MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

AbstractThe emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.</jats:p

Scaling properties of cavity-enhanced atom cooling

We extend an earlier semiclassical model to describe the dissipative motion of N atoms coupled to M modes inside a coherently driven high-finesse cavity. The description includes momentum diffusion via spontaneous emission and cavity decay. Simple analytical formulas for the steady-state temperature and the cooling time for a single atom are derived and show surprisingly good agreement with direct stochastic simulations of the semiclassical equations for N atoms with properly scaled parameters. A thorough comparison with standard free-space Doppler cooling is performed and yields a lower temperature and a cooling time enhancement by a factor of M times the square of the ratio of the atom-field coupling constant to the cavity decay rate. Finally it is shown that laser cooling with negligible spontaneous emission should indeed be possible, especially for relatively light particles in a strongly coupled field configuration.Comment: 7 pages, 5 figure

On-Line Monitoring of Environment-Assisted Cracking in Nuclear Piping Using Array Probe Direct Current Potential Drop

A direct current potential drop method utilizing array probes with measurement ends maintaining an equalized potential designated as equi-potential switching array probe direct current potential drop (ESAP-DCPD) technique has been developed earlier at Seoul National University. This paper validates ESAP-DCPD technique by showing consistency among experimental measurements, analytical solution and numerical predictions using finite element analysis (FEA) of electric field changes with crack growth in metals. In order to examine its viability as an on-line monitoring of environment assisted crack growth at the inner surface of piping welds, artificial inner surface cracks were introduced in a full-scale weldment mockup pipe and stainless steel metal mockup pipe. The weldment was joined by low alloy steel and stainless steel pipes. The pipes were monitored by using ESAP-DCPD in laboratory environments. Optimization of electrical wiring configuration has produced results with significantly reduced noise for adequately long period of time. Then optimized experimental results were compared with the FEA prediction results for the mockup to show a good agreement. Also a round-robin measurement has been made at three laboratories. It has been found that the developed ESAP-DCPD can detect circumferential cracks with a depth of 40 % of wall thickness in stainless steel with a good detectability for further growth behaviors. For axial cracks, however, the measurements showed poor detectability. Hence the developed ESAP-DCPD system can be used to monitor large circumferential cracks that existing non-destructive examination techniques often fail to detect until leakage takes place.Korea (South). Ministry of Trade, Industry and Energy. Korea Institute of Energy Technology Evaluation and Plannin

DNA Methylation as a Biomarker for Cardiovascular Disease Risk

Elevated serum homocysteine is associated with an increased risk of cardiovascular disease (CVD). This may reflect a reduced systemic remethylation capacity, which would be expected to cause decreased genomic DNA methylation in peripheral blood leukocytes (PBL).We examined the association between prevalence of CVD (myocardial infarction, stroke) and its predisposing conditions (hypertension, diabetes) and PBL global genomic DNA methylation as represented by ALU and Satellite 2 (AS) repetitive element DNA methylation in 286 participants of the Singapore Chinese Health Study, a population-based prospective investigation of 63,257 men and women aged 45-74 years recruited during 1993-1998. Men exhibited significantly higher global DNA methylation [geometric mean (95% confidence interval (CI)): 159 (143, 178)] than women [133 (121, 147)] (P = 0.01). Global DNA methylation was significantly elevated in men with a history of CVD or its predisposing conditions at baseline (P = 0.03) but not in women (P = 0.53). Fifty-two subjects (22 men, 30 women) who were negative for these CVD/predisposing conditions at baseline acquired one or more of these conditions by the time of their follow-up I interviews, which took place on average about 5.8 years post-enrollment. Global DNA methylation levels of the 22 incident cases in men were intermediate (AS, 177) relative to the 56 male subjects who remained free of CVD/predisposing conditions at follow-up (lowest AS, 132) and the 51 male subjects with a diagnosis of CVD or predisposing conditions reported at baseline (highest AS 184) (P for trend = 0.0008) No such association was observed in women (P = 0.91). Baseline body mass index was positively associated with AS in both men and women (P = 0.007).Our findings indicate that elevated, not decreased, PBL DNA methylation is positively associated with prevalence of CVD/predisposing conditions and obesity in Singapore Chinese

Vortex Fluctuations in High-Tc Films: Flux Noise Spectrum and Complex Impedance

The flux noise spectrum and complex impedance for a 500 {\AA} thick YBCO film are measured and compared with predictions for two dimensional vortex fluctuations. It is verified that the complex impedance and the flux noise spectra are proportional to each other, that the logarithm of the flux noise spectra for different temperatures has a common tangent with slope $\approx -1$, and that the amplitude of the noise decreases as $d^{-3}$, where $d$ is the height above the film at which the magnetic flux is measured. A crossover from normal to anomalous vortex diffusion is indicated by the measurements and is discussed in terms of a two-dimensional decoupling.Comment: 5 pages including 4 figures in two columns, to appear in Phys. Rev. Let

Corner Exponents in the Two-Dimensional Potts Model

The critical behavior at a corner in two-dimensional Ising and three-state Potts models is studied numerically on the square lattice using transfer operator techniques. The local critical exponents for the magnetization and the energy density for various opening angles are deduced from finite-size scaling results at the critical point for isotropic or anisotropic couplings. The scaling dimensions compare quite well with the values expected from conformal invariance, provided the opening angle is replaced by an effective one in anisotropic systems.Comment: 11 pages, 2 eps-figures, uses LaTex and eps

Bosonization of interacting fermions in arbitrary dimension beyond the Gaussian approximation

We use our recently developed functional bosonization approach to bosonize interacting fermions in arbitrary dimension $d$ beyond the Gaussian approximation. Even in $d=1$ the finite curvature of the energy dispersion at the Fermi surface gives rise to interactions between the bosons. In higher dimensions scattering processes describing momentum transfer between different patches on the Fermi surface (around-the-corner processes) are an additional source for corrections to the Gaussian approximation. We derive an explicit expression for the leading correction to the bosonized Hamiltonian and the irreducible self-energy of the bosonic propagator that takes the finite curvature as well as around-the-corner processes into account. In the special case that around-the-corner scattering is negligible, we show that the self-energy correction to the Gaussian propagator is negligible if the dimensionless quantities $( \frac{q_{c} }{ k_{F}} )^d F_{0} [ 1 + F_{0} ]^{-1} \frac{\mu}{\nu^{\alpha}} | \frac{ \partial \nu^{\alpha} }{ \partial \mu} |$ are small compared with unity for all patches $\alpha$. Here $q_{c}$ is the cutoff of the interaction in wave-vector space, $k_{F}$ is the Fermi wave-vector, $\mu$ is the chemical potential, $F_{0}$ is the usual dimensionless Landau interaction-parameter, and $\nu^{\alpha}$ is the {\it{local}} density of states associated with patch $\alpha$. We also show that the well known cancellation between vertex- and self-energy corrections in one-dimensional systems, which is responsible for the fact that the random-phase approximation for the density-density correlation function is exact in $d=1$, exists also in $d> 1$, provided (1) the interaction cutoff $q_{c}$ is small compared with $k_{F}$, and (2) the energy dispersion is locally linearized at the Fermi the Fermi surface. Finally, we suggest a new systematic method to calculate corrections to the RPA, which is based on the perturbative calculation of the irreducible bosonic self-energy arising from the non-Gaussian terms of the bosonized Hamiltonian.Comment: The abstract has been rewritten. No major changes in the text

Quasi-particle behavior of composite fermions in the half-filled Landau level

We calculate the effect of infrared fluctuations of the Chern-Simons gauge field on the single-particle Green's function of composite fermions in the half-filled Landau level via higher-dimensional bosonization on a curved Fermi surface. We find that composite fermions remain well-defined quasi-particles, with an effective mass given by the mean-field value, but with anomalously large damping and a spectral function that contains considerable weight away from the quasi-particle peak.Comment: reference added; accepted for publication in Phys. Rev. Let

Incremental Mutual Information: A New Method for Characterizing the Strength and Dynamics of Connections in Neuronal Circuits

Understanding the computations performed by neuronal circuits requires characterizing the strength and dynamics of the connections between individual neurons. This characterization is typically achieved by measuring the correlation in the activity of two neurons. We have developed a new measure for studying connectivity in neuronal circuits based on information theory, the incremental mutual information (IMI). By conditioning out the temporal dependencies in the responses of individual neurons before measuring the dependency between them, IMI improves on standard correlation-based measures in several important ways: 1) it has the potential to disambiguate statistical dependencies that reflect the connection between neurons from those caused by other sources (e. g. shared inputs or intrinsic cellular or network mechanisms) provided that the dependencies have appropriate timescales, 2) for the study of early sensory systems, it does not require responses to repeated trials of identical stimulation, and 3) it does not assume that the connection between neurons is linear. We describe the theory and implementation of IMI in detail and demonstrate its utility on experimental recordings from the primate visual system