63 research outputs found

    Experimental validation of a novel compact focusing scheme for future energy-frontier linear lepton colliders.

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    A novel scheme for the focusing of high-energy leptons in future linear colliders was proposed in 2001 [P. Raimondi and A. Seryi, Phys. Rev. Lett. 86, 3779 (2001)]. This scheme has many advantageous properties over previously studied focusing schemes, including being significantly shorter for a given energy and having a significantly better energy bandwidth. Experimental results from the ATF2 accelerator at KEK are presented that validate the operating principle of such a scheme by demonstrating the demagnification of a 1.3 GeVelectron beam down to below 65 nm in height using an energy-scaled version of the compact focusing optics designed for the ILC collider

    Complex folding and misfolding effects of deer-specific amino acid substitutions in the β2-α2 loop of murine prion protein

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    The β2–α2 loop of PrPC is a key modulator of disease-associated prion protein misfolding. Amino acids that differentiate mouse (Ser169, Asn173) and deer (Asn169, Thr173) PrPC appear to confer dramatically different structural properties in this region and it has been suggested that amino acid sequences associated with structural rigidity of the loop also confer susceptibility to prion disease. Using mouse recombinant PrP, we show that mutating residue 173 from Asn to Thr alters protein stability and misfolding only subtly, whilst changing Ser to Asn at codon 169 causes instability in the protein, promotes oligomer formation and dramatically potentiates fibril formation. The doubly mutated protein exhibits more complex folding and misfolding behaviour than either single mutant, suggestive of differential effects of the β2–α2 loop sequence on both protein stability and on specific misfolding pathways. Molecular dynamics simulation of protein structure suggests a key role for the solvent accessibility of Tyr168 in promoting molecular interactions that may lead to prion protein misfolding. Thus, we conclude that ‘rigidity’ in the β2–α2 loop region of the normal conformer of PrP has less effect on misfolding than other sequence-related effects in this region

    Safety and Immunogenicity of an HIV-1 Gag DNA Vaccine with or without IL-12 and/or IL-15 Plasmid Cytokine Adjuvant in Healthy, HIV-1 Uninfected Adults

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    DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques.We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response.This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.Clinicaltrials.gov NCT00115960 NCT00111605

    High prevalence of lack of knowledge of symptoms of acute myocardial infarction inPakistan and its contribution to delayed presentationto the hospital

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    <p>Abstract</p> <p>Background</p> <p>We conducted an observational study to determine the delay in presentation to hospital, and its associates among patients experiencing first Acute Myocardial Infarction (AMI) in Karachi, Pakistan.</p> <p>Methods</p> <p>A hospital based cross-sectional study was conducted at National Institute of Cardiovascular Disease (NICVD) in Karachi. A structured questionnaire was used to collect data. The primary outcome was delay in presentation, defined as a time interval of six or more hours from the onset of symptoms to presentation to hospital. Logistic regression analysis was performed to determine the factors associated with prehospital delay.</p> <p>Results</p> <p>A total of 720 subjects were interviewed; 22% were females. The mean age (SD) of the subjects was 54 (± 12) years. The mean (SE) and median (IQR) time to presentation was 12.3 (1.7) hours and 3.04 (6.0) hours respectively. About 34% of the subjects presented late. Lack of knowledge of any of the symptoms of heart attack (odds ratio (95% CI)) (1.82 (1.10, 2.99)), and mild chest pain (10.05 (6.50, 15.54)) were independently associated with prehospital delay.</p> <p>Conclusion</p> <p>Over one-third of patients with AMI in Pakistan present late to the hospital. Lack of knowledge of symptoms of heart attack, and low severity of chest pain were the main predictors of prehospital delay. Strategies to reduce delayed presentation in this population must focus on education about symptoms of heart attack.</p

    The disruption of proteostasis in neurodegenerative diseases

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    Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

    A sub-micron resolution, bunch-by-bunch beam trajectory feedback system and its application to reducing wakefield effects in single-pass beamlines

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    A high-precision intra-bunch-train beam orbit feedback correction system has been developed and tested at the KEK Accelerator Test Facility, ATF2. The system uses the vertical position of the bunch measured at two beam position monitors to calculate a pair of kicks which are applied to the next bunch using two upstream kickers, thereby correcting both the vertical position and trajectory angle. Using trains of two electron bunches separated in time by 187.6ns, the system was optimised so as to stabilize the beam offset at the feedback BPMs to better than 350nm, yielding a local trajectory angle correction to within 250nrad. The quality of the correction was verified using three downstream witness BPMs and the results were found to be in agreement with the predictions of a linear lattice model used to propagate the beam trajectory from the feedback region. This same model predicts a corrected be am jitter of c.1nm at the focal point of the accelerator. Measurements with a beam size monitor at this location demonstrate that reducing the trajectory jitter of the beam by a factor of 4 also reduces the increase in the measured beam size as a function of beam charge by a factor of ~1.6

    High-resolution, low-latency, bunch-by-bunch feedback systems for nanobeam production and stabilization

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    High-precision intra-bunch-train beam orbit feedback correction systems have been developed and tested in the ATF2 beamline of the Accelerator Test Facility at the High Energy Accelerator Research Organization in Japan. Two systems are presented: 1) The vertical position of the bunch measured at two beam stripline position monitors (BPMs) is used to calculate a pair of kicks which are applied to the next bunch using two upstream kickers, thereby correcting both the vertical position and trajectory angle. This system was optimized so as to stabilize the beam offset at the feedback BPMs to better than 350 nm, yielding a local trajectory angle correction to within 250 nrad. Measurements with a beam size monitor at the focal point (IP) demonstrate that reducing the trajectory jitter of the beam by a factor of 4 also reduces the observed wakefield-induced increase in the measured beam size as a function of beam charge by a factor of c. 1.6. 2) High-resolution cavity BPMs were used to provide local beam stabilization in the IP region. The BPMs were demonstrated to achieve an operational resolution of ~20 nm. With the application of single-BPM and two-BPM feedback, beam stabilization of below 50 nm and 41 nm respectively has been achieved with a closed-loop latency of 232 ns
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