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Einsatz von künstlicher Intelligenz (SoundTalks®) zur Überwachung respiratorischer Erkrankungen in Kombination mit dem Monitoring von PRDC (porcine respiratory disease complex)-assoziierten Pathogenen mittels oral fluid samples sowie Bioaerosolen in einer Ferkelaufzucht
Get PDFFibroblast Growth Factor 21 im Kontext von Glukosestoffwechsel und Metabolischem Syndrom in einer humanen Kohortenstudie
Get PDFTowards EPID-based 3D in vivo dosimetry for modern radiation therapy
Get PDFModern radiotherapy techniques, such as Intensity Modulated Radiation Therapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT), can deliver highly conformal dose distributions, with steep dose gradients between the target and organs at risk. This increases the demands on proper quality assurance and dose verification before (pre-treatment) and during (in vivo) patient irradiation. This project proposes a methodology for EPID-based in vivo dosimetry, combining the accuracy of Monte Carlo (MC) methods for dose simulation in patient geometry, with the time-efficiency of deep neural networks. The Deep Dose Estimation (DDE) network, originally developed for dose estimation in radiological computed tomography (CT) exams, has been extended and trained to predict 3D dose distributions due to IMRT fields, inside a patient, with accuracy comparable to MC methods.
The DDE uses as input a patient CT image and an approximated dose distribution,
called first order dose approximation (FOD), reconstructed from simulated EPID signals. The network was trained to map this two-channel input to an accurate dose distribution (ADD) inside the same patient CT, simulated using MC methods. The FODs are simplified 3D dose distributions produced as backprojections of the simulated EPID signals, accounting for magnification and inverse square law corrections, and attenuation through the virtual patient model. The FODs do not account for several effects, such as the build-up, beam hardening and scattering within the patient, all of which were properly considered in the ADDs.
Hence, the methodology relies strongly on the MC model used to produce both the
ADD and the transmitted EPID signals. A reliable MC model of the linac considered in this work was constructed and extensively validated. The patient-dependent part of the linac head, namely the multi-leaf collimator (MLC) system, was produced based entirely on information available in the literature. A virtual model of the EPID was also included in the patient-dependent part, to simultaneously record the transmitted signal through the virtual patient. The patient-independent part, i.e. the static parts of the linac head, was constructed based on confidential information provided by the vendor, and used to produce phase space (PhSp) files. These PhSp files were subsequently used as primary particle generators to simulate the ADDs and EPID signals. An alternative methodology for optimization of existing IAEA PhSp files was developed as a side project, which can be used to model the patient-independent part of the linac head when confidential vendor information is not available.
The ADDs for clinical prostate IMRT fields, and respective transmitted EPID signals,
were simulated inside 83 pelvic CTs, with gantry at 0�. In total, 581 different ADD-FOD sets were produced, with seven different fields per patient CT. The network was trained using the data sets of 67 patients (training set). The data of the remaining 16 patients were used for validation (test set). An additional dataset with eight fields simulated with gantry at 90� (lateral set) was used for evaluating the performance of the trained DDE for other irradiation directions.
The quality of the DDE-predicted dose distributions (DDEP) on the test and lateral
sets was quantified in terms of the gamma analysis with respect to the ADD (3%, 2 mm criteria). To evaluate the improvement obtained with the DDE, the same evaluation was performed for FODs and respective ADDs. The gamma passing rates between FODs and ADDs were as low as 46%, while for DDEPs the passing rates were above 97% for all fields on the test set. For the fields in the lateral set, the DDE was able to improve the passing rates from 88% to above 95%. The high passing rates for DDEPs indicate that the DDE was able to convert the FODs into ADDs, properly accounting for all missing effects. Moreover, once trained, the DDE can predict the dose inside a patient CT within 0.6 s per field (using a GPU), in contrast to 14 h needed for MC simulations (using a CPU-cluster). The dose delivered to a patient due to an entire prostate treatment session can therefore be predicted in less than one minute. With the proposed methodology, 3D in vivo dose
distributions due to clinical patient irradiation can be obtained within seconds, potentially paving the way towards a clinically viable, real-time EPID-based in vivo dosimetry
PsyCoP – a novel platform for deep behavioral phenotyping and its use for the characterization of high validity psychiatric mouse models
Get PDFThere is still an urgent clinical need for new psychopharmacological treatments due to this far unaddressed symptoms and treatment resistance. In the last decades most developments failed, also because of the lack of appropriate and well characterized cellular and animal models. In recent years, advances in human genetics and patient-derived cellular models fostered new insights in the pathogenesis of and recovery from psychiatric disorders. The aim of this thesis was to make use of these advances to identify targets and characterize high construct validity mouse models based on these targets, with the help of a novel approach to behavioral profiling and single-cell transcriptomics, to increase predictive value.
For deep phenotyping, we developed a standardized platform for systematic and semi-automated cognitive and behavioral profiling (PsyCoP), investigating the Cry1/2-/- double-knockout (Cry DKO) mouse model in the process. Further, we paired the Cry DKO genetic factor with a shift work paradigm as environmental factor to gain a high construct validity ‘two-hit’ model of a changed risk for alcohol use disorder (AUD).
In addition, I established an improved data analysis pipeline for PsyCoP, adopting the Research Domain Criteria (RDoC) framework for high translational value. We then used PsyCoP first to characterize the Tcf4-transgenic social defeat (Tcf4xSD) ‘two-hit’ model, revealing gene x environment (GxE) interactions producing severe cognitive dysfunctions found in schizophrenia and other psychotic disorders. Further, we validated the beneficial effect of the repurposed compound spironolactone on cognitive functions in the Tcf4xSD mouse model.
We went on to investigate the genetics underlying lithium responsiveness with gene-set-based enrichment analyses, finding a strong association of the circadian core clock and lithium therapy outcome. Further, we identified the circadian modulator BHLHE41 as a top hit. Then, we demonstrated partial lithium non-responsiveness of Bhlhe40/41-/- double-knockout (Bhl-he40/41 DKO) mice in several cognitive tasks. Further, we found reduced neuronal excitability and synaptic plasticity in response to lithium treatment, again, with a partial or total non-responsiveness of Bhlhe40/41 DKO mice. These findings suggest neuronal excitability modulation as a central mechanism of lithium’s therapeutic effect and Bhlhe40/41 DKO mice as a potential model for non-responder patients.
Lastly, we improved the characterization of a patient-derived cellular model of myelination with the help of RNA velocity analysis. With the help of these models, we will hopefully be able to identify targets for improved mouse models of disturbed myelination.
In summary, we were able to characterize and use several high validity mouse models psychiatric disorder endophenotypes with the help of the PsyCoP that will hopefully help to improve the translational value preclinical animal study and thus the success of psychopharmacological development to meet psychiatric clinical needs.Es besteht nach wie vor dringender Bedarf an neuen psychopharmakologischen Medikamenten. Jedoch scheiterten bisher die meisten Entwicklungsversuche unter anderem aufgrund des Mangels an geeigneten und gut charakterisierten Zell- und Tiermodellen. In den letzten Jahren haben wissenschaftliche Fortschritte neue Einblicke in die Pathogenese von psychiatrischen Störungen und deren Heilung ermöglicht. Ziel dieser Arbeit war es, diese Fortschritte zu nutzen, um Targets zu identifizieren und Mausmodelle mit hoher Konstrukt-Validität zu charakterisieren. Dazu wurde ein neuartiger Ansatz zur Verhaltensprofilierung verwendet, um den prädiktiven Wert der Studien zu erhöhen.
Für eine tiefgreifende Phänotypisierung entwickelten wir eine standardisierte Plattform für die systematische und halbautomatische Erstellung von kognitiven und Verhaltensprofilen (PsyCoP) und untersuchten dabei das Cry1/2-/--Doppelknockout (Cry-DKO) -Mausmodell. Darüber hinaus haben wir den genetischen Faktor Cry-DKO mit einem Schichtarbeitssystem als Umweltfaktor kombiniert, um ein ätiologisch valides "Two-Hit"-Modell eines veränderten Risikos für Alkoholmissbrauchsstörungen (AUD) zu erhalten.
Des Weiteren habe ich eine Datenanalyse-Pipeline für PsyCoP entwickelt, die das Research Domain Criteria (RDoC)-Konzept für einen hohen translationalen Wert nutzt. Wir nutzten PsyCoP dann zunächst zur Charakterisierung des Tcf4-transgenen Modells gepaart mit psychosozialem Stress durch wiederholte soziale Niederlagen (Social Defeat; Tcf4xSD), um die Wechselwirkungen zwischen Genetik und Umgebung (GxE) zu untersuchen, die zu schweren kognitiven Störungen bei Schizophrenie und anderen psychotischen Störungen führen. Darüber hinaus validierten wir die positive Wirkung des kürzlich als pro-kognitiv wirkend identifizierten Wirkstoffs Spironolacton auf die kognitiven Funktionen im Tcf4xSD-Mausmodell.
Anschließend untersuchten wir die genetischen Grundlagen der Lithiumantwort mit Hilfe von Gen-Set-basierten Enrichment-Analysen und fanden einen starken Zusammenhang zwischen der zirkadianen Uhr und Lithiumtherapie-Erfolg. Darüber hinaus identifizierten wir den zirkadianen Modulator BHLHE41 als einen Top-Hit. Anschließend wiesen wir nach, dass Bhlhe40/41-/--Doppelknockout-Mäuse (Bhlhe40/41-DKO) bei verschiedenen kognitiven Aufgaben teilweise nicht auf Lithium ansprechen. Diese verschlechterte Antwort fand sich auch für den Effekt von Lithium auf die neuronale Erregbarkeit und synaptische Plastizität. Diese Ergebnisse deuten darauf hin, dass die Modulation der neuronalen Erregbarkeit ein zentraler Mechanismus der therapeutischen Wirkung von Lithium sein könnte und Bhlhe40/41-DKO-Mäuse ein potenzielles Modell für Patienten sind, die nicht auf Lithium ansprechen.
Schließlich haben wir die Charakterisierung eines vom Patienten stammenden zellulären Modells der Myelinisierung mit Hilfe der RNA-Velocity-Analyse verbessert. Mit Hilfe dieser Modelle werden wir hoffentlich in der Lage sein, Targets für verbesserte Mausmodelle einer gestörten Myelinisierung zu identifizieren
On computations and their maintenance in the mouse visual system
Get PDFThe mammalian visual system is composed of several stages of stimulus feature extraction, distributed across multiple visual areas. Brain areas of the visual system are hierarchically organized from retina, to thalamus and superior colliculus, to primary visual cortex and higher visual areas. Each of these areas is uniquely adapted to perform specific computations on the visual information it receives. These computations arise through the anatomical arrangement of axons and dendrites, as well as experience dependent plasticity mechanisms, which form specific circuit motifs over the course of development. However, once these circuits are established, parts of this system remain plastic, allowing for some degree of adaptability. In this thesis, I will pose the following two questions. First, what are the connectivity rules in the visual thalamus, which result in visual channel segregation? I will focus on the convergence of eye-specific inputs to thalamic neurons as my model. Second, what is the stability of visual feature tuning in the primary visual cortex, and what are the factors that modulate their stability? Here, I will use orientation preference of layer 2/3 neurons as my model.
In the first study, I evaluated the convergence of retinal ganglion cell (RGC) inputs from the two eyes onto thalamocortical (TC) neurons in the dorsal lateral geniculate nucleus (dLGN) of the mouse. The canonical view of this brain region in mammals is that it maintains the separation of distinct visual channels. This includes the separation of information from the two eyes. In the past, several conflicting reports have been published on the level of such binocular convergence in the mouse. I employed a dual colour optogenetic input mapping approach and demonstrated that the level of binocularity of TC neurons is relatively low. This is because individual TC neurons receive disproportionately stronger input from one eye compared to the other. I next tested whether limited axodendritic overlap, between RGC axons and TC neuron dendrites, could explain this low level of binocular convergence. Although the segregation of RGC projections from the two eyes into two distinct zones does result in regions where ipsilateral dominant neurons are more numerous, limited axodendritic overlap cannot explain the low level of convergence onto individual neurons. Instead, synaptic selection and refinement prevents the mixing of information from the two eyes at this level of the mouse visual system.
In the second study, I investigated representational drift in the mouse primary visual cortex (V1), using chronic two-photon calcium imaging. Representational drift, the time dependent decrease in the similarity of neuronal responses to sensory stimuli, has been observed across multiple brain regions, including V1. However, so far, a specific tuning feature that undergoes such time dependent drift has not been demonstrated. Furthermore, a recent study showed that the frequency of exposure to an odour correlates with the stability of its representations in the olfactory cortex. My results demonstrate that the preferred orientation of neurons is one visual feature that undergoes time dependent representational drift. I then used cylinder lens goggles to alter the range of orientations a mouse experiences for several weeks, and found that this did not alter the drift rate of preferred orientation. Nevertheless, the distorted visual experience altered the direction of preferred orientation drift in favour of the experienced orientation, resulting in a shift of the overall distribution of preferred orientations. This suggests that ongoing representational drift may allow the visual system to adapt to changes in the statistics of the visual environment.
Taken together, in this thesis I explore how both anatomy and experience shape computations and their maintenance in the mouse visual system
Voix plurielles, voies de traverse
Get PDFLes peintres anglais exposent peu dans l’Allemagne du XIXe siècle ce qui a fait dire à certains historiens de l'art allemands que l'on n'avait rien vu de l'art anglais avant le tournant du siècle. Pourtant l'art anglais y avait été bien présent tout au long du siècle. De ce paradoxe est né ce projet de thèse qui souhaite éclairer les voies et voix plurielles d'une réception à la fois populaire et critique qui ne se construit pas seulement face aux originaux, mais aussi, et parfois essentiellement, face aux reproductions, par des biais culturels variés. En mettant l'accent sur le genre de la peinture de paysage, il est possible de retracer l’évolution au long cours de cette réception riche et protéiforme, d’analyser les mécanismes culturels et idéologiques qui la sous-tendent, et d’identifier ses lacunes et ses contradictions. Une question centrale revient tout au long de la période : celle de l’anglicité de l'art anglais. Cette question s'inscrit dans une vision plus large et fantasmée de l’Angleterre. Aussi, en travaillant sur ce complexe contexte de réception, il est possible d'observer le laboratoire d'une histoire de l'art dont l'une des convictions était la définition dans l'art de constantes nationales et identitaire
Notwendigkeit der Perfusionsbildgebung in der MRT-Diagnostik des Prostatakarzinoms in Zeiten der Hochfeld-Diffusionsbildgebung
Get PDFAnalysis of the structure and function of dendrites and dendritic spines
Get PDFA single pyramidal cell carries about 30,000 synapses, and almost all of them can be found on dendritic spines. Spines are, therefore, an integral part of neuronal architectures. They are also
essential for the mammalian nervous system. Despite their importance in memory formation and the integration of synaptic input, many aspects of the function of dendritic spines remain under debate.
Unfortunately, the small size of dendritic spines makes experimental investigation difficult, and a better understanding of their complex interactions with other parts of the nervous system requires the study of various aspects across different scales, including molecular organization, morphology, and the dendritic tree as a whole.
Quantitative theoretical models are needed to reveal the function of dendritic spines. The objective of this thesis is to explore different aspects of the structure and function of dendritic spines and dendrites, and to develop simplified but accurate descriptions of these systems. By building on the relationships between these elements, this work aims to develop a solid theoretical framework to improve our understanding of dendritic spines' role in synaptic integration and plasticity
