Evaluating 5-nitrofurans as trypanocidal agents

The nitroheterocycle nifurtimox, as part of a nifurtimox-eflornithine combination therapy, represents one of a limited number of treatments targeting Trypanosoma brucei, the causative agent of human African trypanosomiasis. The mode of action of this prodrug involves an initial activation reaction catalysed by a type I nitroreductase (NTR), an enzyme found predominantly in prokaryotes, leading to the formation of a cytotoxic unsaturated open chain nitrile metabolite. Here, we evaluate the trypanocidal activity of a library of other 5-nitrofurans against bloodstream form T. brucei as a preliminary step in the identification of additional nitroaromatic compounds that could potentially partner eflornithine. Biochemical screening against purified enzyme revealed that all 5-nitrofurans were effective substrates for TbNTR with the preferred compounds having apparent kcat/KM values approximately 50-fold greater than nifurtimox. For several compounds, in vitro reduction by this nitroreductase yielded products characterized by mass spectroscopy as either unsaturated or saturated open chain nitriles. When tested against bloodstream form T. brucei, many of the derivatives displayed significant growth inhibitory properties with the most potent compounds generating IC50 values around 200 nM. The anti-parasitic activity of the most potent agents was demonstrated to be NTR dependent as parasites having reduced levels of the enzyme displayed resistance to the compounds while parasites over expressing TbNTR showed hypersensitivity. We conclude that other members of the 5-nitrofurans class of nitroheterocycles have potential to treat human African trypanosomiasis perhaps as an alternative partner prodrug to nifurtimox in the next generation of eflornithine-based combinational therapies

Fractal Spectrum of a Quasi_periodically Driven Spin System

We numerically perform a spectral analysis of a quasi-periodically driven spin 1/2 system, the spectrum of which is Singular Continuous. We compute fractal dimensions of spectral measures and discuss their connections with the time behaviour of various dynamical quantities, such as the moments of the distribution of the wave packet. Our data suggest a close similarity between the information dimension of the spectrum and the exponent ruling the algebraic growth of the 'entropic width' of wavepackets.Comment: 17 pages, RevTex, 5 figs. available on request from [email protected]

Environmental Regulation Can Arise Under Minimal Assumptions

Models that demonstrate environmental regulation as a consequence of organism and environment coupling all require a number of core assumptions. Many previous models, such as Daisyworld, require that certain environment-altering traits have a selective advantage when those traits also contribute towards global regulation. We present a model that results in the regulation of a global environmental resource through niche construction without employing this and other common assumptions. There is no predetermined environmental optimum towards which regulation should proceed assumed or coded into the model. Nevertheless, polymorphic stable states that resist perturbation emerge from the simulated co-evolution of organisms and environment. In any single simulation a series of different stable states are realised, punctuated by rapid transitions. Regulation is achieved through two main subpopulations that are adapted to slightly different resource values, which force the environmental resource in opposing directions. This maintains the resource within a comparatively narrow band over a wide range of external perturbations. Population driven oscillations in the resource appear to be instrumental in protecting the regulation against mutations that would otherwise destroy it. Sensitivity analysis shows that the regulation is robust to mutation and to a wide range of parameter settings. Given the minimal assumptions employed, the results could reveal a mechanism capable of environmental regulation through the by-products of organisms

Study of high-pT charged particle suppression in PbPb compared to pp collisions at √sNN = 2.76 TeV

The transverse momentum spectra of charged particles have been measured in pp and PbPb collisions at √sNN=276 TeV by the CMS experiment at the LHC. In the transverse momentum range p_T = 5–10 GeV/c, the charged particle yield in the most central PbPb collisions is suppressed by up to a factor of 7 compared to the pp yield scaled by the number of incoherent nucleon–nucleon collisions. At higher p_T, this suppression is significantly reduced, approaching roughly a factor of 2 for particles with p_T in the range p_T=40–100 GeV/c

Search for the standard model Higgs boson decaying into two photons in pp collisions at √s = 7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a center-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 fb^(−1). Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1σ. The global significance of observing an excess with a local significance ⩾3.1σ anywhere in the search range 110–150 GeV is estimated to be 1.8σ. More data are required to ascertain the origin of this excess

Jet production rates in association with W and Z bosons in pp collisions at √s = 7 TeV

Measurements of jet production rates in association with W and Z bosons for jet transverse momenta above 30 GeV are reported, using a sample of proton-proton collision events recorded by CMS at √s = 7TeV, corresponding to an integrated luminosity of 36 pb^(-1). The study includes the measurement of the normalized inclusive rates of jets σ(V+ ≥n jets)/σ(V), where V represents either a W or a Z. In addition, the ratio of W to Z cross sections and the W charge asymmetry as a function of the number of associated jets are measured. A test of scaling at √s = 7TeV is also presented. The measurements provide a stringent test of perturbative-QCD calculations and are sensitive to the possible presence of new physics. The results are in agreement with the predictions of a simulation that uses explicit matrix element calculations for nal states with jets

Measurement of energy flow at large pseudorapidities in pp collisions at √s = 0.9 and 7 TeV

The energy flow, dE/dη, is studied at large pseudorapidities in proton-proton collisions at the LHC, for centre-of-mass energies of 0.9 and 7 TeV. The measurements are made using the CMS detector in the pseudorapidity range 3.15 < |η| < 4.9, for both minimum-bias events and events with at least two high-momentum jets. The data are compared to various pp Monte Carlo event generators whose theoretical models and input parameter values are sensitive to the energy-flow measurements. Inclusion of multiple-parton interactions in the Monte Carlo event generators is found to improve the description of the energy-flow measurements

Measurement of isolated photon production in pp and PbPb collisions at √snn = 2.76 TeV

Isolated photon production is measured in proton–proton and lead–lead collisions at nucleon–nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |η|<1.44 and transverse energies E_T between 20 and 80 GeV with the CMS detector at the LHC. The measured E_T spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon E_T-differential yields, scaled by the number of incoherent nucleon–nucleon collisions, is consistent with unity for all PbPb reaction centralities