Synthese und Evaluation neuer Inhibitoren und Modulatoren von Proteasen und Kinasen in Modellen der Alzheimer-Demenz und akuter myeloischer Leukämie

Infolge des demographischen Wandels und einer immer älter werdenden Gesellschaft ist die Alzheimer-Demenz eine der verheerendsten Krankheiten in der heutigen Zeit. Trotz des immensen Forschungsaufwandes auch von Seiten verschiedener Pharmaunternehmen und klinischen Studien bleibt die Alzheimer-Demenz bislang unheilbar. Es werden diverse Therapieansätze diskutiert, da die Ursache der Alzheimer-Demenz bislang nicht eindeutig belegt ist. Nach der Amyloid-Hypothese ist die Alzheimer-Demenz die Folge der Akkumulation und Aggregation amyloider extrazellulärer Plaques im Gehirn. Die amyloiden Plaques bestehen aus verschiedenen Abeta-Peptiden, die aus dem amyoiden Vorläuferprotein APP durch den proteolytischen Abbau verschiedener Proteasen generiert werden. Zu diesen Proteasen gehören unter anderem die beta- und gamma-Sekretase sowie die Metalloprotease Meprin beta. Die Modulation bzw. Inhibition dieser Enzyme sind interessante therapeutische Ansätze zur Behandlung der Alzheimer-Demenz. Im Rahmen dieser Arbeit wurden verschiedene gamma-Sekretase-Modulatoren basierend auf unterschiedlichen Strukturmotiven synthetisiert, die in zellulären Assay-Systemen evaluiert wurden. Weiterhin wurden Meprin beta- Inhibitoren synthetisiert, deren Strukturmotiv ausgehend von einem virtuellen screening gefunden wurde. Die Inhibition von FLT3 – einer Tyrosinkinase – ist ein möglicher Therapieansatz zur Behandlung der akuten myeloischen Leukämie. Das strukturbasierte Design und die Synthese von FLT3-Inhibitoren war ein weiterer Teil dieser Arbeit

Altered processing of food stimuli in adolescents with loss of control eating

Loss of control eating (LOC) constitutes a common eating pathology in childhood and adolescence. Models developed for adult patients stress a biased processing of food-related stimuli as an important maintaining factor. To our knowledge, however, no EEG study to date investigated the processing of visual food stimuli in children or adolescents with LOC. Adolescents with at least one self-reported episode of LOC in the last four weeks and a matched control group completed a modified Go/NoGo task, with a numerical target or non-target stimulus being presented on one side of the screen and an irrelevant high-calorie food or neutral stimulus being presented on the opposite side. Mean P3 amplitudes were analyzed. In Go trials, the LOC group’s mean P3 amplitudes were comparable irrespective of distractor category, while for NoGo trials, mean P3 amplitudes were significantly higher when the distractor was a high-calorie food stimulus. This pattern was reversed in the control group. Results are interpreted in light of Gray’s reinforcement sensitivity theory. They might reflect altered processes of behavioral inhibition in adolescents with LOC upon confrontation with visual food stimuli

Convergent Evidence from Animal and Human Studies

Schizophrenia is a highly heritable disorder with diverse mental and somatic symptoms. The molecular mechanisms leading from genes to disease pathology in schizophrenia remain largely unknown. Genome-wide association studies (GWASs) have shown that common single-nucleotide polymorphisms associated with specific diseases are enriched in the recognition sequences of transcription factors that regulate physiological processes relevant to the disease. We have used a “bottom-up” approach and tracked a developmental trajectory from embryology to physiological processes and behavior and recognized that the transcription factor NK2 homeobox 1 (NKX2-1) possesses properties of particular interest for schizophrenia. NKX2-1 is selectively expressed from prenatal development to adulthood in the brain, thyroid gland, parathyroid gland, lungs, skin, and enteric ganglia, and has key functions at the interface of the brain, the endocrine-, and the immune system. In the developing brain, NKX2-1-expressing progenitor cells differentiate into distinct subclasses of forebrain GABAergic and cholinergic neurons, astrocytes, and oligodendrocytes. The transcription factor is highly expressed in mature limbic circuits related to context-dependent goal-directed patterns of behavior, social interaction and reproduction, fear responses, responses to light, and other homeostatic processes. It is essential for development and mature function of the thyroid gland and the respiratory system, and is involved in calcium metabolism and immune responses. NKX2-1 interacts with a number of genes identified as susceptibility genes for schizophrenia. We suggest that NKX2-1 may lie at the core of several dose dependent pathways that are dysregulated in schizophrenia. We correlate the symptoms seen in schizophrenia with the temporal and spatial activities of NKX2-1 in order to highlight promising future research areas

Monitoring Neural Activity with Bioluminescence during Natural Behavior

Existing techniques for monitoring neural activity in awake, freely behaving vertebrates are invasive and difficult to target to genetically identified neurons. We used bioluminescence to non-invasively monitor the activity of genetically specified neurons in freely behaving zebrafish. Transgenic fish with the Ca$^{2+}$-sensitive photoprotein green fluorescent protein (GFP)-Aequorin in most neurons generated large and fast bioluminescent signals that were related to neural activity, neuroluminescence, which could be recorded continuously for many days. To test the limits of this technique, we specifically targeted GFP-Aequorin to the hypocretin-positive neurons of the hypothalamus. We found that neuroluminescence generated by this group of ~20 neurons was associated with periods of increased locomotor activity and identified two classes of neural activity corresponding to distinct swim latencies. Our neuroluminescence assay can report, with high temporal resolution and sensitivity, the activity of small subsets of neurons during unrestrained behavior.Molecular and Cellular Biolog

Towards an\u2028 EU research and innovation policy agenda for nature-based solutions & re-naturing cities. Final report of the Horizon 2020 expert group on nature-based solutions and re-naturing cities.

1. Nature-based solutions harness the power and sophistication of nature to turn environmental, social and economic challenges into innovation opportunities. They can address a variety of societal challenges in sustainable ways, with the potential to contribute to green growth, 'future-proofing' society, fostering citizen well-being, providing business opportunities and positioning Europe as a leader in world markets. \u2028 2. Nature-based solutions are actions which are inspired by, supported by or copied from nature. They have tremendous potential to be energy and resource-efficient and resilient to change, but to be successful they must be adapted to local conditions. \u2028 3. Many nature-based solutions result in multiple co-benefits for health, the economy, society and the environment, and thus they can represent more efficient and cost-effective solutions than more traditional approaches. \u2028 4. An EU Research & Innovation (R&I) agenda on nature-based solutions will enable Europe to become a world leader both in R&I and in the growing market for nature-based solutions. For this, the evidence base for the effectiveness of nature-based solutions needs to be developed and then used to implement solutions. Both need to be done in conjunction with stakeholders. The potential for transferability and upscaling of solutions also requires further investigation. There is also a need to develop a systemic approach that combines technical, business, finance, governance, regulatory and social innovation. \u2028 5. Four principal goals have been identified that can be addressed by nature-based solutions: �� Enhancing sustainable urbanisation through nature-based solutions can stimulate economic growth as well as improving the environment, making cities more attractive, and enhancing human well-being. \u2028 �� Restoring degraded ecosystems using nature-based solutions can improve the resilience of ecosystems, enabling them to deliver vital ecosystem services and also to meet other societal challenges. \u2028 �� Developing climate change adaptation and mitigation using nature-based solutions can provide more resilient responses and enhance the storage of carbon. \u2028 �� Improving risk management and resilience using nature-based solutions can lead to greater benefits than conventional methods and offer synergies in reducing multiple risks. \u2028 6. Based on the four goals, seven nature-based solutions for R&I actions are recommended to be taken forward by the European Commission and Member States: �� Urban regeneration through nature-based solutions \u2028 �� Nature-based solutions for improving well-being in urban areas \u2028 �� Establishing nature-based solutions for coastal resilience \u2028 �� Multi-functional nature-based watershed management and ecosystem restoration \u2028 �� Nature-based solutions for increasing the sustainability of the use of matter and energy \u2028 �� Nature-based solutions for enhancing the insurance value of ecosystems \u2028 �� Increasing carbon sequestration through nature-based solutions \u2028This report was produced by the Horizon 2020 Expert Group on 'Nature-Based Solutions and Re- Naturing Cities', informed by the findings of an e-consultation and a stakeholder workshop. \u202

Neuromechanical simulation of zebrafish optomotor response

The 11th International Symposium on Adaptive Motion of Animals and Machines. Kobe University, Japan. 2023-06-06/09. Adaptive Motion of Animals and Machines Organizing Committee.Poster Session P1