with other tumor entities, the survival of SCC patients is limited,
and the efficacy of the current therapies is rather low. Considering the rising incidences of these tumor entities,
the development of novel SCC therapies is urgently required. Targeting ∆Np63, the transcription factor, is a
potential alternative to improve the therapeutic response and clinical outcomes of SCC patients.
However, ∆Np63 is considered “undruggable.” As is commonly observed in transcription factors, ∆Np63 does
not provide any suitable domains for the binding of small molecule inhibitors. ∆Np63 regulates a plethora of
different pathways and cellular processes, making it difficult to counteract its function by targeting
downstream effectors. As ∆Np63 is strongly regulated by the ubiquitin–proteasome system (UPS), the
development of deubiquitinating enzyme inhibitors has emerged as a promising therapeutic strategy to target
∆Np63 in SCC treatment.
This work involved identifying the first deubiquitinating enzyme that regulates ∆Np63 protein stability. Stateof-the-art SCC models were used to prove that USP28 deubiquitinates ∆Np63, regulates its protein stability,
and affects squamous transcriptional profiles in vivo and ex vivo. Accordingly, SCC depends on USP28 to
maintain essential levels of ∆Np63 protein abundance in tumor formation and maintenance. For the first time,
∆Np63, the transcription factor, was targeted in vivo using a small molecule inhibitor targeting the activity of
USP28. The pharmacological inhibition of USP28 was sufficient to hinder the growth of SCC tumors in
preclinical mouse models.
Finally, this work demonstrated that the combination of Cisplatin with USP28 inhibitors as a novel therapeutic
alternative could expand the limited available portfolio of SCC therapeutics. Collectively, the data presented
within this dissertation demonstrates that the inhibition of USP28 in SCC decreases ∆Np63 protein abundance,
thus downregulating the Fanconi anemia (FA) pathway and recombinational DNA repair. Accordingly, USP28
inhibition reduces the DNA damage response, thereby sensitizing SCC tumors to DNA damage therapies, such
as Cisplatin.
Use of polyhexanide and nanomedicine approach for effective treatments of cutaneous leishmaniasis
(2015)
Despite huge suffering caused by cutaneous leishmaniasis (CL), there is no effective and affordable treatment strategy against CL and no licensed vaccines. The current treatments show limited efficacy and high toxicity. Improved therapies through discovery of novel drugs and/or an alternative treatment approaches are/is urgently needed. We aimed at identifying a novel antileishmanial agent and developing an innovative nanoparticle (NP) based platform for safe and effective treatments against CL. We discovered that polyhexanide (PHMB), a widely used antimicrobial polymer and wound antisepsis, shows an inherent antileishmanial activity at submicromolar concentrations. PHMB appears to kill L. major parasites via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation. However, host chromosomes binding appear to be limited by exclusion from mammalian cell nuclei. Moreover, we attempted to establish effective drug delivery systems that overcome the various shortcomings in the present treatment of CL. In this scenario, we initially studied the cellular interactions of NPs and their uptake mechanisms into mammalian cells before applying them in drug delivery system. We obtained clear evidence for the involvement of multiple endocytic routes to internalize NPs. Physicochemical properties of NPs, cell type, temperature and pathogenesis of the target diseases were shown to be determinant factors. Thereafter, a mechanism based host- and pathogen-directed combination therapy comprising PHMB and CpG ODN immunomodulator was established for overall synergistic effect against CL. It simultaneously targets the pathogen and the host immunity with effective delivery system. The results show that PHMB binds to CpG ODN and form stable nanopolyplexes for efficient cell entry and therapy. The nanopolyplexes displayed enhanced cellular uptake and antileishmanial potency while drastically reducing the toxicity against mammalian cells. In conclusion, our findings clearly indicate that PHMB can be used as effective candidate drug against CL and as non-viral delivery of immunomodulatorynucleic acids. Moreover, our proof-of concept study showed nanomedicine approaches are effective strategy to challenge CL and other human diseases.
Kinasen der SRC-Familie (SFKs) sind sowohl in Wachstum und Metastasierung von Tumor- und Leukämiezellen als auch an prominenter Stelle in vielgestaltige Signalwege aller Immunzellen involviert. Eine Hemmung von SFKs ist damit ein vielversprechendes Mittel zur Therapie maligner Erkrankungen, kann aber darüber hinaus auch sehr effektiv zur Immunmodulation genutzt werden. Für den zur Therapie von CML und AML zugelassenen Tyrosinkinaseinhibitor (TKI) Dasatinib (Handelsname Sprycel®), für den unter anderem SFKs die Hauptziele darstellen, wurden, neben der antitumoralen Wirkung, sowohl immunsuppressive als auch immunstimulierende Effekte beschrieben. Aus diesem Grund könnte Dasatinib ein für die Modulation von Immunantworten sehr interessantes Hilfsmittel darstellen. In der vorliegenden Arbeit werden die hemmenden und fördernden Einflüsse von Dasatinib auf zwei Typen von Immunzellen genauer untersucht, um so die Auswirkungen einer Dasatinib-Behandlung auf Zellen des Immunsystems besser zu verstehen und sich das immunmodulatorische Potenzial von Dasatinib besser nutzbar machen zu können.
Der erste Teil der Arbeit beschäftigt sich mit der Untersuchung möglicher kombinatorischer Effekte zwischen Dasatinib und dem Glucocorticoid Dexamethason auf verschiedene Subsets von T-Zellen vor dem Hintergrund eines potentiellen Einsatzes der Kombination bei der allogenen Hämatopoetischen Stammzelltransplantation (HSCT) zur Separation von Graft-versus-Leukemia (GvL)-Effekten und der Graft-versus-host Disease (GvHD). Während keine kombinatorischen Effekte bei der Aktivierung von T-Zellen auftraten, ergaben sich bei der Untersuchung des Einflusses auf die Proliferation besonders in CD8+ T-Zellen additive Effekte durch die Kombination. Die Proliferation naiver T-Zell-Subsets wurde bereits durch die beiden Einzelsubstanzen alleine stark gehemmt. Dagegen waren Memory T-Zell-Subsets deutlich unempfindlicher, allerdings konnte durch eine Kombination von Dexamethason und Dasatinib auch die Proliferation dieser Memory Subsets effektiv gehemmt werden. Hierbei zeigten sich bei CD8+ Memory Subsets die deutlichsten synergistischen Effekte. Da eine Kombination in stärkerem Maße auch CD8+ gegenüber CD4+ Memory Subsets hemmt und diese Subsets unterschiedliche Rollen in der Induktion von GvL-Effekten und der Auslösung einer GvHD zu spielen scheinen, ist eine Steigerung der GvL-Effektivität durch die Medikamenten-Kombination bei gleichzeitiger Minimierung eines GvHD-Risikos in Zusammenhang mit anderen publizierten Ergebnissen durchaus denkbar. Weil eine starke Hemmung von virus-spezifischen T-Zellen nur bei sehr hohen Konzentrationen auftrat, ist zudem das Risiko einer Virus-Reaktivierung, die ein großes Problem bei einer HSCT darstellt, eher als gering einzuschätzen.
Der zweite Teil der Arbeit befasst sich mit dem Einfluss von Dasatinib auf aus Monozyten generierte Dendritische Zellen (moDCs) mit einem Fokus auf der Beeinflussung ihrer Migration. Während eine Behandlung mit Dasatinib nur sehr geringe Auswirkungen auf die Ausreifung der moDCs und die Expression von kostimulatorischen Molekülen hatte, führte eine Dasatinib-Behandlung zu einer Zeit- und Dosis-abhängigen Verringerung der Zytokinsekretion (IL-10 und IL-12). Im Gegensatz dazu hatte Dasatinib keinen Einfluss auf die phagozytotische Aktivität der moDCs und auf ihre Fähigkeit, Virus-spezifische T-Zell-Antworten auszulösen. Dasatinib zeigte dagegen einen deutlich steigernden Einfluss auf die Migration von moDCs gegen einen CCL19-Gradienten im Transwell-Assay, ohne die Expression des CCL19-Rezeptors CCR7 zu beeinflussen. Da ähnliche Migrations-steigernde Effekte auch bei einer Behandlung mit dem spezifischen SFK-Inhibitor SKI-1 auftraten, eine Behandlung mit Nilotinib, einem TKI der nicht auf SFKs wirkt, im Gegensatz dazu aber zu einer Hemmung der Migration führte, liegt es nahe dass die Migrations-steigernde Wirkung von Dasatinib über SFKs vermittelt wird. Dasatinib führte zu einer deutlichen Inhibierung der Phosphorylierung der inhibitorischen Immunrezeptoren Siglec-9 und Siglec-3 (CD33) ohne ihre Expressionslevel zu beeinflussen. Eine mit spezifischen Antikörpern durchgeführte Blockierung dieser Immunrezeptoren, deren ITIM-Domänen mutmaßlich von SFKs phosphoryliert werden, hatte eine deutliche Steigerung der Migration und eine verringerte Phosphorylierung von Siglec-9, Siglec-3 und SHP-2 zur Folge. Letztere ist eine Phosphatase, die nach Bindung an phosphorylierte ITIM-Domänen von Rezeptoren wie den Siglecs verschiedene Zielmoleküle dephosphoryliert. Die Ergebnisse dieser Arbeit legen nahe, dass die Migrations-steigernde Wirkung von Dasatinib über eine Hemmung von SFKs und daraus resultierend auf dem Wegfall eines inhibitorischen Signalwegs erfolgt. Diese Steigerung der Migration könnte in der Tumor-Therapie von großem Nutzen sein, da bei einer Vakzinierung mit autologen DCs, die mit Tumor-assoziierten Antigenen stimuliert wurden, die schlechte Einwanderung in die Lymphknoten eines der Hauptprobleme darstellt. Zur Überwindung dieses Problems könnte Dasatinib ein sehr effektives Hilfsmittel darstellen und die Therapie-Effizienz deutlich verbessern. Da Dasatinib aber auch eine ganze Reihe weiterer, sehr vielfältiger Einflüsse auf alle Arten von Immunzellen ausübt, scheint eine Verwendung spezifischer blockierender α-Siglec-Antikörper auf Grund geringerer Nebenwirkungen im Vergleich zu Dasatinib möglicherweise sogar noch deutlich besser geeignet zu sein, das Migrationsverhaltens Dendritischer Zellen positiv zu beeinflussen. Die Verwendung gegen Siglec-Rezeptoren gerichteter Antikörper als Adjuvantien könnte somit zu einem erfolgreicheren Einsatz der Vakzination mit Dendritischen Zellen in der Tumor-Therapie führen.
Die asexuellen Sporen von Aspergillus fumigatus sind ubiquitär verbreitete Luftkeime. Als Saprophyt ist dieser opportunistisch humanpathogene Pilz darauf spezialisiert, polymere Substanzen aus dem umgebenden Milieu zu zersetzen, um daraus die von ihm benötigten Nährstoffe zu generieren und aufzunehmen. Die Fähigkeit, verschiedene Stickstoff- und Kohlenstoffquellen zu verwerten, trägt dabei zu seiner Virulenz bei und hierbei scheint die extrazelluläre Proteolyse eine wichtige Rolle zu spielen. Sekretierte Proteasen, die das umgebende Gewebe während einer Infektion mit A. fumigatus erschließen, könnten somit zu dessen Pathogenität beitragen. Dementsprechend sollte im Rahmen dieser Arbeit die Bedeutung einer Regulation der extrazellulären proteolytischen Aktivität von A. fumigatus für dessen Virulenz untersucht werden. Dies geschah durch Untersuchungen eines konservierten Transkriptionsfaktors, PrtT. Dabei stellte sich heraus, dass PrtT die Expression der drei Hauptproteasen von A. fumigatus, Alp, Mep und Pep stark beeinflusst, in einem murinen Tiermodell der pulmonaren Aspergillose scheint dieser Regulator jedoch keine Rolle für die Pathogenität von A. fumigatus zu spielen. Um einen weiteren Aspekt des pilzlichen Aminosäurestoffwechsels zu beleuchten, wurde die Biosynthese der aromatischen Aminosäuren als mögliche Virulenzdeterminate untersucht. Für den Menschen sind diese Aminosäuren essentiell, weshalb dieser Syntheseweg ein mögliches Ziel für antimykotische Substanzen darstellen könnte. Es konnten mehrere für A. fumigatus essentielle Komponenten des Shikimatweges identifiziert werden, des Weiteren wurden Deletionsmutanten in den Genen aroC und trpA, die für die Chorismatmutase bzw. Anthranilatsynthase der Biosynthese von Phenylalanin und Tyrosin bzw. Tryptophan kodieren, erzeugt und phänotypisch charakterisiert. Deren Untersuchung in einem alternativen Tiermodell der Aspergillose zeigte eine deutlich attenuierte Virulenz. Diese Ergebnisse verdeutlichen, wie wichtig die Biosynthese der aromatischen Aminosäuren für das Wachstum von A. fumigatus ist, und dass ein Eingriff in diesen Syntheseweg eine lohnende Strategie zur Entwicklung neuer Antimykotika sein könnte. Die hier präsentierten Ergebnisse unterstreichen die für den Schimmelpilz A. fumigatus typische Redundanz bezüglich extrazellulärer proteolytischer Enzyme und dass diese nur bedingt hinsichtlich ihres Virulenzbeitrags untersucht werden können. Im Gegensatz hierzu lassen sich bestimmte Stoffwechselwege, die oftmals durch einzigartige Genprodukte katalysiert werden, unter Umständen besser als unspezifische aber vielversprechende Virulenzdeterminanten identifizieren.
Das Schädel-Hirn-Trauma (SHT) entsteht durch äußere Gewalteinwirkung auf den Kopf und verursacht mechanisch eine Schädigung des Hirngewebes. Zusätzlich tragen sekundäre Pathomechanismen, wie Entzündungsprozesse und die Schädigung der Blut-Hirn-Schranke (BHS), dazu bei, dass sich das initial geschädigte Läsionsareal im Laufe der Zeit vergrößert. Vor allem bei jungen Erwachsenen ist das SHT eine der häufigsten Ursachen für bleibende Behinderungen und Todesfälle. Aufgrund der schweren Auswirkungen des SHT und der bislang fehlenden Therapieoptionen ist die Identifizierung neuer Zielstrukturen für eine kausale Therapie von größter Bedeutung. Ausgehend von tierexperimentellen Studien ist das Kallikrein-Kinin-System (KKS) ein besonders erfolgversprechender Angriffspunkt zur Behandlung des SHT. Die Aktivierung des KKS über den Gerinnungsfaktor XII (FXII) und die darauf folgende Bildung von Bradykinin sind mit dem Entstehen von Hirnödemen und Entzündungsreaktionen assoziiert. Vorangegangene Studien haben weiterhin die Frage aufgeworfen, ob und in welchem Maße thrombotische Prozesse einen Einfluss auf die Pathophysiologie und die sekundären Hirnschädigungen nach SHT haben. Da FXII sowohl das KKS als auch die intrinsische plasmatische Gerinnungskaskade initiiert und somit zur Fibrinbildung beiträgt, stand FXII im Mittelpunkt der Untersuchungen dieser Dissertation. Die vorliegende Arbeit beschäftigt sich mit den Fragen, (I) inwiefern FXII eine Rolle bei der sekundären Hirnschädigung nach Trauma spielt und (II) ob thrombotische Prozesse ein pathophysiologisches Merkmal nach Trauma darstellen. In zwei unterschiedlichen Trauma-Modellen wurden FXII-defiziente Tiere und mit einem spezifischen Inhibitor des aktivierten FXII (FXIIa) behandelte Tiere gegen Kontrolltiere nach SHT verglichen. Die Analyse der funktionellen Ausfallerscheinungen und des Ausmaßes an neuronaler Degeneration zeigte, dass FXII-Defizienz und FXIIa-Inhibition vor den Auswirkungen eines SHT schützen. Als zugrundeliegende Mechanismen wurden die Reduktion von thrombotisch verschlossenen Gefäßen in der Mikrovaskulatur des Gehirns sowie der Schutz vor BHS-Störungen und verringerte inflammatorische Prozesse identifiziert. Weiterhin wurde festgestellt, dass eine Blockade der intrinsischen Gerinnungskaskade über FXII keine intrazerebralen Blutungen auslöst. In Gewebeproben von Patienten mit SHT wurde gezeigt, dass Thrombozytenaggregate auch im klinischen Verlauf auftreten und sich somit die tierexperimentellen Befunde auf die humane Situation übertragen lassen. Insgesamt tragen die Ergebnisse dazu bei, die komplexen und vielfältigen Pathomechanismen nach SHT besser zu verstehen und vor allem die Relevanz thrombo-inflammatorischer Prozesse nach SHT aufzuzeigen. Die gezielte Blockade des FXII(a) könnte als therapeutisches Prinzip zur Abschwächung der Sekundärschaden nach SHT geeignet sein.
Die Regulation des Tonus glatter Muskelzellen wird entscheidend von den beiden antagonistisch wirkenden second messengern cAMP und Ca2+ beeinflusst. Ein Ziel dieser Arbeit war herauszufinden, ob diese beiden Botenstoffe auch direkten Einfluss aufeinander haben können und welche Enzyme in diesem Fall an den Prozessen beteiligt sind. cAMP-Signale in intakten Zellen konnten wir in Echtzeit mit Hilfe des FRET-basierten cAMP-Sensors Epac1-camps beobachten; Ca2+-Signale durch Markieren der Zellen mit Fura-2. Anstiege der intrazellulären Ca2+-Konzentration in VSMCs wurden durch Aktivierung von endogen exprimierten, Gq-gekoppelten P2Y6-Rezeptoren mit Uridindiphosphat (UDP) ausgelöst. Durch eine zusätzliche in-vitro Kalibrierung des Epac1-camps konnten darüber hinaus absolute cAMP-Konzentrationen in einzelnen lebenden Zellen berechnet werden. Während ein Anstieg der Ca2+-Konzentration auf nicht vorstimulierte VSMCs keinen signifikante Einfluss auf die intrazellulären cAMP-Konzentrationen hatte, bewirkte die Aktivierung der purinergen Rezeptoren einen deutlichen Rückgang der intrazellulären cAMP-Konzentration in mit Isoproterenol vorstimulierten VSMCs. Dieser Effekt konnte sowohl durch die Komplexierung von Ca2+ mit BAPTA-AM als auch durch die Überexpression der Ca2+-insensitiven AC4 antagonisiert werden. Adenylatcyclase-Aktivitäts-Assays in VSMC-Membranen zeigten ebenfalls einen Rückgang der Cyclaseaktivität nach Zugabe von 2 und 5 μM freiem Ca2+. Die Hemmung der einzigen Ca2+-regulierbaren PDE1 mit dem selektiven PDE1-Inhibitor 8-Methoxymethyl-IBMX (8-MM-IBMX) hatte im Gegensatz dazu keinen Einfluss auf die durch UDP verursachte Änderung der cAMP-Konzentration in vorstimulierten VSMCs. Schließlich bewirkte die Herunterregulation der Ca2+-inhibierbaren AC5 und 6 mit siRNA einen signifikante Hemmung des durch UDP verursachten Effekts. Fasst man alle diese Ergebnisse zusammen, so lässt sich folgende Schlussfolgerung ziehen: Der durch purinerge Stimulation verursachte Rückgang der cAMP-Konzentration in mit Isoproterenol vorstimulierten VSMCs wird durch eine Hemmung der Ca2+-hemmbaren AC5 und 6 vermittelt. Dadurch sind zwei für die Regulation des Tonus wichtige Signalwege in VSMCs miteinander verbunden, die sich somit gegenseitig entscheidend beeinflussen können. Ein weiterer Bestandteil dieser Arbeit war die Entwicklung eines transgenen Mausmodells, das glattmuskelspezifisch den cAMP-Sensor Epac1-camps exprimiert. Mit Hilfe eines solchen Tiermodells könnten in Zukunft cAMP-Änderungen in intakten Geweben und vielleicht sogar in lebenden Tieren beobachtet werden. Durch Anwendung des Cre-loxP-Rekombinationssystems gelang es eine glatt¬muskelspezifische, für den Epac1-camps transgene Mauslinie zu generieren. Mit isolierten VSMCs dieser Tiere konnten bereits erste FRET-Messungen durchgeführt und agonistinduzierte cAMP-Änderungen beobachtet werden.
Ein Schlüsselereignis, welches dem prognosebestimmenden Organversagen bei systemi-schen Entzündungsprozessen und Sepsis vorangeht, ist die Entwicklung einer mikrovas-kulären endothelialen Schrankenstörung. Das vaskuläre endotheliale (VE-) Cadherin als mechanischer Stabilisator der Endothelbarriere spielt dabei eine wichtige Rolle. In der Inflammation werden Spaltprodukte von VE-Cadherin (sVE-Cadherin) gebildet. Ge-genstand der vorliegenden Arbeit war die Untersuchung der Hypothese ob diese Spalt-produkte selbst an der Störung der endothelialen Barrierefunktion beteiligt sind.
Es wurde hierfür humanes sVE-Cadherin bestehend aus den extrazellulären Domänen EC1-5 (sVE-CadherinEC1-5) generiert. In Messungen des transendothelialen elektrischen Widerstands (TER), mit Immunfluoreszenzfärbungen und Western Blot Analysen wird gezeigt, dass sVE-Cadherin dosisabhängig die Barriere Integrität in primären humanen dermalen Endothelzellen stört. Dies führt zu einer Reduktion von VE-Cadherin und den assoziierten Proteinen α-, γ- und δ-Catenin und ZO-1, die nach der Applikation von sVE-Cadherin an den Zellgrenzen reduziert sind. Die Interaktion zwischen VE-PTP und VE-Cadherin wird durch sVE-CadherinEC1-5 reduziert. Durch pharmakologische Hem-mung der Phosphataseaktivität von VE-PTP mittels AKB9778 wird der durch sVE-CadherinEC1-5-induzierte Verlust der Endothelbarriere aufgehoben. Dagegen zeigt die direkte Aktivierung von Tie-2 mittels Angiopoetin-1 keinen protektiven Effekt auf die durch sVE-CadherinEC1-5 gestörte Endothelbarriere. Weitere Analysen zeigen eine erhöh-te Expression von GEF-H1 durch sVE-CadherinEC1-5. Diese ist ebenfalls durch AKB9778 hemmbar.
Zusätzlich zu diesen Untersuchungen wurden die Konstrukte EC1-4 und EC3-5 in ver-schiedene Vektoren kloniert, um zu bestimmen, ob die extrazelluläre Domäne 5 von VE-Cadherin die dominante Rolle bei den sVE-Cadherin-vermittelten Effekten spielt.
Zusammenfassend zeigen diese Untersuchungen zum ersten Mal, dass sVE-CadherinEC1-5 unabhängig von proinflammatorischen Auslösern über die Aktivierung des VE-PTP/RhoA-Signalweges den Zusammenbruch der Endothelbarriere mitversursacht. Dies stellt einen neuen pathophysiologischer Mechanismus dar, der zum Gesamtverständnis der entzündungsinduzierten Barriereveränderungen des Endothels beiträgt.
Das Ziel der Arbeit war zu untersuchen, ob der Stoffwechsel kolorektaler Karzi-nomzellen geeignete Targetstrukturen für mögliche therapeutische Ansätze aufweist. In Krebszellen induziert sowohl der Warburg-Effekt bei Normoxie als auch die anaerobe Glykolyse bei Hypoxie eine massive Bildung von Laktat. Wird die Krebszelle dauerhaft daran gehindert, die für die Glykolyse notwendi-gen Reduktionsäquivalente NADH+H+ mit Hilfe der Laktatdehydrogenase zu reoxidieren und/oder Laktat über die Transporter MCT1 und MCT4 nach außen zu schleusen, dann löst diese Kombination aus Mangelsituation und intrazellulärer Ansäuerung den apoptotischen Zelltod aus. Für die Situation in vivo ist entscheidend, dass auch Zellen von Normalgeweben zwar Laktat in Hypoxie bilden, dies jedoch keine vorherrschende physiologische Situation darstellt.
Die Hemmstoffe Natriumoxamat (NaOx) für die Laktatdehydrogenase und α-Cyano-4-Hydroxycinnamat (αCHC) für MCT1 und MCT4 wurden an den sechs humanen kolorektalen Karzinomzelllinien Colo741, HCT116, HT29, LS174T, SW620 und WiDr untersucht. Zusätzlich wurde der Glukoseverbrauch und die Laktatbildung bestimmt und die Funktion der Atmungskette überprüft. Die IC50-Werte für 5-FU, NaOx und αCHC wurden bestimmt und danach NaOx in einer Konzentration von 40x10-3 mol/L, αCHC in einer Konzentration von 2x10-3 mol/L und 5-FU in einer Konzentration von 5x10-6 mol/L eingesetzt. Die Zellen wurden bei tumorphysiologischen Sauerstoffkonzentrationen von 5 % und 1 % Sauerstoff für bis zu 120 Stunden inkubiert.
Die Funktion der Atmungskette in den Mitochondrien der kolorektalen Karzi-nomzellen wurde u. a. durch Bestimmung wichtiger Kenngrößen wie dem P:O Quotienten und des respiratorischen Kontrollindex (RKI) nachgewiesen. Fünf der sechs Karzinomzelllinien wiesen im Vergleich zur Kontrollzelllinie J774 einen verringerten P:O-Quotienten und respiratorischen Kontrollindex (RKI) auf, was darauf hindeutet, dass die Funktion der Mitochondrien dieser Zellen im Vergleich zu Kontrollzellen zwar verringert war, aber nicht vollständig aufgehoben. Dieses Ergebnis stützt die allgemein akzeptierte Auffassung, dass die meisten Tumore über funktionelle Mitochondrien verfügen.
Durch die Analyse des Glukosestoffwechsels wurden die sechs kolorektalen Zelllinien, die einen unterschiedlich stark ausgeprägten glykolytischen Phänotyp aufwiesen, nach der Stärke der Laktatbildung bei 5 % Sauerstoff in drei Kategorien eingeordnet. Zudem wurde für jede der sechs Zelllinien die Expression von LDH-A, LDH-B sowie MCT-1 und MCT-4 auf Proteinebene nachgewiesen.
Wesentliches Ziel der Untersuchungen war die Überprüfung des antiprolife-rativen Potentials der beiden Inhibitoren NaOx und αCHC einzeln oder in Kombination mit 5-FU bei den tumorspezifischen Sauerstoffkonzentrationen von 5 % und 1 %. Die Kombination aus NaOx und αCHC induzierte bei 1 % Sauerstoff nach 9 Tagen in Kultur zytotoxische Effekte und war damit so wirksam wie 5x10-6 mol/L 5-FU. Die Zugabe von 5-FU zur Kombination aus NaOx und αCHC führte zu keiner Steigerung des zelltoxischen Effektes. Die beiden Inhibitoren NaOx und αCHC waren für SW620 Zellen weniger wirksam als für Zellen der anderen fünf Zelllinien. Das mehr „oxidative“ Profil von SW620 Zellen (bester P:O-Quotient, geringste Laktatbildung bei 5 % und 1 % Sauerstoff; zudem die höchsten IC50-Werte für NaOx und αCHC) könnte erklären, warum die beiden Stoffwechselinhibitoren, die einen glykolytischen Phänotyp (starke Bildung von Laktat) erfordern, für SW620 Zellen von geringerer Wirksamkeit waren.
Für die Hemmstoffe NaOx und αCHC wurden zytostatische bzw. zytotoxische Effekte in kolorektalen Karzinomzellen gezeigt. Dies deutet darauf hin, dass Krebszellen auf einen ungehinderten glykolytischen Stoffwechsel angewiesen sind. Für beide Hemmstoffe wurde ebenfalls gezeigt, dass sie auch bei tumorre-levanten Sauerstoffkonzentrationen von 5 % und 1 % wirksam sind.
Beim ischämischen Schlaganfall führt ein thrombotischer Verschluss von gehirnversorgenden Arterien zu einer akuten Durchblutungsstörung, mit der Folge von neurologischen Defiziten. Primäres Therapieziel ist es, diese Blutgerinnsel aufzulösen, um die Sauerstoffversorgung des Gehirns wiederherzustellen und den ischämischen Hirnschaden zu begrenzen. Dazu stehen die intravenösen Thrombolyse mit rt-PA (rekombinanter Gewebe-Plasminogen-Aktivator) sowie die endovaskuläre mechanische Thrombektomie zur Verfügung. Häufig kann ein Schlaganfall, trotz erfolgreicher Rekanalisation der Gefäße, zu einer weiteren Größenzunahme des Infarktes und neurologischen Defiziten bei den Patienten führen. Diese Größenzunahme beruht zum einen auf einem sich entwickelnden Hirnödem und zum anderen auf entzündlichen Prozessen. Zahlreiche Hinweise deuten darauf hin, dass der Schlaganfall ein Zusammenspiel aus thrombotischen und entzündlichen Ereignissen ist, ein Phänomen, das als Thromboinflammation bezeichnet wird. Aufgrund der begrenzten Behandlungsmöglichkeiten ist die Entwicklung neuer Therapieansätze für den ischämischen Schlaganfall besonders wichtig. Agaphelin und Ixolaris sind Proteine aus den Speicheldrüsen von Hämatophagen, für welche in früheren Studien eine starke antithrombotische Wirkung bei gleichzeitig geringem Blutungsrisiko nachgewiesen wurde. Diese möglichen antithrombotischen Effekte wurden in dieser Studie im Hinblick auf ihre Wirksamkeit und Sicherheit im Mausmodell der zerebralen Ischämie untersucht. Die Behandlung der Mäuse mit Agaphelin 1 Stunde nach transienter Okklusion der Arteria cerebri media (tMCAO) führte zu kleineren Schlaganfallvolumina und geringeren neurologischen Defiziten an Tag 1 nach dem Schlaganfall. Die Mortalität der Mäuse war bis Tag 7 deutlich gesunken. Aus klinischer Sicht ist ebenfalls relevant, dass der starke antithrombotische Effekt von Agaphelin im Mausmodell nicht mit einem erhöhten Risiko für intrazerebrale Blutungen einherging. Diesem protektiven Effekt von Agaphelin lagen eine verminderte intrazerebrale Thrombusbildung, eine abgeschwächte Entzündungsantwort und eine Stabilisierung der Blut-Hirn-Schranke sowie eine Reduzierung der Apoptose zugrunde. Nach der Gabe von Ixolaris 1 Stunde nach tMCAO waren zwar signifikant geringere Infarktgrößen messbar, diese führten allerdings nicht zu einer Verbesserung der neurologischen Defizite. Zudem verursachte die Gabe von Ixolaris schon 24 Stunden nach tMCAO erhebliche intrazerebrale Blutungen und auch die Mortalität der Mäuse war zu diesem Zeitpunkt bereits erhöht. Aufgrund dieser massiven Nebenwirkungen scheint Ixolaris kein geeigneter Kandidat für eine humane Anwendung zu sein. Bei Agaphelin hingegen könnte es
sich um einen vielversprechenden Kandidaten für die Behandlung des ischämischen Schlaganfalls handeln. Vor einer möglichen Testung von Agaphelin in klinischen Studien, sind weitere translationale Untersuchungen notwendig, um ein noch präziseres Verständnis für die Wirksamkeit und Sicherheit von Agaphelin zu gewinnen. Insgesamt stellt die Hemmung thromboinflammatorischer Prozesse, ohne eine Erhöhung der Blutungskomplikationen, eine vielversprechende Option zur Behandlung des ischämischen Schlaganfalls dar.
In dieser Arbeit wurden Einzelmolekültechniken zur Untersuchung von G-Protein-gekoppelten Rezeptoren (GPCR) und G-Proteinen in der Zellmembran lebender Zellen etabliert und angewendet. GPCR stellen die größte Familie membrangebundener Rezeptoren dar und leiten Signale über heterotrimere G-Proteine in das Zellinnere weiter. Auch wenn jüngst sowohl inaktive, als auch aktive Konformationen von GPCR und G-Proteinen mittels Röntgenstrukturanalyse aufgelöst werden konnten, sind die Dynamiken ihrer Aktivierung und Deaktivierung bisher nur bruchstückhaft bekannt. In der Vergangenheit wurden die Schritte der Signalkaskade, beginnend mit der Bindung des Rezeptorliganden bis hin zur Bildung von sekundären Botenstoffen, erfolgreich mit Fluoreszenz-Resonanz-Energie-Transfer-Techniken aufgeklärt. Diesen experimentell bestimmten Aktivierungszeiten stehen Daten aus Modellierungsstudien gegenüber, die sehr viel schnellere Konformationsänderungen vorhersagen, welche bereits in Studien mittels Kernspinresonanzspektroskopie nachgewiesen werden konnten. Folglich ist anzunehmen, dass die Zeitdomäne, innerhalb der die Aktivierung der GPCR stattfindet, sehr breit gefächert ist.
Ein Ziel der vorliegenden Arbeit war es, diese mehrere Größenordnungen umfassenden Zeitskalen der GPCR-Aktivierung, welche in der Literatur beschrieben werden, mittels bildgebender Einzelmolekülverfolgung (SPT) und Fluoreszenz-Korrelations-Spektroskopie (FCS) zu untersuchen. Beide Verfahren liefern durch Einzelmolekülspuren oder Korrelationskurven eine Art Fingerabdruck des dynamischen Verhaltens des untersuchten Systems, was jeweils mit Vor- und Nachteilen verbunden ist. Die Stärke der Techniken zeigte sich bei dem vorliegenden Projekt vor allem in ihrer Kombination: Die klassische FCS bietet die Möglichkeit, Dynamiken über einen weiten Zeitraum von Mikrosekunden bis Sekunden auszuwerten, allerdings nur innerhalb eines kleinen, optisch definierten Detektionsvolumens. Die bildgebende Einzelmolekülverfolgung liefert hingegen ein großes Sichtfeld und ermöglicht somit die parallele Analyse vieler Einzelmolekülereignisse über die Zelle verteilt, jedoch auf Kosten der Zeitauflösung.
Durch die Anwendung von SPT und FCS konnte in dieser Arbeit ein Zeitbereich der Rezeptor- (und G-Protein-) Dynamiken von Mikrosekunden bis Sekunden gefunden und diskutiert werden. Um die selektive Anregung der Plasmamembran zu gewährleisten, wurde die Interne Totalreflexionsfluoreszenzanregung verwendet. Diese eignet sich ideal als Grundlage für die spätere Analyse mittels SPT und FCS, welche komplementär nutzbar sind und mit dem gleichen zellulären Assay und unter Verwendung der gleichen Fluoreszenzmarker betrieben werden können.
Die Studie am Beispiel der α2A- und β2-adrenergen Rezeptoren sowie des Gαi1-Proteins demonstrierte das enorme Potential dieser Einzelmolekültechniken für die Untersuchung von GPCR und skizziert die Komplexität deren Dynamik, wie sie auch durch neueste Modellierungsstudien vorhergesagt wird.
Neuronale Stammzellen wurden kürzlich im unteren Colliculus inferior (CI) identifiziert. Diese Zellen sind von besonderem Interesse, da es keine therapeutischen Optionen für geschädigte neuronale Strukturen gibt. Ziel dieses Forschungsprojekts ist es, das neurogene Potenzial im CI der Ratte von den ersten postnatalen Tagen bis zum Erwachsenenalter zu untersuchen. Der CI von Ratten vom 6. bis zum 48. postnatalen Tag wurde mit Neurosphären-Assays und histologischen Schnitten untersucht. In frei schwimmenden CI-Zellkulturen bildeten sich Neurosphären bei Tieren vom frühen postnatalen Alter bis zum Erwachsenenalter. Die Menge der gebildeten Neurosphären nahm im höheren Alter ab und stieg mit der Anzahl der Zelllinienpassagen. Die Zellen in den Neurosphären und die histologischen Schnitte zeigten eine positive Färbung mit neuronalen Stammzell-Markern (Doublecortin, Sox-2, Musashi-1, Nestin und Atoh1). Dissoziierte Einzelzellen aus den Neurosphären differenzierten und wurden positiv für die neuralen Abstammungsmarker β-III-Tubulin, GFAP und MBP angefärbt. Darüber hinaus wurden neuronalen Stammzell-Marker (Doublecortin, Sox-2, CDK5R1 und Ascl-1) mittels qRT-PCR untersucht. Zusammenfassend lässt sich sagen, dass ein neurogenes Potenzial im CI der Ratte von den frühen postnatalen Tagen bis zum Erwachsenenalter nachgewiesen und bewertet wurde. Die Identifizierung von neuronalen Stammzellen im CI der Ratte und ihre altersspezifischen Merkmale tragen zu einem besseren Verständnis der Entwicklung und der Plastizität der Hörbahn bei und könnten für eine therapeutische Nutzung aktiviert werden.
Untersuchung der Rolle von Rhodopsin 7 und Cryptochrom im Sehprozess von Drosophila melanogaster
(2015)
Ausgangspunkt für die Detektion von Licht ist im gesamten Tierreich die Absorption von Photonen durch photorezeptive Proteine, die sogenannten Opsine und in geringerem Ausmaß die Typ 1 Cryptochrome. Die Taufliege Drosophila melanogaster besitzt sechs eingehend charakterisierte, auch als Rhodopsine bezeichnete Opsine (Rh1-Rh6) und ein Cryptochrom (CRY). Neben den Ocellen und den Hofbauer-Buchner Äuglein werden die Rhodopsine in erster Linie in den Photorezeptorzellen der Komplexaugen, den Hauptorganen der Lichtperzeption exprimiert, wo sie der Vermittlung der visuellen Wahrnehmung dienen. Basierend auf Sequenzvergleichen wurde im Jahr 2000 ein neues Protein namens Rh7 zur Gruppe der Drosophila Opsine hinzugefügt. Bis heute fehlt allerdings jeglicher experimentelle Beleg für die photorezeptive Funktion dieses Proteins.
Im Gegensatz dazu wird Cryptochrom in erster Linie in einigen Uhrneuronen des Drosophila Gehirns exprimiert, wo es diesen Neuronen die Fähigkeit zur Lichtdetektion verleiht und das Photoentrainment der inneren Uhr lenkt. Neueren Untersuchungen zu folge spielt CRY allerdings auch bei der visuellen Wahrnehmung der Augen eine Rolle.
Die vorliegende Arbeit zielte nun darauf ab die potentielle Funktion von Rh7 als neuen Photorezeptor in Drosophila sowie die Rolle von CRY bei der visuellen Lichtperzeption zu untersuchen.
Die Aufnahmen der Elektroretinogramme (ERGs) von transgenen Fliegen, die Rh7 anstelle von oder zusammen mit dem dominanten Photorezeptor Rh1 in den Komplexaugen exprimieren, zeigen, dass Rh7 die Phototransduktionskaskade bei Belichtung mit Weißlicht nicht aktivieren kann. Die Abwesenheit von Rh7 sorgt allerdings trotzdem für eine Beeinträchtigung der lichtinduzierten Antwort der Rezeptorzellen im Komplexauge. So zeigen die Intensitäts-Response Kurven der ERG Rezeptorpotentialamplitude von rh7 Knockout-Fliegen unter Weißlicht niedriger und mittlerer Intensität nach einer anfänglichen Dunkeladaptation von 15min eine insgesamt, im Vergleich zur Kontrolle erhöhte Rezeptorpotentialamplitude. Der Verlauf dieser Kurven deutet außerdem darauf hin, dass die Zunahme der Rezeptorpotentialamplitude mit steigender Lichtintensität größer wird. Zudem
zeigt das Aktionsspektrum für die Rezeptorpotentialamplitude der rh7 Knockout-Fliegen, dass diese Empfindlichkeitszunahme im gesamten Bereich von 370-648nm auftritt. Diese Beeinträchtigung scheint jedoch zu fehlen, wenn die Fliegen vor Experimentbeginn nur 1min dunkeladaptiert wurden, oder wenn intensives Blaulicht zur Belichtung verwendet wird. Des weiteren ist auch das 4s nach Ende des Lichtpulses im ERG gemessene Nachpotential bei fehlendem Rh7 reduziert.
Zusammengenommen deuten diese Ergebnisse darauf hin, dass Rh7, wenn auch nicht als Photorezeptor, bei Belichtung mit Weißlicht niedriger und mittlerer Intensität die Lichtantwort in den Rezeptorzellen des Komplexauges in Abhängigkeit von Intensität und Adaptationszustand beeinflusst und dass dieser Einfluss scheinbar nicht durch Licht eines eng begrenzten Wellenlängenbereichs induziert wird. Des weiteren legt die Untersuchung des ERG Nachpotentials nahe, dass Rh7 möglicherweise für eine normale Beendigung der Lichtantwort benötigt wird. Die allgemeine Funktion von Rh7 als Photorezeptor in Drosophila sowie die Eigenschaften der endogenen Funktion von Rh7 werden diskutiert.
Unabhängig davon wird in der vorliegenden Arbeit auch gezeigt, dass Fliegen ohne CRY zwar nach 15-minütiger, nicht jedoch nach 1-minütiger Dunkeladaptation bei Belichtung mit Weißlicht niedriger Intensität eine insgesamt geringere ERG Rezeptorpotentialamplitude aufweisen. Dies könnte auf eine Beeinträchtigung der Dunkeladaptationsprozesse bei Abwesenheit von CRY hindeuten.
Bei der Atherosklerose handelt es sich um eine chronische inflammatorische Erkrankung, die sich an der arteriellen Gefäßinnenwand abspielt. Ihre Haupt-Manifestationsformen Schlaganfall und Herzinfarkt zählen zu den häufigsten Todesursachen weltweit. Eine chronische Endothelbelastung und -funktionsstörung, beeinflusst durch Risikofaktoren wie Diabetes, arterieller Bluthochdruck, Rauchen und Entzündungszustände, führen zur Permeabilitätserhöhung des Endothels, zur Zelleinwanderung, subendothelialen Lipidanreicherung, Migration glatter Muskelzellen und der Ausbildung atherosklerotischer Läsionen. Es kommt zu Aktivierung des Immunsystems und fortschreitender Entzündungsreaktion, schließlich zur Ausbildung eines nekrotischen Kerns und zunehmender Vulnerabilität des Plaques.
Epigenetische Veränderungen betreffen klassischerweise das Chromatingerüst. Durch DNA-Methylierung und -Demethylierung sowie verschiedene Modifikationen der Histon-Proteine kann die DNA in ihrer Zugänglichkeit verändert werden. So kann die Transkription eines bestimmten Genes direkt und potenziell längerfristig beeinflusst werden, ohne dass Alterationen der DNA-Basenfolge selbst stattfinden. Das Enzym SET7 nimmt hierbei eine Sonderrolle ein, da es neben einer Methylierung von Histon 3 auch verschiedene zelluläre Zielstrukturen posttranslational direkt methylieren kann.
Epigenetische Veränderungen im Kontext der Atherosklerose sind bereits vereinzelt beschrieben. Auch sind sie relevant in der Reaktion auf Umwelteinflüsse und bei inflammatorischen Vorgängen. Der Frage, ob epigenetische Mechanismen im atherosklerotischen Geschehen eine Rolle spielen, sollte in dieser Arbeit nachgegangen werden. Dazu wurde in Zellkulturversuchen für Makrophagen und glatte Muskelzellen geprüft, ob die einzelnen pro-atherosklerotischen Stimuli oxLDL, IL-1β, TNFα und LPS bereits zu relevanten Veränderungen epigenetischer Enzyme führen. Dies erfolgte über Vergleich der entsprechenden mRNA mittels qPCR. Zur Untersuchung der genaueren Dynamik wurde für die Enzyme SET7 und DNMT1 der zeitliche Ablauf dieser Reaktion auf TNFα-Stimulation in Makrophagen genauer betrachtet. Unter gleichen Versuchsbedingungen wurde außerdem die Änderung der mRNA-Expression einiger Matrixmetalloproteasen, TIMP-Enzyme, Zytokine und Transkriptionsfaktoren analysiert,um zukünftig kausale Zusammenhänge weiter aufdecken zu können. Auch die Frage nach Veränderungen epigenetischer Enzyme in der Ldlr-/--Maus nach fettreicher Diät im Vergleich zu Ldlr-/--Mäusen ohne Diät sollte hier beantwortet werden. Dazu wurde die mRNA der Zellsuspensionen aus Milz, Aortenwurzel und gesamter Aorta der Tiere mithilfe der qPCR verglichen. Schließlich sollte ein effizienter Weg für einen individuellen und flexiblen SET7 knock-out etabliert werden, um weitere Studien dieses Enzyms zu ermöglichen. Hierzu wurde die Methode des CRISPR/Cas9 Systems gewählt und abschließend die Funktionalität des Systems überprüft.
Unterschiede in Frontaler Kortex Oxygenierung in zweierlei Risikogruppen der Alzheimer Demenz
(2019)
Die verbesserte medizinische Versorgung führt zu einer zunehmenden Lebenserwartung unserer Gesellschaft. Damit steigt auch die sozioökonomische Relevanz neurodegenerativer Erkrankungen kontinuierlich. Für die Alzheimer Demenz (AD), die dabei die häufigste Ursache darstellt, stehen bisher keine krankheitsmodifizierenden Behandlungsoptionen zur Verfügung. Die lange präklinische Phase der Erkrankung birgt jedoch großes Potential für die Entwicklung neuer Behandlungsoptionen. Das Untersuchen von Risikogruppen ist für die Identifikation von Prädiktoren einer späteren AD Manifestation von besonderem Interesse. In diesem Zusammenhang werden insbesondere das Vorliegen genetischer Risikokonstellationen, wie dem Apolipoprotein E (APOE) Ɛ4-Allel, sowie kognitiver Risikofaktoren, wie der „leichten kognitiven Beeinträchtigung“ (MCI), diskutiert. Die Identifikation präklinischer Aktivierungsunterschiede in relevanten Gehirnregionen von Risikogruppen kann als Basis für die Entwicklung neurofunktioneller Früherkennungs-Marker dienen. Der präfrontale Kortex (PFC), welcher mit der Steuerung von Exekutivfunktionen assoziiert wird, hat sich in diesem Zusammenhang in bisherigen Studien als eine relevante Schlüsselregion manifestiert. Aufgrund der aufwendigen und kostenintensiven bildgebenden Untersuchungsmethoden, sind die genauen Prozesse jedoch noch unklar.
Ziel der vorliegenden Arbeit war es daher, Unterschiede in der PFC Oxygenierung in zweierlei Risikogruppen der AD mit einer kostengünstigeren Bildgebungsmethode, der funktionellen Nahinfrarot Spektroskopie (fNIRS), zu untersuchen. Dafür wurde in einem ersten Schritt, der Trailmaking Test (TMT), ein weitverbreiteter neuropsychologischer Test zur Erfassung exekutiver Funktionen, für fNIRS implementiert. Als Grundlage für die Untersuchung frühpathologischer Prozesse, wurden zunächst gesunde Alterungsprozesse betrachtet. Der Vergleich von jungen und älteren Probanden (n = 20 pro Gruppe) wies neben der Eignung der Testimplementierung für fNIRS auf eine spezifische bilaterale PFC Oxygenierung hin, welche bei jungen Probanden rechtshemisphärisch lateralisiert war. Ältere Probanden hingegen zeigten bei vergleichbaren Verhaltensdaten insgesamt mehr signifikante Kanäle sowie eine Abnahme der Lateralisierung. Dies kann als zusätzlicher Bedarf an Ressourcen in gesunden Alterungsprozessen interpretiert werden.
Im Rahmen der Hauptstudie wurden anschließend insgesamt 604 ältere Probanden im Alter von 70 bis 76 Jahren untersucht. Zunächst wurde die genetische Risikogruppe der Ɛ4-Allel-Träger (n = 78) mit den neutralen Ɛ3-Allel-Trägern (n = 216) und den Trägern des als protektiv geltenden Ɛ2-Allels (n = 50) verglichen. Hierbei zeigte sich eine geringere Oxygenierung der Risikogruppe bei geringer Aufgabenschwierigkeit, während sich ein erhöhter Oxygenierungsanstieg im medialen PFC mit steigender Aufgabenschwierigkeit zeigte. Dies deutet auf einen erhöhten Bedarf an neuronalen Kontrollmechanismen der Risikogruppe zur Bewältigung der steigenden Aufgabenschwierigkeit hin. Die protektive Gruppe zeigte hingegen eine erhöhte Oxygenierung im ventralen PFC mit steigender Aufgabenschwierigkeit, was möglicherweise auf einen präventiven Effekt hindeuten könnte.
Weiterführend wurden MCI-Patienten mit gesunden Probanden (n = 57 pro Gruppe) hinsichtlich des kognitiven Risikofaktors verglichen. Hierbei zeigte sich ein punktuell reduzierter Oxygenierunganstieg der MCI Patienten mit steigender Aufgabenschwierigkeit vor allem im ventralen PFC bei ebenfalls stabiler Verhaltensleistung. Die gefundene Reduktion könnte ein Zeichen für eine aufgebrauchte kognitive Reserve sein, welche Einbußen auf Verhaltensebene voranzugehen scheint.
Diese charakteristischen Unterschiede in den frontalen Oxygenierungsmustern von Risikogruppen (APOE, MCI) könnten als Biomarker zur Früherkennung von AD noch vor dem Auftreten kognitiver Einbußen dienen. Die fNIRS-Untersuchung während der Durchführung des TMT hat sich in diesem Zusammenhang als potentielles Instrument zur Frühdiagnose der präklinischen Phase der AD als geeignet erwiesen. Die Ergebnisse werden unter Einbezug des wissenschaftlichen Kontexts interpretiert und Implikationen für weitere notwendige Studien sowie die klinische Anwendbarkeit diskutiert.
Biological systems are in dynamic interaction. Many responses reside in the core concepts of biological systems interplay (competition and cooperation). In infection situation, the competition between a bacterial system and a host is shaped by many stressors at spatial and temporal determinants. Reactive chemical species are universal stressors against all biological systems since they potentially damage the basic requirements of these systems (nucleic acids, proteins, carbohydrates, and lipids). Either produced endogenously or exogenously, reactive chemical species affect the survival of pathogens including the gram-positive
Staphylococcus aureus (S. aureus). Therefore, bacteria developed strategies to overcome the toxicity of reactive species.
S. aureus is a widely found opportunistic pathogen. In its niche, S. aureus is in permanent contact with surrounding microbes and host factors. Deciphering the deterministic factors
in these interactions could facilitate pinpointing novel bacterial targets. Identifying
the aforementioned targets is crucial to develop new strategies not only to kill the pathogenic organisms but also to enhance the normal flora to minimize the pathogenicity and virulence of potential pathogens. Moreover, targeting S. aureus stress response can be used
to overcome bacterial resistance against host-derived factors. In this study, I identify a novel
S. aureus stress response factor against reactive electrophilic, oxygen, and hypochlorite species to better understand its resilience as a pathogen.
Although bacterial stress response is an active research field, gene function is a current bottleneck in characterizing the understudied bacterial strategies to mediate stress conditions. I aimed at understanding the function of a novel protein family integrated
in many defense systems of several biological systems.
In bacteria, fungi, and plants, old yellow enzymes (OYEs) are widely found. Since the first isolation of the yellow flavoprotein, OYEs are used as biocatalysts for decades to reduce activated C=C bonds in α,β-unsaturated carbonyl compounds. The promiscuity
of the enzymatic catalysis is advantageous for industrial applications.
However, the physiological function of OYEs, especially in bacteria, is still puzzling.
Moreover, the relevance of the OYEs in infection conditions remained enigmatic.
Here, I show that there are two groups of OYEs (OYE flavin oxidoreductase, OfrA and OfrB) that are encoded in staphylococci and some firmicutes. OfrA (SAUSA300_0859) is more conserved than OfrB (SAUSA300_0322) in staphylococci and is a part of the staphylococcal core genome.
A reporter system was established to report for ofrA in S. aureus background.
The results showed that ofrA is induced under electrophilic, oxidative, and hypochlorite stress. OfrA protects S. aureus against quinone, methylglyoxal, hydrogen peroxide,
and hypochlorite stress. Additionally, the results provide evidence that OfrA supports
thiol-dependent redox homeostasis. At the host-pathogen interface, OfrA promotes S. aureus fitness in murine macrophage cell line. In whole human blood, OfrA is involved in S. aureus survival indicating a potential clinical relevance to bacteraemia.
In addition, ofrA mutation affects the production of the virulence factor staphyloxanthin via the upper mevalonate pathway. In summary, decoding OfrA function and its proposed mechanism of action in S. aureus shed the light on a conserved stress response within multiple organisms.
A multitude of human tissues, such as bones, tendons, or muscles, are characterized by a hierarchical and highly ordered structure. In many cases, the loss of these tissues requires reconstruction using biocompatible replacement materials. In the field of bone replacement, the pore structure of the material has a crucial influence. Anisotropic porosity would have the advantage of facilitating the ingrowth of cells and newly formed blood vessels as well as the transport of nutrients.
In this thesis, scaffolds with a highly ordered and anisotropic pore structure were fabricated using unidirectional freezing.
Systematic investigations were carried out on biopolymer solutions (alginate and chitosan) to gain a deeper understanding of the freeze-structuring process. The knowledge gained was then applied to the development of anisotropically structured bone substitute materials. Here, the previously existing material platform for anisotropically structured calcium phosphates was extended to low-temperature phases such as calcium deficient hydroxyapatite (CDHA) or the secondary phosphates monetite and brushite.
After the implantation of a biomaterial, the inevitably triggered initial immune response plays a key role in the success of a graft, with immune cells such as neutrophils or macrophages being of particular importance. In this thesis, the influence of anisotropically structured alpha-TCP and CDHA scaffolds as well as their unstructured references on human monocytes/macrophages was investigated. Macrophages produced extracellular traps (ETs) due to mineral nanoparticles formed by the binding of phosphate and calcium ions to human platelet lysate. In particular, incubation of alpha-TCP samples in lysate containing cell culture medium resulted in pronounced particle formation and enhanced release of ETs.
The ubiquitination of proteins serves as molecular signal to control an enormous number of physiological processes and its dysregulation is connected to human diseases like cancer. The versatility of this signal stems from the diverse ways by which ubiquitin can be attached to its targets. Thus, specificity and tight regulation of the ubiquitination are pivotal requirements of ubiquitin signaling. Ubiquitin-conjugating enzymes (E2s) act at the heart of the ubiquitination cascade, transferring ubiquitin from a ubiquitin-activating enzyme (E1) to a ubiquitin ligase (E3) or substrate. When cooperating with a RING-type E3, ubiquitin-conjugating enzymes can determine linkage specificity in ubiquitin chain formation. Our understanding of the regulation of E2 activities is still limited at a structural level.
The work described here identifies two regulation mechanisms in UBE2S, a cognate E2 of the human RING-type E3 anaphase-promoting complex/cyclosome (APC/C). UBE2S elongates ubiquitin chains on APC/C substrates in a Lys11 linkage-specific manner, thereby targeting these substrates for degradation and driving mitotic progression. In addition, UBE2S was found to have a role in DNA repair by enhancing non-homologous end-joining (NHEJ) and causing transcriptional arrest at DNA damage sites in homologous recombination (HR). Furthermore, UBE2S overexpression is a characteristic feature of many cancer types and is connected to poor prognosis and diminished response to therapy.
The first regulatory mechanism uncovered in this thesis involves the intramolecular auto-ubiquitination of a particular lysine residue (Lys+5) close to the active site cysteine, presumably through conformational flexibility of the active site region. The Lys+5-linked ubiquitin molecule adopts a donor-like, ‘closed’ orientation towards UBE2S, thereby conferring auto-inhibition. Notably, Lys+5 is a major physiological ubiquitination site in ~25% of the human E2 enzymes, thus providing regulatory opportunities beyond UBE2S. Besides the active, monomeric state and the auto-inhibited state caused by auto-ubiquitination, I discovered that UBE2S can adopt a dimeric state. The latter also provides an auto-inhibited state, in which ubiquitin transfer is blocked via the obstruction of donor binding. UBE2S dimerization is promoted by its unique C-terminal extension, suppresses auto-ubiquitination and thereby the proteasomal degradation of UBE2S.
Taken together, the data provided in this thesis illustrate the intricate ways by which UBE2S activity is fine-tuned and the notion that structurally diverse mechanisms have evolved to restrict the first step in the catalytic cycle of E2 enzymes.
Humans spontaneously blink several times a minute. These blinks are strongly modulated during various cognitive task. However, the precise function of blinking and the reason for their modulation has not been fully understood. In the present work, I investigated the function of spontaneous blinks through various perceptual and cognitive tasks. Previous research has revealed that blinks rates decrease during some tasks but increase during others. When trying to understand these seemingly contradictory results, I observed that blink reduction occurs when one engages with an external input. For instance, a decrease has been observed due to the onset of a stimulus, sensory input processing and attention towards sensory input. However, for activities that do not involve such an engagement, e.g. imagination, daydreaming or creativity, the blink rate has been shown to increase. To follow up on the proposed hypothesis, I distinguished tasks that involve the processing of an external stimulus and tasks that involve disengagement.
In the first part of the project, I explored blinking during stimulus engagement. If the probability of blinking is low when engaging with the stimulus, then one should find a reduction in blinks specifically during the time period of processing but not during sensory input per se. To this end, in study 1, I tested the influence of task-relevant information duration on blink timing and additionally manipulated the overall sensory input using a visual and an auditory temporal simultaneity judgement task. The results showed that blinks were suppressed longer for longer periods of relevant information or in other words, blinks occurred at the end of relevant information processing for both the visual and the auditory modality. Since relevance is mediated through top-down processes, I argue that the reduction in blinks is a top-down driven suppression. In studies 2 and 3, I again investigated stimulus processing, but in this case, processing was triggered internally and not based on specific changes in the external input. To this end, I used bistable stimuli, in which the actual physical stimulus remains constant but their perception switches between different interpretations. Studies on the involvement of attention in such bistable perceptual changes indicate that the sensory input is reprocessed before the perceptual switch. The results revealed a reduction in eye blink rates before the report of perceptual switches. Importantly, I was able to decipher that the decrease was not caused by the perceptual switch or the behavioral response but likely started before the internal switch. Additionally, periods between a blink and a switch were longer than interblink intervals, indicating that blinks were followed by a period of stable percept. To conclude, the first part of the project revealed that there is a top-down driven blink suppression during the processing of an external stimulus.
In the second part of the project, I extended the idea of blinks marking the disengagement from external processing and tested if blinking is associated with better performance during internally directed processes. Specifically, I investigated divergent thinking, an aspect of creativity, and the link between performance and blink rates as well as the effect of motor restriction. While I could show that motor restriction was the main factor influencing divergent thinking, the relationship between eye blink rates and creative output also depended on restriction. Results showed that higher blink rates were associated with better performance during free movement, but only between subjects. In other words, subjects who had overall higher blink rates scored better in the task, but when they were allowed to sit or walk freely. Within a single subject, trial with higher blink rates were not associated with better performance. Therefore, possibly, people who are able to disengage easily, as indicated by an overall high blink rate, perform better in divergent thinking tasks. However, the link between blink rate and internal tasks is not clear at this point. Indeed, a more complex measurement of blink behavior might be necessary to understand the relationship.
In the final part of the project, I aimed to further understand the function of blinks through their neural correlates. I extracted the blink-related neural activity in the primary visual cortex (V1) of existing recordings of three rhesus monkeys during different sensory processing states. I analyzed spike related multi-unit responses, frequency dependent power changes, local field potentials and laminar distribution of activity while the animal watched a movie compared to when it was shown a blank screen. The results showed a difference in blink-related neural activity dependent on the processing state. This difference suggests a state dependent function of blinks.
Taken altogether, the work presented in this thesis suggests that eye blinks have an important function during cognitive and perceptual processes. Blinks seem to facilitate a disengagement from the external world and are therefore suppressed during intended processing of external stimuli.
Ubiquitylation is a protein post translational modification, in which ubiquitin is covalently attached to target protein substrates resulting in diverse cellular outcomes. Besides ubiquitin, various ubiquitin-like proteins including FAT10 exist, which are also conjugated to target proteins. The underlying modification mechanisms are conserved. In the initial step, ubiquitin or a ubiquitin-like protein is thioester-linked to a catalytic cysteine in the E1activating enzyme in an ATP-dependent manner. The respective protein modifier is then transferred to an E2 conjugating enzyme in a transthioesterification reaction. Finally, an E3 ubiquitin ligase E3 catalyzes the covalent attachment of the protein modifier to a substrate. In the case of ubiquitin, multiple ubiquitin molecules can be attached to a substrate in the form of either linear or branched polyubiquitin chains but also as single ubiquitin modifications. Depending on the nature of the ubiquitin chain, the substrates are destined to various cellular processes such as their targeted destruction by the proteasome but also non-degradative outcomes may occur.
As stated above FAT10 is a ubiquitin-like protein modifier which typically targets proteins for proteasomal degradation. It consists of two ubiquitin-like domains and is mainly expressed in cells of the human immune system. The reported involvement of FAT10 modifications in cancers and other diseases has caught the attention of the scientific community as an inhibition of the FAT10ylation process may provide avenues for novel therapeutic approaches. UBA6 is the E1 activating enzyme that resides at the apex of the FAT10 proteasomal degradation pathway. UBA6 not only recognizes FAT10 but can also activate ubiquitin as efficiently as the ubiquitin specific E1 UBA1. The dual specificity of UBA6 may complicate the inhibition FAT10ylation since targeting the active site of UBA6 will also inhibit the UBA6-catalyzed ubiquitin activation. Therefore, it is important to understand the underlying principles for the dual specificity of UBA6 prior to the development of compounds interfering with FAT10ylation.
In this thesis important novel insights into the structure and function of UBA6 were derived by X-ray crystallography and biochemical methods. The first crystal structure of UBA6 reveals the multidomain architecture of this enzyme in atomic detail. The enzyme is composed of a rigid core including its active and inactive adenylation domains as well as a 4 helix bundle. Overall, the molecule adopts a “Y” shape architecture with the core at the base and the first and second catalytic half domains forming one arm of the “Y” and the ubiquitin fold domain constituting the other arm. While UBA6 shares the same domain architecture as UBA1, substantial differences were revealed by the crystal structure. In particular, the first catalytic half domain undergoes a significant shift to a position more distal from the core. This rigid body movement is assumed to generate room to accommodate the second ubiquitin-like domain of FAT10. Differences are also observed in a hydrophobic platform between the core and the first catalytic half domain and the adenylation active site in the core, which together from the binding sites for ubiquitin and FAT10. Site directed mutagenesis of key residues in these areas altered the UBA6-catalyzed activation of ubiquitin and FAT10. UBA6 variants were generated with the goal of trying to block the activation of FAT10 while still maintaining that of ubiquitin activation, in order to fully explain the dual specificity of UBA6. However, none of these mutations could block the activation of FAT10, while some of these UBA6 variants blocked ubiquitin activation. Preliminary inhibition assays with a group of E1 inhibitors belonging to the adenosyl sulfamate family demonstrated potent inhibition of FAT10ylation for two compounds. The dual specificity of UBA6 hence needs to be further examined by biochemical and structural methods. In particular, the structure of a complex between UBA6 and ubiquitin or FAT10 would provide key insights for further biochemical studies, ultimately allowing the targeted inhibition of the FAT10ylation machinery.
Anxiety patients overgeneralize fear, also because of an inability to perceptually discriminate threat and safety signals. Therefore, some studies have developed discrimination training that successfully reduced the occurrence of fear generalization. The present work is the first to take a treatment-like approach by using discrimination training after generalization has occurred. Therefore, two studies were conducted with healthy participants using the same fear conditioning and generalization paradigm, with two faces as conditioned stimuli (CSs), and four facial morphs between CSs as generalization stimuli (GSs). Only one face (CS+) was followed by a loud scream (unconditioned stimulus, US). In Study 1, participants underwent either fear-relevant (discriminating faces) or fear-irrelevant discrimination training (discriminating width of lines) or a non-discriminative control training between the two generalization tests, each with or without feedback (n = 20 each). Generalization of US expectancy was reduced more effectively by fear-relevant compared to fear-irrelevant discrimination training. However, neither discrimination training was more effective than non-discriminative control training. Moreover, feedback reduced generalization of US expectancy only in discrimination training. Study 2 was designed to replicate the effects of the discrimination-training conditions in a large sample (N = 244) and examine their benefits in individuals at risk for anxiety disorders. Again, feedback reduced fear generalization particularly well for US expectancy. Fear relevance was not confirmed to be particularly fear-reducing in healthy participants, but may enhance training effects in individuals at risk of anxiety disorder. In summary, this work provides evidence that existing fear generalization can be reduced by discrimination training, likely involving several (higher-level) processes besides perceptual discrimination (e.g., motivational mechanisms in feedback conditions). Its use may be promising as part of individualized therapy for patients with difficulty discriminating similar stimuli.
RNA viruses rely entirely on the host machinery for their protein synthesis and harbor non-canonical translation mechanisms, such as alternative initiation and programmed –1 ribosomal frameshifting (–1PRF), to suit their specific needs. On the other hand, host cells have developed a variety of defensive strategies to safeguard their translational apparatus and at times transiently shut down global translation. An infection can lead to substantial translational remodeling in cells and translational control is critical during antiviral response. Due to their sheer diversity, this control is likely unique to each RNA virus and the intricacies of post-transcriptional regulation are unclear in certain viral species.
Here, we explored different aspects of translational regulation in virus-infected cells in detail. Using ribosome profiling, we extensively characterized the translational landscape in HIV-1 infected T cells, uncovering novel features of gene regulation in both host and virus. Additionally, we show that substantial pausing occurs prior to the frameshift site indicating complex regulatory mechanisms involving upstream viral RNA elements that can act as cis- regulators of frameshifting.
We also characterized the mechanistic details of trans- modulation of frameshifting by host- and virus-encoded proteins. Host antiviral protein ZAP-S binds to the SARS-CoV-2 frameshift site and destabilizes the stimulatory structure, leading to frameshift inhibition. On the other hand, EMCV 2A protein stabilizes the viral frameshift site, thereby, activating EMCV frameshifting. While both proteins were shown to be antagonistic in their mechanism, they interact with the host translational machinery. Furthermore, we showed that frameshifting can be regulated not just by proteins, but also by small molecules. High-throughput screening of natural and synthetic compounds identified two potent frameshift inhibitors that also impeded viral replication, namely trichangion and compound 25. Together, this work largely enhances our understanding of gene regulation mechanisms in virus-infected cells and further validates the druggability of viral –1 PRF site.
Mycobacterium tuberculosis is the causative agent of tuberculosis and responsible for more than eight million new infections and about two million deaths each year. Novel chemotherapeutics are urgently needed to treat the emerging threat of multi drug resistant and extensively drug resistant strains. Cell wall biosynthesis is a widely used target for chemotherapeutic intervention in bacterial infections. In mycobacteria, the cell wall is comprised of mycolic acids, very long chain fatty acids that provide protection and allow the bacteria to persist in the human macrophage. The type II fatty acid biosynthesis pathway in Mycobacterium tuberculosis synthesizes fatty acids with a length of up to 56 carbon atoms that are the precursors of the critical mycobacterial cell wall components mycolic acids. KasA, the mycobacterial ß-ketoacyl synthase and InhA, the mycobacterial enoyl reductase, are essential enzymes in the fatty acid biosynthesis pathway and validated drug targets. In this work, KasA was expressed in Mycobacterium smegmatis, purified and co-crystallized in complex with the natural thiolactone antibiotic thiolactomycin (TLM). High-resolution crystal structures of KasA and the C171Q KasA variant, which mimics the acyl enzyme intermediate of the enzyme, were solved in absence and presence of bound TLM. The crystal structures reveal how the inhibitor is coordinated by the enzyme and thus specifically pinpoint towards possible modifications to increase the affinity of the compound and develop potent new drugs against tuberculosis. Comparisons between the TLM bound crystal structures explain the preferential binding of TLM to the acylated form of KasA. Furthermore, long polyethylene glycol molecules are bound to KasA that mimic a fatty acid substrate of approximately 40 carbon atoms length. These structures thus provide the first insights into the molecular mechanism of substrate recognition and reveal how a wax-like substance can be accommodated in a cytosolic environment. InhA was purified and co-crystallized in complex with the slow, tight binding inhibitor 2-(o-tolyloxy)-5-hexylphenol (PT70). Two crystal structures of the ternary InhA-NAD+-PT70 were solved and reveal how the inhibitor is bound to the substrate binding pocket. Both structures display an ordered substrate binding loop and corroborate the hypothesis that slow onset inhibition is coupled to loop ordering. Upon loop ordering, the active site entrance is more restricted and the inhibitor is kept inside more tightly. These studies provide additional information on the mechanistic imperatives for slow onset inhibition of enoyl ACP reductases.
Malaria and HIV are among the most important global health problems of our time and together are responsible for approximately 3 million deaths annually. These two diseases overlap in many regions of the world including sub-Saharan Africa, Southeast Asia and South America, leading to a higher risk of co-infection. In this study, we generated and characterized hybrid molecules to target P. falciparum and HIV simultaneously for a potential HIV/malaria combination therapy. Hybrid molecules were synthesized by covalent fusion between azidothymidine (AZT) and dihydroartemisinin (DHA), tetraoxane or chloroquine (CQ); and a small library was generated and tested for antiviral and antimalarial activity. Our data suggest that dihyate is the most potent molecule in vitro, with antiplasmodial activity comparable to that of DHA (IC50 = 26 nM, SI > 3000), a moderate activity against HIV (IC50 = 2.9 µM; SI > 35) and safe to HeLa cells at concentrations used in the assay (CC50 > 100 µM). Pharmacokinetic studies further revealed that dihyate is metabolically unstable and is cleaved following an O-dealkylation once in contact with cytochrome P450 enzymes. The later further explains the uneffectiveness of dihyate against the CQ-sensitive P. berghei N strain in mice when administered by oral route at 20 mg/kg. Here, we report on a first approach to develop antimalarial/anti-HIV hybrid molecules and future optimization efforts will aim at producing second generation hybrid molecules to improve activity against HIV as well as compound bioavailability. With the emergence of resistant parasites against all the counterpart drugs of artemisinin derivatives used in artemisinin based combination therapies (ACTs), the introduction of antibiotics in the treatment of malaria has renewed interest on the identification of antibiotics with potent antimalarial properties. In this study we also investigated the antiplasmodial potential of thiostrepton and derivatives, synthesized using combinations of tail truncation, oxidation, and addition of lipophilic thiols to the terminal dehydroamino acid. We showed that derivatives SS231 and SS234 exhibit a better antiplasmodial activity (IC50 = 1 µM SI > 59 and SI > 77 respectively) than thiostrepton (IC50 = 8.95 µM, SI = 1.7). The antiplasmodial activity of these derivatives was observed at concentrations which are not hemolytic and non-toxic to human cell lines. Thiostrepton and derivatives appeared to exhibit transmission blocking properties when administered at their IC50 or IC90 concentrations and our data also showed that they attenuate proteasome activity of Plasmodium, which resulted in an accumulation of ubiquitinated proteins after incubation with their IC80 concentrations. Our results indicate that the parasite’s proteasome could be an attractive target for therapeutic intervention. In this regard, thiostrepton derivatives are promising candidates by dually acting on two independent targets, the proteasome and the apicoplast, with the capacity to eliminate both intraerythrocytic asexual and transmission stages of the parasite. To further support our findings, we evaluated the activity of a new class of antimalarial and proteasome inhibitors namely peptidyl sulfonyl fluorides on gametocyte maturation and analogues AJ34 and AJ38 were able to completely suppress gametocytogenesis at IC50 concentrations (0.23 µM and 0.17 µM respectively) suggesting a strong transmission blocking potential. The proteasome, a major proteolytic complex, responsible for the degradation and re-cycling of non-functional proteins has been studied only indirectly in P. falciparum. In addition, an apparent proteasome-like protein with similarity to bacterial ClpQ/hslV threonine-peptidases was predicted in the parasite. Antibodies were generated against the proteasome subunits alpha type 5 (α5-SU), beta type 5 (β5-SU) and pfhslV in mice and we showed that the proteasome is expressed in both sexual and asexual blood stages of P. falciparum, where they localize in the nucleus and in the cytoplasm. However, expression of PfhslV was only observed in trophozoites and shizonts. The trafficking of the studied proteasome subunits was further investigated by generating parasites expressing GFP tagged proteins. The expression of α5-SU-GFP in transgenic parasite appeared to localize abundantly in the cytoplasm of all blood stages, and no additional information was obtained from this parasite line. In conclusion, our data highlight two new tools towards combination therapy. Hybrid molecules represent promising tools for the cure of co-infected individuals, while very potent antibiotics with a wide scope of activities could be useful in ACTs by eliminating resistant parasites and limiting transmission of both, resistances and disease.
The integrity of its DNA is fundamental for every living cell. However, DNA is constantly threatened by exogenous and endogenous damaging agents that can cause a variety of different DNA lesions. The severe consequences of an accumulation of DNA lesions are reflected in cancerogenesis and aging. Several DNA repair mechanisms ensure the repair of DNA lesions and thus maintain DNA integrity. One of these DNA repair mechanisms is nucleotide excision repair (NER), which is famous for its ability to address a large variety of structurally unrelated DNA lesions. A key component of eukaryotic NER is the transcription factor II H (TFIIH) complex, which is not only essential for DNA repair but also for transcription. The TFIIH complex is composed of ten subunits. How these subunits work together during NER to unwind the DNA around the lesion is, however, not yet fully understood. High-resolution structural data and biochemical insights into the function of every subunit are thus indispensable to understand the functional networks within TFIIH. The importance of an intact TFIIH complex is reflected in the severe consequences of patient mutations in the TFIIH subunits XPB, XPD or p8 leading to the hallmark diseases xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Defects in the NER pathway are further associated with several types of cancer including skin cancer.
The herein described work focused on five TFIIH subunits derived from the thermophilic fungus Chaetomium thermophilum, the p34/p44 pair and the ternary XPB/p52/p8 complex. The interaction between p34 and p44 was characterized based on a high-resolution structure of the p34_vWA/p44_RING minimal complex. Biochemical studies of the p34/p44 interaction led to the disclosure of an additional interaction between the p34 and p44 subunits, which had not been characterized so far. The p34/p44 interaction was shown to be central to TFIIH, which justifies the presence of several redundant interfaces to safeguard the interaction between the two proteins and might explain why so far, no patient mutations in these subunits have been identified. The p52 subunit of TFIIH was known to be crucial to stimulate the ATPase activity of XPB, which is required during NER. This work presents the first entire atomic resolution structural characterization of p52, which was derived of several crystal structures of p52 variants and a p52/p8 variant thereby demonstrating the interaction between p52 and p8. The precise structural model of p52 offered the possibility to investigate interactions with other TFIIH subunits in more detail. The middle domain 2 of p52 and the N-terminal domain of XPB were shown to mediate the main interaction between the two subunits. An analysis of the p52 crystal structures within recently published cryo-electron microscopy structures of TFIIH provides a model of how p52 and p8 stimulate the ATPase activity of XPB, which is essential for NER and transcription. The structural and biochemical findings of this work provide an additional building block towards the uncovering of the architecture and function of this essential transcription factor.
The knee joint is a complex composite joint containing the C-shaped wedge-like menisci composed of fibrocartilage. Due to their complex composition and structure, they provide mechanical resilience to the knee joint protecting the articular cartilage. Because of the limited repair potential, meniscal injuries do not only affect the meniscus itself but also lead to altered joint homeostasis and inevitably to secondary osteoarthritis.
The meniscus was characterized focusing on its anatomy, structure and meniscal markers such as aggrecan, collagen type I (Col I) and Col II. The components relevant for meniscus tissue engineering, namely cells, Col I scaffolds, biochemical and biomechanical stimuli were studied. Meniscal cells (MCs) were isolated from meniscus, mesenchymal stem cells (MSCs) from bone marrow and dermal microvascular endothelial cells (d-mvECs) from foreskin biopsies. For the human (h) meniscus model, wedge-shape compression of a hMSC-laden Col I gel was successfully established. During three weeks of static culture, the biochemical stimulus transforming growth factor beta-3 (TGF beta-3) led to a compact collagen structure. On day 21, this meniscus model showed high metabolic activity and matrix remodeling as confirmed by matrix metalloproteinases detection. The fibrochondrogenic properties were illustrated by immunohistochemical detection of meniscal markers, significant GAG/DNA increase and increased compressive properties. For further improvement, biomechanical stimulation systems by compression and hydrostatic pressure were designed. As one vascularization approach, direct stimulation with ciclopirox olamine (CPX) significantly increased sprouting of hd-mvEC spheroids even in absence of auxiliary cells such as MSCs. Second, a cell sheet composed of hMSCs and hd-mvECs was fabricated by temperature triggered cell sheet engineering and transferred onto the wedge-shaped meniscus model. Third, a biological vascularized scaffold (BioVaSc-TERM) was re-endothelialized with hd-mvECs providing a viable vascularized network. The vascularized BioVaSc-TERM was suggested as wrapping scaffold of the meniscus model by using two suture techniques, the all-inside-repair (AIR) for the posterior horn, and the outside-in-refixation (OIR) for the anterior horn and the middle part.
This meniscus model for replacing torn menisci is a promising approach to be further optimized regarding vascularization, biochemical and biomechanical stimuli.
Bei der zystischen Fibrose (CF) sowie der primären Ziliendyskinesie (PCD) handelt es sich um zwei seltene Erkrankungen, die unter anderem den mukoziliären Transport beeinträchtigen. CF gehört hierbei zu den am häufigsten vorkommenden angeborenen Stoffwechselerkrankungen, wobei Betroffene unter einem Defekt des Cystic Fibrosis Transmembrane Conductor Regulator (CFTR)-Gens leiden, der durch die Produktion von hochviskosem Sekret in muzinproduzierenden Organen, wie dem gastrointestinalen Trakt und der Lunge, gekennzeichnet ist. Patienten, die an PCD leiden, weisen Defekte in, zum jetzigen Zeitpunkt, ca. 38 bekannten und PCD-assoziierten Genen auf, die in strukturellen Defekten des ziliären Apparats und somit in dysfunktionalen Kinozilien resultieren. Da aktuell weder für die CF noch für die PCD eine Heilung möglich ist, steht bei der Therapie vor allem die Linderung der Symptome im Fokus. Grundlegendes Ziel ist der langfristige Erhalt der Lungenfunktion sowie die Prävention bakterieller Infekte. Als bisherige Modellsysteme zur Erforschung möglicher Therapeutika gelten Tiermodelle, die den humanen Phänotyp aufgrund von Speziesdiversität nicht vollständig abbilden können. Als vielversprechende Testsysteme für die zystische Fibrose gelten humane intestinale Organoidkulturen. Nachdem allerdings vorwiegend respiratorische Symptome für die Mortalität der Patienten verantwortlich sind, stellen CF-Atemwegsmodelle bessere Testsysteme für zukünftige Therapeutika dar. Atmungsorganoidkulturen wurden verwendet, um die CFTR-Funktionalität zu untersuchen, repräsentieren aber nicht vollständig die in vivo Situation. Deshalb werden zur Entwicklung neuer Therapiestrategien patientenspezifische 3D in vitro Testsysteme der humanen Atemwege benötigt, die insbesondere im Hinblick auf personalisierte Medizin ihren Einsatz finden. In der vorliegenden Arbeit wurde eine für den Lehrstuhl neue Methode zur Zellgewinnung aus nasalen Schleimhautabstrichen etabliert, die eine standardisierte Versorgung mit humanem Primärmaterial garantiert. Zur Generierung einer krankheitsspezifischen Zelllinie, wie beispielsweise einer PCD-Zelllinie mit Hilfe des CRISPR/Cas9-Systems, ist eine Atemwegszelllinie erforderlich, die die in vivo Situation vollständig repräsentiert. So wurden vier verschiedene respiratorische Epithelzelllinien (HBEC3-KT, Calu-3, VA10 und Cl-huAEC) auf ihren mukoziliären Phänotyp hin untersucht, wobei lediglich die Zelllinie HBEC3-KT in zilientragende Zellen differenzierte. Diese zeigten jedoch nur auf ca. 5 % der Modelloberfläche Kinozilien, wodurch die humane respiratorische Mukosa nicht komplett abgebildet werden konnte und die HBEC3-KT-Zelllinie keine geeignete Zelllinie zur Generierung einer PCD-Zelllinie darstellte. Mit Hilfe des Tissue Engineering war es möglich, 3D in vitro Testsysteme basierend auf zwei unterschiedlichen Matrices, der biologischen SIS (small intestinal submucosa) und der synthetischen Polyethylenterephthalat (PET)-Membran, aufzubauen. Es wurden 3D Atemwegstestsysteme mit humanen primären nasalen und tracheobronchialen Epithelzellen generiert. Ergänzend zu histologischen Untersuchungen und zur Charakterisierung spezifischer Marker des respiratorischen Systems mittels Immunfluoreszenz, wurde die Ultrastruktur der Modelle, mit speziellem Fokus auf ziliäre Strukturen, analysiert. Um Rückschlüsse auf die ziliäre Funktionalität ziehen zu können und somit eine hohe in vivo Korrelation zu bestätigen, wurde im Rahmen dieser Arbeit am Lehrstuhl für Tissue Engineering und Regenerative Medizin die Methode der Hochgeschwindigkeitsvideomikroskopie etabliert, welche die Analyse der Zilienschlagfrequenz sowie des mukoziliären Transports ermöglicht. Ebenfalls wurde der Einfluss von isotoner Kochsalzlösung und des � 2-adrenergen Agonisten Salbutamol, das vor allem als Bronchodilatator bei Asthmapatienten eingesetzt wird, auf die Zilienschlagfrequenz analysiert. Es konnte gezeigt werden, dass beide Substanzen den Zilienschlag im Atemwegsmodell erhöhen. Zur Generierung der Testsysteme der beiden seltenen Erkrankungen CF und PCD wurden Epithelzellen der betroffenen Patienten zunächst mittels nicht-invasiver Raman-Spektroskopie auf einen potentiellen Biomarker untersucht, welcher Einsatz in der Diagnostik der beiden Krankheiten finden könnte. Es konnte jedoch weder für die CF noch für die PCD ein Biomarker aufgedeckt werden. Jedoch zeigten PCD-Zellen eine geringe Auftrennung gegenüber nicht-PCD Zellen. Anschließend wurden 3D-Atemwegstestsysteme basierend auf Patientenzellen aufgebaut. Der Phänotyp der CF-Modelle wurde mittels immunhistologischer Färbung und der Analyse des gestörten mukoziliären Transports verifiziert. Strukturelle ziliäre Defekte konnten durch die ultrastrukturelle Analyse von Zilienquerschnitten in drei donorspezifischen PCD-Modellen identifiziert werden. Darüber hinaus konnte die ziliäre Funktionalität mit Hilfe der Hochgeschwindigkeitsvideomikroskopie nicht nachgewiesen werden. Zusammenfassend ist es in dieser Arbeit gelungen, eine neue Methode zur vollständigen Charakterisierung von 3D-Atemwegstestsystemen zu etablieren, die die Analyse der Zilienschlagfrequenz sowie des mukoziliären Transports ermöglicht. Es konnte erstmalig gezeigt werden, dass mit Hilfe des Tissue Engineering ein personalisiertes Krankheitsmodell für die PCD auf Segmenten eines dezellularisierten porzinen Jejunums generiert werden kann, das zukünftig ein Testsystem für potentielle Therapeutika darstellen kann.
Der Meniskus, ein scheibenförmiger Faserknorpel, spielt im Kniegelenk eine bedeutende Rolle, weil er Kräfte und Druck im Kniegelenk gleichmäßig verteilt, Stöße dämpft sowie der Kraftübertragung und Stabilisierung dient. Durch die Entfernung des Gewebes, der sogenannten Totalmeniskektomie, nach einer Meniskusverletzung oder einem Riss, verändern sich die mechanischen Eigenschaften des Gelenks stark und verursachen durch die erhöhte Belastung der Gelenkflächen Arthrose. Arthrose ist weltweit die Häufigste aller Gelenkerkrankungen. Der Erhalt der körperlichen Leistungsfähigkeit und Mobilität bis ins hohe Alter sowie die Bewahrung der Gesundheit von Herz-Kreislauf- und Stoffwechselorganen zählen aufgrund des demografischen Wandels zu den großen medizinischen Herausforderungen. Die Erkrankung des muskuloskelettalen Systems stellte 2010 im Bundesgebiet die am häufigsten vorkommende Krankheitsart dar.
Während Risse in den äußeren Teilen des Meniskus aufgrund des Anschlusses an das Blutgefäßsystem spontan heilen können, können sie dies in tieferen Zonen nicht. Durch die begrenzte Heilungsfähigkeit des Knorpels bleibt langfristig der Einsatz eines Ersatzgewebes die einzige therapeutische Alternative.
In der vorliegenden Arbeit wurde als therapeutische Alternative erfolgreich ein vaskularisiertes Meniskusersatzgewebe mit Methoden des Tissue Engineering entwickelt. Es soll in Zukunft als Implantat Verwendung finden. Tissue Engineering ist ein interdisziplinäres Forschungsfeld, in dem Gewebe außerhalb des Körpers generiert werden. Schlüsselkomponenten sind Zellen, die aus einem Organismus isoliert werden, und Trägerstrukturen, die mit Zellen besiedelt werden. Die Biomaterialien geben den Zellen eine geeignete Umgebung, die die Extrazelluläre Matrix (EZM) ersetzen soll, um die Funktion der Zellen beizubehalten, eigene Matrix zu bilden. Zum Erhalt eines funktionelles Gewebes werden oftmals dynamische Kultursysteme, sogenannte Bioreaktoren, verwendet, die natürliche Stimuli wie beispielsweise den Blutfluss oder mechanische Kompressionskräfte während der in vitro Reifungsphase des Gewebes, zur Verfügung stellen. Das Gewebekonstrukt wurde auf Basis natürlicher Biomaterialien aufgebaut, unter Verwendung ausschließlich primärer Zellen, die später direkt vom Patienten gewonnen werden können und damit Abstoßungsreaktionen auszuschließen sind. Da der Meniskus teilvaskularisiert ist und die in vivo Situation des Gewebes bestmöglich nachgebaut werden sollte, wurden Konstrukte mit mehreren Zelltypen, sogenannte Ko-Kulturen aufgebaut. Neben mikrovaskulären Endothelzellen (mvEZ) und Meniskuszellen (MZ) erfolgten Versuche mit mesenchymalen Stammzellen (MSZ).
Zur Bereitstellung einer zelltypspezifischen Matrixumgebung, diente den mvEZ ein Stück Schweinedarm mit azellularisierten Gefäßstrukturen (BioVaSc®) und den MZ diente eine geeig- nete Kollagenmatrix (Kollagen Typ I Hydrogel). Die Validierung und Charakterisierung des aufgebauten 3D Meniskuskonstrukts, welches in einem dynamischen Perfusions-Bioreaktorsystem kultiviert wurde, erfolgte mit knorpeltypischen Matrixmarkern wie Aggrekan, Kollagen Typ I, II und X sowie mit den Transkriptionsfaktoren RunX2 und Sox9, die in der Knorpelentstehung von großer Bedeutung sind. Zusätzlich erfolgten Auswertungen mit endothelzellspezifischen Markern wie vWF, CD31 und VEGF, um die Vaskularisierung im Konstrukt nachzuweisen. Analysiert wurden auch die Zellvitalitäten in den Konstrukten.
Aufgrund einer nur geringen Verfügbarkeit von MZ wurden Kulturansätze mit alternativen Zellquellen, den MSZ, durchgeführt. Dafür erfolgte zunächst deren Isolation und Charakterisierung und die Auswahl einer geeigneten 3D Kollagenmatrix. Die beste Zellintegration der MSZ konnte auf einer eigens hergestellten elektrogesponnenen Matrix beobachtet werden. Die Matrix besteht aus zwei unterschiedlichen Kollagentypen, die auf insgesamt fünf Schichten verteilt sind. Die Fasern besitzen weiter unterschiedliche Ausrichtungen. Während die Kollagen Typ I Fasern in den äußeren Schichten keiner Ausrichtung zugehören, liegen die Kollagen Typ II Fasern in der mittleren Schicht parallel zueinander. Der native Meniskus war für den Aufbau einer solchen Kollagen-Trägerstruktur das natürliche Vorbild, das imitiert werden sollte. Nach der Besiedelung der Matrix mit MSZ, konnte eine Integration der Zellen bereits nach vier Tagen bis in die Mittelschicht sowie eine spontane chondrogene Differenzierung nach einer insgesamt dreiwöchigen Kultivierung gezeigt werden. Das Biomaterial stellt in Hinblick auf die Differenzierung der Zellen ohne die Zugabe von Wachstumsfaktoren eine relevante Bedeutung für klinische Studien dar.
Zur Kultivierung des 3D Meniskuskonstrukts wurde ein Bioreaktor entwickelt. Mit diesem können neben Perfusion der Gefäßsysteme zusätzlich Kompressionskräfte sowie Scherspannungen auf das Ersatzgewebe appliziert und die Differenzierung von MZ bzw. MSZ während der in vitro Kultur über mechanische Reize stimuliert werden. Ein anderes Anwendungsfeld für den neuartigen Bioreaktor ist seine Verwendung als Prüftestsystem für die Optimierung und Qualitätssicherung von Gewebekonstrukten.
Eine ausgeprägte Mundtrockenheit, Xerostomie, entsteht häufig durch eine irreversible Funktionseinschränkung der Speicheldrüsen. Diese ist unter anderem durch die Einnahme bestimmter Medikamente, Autoimmunerkrankungen, fortgeschrittenes Alter oder die Bestrahlungstherapie von Tumoren der Kopf-Hals-Region bedingt, wobei letztere eine der häufigsten Ursachen darstellt. Konsequenzen der eingeschränkten Drüsenfunktion sind herabgesetzte Speichelflussraten, eine Reduktion des Mund-pH-Werts, eine veränderte Elektrolyt- und Immunglobulin-Zusammensetzung des Speichels und somit eine Verringerung des Infektionsschutzes. Die resultierenden Komplikationen erstrecken sich von Karies und rezidivierenden Infektionen bis hin zu Pilzbesiedelungen der Mundschleimhaut. Diese schränken die Lebensqualität der Patienten stark ein und führen häufig zu Therapieunterbrechungen. Fast die Hälfte der Patienten leidet unter Depressionen oder psychischen Belastungszuständen. Es gibt wenige Therapieansätze zur Behandlung der postradiogenen Xerostomie: Pilocarpin erhöht zwar die Speichelflussraten, hat jedoch keinen signifikanten Effekt auf die Lebensqualität. Die operative Translokation der Glandula submandibularis hat den Weg in die klinische Routine noch nicht gefunden, während die intensitätsmodulierte Bestrahlung (IMRT) nicht für jeden Patienten geeignet ist; beide zeigen jedoch einen positiven Effekt auf die Lebensqualität. Gentechnische und stammzellbasierte Ansätze zur Regeneration des Drüsengewebes befinden sich im Experimentalstadium. Somit ergibt sich ein dringender Bedarf an innovativen Optionen zur Behandlung der postradiogenen Xerostomie. Das Tissue Engineering, die Erstellung einer künstlichen Speicheldrüse aus körpereigenen Zellen, böte hier ein potentielles Behandlungskonzept.
Diese Studie soll deshalb untersuchen, ob humane Speicheldrüsenepithelzellen (hSEZ) auf einer Matrix aus dezellularisiertem, porzinem Jejunum, der sogenannten Small intestinal submucosa + mucosa (SIS-muc), kultiviert werden können. Können die Zellen innerhalb der Wachstumsperiode wichtige physiologische Differenzierungsmarker beibehalten? Kann die Produktion von α-Amylase, einem der wichtigsten Enzyme des menschlichen Speichels, erhalten werden? Welchen Einfluss hat die Kokultur mit mikrovaskulären Endothelzellen (mvEZ)? Und zuletzt: Ist dezellularisierter Schweinedarm eine potentiell geeignete Matrix für das Tissue Engineering der menschlichen Speicheldrüse?
Zunächst erfolgte die Entnahme von humanem Speicheldrüsengewebe, woraus hSEZ isoliert wurden. Diese wurden dann sowohl in Mono- als auch in Kokultur mit mvEZ auf die SIS-muc aufgebracht und auf dieser kultiviert. Die SIS-muc wurde aus kurzen Schweinedarm-Segmenten gewonnen, die in einem mehrstufigen Verfahren dezellularisiert wurden. Die besiedelte SIS-muc wurde mittels konventioneller sowie Immunfluoreszenzfärbungen, Raster- und Transmissionsektronenmikroskopie (REM/TEM) sowie quantitativer Polymerasekettenreaktion (qPCR) untersucht, darüber hinaus erfolgte die Messung der α-Amylase-Enzymaktivität.
Histologisch sowie in der REM zeigte sich sowohl in der Mono- als auch in der Kokultur eine konfluente Besiedelung der SIS-muc mit hSEZ. In der Kokultur formten mvEZ einen Monolayer auf der serosalen Matrixseite. Bei der Charakterisierung der hSEZ zeigte sich in den Immunfluoreszenzaufnahmen eine starke Ausprägung von Zytokeratin, α-Amylase und Aquaporin-5 und eine moderate Ausprägung von Claudin-1. Bei der Untersuchung der Funktion der α-Amylase konnte in der Kokultur von hSEZ mit mvEZ eine im Gegensatz zur Mono- und 2D-Kultur signifikant erhöhte Enzymaktivität der α-Amylase nachgewiesen werden. In der qPCR-Analyse der α-Amylase-Genexpression war die 3D-Kultur der 2D-Kultur überlegen.
Die vorliegende Arbeit zeigt, dass die Kultur von hSEZ auf der SIS-muc möglich ist. Es konnte nachgewiesen werden, dass die Zellen in 3D-Kultur spezifische Differenzierungsmerkmale beibehalten, die in der 2D-Kultur teils verloren gehen und dass hSEZ in Kokultur mit mvEZ eine gegenüber der Monokultur signifikant erhöhte Produktion von α-Amylase aufweisen. Diese Arbeit liefert die Datengrundlage für zukünftige Studien im dynamischen Bioreaktor-Modell (BioVaSc), die auf dem Weg zur klinischen Translation notwendig sind. Somit stellt sie einen wichtigen Schritt in Richtung einer auf Tissue Engineering basierten Therapie der belastenden Xerostomie dar.
Solitary bees in seasonal environments have to align their life-cycles with favorable environmental conditions and resources. Therefore, a proper timing of their seasonal activity is highly fitness relevant. Most species in temperate environments use temperature as a trigger for the timing of their seasonal activity. Hence, global warming can disrupt mutualistic interactions between solitary bees and plants if increasing temperatures differently change the timing of interaction partners. The objective of this dissertation was to investigate the mechanisms of timing in spring-emerging solitary bees as well as the resulting fitness consequences if temporal mismatches with their host plants should occur. In my experiments, I focused on spring-emerging solitary bees of the genus Osmia and thereby mainly on O. cornuta and O. bicornis (in one study which is presented in Chapter IV, I additionally investigated a third species: O. brevicornis).
Chapter II presents a study in which I investigated different triggers solitary bees are using to time their emergence in spring. In a climate chamber experiment I investigated the relationship between overwintering temperature, body size, body weight and emergence date. In addition, I developed a simple mechanistic model that allowed me to unite my different observations in a consistent framework. In combination with the empirical data, the model strongly suggests that solitary bees follow a strategic approach and emerge at a date that is most profitable for their individual fitness expectations. I have shown that this date is on the one hand temperature dependent as warmer overwintering temperatures increase the weight loss of bees during hibernation, which then advances their optimal emergence date to an earlier time point (due to an earlier benefit from the emergence event). On the other hand I have also shown that the optimal emergence date depends on the individual body size (or body weight) as bees adjust their emergence date accordingly. My data show that it is not enough to solely investigate temperature effects on the timing of bee emergence, but that we should also consider individual body conditions of solitary bees to understand the timing of bee emergence.
In Chapter III, I present a study in which I investigated how exactly temperature determines the emergence date of solitary bees. Therefore, I tested several variants degree-day models to relate temperature time series to emergence data. The basic functioning of such degree-day models is that bees are said to finally emerge when a critical amount of degree-days is accumulated. I showed that bees accumulate degree-days only above a critical temperature value (~4°C in O. cornuta and ~7°C in O. bicornis) and only after the exceedance of a critical calendar date (~10th of March in O. cornuta and ~28th of March in O. bicornis). Such a critical calendar date, before which degree-days are not accumulated irrespective of the actual temperature, is in general less commonly used and, so far, it has only been included twice in a phenology model predicting bee emergence. Furthermore, I used this model to retrospectively predict the emergence dates of bees by applying the model to long-term temperature data which have been recorded by the regional climate station in Würzburg. By doing so, the model estimated that over the last 63 years, bees emerged approximately 4 days earlier.
In Chapter IV, I present a study in which I investigated how temporal mismatches in bee-plant interactions affect the fitness of solitary bees. Therefore, I performed an experiment with large flight cages serving as mesocosms. Inside these mesocosms, I manipulated the supply of blossoms to synchronize or desynchronize bee-plant interactions. In sum, I showed that even short temporal mismatches of three and six days in bee-plant interactions (with solitary bee emergence before flower occurrence) can cause severe fitness losses in solitary bees. Nonetheless, I detected different strategies by solitary bees to counteract impacts on their fitness after temporal mismatches. However, since these strategies may result in secondary fitness costs by a changed sex ratio or increased parasitism, I concluded that compensation strategies do not fully mitigate fitness losses of bees after short temporal mismatches with their food plants. In the event of further climate warming, fitness losses after temporal mismatches may not only exacerbate bee declines but may also reduce pollination services for later-flowering species and affect populations of animal-pollinated plants.
In conclusion, I showed that spring-emerging solitary bees are susceptible to climate change as in response to warmer temperatures bees advance their phenology and show a decreased fitness state. As spring-emerging solitary bees not only consider overwintering temperature but also their individual body condition for adjusting emergence dates, this may explain differing responses to climate warming within and among bee populations which may also have consequences for bee-plant interactions and the persistence of bee populations under further climate warming. If in response to climate warming plants do not shift their phenologies according to the bees, bees may experience temporal mismatches with their host plants. As bees failed to show a single compensation strategy that was entirely successful in mitigating fitness consequences after temporal mismatches with their food plants, the resulting fitness consequences for spring-emerging solitary bees would be severe. Furthermore, I showed that spring-emerging solitary bees use a critical calendar date before which they generally do not commence the summation of degree-days irrespective of the actual temperature. I therefore suggest that further studies should also include the parameter of a critical calendar date into degree-day model predictions to increase the accuracy of model predictions for emergence dates in solitary bees. Although our retrospective prediction about the advance in bee emergence corresponds to the results of several studies on phenological trends of different plant species, we suggest that more research has to be done to assess the impacts of climate warming on the synchronization in bee-plant interactions more accurately.
Ants belong to the most successful insects living on our planet earth. One criterion of their tremendous success is the division of labor among workers that can be related to age (age¬– or temporal polyethism) and/ or body size (size–related polymorphism). Young ants care for the queen and brood in the nest interior and switch to foraging tasks in the outside environment with ongoing age. This highly flexible interior–exterior transition probably allows the ant workers to properly match the colony needs and is one of the most impressive behaviors a single worker undergoes during its life. As environmental stimuli are changing with this transition, workers are required to perform a new behavioral repertoire. This requires significant adaptions in sensory and higher¬–order integration centers in the brain, like the mushroom bodies. Furthermore, foragers need proper time measuring mechanisms to cope with daily environmental changes and to adapt their own mode of life. Therefore, they possess a functional endogenous clock that generates rhythms with a period length of approximately 24 hours. The species–rich genus of Camponotus ants constitute a rewarding model to study how behavioral duties of division of labor were performed and modulated within the colony and how synaptic plasticity in the brain is processed, as they can divide their labor to both, age and body size, simultaneously.
In my PhD thesis, I started to investigate the behavioral repertoire (like foraging and locomotor activity) of two sympatric Camponotus species, C. mus and C. rufipes workers under natural and under controlled conditions. Furthermore, I focused on the division of labor in C. rufipes workers and started to examine structural and ultrastructural changes of neuronal architectures in the brain that are accompanied by the interior–exterior transition of C. rufipes ants.
In the first part of my thesis, I started to analyze the temporal organization of task allocation throughout the life of single C. rufipes workers. Constant video–tracking of individually labeled workers for up to 11 weeks, revealed an age–related division of labor of interior and exterior workers. After emergence, young individuals are tended to by older ones within the first 48 hours of their lives before they themselves start nurturing larvae and pupae. Around 52% switch to foraging duties at an age of 14–20 days. The workers that switched to foraging
tasks are mainly media–sized workers and seem to be more specialized than nurses. Variations in proportion and the age of switching workers between and within different subcolonies indicate how highly flexible and plastic the age–related division of labor occurs in this ant species. Most of the observed workers were engaged in foraging tasks exclusively during nighttime. As the experiments were conducted in the laboratory, they are completely lacking environmental stimuli of the ants´ natural habitat.
I therefore asked in a second study, how workers of the two closely related Camponotus species, C. rufipes and C. mus, adapt their daily activity patterns (foraging and locomotor activity) under natural (in Uruguay, South America) and controlled (in the laboratory) conditions to changing thermal conditions. Monitoring the foraging activity of both Camponotus species in a field experiment revealed, that C. mus workers are exclusively diurnal, whereas C. rufipes foragers are predominantly nocturnal. However, some nests showed an elevated daytime activity, which could be an adaption to seasonally cold night temperatures. To further investigate the impact of temperature and light on the differing foraging activity patterns in the field, workers of both Camponotus species were artificially exposed to different thermal regimes in the laboratory, simulating local winter and summer conditions. Here again, C. mus workers display solely diurnal locomotor activity, whereas workers of C. rufipes shifted their locomotor activity from diurnal under thermal winter conditions to nocturnal under thermal summer conditions. Hence, the combination of both, field work and laboratory studies, shows that daily activity is mostly shaped by thermal conditions and that temperature cycles are not just limiting foraging activity but can be used as zeitgeber to schedule the outside activities of the nests.
Once an individual worker switches from indoor duties to exterior foraging tasks, it is confronted with an entirely new set of sensory information. To cope with changes of the environmental conditions and to facilitate the behavioral switch, workers need a highly flexible and plastic neuronal system. Hence, my thesis further focuses on the underlying neuronal adaptations of the visual system, including the optic lobes as the primary visual neuropil and the mushroom bodies as secondary visual brain neuropil, that are accompanied with the behavioral switch from nursing to foraging. The optic lobes as well as the mushroom bodies of light–deprived workers show an `experience–independent´ volume increase during the first two weeks of adulthood. An additional light exposure for 4 days induces an `experience–dependent´ decrease of synaptic complexes in the mushroom body collar,
followed by an increase after extended light exposure for 14 days. I therefore conclude, that the plasticity of the central visual system represents important components for the optimal timing of the interior–exterior transitions and flexibility of the age–related division of labor. These remarkable structural changes of synaptic complexes suggest an active involvement of the mushroom body neuropil in the lifetime plasticity that promotes the interior–exterior transition of Camponotus rufipes ants. Beside these investigations of neuronal plasticity of synaptic complexes in the mushroom bodies on a structural level, I further started to examine mushroom body synaptic structures at the ultrastructural level. Until recently, the detection of synaptic components in projection neuron axonal boutons were below resolution using classical Transmission Electron Microscopy. Therefore, I started to implement Electron Tomography to increase the synaptic resolution to understand architectural changes in neuronal plasticity process. By acquiring double tilt series and consecutive computation of the acquired tilt information, I am now able to resolve individual clear–core and dense–core vesicles within the projection neuron cytoplasm of C. rufipes ants. I additionally was able to reveal single postsynaptic Kenyon cell dendritic spines (~62) that surround one individual projection neuron bouton. With this, I could reveal first insights into the complex neuronal architecture of single projection neuron boutons in the olfactory mushroom body lip region. The high resolution images of synaptic architectures at the ultrastructural level, received with Electron Tomography would promote the understanding of architectural changes in neuronal plasticity.
In my PhD thesis, I demonstrate that the temporal organization within Camponotus colonies involves the perfect timing of different tasks. Temperature seems to be the most scheduling abiotic factors of foraging and locomotor activity. The ants do not only need to adapt their behavioral repertoire in accordance to the interior–exterior switch, also the parts in the peripheral and central that process visual information need to adapt to the new sensory environment.
I. Timing is a crucial feature in organisms that live within a variable and changing environment. Complex mechanisms to measure time are wide-spread and were shown to exist in many taxa. These mechanisms are expected to provide fitness benefits by enabling organisms to anticipate environmental changes and adapt accordingly. However, very few studies have addressed the adaptive value of proper timing. The objective of this PhD-project was to investigate mechanisms and fitness consequences of timing decisions concerning colony phenology and foraging activity in the honey bee (Apis mellifera), a social insect species with a high degree of social organization and one of the most important pollinators of wild plants and crops. In chapter II, a study is presented that aimed to identify the consequences of disrupted synchrony between colony phenology and the local environment by manipulating the timing of brood onset after hibernation. In a follow-up experiment, the importance of environmental factors for the timing of brood onset was investigated to assess the potential of climate change to disrupt synchronization of colony phenology (Chapter III). Chapter IV aimed to prove for the first time that honey bees can use interval time-place learning to improve foraging activity in a variable environment. Chapter V investigates the fitness benefits of information exchange between nest mates via waggle dance communication about a resource environment that is heterogeneous in space and time.
II. In the study presented in chapter II, the importance of the timing of brood onset after hibernation as critical point in honey bee colony phenology in temperate zones was investigated. Honey bee colonies were overwintered at two climatically different sites. By translocating colonies from each site to the other in late winter, timing of brood onset was manipulated and consequently colony phenology was desynchronized with the local environment. Delaying colony phenology in respect to the local environment decreased the capability of colonies to exploit the abundant spring bloom. Early brood onset, on the other hand, increased the loads of the brood parasite Varroa destructor later in the season with negative impact on colony worker population size. This indicates a timing related trade-off and illustrates the importance of investigating effects of climate change on complex multi-trophic systems. It can be concluded that timing of brood onset in honey bees is an important fitness relevant step for colony phenology that is highly sensitive to climatic conditions in late winter. Further, phenology shifts and mismatches driven by climate change can have severe fitness consequences.
III. In chapter III, I assess the importance of the environmental factors ambient temperature and photoperiod as well as elapsed time on the timing of brood onset. Twenty-four hibernating honey bee colonies were placed into environmental chambers and allocated to different combinations of two temperature regimes and three different light regimes. Brood onset was identified non-invasively by tracking comb temperature within the winter cluster. The experiment revealed that ambient temperature plays a major role in the timing of brood onset, but the response of honey bee colonies to temperature increases is modified by photoperiod. Further, the data indicate the involvement of an internal clock. I conclude that the timing of brood onset is complex but probably highly susceptible to climate change and especially spells of warm weather in winter.
IV. In chapter IV, it was examined if honey bees are capable of interval time-place learning and if this ability improves foraging efficiency in a dynamic resource environment. In a field experiment with artificial feeders, foragers were able to learn time intervals and use this ability to anticipate time periods during which feeders were active. Further, interval time-place learning enabled foragers to increase nectar uptake rates. It was concluded that interval time-place learning can help honey bee foragers to adapt to the complex and variable temporal patterns of floral resource environments.
V. The study presented in chapter V identified the importance of the honey bee waggle dance communication for the spatiotemporal coordination of honey bee foraging activity in resource environments that can vary from day to day. Consequences of disrupting the instructional component of honey bee dance communication were investigated in eight temperate zone landscapes with different levels of spatiotemporal complexity. While nectar uptake of colonies was not affected, waggle dance communication significantly benefitted pollen harvest irrespective of landscape complexity. I suggest that this is explained by the fact that honey bees prefer to forage pollen in semi-natural habitats, which provide diverse resource species but are sparse and presumably hard to find in intensively managed agricultural landscapes. I conclude that waggle dance communication helps to ensure a sufficient and diverse pollen diet which is crucial for honey bee colony health.
VI. In my PhD-project, I could show that honey bee colonies are able to adapt their activities to a seasonally and daily changing environment, which affects resource uptake, colony development, colony health and ultimately colony fitness. Ongoing global change, however, puts timing in honey bee colonies at risk. Climate change has the potential to cause mismatches with the local resource environment. Intensivation of agricultural management with decreased resource diversity and short resource peaks in spring followed by distinctive gaps increases the probability of mismatches. Even the highly efficient foraging system of honey bees might not ensure a sufficiently diverse and healthy diet in such an environment. The global introduction of the parasitic mite V. destructor and the increased exposure to pesticides in intensively managed landscapes further degrades honey bee colony health. This might lead to reduced cognitive capabilities in workers and impact the communication and social organization in colonies, thereby undermining the ability of honey bee colonies to adapt to their environment.
Due to the rotation of the earth in the solar system all inhabitants of our planet are exposed to regular environmental changes since more than 3.5 billion years. In order to anticipate these predictable changes in the environment, evolutionarily conserved biological rhythms have evolved in most organisms – ranging from ancient cyanobacteria up to human beings – and also at different levels of organization – from single cells up to behavior. These rhythms are endogenously generated by so called circadian clocks in our body and entrained to the 24 h cycle by external timing cues. In multi-cellular organisms the majority of the cells in the body is equipped with such an oscillator. In mammals, the circadian system is structured in a hierarchical fashion: A central pacemaker resides in the bilateral suprachiasmatic nucleus (SCN) of the hypothalamus, while subsidiary peripheral clocks exist in nearly every tissue and organ.
In contrast to the aforementioned recurrent environmental changes most organisms are also exposed to unpredictable changes in the environment. In order to adapt to these sudden alterations the acute activation of the stress response system, involving the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, displays a fundamental survival mechanism. However, if activation of the stress system becomes chronic, devastating somatic and affective disorders might be the consequence.
At first glance, the circadian and the stress system seem to represent two separate bodily control systems that are involved in adaptation to predictable and unpredictable stimuli, respectively. However, both systems are fundamental for survival, and thus, communicate with each other at various levels. Early studies already demonstrated that stressor exposure at different times of the diurnal cycle generates different stress effects, whereupon the type of stressor plays a pivotal role. Moreover, alterations in the SCN and peripheral circadian clocks could be shown following stressor exposure.
In cooperation with various co-workers, I investigated whether the stress responsiveness is modulated by the endogenous clock in a diurnal fashion and whether repeated psychosocial stress impacts the circadian clock depending on the time of day of stressor exposure. Therefore, male C57BL/6 mice were repeatedly exposed to a psychosocial stressor, either at the beginning of the inactive/light phase (SDL mice) or active/dark phase (SDD mice).
Subsequently, different behavioral, physiological/endocrine and immunological/ inflammatory consequences were assessed. It could be shown that the effects of repeated psychosocial stressor exposure strongly depend on the time of day of stressor exposure. The present results demonstrate that repeated daily stressor exposure has a more negative outcome when applied during the active/dark phase compared to the inactive/light phase. Stressor exposure during the active phase resulted in a loss of general activity, decreased interest in an unfamiliar conspecific, a shift towards a more pro-inflammatory body milieu, and rhythm disturbances in plasma hormones, all representing well-accepted hallmarks of depression. In contrast, C57BL/6 mice exposed to the stressor in their inactive phase exhibited minor physiological alterations that might prevent the formation of the maladaptive consequences mentioned above, thus representing beneficial adaptations.
The second focus of this thesis was put on the investigation of the effects of repeated psychosocial stressor exposure at different times of the light-dark cycle on various levels of the circadian system. An increased expression of the PERIOD2 (PER2) protein, which represents an essential core clock component, could be found in the SCN of mice repeatedly exposed to the stressor during their active phase. In consistence with the alterations in the central circadian pacemaker, the daily rhythm of different hormones and the activity rhythm were considerably affected by SDD. Mice exposed to the psychosocial stressor in their active phase showed a shifted, or absent, rhythm of the hormones corticosterone and leptin. Moreover, their activity was found to be phase-delayed, which seems to be attributable to the Period (Per) gene since Per1/Per2 double-mutants still exhibited their normal activity rhythm following 19 days of stressor exposure during the active phase. In contrast, a phase-advance in the peripheral adrenal gland clock could be seen in C57BL/6 mice subjected to the stressor during their inactive phase. This phase-shift might be required for maintaining the normal rhythmicity in hormonal release and activity.
It has previously been suggested that activation of the HPA axis upon stressor exposure at different times of the light-dark cycle is depending on whether the stressor is of physical or psychological nature. Data from the HPA axis analysis now refine previous findings, indicating that psychosocial stressors also modulate HPA axis responses based on the time of day of stressor presentation. The present results demonstrate that HPA axis activity was reduced following repeated stressor exposure during the active phase. It is reasonable to speculate that this reduced basal activity of the stress system represents a failure in HPA axis adjustment, which could contribute to the negative consequences of repeated psychosocial stressor exposure during the dark phase.
Taken together, it can be concluded that the endogenous clock in mice modulates the stress responsiveness in a circadian fashion and that repeated psychosocial stressor exposure affects the biological clock depending on the time of day of stressor presentation. Thereby, stressor exposure during the active phase results in a more negative outcome as compared to stressor experience during the inactive phase. It is assumed that the interaction between the circadian clock and the stress system is a complex issue that might ensure that the endogenous clock does not get out of synchrony in any order.
In several countries, a decline in mortality, case-fatality and recurrence rates of stroke was observed. However, studies investigating sex-specific and subtype-specific (pathological and etiological) time trends in stroke mortality, case-fatality and recurrence rates are scarce, especially in Germany. The decline in ischemic stroke mortality and case-fatality might be associated with the high quality of acute care of ischemic stroke, but the exact determinants of early outcome remains unknown for Germany.
Therefore, as first step of this thesis, we investigated the time trends of subtype- and sex-specific age- standardized stroke mortality rates in Germany from 1998 to 2015, by applying joinpoint regression on official causes of death statistics, provided by the Federal Statistical Office. Furthermore, a regional comparison of the time trends in stroke mortality between East and West was conducted. In the second step, time trends in case-fatality and stroke recurrence rates were analyzed using data from a population- based stroke register in Germany between 1996 and 2015. The analysis was stratified by sex and etiological subtype of ischemic stroke. In the third step, quality of stroke care and the association between adherence to measures of quality of acute ischemic stroke care and in-hospital mortality was estimated based on data from nine regional hospital-based stroke registers in Germany from the years 2015 and 2016.
We showed that in Germany, age-standardized stroke mortality declined by over 50% from 1998 to 2015 both, in women and men. Stratified by the pathological subtypes of stroke, the decrease in mortality was larger in ischemic stroke compared to hemorrhagic stroke. Different patterns in the time trends of stroke were observed for stroke subtypes, regions in Germany (former Eastern part of Germany (EG), former Western part of Germany (WG)) and sex, but in all strata a decline was found. By applying joinpoint regression, the number of changes in time trend differed between the regions and up to three changes in the trend in ischemic stroke mortality were detected. Trends in hemorrhagic stroke were in parallel between the regions with up to one change (in women) in joinpoint regression. Comparing the regions, stroke mortality was higher in EG compared to WG throughout the whole observed time period, however the differences between the regions started to diminish from 2007 onwards.
Further it was found that, based on the population-based Erlangen Stroke Project (ESPro), case-fatality and recurrence rates in ischemic stroke patients are still high in Germany. 46% died and 20% got a recurrent stroke within the first five years after stroke. Case-fatality rates declined statistically significant from 1996 to 2015 across all ischemic stroke patients and all etiological subtypes of ischemic stroke. Based on Cox regression no statistically significant decrease in stroke recurrence was observed.
Based on the pooled data of nine regional hospital-based stroke registers from the years 2015 and 2016 covering about 80% of all hospitalized stroke patients in Germany, a high quality of care of acute ischemic stroke patients, measured via 11 evidence-based quality indicators (QI) of process of care, was observed. Across all registers, most QI reached the predefined target values for good quality of stroke care. 9 out of 11 QI showed a significant association with 7-day in-hospital mortality. An inverse linear association between overall adherence to QI and 7-day in-hospital mortality was observed.
In conclusion, stroke mortality and case-fatality showed a favorable development over time in Germany, which might partly be due to improvements in acute treatment. This is supported by the association between overall adherence to quality of care and in-hospital mortality. However, there might be room for improvements in long-term secondary prevention, as no clear reduction in recurrence rates was observed.
Sepsis ist eine dysregulierte Reaktion des Organismus auf eine Infektion. Bei Sepsis werden oft Blutungs- und Thromboseereignisse beobachtet, welche in einer Disseminierten Intravasalen Gerinnung (DIG) gipfeln können. Thrombozyten sind die Schlüsselzellen von Thrombose und Hämostase. Bei Sepsis und DIG kommt es häufig zu einem Abfall der Thrombozytenzahl, doch Blutungs- und Thromboseereignisse können unabhängig von der Thrombozytenzahl auftreten, was zusätzlich eine Veränderung der Thrombozytenfunktion nahelegt.
In dieser Arbeit wurde deshalb die Thrombozytenfunktion bei 15 Patienten mit Sepsis zu drei Zeitpunkten im Krankheitsverlauf untersucht. Es konnte bei unauffälliger Rezeptorexpression keine Voraktivierung der Thrombozyten mittels Durchflusszytometrie festgestellt werden. Jedoch war die Aktivierung nach Stimulation mit multiplen Agonisten signifikant reduziert. Besonders ausgeprägt war die Hyporeaktivität bei Stimulation des Kollagen-Rezeptors GPVI mit dem Agonisten CRP-XL. Es wurde gezeigt, dass nach GPVI-Stimulation eine reduzierte Phosphorylierung der nachgeschalteten Proteine Syk und LAT im Vergleich zum Gesundspender induziert wird. In Kreuzinkubationsexperimenten hatte die (Co )Inkubation von Thrombozyten in Plasma von Sepsispatienten oder mit Bakterienisolaten aus Sepsis-Blutkulturen keinen Effekt auf die Thrombozytenreaktivität. Allerdings konnte durch Sepsis-Vollblut eine signifikante GPVI-Hyporeaktivität in Thrombozyten von gesunden Probanden induziert werden, was einen zellulären Mediator als Ursache des Defekts nahelegt. In dieser Arbeit wurde gezeigt, dass insbesondere die GPVI-Signalkaskade bei Sepsis massiv beeinträchtigt ist. Der Immunorezeptor GPVI ist ein vielversprechendes Zielmolekül, um die Pathogenese der Sepsis, des Capillary Leak und die immunregulatorische Rolle von Thrombozyten besser zu verstehen. Die GPVI-Hyporeaktivität könnte als zukünftiger Biomarker für die Sepsis-Frühdiagnose genutzt werden.
Sepsis ist ein häufiges und akut lebensbedrohliches Syndrom, das eine Organfunktionsstörung in Folge einer dysregulierten Immunantwort auf eine Infektion beschreibt. Eine frühzeitige Diagnosestellung und Therapieeinleitung sind von zentraler Bedeutung für das Überleben der Patient:innen. In einer Pilotstudie konnte unsere Forschungsgruppe mittels Durchflusszytometrie eine ausgeprägte Hyporeaktivität der Thrombozyten bei Sepsis nachweisen, die einen potenziell neuen Biomarker zur Sepsis-Früherkennung darstellt. Zur Evaluation des Ausmaßes und Entstehungszeitpunktes der detektierten Thrombozytenfunktionsstörung wurden im Rahmen der vorliegenden Arbeit zusätzlich zu Patient:innen mit Sepsis (SOFA-Score ≥ 2; n=13) auch hospitalisierte Patient:innen mit einer Infektion ohne Sepsis (SOFA-Score < 2; n=12) rekrutiert. Beide Kohorten wurden zu zwei Zeitpunkten (t1: <24h; t2: Tag 5-7) im Krankheitsverlauf mittels Durchflusszytometrie und PFA-200 untersucht und mit einer gesunden Kontrollgruppe (n=28) verglichen.
Phänotypische Auffälligkeiten der Thrombozyten bei Sepsis umfassten: (i) eine veränderte Expression verschiedener Untereinheiten des GPIb-IX-V-Rezeptorkomplexes, die auf ein verstärktes Rezeptor-Shedding hindeutet; (ii) ein ausgeprägtes Mepacrin-Beladungsdefizit, das auf eine zunehmend reduzierte Anzahl von δ-Granula entlang des Infektion-Sepsis Kontinuums hinweist; (iii) eine Reduktion endständig gebundener Sialinsäure im Sinne einer verstärkten Desialylierung. Die funktionelle Analyse der Thrombozyten bei Sepsis ergab bei durchflusszytometrischer Messung der Integrin αIIbβ3-Aktivierung (PAC-1-Bindung) eine ausgeprägte generalisierte Hyporeaktivität gegenüber multiplen Agonisten, die abgeschwächt bereits bei Infektion nachweisbar war und gemäß ROC-Analysen gut zwischen Infektion und Sepsis diskriminierte (AUC >0.80 für alle Agonisten). Im Gegensatz dazu zeigten Thrombozyten bei Sepsis und Analyse mittels PFA-200 unter Einfluss physiologischer Scherkräfte eine normale bis gar beschleunigte Aggregation.
Die Reaktivitätsmessung von Thrombozyten mittels Durchflusszytometrie stellt weiterhin einen vielversprechenden Biomarker für die Sepsis-Früherkennung dar. Für weitere Schlussfolgerungen ist jedoch eine größere Kohorte erforderlich. In nachfolgenden Untersuchungen sollten zudem mechanistische Ursachen der beschriebenen phänotypischen und funktionellen Auffälligkeiten von Thrombozyten bei Infektion und Sepsis z.B. mittels Koinkubationsexperimenten untersucht werden.
The thesis provides insights in reconstruction and analysis pipelines for processing of
three-dimensional cell and vessel images of megakaryopoiesis in intact murine bone.
The images were captured in a Light Sheet Fluorescence Microscope. The work
presented here is part of Collaborative Research Centre (CRC) 688 (project B07) of
the University of Würzburg, performed at the Rudolf-Virchow Center. Despite ongoing
research within the field of megakaryopoiesis, its spatio-temporal pattern of
megakaryopoiesis is largely unknown. Deeper insight to this field is highly desirable to
promote development of new therapeutic strategies for conditions related to
thrombocytopathy as well as thrombocytopenia. The current concept of
megakaryopoiesis is largely based on data from cryosectioning or in vitro studies
indicating the existence of spatial niches within the bone marrow where specific stages
of megakaryopoiesis take place. Since classic imaging of bone sections is typically
limited to selective two-dimensional views and prone to cutting artefacts, imaging of
intact murine bone is highly desired. However, this has its own challenges to meet,
particularly in image reconstruction. Here, I worked on processing pipelines to account
for irregular specimen staining or attenuation as well as the extreme heterogeneity of
megakaryocyte morphology. Specific challenges for imaging and image reconstruction
are tackled and solution strategies as well as remaining limitations are presented and
discussed. Fortunately, modern image processing and segmentation strongly benefits
from continuous advances in hardware as well as software-development. This thesis
exemplifies how a combined effort in biomedicine, computer vision, data processing
and image technology leads to deeper understanding of megakaryopoiesis. Tailored
imaging pipelines significantly helped elucidating that the large megakaryocytes are
broadly distributed throughout the bone marrow facing a surprisingly dense vessel
network. No evidence was found for spatial niches in the bone marrow, eventually
resulting in a revised model of megakaryopoiesis.
Fabry disease (FD) is an X-linked lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A deficiency. We studied α-galactosidase A knockout mice (GLA KO) as a model for sensory disturbance and pain in FD.
Pain associated behavior of young (3 months) and old (≥18 months) GLA KO mice and wildtype (WT) littermates in an inflammatory and a neuropathic pain model was investigated. Furthermore, affective and cognitive behavior was assessed in the naïve state and in an inflammatory pain model. Gene and protein expression of pain associated ion channels and Gb3 accumulation in dorsal root ganglion (DRG) neurons was determined. We also performed patch clamp analysis on cultivated DRG neurons and human embryonic kidney 293 (HEK) cells expressing voltage-gated-sodium channel 1.7 (Nav1.7) as an in vitro model of FD. Intracellular Gb3 deposits were modulated using shRNA silencing of α-galactosidase A.
After intraplantar injection of complete Freund`s adjuvant (CFA) and chronic constriction injury (CCI) of the right sciatic nerve, old GLA KO mice did not develop heat and mechanical hypersensitivity in contrast to young GLA KO and old WT mice. Additionally, we found no relevant differences between genotypes and age-groups in affective and cognitive behavior in the naïve state and after CFA injection. Gene and protein expression analysis provided no explanation for the observed sensory impairment. However, cultured DRG neurons of old GLA KO mice revealed a marked decrease of sodium and Ih-currents compared to young GLA KO and old WT mice. DRG neurons of old GLA KO mice displayed substantial intracellular accumulation of Gb3 compared to young GLA KO and old WT mice. Similar to cultured neurons, sodium currents were also decreased in HEK cells treated with shRNA and consecutively increased intracellular Gb3 deposits compared to the control condition, but could be rescued by treatment with agalsidase-alpha.
Our study unveils that, similar to patients with FD, GLA KO mice display age-dependent sensory deficits. However, contrary to patients, GLA KO mice are also protected from hypersensitivity induced by inflammation and nerve lesion due to Gb3-dependent and reversible reduction of neuronal sodium- and Ih-currents. Our data provide evidence for direct Gb3-dependent ion channel impairment in sensory DRG neurons as a potential contributor to sensory dysfunction and pain in FD.
After almost two decades of extensive research, some controversy has remained regarding the self-renewal of resident macrophages of the central nervous system (CNS). Concurrently, the vessel wall has emerged as a potentially ubiquitous niche for stem and progenitor cells, including committed macrophage precursors. It is conceivable that their occurrence in the CNS might explain the brain-resident hematopoietic potential, which has repeatedly been observed but not yet characterized in detail. In this work, the presence of hematopoietic progenitors inside and outside the vessel wall was studied in the adult mouse brain, as well as their possible contribution to the resident macrophage pool. An immunohistological analysis did not corroborate CD45+ SCA-1+ macrophage progenitors, which have been characterized in peripheral arteries, in the circle of Willis. Accordingly, the ex vivo culture of CNS vessels did not provide evidence for de novo formation of macrophages, but for the extensive proliferative capacity of mature cells. However, when analyzing whole brain suspensions in colony-forming unit (CFU) assays, rare Iba1- Cx3cr1- (immature) clonogenic cells were detected, which were enriched at the cerebral surface/meninges and differentiated into macrophages in culture. Intravenous antibody injection and cell sorting confirmed their residence behind the blood-brain barrier. Intriguingly, brain-derived CFUs produced a unique pattern of colony types compared to cells from bone marrow (BM) or blood. Still they displayed the same immunophenotype as BM-resident myeloid progenitors (CD45lo, LIN-, SCA-1-, IL7Rα-, c-KIT+) and could be further stratified into a progenitor hierarchy giving rise to all erythro-myeloid cell types in vitro. This similarity was substantiated by labeling of their progeny in Flt3Cre x Rosa26mT/mG mice, which indicated a descendance from hematopoietic stem cells. While forced repopulation of brain macrophages using the CSF-1R inhibitor PLX5622 did not point to a role of progenitors in in vivo microglia/macrophage maintenance, recent advances in hematology imply that they might be involved in CNS immunosurveillance. In conclusion, though there was no evidence for adventitial macrophage precursors in the CNS, this study confirms the presence of myeloid progenitors in the adult brain and provides the anatomical and phenotypical details necessary to elucidate their relevance in neuroinflammation.
This dissertation highlights various aspects of basic social attention by choosing versatile approaches to disentangle the precise mechanisms underlying the preference to focus on other human beings. The progressive examination of different social processes contrasted with aspects of previously adopted principles of general attention. Recent research investigating eye movements during free exploration revealed a clear and robust social bias, especially for the faces of depicted human beings in a naturalistic scene. However, free viewing implies a combination of mechanisms, namely automatic attention (bottom-up), goal-driven allocation (top-down), or contextual cues and inquires consideration of overt (open exploration using the eyes) as well as covert orienting (peripheral attention without eye movement). Within the scope of this dissertation, all of these aspects have been disentangled in three studies to provide a thorough investigation of different influences on social attention mechanisms.
In the first study (section 2.1), we implemented top-down manipulations targeting non-social features in a social scene to test competing resources. Interestingly, attention towards social aspects prevailed, even though this was detrimental to completing the requirements. Furthermore, the tendency of this bias was evident for overall fixation patterns, as well as fixations occurring directly after stimulus onset, suggesting sustained as well as early preferential processing of social features. Although the introduction of tasks generally changes gaze patterns, our results imply only subtle variance when stimuli are social. Concluding, this experiment indicates that attention towards social aspects remains preferential even in light of top-down demands.
The second study (section 2.2) comprised of two separate experiments, one in which we investigated reflexive covert attention and another in which we tested reflexive as well as sustained overt attention for images in which a human being was unilaterally located on either the left or right half of the scene. The first experiment consisted of a modified dot-probe paradigm, in which peripheral probes were presented either congruently on the side of the social aspect, or incongruently on the non-social side. This was based on the assumption that social features would act similar to cues in traditional spatial cueing paradigms, thereby facilitating reaction times for probes presented on the social half as opposed to the non-social half. Indeed, results reflected such congruency effect. The second experiment investigated these reflexive mechanisms by monitoring eye movements and specifying the location of saccades and fixations for short as well as long presentation times. Again, we found the majority of initial saccades to be congruently directed to the social side of the stimulus. Furthermore, we replicated findings for sustained attention processes with highest fixation densities for the head region of the displayed human being.
The third study (section 2.3), tackled the other mechanism proposed in the attention dichotomy, the bottom-up influence. Specifically, we reduced the available contextual information of a scene by using a gaze-contingent display, in which only the currently fixated regions would be visible to the viewer, while the remaining image would remain masked. Thereby, participants had to voluntarily change their gaze in order to explore the stimulus. First, results revealed a replication of a social bias in free-viewing displays. Second, the preference to select social features was also evident in gaze-contingent displays. Third, we find higher recurrent gaze patterns for social images compared to non-social ones for both viewing modalities. Taken together, these findings imply a top-down driven preference for social features largely independent of contextual information.
Importantly, for all experiments, we took saliency predictions of different computational algorithms into consideration to ensure that the observed social bias was not a result of high physical saliency within these areas. For our second experiment, we even reduced the stimulus set to those images, which yielded lower mean and peak saliency for the side of the stimulus containing the social information, while considering algorithms based on low-level features, as well as pre-trained high-level features incorporated in deep learning algorithms.
Our experiments offer new insights into single attentional mechanisms with regard to static social naturalistic scenes and enable a further understanding of basic social processing, contrasting from that of non-social attention. The replicability and consistency of our findings across experiments speaks for a robust effect, attributing social attention an exceptional role within the general attention construct, not only behaviorally, but potentially also on a neuronal level and further allowing implications for clinical populations with impaired social functioning.
This thesis aimed at searching for new effective agents against Multidrug-Resistant Enterobacteriaceae. This is necessitated by the urgent need for new and innovative antibacterial agents addressing the critical priority pathogens prescribed by the World Health Organization (WHO). Among the available means for antibiotics discovery and development, nature has long remained a proven, innovative, and highly reliable gateway to successful antibacterial agents. Nevertheless, numerous challenges surrounding this valuable source of antibiotics among other drugs are limiting the complete realization of its potential. These include the availability of good quality data on the highly potential natural sources, limitations in methods to prepare and screen crude extracts, bottlenecks in reproducing biological potentials observed in natural sources, as well as hurdles in isolation, purification, and characterization of natural compounds with diverse structural complexities.
Through an extensive review of the literature, it was possible to prepare libraries of plant species and phytochemicals with reported high potentials against Escherichia coli and Klebsiella pneumnoniae. The libraries were profiled to highlight the existing patterns and relationships between the reported antibacterial activities and studied plants’ families and parts, the type of the extracting solvent, as well as phytochemicals’ classes, drug-likeness and selected parameters for enhanced accumulation within the Gram-negative bacteria. In addition, motivations, objectives, the role of traditional practices and other crucial experimental aspects in the screening of plant extracts for antibacterial activities were identified and discussed.
Based on the implemented strict inclusion criteria, the created libraries grant speedy access to well-evaluated plant species and phytochemicals with potential antibacterial activities. This way, further studies in yet unexplored directions can be pursued from the indicated or related species and compounds. Moreover, the availability of compound libraries focusing on related bacterial species serves a great role in the ongoing efforts to develop the rules of antibiotics penetrability and accumulation, particularly among Gram-negative bacteria. Here, in addition to hunting for potential scaffolds from such libraries, detailed evaluations of large pool compounds with related antibacterial potential can grant a better understanding of structural features crucial for their penetration and accumulation. Based on the scarcity of compounds with broad structural diversity and activity against Gram-negative bacteria, the creation and updating of such libraries remain a laborious but important undertaking.
A Pressurized Microwave Assisted Extraction (PMAE) method over a short duration and low-temperature conditions was developed and compared to the conventional cold maceration over a prolonged duration. This method aimed at addressing the key challenges associated with conventional extraction methods which require long extraction durations, and use more energy and solvents, in addition to larger quantities of plant materials. Furthermore, the method was intended to replace the common use of high temperatures in most of the current MAE applications. Interestingly, the yields of 16 of 18 plant samples under PMAE over 30 minutes were found to be within 91–139% of those obtained from the 24h extraction by maceration. Additionally, different levels of selectivity were observed upon an analytical comparison of the extracts obtained from the two methods. Although each method indicated selective extraction of higher quantities or additional types of certain phytochemicals, a slightly larger number of additional compounds were observed under maceration. The use of this method allows efficient extraction of a large number of samples while sparing heat-sensitive compounds and minimizing chances for cross-reactions between phytochemicals.
Moreover, findings from another investigation highlighted the low likelihood of reproducing antibacterial activities previously reported among various plant species, identified the key drivers of poor reproducibility, and proposed possible measures to mitigate the challenge. The majority of extracts showed no activities up to the highest tested concentration of 1024 µg/mL. In the case of identical plant species, some activities were observed only in 15% of the extracts, in which the Minimum Inhibitory Concentrations (MICs) were 4 – 16-fold higher than those in previous reports. Evaluation of related plant species indicated better outcomes, whereby about 18% of the extracts showed activities in a range of 128–512 μg/mL, some of the activities being superior to those previously reported in related species.
Furthermore, solubilizing plant crude extracts during the preparation of test solutions for Antibacterial Susceptibility Testing (AST) assays was outlined as a key challenge. In trying to address this challenge, some studies have used bacteria-toxic solvents or generally unacceptable concentrations of common solubilizing agents. Both approaches are liable to give false positive results. In line with this challenge, this study has underscored the suitability of acetone in the solubilization of crude plant extracts. Using acetone, better solubility profiles of crude plant extracts were observed compared to dimethyl sulfoxide (DMSO) at up to 10 %v/v. Based on lacking toxicity against many bacteria species at up to 25 %v/v, its use in the solubilization of poorly water-soluble extracts, particularly those from less polar solvents is advocated.
In a subsequent study, four galloylglucoses were isolated from the leaves of Paeonia officinalis L., whereby the isolation of three of them from this source was reported for the first time. The isolation and characterization of these compounds were driven by the crucial need to continually fill the pre-clinical antibiotics pipeline using all available means. Application of the bioautography-guided isolation and a matrix of extractive, chromatographic, spectroscopic, and spectrometric techniques enabled the isolation of the compounds at high purity levels and the ascertainment of their chemical structures.
Further, the compounds exhibited the Minimum Inhibitory Concentrations (MIC) in a range of 2–256 µg/mL against Multidrug-Resistant (MDR) strains of E. coli and K. pneumonia exhibiting diverse MDR phenotypes. In that, the antibacterial activities of three of the isolated compounds were reported for the first time. The observed in vitro activities of the compounds resonated with their in vivo potentials as determined using the Galleria mellonella larvae model. Additionally, the susceptibility of the MDR bacteria to the galloylglucoses was noted to vary depending on the nature of the resistance enzymes expressed by the MDR bacteria. In that, the bacteria expressing enzymes with higher content of aromatic amino acids and zero or positive net charges were generally more susceptible. Following these findings, a plausible hypothesis for the observed patterns was put forward.
The generally challenging pharmacokinetic properties of galloylglucoses limit their further development into therapeutic agents. However, the compounds can replace or reduce the use of antibiotics in livestock keeping as well as in the treatment of septic wounds and topical or oral cavity infections, among other potential uses.
Using nature-inspired approaches, a series of glucovanillin derivatives were prepared following feasible synthetic pathways which in most cases ensured good yields and high purity levels. Some of the prepared compounds showed MIC values in a range of 128 – 512 μg/mL against susceptible and MDR strains of Klebsiella pneumoniae, Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococcus faecium (VRE). These findings emphasize the previously reported essence of small molecular size, the presence of protonatable amino groups and halogen atoms, as well as an amphiphilic character, as crucial features for potential antibacterial agents.
Due to the experienced limited success in the search for new antibacterial agents using purely synthetic means, pursuing semi-synthetic approaches as employed in this study are highly encouraged. This way, it is possible to explore broader chemical spaces around natural scaffolds while addressing their inherent limitations such as solubility, toxicity, and poor pharmacokinetic profiles.
In daily life, olfactory stimuli are potential generators of affective states, but also have a strong influence on social interaction. Pleasant odors have been shown to increase perceived attractiveness and pro-social behavior, whereas unpleasant body odors are often associated with negative personality traits. Since both pleasant odors and positive affective state facilitate pro-social behavior, it is conceivable that the influence of the odors on social interaction is mediated by the induced affective state elicited by the odor itself. The present thesis aims at exploring the impact of hedonic, i.e., pleasant or unpleasant, odors on the processing and evaluation of social stimuli as assessed by verbal, physiological, and behavioral indices. First, I investigate the effects of initially neutral odors which gained threatening value through an aversive conditioning procedure on social stimuli (Study 1). Second, I study the influence of naturally hedonic odors on social interaction. Third, this thesis aims at disentangling differences in the effects of an odor attributed to either a social interaction partner or the environment where the social encounter takes place (Study 2, 3, and 4).
In the first study, a context conditioning procedure was applied, during which one out of two long-lasting neutral odors was paired with an unpredictable aversive unconditioned stimulus (US, i.e., white noise). This odor (CTX+) thereby gained threatening value, while another odor (CTX-) remained unpaired and therefore signaled safety. During a test session, facial stimuli were presented within both conditioned olfactory contexts. Results indicate that autonomic arousal was increased to faces when presented in the threatening odor context. Additionally, participants rated facial stimuli as more aversive when presented in the threatening odor as compared to the safety odor, indicating that faces acquire hedonic value from the odor they were presented in. Strikingly, angry facial expressions received additional processing resources when presented within a threatening olfactory context, as reflected on verbal reports and electrodermal activity (EDA). This latter finding suggests that threat-related stimuli, here angry faces, are preferentially processed within an olfactory context where a threat might happen.
Considering that the hedonic value of an odor may be quite subjective, I conducted a pilot study in order to identify odors with pleasant vs. unpleasant properties for most participants. Seven odors (four pleasant and three unpleasant) were rated with respect to their valence (pleasant vs. unpleasant), arousal (arousing vs. calm), and intensity. Additionally, EDA was measured. Two pleasant (Citral and Eucalyptol) and two unpleasant (“Animalis” and Isobutyraldehyde) odors were chosen from the original seven. The unpleasant odors were rated as more negative, arousing, and intense than the positive ones, but no differences were found regarding EDA.
These four odors were subsequently used in a virtual reality (VR) paradigm with two odor attribution groups. Participants of the social attribution group (n = 59) were always passively guided into the same room (an office) towards one out of two virtual agents who were either paired with the pleasant or the unpleasant odor. Participants of the contextual attribution group (n = 58) were guided into one out of two rooms which were either paired with the pleasant or the unpleasant odor and where they always met the same agent. For both groups, the agents smiled, frowned or remained with a neutral facial expression. This design allowed evaluating the influence of odor valence as a within-subjects factor and the influence of odor attribution as a between-subjects factor. Unpleasant odors facilitated the processing of social cues as reflected by increased verbal and physiological arousal as well as reduced active approach behavior. Specific influence of odor valence on emotional facial expressions was found for ratings, EDA, and facial mimicry, with the unpleasant odor causing a levelling effect on the differences between facial expressions. The social attribution group exhibited larger differences between odors than the contextual group with respect to some variables (i.e., ratings and EDA), but not to others (i.e., electrocortical potentials – ERPs – and approach behavior). In sum, unpleasant in comparison to pleasant odors diminished emotional responses during social interaction, while an additional enhancing effect of the social attribution was observed on some variables. Interestingly, the awareness that an interaction partner would smell (pleasantly or unpleasantly) boosted the emotional reactivity towards them.
In Study 3, I adapted the VR paradigm to a within-subjects design, meaning that the different attribution conditions were now manipulated block-wise. Instead of an approach task, participants had to move away from the virtual agent (withdrawal task). Results on the ratings were replicated from Study 2. Specifically, the difference between pleasant and unpleasant odors on valence, arousal, and sympathy ratings was larger in the social as compared to the contextual attribution condition. No effects of odor or attribution were found on EDA, whereas heart rate (HR) showed a stronger acceleration to pleasant odors while participants were passively guided towards the agent. Instead of an approach task, I focused on withdrawal behavior in this study. Interestingly, independently of the attribution condition, participants spent more time withdrawing from virtual agents, when an unpleasant odor was presented. In sum, I demonstrated that the attribution of the odors to the social agent itself had an enhancing effect on their influence on social interaction.
In the fourth and last study, I applied a similar within-subjects protocol as in Study 3 with an additional Ultimatum Game task as a measure of social interaction. Overall findings replicated the results of Study 3 with respect to HR and EDA. Strikingly, participants offered less money to virtual agents in the bad smelling room than in the good smelling room. In contrast to Study 3, no effects of odor attribution were found in Study 4. In sum, again I demonstrated that unpleasant odor may lessen social interaction not only when the interaction partner smells badly, but also in more complex interaction situations.
In conclusion, I demonstrated that hedonic odors in general influence social interaction. Thus, pleasant odors seem to facilitate, while unpleasant odors seem to reduce interpersonal exchanges. Therefore, the present thesis extends the body of literature on the influence of odors on the processing of social stimuli. Although I found a direct influence of odors on social preferences as well as on the physiological and behavioral responses to social stimuli, I did not disentangle impact of odor per se from the impact of the affective state. Interestingly, odor attribution might play an additional role as mediator of social interactions such as odor effects in social interactions might be boosted when the smell is attributed to an individual. However, the results in this regard were less straightforward, and therefore further investigations are needed. Future research should also take into account gender or other inter-individual differences like social anxiety.
The human specific gram-negative bacterium Neisseria meningitidis (Nme, meningococci) is a common colonizer of the upper respiratory tract. Upon becoming invasive, Nme can cause meningitis and life-threatening sepsis. The most important immune defense mechanism in invasive meningococcal disease (IMD) is the complement mediated killing of bacteria. The complement cascade is activated through different pathogen associated patterns and finally leads to the lysis of the bacteria by the membrane attack complex. In addition to the direct bacterial killing, the complement system is also an important player in different inflammatory processes. A hallmark of IMD is an overreaction of the immune system and the release of the potent anaphylatoxins C3a and C5a by the complement system is an important factor hereby. There are three anaphylatoxin receptors (ATRs), the C3aR, the C5aR1 and the C5aR2, capable of detecting these anaphylatoxins. It has already been shown that blocking the ATR C5aR1 strongly benefitted the outcome of IMD in a murine sepsis model. However, the roles of ATRs C3aR and C5aR2 in IMD are still unclear. This work aims to analyze the role of these ATRs in meningococcal sepsis and to identify possible underlying mechanisms. Furthermore, a possible involvement of the complement system, the ATRs and the type II CRISPR/Cas system on nasopharyngeal colonization is analyzed.
In vivo depletion experiments showed that without neutrophils or monocytes/macrophages the complement system alone was not able to clear a low dose Nme infection, which highlights the importance of cellular components in IMD. Analyzing the role of the ATRs in knock-out mice with high dose Nme infections, revealed that the lack of C5aR2, like the lack of C5aR1, was beneficial for the outcome of meningococcal induced sepsis. In contrast, the lack of C3aR in knock-out mice was detrimental. The positive outcome associated with the C5aRs could be reproduced by using an antagonist against both C5aRs or an antagonist specifically against C5aR1 in WT mice. These findings are giving hope to future therapeutic applications. Next, a possible contribution of neutrophils to this positive outcome was analyzed. Absence of C5aR1 led to a decrease of degranulation by neutrophils in a murine whole blood model, while the other ATRs showed no effect. Neutrophil analysis in human whole blood, on the other hand, revealed a reduced oxidative burst and IL-8 secretion upon inhibition of all three ATRs. A functional difference between the C5aRs and the C3aR in neutrophils was observed in phagocytosis, which was reduced upon C3aR inhibition, but was unaltered with C5aR1 or C5aR2 inhibition. Possible underlying mechanisms in the phosphorylation of ERK1/2 were analyzed in bone marrow derived macrophages isolated from ATR knock-out mice. The later phosphorylation of ERK1/2 in macrophages without C5aR1 or C5aR2 expression might explain, why blocking the C5aRs is beneficial for the outcome of IMD in mice. In contrast to these findings, the colonization of the nasopharynx in huCEACAM 1 expressing mice by Nme did not seem to depend on the Complement system factors C3 and C5 nor the ATRs. Additionally, no difference in the colonization could be observed in this model using Nme mutants lacking different parts of the type 2 CRISPR/Cas system.
Conclusively, this work highlights the importance of the complement system, the ATRs and the cellular components in IMD. Contrariwise, these factors did not play a role in the analyzed nasopharyngeal infection model. The beneficial effects of C5aR1 and C5aR2 lack/inhibition in IMD might have medicinal applications, which could support the standard therapies of IMD in the future.
Strumpellin is a member of the highly conserved pentameric WASH complex, which stimulates the Arp2/3 complex on endosomes and induces the formation of a branched actin network. The WASH complex is involved in the formation and stabilisation of endosomal retrieval subdomains and transport carriers, into which selected proteins are packaged and subsequently transported to their respective cellular destination, e.g. the plasma membrane. Up until now, the role of Strumpellin in platelet function and endosomal trafficking has not been researched. In order to examine its role, a conditional knockout mouse line was generated, which specifically lacked Strumpellin in megakaryocytes and platelets.
Conditional knockout of Strumpellin resulted in only a mild platelet phenotype. Loss of Strumpellin led to a decreased abundance of the αIIbβ3 integrin in platelets, including a reduced αIIbβ3 surface expression by approximately 20% and an impaired αIIbβ3 activation after platelet activation. The reduced surface expression of αIIbβ3 was also detected in megakaryocytes. The expression of other platelet surface glycoproteins was not affected. Platelet count, size and morphology remained unaltered. The reduction of αIIbβ3 expression in platelets resulted in a reduced fibrinogen binding capacity after platelet activation. However, fibrinogen uptake under resting conditions, although slightly delayed, as well as overall fibrinogen content in Strumpellin-deficient platelets were comparable to controls. Most notably, reduced αIIbβ3 expression did not lead to any platelet spreading and aggregation defects in vitro. Furthermore, reduced WASH1 protein levels were detected in the absence of Strumpellin.
In conclusion, loss of Strumpellin does not impair platelet function, at least not in vitro. However, the data demonstrates that Strumpellin plays a role in selectively regulating αIIbβ3 surface expression. As a member of the WASH complex, Strumpellin may regulate αIIbβ3 recycling back to the platelet surface. Furthermore, residual WASH complex subunits may still assemble and partially function in the absence of Strumpellin, which could explain the only 20% decrease in αIIbβ3 surface expression. Nonetheless, the exact mechanism still remains unclear.
During development of the nervous system, spontaneous Ca2+ transients are observed that regulate the axon growth of motoneurons. This form of spontaneous neuronal activity is reduced in motoneurons from a mouse model of spinal muscular atrophy and this defect correlates with reduced axon elongation. Experiments from our group demonstrated that voltage-gated sodium channel pore blockers decrease spontaneous neuronal activity and
axon growth in cultured motoneurons, too. In these experiments, saxitoxin was more potent than tetrodotoxin. We identified the saxitoxin-sensitive/tetrodotoxin-insensitive voltage-gated sodium channel NaV1.9 as trigger for the opening of voltage-gated calcium channels. In motoneurons, expression of NaV1.9 was verified via quantitative RT-PCR. Immuno labelling
experiments revealed enrichment of the channel in axonal growth cones and at the nodes of Ranvier of isolated nerve fibres from wild type mice. Motoneurons from NaV1.9 knock-out mice show decreased spontaneous activity and reduced axonal elongation. This growth defect can be rescued by NaV1.9 overexpression. In motoneurons from Smn-deficient mice, NaV1.9 distribution appeared to be normal.
Recently, patients carrying a missense mutation in the NaV1.9-encoding gene SCN11A were identified. These patients are not able to feel pain and suffer from muscular weakness and a delayed motor development. Molecular biological work during this dissertation supported the analysis of this mutation in a mouse model carrying the orthologous alteration in the Scn11a
locus. The cooperation study confirmed that a gain-of-function mechanism underlies the NaV1.9-mediated channelopathy, thus suggesting a functional role of NaV1.9 in human motoneurons.
An earlier study showed in hippocampal neurons that the receptor tyrosine kinase tropomyosin receptor kinase B (TrkB) can open the NaV1.9 channel. TrkB is localized in
growth cones of motoneurons and subsequently found in close proximity to NaV1.9. In order to proof whether TrkB is involved in spontaneous excitability in motoneurons, TrkB knock-out mice were analysed. Isolated motoneurons from TrkB knock-out mice show a reduced spontaneous activity and axon elongation. It remains to be studied whether TrkB and NaV1.9 are functionally connected.