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The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe targeting the bromodomain of BPTF with an attractive pharmacokinetic profile enabling cellular and in vivo experiments in mice. Microarray-based transcriptomics in presence of the probe in two lung cancer cell lines revealed only minor effects on the transcriptome. Profiling against a panel of cancer cell lines revealed that the antiproliferative effect does not correlate with BPTF dependency score in depletion screens. Both observations and the multi-domain architecture of BPTF suggest that depleting the protein by proteolysis targeting chimeras (PROTACs) could be a promising strategy to target cancer cell proliferation. We envision that the presented chemical probe and the related negative control will enable the research community to further explore scientific hypotheses with respect to BPTF bromodomain inhibition.
Introduction: The rational development of new therapeutics requires a thorough understanding of how aberrant signalling affects cellular homeostasis and causes human disease. Chemical probes are tool compounds with well-defined mechanism-of-action enabling modulation of, for example, domain-specific protein properties in a temporal manner, thereby complementing other target validation methods such as genetic gain- and loss-of-function approaches.
Areas covered: In this review, the authors summarize recent advances in chemical probe development for emerging target classes such as solute carriers and ubiquitin-related targets and highlight open resources to inform and facilitate chemical probe discovery as well as tool compound selection for target validation and phenotypic screening.
Expert opinion: Chemical probes are powerful tools for drug discovery that have led to fundamental insights into biological processes and have paved the way for the development of first-in-class drugs. Open resources can inform on various aspects of chemical probe development and provide access to data and recommendations on use of chemical probes to catalyse collaborative science and help accelerate drug target identification and validation.
Covalent inhibition has become more accepted in the past two decades, as illustrated by the clinical approval of several irreversible inhibitors designed to covalently modify their target. Elucidation of the structure-activity relationship and potency of such inhibitors requires a detailed kinetic evaluation. Here, we elucidate the relationship between the experimental read-out and the underlying inhibitor binding kinetics. Interactive kinetic simulation scripts are employed to highlight the effects of in vitro enzyme activity assay conditions and inhibitor binding mode, thereby showcasing which assumptions and corrections are crucial. Four stepwise protocols to assess the biochemical potency of (ir)reversible covalent enzyme inhibitors targeting a nucleophilic active site residue are included, with accompanying data analysis tailored to the covalent binding mode. Together, this will serve as a guide to make an educated decision regarding the most suitable method to assess covalent inhibition potency. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.
The (mis)management of rapport amongst groups in Niger Delta (ND) communities has become a significant issue, which Ahmed Yerima's Hard Ground (HG) depicts as having the capacity to aid or control the conflicts in the region. Linguistic studies on Yerima's drama from the perspective of pragmatics have tended to use pragmatic acts to identify the discourse value of proverbs and functions of characters' utterances but have not accounted for the politeness strategies utilised for rapport management, especially in conflict situations. This article, drawing on a rapport management model of politeness and aspects of speech act discourse, identifies the face, sociality rights, and interactional goals that characterise the conflict-motivated dialogues sampled in HG, and reveals the rapport management (RM) strategies through which these are managed in the text. Three conflict situations can be observed as prompting different RM strategies: cause-effect identification (CEI), militancy support (MSP), and disagreement (DSG) situations. CEI is marked by incriminating (involving eliciting and informing acts) and exonerating (including complimenting and acknowledging acts) strategies; MSP is indexed by strategies of persuasion (realised with face-enhancing/threatening acts), whereas DSG is typified by requesting (featuring explicit head acts and alerters) and blaming strategies (including insulting and threatening, aggravating moves). Generally, the requesting, blaming, and exonerating strategies are largely used by the ND youth in HG to probe, threaten, or disagree on specific issues, while the incriminating and persuasion strategies are mainly employed by the women to indict, influence, and predict future actions. The study of RM in the conflict situations depicted in the play sheds light on the often neglected cause of conflicts in contemporary Africa.
Eine der primären Aufgaben nicht nur der Komparatistik, sondern der Literaturwissenschaft im Allgemeinen sollte es sein, Literatur als ein globales Phänomen zu erfassen und zu beschreiben. Manifestiert sich der globale Charakter von Literatur auch am augenscheinlichsten im Rahmen einer Poetik der imitatio in motivischer, thematischer und gattungsgeschichtlicher Hinsicht, so besteht er dennoch auch dann, wenn bestimmte Techniken eine internationale Präsenz besitzen. Dies gilt beispielsweise für die Konkrete Poesie, deren Funktion als einer der Katalysatoren der Globalität von Literatur im Folgenden erläutert wird.
Konkrete Poesie ist per se ein internationales Phänomen, oder wie Eugen Gomringer es formuliert hat: „die konkrete poesie […] ist einer der konsequentesten versuche, poesie inter- und übernational zu begründen.“ Zunächst müssen wir – im Sinne wissenschaftlicher Eindeutigkeit – zwischen einem engeren und einem weiteren Begriff der Konkreten Poesie unterscheiden. Die Konkrete Poesie im engeren Sinne meint eine seit den 1970er Jahren historisch gewordene Dichtung. Ihre ‘Geburtsstunde’ lässt sich zu Recht als „transatlantic baptism“ , nämlich durch Eugen Gomringer und Décio Pignatari in der Hochschule für Gestaltung im Jahre 1955 in Ulm, bezeichnen. In den frühen 1950er Jahren sowohl in Deutschland als auch Brasilien entstanden, findet sie Aufnahme in fast allen europäischen Ländern, Nordamerika und Japan. Im Folgenden soll der Begriff der Konkreten Poesie jedoch nicht in diesem unnötig eingeschränkten historischen Sinn gebraucht werden, sondern in einem sehr viel umfassenderen Sinn: Er ist all jenen Gedichten vorbehalten, in denen eine Transpa-renz des Zeichengebrauchs nicht gegeben ist, sondern stattdessen die Materialität der jeweils eingesetzten Zeichen im Vordergrund steht, wie dies auf ähnliche Weise schon im Futurismus und Dadaismus betrieben wurde, bevor der Surrealismus diesen Experimenten ein jähes Ende bereitet hat. Gilt dies auch für die Bereiche der Lautdichtung, der Gedichtobjekte u. ä., so beschränken sich die folgenden Ausführungen auf den visuellen Bereich, und zwar auf visuelle Konkrete Poesie nach 1945, zumal in der Dichtung aus dieser Zeit eine starke Tendenz zu konkretistischen Verfahrensweisen herrscht.
During the 1930s through the 1940s and into the 1950s, Spanish and German presentations in opposition to ardent nationalism share strikingly common aesthetic and ideological strategies supporting claims to a transnational, international space. Specific examples of common geography, identity and language in German and Spanish presentations (theater, short stories, reports, essays, speeches and poetry) in Spain and Latin America by German (Regler, Renn, Uhse), Spanish (J. Bergamin, R. Alberti, M. Aub) and Latin American (D. Rivera, P. Neruda, C. Vallejo) intellectuals, artists and activists during the 1930s through the 1950s will be explored. For example, German-speaking audiences and artists in Spain and Mexico shared a common lived and aesthetic space as Spanish-speaking audiences and artists. Further, many German presentations were translated into Spanish and visa versa. Here, presentations in “Das Wort” and “El Mono Azul” in Spain as well as “Freies Deutschland/Alemania libre” in Mexico will be referenced in developing a sense of re-definition of the concept of ‘foreign’ and ‘commonness’ beyond simply nationality (tradition, history and geography) and language. The impetus for an alternative, international and even revolutionary ‘space’ (as defined by Henri Lefebvre in The Production of Space) was produced in and through common Spanish and German strategies and realizations in their presentations. This Spanish-German example from the early/mid-part of the 20th century is a significant contribution to contemporary interdisciplinary discussions in the 21st century.
„Die Lose ähneln sich, die Odysseen“. Dieser Vers Ingeborg Bachmanns aus ihrem Gedicht Von einem Land, einem Fluss und den Seen behauptet, die Irrfahrten und Schicksale der vielen Odysseus-Gestalten seien einander ähnlich. Wenn sich aber die Schicksale und Heimkehrreisen der Umherwandernden ähneln, dann könnten sich auch ihre literarischen Werke ähnlich sein. Ausgehend von dieser Vermutung sollen im folgenden Beitrag zwei große Lyriker des 20. Jahrhunderts gegenübergestellt werden, die sich mit der Frage des Exils und seiner Überwindung beschäftigt haben: die Österreicherin Ingeborg Bachmann und der Iraker Sa'dī Yūsuf. Zwar gehören beide unterschiedlichen Sprachräumen und Literaturtraditionen an. Zugleich sind sie aber aus diesen Räumen ausgebrochen, um neue geografische, sprachliche und gedankliche (W)orte zu erkunden, die keine fest umrissenen Grenzen mehr kennen. Darüber hinaus haben sie in ihren Texten auf ähnliche Weise Untergänge und Auferstehungen inszeniert, die meines Erachtens den Erfahrungen ihres Exils entspringen. Ihre Sichtweisen auf das Eigene und Fremde fordern uns auf, unseren eigenen Blick in einer Zeit zunehmenden und zugleich konfliktreicheren Zusammenlebens zu öffnen und zu hinterfragen.
Around 1800, aesthetic debate suddenly places music at the very top in the hierarchy of the arts, even superseding poetry: This has become a commonplace not only in scholarly discourse. The protagonists of this re-arrangement of the artistic disciplines are Wilhelm Heinrich Wackenroder, E.T.A. Hoffmann and Ludwig Tieck. In their programmatic texts, they state that music is to be free and absolute and stress its metaphysical quality and its close relation to the supernatural. Furthermore, music is supposed to be no longer dependent on the other arts, and music releases the listener or the musician from prosaic everyday life. As Wackenroder writes in Die Wunder der Tonkunst, […] [a]ll sickening thoughts which, according to Wackenroder, are the illness of mankind vanish with a piece of music, making our mind sane again. Literary romanticism here recurs to a long tradition that reaches back to the classical ages in Greece and Arabia: Music is used as a remedy for curing illnesses of various kinds. In classical antiquity, Apollo is the god of music, poetry and dancing as well as the god of healing. He was also named “Iatros” (physician) or Apollo Medicus. […] Orpheus as a bard and demigod was also said to be capable of curing diseases by means of his music. […] Thus, music in history is part of treating physical illness on the one hand, but on the other hand is more and more considered to provide a remedy especially for mental deficiencies. Music is meant to improve nervous disorders and sometimes it is even prescribed as a regular medicine. As we will see in Hoffmann’s text Die Genesung, there is a connection between the ritual healing processes in the temples of Aesculapius and the setting of the forest in which the old man regains his health.
When, some two centuries ago, German Romantics turned their backs on modernity – industrialisation, urbanisation, commerce and secularisation – they turned to ancient India. For them, India exemplified the primordial unity of mankind with this and the afterworld. For sections of the emerging nationalist movement in Germany, found the deployment of India handy to question the cultural hegemony, and eventually break the political dominance, of France. They tried to surpass the French, who claimed the ancient Roman heritage, by claiming an even older heritage for the Germans. Friedrich Schlegel for example suggested that the German language, and not the French, stood in unbroken continuity with ancient Sanskrit. For Romantics such as he, Sanskrit, the oldest surviving Indo-European language, was closest to the language of original divine revelation. This lead Schlegel to romanticise India in a way that stood in marked contrast to the Orientalist clichés current in other parts of Europe at the time. For him, the link between Sanskrit and German made Germany the true oriental self of Europe. The importance of this particular representation of India for the German national movement is underlined by the great number of university chairs that sprang up in the course of the nineteenth century: twenty two in Germany as opposed to only three in the United Kingdom. This paper explores the particular kind of ‘inverse’ Orientalism of the Germans in the context of its recent post-colonial critique.
Ein Vordenker, der in der internationalen Diskussion um « cultural translation » so gut wie nie diskutiert wird, ist Antonio Gramsci. Der Philosoph aus Sardinien, von Kindes Tagen an in Zweisprachigkeit (Sardisch-Italienisch) geübt, hat ein feines Sensorium für kulturelle Differenzen ausgebildet. In seinen Gefängnisjahren übersetzt er – als intellektuelles Training – aus dem Russischen und dem Deutschen ins Italienische, und in den Gefängnisheften setzt er sich wiederholt mit dem Begriff der traducibilità (Übersetzbarkeit) auseinander: Übersetzbarkeit von Sprachen, aber auch von Kulturen. Der Artikel geht den Linien nach, die von Gramscis Überlegungen zu der aktuellen Diskussion gezogen werden können, und diskutiert am Ende vergleichend die Positionen Homi K. Bhabhas und Gayatri Spivaks.