Chemical-genetic screen identifies riluzole as an enhancer of Wnt/β-catenin signaling in melanoma

To identify new protein and pharmacological regulators of Wnt/β-catenin signaling, we used a cell-based reporter assay to screen a collection of 1857 human-experienced compounds for their ability to enhance activation of the β-catenin reporter by a low concentration of WNT3A. This identified 44 unique compounds, including the FDA-approved drug riluzole, which is presently in clinical trials for treating melanoma. We found that treating melanoma cells with riluzole in?vitro enhances the ability of WNT3A to regulate gene expression, to promote pigmentation, and to decrease cell proliferation. Furthermore riluzole, like WNT3A, decreases metastases in a mouse melanoma model. Interestingly, siRNAs targeting the metabotropic glutamate receptor, GRM1, a reported indirect target of riluzole, enhance β-catenin signaling. The unexpected regulation of β-catenin signaling by both riluzole and GRM1 has implications for the future uses of this drug.     

Global QSAR models of skin sensitisers for regulatory purposes

Background

The new European Regulation on chemical safety, REACH, (Registration, Evaluation, Authorisation and Restriction of CHemical substances), is in the process of being implemented. Many chemicals used in industry require additional testing to comply with the REACH regulations. At the same time EU member states are attempting to reduce the number of animals used in experiments under the 3 Rs policy, (refining, reducing, and replacing the use of animals in laboratory procedures). Computational techniques such as QSAR have the potential to offer an alternative for generating REACH data. The FP6 project CAESAR was aimed at developing QSAR models for 5 key toxicological endpoints of which skin sensitisation was one.

Results

This paper reports the development of two global QSAR models using two different computational approaches, which contribute to the hybrid model freely available online.

Conclusions

The QSAR models for assessing skin sensitisation have been developed and tested under stringent quality criteria to fulfil the principles laid down by the OECD. The final models, accessible from CAESAR website, offer a robust and reliable method of assessing skin sensitisation for regulatory use.

     

A novel liquid plasma AOP device integrating microwaves and ultrasounds and its evaluation in defluorinating perfluorooctanoic acid in aqueous media

A simplified and energy-saving integrated device consisting of a microwave applicator and an ultrasonic homogenizer has been fabricated to generate liquid plasma in a medium possessing high dielectric factors, for example water. The microwave waveguide and the ultrasonic transducer were interconnected through a tungsten/titanium alloy stick acting both as the microwave antenna and as the horn of the ultrasonic homogenizer. Both microwaves and ultrasonic waves are simultaneously transmitted to the aqueous media through the tungsten tip of the antenna. The microwave discharge liquid plasma was easily generated in solution during ultrasonic cavitation. The simple device was evaluated by carrying out the degradation of the perfluorooctanoic acid (PFOA), a system highly recalcitrant to degradation by conventional advanced oxidation processes (AOPs). PFOA is 59% degraded in an aqueous medium after only 90 s of irradiation by the plasma. Intermediates were identified by electrospray mass spectral techniques in the negative ion mode.     

Growth in solvable subgroups of {{\mathrm{GL}}}_r({\mathbb {Z}}/p{\mathbb {Z}})

Let \(K={\mathbb {Z}}/p{\mathbb {Z}}\) and let \(A\) be a subset of \({{\mathrm{GL}}}_r(K)\) such that \(\langle A \rangle \) is solvable. We reduce the study of the growth of \(A\) under the group operation to the nilpotent setting. Fix a positive number \(C\ge 1\) ; we prove that either \(A\) grows (meaning \(|A_3|\ge C|A|\) ), or else there are groups \(U_R\) and \(S\) , with \(U_R\unlhd S \unlhd \langle A\rangle \) , such that \(S/U_R\) is nilpotent, \(A_k\cap S\) is large and \(U_R\subseteq A_k\) , where \(k\) depends only on the rank \(r\) of \({{\mathrm{GL}}}_r(K)\) . Here \(A_k = \{x_1 x_2 \cdots x_k : x_i \in A \cup A^{-1} \cup \{1\}\}\) . When combined with recent work by Pyber and Szabó, the main result of this paper implies that it is possible to draw the same conclusions without supposing that \(\langle A \rangle \) is solvable.     

Bounds on the diameter of Cayley graphs of the symmetric group

In this paper we are concerned with the conjecture that, for any set of generators S of the symmetric group \(\operatorname {Sym}(n)\) , the word length in terms of S of every permutation is bounded above by a polynomial of n. We prove this conjecture for sets of generators containing a permutation fixing at least 37 % of the points.     

CanSAS‐IV

A two-day workshop on beamline integration and data formatting (HDF5/NeXus) of the EIGER detector was held in Baden, Switzerland, January 24–25, 2013. Its aim was to discuss the technical challenges inherent with the next generation of high-frame-rate, high-resolution X-ray imaging detectors, and specifically with the EIGER detector. EIGER is a photon-counting hybrid pixel detector developed at the Paul Scherrer Institute (PSI) and DECTRIS Ltd. With even higher spatial resolution and frame rates than its predecessor, the PILATUS detector, it will be able to continuously produce up to 3000 images per second. The corresponding extreme data rates generated by this and future detectors present a significant challenge for beamline integration of the detectors, for data handling by the users, and for data processing software. Efficient data flow, storage, and processing must be achieved to handle the huge data sets that will be produced in seconds by these devices.     

Sensitivity to point-spread function parameters in medical ultrasound image deconvolution

Clinical ultrasound images are often perceived as difficult to interpret due to image blurring and speckle inherent in the ultrasound imaging. But the image quality can be improved by deconvolution using an estimate of the point-spread function. However, it is difficult to obtain a sufficiently accurate estimate of the point-spread function in vivo because of the unknown properties of the soft tissue in clinical applications. Local variations in the speed of sound and attenuation change the pulse and beam shape. These in turn affect the point-spread function. The purpose and novelty of this paper is therefore to explore the sensitivity of a state-of-the-art deconvolution algorithm to uncertainty in the point-spread function. The point-spread function in our restoration algorithm is made shift invariant in the lateral dimension but shift dependent in the axial direction, and is modelled to match a 128-element 1D linear array often found in clinical use. We present simulated and in vitro sensitivity analyses of two-dimensional deconvolution while varying six parameters on which the point-spread function depends. Uncertainty in the ultrasound machine is analysed by varying the axial depths of lateral and elevational foci alongside height and width of transducer elements. Sensitivity to tissue influence is investigated by varying the speed of sound and frequency-dependent attenuation of the electro-mechanical impulse response. The results are analysed both quantitatively and in terms of the perceived image quality. First, the assessment of deconvolution using the logarithmic image amplitude is found to be a better indicator of the perceived improvement in the restoration. Secondly, the two most critical parameters for two-dimensional deconvolution are discovered to be the lateral focus and the speed of sound, because the success of deconvolution is perceived primarily in terms of deblurring. We also observed similar patterns for the simulation and in vitro experiment. Finally, we show that it is possible to restore in vivo ultrasound images using an assumed point-spread function and hence conclude that an exact point-spread function is not necessary for enhancing ultrasound image quality by deconvolution.     

Semi‐analytical method for departure point determination

A new method for departure point determination on Cartesian grids, the semi‐analytical upwind path line tracing (SUT) method, is presented and compared to two typical departure point determination methods used in semi‐Lagrangian advection schemes, the Euler method and the four‐step Runge–Kutta method. Rigorous comparisons of the three methods were conducted for a severely curving hypothetical flow field and for advective transport in the rotation of a Gaussian concentration hill. The SUT method was shown to have equivalent accuracy to the Runge–Kutta method but with significantly improved computational efficiency. Depending on the case being simulated, the SUT method provides either far greater or equivalent computational efficiency and more certain accuracy than the Euler method. Copyright © 2004 John Wiley & Sons, Ltd.