Toward a generalized computational workflow for exploiting transient pockets as new targets for small molecule stabilizers: Application to the homogentisate 1,2-dioxygenase mutants at the base of rare disease Alkaptonuria

Alkaptonuria (AKU) is an inborn error of metabolism where mutation of homogentisate 1,2-dioxygenase (HGD) gene leads to a deleterious or misfolded product with subsequent loss of enzymatic degradation of homogentisic acid (HGA) whose accumulation in tissues causes ochronosis and degeneration. There is no licensed therapy for AKU. Many missense mutations have been individuated as responsible for quaternary structure disruption of the native hexameric HGD. A new approach to the treatment of AKU is here proposed aiming to totally or partially rescue enzyme activity by targeting of HGD with pharmacological chaperones, i.e. small molecules helping structural stability. Co-factor pockets from oligomeric proteins have already been successfully exploited as targets for such a strategy, but no similar sites are present at HGD surface; hence, transient pockets are here proposed as a target for pharmacological chaperones. Transient pockets are detected along the molecular dynamics trajectory of the protein and filtered down to a set of suitable sites for structural stabilization by mean of biochemical and pharmacological criteria. The result is a computational workflow relevant to other inborn errors of metabolism requiring rescue of oligomeric, misfolded enzymes.     

Conductivity anomalies in Y–Ba–Cu–O at 40K and 100K under high quasihydrostatic pressures

Electrical resistance measurements at low temperatures and high quasihydrostatic pressures on superconducting and non-superconducting varieties of Y_0.8Ba_1.2Cu₂O₅ (obtained by annealing in oxygen and air respectively) show striking anomalies in the vicinity of 100K and 40K. Arguments are presented to show that these anomalies as also the occurrence of T 's in the oxide superconductors either in the vicinity of 100K or of 40K are connected with their layered structure containing planes of Cu-O otahedral complexes.     

Ffast Transient Fluorescence Technique to Study Critical Exponents at the Glass Transition

The fast transient fluorescence (FTRF) technique was used to study critical exponents at the glass transition in free-radical crosslinking copolymerization (FCC) for two different monomeric systems, methyl methacrylate (MMA) and styrene (S). Pyrene (P_y ) was used as a fluorescence probe. The fluorescence lifetimes of P_y from its decay traces were measured and used to monitor the gelation process. Changes in the viscosity of the pregel solutions due to glass formation dramatically enhance the fluorescent yield of aromatic molecules. This effect is used to study the glass transition upon gelation of MMA and S monomeric systems as a function of time, at various temperatures and crosslinker concentrations. The results are interpreted in the view of percolation theory. The gel fraction and weight average degree of polymerization exponents β and γ are found to be 0.37 ± 0.02 and 1.66 ± 0.07 in agreement with percolation results.     

Performance of ring oscillators composed of gate-all-around FETs with varying numbers of nanowire channels using TCAD simulation

In this paper, we investigate the performance of ring oscillators composed of gate-all-around (GAA) silicon nanowire (NW) field-effect transistors (FETs) with four different numbers of NW channels, for sub-10-nm logic applications. Our simulations reveal that ring oscillators with double, triple, and quadruple NW channels exhibit improvements of up to 50%, 85%, and 97%, respectively, in the oscillation frequencies (f_osc), compared to a ring oscillator with a single NW channel, due to the large drive current, in spite of the increased intrinsic capacitance of a given device. Moreover, our work shows that the f_osc improvement ratio of the ring oscillators becomes saturated with triple NW channels with additional load capacitances of 0.1 fF and 0.01 fF, which are similar to, or less than the intrinsic device capacitance (∼0.1 fF). Thus, our study provides an insight for determining the capacitive load and optimal number of NW channels, for device development and circuit design of GAA NW FETs.     

Optical time-resolved study of the excitation dynamics*

Transient behaviour of the excited states originated from the neutral and the charged species is discussed using data from time-resolved experiments. Complex transient characteristics obtained for the slightly charged poly-(bithiophene) film during electrochemical doping were explained in terms of sequential molar fraction changes of the neutral species, the radical cation and the π-dimerized radical cations. Femtosecond transient absorption measurement carried out in time range of 0-4 ns for a two-photon excited dye reveals a multi-exponent decay with well separated relaxation times and the distinct relaxation mechanisms. At high irradiance and a sufficient fluence, the multi-photon excitation processes affect the subpicosecond response and lead to formation of the photo-products.     

Dynamics of excitons and carriers at the NPB/C60 interface by transient photocurrents

The transient photocurrent (TPC) technique was performed to explore the dynamics of excitons and carriers at organic active layer/buffer layer interfaces. A special device with ITO/PEIE/NPB/C₆₀/Al structure was designed to study the interfacial processes at the NPB/C₆₀ interface. An external electrical field was provided to neutralize the built-in electrical field of the device. Interestingly, a new phenomenon was observed, wherein the polarity of the TPC changed from negative to positive under an external electrical field. The initial negative signal was ascribed to exciton separation by the built-in field in C₆₀, and the subsequent positive signal can be attributed to the diffusion of electrons that accumulate at the NPB/C₆₀ interface. TPC measurements shown that further increasing the external electrical field causes polarity to change twice. Analyzing the two changes in polarity revealed that the NPB did not only extract holes from C₆₀ but also provided an effective interface for exciton dissociation.     

Transient finite element for in-bore analysis of 9 mm pistols

The in-bore process that occurs when a pistol is fired involves multiple physical models. This process is brief and typically measured in microseconds. Furthermore, propellants produce high temperatures and pressure gases during the burning process. These factors have made experimentation and simulation of the in-bore behavior of bullets difficult. This study uses a nonlinear transient finite element method (FEM) to simulate the in-bore behavior of a 9 mm bullet after being fired, where the chamber pressure is calculated by Vallier–Heydenreich formula and is used as the input loading. A gunshot experiment is conducted to verify the accuracy of computational results. The maximum difference between the numerical results and real experimental data is only 2.56% (including muzzle velocity and width and depth of engraved bullet vestiges), indicating that the simulation is credible.The discussed simulation is capable of obtaining the plastic deformation and kinematic status of the bullet and the stress history and distribution of the gun barrel. The numerical results can provide complete data of the entire in-bore process, improve the drawbacks during real in-bore ballistic research experiments, and assist engineers in designing and developing other novel systems. The simulation can save considerable time when designing small arms barrels.     

Real-Time Monitoring of the Mechanical Properties of a Soy Protein and Rubber Polymer during its Production Using Transient Infrared Spectroscopy

Soy protein–based polymers offer promising performance properties, but their characteristics are sensitively dependent on production conditions, so on-line monitoring could help provide the needed control during production. Mid-infrared spectroscopy combined with partial least squares offer the needed analysis, but the opacity of many materials in the mid-infrared range limits its conventional application. Transient infrared spectroscopy is a method of acquiring mid-infrared spectra from moving streams in real time that avoids the opacity problem. We apply transient infrared spectroscopy to a polymer of soy protein and polyisoprene-graft-maleic anhydride–modified natural rubber during its compounding extrusion to measure tensile strength and Young's modulus.     

PHYSICAL STRUCTURE AND PHASE PROPERTIES OF AQUEOUS SYSTEMS OF LIPIDS FROM RYE AND TRITICALE IN RELATION TO WHEAT LIPIDS

In connection with studies of technical functionality of lipids in cereals, the aqueous systems of lipids from rye and tri-ticale flour are described and compared to different wheat culti-vars. Rye lipids give a lamellar liquid-crystalline phase with very small ordered regions, and this phase is continuously changed into an L2-phase with increasing water content. Triticale lipids exhibit phase equilibria in between lipids of wheat and of rye. Evidence is given for a significant role of the lamellar liquid--crystalline phase with regard to technical functionality when the cereal flour is worked in water to give a dough.