Optical imaging has exceptional potential for medical diagnosis, because it can provide high spatial resolution and molecular contrast. However, for in vivo imaging in humans, the poor penetration of only a few millimetres is a major obstacle. Optical endoscopes solve this problem, but currently most of them only perform non-advanced, classical white light imaging. Also, the speed of current devices is not sufficient to comprehensively scan entire organs at microscopic resolution. Hence, medical imaging is still dominated by non-optical techniques like X-ray, ultrasound and magnetic resonance imaging. The objective of ENCOMOLE-2i is to push the performance of advanced optical in vivo imaging techniques to cross the application threshold for clinical research and practice. An endoscopic multi-modal molecular imaging platform will be developed with unprecedented capabilities for the diagnosis of disease. The hardware technology development includes three novel imaging modalities. Optical coherence tomography with line rates of several Megahertz will be used for comprehensive structural imaging over large areas. Time encoded stimulated Raman sensing, supported by a new type of two photon microscopy, will be used for guided and referenced molecular imaging. Combining these techniques into one system and interfacing it with a newly developed endoscope will generate great synergy. Moreover, the unique synchronization capabilities of these modalities enable a radically new strategy for more efficient data acquisition: The concept of adaptive “Intelligent Imaging”. The goal is to develop a universal endoscopy platform which can then be specifically tailored to the individual application. In the project the focus is on gastrointestinal imaging. The synergy between technological and algorithmic advances in ENCOMOLE-2i will break ground for more optical in vivo imaging in clinical research and routine, which can finally lead to improved diagnosis of many types of disease.

The last decade of research in enteric virus infection produced a body of compelling evidences that challenged the paradigm of the single infection unit, where a single virus is able to elicit infection of a target cell. Instead, observational studies of infection in vivo and in vitro suggest that enteric viruses travel in groups: in vesicles with inverted phosphatidylserine topology or at the surface of commensal bacteria. It has been proposed that both strategies increase locally the viral multiplicity of infection, thus favoring viral complementation of defective genomes. There is a lack of knowledge on the biological relevance of the so-called multiple infection unit (MIU) as it has not been mechanistically studied in physiologically relevant model of the GI tract. In addition, the MIU is a strategy employed by all the enteric viruses so far tested, therefore it might represent a valuable target for the design of broad spectrum therapeutics. The central hypothesis of this project is that targeting MIU will inhibit enteric virus infection ex vivo and in vivo. My model of enteric virus is human norovirus (HNoV) for its clinical relevance and for its well described interaction with commensal bacteria. In work package (WP)1, to gain insight on the biological relevance of MIU in ex vivo physiologically relevant models, I will test the hypothesis that MIU increases HNoV infection in human intestinal enteroids. In aim 2, I will develop an in vitro screening platform by pulldown assay with His-tagged HNoV virus-like particles to i) screen for small molecules inhibitors of the infection and ii) identify bacterial species that are bound to HNoV in stool derived from healthy volunteer and diseased patients (i.e. inflammatory bowel disease, Crohn) . In aim 3, in order to provide evidence that targeting MIU blocks viral infection, I will test the efficacy of the small molecules identified in aim 2 in the ex-vivo model established in aim 1 and/or in-vivo, in a murine model.

Humans in principle adapt well to sensory degradations. In order to do so, our cognitive strategies need to adjust accordingly (a process we term “adaptive control”).The auditory sensory modality poses an excellent, although under-utilised, research model to understand these adjustments, their neural basis, and their large variation amongst individuals. Hearing abilities begin to decline already in the fourth life decade, and our guiding hypothesis is that individuals differ in the extent to which they are neurally, cognitively, and psychologically equipped to adapt to this sensory decline. The project will pursue three specific aims: (1) We will first specify the neural dynamics of “adaptive control” in the under-studied target group of middle-aged listeners compared to young listeners. We will employ advanced multi-modal neuroimaging (EEG and fMRI) markers and a flexible experimental design of listening challenges. (2) Based on the parameters established in (1), we will explain interindividual differences in adaptive control in a large-scale sample of middle-aged listeners, and aim to re-test each individual again after approximately two years. These data will lead to (3) where we will employ statistical models that incorporate a broader context of audiological, cognitive skill, and personality markers and reconstructs longitudinal “trajectories of change” in adaptive control over the middle-age life span. Pursuing these aims will help establish a new theoretical framework for the adaptive ageing brain. The project will further break new ground for future classification and treatment of hearing difficulties, and for developing individualised hearing solutions. Profiting from an excellent research environment and the principle investigator’s pre-established laboratory, this research has the potential to challenge and to transform current understanding and concepts of the ageing human individual.

This research project is concerned with the following three topics in approximation theory and Fourier analysis: 1) Simultaneous approximation of functions and their derivatives in Lp, 00. We expect to obtain sufficient conditions of the boundedness for such operators in terms of the simultaneous behavior of a multiplier and its derivatives in different functional spaces, and to apply such conditions for solving problems from this proposal. In our approaches we will combine the methods from approximation theory and Fourier analysis simultaneously, contrary to the previous research concerning the mentioned tasks. Moreover, by using and developing the newly introduced concepts of families of multiplier operators in Lp, 0