Switching the Inhibitor-Enzyme Recognition Profile via Chimeric Carbonic Anhydrase XII

A key part of the optimization of small molecules in pharmaceutical inhibitor development is to vary the molecular design to enhance complementarity of chemical features of the compound with the positioning of amino acids in the active site of a target enzyme. Typically this involves iterations of synthesis, to modify the compound, and biophysical assay, to assess the outcomes. Selective targeting of the anti-cancer carbonic anhydrase isoform XII (CA XII), this process is challenging because the overall fold is very similar across the twelve CA isoforms. To enhance drug development for CA XII we used a reverse engineering approach where mutation of the key six amino acids in the active site of human CA XII into the CA II isoform was performed to provide a protein chimera (chCA XII) which is amenable to structure-based compound optimization. Through determination of structural detail and affinity measurement of the interaction with over 60 compounds we observed that the compounds that bound CA XII more strongly than CA II, switched their preference and bound more strongly to the engineered chimera, chCA XII, based on CA II, but containing the 6 key amino acids from CA XII, behaved as CA XII in its compound recognition profile. The structures of the compounds in the chimeric active site also resembled those determined for complexes with CA XII, hence validating this protein engineering approach in the development of new inhibitors.     

On extensions of characteristic functions

Here we deal with the following question: Is it true that, for any closed interval on the real line ? that does not contain the origin, there exists a characteristic function f such that f(x) coincides with the normal characteristic function \( {\mathrm{e}}^{-{x}^2/2} \) on this interval but f(x) ? \( {\mathrm{e}}^{-{x}^2/2} \) on ?? The answer to this question is positive. We study a more general case of an arbitrary characteristic function g of a continuous probability density, instead of \( {\mathrm{e}}^{-{x}^2/2} \).     

Approximation of entire functions of exponential type by exponential sums<Superscript>*</Superscript>

Let K be a compact set in \( {{\mathbb R}^n} \). For \( 1 \leqslant p \leqslant \infty \), the Bernstein space \( B_K^p \) is the Banach space of all functions \( f \in {L^p}\left( {{{\mathbb R}^n}} \right) \)such that their Fourier transform in a distributional sense is supported on K. If \( f \in B_K^p \), then f is continuous on \( {{\mathbb R}^n} \) and has an extension onto the complex space \( {{\mathbb C}^n} \) to an entire function of exponential type K. We study the approximation of functions in \( B_K^p \) by finite τ -periodic exponential sums of the form

$ \sum\limits_m {{c_m}{e^{2\pi {\text{i}}\left( {x,m} \right)/\tau }}} $

in the \( {L^p}\left( {\tau {{\left[ { - 1/2,1/2} \right]}^n}} \right) \)-norm as τ → ∞ when K is a polytope in \( {{\mathbb R}^n} \).

     

On extreme values in open queueing networks

This paper presents heavy traffic limit theorems for the extreme virtual waiting time of a customer in an open queueing network. In this paper, functional limit theorems are proved for extreme values of important probability characteristics of the open queueing network investigated as the maximum and minimum of the total virtual waiting time of a customer, and the maximum and minimum of the virtual waiting time of a customer. Also, the paper presents the previous related works for extreme values in queues and the virtual waiting time in heavy traffic.     

Discrete damage traces from filamentation of Gauss-Bessel pulses

Filamentation of Bessel-Gauss pulses propagating in borosilicate glass is found to produce damage lines extending over hundreds of micrometers and consisting of discrete, equidistant damage spots. These discrete damage traces are explained by self-regeneration of Gauss-Bessel beams during propagation and are potentially applicable in laser microfabrication of transparent materials.     

First Principles Calculations Toward Understanding SERS of 2,2′-Bipyridyl Adsorbed on Au,Ag, and Au–Ag Nanoalloy

First principles electrodyanmics and quantum chemical simulations are performed to gain insights into the underlying mechanisms of the surface enhanced Raman spectra of 22BPY adsorbed on pure Au and Ag as well as on Au–Ag alloy nanodiscs. Experimental SERS spectra from Au and Ag nanodiscs show similar peaks, whereas those from Au–Ag alloy reveal new spectral features. The physical enhancement factors due to surface nano-texture were considered by numerical FDTD simulations of light intensity distribution for the nano-textured Au, Ag, and Au–Ag alloy and compared with experimental results. For the chemical insights of the enhancement, the DFT calculations with the dispersion interaction were performed using Au₂₀, Ag₂₀, and Au₁₀Ag₁₀ clusters of a pyramidal structure for SERS modeling. Binding of 22BPY to the clusters was simulated by considering possible arrangements of vertex and planar physical as well as chemical adsorption models. The DFT results indicate that 22BPY prefers a coplanar adsorption on a (111) face with trans-conformation having close energy difference to cis-conformation. Binding to pure Au cluster is stronger than to pure Ag or Au–Ag alloy clusters and adsorption onto the alloy surface can deform the surface. The computed Raman spectra are compared with experimental data and assignments for pure Au and Ag models are well matching, indicating the need of dispersion interaction to reproduce strong Raman signal at around 800 cm^–1. This work provides insight into 3D character of SERS on nanorough surfaces due to different binding energies and bond length of nanoalloys. © 2018 Wiley Periodicals, Inc.     

Femtosecond laser‐assisted formation of channels in sapphire using KOH solution

We report on wet etching of photomodified regions in crystalline sapphire using KOH solution. Tightly focused femtosecond laser pulses (150 fs at 800 nm wavelength) were used to create void structures enclosed in an amorphised sapphire shell inside the bulk of a crystalline host. The diameter of the amorphous regions can be controlled by pulse energy and was typically 0.5–1.5 µm. The etching rate depends on the distance between adjacent irradiation spots, pulse energy, concentration of etchant and ultrasonic agitation.

     

Influence of hydrodynamic conditions of the solution on the sensitivity of stripping analysis of trace metals

Possibilities to increase the sensitivity of stripping analysis by optimising the hydrodynamic conditions of the solution during the deposition and rest period are evaluated. Rotation rates as high as 13 000 rpm can be applied during the deposition step at a mercury film rotating disc electrode for Zn, Cd, Pb, In and Tl determinations when 10–20 mg/l of Hg²⁺ for the renewal of the mercury film is added. Because of the extreme sensitivity on the properties of the mercury film in the case of Ga only 4000–5000 rpm are recommended. The highest stirring efficiencies using a magnetic stirrer are equivalent to 2500–3000 rpm when a rotating disc electrode is used. The effect of the duration of the rest period is not significant for square wave stripping voltammetry, however, analytical signals can be increased 10 and more times when potentiometric stripping analysis is applied.