Beam feasibility study of a collimator with in-jaw beam position monitors

At present, the beam-based alignment of the LHC collimators is performed by touching the beam halo with both jaws of each collimator. This method requires dedicated fills at low intensities that are done infrequently and makes this procedure time consuming. This limits the operational flexibility, in particular in the case of changes of optics and orbit configuration in the experimental regions. The performance of the LHC collimation system relies on the machine reproducibility and regular loss maps to validate the settings of the collimator jaws. To overcome these limitations and to allow a continuous monitoring of the beam position at the collimators, a design with jaw-integrated Beam Position Monitors (BPMs) was proposed and successfully tested with a prototype (mock-up) collimator in the CERN SPS. Extensive beam experiments allowed to determine the achievable accuracy of the jaw alignment for single and multi-turn operation. In this paper, the results of these experiments are discussed. The non-linear response of the BPMs is compared to the predictions from electromagnetic simulations. Finally, the measured alignment accuracy is compared to the one achieved with the present collimators in the LHC.peer-reviewe

Assessing the quality of life of health-referred children and adolescents with short stature: development and psychometric testing of the QoLISSY instrument

10.1186/1477-7525-11-76Health and Quality of Life Outcomes1117

HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness

High spliceosome activity is a dependency for cancer cells, making them more vulnerable to perturbation of the splicing machinery compared to normal cells. To identify splicing factors important for prostate cancer (PCa) fitness, we performed pooled shRNA screens in vitro and in vivo. Our screens identified HNRNPM as a regulator of PCa cell growth. RNA- and eCLIP-sequencing identified HNRNPM binding to transcripts of key homeostatic genes. HNRNPM binding to its targets prevents aberrant exon inclusion and back-splicing events. In both linear and circular mis-spliced transcripts, HNRNPM preferentially binds to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching-antisense-oligonucleotides (SSOs) was sufficient to inhibit PCa cell growth. This suggests that PCa dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Our results have further been confirmed in other solid tumors. Taken together, our data reveal a role for HNRNPM in supporting cancer cell fitness. Inhibition of HNRNPM activity is therefore a potential therapeutic strategy in suppressing growth of PCa and other solid tumors

Handling 1 MW losses with the LHC collimation system

The LHC superconducting magnets in the dispersion suppressor of IR7 are the most exposed to beam losses leaking from the betatron collimation system and represent the main limitation for the halo cleaning. In 2013, quench tests were performed at 4 TeV to improve the quench limit estimates, which determine the maximum allowed beam loss rate for a given collimation cleaning. The main goal of the collimation quench test was to try to quench the magnets by increasing losses at the collimators. Losses of up to 1 MW over a few seconds were generated by blowing up the beam, achieving total losses of about 5.8 MJ. These controlled losses exceeded by a factor 2 the collimation design value, and the magnets did not quench.peer-reviewe

Quench tests at the Large Hadron Collider with collimation losses at 3.5 Z TeV

The Large Hadron Collider (LHC) has been operating since 2010 at 3.5 TeV and 4.0 TeV without experiencing quenches induced by losses from circulating beams. This situation might change at 7 TeV where the quench margins in the super-conducting magnets are reduced. The critical locations are the dispersion suppressors (DSs) at either side of the cleaning and experimental insertions, where dispersive losses are maximum. It is therefore crucial to understand the quench limits with beam loss distributions alike those occurring in standard operation. In order to address this aspect, quench tests were performed by inducing large beam losses on the primary collimators of the betatron cleaning insertion, for proton and lead ion beams of 3.5 Z TeV, to probe the quench limits of the DS magnets. Losses up to 500 kW were achieved without quenches. The measurement technique and the results obtained are presented, with observations of heat loads in the cryogenics system.peer-reviewe

Collimation for the LHC high intensity beams

The unprecedented design intensities of the LHC require several important advances in beam collimation. With its more than 100 collimators, acting on various planes and beams, the LHC collimation system is the biggest and most performing such system ever designed and constructed. The solution for LHC collimation is explained, the technical components are introduced and the initial performance is presented. Residual beam leakage from the system is analysed. Measurements and simulations are presented which show that collimation efficiencies of better than 99.97 % have been measured with the 3.5 TeV proton beams of the LHC, in excellent agreement with expectations.peer-reviewe

Immune responses in allergic and HIV positive patients

Über 25% der Bevölkerung leidet an Allergien und diese Raten sind immer noch am Steigen. Umso wichtiger wird es, exakte Diagnosen, mit z.B.: Allergenchips, zu stellen um die einzige krankheits-modifizierende Therapie, die spezifische Immuntherapie, richtig auszuwählen. Auch ermöglichen die Allergenchips ein Monitieren der Therapieeffizienz. Ziel dieser Dissertation war es, immunologische Muster in allergischen Patienten sowie Patienten, die sensibilisiert, aber klinisch tolerant gegenüber Allergenen sind, zu untersuchen. Darüber hinaus wollten wir die technischen Merkmale der Allergen-Chips analysieren. Material und Methoden: Patienten-Seren wurden für immunologische Muster mit ImmunoCAP, ISAC Allergen-Peptid-Arrays und Basophilenaktivierungstests, zur Untersuchung der allergenspezifischen IgE-Funktionalität, analysiert. Ergebnisse: In diesen Studien konnten wir zeigen, dass Patienten aus Simbabwe, die Erdnuss-sensibilisiert waren, unterschiedliche IgE-Epitope des Hauptallergen Ara h 2 erkannten und auch eine 7fach niedrigere ß-Hexosaminidase-Freisetzung hatten im Vergleich zu Erdnussallergikern aus Schweden. Die Erdnuss tolerante schwedische Gruppe erkannte hauptsächlich das Bet v 1-verwandte Ara h 8 und liefert somit die Erklärung für deren klinische Toleranz. Die klinische Toleranz in der afrikanische Gruppe ließ sich großteils durch IgE gegen niedrig allergene komparative Profiline und CCDs gerichtet, erklären. Der ISAC-Chip ist in der Lage, die klinische Besserung der spezifischen Immuntherapie darzustellen. Die Bildung von blockierenden allergen-spezifischen IgG-Antikörpern liefert hierzu die Erklärung. Die Patienten in der aktiv behandelten Gruppe verbesserten sich in den nasalen Provokationstest und in serologischen Untersuchungen. Fazit: Natürliche klinischen Toleranz in der afrikanischen Patientengruppe lässt sich durch IgE, welches gegen nicht-allergene Erdnuss Komponenten gerichtet ist, erklären und einer niedrigen allergenen Aktivität dieses IgEs. Der ISAC Test kann ein hilfreiches und nicht-invasives Werkzeug zur Überwachung und Therapiekontrolle der allergenspezifischen Immuntherapie sein.More than 25% of the population suffer from allergic diseases and rates are still on the increase. Exact diagnosis e.g. by allergen microarrays, is therefore one of the most important tools to choose the correct allergen-specific immunotherapy, the only disease modifying treatment. Objective: Aim of my thesis was to investigate immunological patterns in allergic patients as well as in patients who are sensitized, but clinically tolerant to the allergens. In addition we wanted to investigate the technical features of the allergen chip. Material and Methods: Patients sera were analysed for immunological patterns by ImmunoCAP, microarrayed allergens, allergen peptide arrays and basophil activation tests for investigation of allergen-specific IgE functionality. Results: In these studies we were able to show that patients from Zimbabwe who were sensitized to peanut recognized different IgE epitopes of the major allergen Ara h 2 and also had a 7times lower ß-hexosaminidase release compared to peanut allergic patients from Sweden. The peanut tolerant Swedish group mainly recognized the Bet v 1 related Ara h 8 and therefor provided a reason for their clinical tolerance. The Zimbabwean group had IgE directed towards profilins and cross-reactive carbohydrates (CCDs). The ISAC chip is able to reflect the clinical improvement due to specific immunotherapy by revealing the induction of blocking allergen-specific IgG antibodies. Patients in actively treated groups improved in nasal provocation tests and in serological allergen chip testing. Conclusion: Natural clinical tolerance can be explained for the African patient group by IgE directed to non-allergenic peanut components and a lower allergenic activity of IgE. The ISAC test can be a helpful and non-invasive tool to monitor allergen specific immunotherapy.submitted by Dr. med. univ. Eva WollmannZusammenfassung in deutscher SpracheAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2016OeBB(VLID)171618

Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe)

Carvajal syndrome is an autosomal dominant or autosomal recessive disorder, manifesting with dilated cardiomyopathy, woolly hair, and palmoplantar keratoma. Additional manifestations can be occasionally found. Carvajal syndrome may be due to mutations in the desmocollin-2, desmoplakin, or plakophilin-2 gene. We report a family with Carvajal syndrome which additionally presented with hypoacusis, noncompaction, recurrent pharyngeal infections, oligodontia, and recurrent diarrhoea. Father and brother were also affected and had died suddenly, the father despite implantation of a cardioverter defibrillator (ICD). Genetic studies revealed the novel pathogenic mutation c.1678A > T in the desmoplakin gene resulting in the amino acid change Ile to Phe at position 560 in the index case and her brother. The index case underwent ICD implantation recently. Phenotypic manifestations of Carvajal syndrome are even broader than so far anticipated, the number of mutations in the desmoplakin gene responsible for Carvajal syndrome is still increasing, and these patients require implantation of an ICD as soon as their diagnosis is established

Persistence of IgE-associated allergy and allergen-specific IgE despite CD4+ T cell loss in AIDS

The infection of CD4+ cells by HIV leads to the progressive destruction of CD4+ T lymphocytes and, after a severe reduction of CD4+ cells, to AIDS. The aim of the study was to investigate whether HIV-infected patients with CD4 cell counts <200 cells/µl can suffer from symptoms of IgE-mediated allergy, produce allergen-specific IgE antibody responses and show boosts of allergen-specific IgE production. HIV-infected patients with CD4 counts ≤ 200 cells/µl suffering from AIDS and from IgE-mediated allergy were studied. Allergy was diagnosed according to case history, physical examination, skin prick testing (SPT), and serological analyses including allergen microarrays. HIV infection was confirmed serologically and the disease was staged clinically. The predominant allergic symptoms in the studied patients were acute allergic rhinitis (73%) followed by asthma (27%) due to IgE-mediated mast cell activation whereas no late phase allergic symptoms such as atopic dermatitis, a mainly T cell-mediated skin manifestation, were found in patients suffering from AIDS. According to IgE serology allergies to house dust mites and grass pollen were most common besides IgE sensitizations to various food allergens. Interestingly, pollen allergen-specific IgE antibody levels in the patients with AIDS and in additional ten IgE-sensitized patients with HIV infections and low CD4 counts appeared to be boosted by seasonal allergen exposure and were not associated with CD4 counts. Our results indicate that secondary allergen-specific IgE production and IgE-mediated allergic inflammation do not require a fully functional CD4+ T lymphocyte repertoire