Benchmark of the FLUKA model of crystal channeling against the UA9-H8 experiment

AbstractChanneling in bent crystals is increasingly considered as an option for the collimation of high-energy particle beams. The installation of crystals in the LHC has taken place during this past year and aims at demonstrating the feasibility of crystal collimation and a possible cleaning efficiency improvement. The performance of CERN collimation insertions is evaluated with the Monte Carlo code FLUKA, which is capable to simulate energy deposition in collimators as well as beam loss monitor signals. A new model of crystal channeling was developed specifically so that similar simulations can be conducted in the case of crystal-assisted collimation. In this paper, most recent results of this model are brought forward in the framework of a joint activity inside the UA9 collaboration to benchmark the different simulation tools available. The performance of crystal STF 45, produced at INFN Ferrara, was measured at the H8 beamline at CERN in 2010 and serves as the basis to the comparison. Distributions of deflected particles are shown to be in very good agreement with experimental data. Calculated dechanneling lengths and crystal performance in the transition region between amorphous regime and volume reflection are also close to the measured ones

Design optimization of multibody systems by sequential approximation

Abstract. Design optimization of multibody systems is usually established by a direct coupling of multibody system analysis and mathematical programming algorithms. However, a direct coupling is hindered by the transient and computationally complex behavior of many multibody systems. In structural optimization often approximation concepts are used instead to interface numerical analysis and optimization. This paper shows that such an approach is valuable for the optimization of multibody systems as well. A design optimization tool has been developed for multibody systems that generates a sequence of approximate optimization problems. The approach is illustrated by three examples: an impact absorber, a slider-crank mechanism, and a stress-constrained four-bar mechanism. Furthermore, the consequences for an accurate and efficient accompanying design sensitivity analysis are discussed

Synaptic transmission parallels neuromodulation in a central food-intake circuit

NeuromedinU is a potent regulator of food intake and activity in mammals. In Drosophila, neurons producing the homologous neuropeptide hugin regulate feeding and locomotion in a similar manner. Here, we use EM-based reconstruction to generate the entire connectome of hugin-producing neurons in the Drosophila larval CNS. We demonstrate that hugin neurons use synaptic transmission in addition to peptidergic neuromodulation and identify acetylcholine as a key transmitter. Hugin neuropeptide and acetylcholine are both necessary for the regulatory effect on feeding. We further show that subtypes of hugin neurons connect chemosensory to endocrine system by combinations of synaptic and peptide-receptor connections. Targets include endocrine neurons producing DH44, a CRH-like peptide, and insulin-like peptides. Homologs of these peptides are likewise downstream of neuromedinU, revealing striking parallels in flies and mammals. We propose that hugin neurons are part of an ancient physiological control system that has been conserved at functional and molecular level.SFB 645 and 704, DFG Cluster of Excellence ImmunoSensation, DFG grant PA 787, HHMI Janeli

Comparison of size distribution and (Pro249-Ser258) epitope exposure in in vitro and in vivo derived Tau fibrils

Background: Although several studies demonstrate prion-like properties of Tau fibrils, the effect of size in the seeding capacity of these aggregates is not fully understood. The aim of this study is to characterize Tau seeds by their size and seeding capacity. Methods: Tau aggregates were isolated from postmortem AD brain tissue and separated from low molecular weight species by sucrose gradient ultracentrifugation. Biochemical characterization of the different fractions was done by non-reducing Western blotting and aggregate-specific immuno-assays using in house developed anti-Tau monoclonal antibodies, including PT76 which binds to an epitope close to the microtubule-binding domain and, hence, also to K18. Seeding efficiency was then assessed in HEK293 cells expressing K18 FRET sensors. Results: We observed that upon sonication of Tau aggregates different size-distributed tau aggregates are obtained. In biochemical assays, these forms show higher signals than the non-sonicated material in some aggregation-specific Tau assays. This could be explained by an increased epitope exposure of the smaller aggregates created by the sonication. By analyzing human brain derived and recombinant (K18) Tau aggregates in a cellular FRET assay, it was observed that, in the absence of transfection reagent, sonicated aggregates showed higher aggregation induction. Preparations also showed altered profiles on native PAGE upon sonication and we could further separate different aggregate species based on their molecular weight via sucrose gradients. Conclusions: This study further elucidates the molecular properties regarding relative aggregate size and seeding efficiency of sonicated vs. non-sonicated high molecular weight Tau species. This information will provide a better knowledge on how sonication, a commonly used technique in the field of study of Tau aggregation, impacts the aggregates. In addition, the description of PT76-based aggregation specific assay is a valuable tool to quantify K18 and human AD Tau fibrils

The UA9 experimental layout

The UA9 experimental equipment was installed in the CERN-SPS in March '09 with the aim of investigating crystal assisted collimation in coasting mode. Its basic layout comprises silicon bent crystals acting as primary collimators mounted inside two vacuum vessels. A movable 60 cm long block of tungsten located downstream at about 90 degrees phase advance intercepts the deflected beam. Scintillators, Gas Electron Multiplier chambers and other beam loss monitors measure nuclear loss rates induced by the interaction of the beam halo in the crystal. Roman pots are installed in the path of the deflected particles and are equipped with a Medipix detector to reconstruct the transverse distribution of the impinging beam. Finally UA9 takes advantage of an LHC-collimator prototype installed close to the Roman pot to help in setting the beam conditions and to analyze the efficiency to deflect the beam. This paper describes in details the hardware installed to study the crystal collimation during 2010.Comment: 15pages, 11 figure, submitted to JINS

Novel highly potent CD4bs bNAb with restricted pathway to HIV-1 escape

Purpose: Broadly HIV-1 neutralizing antibodies (bNAbs) can suppress viremia in humans and represent a novel approach for effective immunotherapy. However, bNAb monotherapy selects for antibody-resistant viral variants. Thus, we focused on the identification of new antibody combinations and/or novel bNAbs that restrict pathways of HIV-1 escape. Methods: We screened HIV-1 positive patients for their neutralizing capacities. Following, we performed single cell sorting and PCR of HIV-1 Env-reactive mature B cells of identified elite neutralizers. Found antibodies were tested for neutralization and binding capacities in vitro. Further, their antiviral activity was tested in an HIV-1 infected humanized mouse model. Results: Here we report the isolation of antibody 1–18, a VH1–46-encoded CD4 binding site (CD4bs) bNAb identified in an individual ranking among the top 1% neutralizers of 2,274 HIV-1-infected subjects. Tested on a 119-virus panel, 1–18 showed to be exceptionally broad and potent with a coverage of 97% and a mean IC50 of 0.048 lg/mL, exceeding the activity of most potent CD4bs bNAbs described to-date. A 2.4 Å cryo-EM structure of 1–18 bound to a native-like Env trimer revealed that it interacts with HIV-1 env similar to other CD4bs bNAbs, but includes additional contacts to the V3 loop of the adjacent protomer. Notably, in vitro, 1–18 maintained activity against viruses carrying mutations associated with escape from VRC01-class bNAbs. Further, its HIV-1 env wide escape profile differed critically from other CD4bs bNAbs. In humanized mice, monotherapy with 1–18 was sufficient to prevent the development of viral escape variants that rapidly emerged during treatment with other CD4bs bNAbs. Finally, 1–18 overcame classical HIV-1 mutations that are driven by VRC01-like bNAbs in vivo. Conclusion: 1–18 is a highly potent and broad bNAb that restricts escape and overcomes frequent CD4bs escape pathways, providing new options for bNAb combinations to prevent and treat HIV-1 infection