The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony

A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for ≥6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria

Accuracy of diagnosing atrial fibrillation on electrocardiogram by primary care practitioners and interpretative diagnostic software: analysis of data from screening for atrial fibrillation in the elderly (SAFE) trial

Objective To assess the accuracy of general practitioners, practice nurses, and interpretative software in the use of different types of electrocardiogram to diagnose atrial fibrillation. Design Prospective comparison with reference standard of assessment of electrocardiograms by two independent specialists. Setting 49 general practices in central England. Participants 2595 patients aged 65 or over screened for atrial fibrillation as part of the screening for atrial fibrillation in the elderly (SAFE) study; 49 general practitioners and 49 practice nurses. Interventions All electrocardiograms were read with the Biolog interpretative software, and a random sample of 12 lead, limb lead, and single lead thoracic placement electrocardiograms were assessed by general practitioners and practice nurses independently of each other and of the Biolog assessment. Main outcome measures Sensitivity, specificity, and positive and negative predictive values. Results General practitioners detected 79 out of 99 cases of atrial fibrillation on a 12 lead electrocardiogram (sensitivity 80%, 95% confidence interval 71% to 87%) and misinterpreted 114 out of 1355 cases of sinus rhythm as atrial fibrillation (specificity 92%, 90% to 93%). Practice nurses detected a similar proportion of cases of atrial fibrillation (sensitivity 77%, 67% to 85%), but had a lower specificity (85%, 83% to 87%). The interpretative software was significantly more accurate, with a specificity of 99%, but missed 36 of 215 cases of atrial fibrillation (sensitivity 83%). Combining general practitioners' interpretation with the interpretative software led to a sensitivity of 92% and a specificity of 91%. Use of limb lead or single lead thoracic placement electrocardiograms resulted in some loss of specificity. Conclusions Many primary care professionals cannot accurately detect atrial fibrillation on an electrocardiogram, and interpretative software is not sufficiently accurate to circumvent this problem, even when combined with interpretation by a general practitioner. Diagnosis of atrial fibrillation in the community needs to factor in the reading of electrocardiograms by appropriately trained peopl

Automated Estimating System (AES): Version 6.1: User`s manual. Revision 6

This document describes Version 6.1 of the Automated Estimating System (AES), a personal computer-based software package. The AES is designed to aid in the creation, updating, and reporting of project cost estimates for the Estimating and Scheduling Engineering Department of Central Engineering Services of Lockheed Martin Energy Systems,Inc. AES provides formatted input screens to guide the user through the estimate creation/update process and provides several standardized reports that allow cost to be sorted and summarized in many different formats and at several levels of aggregation

Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: Screening versus routine practice in detection cluster randomised controlled trial

Objectives : To assess whether screening improves the detection of atrial fibrillation (cluster randomisation) and to compare systematic and opportunistic screening. Design : Multicentred cluster randomised controlled trial, with subsidiary trial embedded within the intervention arm. Setting : 50 primary care centres in England, with further individual randomisation of patients in the intervention practices. Participants : 14,802 patients aged 65 or over in 25 intervention and 25 control practices. Interventions : Patients in intervention practices were randomly allocated to systematic screening (invitation for electrocardiography) or opportunistic screening (pulse taking and invitation for electrocardiography if the pulse was irregular). Screening took place over 12 months in each practice from October 2001 to February 2003. No active screening took place in control practices. Main outcome measure : Newly identified atrial fibrillation. Results : The detection rate of new cases of atrial fibrillation was 1.63% a year in the intervention practices and 1.04% in control practices (difference 0.59%, 95% confidence interval 0.20% to 0.98%). Systematic and opportunistic screening detected similar numbers of new cases (1.62% v 1.64%, difference 0.02%, −0.5% to 0.5%). Conclusion : Active screening for atrial fibrillation detects additional cases over current practice. The preferred method of screening in patients aged 65 or over in primary care is opportunistic pulse taking with follow-up electrocardiography. Trial registration Current Controlled Trials ISRCTN19633732

OSETI with STACEE: A Search for Nanosecond Optical Transients from Nearby Stars

We have used the STACEE high-energy gamma-ray detector to look for fast blue-green laser pulses from the vicinity of 187 stars. The STACEE detector offers unprecedented light-collecting capability for the detection of nanosecond pulses from such lasers. We estimate STACEE's sensitivity to be approximately 10 photons per square meter at a wavelength of 420 nm. The stars have been chosen because their characteristics are such that they may harbor habitable planets and they are relatively close to Earth. Each star was observed for 10 minutes and we found no evidence for laser pulses in any of the data sets.Comment: 38 pages, 12 figures. Accepted for publication in Astrobiolog

Very high energy observations of the BL Lac objects 3C 66A and OJ 287

Using the Solar Tower Atmospheric Cherenkov Effect Experiment (STACEE), we have observed the BL Lac objects 3C 66A and OJ 287. These are members of the class of low-frequency-peaked BL Lac objects (LBLs) and are two of the three LBLs predicted by Costamante and Ghisellini to be potential sources of very high energy (>100 GeV) gamma-ray emission. The third candidate, BL Lacertae, has recently been detected by the MAGIC collaboration. Our observations have not produced detections; we calculate a 99% CL upper limit of flux from 3C 66A of 0.15 Crab flux units and from OJ 287 our limit is 0.52 Crab. These limits assume a Crab-like energy spectrum with an effective energy threshold of 185 GeV.Comment: 24 pages, 15 figures, Accepted for publication in Astroparticle Physic

The First VERITAS Telescope

The first atmospheric Cherenkov telescope of VERITAS (the Very Energetic Radiation Imaging Telescope Array System) has been in operation since February 2005. We present here a technical description of the instrument and a summary of its performance. The calibration methods are described, along with the results of Monte Carlo simulations of the telescope and comparisons between real and simulated data. The analysis of TeV $\gamma$-ray observations of the Crab Nebula, including the reconstructed energy spectrum, is shown to give results consistent with earlier measurements. The telescope is operating as expected and has met or exceeded all design specifications.Comment: Accepted by Astroparticle Physic

Gamma-Hadron Separation Methods for the VERITAS Array of Four Imaging Atmospheric Cherenkov Telescopes

Ground-based arrays of imaging atmospheric Cherenkov telescopes have emerged as the most sensitive gamma-ray detectors in the energy range of about 100 GeV and above. The strengths of these arrays are a very large effective collection area on the order of 100,000 square meter, combined with excellent single photon angular and energy resolutions. The sensitivity of such detectors is limited by statistical fluctuations in the number of Cosmic Ray initiated air showers that resemble gamma-ray air showers in many ways. In this paper, we study the performance of simple event reconstruction methods when applied to simulated data of the Very Energetic Radiation Imaging Telescope Array System (VERITAS) experiment. We review methods for reconstructing the arrival direction and the energy of the primary photons, and examine means to improve on their performance. For a software threshold energy of 300 GeV (100 GeV), the methods achieve point source angular and energy resolutions of sigma[63%]= 0.1 degree (0.2 degree) and sigma[68%]= 15% (22%), respectively. The main emphasis of the paper is the discussion of gamma-hadron separation methods for the VERITAS experiment. We find that the information from several methods can be combined based on a likelihood ratio approach and the resulting algorithm achieves a gamma-hadron suppression with a quality factor that is substantially higher than that achieved with the standard methods used so far.Comment: Astroparticle Physics, in press, 22 pages, 10 figure

Gamma-ray Observations Under Bright Moonlight with VERITAS

Imaging atmospheric Cherenkov telescopes (IACTs) are equipped with sensitive photomultiplier tube (PMT) cameras. Exposure to high levels of background illumination degrades the efficiency of and potentially destroys these photo-detectors over time, so IACTs cannot be operated in the same configuration in the presence of bright moonlight as under dark skies. Since September 2012, observations have been carried out with the VERITAS IACTs under bright moonlight (defined as about three times the night-sky-background (NSB) of a dark extragalactic field, typically occurring when Moon illumination > 35%) in two observing modes, firstly by reducing the voltage applied to the PMTs and, secondly, with the addition of ultra-violet (UV) bandpass filters to the cameras. This has allowed observations at up to about 30 times previous NSB levels (around 80% Moon illumination), resulting in 30% more observing time between the two modes over the course of a year. These additional observations have already allowed for the detection of a flare from the 1ES 1727+502 and for an observing program targeting a measurement of the cosmic-ray positron fraction. We provide details of these new observing modes and their performance relative to the standard VERITAS observations

Flux Phase as a Dynamic Jahn-Teller Phase: Berryonic Matter in the Cuprates?

There is considerable evidence for some form of charge ordering on the hole-doped stripes in the cuprates, mainly associated with the low-temperature tetragonal phase, but with some evidence for either charge density waves or a flux phase, which is a form of dynamic charge-density wave. These three states form a pseudospin triplet, demonstrating a close connection with the E X e dynamic Jahn-Teller effect, suggesting that the cuprates constitute a form of Berryonic matter. This in turn suggests a new model for the dynamic Jahn-Teller effect as a form of flux phase. A simple model of the Cu-O bond stretching phonons allows an estimate of electron-phonon coupling for these modes, explaining why the half breathing mode softens so much more than the full oxygen breathing mode. The anomalous properties of $O^{2-}$ provide a coupling (correlated hopping) which acts to stabilize density wave phases.Comment: Major Revisions: includes comparisons with specific cuprate phonon modes, 16 eps figures, revte