Covering arrays from m-sequences and character sums

A covering array of strength t on v symbols is an array with the property that, for every t-set of column vectors, every one of the \(v^t\) possible t-tuples of symbols appears as a row at least once in the sub-array defined by these column vectors. Arrays constructed using m-sequences over a finite field possess many combinatorial properties and have been used to construct various combinatorial objects; see the recent survey Moura et al. (Des Codes Cryptogr 78(1):197–219, 2016). In this paper we construct covering arrays whose elements are the remainder of the division by some integer of the discrete logarithm applied to selected m-sequence elements. Inspired by the work of Colbourn (Des Codes Cryptogr 55(2–3):201–219, 2010), we prove our results by connecting the covering array property to a character sum, and we evaluate this sum by taking advantage of the balanced way in which the m-sequence elements are distributed. Our results include new infinite families of covering arrays of arbitrary strength.     

Synthetic strategies to a telomere-targeted pentacyclic heteroaromatic salt

Three routes have been explored to synthesise the telomere-targeted agent 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate . Application of a 6-(2-azidophenyl)phenanthridine precursor gave an entry to the indazolo[2,3-f]phenanthridine ring system not the required quino[4,3,2-kl]acridine. A six step synthesis starting from 2,6-dibromo-4-methylbenzonitrile via a 1-arylacridin-9(10H)-one intermediate, or , gave the required in low overall yield (<10%). The most efficient route entailed the one-pot (five step) conversion of 1,2-dimethyl-6-fluoroquinolinium methosulfate to in 33% yield employing triethylamine as base and nitrobenzene as solvent.     

In‐Membrane Chemical Modification (IMCM) for Site‐Specific Chromophore Labeling of GPCRs

We present in‐membrane chemical modification (IMCM) for obtaining selective chromophore labeling of intracellular surface cysteines in G‐protein‐coupled receptors (GPCRs) with minimal mutagenesis. This method takes advantage of the natural protection of most cysteines by the membrane environment. Practical use of IMCM is illustrated with the site‐specific introduction of chromophores for NMR and fluorescence spectroscopy in the human κ‐opioid receptor (KOR) and the human A_2A adenosine receptor (A_2AAR). IMCM is applicable to a wide range of in vitro studies of GPCRs, including single‐molecule spectroscopy, and is a promising platform for in‐cell spectroscopy experiments.     

Height-dependence of spatio-temporal spectra of wall-bounded turbulence – LES results and model predictions

Wavenumber–frequency spectra of the streamwise velocity component obtained from large-eddy simulations (LES) are presented. Following recent work we show that the main features, a Doppler shift and a Doppler broadening of frequencies, are captured by an advection model based on the Tennekes–Kraichnan random-sweeping hypothesis with additional mean flow. In this paper, we focus on the height-dependence of the spectra within the logarithmic layer of the flow. We furthermore benchmark an analytical model spectrum that takes the predictions of the random-sweeping model as a starting point and find good agreement with the LES data. We also quantify the influence of the LES grid resolution on the wavenumber–frequency spectra.     

Applying medicinal chemistry transformations and multiparameter optimization to guide the search for high-quality leads and candidates

In this article we describe a computational method that automatically generates chemically relevant compound ideas from an initial molecule, closely integrated with in silico models, and a probabilistic scoring algorithm to highlight the compound ideas most likely to satisfy a user-defined profile of required properties. The new compound ideas are generated using medicinal chemistry 'transformation rules' taken from examples in the literature. We demonstrate that the set of 206 transformations employed is generally applicable, produces a wide range of new compounds, and is representative of the types of modifications previously made to move from lead-like to drug-like compounds. Furthermore, we show that more than 94% of the compounds generated by transformation of typical drug-like molecules are acceptable to experienced medicinal chemists. Finally, we illustrate an application of our approach to the lead that ultimately led to the discovery of duloxetine, a marketed serotonin reuptake inhibitor.     

Rate constants for the gas-phase reactions of OH and O3 with β-ocimene, β-myrcene, and α- and β-farnesene as a function of temperature

The rate constants for the gas-phase reactions of hydroxyl radicals and ozone with the biogenic hydrocarbons β-ocimene, β-myrcene, and α- and β-farnesene were measured using the relative rate technique over the temperature ranges 313-423 (for OH) and 298-318 K (for O?) at about 1 atm total pressure. The OH radicals were generated by photolysis of H?O?, and O? was produced from the electrolysis of O?. Helium was used as the diluent gas. The reactants were detected by online mass spectrometry, which resulted in high time resolution, allowing large amounts of data to be collected and used in the determination of the Arrhenius parameters. The following Arrhenius expressions have been determined for these reactions (in units of cm3 molecules?1 s?1): for β-ocimene + OH, k = (4.35(-0.66)(+0.78)) × 10?11 exp[(579 ± 59)/T]; for β-ocimene + O?, k = (3.15(-0.95)(+1.36)) × 10?1? exp[-(626 ± 110)/T]; for β-myrcene + O?, k = (2.21(-0.66)(+0.94)) × 10?1? exp[-(520 ± 109)/T]; for α-farnesene + OH, k(OH) = (2.19 ± 0.11) × 10?1? for 23-413 K; for α-farnesene + O?, k = (3.52(-2.54)(+9.09)) × 10?12 exp[-(2589 ± 393)/T]; for β-farnesene + OH, k(OH) = (2.88 ± 0.15) × 10?1? for 323-423 K; for β-farnesene + O?, k = (1.81(-1.19)(+3.46)) × 10?12 exp[-(2347 ± 329)/T]. The Arrhenius parameters here are the first to be reported. The reactions of α- and β-farnesene with OH showed no significant temperature dependence. Atmospheric residence times due to reactions with OH and O? were also presented.     

Directing energy transfer in discrete one-dimensional oligonucleotide-templated assemblies

Monodisperse DNA-templated one dimensional dye assemblies have been constructed in which the energy transfer can be directed. Fluorescence experiments suggest an optimum transfer efficiency for stacks of 30 bases long.     

Influence of water on anharmonicity, stability, and vibrational energy distribution of hydrogen-bonded adducts in atmospheric reactions: case study of the OH + isoprene reaction intermediate using ab initio molecular dynamics

The effect of water on the stability and vibrational states of a hydroxy-isoprene adduct is probed through the introduction of 1-15 water molecules. It is found that when a static nuclear harmonic approximation is invoked there is a substantial red-shift of the alcohol O-H stretch (of the order of 800 cm(-1)) as a result of introduction of water. When potential energy surface sampling and associated anharmonicities are introduced through finite temperature ab initio dynamics, this hydroxy-isoprene OH stretch strongly couples with all the water vibrational modes as well as the hydroxy-isoprene OH bend modes. A new computational technique is introduced to probe the coupling between these modes. The method involves a two-dimensional, time-frequency analysis of the finite temperature vibrational properties. Such an analysis not only provides information about the modes that are coupled as a result of finite-temperature analysis, but also the temporal evolution of such coupling.     

Ultrafast dynamics of nonequilibrium resonance energy transfer and probing globular protein flexibility of myoglobin

Protein structural plasticity is critical to many biological activities and accurate determination of its temporal and spatial fluctuations is challenging and difficult. Here, we report our extensive characterization of global flexibility of a globular heme protein of myoglobin using resonance energy transfer as a molecular ruler. With site-directed mutagenesis, we use a tryptophan scan to examine local structural fluctuations from B to H helices utilizing 10 tryptophan-heme energy transfer pairs with femtosecond resolution. We observed ultrafast resonance energy transfer dynamics by following a nearly single exponential behavior in 10-100 ps, strongly indicating that the globular structure of myoglobin is relatively rigid, with no observable static or slow dynamic conformational heterogeneity. The observation is against our molecular dynamics simulations, which show large local fluctuations and give multiple exponential energy transfer behaviors, suggesting too flexible of the global structure and thus raising a serious issue of the force fields used in simulations. Finally, these ultrafast energy transfer dynamics all occur on the similar time scales of local environmental relaxations (solvation), leading to nonexponential processes caused by energy relaxations, not structural fluctuations. Our analyses of such processes reveal an intrinsic compressed- and/or stretched-exponential behaviors and elucidate the nature of inherent nonequilibrium of ultrafast resonance energy transfer in proteins. This new concept of compressed nonequilibrium transfer dynamics should be applied to all protein studies by time-resolved F?rster resonance energy transfer (FRET).