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Jüdisches Engagement im Schweizer Breitensport. Emmi und Otto Bloch in der Schweizer Wandervogelbewegung von 1908-1919
No full textNormal traces and applications to continuity equations on bounded domains
Get PDFIn this work, we study several properties of the normal Lebesgue trace of vector fields introduced by the second and third author in [18] in the context of the energy conservation for the Euler equations in Onsager-critical classes. Among several properties, we prove that the normal Lebesgue trace satisfies the Gauss-Green identity and, by providing explicit counterexamples, that it is a notion sitting strictly between the distributional one for measure-divergence vector fields and the strong one for functions. These results are then applied to the study of the uniqueness of weak solutions for continuity equations on bounded domains, allowing to remove the assumption in [15] of global regularity up to the boundary, at least around the portion of the boundary where the characteristics exit the domain or are tangent. The proof relies on an explicit renormalization formula completely characterized by the boundary datum and the positive part of the normal Lebesgue trace. In the case when the characteristics enter the domain, a counterexample shows that achieving the normal trace in the Lebesgue sense is not enough to prevent non-uniqueness, and thus a assumption seems to be necessary for the uniqueness of weak solutions
Functional selection of DNA-encoded library
No full textFirst, we report that the BPyr heterocycle can be cleanly formed on DNA and is compatible with a wide range of substrates. Although commercial sources of FBs can presently support a split-size of only ∼100, combining with one other major diversifying reaction (i.e., a two-cycle library) can already produce a small DEL (105 members). Given that the BPyr heterocycle has the special ability to engage in reversible covalent interactions with hydroxyl side chains in proteins, even modest-sized libraries would be important because they offer something distinct from other DELs.
Second, our research has demonstrated that DNA hybridization-induced proximity can accelerate selective Ub-transfer. We have developed a template-based encoding strategy to facilitate library development and ensure catalytic turnover of the Ub-transfer signal during selections. The method continues to deliver strong enrichment signal even with simulated libraries of up to 100,000 members—a size sufficient for large-scale library selections. While DNA-Encoded Library (DEL) selections are now standard in early drug discovery, conducting functional selections in a pooled format continues to pose challenges. Recent innovative efforts underscore the significant commitment to establishing functional DEL selections. Our work introduces a novel functional selection applicable to pooled format that identifies optimal pairs of MGDs and protein substrates for Ub-transfer reactions. We focus on Ub-transfer due to the significant challenge of discovering novel MGDs in contemporary medicinal chemistry. However, we anticipate that the assay could be adapted for other functional selections, such as SUMOylation or phosphorylation or any other post-translational modification. A drawback of our approach is the need for custom library synthesis for each selection. Hence the application needs to be carefully chosen such that the insights gained from the resulting dataset justify the effort in library construction. The current application, which connects MGDs with potential substrates, is particularly well-suited for this approach. Over the past decade, considerable efforts have been made across numerous research labs to define both the small molecule structure-activity relationship (SAR) and the optimal protein degrome for specific immunomodulatory drugs. The library we have would provide comprehensive Ub-transfer activity data for both small molecules and protein substrates in a single dataset. The future of this project will be the synthesis of a glutarimide-based DEL to generate this dataset
From antigenic variation to cell cycle progression: a functional analysis of the putative "var" gene regulator PfSET10 and its interaction partners in "Plasmodium falciparum"
No full textPlasmodium falciparum causes the most devastating form of human malaria. Its remarkable replication potential is crucial to overcoming the complex life cycle bottlenecks. During blood-stage infection, parasites undergo repeated rounds of red blood cell (RBC) invasion and asexual replication that rapidly increase the parasite load in the human host. To avoid parasite clearance by the adaptive immune system, P. falciparum employs antigenic variation of surface antigens, such as P. falciparum erythrocyte membrane protein 1 (PfEMP1). Furthermore, PfEMP1 medi-ates cytoadherence of infected RBCs to vascular endothelium, which on the one hand prevents their passage through and removal by the spleen and on the other hand contributes strongly to malaria pathogenesis. Hence, the massive parasite replication combined with antigenic variation is crucial to parasite survival and transmission, and at the same time a major cause for severe disease outcomes.
PfEMP1 is encoded by 60 var gene paralogs, which are expressed in a mutually exclusive man-ner. var gene activation and switching are associated with nuclear repositioning to a specific perinuclear site termed var gene expression site (VES). However, the molecular details of the underlying regulatory mechanisms have yet to be entirely understood. To date, PfSET10 re-mains the only protein presumed to exclusively localise to the VES. Hence, during my PhD studies, I set out to scrutinize the role of PfSET10 and further describe its role in antigenic varia-tion. Additionally, I aimed to identify and characterise additional proteins associated with the VES. In the first study, I could convincingly rule out that PfSET10 regulates var gene expres-sion, thereby correcting the long-standing model of var gene regulation. The results from co-immunoprecipitation and in vivo proximity-dependent biotinylation experiments using PfSET10 as bait provide the foundation for the second study, where I conducted functional analyses of putative PfSET10 interaction partners. Here, the conditional knockout of one of these factors (Pf3D7_1322300) prevents further rounds of genome replication beyond the first S-phase dur-ing schizogony and male gametogenesis. This unique loss-of-function phenotype highlights that Pf3D7_1322300 is an essential and novel component of the parasite's replication machinery and provides the first evidence for an intra-S-phase checkpoint-like activities in P. falciparum. Moreover, we found that the PfSET10 complex interacts with the cohesin complex at the peri-centromeric region, thereby, our study provides the foundation for the intriguing possibility that the VES may be tethered via an unknown mechanism to the CP or the centromeric cluster. In the third study, we investigated the three Aurora-related kinase of malaria parasites and gained valuable insight into their expression dynamics and subcellular localisation to mitotic structures and cell division machinery during schizogony and gametocytogenesis. Collectively, the work presented here provides fascinating new insight into the molecular mechanisms underlying the control of cell cycle progression and var gene regulation, offering new perspectives for future research
Akute Effekte einer moderaten Sporteinheit auf die affektive Impulskontrolle bei Kindern mit einer Autismus-Spektrum-Störung
No full textDiese Masterarbeit untersucht die Effekte einer akuten moderaten Sporteinheit auf die affek-tive Impulskontrolle bei Kindern mit einer Autismus-Spektrum-Störung (ASS). Autismus ist eine neurobiologische Entwicklungsstörung, die durch Beeinträchtigungen in der sozialen Interak-tion und der Kommunikation sowie durch repetitive Verhaltensmuster gekennzeichnet ist. Bis-herige Forschungsarbeiten zeigen, dass körperliche Aktivität positive Auswirkungen auf die kognitive Funktion und das Stressniveau haben kann.
Ziel dieser Studie ist, diese Effekte bei Kindern mit ASS zu analysieren, indem die kognitiven Leistungen bei einer Gesichts- versus Objekterkennungsaufgabe unter zwei Bedingungen, ei-ner Bewegungsintervention in Form einer einmaligen moderaten 20-minütigen Ausdauertrai-ningseinheit auf einem Ergometer sowie einer Kontrollintervention bestimmt werden. Zu meh-reren Zeitpunkten der Durchführungen werden Speichelcortisolwerte entnommen, um den Stresslevel der Proband*innen zu bestimmen.
Die Ergebnisse zeigen eine signifikante Erhöhung der Reaktionszeiten für die Gesichtserken-nung nach der Sporteinheit (p = 0.044), was auf eine Beeinträchtigung der kognitiven Leistung schliessen lässt. Die Interaktion zwischen Bedingung und Zeitpunkt zeigt einen moderaten Effekt (Wilks-Lambda = 0.815, F(2,27) = 3.064, p = 0.063), was auf eine mögliche, jedoch nicht signifikante, Wechselwirkung hindeutet. Im Gegensatz dazu bleiben die Fehlerraten bei der aktiven sowie bei der Kontrollgruppe unverändert (p = 0.374 bzw. p = 0.537). Eine signifikante Reduktion der Cortisolwerte nach der Bewegungsintervention (p = 0.001) bei der aktiven Gruppe, weist auf eine Verringerung des physiologischen Stressniveaus hin.
Diese Ergebnisse zeigen, dass körperliche Aktivität kurzfristig die kognitive Leistung bei Kin-dern mit ASS beeinträchtigen kann, jedoch das Stressniveau senkt. Die erhöhte Reaktionszeit könnte durch eine vorübergehende Überlastung des Nervensystems durch die körperliche An-strengung, kombiniert mit den Anforderungen der Gesichtserkennungsaufgabe bedingt sein. Die stressregulierenden Effekte der Aktivität könnten die Reduktion der Cortisolwerte verur-sacht haben.
Dass signifikante Reaktionen ausgelöst wurden, zeigt, dass über Anpassungen von Zeitpara-metern, Übungszeit und -form Effektverbesserungen erreicht werden könnten. Dies unter-streicht die Notwendigkeit weiterer Forschung, wie sich über individuelle Dosierung positive Effekte auf die Gesichtserkennung und das Wohlbefinden erreichen lassen
Zusammenhang von BMI, Alter, Geschlecht und der Verbesserung der maximalen Sauerstoffaufnahme bei Trainingsinterventionen mit Patienten mit HF mit erhaltener Ejektionsfraktion
No full textHintergrund: Die Pathogenese von Herzinsuffizienz mit erhaltener Ejektionsfraktion (HFpEF) wird durch ein breites Spektrum an Risikofaktoren beeinflusst, was das klinische Management und die Forschung erschwert. Zwei der wichtigsten Risikofaktoren für die Entwicklung von HFpEF sind höheres Alter und Übergewicht. Für eine optimale Therapie ist ein besseres Ver-ständnis der Wechselwirkungen zwischen Risikofaktoren und pathologischen Veränderungen erforderlich. Diese Arbeit untersuchte den Zusammenhang von Body-Mass-Index (BMI), Alter und Geschlecht mit der Verbesserung der maximalen Sauerstoffaufnahme (VO₂peak) bei Trai-ningsinterventionen mit HFpEF-Patienten.
Methoden: In einem narrativen Review mit systematischer Literatursuche wurden sieben rand-omisiert-kontrollierte Trainingsinterventionsstudien mit HFpEF-Patienten identifiziert. Aus diesen wurden BMI, Alter, Geschlecht und VO2peak extrahiert. Zusätzlich wurden vier weitere Studien für eine Sekundäranalyse mit den Interventionsgruppen isoliert identifiziert. Die Daten wurden mithilfe einer univariablen linearen Regressionsanalyse ausgewertet, um den Zusam-menhang zwischen den demografischen Variablen und der Veränderung der VO₂peak in den Interventionsgruppen im Vergleich zu den Kontrollgruppen (Primäranalyse) sowie innerhalb der Interventionsgruppen (Sekundäranalyse) zu untersuchen.
Ergebnisse: Primäranalyse: BMI (p=0.001, β=0.034, R²=0.019), Alter (p<0.001, β=-0.098, R²=0.331) und Geschlecht (p<0.001, β=-0.009,R²=0.040) waren signifikant mit der Verbesse-rung der VO2peak assoziiert. Sekundäranalyse: BMI (p<0.001, β=-0.122, R=0.131), Alter (p<0.001, β=0.120, R²=0.474) und Geschlecht (p<0.001, β=0.011, R²=0.068) waren ebenfalls signifikant mit der VO2peak assoziiert.
Schlussfolgerungen: Die Ergebnisse deuten darauf hin, dass das Alter einen signifikanten Ein-fluss auf die Verbesserung der VO₂peak hat. Ein Zusammenhang zwischen Übergewicht und der Verbesserung der VO₂peak ist ebenfalls erkennbar, jedoch mit geringerer Evidenz. Im Ge-gensatz dazu scheint das Geschlecht aufgrund widersprüchlicher Ergebnisse keinen eindeutigen Einfluss auf die Verbesserung der VO₂peak zu haben
Antikommunistische Organisationen und Netzwerke in der deutsch-, französisch- und italienischsprachigen Schweiz, 1945-1990
No full textMaking clinical trials more efficient: trial costs, budget planning, and platform trials
No full textConducting high quality clinical trials is complex, time consuming and expensive. Consequently, making clinical trials more efficient will play an integral part in their sustainability in the future, in addition to reducing research waste. In this thesis we aimed to make clinical trials more efficient by conducting three research projects. Firstly, we determined the costs and resources required to plan, conduct and finalize an investigator initiated randomized controlled trial in Switzerland, Germany and the United Kingdom. Secondly, we investigated the tools and approaches used by Swiss Clinical Trial Units (CTUs) and the Swiss National Science Foundation (SNSF) to calculate trial budgets and compare them to internationally available tools and determine areas of improvement. Thirdly, we explored the platform trial design, to determine if this innovative approach may improve clinical trial efficiency by conducting a systematic review, and through practical experience gained as a trial coordinator for the Corona VaccinE tRiAL pLatform (COVERALL-2).
For the first project, we determined that writing of the protocol, data management and patient follow up contributed the highest proportion to total trial costs. Reduction in these areas has the potential to lead to more cost-effective investigator initiated randomized controlled trials (RCTs). In addition, based on the actual trial costs determined in our work, investigators now have cost estimates and proportions available, on which they can base future budget calculations, since 83% of these RCTs exceeded their original budget. Secondly, we determined that budgeting tools and approaches used by Swiss CTUs and SNSF are lacking, not tested, and do not include all cost relevant items or provide cost ranges for investigators to rely on. As such, we discuss standardizing and improving budgeting approaches and tools across Swiss CTUs. Thirdly, our systematic review identified 127 platform trials in various medical fields. These platform trials also showed lower rates of trial discontinuation and answered many research questions by adding new arms to the trial. Nevertheless, some did not add new arms, and consequently incur higher planning costs and not benefit from the cost savings of adding new arms. The prolific nature of platform trials was confirmed firsthand by the COVERALL trial, which resulted in 3 subprotocols and 7 publications.
In conclusion of this work, we emphasize the importance of confronting the challenge of collecting and sharing clinical trial cost data, ultimately contributing to future success of clinical research. We discuss efforts being made to make trial costs more transparent, such as the 72nd World Health Assembly (WHO, 2019) and The Pharmaceutical Research Transparency Act of 2022 and 2023. Secondly, we also highlight the growing significance of platform trials and identified barriers such as infrastructure challenges, methodological issues, and lack of regulatory guidelines. We discuss recommendations for the future of platform trials and include ongoing efforts made by stakeholders (such as EU-PEARL and EU-Response) to transform platform trial methodology and streamline regulatory processes
Piloting multiple first-line artemisinin-based combination therapies as an innovative approach for managing uncomplicated malaria in the healt district of Kaya, Burkina Faso
Get PDFDespite coordinated control efforts, sub-Saharan Africa (SSA) still bears the major burden of malaria, a preventable and treatable infectious disease. 95% of the 247 million new cases and 96% of the 625’000 deaths occurred on this continent in 2021. The disease is also responsible for an unacceptable number of hospital admissions and outpatient visits and greatly contributes to poverty in most of SSA countries. In Burkina Faso, malaria remains the leading cause of morbidity (39.8%), and mortality (27.4%) and the country ranked among the six countries with the highest number of malaria cases worldwide, contributing for 3.4% of all cases. The World Health Organization (WHO) recommends a three-day treatment course of artemisinin-based combination therapy (ACTs) for treatment of uncomplicated malaria. The deployment of ACTs contributed substantially to reducing malaria burden. However, partial resistance to artemisinin derivatives or ACT partner drugs has recently emerged and is threatening all gains made in the past decades. To mitigate this threat, a strategy to optimize the use of the ACTs for malaria treatment in SSA countries is urgently needed. As demonstrated in mathematical models, the simultaneous deployment of multiple first-line therapies (MFT) for uncomplicated malaria may extend the useful therapeutic life of the current ACTs. The expected effect was to reduce drug pressure and slowing the spread of resistance without putting patients’ life at risk. We hypothesized that a simultaneous deployment of three different ACTs in Burkina Faso is feasible, acceptable, and can achieve a high coverage rate if potential barriers are properly identified and addressed. We conducted a quasi- experimental study in the health district of Kaya in order to generate evidence on the operational aspects of implementing MFT strategy in malaria endemic settings.
In the framework of this study, this PhD project aimed to assess the feasibility and the acceptability of the MFT strategy deployment for uncomplicated malaria cases management in Burkina Faso. The specific objectives included i) to investigate the treatment-seeking and case management practices for suspected uncomplicated malaria before the deployment of MFT; ii) to understand stakeholder’s perceptions about the deployment of this new strategy; iii) to assess the feasibility and the acceptability of the MFT strategy for uncomplicated malaria management.
As a prelude to the implementation of a pilot MFT program, we conducted a cross-sectional mixed methods study to identify potential facilitators or barriers and to inform a health district-wide implementation of the program. Findings showed that local populations have a good knowledge about malaria. A majority of 76.4% of those interviewed used health facilities (HF) as first recourse to care when they experienced fever / malaria episode, and 66.5% did so within 24 hours of fever onset. We also
confirmed that only one ACT (artemether-lumefantrine) was used for malaria case management (98.2
%). Visiting HF was associated with geographical proximity to the HF (AOR=1.5, 95%CI: 1.2-2.1) and free care of vulnerable populations (children under five and pregnant women). This first part showed that the community has an appropriate knowledge about malaria and positive care-seeking behaviour at health centres for fever/malaria episodes. This was considered to potentially facilitate the implementation of a MFT pilot program in public health facilities (PHF) of the district.
A qualitative survey performed with key stakeholders in the health system and community members revealed a positive perception of stakeholders on the implementation of the MFT programme. This strategy was perceived as an opportunity to strengthen the supply of antimalarial drugs and improve the management of fever and malaria. Thus, the success of this pilot programme was likely dependent on the efficacy of the proposed drugs, low frequency of side effects, affordability and availability of ACTs used.
After one year of deploying the MFT strategy at PHFs, we assessed its feasibility and acceptability. The findings showed good compliance with the strategy guidelines. We also noted a good management of study drugs stocks. 86.1% of malaria cases were treated according the study guidelines. The odds of using PHF as the first source of care increased after the intervention (aOR = 1.6; 95% CI, 1.3–1.9). Qualitative results showed a good acceptance of the MFT strategy with positive opinions from all stakeholders.
This PhD thesis established the feasibility, acceptability and the effect of MFT strategy in Burkina Faso. Implementing an MFT strategy is operationally feasible and acceptable by stakeholders in the health systems in Burkina Faso. As a pre-emptive approach to malaria drug-resistance management, this study provides evidence to support the simultaneous use of multiple first-line artemisinin combination therapies in malaria-endemic countries such as Burkina Faso
Creating true and false memories from forgotten information in Drosophila
Get PDFRecovering forgotten memories is a double-edged sword. While regaining access to forgotten information can be beneficial, targeted memory recovery carries the risk of generating false memories. The current understanding of neuronal circuits governing memory recovery or false memory implantation remains limited. We find in fruit flies that a reminder can recover forgotten aversive memories. This recovery requires a silent memory to recruit a specific pair of dopaminergic neurons. Modifying the reminder can mislead the recovery process and implant a false aversive memory. The effectiveness of this false memory implantation depends on the contextual boundaries of the training event. Compared to memory recovery, false memory implantation recruits a distinct dopamine pathway. Understanding these distinctions between true and false memory formation is essential for preventing and rectifying the acquisition of misleading information