410 research outputs found
Electrophysiological charcterization of intramolecular interactions in the STIM1 C-terminus
No full textAuthor Verena Steineck, BSc.Masterarbeit Universität Linz 2023Arbeit gesperr
EU-AKP PEU-AKP PTAs und ihre Auswirkung auf die Menschenrechtseinhaltung: ein qualitativer Ansatz
No full textauthor: Verena Handle (Kretzschmar)Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersBachelorarbeit mit eingebundenMasterarbeit Universität Innsbruck 201
EU-AKP PEU-AKP PTAs und ihre Auswirkung auf die Menschenrechtseinhaltung: ein qualitativer Ansatz
No full textauthor: Verena Handle (Kretzschmar)Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersBachelorarbeit mit eingebundenMasterarbeit Universität Innsbruck 201
EU-AKP PEU-AKP PTAs und ihre Auswirkung auf die Menschenrechtseinhaltung: ein qualitativer Ansatz
No full textauthor: Verena Handle (Kretzschmar)Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersBachelorarbeit mit eingebundenMasterarbeit Universität Innsbruck 201
The Institutionalisation of a Creative Practice: Changing Roles of Regional Design in Dutch National Planning
No full textThis chapter discusses the organisational setting of regional design in the realms of spatial planning and territorial governance. As a starting point, it argues that rules on how imagined design solutions function in an abstract, simplified ‘planning world’ are an important regional design product. When focusing on these rules, regional design practice resembles discretionary action. As such, it aims to improve planning decisions by judging the implications of planning frameworks when applied to particular situations. This implies that the involvement of actors in design practice requires careful consideration. As in any form of legitimate rule-building, a critical distance between those who initiate practices and conduct design, and those who judge the quality and relevance of design outcomes is essential. On the basis of these considerations the chapter investigates regional design practices that occurred between the 1980s and 2010s in the context of Dutch national planning. It shows how they transformed from being a form of professional advocacy, criticising planning, into a practice that was pragmatically used to implement a national planning agenda. The chapter concludes by discussing this institutionalisation of a creative practice in the Netherlands, reflecting upon the implications of these outcomes for territorial governance in particular.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Spatial Planning and Strateg
Depolymerization of technical lignins by heterogeneous catalysis
No full textAuthor Verena Aschauer, BScMasterarbeit Johannes Kepler Universität Linz 2024Arbeit nach Ablauf der Sperre auf den öffentlichen PCs in den Bibliotheken der JKU+Medizin abrufba
Open WIN Ambassadors: Call notes and documentation drafts
No full textCall notes, documentation and comms created by the Open WIN Ambassadors, Wellcome Centre for Integrative Neuroimaging, University of Oxford.
Please refer to the GitLab repository for most up-to-date materials and contributions: https://git.fmrib.ox.ac.uk/open-science/community/open-win-ambassadors
This version issued at the end of the 2021-2022 cohort.
Author Contributions (credit):
Conceptualization: Stuart Clare, Cassandra D. Gould van Praag, Clare E. Mackay.
Data curation: Cassandra D. Gould van Praag.
Formal analysis: Cassandra D. Gould van Praag.
Funding acquisition: Stuart Clare, Clare E. Mackay.
Investigation: Cassandra D. Gould van Praag.
Methodology: Stuart Clare, Cassandra D. Gould van Praag, Clare E. Mackay.
Project administration: Stuart Clare, Dejan Draschkow, Yingshi Feng, Cassandra Gould van Praag, Clare E. Mackay, Verena Sarrazin, Bernd Taschler.
Resources: Dejan Draschkow, Yingshi Feng, Cassandra Gould van Praag, Verena Sarrazin, Bernd Taschler.
Software: Dejan Draschkow, Yingshi Feng, Cassandra Gould van Praag, Verena Sarrazin, Bernd Taschler.
Supervision: Stuart Clare, Cassandra D. Gould van Praag, Clare E. Mackay.
Visualization: Dejan Draschkow, Yingshi Feng, Cassandra Gould van Praag, Verena Sarrazin, Bernd Taschler.
Writing - original draft: Dejan Draschkow, Yingshi Feng, Cassandra Gould van Praag, Verena Sarrazin, Bernd Taschler.
Writing - review & editing: Dejan Draschkow, Yingshi Feng, Cassandra Gould van Praag, Verena Sarrazin, Bernd Taschler
Aneuploidy triggers a conserved global response and impairs cellular homeostasis
No full textAneuploidy, or unbalanced chromosome number, has often detrimental physiological effects in eukaryotic cells. Aneuploidy is associated with congenital trisomy syndromes, e.g. Down syndrome, but it is also linked to several other pathological states such as Alzheimer's disease, schizophrenia and autism. In addition, aneuploidy is often found in cancer cells and high rates of aneuploidy in tumors correlate with poor prognosis and drug resistance. Although it has been proposed that aneuploidy could contribute to tumorigenesis by facilitating genomic instability, whether and how aneuploidy can lead to genomic instability remains elusive.
To study aneuploidy in human cells, we have previously generated cell lines carrying one or two supernumerary chromosomes in an otherwise diploid background by microcell mediated chromosome transfer. Similarly to other aneuploid model systems of earlier studies, our human aneuploid cell lines showed impaired proliferation and a conserved cellular response to the presence of extra chromosomes. Moreover, we found that aneuploidy alters protein homeostasis and impairs induction of heat shock response in human cells. Pathway analysis based on transcriptome and proteome data revealed characteristic gene expression changes called aneuploidy response pattern that is defined, among others, by down-regulation of factors involved in DNA replication and repair. Consistent with these observations we found that aneuploidy increases the frequency of anaphase chromatin bridges, broken chromosomes and ultrafine DNA bridges. Moreover, aneuploid cells accumulate more DNA damage even in unperturbed conditions and display higher sensitivity to replication stress than diploids. Using next generation sequencing we determined that a presence of extra chromosomes elevates frequency of chromosomal rearrangements with a breakpoint junction pattern suggestive of replication defects. Finally, we demonstrated that the observed decreased levels of MCM2-7 contribute to the replication stress and consequent genomic instability detected in aneuploid cells.
Taken together, these results provide a new insight into the possible mechanisms responsible for impaired genomic stability in response to aneuploidy. Our study provides the first evidence that a gain of chromosomes triggers replication defects and accumulation of DNA lesions, thus promoting genomic instability and possibly contributing to tumor development
Lysosomal Membrane Permeabilization Sensitizes Ctss-Hyperactive Tumors to BCL2-Targeting Therapies
No full textHyperactivity of the cysteine protease cathepsin S (CTSS) -either through Y132 mutations or amplification/overexpression- is a recurrent alteration in follicular lymphoma (FL) and promotes tumor growth by inducing a supportive immune microenvironment (Bararia et al, 2020). Of note, patients with CTSS-hyperactive FL had better outcomes with standard therapies, suggesting that CTSS-hyperactivity can sensitize tumors to treatment. CTSS hyperactivity has also been reported in other B cell lymphomas (BCLs) (Dheilly et al, 2020) and solid cancers (Olson & Joyce, 2015).
CTSS is mainly localized intralysosomally but can be released into the cytosol by lysosomal membrane permeabilization (LMP). Low level LMP can occur spontaneously (e.g., during cell division) and can be enhanced by treatment. Unlike other cathepsins, cytosolically released CTSS maintains its enzymatic activity at non-acidic pH. Thus, we aimed to (i) identify the determinants of the cytosolic CTSS activity, (ii) determine its impact on the regulation of apoptosis, and (iii) study LMP as a therapeutic approach for CTSS-hyperactive tumors.
First, we accrued biochemical, functional, and clinical data supporting the role of cystatin B (CSTB) as a clinically relevant endogenous CTSS inhibitor in BCLs. Through unbiased and complementary proteomics (BioID2 labelling and co-IP followed by LC-MS/MS) we identified CSTB as a direct CTSS-interacting protein (8-fold enriched in the BCL cell line Karpas422 engineered to express CTSS wild type (WT) or Y132D vs CTSS knock-out (KO), P=0.0002). Single-cell RNA-Seq of primary FL (N=10) showed significantly higher CSTB expression in FL cells compared to normal B cells ( P=0.004). Moreover, shRNA mediated knock-down (k/d) of CSTB increased the overall cathepsin activity in BCL cell lines (N=8) by 1.5 to 5.5-fold, most notably in CTSS-hyperactive cells ( Fig A, top). We next employed LMP-inducing tool compounds (LLOMe) and clinically used drugs or analogs (desipramine, hexamethylene amiloride) to release cathepsins into the cytosol. CTSS-hyperactive Karpas422 were significantly more sensitive to LMP-inducing treatments compared to native cells (1.5 to 10-fold reduction of IC50). Importantly, CTSS hyperactivity and CSTB k/d increased LMP-mediated cell killing ( Fig A, bottom). Thus, the cytosolic CTSS/CSTB interaction determines the net cytosolic cathepsin activity and sensitivity of cells to undergo LMP-induced cell death.
Next, we hypothesized that LMP-induced cytosolic CTSS hyperactivity could prime BCLs towards apoptosis. We used BH3 profiling to functionally quantify the dependencies and interactions of BCL2 family members in BCLs with and without CTSS hyperactivity. In Karpas422 cells expressing CTSS Y132D, LMP increased overall apoptotic priming and dependencies on the anti-apoptotic proteins MCL-1 (delta priming >30 % at 10 µM, P=0.04), BCL-xL (>45 % at 10 µM, P=0.0006) and BCL2 (> 45 % at 0.5 and 1 µM, P=0.0001). We hypothesized that BCL2 family members are proteolytically cleaved by cytosolic CTSS. Indeed, e.g., BCL2 protein levels were 2.5 to 3.5-fold lower in LLOMe-treated Karpas422 cells with CTSS-hyperactivity compared to CTSS KO, and CSTB k/d further decreased BCL2 levels. To validate CTSS-mediated cleavage of BCL2, we purified FLAG-tagged BCL2 and CTSS WT and Y132D. CTSS WT efficiently cleaved BCL2 in vitro <1 hour at the top ranked predicted cleavage site and the reaction rate increased 1.3-fold for CTSS Y132D.
Finally, we hypothesized that LMP sensitizes cells to BCL2-targeting therapies ( Fig B). The combination of LLOMe-induced LMP and the BCL2 inhibitor venetoclax (VEN) showed increased cytotoxicity in CTSS-hyperactive Karpas422 cells compared to monotherapy and CSTB k/d enhanced this phenotype ( Fig A, bottom). We assessed cathepsin activities and generated dose-response curves for VEN with and without LLOMe-induced LMP in 15 primary CLL samples. Thereof, 12 samples had intermediate or high cathepsin activities and LLOMe-induced LMP increased their sensitivity to VEN, including a VEN-resistant sample in which the IC50 decreased to <3 nM.
In summary, we show that CSTB is a functionally relevant inhibitor that determines the net activity of LMP-released cytosolic CTSS. Furthermore, LMP-inducing therapies may be a promising approach to sensitize CTSS-hyperactive tumors towards apoptosis by proteolytic cleavage of BCL2 family members
Homoerotic tendencies in Thomas Mann’s selected works. A historical, author-immanent and psychoanalytic discourse
No full textIn dieser Arbeit wird Thomas Manns Umgang mit dem Thema ?Homosexualität? in seinem literarischen Werk besprochen. Die Ehe mit Katia Pringsheim und einzelne kritische Äußerungen des Autors gegen gleichgeschlechtliche Liebe zu Lebzeiten deuteten zunächst auf eine dem Bild der Zeit geforderte heterosexuelle Orientierung hin. Durch die Veröffentlichung seiner Tagebücher, in welchen seine eigenen homosexuellen Phantasien zum Vorschein kamen, eröffneten sich aber nach seinem Tode neue Interpretationsmöglichkeiten seiner literarischen Texte.Der Analyseschwerpunkt dieser Arbeit liegt auf vier, während unterschiedlicher Lebensphasen verfassten Werken (Tonio Kröger, Der Tod in Venedig, Der Zauberberg, Bekenntnisse des Hochstaplers Felix Krull), in welchen der kontinuierlich zunehmende Drang zur Offenbarung seines homosexuellen Verlangens implizit und explizit zum Ausdruck kommt. Wie eine Betrachtung der historischen Entwicklung des ?Homosexualitäts?-Begriffes zeigt, galt ein Ausleben des homosexuellen Verlangens zu mannschen Lebzeiten als verpönt, weshalb der Autor seine im Realen gelebten konservativen Moralvorstellungen auch in seinen Texten oftmals konkretisierte. Mithilfe von speziellen Strategien des Verbergens und Verhüllens von Homoerotischem ließ Thomas Mann dennoch auch seine nicht gelebte Homosexualität in sein Werk einfließen. Marita Keilson-Lauritz, Heinrich Detering, Seong Joo und Karl Werner Böhm entwickelten wissenschaftliche Ansätze, die die verschiedenen Verschleierungstaktiken des Homoerotischen in literarischen Texten darlegen. Auch Thomas Mann bediente sich diverser Maskierungstechniken, angefangen mit der Darstellung von homosexuellen Protagonisten bis hin zur Rechtfertigung durch Zitate aus dem literarischen Kanon. Auch mithilfe der Einbindung narzisstisch veranlagter Figuren verwies Mann implizit auf das verschweigungswürdige Thema ?Homosexualität?, die Todessehnsucht und offenbarte damit auch literarisch seine eigenen sexuellen Sehnsüchte.This thesis investigates how Thomas Mann elaborates the topic ?homosexuality? in his literary work. His marriage with Katia Pringsheim and some critical statements against homosexual love were evidence to suggest that the author was living a morally exemplary life according to the standards of the period. Following the publication of his diaries after his death, in which his own homosexual imaginations came to light, a lot of new possibilities for text interpretations were offered.The analysis focuses on four works (Tonio Kröger; Death in Venice; The Magic Mountain; The Confessions of Felix Krull, Confidence Man), which were written at different stages of Mann?s life and in which his continuously increasing urge for revelation of his homosexual desire is, implicitly or explicitly, expressed. Living a homosexual lifestyle was proscribed during his lifetime, so the author mostly illustrated his conservative idea of morality in his texts. Thomas Mann nevertheless used special strategies of hiding and veiling of the homoerotic to discuss his own homosexuality, which had not yet been lived. Marita Keilson-Lauritz, Heinrich Detering, Seong Joo and Karl Werner Böhm have devised scientific approaches which describe different methods of concealment. Thomas Mann was using such masking techniques, e.g. featuring homosexual protagonists or justifying himself by the literary canon. Mann implicitly referred to the topic of homosexuality also by the use of narcissistic characters. Thus he revealed his own sexual desires and the death wish in his literary work.vorgelegt von Verena PlatzerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassungen in dt. und engl. SpracheGraz, Univ., Masterarb., 2014 2.039
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