K-adaptability in stochastic optimization

In dieser Dissertation untersuchen wir eine neue Strategie, um mit stochastischen Optimierungsproblemen umzugehen. Die stochastische Optimierung beschäftigt sich mit Problemen mit unsicheren Parametern. Unter der Annahme, dass die Verteilung dieser unsicheren Parameter bekannt ist, soll der Erwartungswert der Zielfunktion optimiert werden. Wir führen den Min-E-Min-Ansatz ein, bei dem anstatt einer Lösung K Lösungen berechnet werden. Nachdem die Realisierung der unsicheren Parameter beobachtet worden ist, wird die für die Realisierung beste Lösung ausgewählt. Wir untersuchen die Komplexität des Min-E-Min-Problems, indem wir NP-Schwere, parametrisierte Komplexität und Approximationseigenschaften detailliert analysieren. Wir zeigen, dass das Problem NP-schwer und W[2]-schwer ist, im Fall, dass K Teil des Inputs ist, selbst wenn die Menge der zulässigen Lösungen polynomiell von der Eingabegröße abhängt. Für festes K bleibt das Problem NP-schwer, wenn K größer als zwei ist. Zusätzlich beweisen wir, dass die Existenz eines polynomiellen Algorithmus mit einer konstanten Approximationsgüte für das Min-E-Min-Problem impliziert, dass P und NP gleich sind. Für das Min-E-Min-Problem mit kontinuierlicher Verteilung zeigen wir, dass allein das Evaluieren der Zielfunktion #P-schwer ist. Nichtsdestotrotz beweisen wir, dass man solche Probleme lösen kann, indem man die kontinuierliche Verteilung mit einer ausreichend großen Anzahl an Stichproben, welche derselben Verteilung folgen, diskretisiert. Neben den Komplexitätsresultaten stellen wir auch verschiedene exakte Algorithmen, unter anderem einen Branch-and-price-Algorithmus, zur Lösung des Problems vor. In einer ausführlichen experimentellen Untersuchung können wir belegen, dass je nach Situation jeder der vorgestellten Algorithmen am sinnvollsten sein kann. Darüber hinaus stellen wir verschiedene Varianten einer von uns entwickelten Heuristik vor und demonstrieren, dass diese das Min-E-Min-Problem schnell und genau lösen können. Zu guter Letzt betrachten wir auch verwandte Probleme und untersuchen ihre Komplexität

The role of Sphingosine-1-phosphate receptors in adipocytes and adipose tissues

Obesity is a worldwide health issue with increasing numbers of patients every year. Moreover, the prevalence of obesity gives rise to related cardiovascular diseases and various other comorbidities influencing quality of life and burdening the healthcare systems. To date no pharmacological therapy exists to treat obesity. Therefore, new biological targets for therapy of the obesity pandemic are extensively searched for. In recent years brown adipose tissue has attracted attention in the scientific community due to its ability to burn calories in form of fat and transform them into heat. Activation of brown adipocytes or transformation of white adipocytes into ‘brown-like’ beige adipocytes could be a new way of treating excess overweight. Sphingosine-1-phosphate (S1P) is a versatile biological messenger involved in a plethora of physiological functions. It agonizes five different G protein-coupled Sphingosine-1-phosphate receptors (S1PRs) which are broadly expressed throughout human and murine tissues. The role of S1P in the immune system is already quite well elucidated whereas the knowledge about the role of S1P in obesity is still in its infancy. This study broadly investigates the role of S1P and S1PRs in brown and white adipocytes, as well as in adipose tissues and attempts to give an overview of the different most important S1PRs, their function and their downstream signaling moieties. In this work it was found that all known five Sphingosine-1-phosphate receptors (S1PRs) are expressed in murine brown and white adipocytes. In vitro, chronic S1P treatment decreases adipogenesis of brown and white adipocytes. Signaling not only via Sphingosine-1-phosphate receptor 2 (S1PR2) but also via Sphingosine-1-phosphate receptor 1 (S1PR1) inhibits the differentiation of brown adipocytes. Putative underlying downstream signaling mechanisms of S1P might include activation of Gi, Gq and G12/13 pathways. Furthermore, S1P potently increases intracellular calcium in brown preadipocytes in a Gq dependent manner. The expression of S1PR1 and S1PR2 in adipose tissues is differentially regulated during high fat diet or cold exposure. To evaluate if pharmacological modulation of S1PR1 or S1PR2 has therapeutic potential, mice were injected for one week with compounds targeting S1PR1 and S1PR2. Agonism of S1PR2 diminishes fat tissue mass presenting S1PR2 agonism as a potential treatment against obesity. Overall, this thesis reveals that S1P imposes promising actions on adipose tissues. It is of value to uncover the full potential of S1P receptor modulation as a novel target for combating obesity

LED-generated Multifocal ERG On- and Off-responses in Complete Congenital Stationary Night Blindness - A Case Report

We report on the application of a light emitting diode (LED) screen to elicit multifocal ERG on- and off-responses in a patient presenting with the complete type of congenital stationary night blindness (cCSNB): A 63-years old woman was diagnosed with cCSNB by means of standard ERG procedures and dark adaptometry. To confirm this diagnosis and to investigate topographical differences of on- and off-responses a multifocal approach employing long-duration stimuli was added. Results of mfERG-testing were averaged in three groups (a central area of 7.5°, a ring area of 7.5-21.9° and a peripheral ring of 21.9-31.1°). When compared to normal controls (n = 4) on-responses (P1-amplitudes) were severely reduced symmetrically at all eccentricities, while off-responses showed no reduction resulting in an increased off/on-ratio. Furthermore on-latencies of P1 were delayed symmetrically at all eccentricities, whereas off-latencies were normal. To our knowledge this is the first report of multifocal on- and off-responses in a CSNB-patient. Stimulus-generation with a LED-screen provides the advantage of a stable luminance during the long-duration on-phas

Selectively targeting prostanoid E (EP) receptor-mediated cell signalling pathways: Implications for lung health and disease

© 2018 Elsevier Ltd Arachidonic acid is metabolized by cyclooxygenases (COX-1 and COX-2) into various prostanoids which exert different functions in mammalian physiology. One of these prostanoids, prostaglandin E 2 (PGE 2 ), interacts with four different G protein-coupled receptors, named EP 1 , EP 2 , EP 3 and EP 4 , to initiate different downstream signalling pathways. Prostanoid receptors are diversely expressed throughout different tissues all over the body and PGE 2 is responsible for a large variety of beneficial and disadvantageous effects. We have recently achieved a greater understanding of the biology of prostanoid E receptors and the potential for specific drug targeting with the advent of potent and selective EP receptor agonists and antagonists. This has important implications for lung health and disease as PGE 2 -mediated EP receptor activation impacts upon migration of airway smooth muscle cells, airway microvascular leak, tone regulation of pulmonary blood vessels, mast cell degranulation, bronchodilatation, cough, angiogenesis and airway inflammation, to name a few. In this review, we overview the EP receptor family and the related signalling pathways, summarize a variety of EP 1-4 receptor agonists and antagonists, provide an overview of pharmacological tools used to implicate EP receptor function in the context of respiratory health and disease and finally highlight some of the more selective pharmacological reagents that have recently been developed. The availability of selective pharmacological agonists and antagonists for the distinct EP receptors, as well as the development of specific prostanoid receptor knock-out mice, offer hitherto unattainable opportunities for achieving an in depth understanding of the role and function of PGE 2 in respiratory disease and the exciting potential of targeting EP receptors more broadly

Brolucizumab in Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: Ophthalmology and Diabetology Treatment Aspects.

Anti-vascular endothelial growth factor (anti-VEGF) therapies have become the standard of care in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), resulting in a remarkable decrease in disease-related vision loss. However, the need for regular injections places a significant burden on patients, caregivers, and the healthcare system and improvements in vision may not be maintained long term. As a result of its drying potency and duration of action, brolucizumab, an intravitreal anti-VEGF therapy approved for the treatment of nAMD and DME, could decrease injection frequency for patients and provide an efficacious treatment; however, balancing its benefits and risks can be challenging. There have been reports of intraocular inflammation (IOI) in patients treated with brolucizumab, which, if left untreated, may result in severe vision loss. Recent evidence, however, indicates that early recognition of IOI and prompt and aggressive systemic corticosteroid treatment in response to posterior segment involvement can lead to favorable outcomes in these relatively rare but severe cases. A series of consensus meetings were conducted in 2022 between Swiss medical retina experts and diabetologists, discussing the current data for brolucizumab and exploring various challenges to its use, including the associated risk of IOI. The outcome is a collation of practical insights and guidance for ophthalmologists on the use of brolucizumab in patients with nAMD and DME, including patient selection and assessment, treatment regimen and monitoring, and the recognition and management of adverse events

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E2 (PGE2) production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE2 secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism

Industrial Segment Anything -- a Case Study in Aircraft Manufacturing, Intralogistics, Maintenance, Repair, and Overhaul

Deploying deep learning-based applications in specialized domains like the aircraft production industry typically suffers from the training data availability problem. Only a few datasets represent non-everyday objects, situations, and tasks. Recent advantages in research around Vision Foundation Models (VFM) opened a new area of tasks and models with high generalization capabilities in non-semantic and semantic predictions. As recently demonstrated by the Segment Anything Project, exploiting VFM's zero-shot capabilities is a promising direction in tackling the boundaries spanned by data, context, and sensor variety. Although, investigating its application within specific domains is subject to ongoing research. This paper contributes here by surveying applications of the SAM in aircraft production-specific use cases. We include manufacturing, intralogistics, as well as maintenance, repair, and overhaul processes, also representing a variety of other neighboring industrial domains. Besides presenting the various use cases, we further discuss the injection of domain knowledge

Giant cell arteritis with vertebral artery involvement—baseline characteristics and follow-up of a monocentric patient cohort

Vertebral artery (VA) involvement in giant cell arteritis (GCA) has rarely been reported. We aimed to evaluate the prevalence, patients’ characteristics, and immunotherapies used in patients with GCA and VA involvement at diagnosis and 1 year follow-up, retrospectively including patients being diagnosed between January 2011 and March 2021 in our department. Clinical features, laboratory data, VA imaging, immunotherapy, and 1 year follow-up data were analyzed. Baseline characteristics were compared to GCA patients without VA involvement. Among all 77 cases with GCA, 29 patients (37.7%) had VA involvement, as diagnosed by imaging and/or clinical signs and symptoms. Gender distribution and erythrocyte sedimentation rate (ESR) were significantly different in the groups with and without VA involvement, with more women being affected (38/48 patients, 79.2%) and a significantly higher median ESR in patients without VA involvement (62 vs. 46 mm/h; p = 0.012). MRI and/or CT showed vertebrobasilar stroke at GCA diagnosis in 11 cases. 67/77 patients (87.0%) received high-dose intravenous glucocorticosteroids (GCs) at diagnosis, followed by oral tapering. Six patients were treated with methotrexate (MTX), one with rituximab, and five with tocilizumab (TCZ). 2/5 TCZ patients achieved clinical remission after 1 year, vertebrobasilar stroke within the first year occurred in 2/5 patients. Diagnosis of VA involvement might be underrecognized in GCA patients. VA imaging should be performed in elderly patients with vertebrobasilar stroke presenting with GCA symptoms, not to miss GCA as the etiology of stroke. Efficacy of immunotherapies in GCA with VA affection and long-term outcomes need to be investigated further.</p