On the molecular mechanism of drug intercalation into DNA: a simulation study of the intercalation pathway, free energy, and DNA structural changes

Intercalation into DNA (insertion between a pair of base pairs) is a critical step in the function of many anticancer drugs. Despite its importance, a detailed mechanistic understanding of this process at the molecular level is lacking. We have constructed, using extensive atomistic computer simulations and umbrella sampling techniques, a free energy landscape for the intercalation of the anticancer drug daunomycin into a twelve base pair B-DNA. A similar free energy landscape has been constructed for a probable intermediate DNA minor groove-bound state. These allow a molecular level understanding of aspects of the thermodynamics, DNA structural changes, and kinetic pathways of the intercalation process. Key DNA structural changes involve opening the future intercalation site base pairs toward the minor groove (positive roll), followed by an increase in the rise, accompanied by hydrogen bonding changes of the minor groove waters. The calculated intercalation free energy change is -12.3 kcal/mol, in reasonable agreement with the experimental estimate -9.4 kcal/mol. The results point to a mechanism in which the drug first binds to the minor groove and then intercalates into the DNA in an activated process, which is found to be in general agreement with experimental kinetic results.     

A stereocontrolled total synthesis of methyl (±)-O-methylpodocarpate

A stereocontrolled total synthesis of methyl (±)-O-methyl podocarpate (4) has been successfully accomplished using the trans-fused diester 21 as a key intermediate. Intramolecular Michael reaction of the enone-diester 18 afforded the cis-fused keto-diester 19 in high yield which was stereoselectively converted into 21 via the enone 20.     

First on-line test of the LINAC superbuncher at nuclear science centre

An on-line test of the LINAC superbuncher at Nuclear Science Centre has been successfully performed. DC O⁷⁺ beam of nominal energy 92 MeV was accelerated through the superbuncher resonator, operating at a field of 4.54 MV/m. The total energy gain of the beam was measured to be 4.5 MeV. For the pulsed beam test a phase locked bunched beam of O⁷⁺ of nominal energy 92 MeV, FWHM 1.3 ns from the pre-tandem multiharmonic buncher was injected into the superbuncher. By properly adjusting the phase and amplitude of the resonator, the best FWHM of the bunched beam was measured to be 185 ps near the entrance of the first LINAC module. Fully depleted cooled surface barrier detector was used for measuring the time width. In a separate experiment the intrinsic time resolution of the same detector was measured to be 134 ps. Consequently the intrinsic time width of the bunched beam, after correcting for the detector resolution, would be 127 ps. Details of the experiment and results are presented.     

Apparent diffusion coefficient (ADC) measurements may be more reliable and reproducible than lesion volume on diffusion-weighted images from patients with acute ischaemic stroke-implications for study design

Early ischemic change after stroke can be demonstrated with diffusion-weighted imaging (DWI) and quantified by measuring the apparent diffusion coefficient (ADC) and/or lesion volume. We examined the reliability and reproducibility of lesion volume and ADC measurement on DWI images, and discuss the implications for clinical studies. Using 38 DWI scans from 15 stroke patients, two observers (a physicist and a neuroscience graduate) blind to each other, recorded the lesion volume on DWI sequences, measured the ADC values in this volume and calculated the ratio of ischemic: control ADC (ADCr). One observer repeated his measurements blind to his first, and also examined the effect on lesion volume and ADC of deliberately varying by only one pixel, the outline of the visible boundary of the lesion. The inter and intra-rater reliability were worse for lesion volume than ADC or ADCr measurements: lesion volume, inter-rater coefficient of variation (CoV) 85 +/- 130%, intra-rater CoV 20+/-SD80% (p < 0.05); ADC inter-rater CoV 7.7 +/- SD 19%, intra-rater CoV 0.2 +/- SD 12% (p = NS); and ADCr inter-rater CoV 8 +/- SD27%, intra-rater CoV 0.8 +/- SD73% (p = NS). Altering the position of the outline tracing of the lesion boundary by one pixel altered the measured volumes by 22 +/- SD25% (p < 0.05), but ADC values were altered by only 2.9 +/- SD4.9% and ADCr by 2.7 +/- SD4.8% (p = NS). ADC and ADCr values are more reliable and reproducible than DWI lesion size in acute ischemic stroke because altering where the lesion boundary is measured has a much greater impact on lesion volume than on the ADC or ADCr. This effect is greatest in large lesions.     

Standing and travelling waves in the shallow-water circular hydraulic jump

A wave equation for a time-dependent perturbation about the steady shallow-water solution emulates the metric an acoustic white hole, even upon the incorporation of nonlinearity in the lowest order. A standing wave in the sub-critical region of the flow is stabilised by viscosity, and the resulting time scale for the amplitude decay helps in providing a scaling argument for the formation of the hydraulic jump. A standing wave in the super-critical region, on the other hand, displays an unstable character, which, although somewhat mitigated by viscosity, needs nonlinear effects to be saturated. A travelling wave moving upstream from the sub-critical region, destabilises the flow in the vicinity of the jump, for which experimental support has been given.     

A new route to Explosive Percolation

The biased link occupation rule in the Achlioptas process (AP) discourages the large clusters from growing much ahead of others and encourages faster growth of clusters which lag behind. In this paper we propose a model where this tendency is sharply reflected in the Gamma distribution of the cluster sizes, unlike the power law distribution in AP. In this model single edges between pairs of clusters of sizes s_i and s_j are occupied with a probability ∝(s_is_j)^α. The parameter α is continuously tunable over the entire real axis. Numerical studies indicate that for α<α_c the transition is first order, α_c=0 for a square lattice and α_c=−1/2 for random graphs. In the limits of α=−∞,+∞ this model coincides with models well established in the literature.     

Predicting solar cycle 24 with a solar dynamo model

Whether or not the upcoming cycle 24 of solar activity will be strong is being hotly debated. The solar cycle is produced by a complex dynamo mechanism. We model the last few solar cycles by "feeding" observational data of the Sun's polar magnetic field into our solar dynamo model. Our results fit the observed sunspot numbers of cycles 21-23 reasonably well and predict that cycle 24 will be about 35% weaker than cycle 23.     

A Dichotomy for the Gelfand–Kirillov Dimensions of Simple Modules over Simple Differential Rings

The Gelfand–Kirillov dimension has gained importance since its introduction as a tool in the study of non-commutative infinite dimensional algebras and their modules. In this paper we show a dichotomy for the Gelfand–Kirillov dimension of simple modules over certain simple rings of differential operators. We thus answer a question of J. C. McConnell in Representations of solvable Lie algebras V. On the Gelfand-Kirillov dimension of simple modules. McConnell (J. Algebra 76(2), 489–493, 1982) concerning this dimension for a class of algebras that arise as simple homomorphic images of solvable lie algebras. We also determine the Gelfand–Kirillov dimension of an induced module.     

Non-intrinsic superconductivity in InN epilayers: Role of Indium Oxide

In recent years there have been reports of anomalous electrical resistivity and the presence of superconductivity in semiconducting InN layers. By a careful correlation of the temperature dependence of resistivity and magnetic susceptibility with structural information from high-resolution x-ray diffraction measurements, we show that superconductivity is not intrinsic to InN and is seen only in samples that show traces of oxygen impurity. We hence believe that InN is not intrinsically a superconducting semiconductor.