Electron Cloud Buildup Characterization Using Shielded Pickup Measurements and Custom Modeling Code at CESRTA

The Cornell Electron Storage Ring Test Accelerator experimental program includes investigations into electron cloud buildup, applying various mitigation techniques in custom vacuum chambers. Among these are two 1.1-m-long sections located symmetrically in the east and west arc regions. These chambers are equipped with pickup detectors shielded against the direct beam-induced signal. They detect cloud electrons migrating through an 18-mm-diameter pattern of small holes in the top of the chamber. A digitizing oscilloscope is used to record the signals, providing time-resolved information on cloud development. Carbon-coated, TiN-coated and uncoated aluminum chambers have been tested. Electron and positron beams of 2.1, 4.0 and 5.3 GeV with a variety of bunch populations and spacings in steps of 4 and 14 ns have been used. Here we report on results from the ECLOUD modeling code which highlight the sensitivity of these measurements to the physical phenomena determining cloud buildup such as the photoelectron production azimuthal and energy distributions, and the secondary yield parameters including the true secondary, re-diffused, and elastic yield values.Comment: Presented at ECLOUD'12: Joint INFN-CERN-EuCARD-AccNet Workshop on Electron-Cloud Effects, La Biodola, Isola d'Elba, Italy, 5-9 June 2012; CERN-2013-002, pp. 241-25

TE Wave Measurement and Modeling

In the TE wave method, microwaves are coupled into the beam-pipe and the effect of the electron cloud on these microwaves is measured. An electron cloud (EC) density can then be calculated from this measurement. There are two analysis methods currently in use. The first treats the microwaves as being transmitted from one point to another in the accelerator. The second more recent method, treats the beam-pipe as a resonant cavity. This paper will summarize the reasons for adopting the resonant TE wave analysis as well as give examples from CESRTA and DA{\Phi}NE of resonant beam-pipe. The results of bead-pull bench measurements will show some possible standing wave patterns, including a cutoff mode (evanescent) where the field decreases exponentially with distance from the drive point. We will outline other recent developments in the TE wave method including VORPAL simulations of microwave resonances, as well as the simulation of transmission in the presence of both an electron cloud and magnetic fields.Comment: Presented at ECLOUD'12: Joint INFN-CERN-EuCARD-AccNet Workshop on Electron-Cloud Effects, La Biodola, Isola d'Elba, Italy, 5-9 June 2012; CERN-2013-002, pp. 193-20

Constraints on Acoustic Signaling Among Birds Breeding in Secondary Cavities: The Effects of Weather, Cavity Material, and Noise on Sound Propagation

Increasing evidence suggests that anthropogenic noise from urbanization affects animal acoustic communication. We investigated whether the begging calls of nestling Eastern Bluebirds (Sialia sialis) varied along a disturbance gradient of ambient noise. Contrary to our prediction and the results of a previous study of nestling Tree Swallows (Tachycineta bicolor), we found that nestling Eastern Bluebirds did not increase the amplitude or structural characteristics—including frequency, rate, and duration—of their vocalizations in response to ambient noise. However, we found that prevalent temperature and humidity conditions attenuated begging calls. Specifically, in warmer, more humid weather, vocalizations of nestling Eastern Bluebirds attenuated outside the nest box; this is consistent with research conducted on the propagation of sound in various mediums and temperatures. Finally, our results indicate that increased ambient noise is associated with a decrease in the signal-to-noise ratio of nestling vocalizations. In other words, loud ambient noise likely masks chick begging calls, which suggests that chicks and parents may experience communication difficulties in noisy environments. We suggest that future studies explore the effects of ambient noise on parental behavior and aspects of parent—offspring communication and conflict that are related to raising a brood of nestlings

Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis

Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo. Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66. Results: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm. Conclusion: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.This research was funded by Akcea Therapeutics and Ionis Pharmaceuticals, Incinfo:eu-repo/semantics/publishedVersio

Exploiting antitumor immunity to overcome relapse and improve remission duration

Cancer survivors often relapse due to evolving drug-resistant clones and repopulating tumor stem cells. Our preclinical study demonstrated that terminal cancer patient’s lymphocytes can be converted from tolerant bystanders in vivo into effective cytotoxic T-lymphocytes in vitro killing patient’s own tumor cells containing drug-resistant clones and tumor stem cells. We designed a clinical trial combining peginterferon α-2b with imatinib for treatment of stage III/IV gastrointestinal stromal tumor (GIST) with the rational that peginterferon α-2b serves as danger signals to promote antitumor immunity while imatinib’s effective tumor killing undermines tumor-induced tolerance and supply tumor-specific antigens in vivo without leukopenia, thus allowing for proper dendritic cell and cytotoxic T-lymphocyte differentiation toward Th1 response. Interim analysis of eight patients demonstrated significant induction of IFN-γ-producing-CD8+, -CD4+, -NK cell, and IFN-γ-producing-tumor-infiltrating-lymphocytes, signifying significant Th1 response and NK cell activation. After a median follow-up of 3.6 years, complete response (CR) + partial response (PR) = 100%, overall survival = 100%, one patient died of unrelated illness while in remission, six of seven evaluable patients are either in continuing PR/CR (5 patients) or have progression-free survival (PFS, 1 patient) exceeding the upper limit of the 95% confidence level of the genotype-specific-PFS of the phase III imatinib-monotherapy (CALGB150105/SWOGS0033), demonstrating highly promising clinical outcomes. The current trial is closed in preparation for a larger future trial. We conclude that combination of targeted therapy and immunotherapy is safe and induced significant Th1 response and NK cell activation and demonstrated highly promising clinical efficacy in GIST, thus warranting development in other tumor types

Why High-Performance Modelling and Simulation for Big Data Applications Matters

Modelling and Simulation (M&S) offer adequate abstractions to manage the complexity of analysing big data in scientific and engineering domains. Unfortunately, big data problems are often not easily amenable to efficient and effective use of High Performance Computing (HPC) facilities and technologies. Furthermore, M&S communities typically lack the detailed expertise required to exploit the full potential of HPC solutions while HPC specialists may not be fully aware of specific modelling and simulation requirements and applications. The COST Action IC1406 High-Performance Modelling and Simulation for Big Data Applications has created a strategic framework to foster interaction between M&S experts from various application domains on the one hand and HPC experts on the other hand to develop effective solutions for big data applications. One of the tangible outcomes of the COST Action is a collection of case studies from various computing domains. Each case study brought together both HPC and M&S experts, giving witness of the effective cross-pollination facilitated by the COST Action. In this introductory article we argue why joining forces between M&S and HPC communities is both timely in the big data era and crucial for success in many application domains. Moreover, we provide an overview on the state of the art in the various research areas concerned

One origin for metallo-β-lactamase activity, or two? An investigation assessing a diverse set of reconstructed ancestral sequences based on a sample of phylogenetic trees

This work was supported by BBSRC (grant BB/F016778/1)Bacteria use metallo-β-lactamase enzymes to hydrolyse lactam rings found in many antibiotics, rendering them ineffective. Metallo-β-lactamase activity is thought to be polyphyletic, having arisen on more than one occasion within a single functionally diverse homologous superfamily. Since discovery of multiple origins of enzymatic activity conferring antibiotic resistance has broad implications for the continued clinical use of antibiotics, we test the hypothesis of polyphyly further; if lactamase function has arisen twice independently, the most recent common ancestor (MRCA) is not expected to possess lactam-hydrolysing activity. Two major problems present themselves. Firstly, even with a perfectly known phylogeny, ancestral sequence reconstruction is error prone. Secondly, the phylogeny is not known, and in fact reconstructing a single, unambiguous phylogeny for the superfamily has proven impossible. To obtain a more statistical view of the strength of evidence for or against MRCA lactamase function, we reconstructed a sample of 98 MRCAs of the metallo-β-lactamases, each based on a different tree in a bootstrap sample of reconstructed phylogenies. InterPro sequence signatures and homology modelling were then used to assess our sample of MRCAs for lactamase functionality. Only 5 % of these models conform to our criteria for metallo-β-lactamase functionality, suggesting that the ancestor was unlikely to have been a metallo-β-lactamase. On the other hand, given that ancestral proteins may have had metallo-β-lactamase functionality with variation in sequence and structural properties compared with extant enzymes, our criteria are conservative, estimating a lower bound of evidence for metallo-β-lactamase functionality but not an upper bound.Publisher PDFPeer reviewe

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio