Prioritization of high throughput screening data of compound mixtures using molecular similarity

This work addresses the problem of enriching high throughput screening (HTS) data of mixtures of five compounds/well without any redundancies and where no structural information of the drug target is available. Devising a mathematical model for mixtures of compounds is extremely difficult. Instead, we employed extended-connectivity fingerprints (ECFPs), which are a new class of fingerprints for molecular characterization. We calculated the Tanimoto similarity between all the compounds which appeared in the active mixtures and ranked them in order of decreasing similarity. This methodology enriched the data in three recent in-house HTS campaigns that were conducted in five compounds/well mixtures. The top 10% most similar compounds captured between 29% and 41% of the active compounds. Although this methodology is not particularly sensitive, considering the quality of the data (ca. 80% noise presumed to be inactive) and the simplicity of the method, we find it useful. It offers a true opportunity to quickly prioritize and enrich primary screening data from mixtures of compounds and therefore reduce the time and the high costs of the secondary screening.     

Enhanced effect of magnetic field gradients using multiple quantum NMR spectroscopy applied to self-diffusion coefficient measurement

NMR spectroscopy can be used to measure molecular self-diffusion coefficients using a modified spin-echo pulse sequence known as the longitudinal eddy current delay (LED) method which incorporates pulsed magnetic field gradients. The effect of such gradients on multiple quantum coherences is investigated and shown to be of benefit for the measurement of diffusion coefficients using modest gradient strengths. The multiple quantum coherences involved in the spin operator 8I _x I _y I _y S _y of a weakly coupled SI₃ spin system (¹³CH₃ at natural abundance, in alanine in this case) were studied. The multiple quantum coherences included the quadruple-quantum (QQ) order of (3I + S), double-quantum (DQ) order of (3I - S) and (3I + S), and zero-quantum (ZQ) order of (I - S) with effective magnetogyric ratios of (3γ_H + γ_C), (3γ_H - γ_C), (γ_H + γ_C) and (γ_H - γ_C) respectively. The results show that the use of higher level quantum coherences for diffusion coefficient measurement can have the practical effect of significantly enhancing the gradient strength and this is important for slowly diffusing species.     

The sensitive detection of NO by Faraday modulation spectroscopy with a quantum cascade laser

A spectrometer based on a quantum cascade laser and capable of operating at particular wavelengths in the mid-infrared with very high sensitivity for the detection of open-shell molecules has been developed. It exploits magnetic field modulation in the Faraday rotation configuration. The signals for nitric oxide (NO) that may be observed with this instrument have been studied and their dependence on the J and Ω quantum numbers investigated with a simulation program. It is shown that the Q(3/2) transition of NO in the ²Π_3/2 component at 1875.8 cm^?1 would provide the greatest sensitivity for detection. The experimental observation of the R(21/2) transition of the Ω = 1/2 component gives a detection limit of 41 ppb of NO in air at a pressure of 25 mbar. Detection of NO through the Q(3/2) transition would provide a detection limit of 4 ppb at this pressure.     

Two avenues to self-interaction correction within Kohn—Sham theory: unitary invariance is the shortcut

The most widely used density functionals for the exchange-correlation energy are inexact for one-electron systems. Their self-interaction errors can be severe in some applications. The problem is not only to correct the self-interaction error, but to do so in a way that will not violate size-consistency and will not go outside the standard Kohn-Sham density functional theory. The solution via the optimized effective potential (OEP) method will be discussed, first for the Perdew-Zunger self-interaction correction (whose performance for molecules is briefly summarized) and then for the more modern self-interaction corrections based upon unitarily invariant indicators of iso-orbital regions. For the latter approaches, the OEP construction is greatly simplified. The kinetic-energy-based iso-orbital indicator T^W σ(r)/Tσ(r) will be discussed and plotted, along with an alternative exchange-based indicator.     

Experimental verification of the Stokes-Einstein relation in liquid Fe—FeS at 5 GPa

Experiments have been performed at 5 GPa on liquid Fe-FeS in order to determine Fe and S self-diffusivity as a function of temperature. The viscosity of the sample was then obtained using the Stokes-Einstein relation. The results are in excellent agreement with previous experiments where the viscosity of a material of the same composition under similar conditions was measured directly. These results support high, near-metallic, values of diffusivity and low viscosity in liquid Fe-S up to a few hundred K above the eutectic temperature, in contrast with some previous studies. Moreover, these results fully confirm the validity of the Stokes-Einstein relation between viscosity and diffusion coefficients for Fe_0.61S_0.39.     

Further Exact and Approximate Considerations of the Barrier Problem

When the second order differential equation governing transmissionof waves through a potential barrier is solved approximately,two approximate solutions arise within the barrier, one exponentiallylarge and one exponentially small. When a linear combinationof these solutions is considered, the error involved in theexponentially large solution is much larger than the actualsmaller solution, leading to conceptual difficulties as to howthis small solution is to be interpreted within the linear combination.Here, a new approach is adopted, whereby linear combinationsof approximate solutions are avoided. The reflection coefficientof the barrier is derived and the series expansion of its modulusis obtained before approximations are introduced. The analysisis so arranged that ratios rather than linear combinations enterthis modulus, and error analysis then shows exactly why theerror consists of certain unexpected exponentially small termsrather than expected terms of larger order of magnitude.     

LASER FLASH SPECTROSCOPY OF METHYLENE BLUE WITH NUCLEIC ACIDS. EFFECTS OF IONIC STRENGTH AND pH

Laser flash spectroscopic measurements were made on methylene blue complexed to the synthetic polynucleotides poly[d(G-C)] and poly[d(A-T)] in solutions of varying ionic strength and pH. Triplet decay rates and rates of triplet quenching by oxygen have been measured for the polymer/dye solutions. The triplet decay and oxygen quenching rates of methylene blue in complex with poly[d(A-T)] are much less sensitive than those with poly[d(G-C)] with respect to variations in ionic strength. It is also shown that protonation of the triplet state of MB+ with poly[d(A-T)] is slower than that of free dye. These results indicate strong binding of the dye to poly[d(A-T)]. Excitation of the MB+/poly[d(A-T)] complex at 665 nm yielded single exponential decay kinetics, in contrast with excitation at 600 nm where double exponential kinetics were measured. This is tentatively assigned to excitation of dye dimer bound to this polymer.     

REBUILDING THE EASTERN BALTIC COD STOCK UNDER ENVIRONMENTAL CHANGE–A PRELIMINARY APPROACH USING STOCK,ENVIRONMENTAL, AND MANAGEMENT CONSTRAINTS

ABSTRACT. . The population dynamics of the Eastern Baltic cod (Gadus morhua callarias L.), unlike many other stocks, shows a strong dependency on environmental conditions. To test the implications of different management policies on the stock and the fishery in a system of global environmental change, we apply a spatially disaggregated, discrete time, age‐structured model of the Eastern Baltic cod stock in 50 year simulation analyses. The simulation provides an analysis of stock, yield, and revenue development under various management policies and environmental scenarios. The policy analysis, focusing on different regulations of fishing mortality, is embedded into three environmental scenarios, assuming low, medium, or high climate and environmental change. The environmental assumptions are based on simulation results from a coupled atmosphere‐ocean regional climate model, which project salinity in the Baltic Sea to decrease by 7–47% in the period 2071–2100 relative to the reference period 1961 1990. Our simulation results show that a significant reduction in fishing mortality is necessary for achieving high long‐term economic yields. Moreover, under the environmental scenarios presented, a stock collapse cannot be prevented. It can, however, be postponed by the establishment of a marine reserve in ICES subdivision 25.