Multistage Zeeman deceleration of atomic and molecular oxygen

Multistage Zeeman deceleration is a technique used to reduce the velocity of neutral molecules with a magnetic dipole moment. Here we present a Zeeman decelerator that consists of 100 solenoids and 100 magnetic hexapoles, that is based on a short prototype design presented recently [Phys. Rev. A 95, 043415 (2017)]. The decelerator features a modular design with excellent thermal and vacuum properties, and is robustly operated at a 10 Hz repetition rate. This multistage Zeeman decelerator is particularly optimized to produce molecular beams for applications in crossed beam molecular scattering experiments. We characterize the decelerator using beams of atomic and molecular oxygen. For atomic oxygen, the magnetic fields produced by the solenoids are used to tune the final longitudinal velocity in the 500 - 125 m/s range, while for molecular oxygen the velocity is tunable in the 350 - 150 m/s range. This corresponds to a maximum kinetic energy reduction of 95% and 80% for atomic and molecular oxygen, respectively.Comment: Latest version as accepted by Physical Review

Design and construction of a multistage Zeeman decelerator for crossed molecular beams scattering experiments

Zeeman deceleration is a relatively new technique used to obtain full control over the velocity of paramagnetic atoms or molecules in a molecular beam. We present a detailed description of a multistage Zeeman decelerator that has recently become operational in our laboratory [Cremers \emph{et al.}, Phys. Rev. A 98, 033406 (2018)], and that is specifically optimized for crossed molecular beams scattering experiments. The decelerator consists of an alternating array of 100 solenoids and 100 permanent hexapoles to guide or decelerate beams of paramagnetic atoms or molecules. The Zeeman decelerator features a modular design that is mechanically easy to extend to arbitrary length, and allows for solenoid and hexapole elements that are convenient to replace. The solenoids and associated electronics are efficiently water cooled and allow the Zeeman decelerator to operate at repetition rates exceeding 10 Hz. We characterize the performance of the decelerator using various beams of metastable rare gas atoms. Imaging of the atoms that exit the Zeeman decelerator reveals the transverse focusing properties of the hexapole array in the Zeeman decelerator

Reactivation of Latent Tuberculosis in Cynomolgus Macaques Infected with SIV Is Associated with Early Peripheral T Cell Depletion and Not Virus Load

HIV-infected individuals with latent Mycobacterium tuberculosis (Mtb) infection are at significantly greater risk of reactivation tuberculosis (TB) than HIV-negative individuals with latent TB, even while CD4 T cell numbers are well preserved. Factors underlying high rates of reactivation are poorly understood and investigative tools are limited. We used cynomolgus macaques with latent TB co-infected with SIVmac251 to develop the first animal model of reactivated TB in HIV-infected humans to better explore these factors. All latent animals developed reactivated TB following SIV infection, with a variable time to reactivation (up to 11 months post-SIV). Reactivation was independent of virus load but correlated with depletion of peripheral T cells during acute SIV infection. Animals experiencing reactivation early after SIV infection (<17 weeks) had fewer CD4 T cells in the periphery and airways than animals reactivating in later phases of SIV infection. Co-infected animals had fewer T cells in involved lungs than SIV-negative animals with active TB despite similar T cell numbers in draining lymph nodes. Granulomas from these animals demonstrated histopathologic characteristics consistent with a chronically active disease process. These results suggest initial T cell depletion may strongly influence outcomes of HIV-Mtb co-infection

final results of a noninterventional study

Background Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)–targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. Methods Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. Results In the total population (N = 334), median follow-up was 5.2 months (range, 0–32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5–8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5–9 months) and median PFS was 6.9 months (5–9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. Conclusions This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies (http://www.vfa.de/de/forschung/nisdb/ webcite)

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study

Background: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. Methods: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. Results: In the total population (N = 334),median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211),median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%),anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. Conclusions: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC

Sequence‐based SNP genotyping in durum wheat

Summary: Marker development for marker-assisted selection in plant breeding is increasingly based on next-generation sequencing (NGS). However, marker development in crops with highly repetitive, complex genomes is still challenging. Here we applied sequence-based genotyping (SBG), which couples AFLP®-based complexity reduction to NGS, for de novo single nucleotide polymorphisms (SNP) marker discovery in and genotyping of a biparental durum wheat population. We identified 9983 putative SNPs in 6372 contigs between the two parents and used these SNPs for genotyping 91 recombinant inbred lines (RILs). Excluding redundant information from multiple SNPs per contig, 2606 (41%) markers were used for integration in a pre-existing framework map, resulting in the integration of 2365 markers over 2607 cM. Of the 2606 markers available for mapping, 91% were integrated in the pre-existing map, containing 708 SSRs, DArT markers, and SNPs from CRoPS technology, with a map-size increase of 492 cM (23%). These results demonstrate the high quality of the discovered SNP markers. With this methodology, it was possible to saturate the map at a final marker density of 0.8 cM/marker. Looking at the binned marker distribution (Figure 2), 63 of the 268 10-cM bins contained only SBG markers, showing that these markers are filling in gaps in the framework map. As to the markers that could not be used for mapping, the main reason was the low sequencing coverage used for genotyping. We conclude that SBG is a valuable tool for efficient, high-throughput and high-quality marker discovery and genotyping for complex genomes such as that of durum wheat

Mutational impact of culturing human pluripotent and adult stem cells

Genetic changes acquired during in vitro culture pose a potential risk for the successful application of stem cells in regenerative medicine. To assess mutation accumulation risks induced by culturing, we determined genetic aberrations in individual human induced pluripotent stem cells (iPS cells) and adult stem cells (ASCs) by whole genome sequencing analyses. Individual iPS cells, intestinal ASCs and liver ASCs accumulated 3.5±0.5, 7.2±1.0 and 8.4±3.6 base substitutions per population doubling, respectively. The annual in vitro mutation accumulation rate of ASCs adds up to ∼1600 base pair substitutions, which is ∼40-fold higher than the in vivo rate of ∼40 base pair substitutions per year. Mutational analysis revealed a distinct in vitro induced mutational signature that is irrespective of stem cell type and distinct from the in vivo mutational signature. This in vitro signature is characterized by C to A changes that have previously been linked to oxidative stress conditions. Additionally, we observed stem cell-specific mutational signatures and differences in transcriptional strand bias, indicating differential activity of DNA repair mechanisms between stem cell types in culture. We demonstrate that the empirically defined mutation rates, spectra, and genomic distribution enable risk assessment by modelling the accumulation of specific oncogenic mutations during typical in vitro expansion, manipulation or screening experiments using human stem cells. Taken together, we have here for the first time accurately quantified and characterized in vitro mutation accumulation in human iPS cells and ASCs in a direct comparison. These results provide insights for further optimization of culture conditions for safe in vivo utilization of these cell types for regenerative purposes

Whole Genome Profiling provides a robust framework for physical mapping and sequencing in the highly complex and repetitive wheat genome

<p>Abstract</p> <p>Background</p> <p>Sequencing projects using a clone-by-clone approach require the availability of a robust physical map. The SNaPshot technology, based on pair-wise comparisons of restriction fragments sizes, has been used recently to build the first physical map of a wheat chromosome and to complete the maize physical map. However, restriction fragments sizes shared randomly between two non-overlapping BACs often lead to chimerical contigs and mis-assembled BACs in such large and repetitive genomes. Whole Genome Profiling (WGP™) was developed recently as a new sequence-based physical mapping technology and has the potential to limit this problem.</p> <p>Results</p> <p>A subset of the wheat 3B chromosome BAC library covering 230 Mb was used to establish a WGP physical map and to compare it to a map obtained with the SNaPshot technology. We first adapted the WGP-based assembly methodology to cope with the complexity of the wheat genome. Then, the results showed that the WGP map covers the same length than the SNaPshot map but with 30% less contigs and, more importantly with 3.5 times less mis-assembled BACs. Finally, we evaluated the benefit of integrating WGP tags in different sequence assemblies obtained after Roche/454 sequencing of BAC pools. We showed that while WGP tag integration improves assemblies performed with unpaired reads and with paired-end reads at low coverage, it does not significantly improve sequence assemblies performed at high coverage (25x) with paired-end reads.</p> <p>Conclusions</p> <p>Our results demonstrate that, with a suitable assembly methodology, WGP builds more robust physical maps than the SNaPshot technology in wheat and that WGP can be adapted to any genome. Moreover, WGP tag integration in sequence assemblies improves low quality assembly. However, to achieve a high quality draft sequence assembly, a sequencing depth of 25x paired-end reads is required, at which point WGP tag integration does not provide additional scaffolding value. Finally, we suggest that WGP tags can support the efficient sequencing of BAC pools by enabling reliable assignment of sequence scaffolds to their BAC of origin, a feature that is of great interest when using BAC pooling strategies to reduce the cost of sequencing large genomes.</p