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Precise tune determination and split beam emittance reconstruction at the CERN PS synchrotron
(2023)
In accelerator physics, the need to improve the performance and better control the operating point of an accelerator has become, year after year, an increasingly important need in order to achieve higher energies and brightness, as well as point-like particle beams. If this involves increasingly advanced technological developments (in terms, for example, of materials for more intense superconducting magnets), it can not take place in the absence of targeted studies of linear and non-linear beam dynamics. In the context of this Ph.D. thesis in physics, linear and non-linear dynamics of charged particles in circular accelerators is the topic that will be discussed and treated in detail. In particular, the presentation and discussion of the results will be divided in two main topics: the need to know the physical properties of a proton beam; and the development of innovative methods to determine and study the accelerator’s working point. With regard to the first topic, an innovative procedure will be presented to determine the transverse size of the PS beam in the beam extraction phase. Among the different ways the extraction occurs at the PS, the analysed one is based on the transverse splitting of the beam by means of non-linear fields. Thus, the knowledge of the transverse beam size is not trivial since resonant linear and non-linear beam structures (namely, core and islands) arise and, for each of them, the beam size has to be quantified. This parameter is crucial for two main reasons: the accelerator that will receive the beam exiting the upstream accelerator may have restrictions (physical or magnetic) that involve a partial or total loss of the incoming beam; and any experiments located downstream of the considered accelerator may need a beam with a transversal size as constant as possible; consequently, its monitoring and control are essential. The second topic concerns the accurate determination of the working point of an accelerator, defined as the number of transverse oscillations the particle beam travels per unit of accelerator circumference, both horizontally and vertically. This quantity is called horizontal and vertical tune, respectively. Their knowledge is also crucial to understand whether the beam will be stable or unstable. In fact, not all tune values are acceptable, as there are particular values that bring the beam into resonance. In this configuration, the amplitude of the transverse oscillations of the particles increases in an uncontrolled manner and leads to the loss of all or part of the beam. Note that, in particular operating conditions, the resonant conditions are sought and desired to model, in a suitable way, the transversal shape of the beam, such as the above mentioned PS extraction scheme. It is even clearer how much the determination of the machine working point is essential to determine the operating conditions of an accelerator. In this context, several methods (also taken from the field of applied mathematics) to calculate the tune will be demonstrated and tested numerically on different types of synthetic signals. At the end of this description, the use of experimental data will allow to obtain the benchmark of a new method for the direct calculation of some characteristic quantities of non-linear beam dynamics (namely, the amplitude detuning, i.e. the variation of tune as a function of intensity of the perturbation provided to the beam.
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 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.
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.
Cancer cells, including leukemic cells, can react to therapeutic treatment by altering their metabolic phenotype (“metabolic reprogramming”) to keep their accelerated proliferative state, eventually becoming resistant to the treatment. There is an increasing amount of evidence indicating that metabolic reprogramming is one of the key mechanisms of acquisition of drug resistance by cancer cells. In agreement, several metabolic studies targeting leukaemia and specifically acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML), have been conducted over the last decades. However, there is still a lack of understanding the metabolic features of both AML and CML leukaemia specially in the acquisition of drug resistance, that is needed for unveiling novel and effective treatments for resistant and non-resistant patients. Therefore, the main objective of this thesis was to investigate the rewiring of cell metabolism occurring in the process of acquisition of resistance to conventional therapeutic treatments in AML and CML malignancies. Next, by revealing this metabolic rewiring, we intended to highlight potential metabolic and non-metabolic targets that could be exploited to overcome resistance to treatments. To this end, we have performed a comprehensive and comparative multi-OMIC study to analyse the links between the metabolic reprogramming and the resistance acquisition of THP-1 and HL-60 AML cell models sensitive or resistant to cytarabine (AraC) and doxorubicin (Dox), and of KU812 CML cell model sensitive or resistant to imatinib, all under normoxic (21% O2) and hypoxic (1% O2) conditions. The results of this thesis are divided into two chapters. On the one hand, in Chapter 1, the multi-OMIC study performed in AML parental and resistant cells unveiled that the acquisition of AraC resistance causes the reprogramming of the glucose metabolism of THP-1 and HL-60 cells by increasing the glycolytic flux whereas it is not associated with an alteration in the mitochondrial respiration. Moreover, our results also exhibited a possible disfunction of ETC complex I as well as alterations in glutamine and serine-glycine-1C metabolism in AML cells that display a more active mitochondrial metabolism. Moreover, we have also identified that the acquisition of Dox resistance causes alterations in the glucose and amino acid metabolism. Importantly, we have observed an important loss of mitochondrial respiration capacity of AML cells resistant to Dox chemotherapeutic drug, which constitutes a potential metabolic vulnerability that can be exploited for the treatment of AML patients resistant to Dox. On the other hand, in Chapter 2 is shown that the acquisition of imatinib resistance causes the reprogramming of glucose metabolism by enhancing the glycolytic flux, PPP, and glycogen metabolism, thus highlighting these metabolic pathways as potential metabolic weaknesses of KU812 cells resistant to imatinib. Moreover, we have observed a high metabolic plasticity of KU812 cells resistant to imatinib which includes the orchestration of many metabolic routes associated with the amino acid metabolism. Importantly, the CML multi-OMIC study has also unveiled an enhanced mitochondrial respiration capacity, which constitutes another potential vulnerability that can be exploited to overcome imatinib resistance. Finally, both AML and CML multi-OMIC studies have allowed us to propose and/or validate different metabolic and non-metabolic targets. In this regard, in this thesis we have identified and validated a battery of single-hit inhibitions that were able to reduce the cell viability of both parental and resistant AML and CML cells. Finally, we have confirmed that the repurposing of Dox chemotherapeutic drug counteracts the imatinib resistance in the KU812 cells resistant to imatinib.
Die Bewertung der Nitrataustragsgefährdung (NAG) landwirtschaftlich genutzter Flächen in Wasserschutzgebieten (WSG) erfolgte bislang auf Basis bodenkundlicher Kartierungen und wurde seit 1996 nach einem im Staatsanzeiger für das Land Hessen veröffentlichten Merkblatt des ehemaligen Hessischen Landesamtes für Bodenforschung im Rahmen der Muster-Wasserschutzgebietsverordnung geregelt (HLfB 1996, HMUJFG 1996). Infolge der Verfügbarkeit hochauflösender Bodendaten in Form der „Bodenflächendaten 1: 5.000, landwirtschaftliche Nutzfläche“ (BFD5L) wird die Ermittlung der Nitrataustragsgefährdung landwirtschaftlich genutzter Flächen neu geregelt. Die BFD5L liefert Auswertungen der Bodenschätzungsdaten zur Feldkapazität des Wurzelraums sowie weiterer relevanter Parameter, die zur Bewertung der Nitrataustragsgefährdung herangezogen werden können.
Um die Eignung der BFD5L-Daten zur Ermittlung der Nitrataustragsgefährdung zu überprüfen, wurden in den Jahren 2009 bis 2012 bodenkundliche Vergleichskartierungen im Rahmen eines Pilotvorhabens im Wasserschutzgebiet Eschollbrücken/Pfungstadt in Südhessen, im Wassereinzugsgebiet der Quelle Meineringhausen bei Korbach, im Wasserschutzgebiet des Tiefbrunnens Spieß der Gemeinde Bad Emstal sowie im WSG Quelle Ohmes der Stadt Kirtorf durchgeführt. Ziel war es, die Umsetzungsmöglichkeiten bei der Nutzung der BFD5LDaten in organisatorischer und technischer Hinsicht zu erproben und das bisherige Verfahren zu überarbeiten (PETER & MILLER 2009, PETER & MILLER 2010a und 2010b, PETER & MILLER 2012).
Die Ergebnisse der Vergleichskartierungen zeigen, dass sich die Daten der BFD5L grundsätzlich für die Ermittlung der Nitrataustragsgefährdung in Wasserschutzgebieten eignen. Lediglich für Flächen, für die nach den bislang im System BFD5L enthaltenen Methoden keine Kennwerte abgeleitet werden können sowie für Sonderstandorte, muss die Nitrataustragsgefährdung durch bodenkundliche Geländearbeiten ermittelt werden.
Es handelt sich hier um die portugiesische Übersetzung einer an der Universität Wien eingereichten Magisterarbeit aus dem Jahr 2004. Die übersetzte Version wurde im Jahr 2006 zudem um einige Inhalte erweitert.
The early acquisition of Greek compounds by two monolingual Greek girls aged between 1;8 and 3;0 years is studied in a usage-based theoretical framework. Special importance is attached to the morphological structure of Greek compound types occurring in child speech and child-directed speech. Greek nominal compound formation does not consist in the mere juxtaposition of words or roots, but involves stems as well as a compound marker. Major questions addressed are the transparency of compounds and productive nominal compound formation. Evidence for productivity of nominal compound formation has been found with only one of the two girls. In contrast to other languages, neoclassical nominal compounds by far exceed endocentric subordinative ones tokenwise in Greek child speech and child-directed speech providing evidence of entrenchment rather than productivity.
In a cross-linguistic comparison it is shown that, in spite of the fact that both Standard Modern Greek and German are rich in nominal compounds, their number is much more limited in Greek than in German child speech. An explanation for this apparent paradox is provided by an onomasiological approach to lexical typology based on a sample list of nominal compounds occurring in German child language and their Greek translational equivalents. It has been found that while use of nominal compounds is common in colloquial German including child-centered situations, it is more typical of Greek formal than colloquial registers.
El libro pretende brindar un recorrido inicial a través de la fauna de arañas de la Argentina. Está organizado en veintiún capítulos. En el primero de ellos se presentan características generales de las arañas. Cada uno de los capítulos siguientes corresponde a una familia distinta. Se exponen aspectos morfológicos, fisiológicos y etológicos, entre otros. Las arañas de interés sanitario presentes en el país se encuentran incluidas. El libro cuenta con más de 120 fotografías, todas fueron realizadas por el autor, y hasta ahora no habían sido publicadas. La obra está dirigida a todos los que se interesan por el mundo de las arañas, en particular a estudiantes y profesionales de ciencias biológicas, médicas y afines.
Das hethitische Phonem /xw/
(2014)
In the Hittite phonological system there was a labialized velar fricative /xw/ beside the plain velar fricative /x/ parallel to the opposition between the velar stops /kw/ and /k/. The frequent syllable /xwa/ was spelled either hu-(u) or hu-wa. Evidence from the frequency of words with initial hu in the lexicon, from spelling variations and from ablaut alternations is presented to demonstrate the existence of /xw/. It is suggested that Hittite /xw/ regularly corresponds to the reflexes of *w in the non-Anatolian Indo-European languages.
Die Vorgeschichte von "Des Minnesangs Frühling" als einem Gemeinschaftswerk von Karl Lachmann und Moritz Haupt reicht in den Herbst 1934 zurück. Im Oktober dieses Jahres trafen Haupt und Lachmann das erste Mal im Hause von Karl Hartwig Gregor von Meusebach [...] zusammen. [...] Ein Ergebnis der überlieferungshistorisch orientierten Debatte der letzten Jahre liegt, wenn ich richtig sehe, in der Einsicht, daß eine so gut wie ausschließlich auf formale und ästhetische Urteile gegründete Philologie zu sehr diachrone, entwicklungsgeschichtliche Gesichtspunkte favorisiert. [...]) Eine Ausgabe von "Des Minnesangs Frühling", die sich [...] stärker von der Tradition verabschieden, als dies schon durch die Neubearbeitung geschehen ist, müßte [...] wohl ohne die namenlosen Lieder auskommen.
Unter der Signatur VI/273 befinden sich in der Stiftsbibliothek Kremsmünster acht Pergamentstreifen unterschiedlicher Breite (...) und unregelmäßiger Länge (...). Es handelt sich um die Reste von zwei Pergamentdoppelblättern (...). Die Schrift gehört wohl noch dem 12. Jahrhundert an, sie macht jedenfalls einen altertümlicheren Eindruck als die der Göttinger Bruchstücke, der bisher ältesten Überlieferung des Lucidarius (...). Inhaltlich erweist sich die vorliegende Textpartie zugehörig zum 3. Buch des Lucidarius (...).
Im Vorder- und Rückendeckel des Cod. 250 der Stiftsbibliothek Kremsmünster (...) um 1400, ‚In librum quartuor sententiarum’, waren je ein Pergamentdoppelblatt einer Pergamenths. des späten 13. Jahrhunderts in 4° eingeklebt. (...) Über dem Liedtext [des ersten Blattes] stehen, und zwar über allen 3 Strophen, linienlose Neumen. Diese Aufzeichnung der Melodie für mehrere Strophen ist nicht ungewöhnlich, wenngleich auch nicht der Normalfall: sie ist im Codex buranus ebenso belegt wie in jüngeren Liederhss. (...) Hier liegt eine der frühen musikalischen Quellen des Minnesangs vor, älter sind nur der Codex buranus um 1250 (...), Walther N, Schreibers Fragment (beide vor 1300), etwa gleichaltrig die Frankfurter Niedhartbruchstücke O (erste Hälfte des 14. Jahrhunderts) (...).
Einführung zum 4. Tag
(2000)
Der 4. Tag war der Tag der Literaturwissenschaft und der Mystischen "Gebrauchsliteratur", die mit unterschiedlichen Methoden bearbeitet wurde – das Spektrum reichte von vorwiegend inhaltsbezogener, semiotisch fundierter Textauslegung über formalzentrierte Verfahren (Erzählanalyse), Text- und Überlieferungsgeschichte bis hin zu frömmigkeits- und sozialgeschichtlicher Einordnung und literaturwissenschaftlicher Heuristik. Die Frage nach dem "Sitz im Leben" im allgemeinsten und speziellen Sinn erweist sich als Leitmotiv; die Exposés verbinden oft die genannten Methoden in produktiver Weise, um die spezifische ‚Machart’ der Texte zu erschließen und sie zu verorten.
Ursprünglich meinte ‚Formen’ in erster Linie die Medien der Aneignung – Literatur und Film, bildende Kunst und Musik-, bzw. die gesellschaftlichen Institutionen von Wissenschaft und Schule, Museum und Ausstellung. (...) In dem Maße, die Literaturwissenschaft aufgehört hat, das literarische Werk isoliert zu betrachten, ist ein legitimes Interesse auch der Literaturhistoriker an der Rezeption nicht-literarischer Themen und Formen ebenso gegeben wie an den nicht-literarischen Rezeptionsmedien.
Fragmente eines Erzählens von Liebe : Die Konstruktion von Subjektivität bei Heinrich von Morungen
(2005)
[Volker Mertens] Untersuchungen knüpfen (...) [an die Einwände von Dagmar Hirschberg, Hans Irler und Arthur Groos] an, indem sie (...) Eigenart [der höfischen Literatur] als spezifische Variation traditioneller poetischer Verfahrenweisen deutet mit dem Ziel, Subjektivität zu inszenieren. Da dieses Vorgehen prinzipiell für den Minnesang gilt, (...) [wirft Volker Mertens] zunächst einen Blick auf die Tradition. Nach einer relativ offenen Phase des Experimentierens mit verschiedenen Liedtypen – Werbelied, Klagelied, Frauenlied, Wechsel u.a. – wird in der zweiten Phase mit der selektiven Übernahme okzitanischer Muster das minneanalytische Lied favorisiert.
Hartmann von Aue’s borrowing of the world âventiure from French in his ‘Erec’ means that the term was developed further in the field of poetology – it did not only mean an ‘event which was told’, but it also came to mean ‘the act of telling as a (medial) event’, as a successful (or unsuccessful) creation of sense. In the ‘Nibelungenlied ‘,’âventuire’ has the connotation of contingency as establishing order by means of the plot failures. This deficit is compensated by the fascination of the singer’s performance. This is where Wolfram starts.
Die Annahme, Fuß sei ein Minnesänger gewesen, beruht auf der Zuordnung zu drei Personen, die auf diesem Gebiet hervorgetreten sind, und auf der Interpretation der Bezeichnung ‚puler’. Trifft nun schon die Angabe „Minnesänger“ bei Wolfram nur für ein dem späten Mittelalter kaum mehr gegenwärtiges Nebengebiet seines dichterischen Schaffens zu, so bedeutet ‚puler’ in den (...) [Volker Mertens] bekannten Belegen soviel wie „Minner, Liebhaber“, in einem Fall auch „Sachverständiger in Liebesdingen“ (...), aber niemals „Minnesänger“.