4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection.

BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.Methodology/principal findingsBoth acute and chronic animal models infected with wild type or transgenic T. cruzi strains were evaluated. There was no evidence of toxicity in the 28-day dosing study of uninfected animals, as judged by the monitoring of multiple serum and histological parameters. In two acute models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased survival of mice, and prevented liver and heart injury. None of the compounds produced long term sterile cure. In the less severe acute model using the transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug withdrawal. In the chronic model, parasitemia fell to a background level and, as evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two immunosuppression cycles with cyclophosphamide were required to re-activate the parasites. Although no sterile cure was achieved, the suppression of parasitemia in acutely infected mice resulted in drastically reduced inflammation in the heart.Conclusions/significanceThe positive outcomes achieved in the absence of sterile cure suggest that the target product profile in anti-Chagasic drug discovery should be revised in favor of safe re-administration of the medication during the lifespan of a Chagas disease patient. A medication that reduces parasite burden may halt or slow progression of cardiomyopathy and therefore improve both life expectancy and quality of life

A characteristics framework for Semantic Information Systems Standards

Semantic Information Systems (IS) Standards play a critical role in the development of the networked economy. While their importance is undoubted by all stakeholders—such as businesses, policy makers, researchers, developers—the current state of research leaves a number of questions unaddressed. Terminological confusion exists around the notions of “business semantics”, “business-to-business interoperability”, and “interoperability standards” amongst others. And, moreover, a comprehensive understanding about the characteristics of Semantic IS Standards is missing. The paper addresses this gap in literature by developing a characteristics framework for Semantic IS Standards. Two case studies are used to check the applicability of the framework in a “real-life” context. The framework lays the foundation for future research in an important field of the IS discipline and supports practitioners in their efforts to analyze, compare, and evaluate Semantic IS Standard

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Inclusive search for same-sign dilepton signatures in pp collisions at root s=7 TeV with the ATLAS detector

An inclusive search is presented for new physics in events with two isolated leptons (e or mu) having the same electric charge. The data are selected from events collected from p p collisions at root s = 7 TeV by the ATLAS detector and correspond to an integrated luminosity of 34 pb(-1). The spectra in dilepton invariant mass, missing transverse momentum and jet multiplicity are presented and compared to Standard Model predictions. In this event sample, no evidence is found for contributions beyond those of the Standard Model. Limits are set on the cross-section in a fiducial region for new sources of same-sign high-mass dilepton events in the ee, e mu and mu mu channels. Four models predicting same-sign dilepton signals are constrained: two descriptions of Majorana neutrinos, a cascade topology similar to supersymmetry or universal extra dimensions, and fourth generation d-type quarks. Assuming a new physics scale of 1 TeV, Majorana neutrinos produced by an effective operator V with masses below 460 GeV are excluded at 95% confidence level. A lower limit of 290 GeV is set at 95% confidence level on the mass of fourth generation d-type quarks

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurement of inclusive two-particle angular correlations in pp collisions with the ATLAS detector at the LHC

We present a measurement of two-particle angular correlations in proton- proton collisions at s√=900 GeV and 7 TeV. The collision events were collected during 2009 and 2010 with the ATLAS detector at the Large Hadron Collider using a single-arm minimum bias trigger. Correlations are measured for charged particles produced in the kinematic range of transverse momentum p T  > 100 MeV and pseudorapidity |η| < 2.5. A complex structure in pseudorapidity and azimuth is observed at both collision energies. Results are compared to pythia 8 and herwig++ as well as to the AMBT2B, DW and Perugia 2011 tunes of pythia 6. The data are not satisfactorily described by any of these models