Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles

Gaucher disease is a lysosomal storage disorder caused by deficient glucocerebrosidase activity. We have previously shown that the cellular activity of the most common Gaucher disease-associated glucocerebrosidase variant, N370S, is increased when patient-derived cells are cultured with the chemical chaperone N-nonyl-deoxynojirimycin. Chemical chaperones stabilize proteins against misfolding, enabling their trafficking from the endoplasmic reticulum. Herein, the generality of this therapeutic strategy is evaluated with other glucocerebrosidase variants and with additional candidate chemical chaperones. Improved chemical chaperones are identified for N370S glucocerebrosidase. Moreover, we demonstrate that G202R, a glucocerebrosidase variant that is known to be retained in the endoplasmic reticulum, is also amenable to chemical chaperoning. The L444P variant is not chaperoned by any of the active site-directed molecules tested, likely because this mutation destabilizes a domain distinct from the catalytic domain.     

Chlorine‐Enhanced Surface Mobility of Au(100)

Motivated by experimental studies of two‐dimensional Ostwald ripening on Au(100) electrodes in chlorine‐containing electrolytes, we have studied diffusion processes using density functional theory. We find that chlorine has a propensity to temporary form AuCl complexes, which diffuse significantly faster than gold adatoms. With and without chlorine, the lowest activation energy is found for the exchange mechanism. Chlorine furthermore reduces the activation energy for the detachment from kink sites. Kinetic Monte Carlo simulations were performed on the basis of extensive density functional theory calculations. The island‐decay rate obtained from these Monte Carlo simulations, as well as the decay rate obtained from the theoretical activation energies and frequency factors when inserted into analytical solutions for Ostwald ripening, are in agreement with experimental island‐decay rates in chlorine‐containing electrolytes.     

Ab initio predictions of zeolite structures and Si NMR chemical shifts

A recent shell-model potential parameterized on ab initio data is used for predicting the all-silica structures of zeolites MFI, MEI, MTW, TON, FAU and of α-quartz. Cluster models are defined around each site and the ²⁹Si NMR shielding constants are calculated by ab initio techniques (GIAO-HF). Good agreement with observed ²⁹Si NMR chemical shifts is found. Comparison is made with shifts calculated for observed structures. The structures predicted by the ab initio shell-model potential prove as accurate as the observed ones when judged on the quality of the calculated ²⁹Si NMR spectra.     

Formation of Si-nanoparticles in a microwave reactor: Comparison between experiments and modelling

The formation and growth of silicon-nanoparticles from silane in a microwave reactor was investigated. Experiments were performed for the following conditions: precursor concentration 380–2530 ppm, pressures of 20–30 mbar, microwave powers 120–300 W. The formed particles were examined in-situ with a particle mass spectrometer. Additionally, particles were collected on grids and analyzed by transmission electron microscopy, X-ray diffraction, and by determining the specific surface area by BET. The particle size was found to be in the range of 5–8 nm in diameter. A simple model was used to simulate the particle formation processes taking place inside the reactor. The microwave energy coupled into the reactor flow was treated as a spatially distributed energy source resulting in a local temperature increase. The particles were assumed to have a monodisperse size distribution. To allow an approximation of their shape they were characterized by their volume and surface area. The model takes nucleation, convection, coagulation, and coalescence into account. The fluid flow inside the microwave reactor was simulated with the commercial CFD-code Fluent.     

Joint optimization of fleet size and maintenance capacity in a fork-join cyclical transportation system

This article presents an asset management-oriented multi-criteria methodology for the joint estimation of a mobile equipment fleet size, and the maintenance capacity to be allocated in a productive system. Using a business-centred life-cycle perspective, we propose an integrated analytical model and evaluate it using global cost rate, availability and throughput as performance indicators. The global cost components include: (i) opportunity costs associated with lost production, (ii) vehicle idle time costs, and (iii) maintenance resources idle time costs. This multi-criteria approach allows a balanced scorecard to be built that identifies the main trade-offs in the system. The methodology uses an improved closed network queueing model approach to describe the production and maintenance areas. We test the proposed methodology using an underground mining operation case study. The decision variables are the size of a load-haul-dump fleet and specialized maintenance crew levels. Our model achieves savings of 20.6% in global cost terms with respect to a benchmark case. We also optimize the system to achieve desired targets of vehicle availability and system throughput (based on system utilization). The results show increments of 7.1% in vehicle availability and 13.5% in system throughput with respect to baseline case. For the case studied, these criteria also have a maximum, which allows for further improvement if desired. The results also show the importance of using balanced performance measures in the decision process. A multi-criteria optimization was also performed, showing the Pareto front of considered indicators. We discuss the trade-offs among different criteria, and the implications in finding balanced solutions. The proposed analytical approach is easy to implement and requires low computational effort. It also allows for an easy re-evaluation of resources when the business cycle changes and relevant exogenous factors vary.     

Iodine-Containing Mass-Defect-Tuned Dendrimers for Use as Internal Mass Spectrometry Calibrants

Calibrants based on synthetic dendrimers have been recently proposed as a versatile alternative to peptides and proteins for both MALDI and ESI mass spectrometry calibration. Because of their modular synthetic platform, dendrimer calibrants are particularly amenable to tailoring for specific applications. Utilizing this versatility, a set of dendrimers has been designed as an internal calibrant with a tailored mass defect to differentiate them from the majority of natural peptide analytes. This was achieved by incorporating a tris-iodinated aromatic core as an initiator for the dendrimer synthesis, thereby affording multiple calibration points (m/z range 600–2300) with an optimized mass-defect offset relative to all peptides composed of the 20 most common proteinogenic amino acids.

Open image in new window

Graphical abstract ?

     

240-fs pulses with 22-W average power from a mode-locked thin-disk Yb:KY(WO(4))(2) laser

We demonstrate what is to our knowledge the first passively mode-locked thin-disk Yb:KY(WO(4))(2) laser. The laser produces pulses of 240-fs duration with an average power of 22 W at a center wavelength of 1028 nm. At a pulse repetition rate of 25 MHz, the pulse energy is 0.9microJ , and the peak power is as high as 3.3 MW. The beam quality is very close to the diffraction limit, with M(2)=1.1 .