Rational coupled dynamics network manipulation rescues disease-relevant mutant cystic fibrosis transmembrane conductance regulator

Many cellular functions necessary for life are tightly regulated by protein allosteric conformational change, and correlated dynamics between protein regions has been found to contribute to the function of proteins not previously considered allosteric. The ability to map and control such dynamic coupling would thus create opportunities for the extension of current therapeutic design strategy. Here, we present an approach to determine the networks of residues involved in the transfer of correlated motion across a protein, and apply our approach to rescue disease-causative mutant cystic fibrosis transmembrane regulator (CFTR) ion channels, ΔF508 and ΔI507, which together constitute over 90% of cystic fibrosis cases. We show that these mutations perturb dynamic coupling within the first nucleotide-binding domain (NBD1), and uncover a critical residue that mediates trans-domain coupled dynamics. By rationally designing a mutation to this residue, we improve aberrant dynamics of mutant CFTR as well as enhance surface expression and function of both mutants, demonstrating the rescue of a disease mutation by rational correction of aberrant protein dynamics.     

Engineerable femtosecond pulse shaping by second-harmonic generation with Fourier synthetic quasi-phase-matching gratings

We describe a pulse-shaping technique that uses second-harmonic generation with Fourier synthetic quasi-phase-matching gratings. We demonstrate both amplitude and phase tailoring by generating a picosecond squarelike pulse as well as trains of femtosecond pulses with a terahertz-range repetition rate from either a compressed or a chirped pump pulse.     

Understanding volumetric capacitance in conducting polymers

Recent measurements in poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) films show that capacitance scales with film volume. We discuss the ramifications of this finding and propose a simple model that describes capacitance in terms of sites in which ions injected from the electrolyte replace holes that are extracted from the film by a metal contact. We propose that volumetric capacitance is inversely proportional to the average distance between these sites. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 1433–1436     

Effect of spatial heterogeneity on level of rejuvenation in Ni80P20 metallic glass

Understanding the relation between spatial heterogeneity and structural rejuvenation is one of the hottest topics in the field of metallic glasses (MGs). In this work, molecular dynamics (MD) simulation is implemented to discover the effects of initial spatial heterogeneity on the level of rejuvenation in the Ni$_{80}$P$_{20 }$MGs. For this purpose, the samples are prepared with cooling rates of $10^{10}$ K/s-$10^{12}$ K/s to make glassy alloys with different atomic configurations. Firstly, it is found that the increase in the cooling rate leads the Gaussian-type shear modulus distribution to widen, indicating the aggregations in both elastically soft and hard regions. After the primary evaluations, the elastostatic loading is also used to transform structural rejuvenation into the atomic configurations. The results indicate that the sample with intermediate structural heterogeneity prepared with 10$^{11}$ K/s exhibits the maximum structural rejuvenation which is due to the fact that the atomic configuration in an intermediate structure contains more potential sites for generating the maximum atomic rearrangement and loosely packed regions under an external excitation. The features of atomic rearrangement and structural changes under the rejuvenation process are discussed in detail.     

Investigation of the quantitative properties of the quadrupole orthogonal acceleration time-of-flight mass spectrometer with electrospray ionisation using 3,4-methylenedioxymethamphetamine

This paper describes the investigation of the potential of a quadrupole orthogonal acceleration time-of-flight mass spectrometer (Q-TOF) equipped with an atmospheric pressure ionisation interface for quantitative measurements of small molecules separated by reversed phase liquid chromatography. To this end, the detection limits and linear dynamic range in particular were studied in an LC/MS/MS experiment using 3,4-methylenedioxymethamphetamine standards and 3,4-methylenedioxyethylamphetamine for internal standardisation. In a second phase, the experiment was repeated with real biological extracts (whole blood, serum, and vitreous humour). A calibration for 3,4-methylenedioxymethamphetamine and its metabolite 3,4-methylenedioxyamphetamine was prepared in each of these matrices again using 3,4-methylenedioxyethylamphetamine as internal standard. The resulting quantitative data were compared with those obtained by liquid chromatography with fluorescence detection for the same extracts. The Q-TOF results revealed excellent sensitivity and a linear dynamic range of nearly four decades (2-10 000 pg on-column, r(2) = 0.9998, 1/x weighting). Furthermore, all the calibration curves prepared in biological material were superimposable, LC/MS/MS and LC-fluorescence, and the quantitative results for actual samples compared very favourably. It was concluded that the Q-TOF achieves a linear dynamic range for quantitative LC/MS/MS work exceeding that of fluorescence detection and at much better absolute sensitivity. Copyright 1999 John Wiley & Sons, Ltd.     

Containment of explosions in water-filled right-circular cylinders

The formulation of basic explosion-containment equations for idealized water-filled right-circular cylinders is summarized. The equations express explosive-charge weight as a function of vessel geometry and conventional material properties. Extensive experiments with models verified the relations for a wide range of vessels, materials and sizes. The basic containment relations were modified to provide safe and reasonable solutions for less-adverse accident conditions and for real vessels, i.e., vessels with welds, nozzles and end constraints.     

Alchemical molecular dynamics for inverse design

We present a molecular dynamics (MD) implementation of an extended statistical mechanical ensemble that includes ‘alchemical’ degrees of freedom describing particle attributes as thermodynamic variables. We demonstrate the use of this alchemical MD method in inverse design simulations of particles interacting via the Oscillating Pair Potential (OPP) and the Lennard–Jones–Gauss potential (LJG) – two general, previously studied models for which phase diagrams are known. We show that alchemical MD can quickly and efficiently optimise pair potentials for target structures within a specified design space in the low-temperature regime, where internal energy adequately represents the features of the alchemical free energy landscape. We show that alchemical MD can be also used to inversely design pair potentials to achieve target materials properties (here, bulk modulus) directly, without explicit knowledge of the structure–property relationship. Alchemical MD can easily be generalised and applied to any target materials properties or structures and used with any differentiable interaction potential.     

Intramolecular 2h group-transfer in heterocyclic bridged-ring systems (dyotropic rearrangements)

Diarylnitrilimines, derived by thermolysis of appropriate diaryltetrazoles, form(4+2)π cyclo-adducts with dipolarophiles of the isodrin type, e.g. $\text{(1)}$; the resulting 2-pyrazolines thermally rearrange into pyrazoles by hydrogen group transfer. Kinetic data for examples of this and related reactions are reported.     

Evidence for a strongly deformed prolate shape at N = 87 from 154Eu and 152Eu(p,t) reactions

The (p, t) reaction on radioactive targets of ^152,154Eu has been used to study rotational states associated with the configuration in the transitional odd-odd ¹⁵²Eu and ¹⁵⁰Eu nuclei. Our studies yieldcompelling evidence that this configuration in ¹⁵⁰Eu has a prolate structure which is strongly deformed and occurs at excitation energy of 1224 keV.