Protection of the LHC against Unsynchronised Beam Aborts

An unsynchronised beam abort in the LHC could damage downstream accelerator components, in particular the extraction septum magnets, the experimental low-beta triplet magnet apertures and the tertiary collimators. Although the LHC beam dumping system includes design features to minimise their frequency, such unsynchronised aborts cannot be excluded. A system of protection devices comprising fixed and moveable diluters and collimators will protect the downstream LHC aperture from the misdirected bunches in case of such a failure. The sources of unsynchronised aborts are described, together with the requirements and design of the protection devices and their expected performance. The accompanying operational requirements and envisaged solutions are discussed, in particular the problem of ensuring the local orbit at the protection devices

DNA-binding polarity of human replication protein A positions nucleases in nucleotide excision repair

The human single-stranded DNA-binding replication A protein (RPA) is involved in various DNA-processing events. By comparing the affinity of hRPA for artificial DNA hairpin structures with 3'- or 5'-protruding single-stranded arms, we found that hRPA binds ssDNA with a defined polarity; a strong ssDNA interaction domain of hRPA is positioned at the 5' side of its binding region, a weak ssDNA-binding domain resides at the 3' side. Polarity appears crucial for positioning o

A Novel Eddy Current Septum Magnet for SPS Extraction towards LHC and CNGS

A new East Fast-Extraction System is under construction in the SPS, to supply particles with a maximum batch length of 7.8 us and 10.5 us to the LHC and to CNGS (CERN Neutrino to Gran Sasso), respectively. The extraction septum magnets actually used at the SPS have been designed for slow extraction over several seconds, have large cooling and electrical power demands and need frequently maintenance in a high radiation environment. A fast system of only 250 us pulse duration has therefore been developed, using a half-sine excitation pulse with a superimposed third harmonic. The short pulse duration requires very thin magnetic yoke laminations, which can not easily be stamped and stacked. Profiting from a development for the LHC beam dump kicker magnets, the yoke is therefore built-up from tape-wound cylindrical cores, employing 50 um thick Si-steel tape. Thirty two cores are stacked longitudinally to produce a yoke of 3.2 meter length. The aperture is cut radial into each cylinder. The cores are radial compressed by spring-loaded pistons inserted in strong stainless-steel frames to provide mechanical stability. The 5+1 mm thick copper/iron septum is separated from the excitation current loop and acts as a passive eddy current screen. This allows separating the vacuum of the magnet from that of the circulating-beam channel, avoiding the need of using UHV material. This paper presents the magnet and generator prototype design as well as simulation and measurement results

Steel septum magnets for the LHC beam injection and extraction

The Large Hadron Collider (LHC) will be a superconducting accelerator and collider to be installed in the existing underground LEP ring tunnel at CERN. It will provide proton-proton collisions with a centre of mass energy of 14 TeV. The proton beams coming from the SPS will be injected into the LHC at 450 GeV by vertically deflecting kicker magnets and horizontally deflecting steel septum magnets (MSI). The proton beams will be dumped from the LHC with the help of two extraction systems comprising horizontally deflecting kicker magnets and vertically deflecting steel septum magnets (MSD). The MSI and MSD septa are laminated iron-dominated magnets using an all welded construction. The yokes are constructed from two different half cores, called coil core and septum core. The septum cores comprise circular holes for the circulating beams. This avoids the need for careful alignment of the usually wedge-shaped septum blades used in classical Lambertson magnets. The MSI and MSD septum magnets were designed and built in a collaboration between IHEP (Protvino) and CERN (Geneva). This paper presents the magnet design, the experience gathered during the preseries construction, and gives the results of detailed magnetic measurements of the MSIB and MSDC preseries magnets

Initial results from beam commissioning of the LHC beam dump system

Initial commissioning of the LHC beam dump system with beam took place in August and September 2008. The preparation, setting-up and the tests performed are described together with results of the extractions of beam into the dump lines. Analysis of the first detailed aperture measurements of the extraction channels and kicker performance derived from dilution sweep shapes are presented. The performance of the other equipment subsystems is summarised, in particular that of the dedicated dump system beam instrumentation

A new class of tunable acid-sensitive linkers for native drug release based on the trityl protecting group

Core-cross-linked polymeric micelles (CCPMs) are a promising nanoparticle platform due to favorable properties such as their long circulation and tumor disposition exploiting the enhanced permeability and retention (EPR) effect. Sustained release of covalently linked drugs from the hydrophobic core of the CCPM can be achieved by a biodegradable linker that connects the drug and the core. This study investigates the suitability of trityl-based linkers for the design of acid-triggered native active pharmaceutical ingredient (API) release from CCPMs. Trityl linker derivatives with different substituent patterns were synthesized and conjugated to model API compounds such as DMXAA-amine, doxorubicin, and gemcitabine, and their release kinetics were studied. Hereafter, API release from CCPMs based on mPEG-b-pHPMAmLac block copolymers was investigated. Variation of the trityl substitution pattern showed tunability of the API release rate from the trityl-based linker with t1/2 varying from <1.0 to 5.0 h at pH 5.0 and t1/2 from 6.5 to >24 h at pH 7.4, all at 37 °C. A clear difference in release kinetics was found between gemcitabine and doxorubicin, with gemcitabine showing no detectable release for 72 h at pH 5.0 and doxorubicin showing a t1/2 of less than 1 h. Based on these findings, we show that the reaction mechanism of trityl deprotection plays an important role in the API release kinetics. The first step in this mechanism, which is protonation of the trityl-bound amine, is pKa-dependent, which explains the difference in release rate. In conclusion, acid-sensitive and tunable trityl linkers are highly promising for the design of linker–API conjugates and for their use in CCPMs

A New Class of Tunable Acid-Sensitive Linkers for Native Drug Release Based on the Trityl Protecting Group

Core-cross-linked polymeric micelles (CCPMs) are a promising nanoparticle platform due to favorable properties such as their long circulation and tumor disposition exploiting the enhanced permeability and retention (EPR) effect. Sustained release of covalently linked drugs from the hydrophobic core of the CCPM can be achieved by a biodegradable linker that connects the drug and the core. This study investigates the suitability of trityl-based linkers for the design of acid-triggered native active pharmaceutical ingredient (API) release from CCPMs. Trityl linker derivatives with different substituent patterns were synthesized and conjugated to model API compounds such as DMXAA-amine, doxorubicin, and gemcitabine, and their release kinetics were studied. Hereafter, API release from CCPMs based on mPEG-b-pHPMAmLac block copolymers was investigated. Variation of the trityl substitution pattern showed tunability of the API release rate from the trityl-based linker with t1/2 varying from 24 h at pH 7.4, all at 37 °C. A clear difference in release kinetics was found between gemcitabine and doxorubicin, with gemcitabine showing no detectable release for 72 h at pH 5.0 and doxorubicin showing a t1/2 of less than 1 h. Based on these findings, we show that the reaction mechanism of trityl deprotection plays an important role in the API release kinetics. The first step in this mechanism, which is protonation of the trityl-bound amine, is pKa-dependent, which explains the difference in release rate. In conclusion, acid-sensitive and tunable trityl linkers are highly promising for the design of linker-API conjugates and for their use in CCPMs

Positive Regulation of DNA Double Strand Break Repair Activity during Differentiation of Long Life Span Cells: The Example of Adipogenesis

Little information is available on the ability of terminally differentiated cells to efficiently repair DNA double strand breaks (DSBs), and one might reasonably speculate that efficient DNA repair of these threatening DNA lesions, is needed in cells of long life span with no or limited regeneration from precursor. Few tissues are available besides neurons that allow the study of DNA DSBs repair activity in very long-lived cells. Adipocytes represent a suitable model since it is generally admitted that there is a very slow turnover of adipocytes in adult. Using both Pulse Field Gel Electrophoresis (PFGE) and the disappearance of the phosphorylated form of the histone variant H2AX, we demonstrated that the ability to repair DSBs is increased during adipocyte differentiation using the murine pre-adipocyte cell line, 3T3F442A. In mammalian cells, DSBs are mainly repaired by the non-homologous end-joining pathway (NHEJ) that relies on the DNA dependent protein kinase (DNA-PK) activity. During the first 24 h following the commitment into adipogenesis, we show an increase in the expression and activity of the catalytic sub-unit of the DNA-PK complex, DNA-PKcs. The increased in DNA DSBs repair activity observed in adipocytes was due to the increase in DNA-PK activity as shown by the use of DNA-PK inhibitor or sub-clones of 3T3F442A deficient in DNA-PKcs using long term RNA interference. Interestingly, the up-regulation of DNA-PK does not regulate the differentiation program itself. Finally, similar positive regulation of DNA-PKcs expression and activity was observed during differentiation of primary culture of pre-adipocytes isolated from human sub-cutaneous adipose tissue

Essential Factors for Incompatible DNA End Joining at Chromosomal DNA Double Strand Breaks In Vivo

Non-homologous end joining (NHEJ) is a major pathway for the repair of DNA double strand break (DSBs) with incompatible DNA ends, which are often generated by ionizing irradiation. In vitro reconstitution studies have indicated that NHEJ of incompatible DNA ends requires not only the core steps of synapsis and ligation, employing KU80/DNA-PKcs and LIG4, but also additional DNA end processing steps, such as DNA end resection by Artemis and gap-filling by POLλ and POLμ. It seems that DNA end processing steps are important for joining of incompatible DNA ends rather than compatible ends. Despite the fact that DNA end processing is important for incompatible DNA end joining in vitro, the role of DNA processing in NHEJ of incompatible DSBs in vivo has not yet been demonstrated. Here we investigated the in vivo roles of proteins implicated in each step of NHEJ using an assay in which NHEJ of incompatible DNA ends on chromosomal DNA can be assessed in living human cells. siRNA- or inhibitor-mediated impairment of factors in each NHEJ step resulted in a reduction in joining efficiency. Strikingly, stronger effects were observed when DNA end resection and ligation protein functions were impaired. Disruption of synapsis by KU80 and DNA-PKcs impairment, or the disruption of gap filling by POLλ and POLμ depletion, resulted in higher levels of microhomology-mediated joining. The present study indicates that DNA end resection and ligation factors are critical for the efficient joining of incompatible ends in vivo, further emphasizing the importance of synapsis and gap-filling factors in preventing illegitimate joining

Linac4 Technical Design Report

Linac4 is an H- linear accelerator, intended to replace Linac2 as injector to the PS Booster (PSB). By delivering to the PSB a beam at 160 MeV energy, Linac4 will provide the conditions to double the brightness and intensity of the beam from the PSB, thus removing the first bottleneck towards higher brightness for the LHC and simplifying operation. Moreover, this new linac constitutes an essential component of any of the envisaged LHC upgrade scenarios and could open the way to future extensions of the CERN accelerator complex towards higher performance. This Technical Design Report presents a detailed technical overview of the Linac4 design as it stands at end 2006