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Cell type-focused compound screen in human organoids reveals molecules and pathways controlling cone photoreceptor death
Get PDFHuman organoids that mirror their corresponding organs in cell-type diversity present an
opportunity to perform large-scale screens for compounds that protect disease-affected or
damage healthy cell types. However, such screens have not yet been performed. Here, we
generated 20,000 human retinal organoids with GFP-labeled cone photoreceptors. Since
degeneration of cones is a leading cause of blindness, we induced cone death and screened
2,707 compounds with known targets, for those that saved cones or those that further
damaged cones. We identified kinase inhibitors that protected cones in both the short and
longer term, HSP90 inhibitors that saved cones in the short term but damaged them in the
longer term, and broad HDAC inhibition by many compounds that significantly damaged
cones. This resource provides a database for cone-damaging compounds, and it describes
compounds that can be starting points to develop neuroprotection for cones in diseases such
as macular degeneration
Cognitive Disengagement Syndrome bei Kindern und Jugendlichen: Vorbereitung für die Validierungsstudie zum Deutschen Child and Adolescent Behavior Inventory (CABI)
No full textHintergrund: Die Masterarbeit beschäftigt sich mit dem Cognitive Disengagement Syndrome (CDS) und legt dabei einen umfassenden Fokus auf die theoretische Aufarbeitung sowie die verschiedenen Messmethoden zur Erfassung des Syndroms. Das übergeordnete Ziel des Theorieteils besteht darin, eine solide Grundlage für die bevorstehende Validierungsstudie der deutschen Eltern- und Kinderversion des Child and Adolescent Behavior Inventory (CABI) zu schaffen. In diesem Kontext wird die Geschichte, Ätiologie und Pathogenese von CDS eingehend erforscht, wobei die Abspaltung von der unaufmerksamen Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS-IN), aber auch Komorbiditäten und psychopathologische Begleiterscheinungen ausführlich behandelt werden. Zusätzlich wird der aktuelle Stand der Literatur zu CDS in Bezug auf körperliche Aktivität und Schlafqualität beleuchtet. In Bezug auf die Messmethoden zur Erfassung des CDS, insbesondere des CABI, werden Vor- und Nachteile der Messmethoden beleuchtet, sowie bereits durchgeführte Studien zum CABI weltweit einbezogen und kritisch betrachtet.
Methoden: Dies beinhaltet die detaillierte Ausarbeitung des Ethikantrags für die geplante Validierungsstudie des CABI. Zudem wurden die Fragebögen von Englisch auf Deutsch übersetzt und sprachlich an das entsprechende Alter der Zielgruppe angepasst. Im Methodik-Teil wird die geplante Validierungsstudie als Online-Studie beschrieben und der detaillierte Ablauf wird erläutert. Die Bewilligung des Ethikantrags im September 2023 durch die Ethikkommission Nordwest- und Zentralschweiz (EKNZ; Project-ID: 2023-00862) markiert einen wichtigen Meilenstein, der den erfolgreichen Start der Studie ermöglicht.
Ergebnisse: Die konkreten Ergebnisse der Validierungsstudie werden in zukünftigen Masterarbeiten verarbeitet.
Schlussfolgerungen: CDS lässt sich von ADHS-IN abgrenzen, zeigt aber gewisse Ähnlichkeiten mit der Störung auf. Der CABI ist die verlässlichste Messmethode, um CDS zu erfassen
A follow-up analysis: Effects of an aerobic exercise training intervention on self-reported physical activity, depressive symptoms and subjective sleep quality in children and adolescents with inflammatory bowel disease
No full textThis study investigates the effects of an eight-week exergaming intervention on children and adolescents with inflammatory bowel disease (IBD). In addition, it contrasts the outcomes of the initial intervention with a subset of participants’ sleep and movement diaries. The participants were administered follow-up questionnaires on sleep, physical activity, psychological well-being and depressive symptoms three years after completing the initial intervention.
The results indicate only few significant changes in the measured variables. Surprisingly, both the IBD and healthy control groups exhibited significantly higher scores for depressive symptoms and significantly lower scores for physical well-being scores at the follow-up assessment. A cautiously positive note can be made of the 50% increase in physical activity measured in Metabolic Equivalent of Task-minutes (MET), although the change does not reach statistical significance.
The study provides preliminary insights into how exergaming might be a helpful tool for children and adolescents with IBD. To support these results, more studies with a larger population and more frequent and objective measurement points are necessary.
Key words
Inflammatory bowel disease, pediatric health, exergaming intervention, long-term effect
Die interaktive Hervorbringung von Kreativität: eine interaktionslinguistische Perspektive auf Kreativität in Werbeagenturen
Get PDFIm Zeitalter der digitalen Automatisierung wird Kreativität die Gesellschaft von morgen entscheidend gestalten. Dennoch sind empirische Ansätze, welche die tagtägliche Herbeiführung, Verhandlung und Förderung von Kreativität untersuchen, bislang rar. Dieses Buch liefert einen interaktionslinguistischen Beitrag zum Phänomen der Kreativität und bildet die Analyse von über 550 Stunden Videomaterial von nicht elizitierten, kollaborativen
Konstellationen in Werbeagenturen ab. Der Autor entwickelt in seiner Studie eine induktive, interaktionslinguistisch anschlussfähige Definition von Kreativität sowie ein makrostrukturelles Modell der Aushandlungs- und
Zuschreibungsprozesse von Kreativität. Dadurch ermöglicht das Buch nicht nur einen einzigartigen Einblick in die Prozesse der Kreativwirtschaft, sondern bietet durch seinen in der multimodalen Interaktionsanalyse verorteten
methodischen Zugang auch zahlreiche Anknüpfungspunkte für weitere Forschungsvorhaben
Engineering "Drosophila" development at the gene and protein levels
No full textDuring development, cells must differentiate, divide, move and even die in a coordinated manner. These processes must be tightly organized in space and time in order to form functional structures. Cell behavior is coordinated by cell-cell communication via physical and chemical signals. These signals trigger distinct cellular responses depending on the genetic constrains of target cells. This cross- talk between the genome and the cellular environment is responsible of the stunning robustness of development. In this thesis, we have developed technologies to manipulate the genetic sequences and/or their readout (using CRISPR/Cas), the proteins (via protein binders) and the interaction between the two (by combining CRISPR/Cas and protein binders). Using these technologies, we have dissected two biological processes, the mechanisms of gradient formation via morphogens and the control of tissue development via enhancers.
Morphogens are locally-produced signals that form gradients in a target tissue and activate gene expression in a concentration-dependent manner. Gene regulation via morphogens is one of the best studied developmental patterning processes. Yet, the mechanisms by which morphogen gradients are established are still poorly understood. We have dissected the mechanisms of gradient formation of both Bone Morphogenetic Proteins (BMPs) and Hedgehog (Hh). We found that, in the imaginal wing disc of Drosophila, BMPs require the formation of heterodimers for its secretion. Our model explains how two ligands with different but overlapping expression patterns are responsible of the patterning of the wing. In contrast, our experiments on Hh support a model in which Hh travels in association with filopodial structures, in a lipid-dependent fashion. These filopodia bridge distant cells, mediating direct cell-cell exchange of the morphogen.
Enhancers are regions of the genome that integrate the changes in the nuclear proteome to trigger appropriate gene expression. We have focused on the study of the regulation of apterous (ap) during early wing disc development. ap coordinates the division of the wing into ventral and dorsal compartment. We have uncovered the role of the apterous early enhancer, identified some of its regulators and carefully described the consequences of its miss-regulation. Our study uncovered new molecular players of wing formation and sheds light on how the tissue axes are stablished
Play constructed brick by brick: building theory by investigating the implicit in player experience research
Get PDFGiven the recent replication crisis in psychology and the complex nature of play, player experience research requires a closer examination of its theories and methods. Otherwise, the field is at risk of being unable to produce robust empirical evidence and remain in the dark concerning aspects of play that may be implicitly known but not explicitly elaborated on. This thesis contributes to continued meta-critical commitment in player experience research by investigating the implicit. Presented are three manuscripts employing different methods to deepen our understanding of theory in player experience. The first manuscript investigates the current reporting transparency of subjective measures in player experience research and finds a need for increased definitional and theoretical work in the field. The second manuscript thoroughly examines the definitional requirements for play and its theoretical consequences. This theoretical work proposes a working definition for an essential construct in player experience research: immersion. The third manuscript applies psychological theories on overestimating skill and motivation to a community of esports players to explain a folk theory of causal beliefs called ELO Hell. In summary, this thesis concerns current theory use, how to build theory, and how to apply theory to empirical data within player experience research
Molecular epidemiology of "mycobacterium tuberculosis" in the country of Georgia
Get PDFTuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (MTB), is one of the major contributors to human mortality globally. Being attributable to several socio-economic factors, national TB control programs still struggle to prevent transmission and treat active cases of the disease. In order to achieve sustainable development goal for ending TB in 2030, The World Health Organization (WHO) has endorsed the recommendations for prompt diagnosis and integrated molecular surveillance of TB. Molecular typing of MTB is progressively used for strengthening disease surveillance. However, in most limited-resources settings such as low/middle income countries, implementation of the typing methodologies is challenging.
In the first part of the thesis, we implemented a genotyping tool at the National Reference Laboratory (NRL) in Georgia, aiming to support disease surveillance at the molecular level. We took advantage of the isolate biobank, containing MTB isolates from 2009, and performed genotyping for the recurrent TB cases (chapter 3). The generated results gave the opportunity to customize and develop more practical application of MIRU-VNTR typing. The stepwise MIRU-VNTR typing approach described in chapter 4 represents a simplified and less time/cost/workload consuming way of the typing, which can be easily customized for different settings, thereby enhancing the usage of molecular typing for the TB control and surveillance.
Despite of being an ancient disease, treatment of TB remains to be complex, especially throughout evolution of the drug resistant variants, requiring treatment with toxic and expensive medications. Drug resistance is still hindering TB control strategies in Georgia.
Moreover, resistance to the novel, promising medications, such as bedaquiline, bears utmost importance. Since 2019, bedaquiline has been used as the backbone for the treatment regimens for MDR, preXDR and XDR TB. However resistance has already been detected in vivo, translated into 22 (6.9%) of resistant cases in 2020-21 in Georgia. While transmission of resistant MTB strains is threatening TB control, the data for developing molecular test-systems for prompt
detection of such cases is still lacking. This requires collated information of precise phenotypic information associated with corresponding sequencing data. In our second part of the thesis, we combined evidence of any influence between the genomic variants of bedaquiline resistance associated genes and minimum inhibitory concentration values. Simultaneously, we looked for samples identified as phenotypically resistant using single, critical concentration (CC) provided by WHO, and correlated genomic information for those isolates. Herein, the chapter 5 provides valuable and essential data for the further developmental implications
Leaky taps in trees: exploring leaf minimum water conductance in temperate European trees
Get PDFWith ongoing climate change, summer droughts accompanied by hot temperatures (hereafter referred as hot droughts) are emerging as one of the most critical challenges to maintaining forest health. Therefore, a nuanced understanding of the underlying physiological mechanisms behind the critical responses of trees to hot droughts is fundamental for accurate prediction of tree mortality and better forest management. Under severe hot droughts, the minimal water use of a tree after full stomatal closure will directly affect the surviving time of the tree. Yet, this minimal water use has not been quantified, mainly because leaf minimum water conductance (gmin) varies considerably between and within species and exhibit great plasticity potential. In this thesis, we conducted a comprehensive survey of the variability of gmin in nine ecologically and economically important European temperate tree species using a new research tool, the Drought Box. Our findings show that gmin varied considerably among tree species but displayed a similar range of values overall. Based on our data, interspecies variation of gmin was associated with leaf cuticular and stomatal traits, but the cause of intraspecific variation is unclear. At the same time, we have revealed the remarkable acclimation of gmin to soil water availability in deciduous broadleaf tree species but not in evergreen conifers. These findings have important implications for European forest management. We further show that the seasonal variation of gmin was very limited in the studied species and, thus, unlikely to cause an ecologically significant change in tree drought tolerance. At the same time, our findings also highlight the remarkable response of gmin to increasing temperatures, providing novel insights into the mechanisms underlying rapid tree dieback under hot droughts. Finally, we confirm that even when stomates are fully closed during a hot drought, different tree species need substantial amounts of water to remain hydrated. Through in-depth studies in three chapters, we conclude that gmin display a large amount of variation among tree species and strong acclimation to the changes in soil water availability and temperature. Accordingly, tree residual transpiration, mainly dependent on gmin, may further amplify differences in drought vulnerability between tree species, and simplified modelling of residual transpiration currently appears to be challenging
Counteracting resistance to cancer immunotherapy with neoadjuvant immune checkpoint blockade and targeting of novel regulators of T cell exhaustion
No full textThe interactions between cancer and the immune system reveal a dual role of the latter, best described with the concept of immunoediting: initially, the immune system readily eliminates nascent tumor cells, some which gain the ability to circumvent immune recognition, resulting in equilibrium, and eventually, immune escape. Recognition of cancerous cells rests on both genetic and epigenetic mechanisms: mutations give rise to novel protein sequences that are recognized as neoantigens, while epigenetic dysregulation enables expression of proteins that are normally restricted to distinct developmental phases or to immunoprivileged sites. Dendritic cells process such antigen from dying cancer cells, migrate to secondary lymphoid organs and prime naïve T cells. T cells seed back to the tumor bed and exert direct and indirect cytotoxicity onto cancer cells, which in turn promotes release of new antigen to dendritic cells. However, the anti-tumor T cell response is blunted by several mechanisms, including T cell exhaustion, an adaptive response to chronically elevated antigen levels which preserves some level of immune protection without causing immunopathology that is also observed in virus-specific T cells. Exhausted T cells express inhibitory receptors such as PD-1 and CTLA4 which dampen signaling through their T cell receptor. Antibodies against these receptors, so called immune checkpoint inhibitors, have shown impressive therapeutic potential in some cancers. However, only a minority of patients profit from this treatment so far, encouraging further studies to optimize treatment strategies and to acquire a deeper molecular understanding of the anti-tumor immune response in general and of T cell exhaustion in particular.
Neoadjuvant administration, that is, systemic therapy prior to surgical tumor resection, has enhanced the efficacy of checkpoint inhibitors, presumably by stimulating the immune response in presence of abundant antigen material. The SAKK 16/14 clinical trial tested a regimen of neoadjuvant chemoimmunotherapy in patients with locally advanced lung cancer and compares well to historical data. A translational analysis of this trial is reported as a first project here. Digital pathology analysis of tissue from pre-treatment biopsies and post-treatment surgical resections shows enhanced infiltration and intratumoral positioning of CD8+ T cells in patients responding well to treatment. These patients also had a more diverse array of T cell clones and systemic proliferation of CD8+ T cells. Furthermore, selected patients had elevated levels of serum CCL15, pointing towards a yet unrecognized signaling axis with the potential to attract tumor-specific T cells to the tumor site. In sum, the results presented here support the view that checkpoint inhibition is more efficacious when administered in a neoadjuvant manner by inducing a systemic immune response.
To further elucidate the molecular drivers of T cell exhaustion, existing studies have overwhelmingly relied on mouse models of chronic infection and transplantable tumors. As chronic antigen exposure is both necessary and sufficient to induce exhaustion, repetitive in vitro stimulation of primary human T cell is increasingly used as a model system. Here, the proteome of in vitro generated exhausted T cells was profiled and found to resemble the proteome of in vivo peers. Genes encoding for overexpressed proteins were used to build a CRISPR/Cas9 knock out library. Enrichment of gene knock outs in cells that had retained the ability to produce effector cytokines after repetitive stimulation included some well characterized exhaustion-related genes. Additionally, ablation of previously uncharacterized exhausted regulators ataxin-1 and leucine carboxyl methyltransferase 1 partially rescued T cells from exhaustion as evidenced by improved cytokine secretion, tumor cell killing capacity and signaling flux. First adoptive T cell transfer experiments support the relevancy of both genes in vivo. Both projects offer numerous observations that will benefit future studies into the systemic interplay of anti-cancer immunity as well as the molecular pathways limiting the efficacy of T cells in the tumor context