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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.
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.