Separation of atomic and molecular ions by ion mobility with an RF carpet

Gas-filled stopping cells are used at accelerator laboratories for the thermalization of high-energy radioactive ion beams. Common challenges of many stopping cells are a high molecular background of extracted ions and limitations of extraction efficiency due to space-charge effects. At the FRS Ion Catcher at GSI, a new technique for removal of ionized molecules prior to their extraction out of the stopping cell has been developed. This technique utilizes the RF carpet for the separation of atomic ions from molecular contaminant ions through their difference in ion mobility. Results from the successful implementation and test during an experiment with a 600~MeV/u $^{124}$Xe primary beam are presented. Suppression of molecular contaminants by three orders of magnitude has been demonstrated. Essentially background-free measurement conditions with less than $1~\%$ of background events within a mass-to-charge range of 25 u/e have been achieved. The technique can also be used to reduce the space-charge effects at the extraction nozzle and in the downstream beamline, thus ensuring high efficiency of ion transport and highly-accurate measurements under space-charge-free conditions.Comment: 8 pages, 4 figure

Status of the BELLE II Pixel Detector

The Belle II experiment at the super KEK B-factory (SuperKEKB) in Tsukuba, Japan, has been collecting $e^+e^−$ collision data since March 2019. Operating at a record-breaking luminosity of up to $4.7×10^{34} cm^{−2}s^{−1}$, data corresponding to $424 fb^{−1}$ has since been recorded. The Belle II VerteX Detector (VXD) is central to the Belle II detector and its physics program and plays a crucial role in reconstructing precise primary and decay vertices. It consists of the outer 4-layer Silicon Vertex Detector (SVD) using double sided silicon strips and the inner two-layer PiXel Detector (PXD) based on the Depleted P-channel Field Effect Transistor (DePFET) technology. The PXD DePFET structure combines signal generation and amplification within pixels with a minimum pitch of $(50×55) μm^2$. A high gain and a high signal-to-noise ratio allow thinning the pixels to $75 μm$ while retaining a high pixel hit efficiency of about $99$. As a consequence, also the material budget of the full detector is kept low at $≈0.21$$\frac{X}{X_0}$ per layer in the acceptance region. This also includes contributions from the control, Analog-to-Digital Converter (ADC), and data processing Application Specific Integrated Circuits (ASICs) as well as from cooling and support structures. This article will present the experience gained from four years of operating PXD; the first full scale detector employing the DePFET technology in High Energy Physics. Overall, the PXD has met the expectations. Operating in the intense SuperKEKB environment poses many challenges that will also be discussed. The current PXD system remains incomplete with only 20 out of 40 modules having been installed. A full replacement has been constructed and is currently in its final testing stage before it will be installed into Belle II during the ongoing long shutdown that will last throughout 2023

The science case of the FRS Ion Catcher for FAIR Phase-0

The FRS Ion Catcher at GSI enables precision experiments with thermalized projectile and fission fragments. At the same time it serves as a test facility for the Low-Energy Branch of the Super-FRS at FAIR. The FRS Ion Catcher has been commissioned and its performance has been characterized in five experiments with 238U and 124Xe projectile and fission fragments produced at energies in the range from 300 to 1000 MeV/u. High and almost element-independent efficiencies for the thermalization of short-lived nuclides produced at relativistic energies have been obtained. High-accuracy mass measurements of more than 30 projectile and fission fragments have been performed with a multiple-reflection time-of-flight mass spectrometer (MR-TOF-MS) at mass resolving powers of up to 410,000, with production cross sections down to the microbarn-level, and at rates down to a few ions per hour. The versatility of the MR-TOF-MS for isomer research has been demonstrated by the measurement of various isomers, determination of excitation energies and the production of a pure isomeric beam. Recently, several instrumental upgrades have been implemented at the FRS Ion Catcher. New experiments will be carried out during FAIR Phase-0 at GSI, including direct mass measurements of neutron-deficient nuclides below 100Sn and neutron-rich nuclides below 208Pb, measurement of β-delayed neutron emission probabilities and reaction studies with multi-nucleon transfer.Peer reviewe

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Hydrophobic bile salts induce pro-fibrogenic proliferation of hepatic stellate cells through PI3K p110 alpha signaling

Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis

Sustainable and cost-effective MAS DNP-NMR at 30 K with cryogenic sample exchange

International audienceWe report here instrumental developments to achieve sustainable, cost-effective cryogenic Helium sample spinning in order to conduct dynamic nuclear polarisation (DNP) and solid-state NMR (ssNMR) at ultra-low temperatures (< 30 K). More specifically, we describe an efficient closed-loop helium system composed of a powerful heat exchanger (95% efficient), a single cryocooler and a single helium compressor to power the sample spinning and cooling. The system is integrated with a newly designed triple-channel NMR probe that minimizes thermal losses without compromising the RF performance and spinning stability (+/- 0.05%). The probe is equipped with an innovative cryogenic sample exchange system that allows swapping samples in minutes without introducing impurities in the close-loop system. We report that significant gain in sensitivity can be obtained at 30-40 K on large micro-crystalline molecules, with unfavorable relaxation timescales, making them difficult or impossible to polarize at 100 K. We also report rotor-synchronized 2D experiments to demonstrate the stability of the system

Removal of molecular contamination in low-energy RIBs by the isolation-dissociation-isolation method

Experiments with low-energy rare ion beams often suffer from a large amount of molecular contaminant ions. We present the simple isolation-dissociation-isolation method to suppress this kind of contamination. The method can be applied to almost all types of low-energy beamlines. In a first step, a coarse isolation of the massto-charge ratio of interest is performed, e.g. by a dipole magnet. In a second step, the ions are dissociated. The last step is again a coarse isolation of the mass-to-charge ratio around the ion of interest. The method was tested at the FRS Ion Catcher at GSI with a radioactive ion source installed inside the cryogenic stopping cell as well as with relativistic ions delivered by the synchrotron SIS-18 and stopped in the cryogenic stopping cell. The isolation and dissociation, here collision-induced dissociation, have been implemented in a gas-filled RFQ beamline. A reduction of molecular contamination by more than 4 orders of magnitude was achieved.peerReviewe