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Expansion of HIV-1 infected cells and the possible influence on tropism dynamics in individuals on antiretroviral therapy & adapting the geno2pheno[coreceptor] tool to HIV-1 subtype CRF01_AE by phenotypic validation using clinical isolates from South-East Asia
Full text linkFor cellular infection HIV-1 interacts with the CD4 receptor and a chemokine receptor, either CCR5 or CXCR4. In the early phase of infection, the virus almost exclusively uses the CCR5-receptor. Only later during disease progression up to 50% of infected individuals without therapy experience a shift to a dominance of CXCR4-tropic viruses, associated with higher CD4 cell depletion rates and an accelerated disease progression. In contrast, under successful therapy a majority of patients show a decrease of CXCR4-tropic variants and only in a few an increase of CXCR4-tropic viruses is observed. As the increase of CXCR4-tropic viruses in patients under therapy was observed to be caused by the outgrowth of a single variant, this study aimed to investigate the possibility of clonal expansion of HIV-1 infected cells by integration site analysis. Although the results confirmed clonal expansion, aberrant cell proliferation due to HIV integration was not observed.
An additional study was performed to validate the popular HIV-1 genotyping tool, Geno2Pheno[coreceptor], for clinical samples of subtype CRF01_AE. The algorithm was shown to have a significant overcalling of X4 variants in this subtype, and by combining phenotypic results with genotypic predictions an adjusted false positive rate (FPR) cut-off was identified to provide more accurate tropism predictions. Included in this work was also the development of a cloning cassette optimized for phenotypic analysis of subtype CRF01_AE samples
Coercive measures in inpatient psychiatry: a look at vulnerable patient groups
No full textIn psychiatric inpatient settings, coercive measures should be used only as a last resort. To reduce coercion, it is necessary to identify the factors that promote the use of coercive measures and those which prevent them. Numerous studies have addressed this question, but the findings are heterogeneous and the methodological quality of some of the studies is weak. Further research that includes a broad range of relevant confounders and applies robust study designs is needed.
In this dissertation, I investigated two factors that have been previously shown to be associated with coercive measures: open-door policies and the COVID-19 pandemic. While it was reported that coercive measures overall increased during the pandemic, previous studies demonstrated that open-door policies are accompanied by a reduction in coercive measures. However, to date, experiences of door policies during previous stays have not yet been investigated.
Paper 1 aimed to answer the question of whether the door policies during the previous and the current inpatient stay are related to the risk of coercive measures during the current inpatient stay. In line with previous research, our findings showed that the ward type (open- versus closed-door policy) to which a person is admitted is associated with the use of coercive measures. The admission to a ward with an open-door policy decreased the risk for coercive measures during this inpatient stay. However, the ward type in previous inpatient stays appears to be unrelated to future coercive measures. Patients who were admitted to a ward with an open-door policy, but then had to be transferred to a ward with a closed-door policy, had almost three times higher odds to experiencing coercive measures than patients who were admitted to a ward with a closed-door policy from the start. This finding highlights the need to identify at risk groups, as well as investigate the emergence of high risk situations in acute mental health settings.
In papers 2 and 3, we addressed the association between the COVID-19 pandemic and coercive measures for diagnostic groups separately as previous research has not addressed these groups individually. The occurrence rate of coercive measures increased in four patient groups, namely organic mental disorders, substance use disorders, schizophrenia and other psychotic disorders (paper 3) and personality disorders (paper 2). In the other groups, we did not find any change within the context of the COVID-19 outbreak (paper 3). All diagnostic groups exhibited unique progression in the use of coercive measures, both before and after the COVID-19 outbreak.
The findings of this doctoral thesis support the claim for flexible mental healthcare, with flexible meaning that treatment is adapted to each person, to each situation individually. The COVID-19 pandemic revealed the fragility and structural weaknesses of our healthcare system. In future, we will need to pay special attention to vulnerable populations, in particular in the context of national or global dynamics, in research as well as in clinical settings
Pigovian Transport Pricing in Practice
Full text linkWe implement Pigovian transport pricing in a field experiment in urban agglomerations of Switzerland over the course of 8 weeks. The pricing considers external costs from climate damages, health outcomes and congestion and varies across time, space and mode of transport. The treatment reduces the external costs of transport of the treated individuals by 4.5% in the short run. The main underlying mechanism is a shift away from driving towards other modes, such as public transport, walking and cycling. Providing information about external costs alone changes behavior of altruists, but not for the whole sample. We estimate the welfare improvements from such a policy to be around 140 US dollars per person and year, which is twice as large as the effects of a fuel tax that generates the same revenue
Vom Hauen und Stechen: eine funktionale Einordnung jung- und endneolithischer Knochenartefakte aus den Feuchtbodensiedlungen Südwestdeutschlands anhand einer Gebrauchsspurenanalyse
Full text linkDiese Arbeit beschäftigt sich mit der Zuordnung der Gebrauchsspuren bei jung- und endneolithischen Knochenartefakten zu einem Werkmaterial oder einer Funktion. In der Regel werden Knochen-, Geweih- und Zahnartefakte nur typologisch untersucht. Dabei werden Begriffe wie etwa „Meißel“, „Pfriem“, „Ahle“, „Schaber“ aufgrund der Form der Artefakte vergeben, ohne jedoch die tatsächliche Funktion bzw. den Verwendungszweck näher zu untersuchen. Experimentalarchäologische Untersuchungen haben gezeigt, dass es durchaus Unterschiede in den Gebrauchsspuren gibt, die wiederum Rückschlüsse auf den tatsächlichen Gebrauch und das bearbeitete Material ermöglichen. Die bisherigen Experimente haben gezeigt, dass sich die Gebrauchsspuren in drei Gruppen einteilen lassen, die wichtige Hinweise auf die Art der Bewegung oder die Handhabung und damit auf das bearbeitete Material geben. Zudem haben die Untersuchungen von nachgebauten Werkzeugen und Artefakten ergeben, dass die Mikrospuren direkt miteinander verglichen werden können
Sein als Selbstgabe. Natur und Gnade bei Paul Tillich und Karl Rahner, dargestellt an den jeweiligen theologisch-philosophischen Hauptmotiven
No full textDietary adaptations in the intestinal tract of cichlids: macro and micro-morphological perspectives and phenotypic plasticity
No full textDietary adaptations play a pivotal role in evolutionary processes and contribute to the diversification of species. They involve changes at different levels of biological organisation that help organisms to exploit novel niches in a habitat, thereby reducing competition and improving food utilisation. Dietary adaptations have also been crucial in the rapid adaptive radiations of East African cichlids. While changes in the food up-take apparatus have been well documented in these closely related species, much less is known about the accompanying morphological, cellular and molecular variations in their intestinal tracts.
This doctoral thesis aims to understand the macro- and micro-morphological aspects of dietary adaptations in the intestines of Lake Tanganyika cichlids and investigate the role of phenotypic plasticity in adapting to various dietary regimes. To do so, we took a holistic approach, combining broad phylogenetic sampling and traditional histology methods with cutting-edge technologies including geometric morphometrics and single-cell transcriptomics, to investigate the morphological, cellular and molecular aspects of dietary adaptations in cichlids.
In the first chapter of the thesis, we first explored the size and shape diversity of abdominal cavities in cichlids. We noticed diet-related patterns in abdominal cavity morphology and found a strong correlation with the intestinal lengths of the respective species. Next, we analysed variations at the micro-morphological level, both along the intestinal axis and between species, by quantifying intestinal ridge patterns and various histoanatomical traits of the intestinal epithelium. Lastly, we performed correlation analyses between macro- and micro-morphological traits and ecological indicators, to decipher potential interrelations.
In the second chapter, we aimed to study to what extent these macro- and micro-morphological traits respond to changes in nutrient composition in plastic manner. To this end, we conducted common garden experiments in which fishes of different species and dietary categories were raised on experimental feeds of varying nutrient compositions. Varied responses in growth, intestinal length plasticity and histoanatomical traits to changes in dietary nutrients were observed. Finally, single-cell transcriptomic analyses of intestinal tissues revealed accompanying changes in cell type proportions and plastic responses at the level of gene expression between individuals from different diet treatment groups, underscoring the importance of phenotypic plasticity in responding to novel dietary sources.
Collectively, through phylogenetic-comparative sampling, interdisciplinary methods and integrative data analyses, the findings of this study broaden our understanding of the intestine’s role in dietary adaptations and, ultimately, organismal diversification
Planning with different representations
Full text linkClassical planning tasks are represented using a logical language. It is common to use a first-order representation, as this makes the description of the tasks more compact. Planners have long relied on translating these first-order representations into propositional ones in a process called grounding. Earlier work showed that grounding can improve the performance of classical planners. But this can also lead to exponentially larger encodings, and tasks with short plans become intractable simply because of the size of their representation.
In this thesis, we focus on lifted planning, which operates directly on the first-order representation. This bypasses the need for grounding, avoiding its computational overhead. We show how to build a lifted planner, called Powerlifted, that uses different techniques from database theory and logic programming to achieve state-of-the-art performance.
First, we show how to perform a state-space search over the lifted representation. We address the lifted successor generation problem and show that this is equivalent to solving conjunctive queries. By exploiting the acyclicity of conjunctive queries, Powerlifted can generate successors efficiently in many domains. Second, we show how to use Datalog to compute delete-relaxation heuristics, such as the additive and the FF heuristics, directly over the lifted representation. Finally, we show how to translate other state-of-the-art techniques, such as preferred operators and width search, from the ground to the lifted setting.
We then show that some ideas from our work on lifted planning can be carried over to the ground setting. Using techniques implemented in Powerlifted, we show how to improve the grounding algorithms commonly used by classical planners. This is significant, as grounding is a crucial phase of most classical planners developed over the last two decades. Our new algorithm uses the grounding via solving paradigm from answer set programming, in which the grounding of a problem is decoupled into several logic programs, which must be solved individually to produce the propositional representation. In our experiments, our method outperforms other commonly used grounders from the literature.
Finally, we propose an extension to the classical planning formalism allowing for object creation within action effects. In practice, we show that Powerlifted can support this fragment almost effortlessly and that lifted planners, in general, seem to be a good fit for planning with object creation. Our experimental results show that object creation does not add overhead to Powerlifted while allowing for more expressive planning formalisms
Safety, pharmacology, and subjective effects of LSD, psilocybin, MDMA and its enantiomers
Full text linkClassic psychedelics such as psilocybin and lysergic acid diethylamide (LSD) and the entactogen 3,4-Methylenedioxymethamphetamine (MDMA) are being investigated for their potential in substance-assisted therapy for various psychiatric and neurological disorders. While first results propose potential in treating these conditions, there is a lack of phase I studies examining the safety, pharmacology, and subjective effects of these compounds in healthy volunteers, as usually is the case in drug development. Previous research has shown that the acute positive effects of psychedelics are linked to their therapeutic benefits, making it essential to enhance these acute subjective effects. MDMA is a racemic substance that has already been investigated more extensively in phase I studies, yet preclinical research suggests that its enantiomers may have different effects, with one potentially being more suitable for substance-assisted therapy, regarding the safety. This thesis includes three projects aimed at expanding our knowledge of the safety, pharmacology and subjective effects of LSD, psilocybin, MDMA and the enantiomers R-MDMA and S-MDMA. The first project involved a clinical study with healthy volunteers where MDMA (100 mg) was used as a pharmacological tool to enhance the psychedelic effects of LSD (100 µg). While the effects profile of the combined LSD + MDMA administration did not differ significantly from LSD alone, the duration of effects was extended by an average of 1.5 hours. This is likely due to MDMA’s strong inhibition of the Cytochrome P450 2D6 (CYP2D6) enzyme, which slowed the metabolization of LSD, resulting in higher plasma concentration and a longer elimination half-life. This finding further supports a role for CYP2D6 in the LSD metabolism. The LSD + MDMA combination induced higher blood pressure and heart rate, with similar minimal increases in body temperature compared with LSD alone. Even though the combined administration is intriguing, it probably offers no additional benefit to LSD-assisted psychotherapy in patients. The second project included three completed studies with 113 psilocybin administrations at doses from 15 to 30 mg in 85 healthy volunteers. Safety data of these studies were pooled and revealed comparable positive effects for 20, 25, and 30 mg psilocybin, while significant “anxiety” was only observed with the 25 and 30 mg doses. Increases in blood pressure (>140 mmHg), heart rate (>100 bpm), and body temperature (>38°C) were noted in 50%, 7%, and 16% of participants, respectively, after psilocybin administration. The autonomic effects of psilocybin were similar to those of LSD and less pronounced than those of MDMA. Acute adverse effects included fatigue, lack of concentration, lethargy, vertigo, feeling of weakness, and decreased appetite. Overall, single-dose administrations of psilocybin up to 30 mg were found to be safe regarding psychological and physical harm in healthy volunteers in a controlled setting. However, risk and benefits of using psilocybin in patients need further investigation. The third project examined the acute and subacute effects of MDMA (125 mg) and its enantiomers R-MDMA (125 and 250 mg) and S-MDMA (125 mg). While small differences in subjective effects were observed with MDMA, R-MDMA and S-MDMA, dose equivalence was not achieved, leaving it unclear whether these differences are due to their distinct binding profiles or the dosing. The results suggest dose equivalence regarding subjective effects with 125 mg MDMA, 300 mg R-MDMA, and 100 mg S-MDMA. The elimination half-life of R-MDMA increased dose-dependently from 11 hours with 125 mg racemic MDMA, to 12 hours with 125 mg R-MDMA, to 14 hours with 250 mg R-MDMA. In contrast, the elimination half-life of S-MDMA decreased when administered without R-MDMA. Additionally, the formation of 4-Hydroxy-3-methoxymethamphetamine (HMMA), a metabolite produced via CYP2D6, did not increase with higher doses of R-MDMA, indicating that R-MDMA dose-dependently inhibits CYP2D6. The extent to which S-MDMA inhibits CYP2D6 remains to be determined. All projects uncovered new findings about these compounds, providing valuable insights to inform and guide future clinical studies in both healthy volunteers and patients
Property in goods and the CISG
Full text linkCan States unify their sales contract law seamlessly without harmonizing property law? This was attempted in 1980 with the UN Convention on Contracts for the International Sale of Goods (CISG). The fundamental question remained. Nearly half a century later, the author aims to address it against the backdrop of the CISG.
The question must be broken down. For example, how can the obligation to transfer property be uniformly interpreted given diverging notions of property under national law? Does the CISG rely on an autonomous notion of property? Does this notion influence the scope of the Convention, especially regarding the common definition of a sales contract? How does the CISG reconcile with English law that the seller's claim to the purchase price arises only after transfer of property?
Ernst Rabel, pioneer of the unification of international sales law, deliberately omitted any references to property in his draft of a unified sales law in 1935. Instead of solely assessing the CISG's success in mitigating conflicts with national property law, this study endeavors to offer a definitive response to the fundamental question raised above through a comprehensive interpretation of the CISG
Ostracism in Everyday Life: A Framework of Threat and Behavioral Responses in Real Life
Full text linkOstracism—being ignored and excluded—is part of many individuals’ daily lives. Yet, ostracism is often studied in laboratory settings and rarely in natural settings. Here, we report one of the first investigations into ostracism in everyday life by documenting how often and where ostracism occurs; who the sources of ostracism are; and how ostracism affects targets’ feelings and behaviors. Two experience sampling studies using event-contingent (N = 323, k = 1,107 ostracism experiences in 14 days) and time-signaling sampling approaches (N = 272, k = 7,943 assessments including 767 ostracism experiences in 7 days) show that ostracism is an aversive experience that takes place in a range of contexts and relationships, as often as two to three times per week on average. Reconciling previously mixed findings regarding ostracism’s effects on behavior and extending existing theory, we propose a novel framework of behavioral reactions based on need-threat levels: When psychological needs are severely threatened, individuals react to everyday ostracism with avoidance (i.e., withdrawal) and antisocial inclinations (i.e., they exhibit significantly stronger antisocial intentions, although they do not engage in antisocial behavior more frequently). Conversely, when psychological needs are threatened to a lesser extent, individuals are more likely to adopt approach behaviors (i.e., prosocial behavior, talking to others, or connecting with them on social media). Our findings considerably extend present theorizing in ostracism research as they allow to understand when and how individuals experience everyday ostracism and how behavioral reactions after ostracism form in real life