Thorhaugecasey2037

Background This article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs). Methods Initial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu2/4 heterodimer (EC50 = 3.4 μM), but was peripherally restricted (rat Kp = 0.03). Optimization of this hit led to PAMs with improved potency (EC50s 2, an ~100-fold increase). Results However, these new amide analogs of febuxostat proved to be either GIRK1/2 and GIRK1/4 activators (primary carboxamide congeners) or mGlu2 PAMs (secondary and tertiary amides) and not selective mGlu2/4 heterodimer PAMs. Conclusion These results required the team to develop a new screening cascade paradigm, and exemplified the challenges in developing allosteric ligands for heterodimeric receptors. © 2019 Bentham Science Publishers.Economic development is increasingly dependent upon on utilizing new knowledge to innovate and create value, even in traditional industries and in low-income countries. This analysis uses evidence on patent families to assess innovation activity throughout sub-Saharan Africa. We find patent activity in sub-Saharan Africa-both by African inventors and by foreign inventors-is comparable to similar regions around the world, when conditioned on economic size. Patent filings in Africa have grown, particularly, since the mid-1990s, but at different rates within different African jurisdictions. Types of technologies being patented in Africa have remained stable over 30 years, with most in pharmaceuticals, chemistry, biotechnology, and engineering. The majority of patent filings in Africa are from Europe, the United States, and other high income countries. Fluorescein-5-isothiocyanate Yet, in South Africa, between 15% and 20% of patent filings are by residents of South Africa, and 3% are from other developing and emerging economies. Only a small share of inventions globally are made in sub-Saharan Africa, but for those inventions that do arise in Africa, foreign filings are made widely outside of Africa. © 2019 The Authors. The Journal of World Intellectual Property published by John Wiley & Sons Ltd.For many important problems the quantity of interest is an unknown function of the parameters, which is a random vector with known statistics. Since the dependence of the output on this random vector is unknown, the challenge is to identify its statistics, using the minimum number of function evaluations. This problem can be seen in the context of active learning or optimal experimental design. We employ Bayesian regression to represent the derived model uncertainty due to finite and small number of input-output pairs. In this context we evaluate existing methods for optimal sample selection, such as model error minimization and mutual information maximization. We show that for the case of known output variance, the commonly employed criteria in the literature do not take into account the output values of the existing input-output pairs, while for the case of unknown output variance this dependence can be very weak. We introduce a criterion that takes into account the values of the output for the existing samples and adaptively selects inputs from regions of the parameter space which have an important contribution to the output. The new method allows for application to high-dimensional inputs, paving the way for optimal experimental design in high dimensions. © 2020 The Author(s).The Hopf fibration has inspired any number of geometric structures in physical systems, in particular, in chiral liquid crystalline materials. Because the Hopf fibration lives on the three sphere, S 3 , some method of projection or distortion must be employed to realize textures in flat space. Here, we explore the geodesic-preserving gnomonic projection of the Hopf fibration, and show that this could be the basis for a new liquid crystalline texture with only splay and twist. We outline the structure and show that it is defined by the tangent vectors along the straight line rulings on a series of hyperboloids. The phase is defined by a lack of bend deformations in the texture, and is reminiscent of the splay-bend and twist-bend nematic phases. We show that domains of this phase may be stabilized through anchoring and saddle-splay. © 2020 The Author(s).We investigate methods for learning partial differential equation (PDE) models from spatio-temporal data under biologically realistic levels and forms of noise. Recent progress in learning PDEs from data have used sparse regression to select candidate terms from a denoised set of data, including approximated partial derivatives. We analyse the performance in using previous methods to denoise data for the task of discovering the governing system of PDEs. We also develop a novel methodology that uses artificial neural networks (ANNs) to denoise data and approximate partial derivatives. We test the methodology on three PDE models for biological transport, i.e. the advection-diffusion, classical Fisher-Kolmogorov-Petrovsky-Piskunov (Fisher-KPP) and nonlinear Fisher-KPP equations. We show that the ANN methodology outperforms previous denoising methods, including finite differences and both local and global polynomial regression splines, in the ability to accurately approximate partial derivatives and learn the correct PDE model. © 2020 The Author(s).For decades, the effect of surfactants in the sea-surface microlayer (SML) on gas transfer velocity (k) has been recognized; however, it has not been quantified under natural conditions due to missing coherent data on in situ k of carbon dioxide (CO2) and characterization of the SML. Moreover, a sea-surface phenomenon of wave-dampening, known as slicks, has been observed frequently in the ocean and potentially reduces the transfer of climate-relevant gases between the ocean and atmosphere. Therefore, this study aims to quantify the effect of natural surfactant and slicks on the in situ k of CO2. A catamaran, Sea Surface Scanner (S3), was deployed to sample the SML and corresponding underlying water, and a drifting buoy with a floating chamber was deployed to measure the in situ k of CO2. We found a significant 23% reduction of k above surfactant concentrations of 200 µg Teq l-1, which were common in the SML except for the Western Pacific. We conclude that an error of approximately 20% in CO2 fluxes for the Western Pacific is induced by applying wind-based parametrization not developed in low surfactant regimes.