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Effekte von neurozentriertem und visuellem Training auf handballspezifische konditionelle und koordinative Fähigkeiten
No full textEinleitung: Im Leistungssport können Kleinigkeiten über Sieg oder Niederlage entscheiden. Die Trainingszeiten sind limitiert, weshalb neue Wege gefunden werden müssen, um den Trainingsprozess zu optimieren. Bis anhin wurde der Neuroathletik sowie dem visuellen Training im Handballsport kaum Beachtung geschenkt, obwohl das Gehirn und das visuelle System eine wichtige Rolle bei den Bewegungsausführungen spielen. Ziel der Arbeit war es aufzuzeigen, ob neurozentriertes und visuelles Training einen Einfluss auf handballspezifische konditionelle und koordinative Fähigkeiten hat.
Methodik: Teilnehmer der Studie waren die 21 Spieler der ersten Mannschaft von Handball Stäfa. Nach der randomisierten Einteilung in eine Interventionsgruppe und eine Kontrollgruppe wurde der Agility T-Test, die Wurfkraft, die Sprungkraft, das Gleichgewicht und die Akkommodationsflexibilität gemessen und nach einer zehnwöchigen Trainingsintervention wiederholt. Die Interventionsgruppe absolvierte vor jedem Training zusätzlich einen 15-minütigen Trainingsblock mit neurozentrierten und visuellen Übungen. Die Kontrollgruppe absolvierte lediglich die Trainingseinheiten der Mannschaft.
Resultate: Die Interventionsgruppe konnte die Akkommodationsflexibilität in vier der sechs Testungen signifikant verbessern. Die Interventionsgruppe konnte eine subjektive Veränderung auf dem Handballfeld wahrnehmen. Ansonsten konnte weder beim Agility T-Test, der Wurfkraft, der Sprungkraft noch dem Gleichgewicht eine Veränderung zwischen der Interventionsgruppe und der Kontrollgruppe festgestellt werden.
Konklusion: In dieser Arbeit konnte aufgezeigt werden, dass eine zehnwöchige Trainingsintervention mit neurozentrierten und visuellen Übungen die Akkommodations-flexibilität wie auch das subjektive Empfinden verbessert. Auf die Schnelligkeit, Wurf- und Sprungkraft sowie auf das Gleichgewicht konnte kein messbarer Einfluss gemessen werden. Zukünftig sollten die neurozentrierten und visuellen Übungen getrennt betrachtet werden und zusätzlich Untersuchungen stattfinden, ob ein Transfer der verbesserten Akkommodationsflexibilität auf die sportliche Leistung möglich ist
Association of premenstrual syndrome, secondary amenorrhea and oligomenorrhea regarding physical activity intensity and training volume - A cross-sectional study of leisure time physically active females in Switzerland
No full textBackground: Evidence suggests an association of menstrual cycle (MC)-related disorders and physical activity intensity and volume in athletes. Due to missing information on leisure time physically active females, this study was conducted to analyse a possible association of premenstrual syndrome (PMS), secondary amenorrhea and oligomenorrhea regarding physical activity (PA) intensities (light (LPA), moderate (MPA) and vigorous (VPA)), and training volume.
Methods: A cross-sectional survey was distributed to main stakeholders of leisure time physical activity (LTPA) in Switzerland. Chi-square tests (p-value <0.05) were used to investigate the association of PMS, secondary amenorrhoea and oligomenorrhoea regarding PA intensity (LPA, MPA, VPA) and volume (h/week).
Results: A total of 902 leisure time physically active females (age=28.8±8.6, BMI=22.4±3.1), of reproductive age, not using hormonal contraceptives, met the inclusion criteria. PMS prevalence was 17.0% (n=153) with no significant association to PA intensities LPA (p=0.416), MPA (p=0.991), VPA (p=0.097) and training volume (p=0.155). The prevalence of secondary amenorrhea was 2.9% (n=26) and no significant association regarding PA intensities LPA (p=0.224), MPA (p=0.156) and VPA (p=0.122) but significant association regarding training volume (p=0.005) was found. The prevalence of oligomenorrhea was 18.2% (n=164) and no significant association regarding PA intensities LPA (p=0.167), MPA (p=0.795) and VPA (p=0.514) but significant association regarding training volume (p=0.035).
Conclusion: The study shows only significant associations with small effect sizes in secondary amenorrhea and oligomenorrhea regarding training volume. Due to the high prevalence of MC-related disorders, there is still a need for action and future studies in which further factors should be included
Exploiter commercialement la misère humaine? : Versicherungspolitik während der Formationsphase des französischen Wohlfahrtsstaats (1900-1950)
Full text linkDie vorliegende Dissertation von Beat Stüdli untersucht die Versicherungspolitik während der Entstehungsphase des französischen Wohlfahrtsstaats zwischen 1900 und 1950. Aufgrund veränderter gesellschaftlicher Bedürfnisse waren seit dem späten 19. Jahrhundert immer mehr Menschen auf Versicherungen angewiesen. Deswegen mussten die Versicherungen stärker reguliert werden und sozial besonderes relevante Versicherungstypen wie die Versicherung gegen Arbeitsunfälle staatlich gefördert werden. Ziel dieser Arbeit ist es, die Rolle der privaten Versicherungswirtschaft in diesen versicherungspolitischen Prozessen zu definieren. Der Autor verwendet historische Quellen wie die Debatten über den gesellschaftlichen Status der Versicherungen und über die Ausarbeitung der verschiedenen staatlichen Regulierungsformen. Dabei wird deutlich, dass die privaten Versicherungsakteure in Frankreich lange eine wichtige Rolle in der sozialen Sicherheit spielten, bis die Krisen der 1930er-Jahre und der Zweite Weltkrieg den Weg zu staatlichen Versicherungssystemen begünstigten und die Versicherungsregulierung beschleunigten. Die Dissertation bietet Einblicke in die Herausforderungen und Entwicklungen im französischen Wohlfahrtsstaat und zeigt die historische Bedeutung der Versicherungspolitik auf
Die Höhenbefestigungen Samniums vom 4.–1. Jh. v. Chr. - Eine landschafts- und siedlungsarchäologische Analyse
Full text linkOrganoids as preclinical cancer models of hepatocellular carcinoma to study doxorubicin response
No full textBackground & Aims: Transarterial chemoembolization (TACE) is the first-line treatment for intermediate-stage hepatocellular carcinoma (HCC). However, the response rate to TACE varies, and the molecular mechanisms underlying variable responses are poorly understood. Patient-derived HCC organoids (HCCOs) offer a novel platform to investigate variability of doxorubicin responses, the impact of hypoxia on tumor cell proliferation, and the molecular mechanisms underlying doxorubicin resistance.
Methods: We evaluated the effects of hypoxia and doxorubicin on cell viability and cell cycle distribution in twenty patient-derived HCCO models. We also identified HCCO-intrinsic determinants of doxorubicin response by comparing the transcriptomes of sensitive to resistant HCCOs. To validate candidate genes, we used small molecule inhibition and quantified intracellular doxorubicin levels.
Results: Hypoxia reduced the proliferation of HCCOs and increased the number of cells in the G0/G1 phase of the cell cycle, while decreasing the number in the S phase. The IC50s of the doxorubicin response varied widely, from 29nM to >1μM. Doxorubicin and hypoxia did not exhibit synergistic effects but were additive in some HCCOs. Doxorubicin reduced the number of cells in the G0/G1 and S phases and increased the number in the G2 phase under both normoxia and hypoxia. Genes related to drug metabolism and export, most notably ABCB1, were differentially expressed between doxorubicin-resistant and sensitive HCCOs. Small molecule inhibition of ABCB1 increased intracellular doxorubicin levels and decreased drug tolerance in resistant HCCOs.
Conclusions: The inhibitory effects of doxorubicin treatment and hypoxia on HCCO proliferation are variable, suggesting an important role of tumor-cell intrinsic properties in doxorubicin resistance. ABCB1 is a determinant of doxorubicin response in HCCOs
Targeting dendritic cells to improve antitumor immunity
Full text linkDespite the major success and recent advances in therapies treating cancer, including ICI and cancer vaccines, these agents often fail to induce durable responses or complete remissions in the majority of patients. One of the reasons may be the poor network linking innate and adaptive immunity. In this thesis, we focus on targeting the innate immune system, particularly DCs, as recent evidence has highlighted the fundamental role of these cells in orchestrating cancer immunity. First, I described how chemotherapeutics, particularly microtubule-destabilizing agents, initially designed to target the proliferation or induce cell death of malignant cells, also induce direct DC maturation through GEF-H1. Second, I present a work where we used an ASO-based technology with the dual capacity of trigger DC activation via TLR9 engagement and control of PD-L1 in mice to overcome the limited therapeutic efficacy of anti-PD-L1 mAb. This work provides a mechanistic groundwork for future therapy design and shows how activating intratumoral DCs with chemotherapy or immunomodulatory ASOs improve antitumor immunity, having even greater efficacy when combined with other ICIs for the treatment of solid tumors
Novel microtubule-targeting agents: synthesis and structural determination of their interactions
Full text linkThis thesis, performed within the EU-funded Innovative Training Network - European Joint Doctorate TubInTrain, via the cotutelle agreement for a double degree between University of Milan and University of Basel, is focused on the microtubules dynamics and its breakdown associated to neurodegenerative diseases. Microtubule-targeting agents constitute a large group of chemically diverse molecules that bind tubulin and perturb the stability and functions of microtubules. While microtubule-targeting agents constitute a successful class of cancer drugs, the way in which tubulin binders can face neurodegeneration and neurotoxicity has yet to be determined. We aimed to develop a set of tubulin binders acting as chemical probes to explore different ligand-tubulin interactions modes and to potentially study how they affect the behaviour of microtubules in cell free systems. The chosen compounds are further studied in neuronal models, in order to clarify how small molecules affect microtubule dynamics in neurons. In Chapter I, the introduction on microtubules, their structure, and functions, and in particular the microtubule-targeting agents is described. The chemical structures of the representative tubulin binders, their respective bindings sites and therapeutic applications are addressed. Furthermore, the aims and objectives of the thesis are discussed. Within the workflow, the main objectives of my project included the synthesis of new tubulin binders, performed at the University of Milan. This was complemented by the X-ray crystallography structure determination of individual tubulin-compound complexes, which was performed in the course of my one-year secondment period at the Paul Scherrer Institute. Based on that, Chapter II covers the synthetic part of the work, while Chapter III covers structural determination of ligands-tubulin complexes. More precisely, Chapter II includes four different projects. Section 2.1 focuses on the functionalization of a natural product maytansinol. Maytansinoids represent a successful class of natural and semisynthetic tubulin binders, known for their potent cytotoxic activity. Their wider application as cytotoxins and chemical probes to study tubulin dynamics was set back due to the complexity of natural product chemistry and lack of SAR studies. Natural product maytansinol is a valuable precursor for the preparation of maytansine derivatives. Thus, one of the main objectives was to establish synthetic routes for the functionalization of maytansinol and to synthesize a set of maytansine analogues with different side chain substituents in C3-position, in order to investigate the effect of bulky substituents in the C3-position on the binding mode and activity of maytansinoids. Design, synthesis and biological evaluation of short-chain, long-chain and maytansinoid conjugates is described. Section 2.2 focuses on the synthetic efforts towards the total synthesis of a natural product glycybridin B. We aimed to identify and synthesize new maytansine site binders, structurally less complex than the family of maytansinoids. A natural product glycybridin B, isolated for the first time in 2017 from the herbal medicine Glycyrrhiza glabra, has been chosen for synthesis based on the computational screening. It attracted our interest due to the following factors: a) its total synthesis has not yet been reported in literature; b) different biological studies attribute it a variety of biological activities; c) it has been predicted to bind to maytansine site in computational studies. Therefore, synthetic efforts to synthesize the desired glycybridin B are described. Section 2.3 and 2.4 both focus on the covalent-targeting strategy to target tubulin. Covalent probes are characterized by prolonged duration of action, improved potency, and exquisite selectivity. Moreover, they could be used e.g., to immobilize the protein of interest, tubulin. In Section 2.3, the synthesis of simplified biotinylated pironetin analogues is described. Pironetin, a natural product that covalently binds alfa-tubulin, and the possibility of its biotinylation to use then biotin capturing on streptavidin for protein immobilization. Taking into consideration the low availability and time-consuming synthesis of natural pironetin, we designed and synthesized its simpler biotinylated analogues. In its turn, Section 2.4 comprises Todalam site ligands. Todalam targets the most recently discovered eighth small molecule binding site on tubulin and displays a unique molecular mechanism of action. Using the time- and cost-efficient synthetic approaches, we intended to develop novel, different from Todalam scaffolds and then, based on the structural data, rationally optimize them with the idea of site-specific covalent targeting. I was involved both in the chemistry and structural biology aspects of this project. I aimed to obtain and characterize the crystal structures of todalam analogues synthesized in our laboratory in complex with tubulin, to then design (in collaboration with the computational groups) and synthesize a library of optimized warhead-bearing ligands for the covalent targeting. Section 2.4 covers the synthetic work performed on this project, while the structural work including the obtain crystal structures of the developed todalam site ligands in complex with tubulin is described in detail in Section 3.3.5. Chapter III contains the introduction to the methods used to determine protein-ligand interactions, with particular focus on X-ray crystallography, discussed in Section 3.1. In the following Section 3.2, tubulin crystallization systems and the experimental data regarding the used tubulin crystallization system T2R-TTL is described. Finally, the determined tubulin-ligands crystal structures are discussed in detail in Section 3.3. Two training projects, which allowed to acquire skills in protein expression and purification; crystallization, crystal harvesting and cryo-cooling, data collection at synchrotron, model building and refinement, are contained in Sections 3.3.1 and 3.3.2. Both training projects focus on the colchicine site ligands: the analogues of combretastatin A4 and the stilbene-derived derivatives. Section 3.3.3 addresses the results of the crystallographic screening of other sixty-eight compounds derived from synthesis or virtual screening of Enamine libraries. As a result of the screening campaign, we managed to identify another colchicine site ligand, specifically binding to β3 isotype of tubulin. Isotype-specific ligands present an advantage as they can target certain isotypes, overexpressed in specific cells and therefore can be selectively used for certain types of diseases (e.g. beta3 tubulin present mostly in neurons). The relevant results and the successfully obtained crystal structure of the hit are described in this Section
Advances in medical nutrition: strategies and innovations in dietetics, obesity management, and nutritional support
Full text linkThis dissertation examines and adds to strategies and innovations in medical nutrition, covering more specifically the areas of dietetics, obesity management, and nutritional support. Medical nutrition encompasses all nutritional interventions under medical or nursing supervision as well as the structure, conception, and scientific derivation of these interventions. Medical nutrition overlaps with clinical nutrition but extends to nutritional care for selected healthy individuals.
1. Dietetics
Dietetics includes nutritional assessment and dietary advice with and without nutrition therapy to modify normal nutrition in cases of food allergies, intolerance, and disease, as well as secondary prevention and treatment of specific nutrient deficiencies. Within dietetics, we explored dietary fiber deficiency and its prevalence and found that 87% of the general Swiss population do not achieve the recommended intake of 30 g/day. Dietary fiber intake and ultra-processed food consumption exhibited an inverse dose-dependent association. Moreover, we examined the effects of potentially anti-inflammatory diets (Mediterranean, vegetarian, vegan, and ketogenic) on rheumatoid arthritis through a meta-analysis. These diets led to significant improvements in pain, health assessment questionnaire scores, and swollen joint counts, although the inflammatory markers did not improve.
2. Obesity Management
The clinical nutrition area of obesity management covers the prevention and treatment of obesity and related disorders, including bariatric surgery, and complements public health interventions. Post-bariatric hypoglycemia (PBH) is a frequent complication of bariatric surgery, particularly Roux-en-Y gastric bypass. This condition manifests as recurrent postprandial hypoglycemic events with potentially critical outcomes, such as loss of consciousness, and diminished quality of life (QOL). The PBH Forecast project aimed to prevent hypoglycemic events in patients with PBH and to establish a sustainable strategy for hypoglycemia correction. Hence, we collected data on continuous blood glucose levels, meal intake, symptoms, heart rate, and physical activity during a 50-day observational phase (n = 50). Concurrently, we conducted a randomized crossover clinical trial (n = 8) to investigate different nutritional strategies (15 g glucose vs. 5 g glucose vs. a combination of 10 g protein and 5 g carbohydrate) to correct mixed meal induced hypoglycemia. Our results suggested that diabetes-inspired guidelines for correcting hypoglycemia with 15 g are not suitable for PBH and that an excessive glucose load may induce rebound hypoglycemia. While none of the tested strategies was unequivocally superior, a lower dose appears to adequately elevate glucose levels outside the critical range, and supplementary nutrients such as proteins may offer glycemia-stabilizing benefits. At present, a randomized controlled trial is testing an intervention for hypoglycemia prevention that combines a hypoglycemia prediction model developed using data from the above-mentioned observational phase with a preventive nutritional intervention, i.e. administering 10 g of glucose before reaching hypoglycemia at a time point dictated by the prediction model.
3. Nutritional Support
Nutritional support involves the provision of food or nutrients through conventional nutrition, special diets, food fortification, and medical nutrition therapy (oral nutritional supplements, enteral nutrition, and parenteral nutrition [PN]), as well as concurrent therapies to promote food intake, to prevent or treat malnutrition and improve clinical outcomes and QOL. If medical nutrition therapy is required over a long period, it can be administered outside the hospital, such as home PN (HPN). This requires specialized care and patient monitoring to prevent potentially life-threatening complications.
3.a) Improvements of Outcomes with eHealth
We explored the potential of eHealth to support and improve the QOL and quality of care of patients with HPN by distant monitoring and counseling. To this end, we conducted a multicenter survey on the attitudes and expectations of patients with HPN towards eHealth and substantiated the need for digital support in this population. Subsequently, we developed a smartphone application for patients and a web-based dashboard for health care professionals (HCPs), centered around a patient journal and videoconference consultations. This provides the data for remote monitoring and enables counseling through timely short consultations and interventions as needed despite physical distance, replacing the traditional model of infrequent lengthy consultations. This eHealth platform is currently undergoing evaluation in a nationwide multicenter project.
3.b) Risk Assessment of Toxic Aluminum Exposure Through Parenteral Nutrition
The long-term administration of PN increases the relevance of chronic exposure to potentially toxic contaminating components like aluminum. Currently, a new chapter of the European Pharmacopoeia (Ph. Eur.) is under development to limit the risk of exposure to toxic levels of aluminum through PN. We developed an innovative and highly sensitive analytical method using inductively coupled plasma mass spectrometry to quantitatively measure aluminum and other elements in very low concentrations in commercial products used for all-in-one PN admixtures. Our findings reveal that commercial products can contain critical aluminum concentrations, emphasizing the necessity for regulatory measures to guarantee quality.
In summary, the evolving landscape of medical nutrition is placing an increasing emphasis on patient-reported outcomes and QOL to be supported by preventive actions. Customized digital solutions and eHealth have the potential to enhance patient-reported outcomes, patient safety, and the quality of care while demanding interprofessional collaboration and research among HCPs, scientists, engineers, legal experts, and end users. Such cooperation is required to produce a clinically useful tool that adheres to data security and privacy regulations as well as medical device regulations. These innovations have the potential to advance medical nutrition and to improve nutrition therapy and support. The thesis substantiated advances in medical nutrition in several projects in different populations as well as scientific lab investigations
Revitalizing antibiotic discovery and development through in vitro modelling of in-patient conditions
Full text linkFrom the Alps to Africa: ecology and migration of Northern Wheatears (Oenanthe oenanthe) breeding at high elevation, with insights into an intra-tropical migratory system
Full text linkThe populations of Afro-Palearctic migratory birds are declining. These species are more sensitive to climate change than short-distance migrants or residents. Because mountain ecosystems are under increased pressure of climate and land-use changes, I investigated one of the few long-distance migrants breeding at high elevations in the Alps, the Northern Wheatear Oenanthe oenanthe. The first three chapters of this thesis are focusing on breeding-site ecology in the Swiss Alps and on the avifauna of alpine grasslands. In chapters four and five, I investigated migration of the Northern Wheatear. In the sixth chapter, I broadened the scope by studying a different migration system from the southern hemisphere.
In the first chapter, I identified drivers of nest-site selection and breeding success. Nests were more likely located at lower elevation on gentle, south-exposed slopes. Productive pastures interspersed with rockpiles and bare ground were preferred. As Wheatears are territorial, the surroundings of conspecific nests were avoided for selecting a nest site. Predation was the main driver of breeding failure. Breeding success seemed similar among years with strong inter-annual variation in spring onset, to which laying dates were adjusted.
In the second chapter, the focus shifted to foraging micro-habitat. My colleagues and I observed ringed Northern Wheatears between May and September. Wheatears preferred rocks and short vegetation throughout the presence at the breeding site. The snow front was favoured for foraging only upon arrival from migration, whereas bare ground played an important role while provisioning food for the chicks when the grass layer was high, and after the breeding period. Wheatears preferred the vicinity of burrows of Alpine Marmots Marmota marmota, where bare ground was available. The preference for heterogenous habitats on a small scale suggests sensitivity of Northern Wheatears to landscape homogenization due to intensification, or to bush encroachment as a consequence of land abandonment.
In the third chapter, I extended my research beyond the Northern Wheatear. I considered fine-scale and landscape-scale habitat preferences of co-occurring insectivorous species inhabiting alpine grasslands by conducting repeated surveys. The Water Pipit Anthus spinoletta, an alpine specialist, had higher densities on gentle, productive slopes, and lower densities in dense shrubs. Wheatears preferred open, south-exposed and gentle slopes with human-made rockpiles. While Wheatears avoided shrubs, the closely related Whinchats Saxicola rubetra, a species of conservation concern in Europe, preferred this habitat and had higher densities at lower elevations close to the treeline. Our results underline the importance of high-elevation pastures for the conservation of species that are declining in Europe, as long as low-intensity management maintains patchy habitats.
The following chapters focused on migration, starting with a comparative study in which migration routes and timing of Northern Wheatear populations in the Swiss and Austrian Alps were described. Using light-level geolocators, my co-authors and I compared their migration with a lowland population in Germany. Lowland birds returned earlier compared to birds from the Alps where spring onset is delayed. Wheatears from Switzerland and Austria often directly crossed the Mediterranean Sea, while birds from Germany migrated towards the Iberian Peninsula. All three populations overwintered in the Western Sahel.
In the fifth chapter, I used multi-sensor geolocators to investigate the movements of Northern Wheatears with unprecedented spatial and temporal resolution. Stationary sites were located with enhanced precision compared to light-level geolocation, by correlating the air pressure measured on the birds with global atmospheric pressure data. I identified the role of islands as optional stopover sites while crossing the sea, and I located the main stopover areas between the Mediterranean and the Sahara in the Atlas Mountains. Furthermore, atmospheric pressure data informed on flight altitudes, highlighting longer, faster, and higher flights above the sea and the desert as barrier-crossing behaviour. When the birds returned in May, local altitudinal movements towards the Alpine valley took place in response to unfavourable weather events with snowfall. I also unveiled unexpected diel movements towards roosts a few hundred meters uphill from the breeding territory.
The final chapter extended the new insights on migration to another system in the southern hemisphere, where bird migration is still poorly understood. I applied the analytic framework used for Wheatears to present the full annual cycle of a small-sized intra-African migrant for the first time. Based on multi-sensor logger data, I retrieved stationary sites, flight behaviour and migration timing from five Woodland Kingfishers Halcyon senegalensis breeding in South Africa. These birds tracked rainy seasons in both hemispheres, migrating 4000 km north to the same area in South Sudan, where they found habitats similar to those at the breeding site. Migratory flights occurred at night like in Northern Wheatears but were shorter on average. Post-breeding migration was longer than pre-breeding migration. Woodland Kingfishers changed their flight behaviour above the Congo Basin, where I presumed that less suitable stopover habitat resulted in shorter stops as well as in faster, higher, and longer flights. This was a behaviour comparable to that of Wheatears crossing the Mediterranean Sea and the desert. Such findings became only recently possible for small birds by using multi-sensor loggers, which can be used to study intra-tropical and other migratory systems, promising major future advances for global migration research.
To conclude, this thesis establishes a link between the breeding ecology of the Northern Wheatear in the Alps and the other parts of its annual cycle, and further extending to another migratory system. It sheds light on the remarkable challenges faced by Wheatears, flying thousands of kilometres up to 5000 m in the sky, overcoming the heat of the desert and the dangers of the sea, all to reach our harsh mountains still blanketed in snow with freezing temperatures. Once the Wheatears complete their migration, they must then rear their broods amidst the constant threat of predation before preparing for the next journey, resulting in a truly awe-inspiring annual cycle