Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs

When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL of the free fatty acid receptor 2 (FFA2) could be developed on the basis of pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology modeling and mutational analysis demonstrated a single mutation in human FFA2 of C4.57G resulted in a human FFA2 receptor with ligand selectivity similar to the bovine receptor. This was exploited to generate human FFA2-RASSL by the addition of a second mutation at a known orthosteric ligand interaction site, H6.55Q. The resulting FFA2-RASSL displayed a >100-fold loss of activity to endogenous ligands, while responding to the distinct ligand sorbic acid with pEC(50) values for inhibition of cAMP, 5.83 ± 0.11; Ca(2+) mobilization, 4.63 ± 0.05; ERK phosphorylation, 5.61 ± 0.06; and dynamic mass redistribution, 5.35 ± 0.06. This FFA2-RASSL will be useful in future studies on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs

Renewable Electricity Futures Study. Volume 4: Bulk Electric Power Systems: Operations and Transmission Planning

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a future through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%-90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT)

Extreme Ultra-Violet Spectroscopy of the Lower Solar Atmosphere During Solar Flares

The extreme ultraviolet portion of the solar spectrum contains a wealth of diagnostic tools for probing the lower solar atmosphere in response to an injection of energy, particularly during the impulsive phase of solar flares. These include temperature and density sensitive line ratios, Doppler shifted emission lines and nonthermal broadening, abundance measurements, differential emission measure profiles, and continuum temperatures and energetics, among others. In this paper I shall review some of the advances made in recent years using these techniques, focusing primarily on studies that have utilized data from Hinode/EIS and SDO/EVE, while also providing some historical background and a summary of future spectroscopic instrumentation.Comment: 34 pages, 8 figures. Submitted to Solar Physics as part of the Topical Issue on Solar and Stellar Flare

Myosin-I nomenclature.

We suggest that the vertebrate myosin-I field adopt a common nomenclature system based on the names adopted by the Human Genome Organization (HUGO). At present, the myosin-I nomenclature is very confusing; not only are several systems in use, but several different genes have been given the same name. Despite their faults, we believe that the names adopted by the HUGO nomenclature group for genome annotation are the best compromise, and we recommend universal adoption

Multi-label classification using ensembles of pruned sets

This paper presents a Pruned Sets method (PS) for multi-label classification. It is centred on the concept of treating sets of labels as single labels. This allows the classification process to inherently take into account correlations between labels. By pruning these sets, PS focuses only on the most important correlations, which reduces complexity and improves accuracy. By combining pruned sets in an ensemble scheme (EPS), new label sets can be formed to adapt to irregular or complex data. The results from experimental evaluation on a variety of multi-label datasets show that [E]PS can achieve better performance and train much faster than other multi-label methods

Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

ABSTRACT Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (∼15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation byproducts of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic b-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair

Language and theory of mind in autism spectrum disorder : the relationship between complement syntax and false belief task performance.

This study aimed to test the hypothesis that children with autism spectrum disorder (ASD) use their knowledge of complement syntax as a means of “hacking out” solutions to false belief tasks, despite lacking a representational theory of mind (ToM). Participants completed a “memory for complements” task, a measure of receptive vocabulary, and traditional location change and unexpected contents false belief tasks. Consistent with predictions, the correlation between complement syntax score and location change task performance was significantly stronger within the ASD group than within the comparison group. However, contrary to predictions, complement syntax score was not significantly correlated with unexpected contents task performance within either group. Possible explanations for this pattern of results are considered

Neonatal Lipopolysaccharide Exposure Delays Puberty and Alters Hypothalamic Kiss1 and Kiss1r mRNA Expression in the Female Rat

Immunological challenge experienced in early life can have long-term programming effects on the hypothalamic-pituitary-adrenal axis that permanently influence the stress response. Similarly, neonatal exposure to immunological stress enhances stress-induced suppression of the hypothalamic-pituitary gonadal (HPG) axis in adulthood, but may also affect earlier development, including the timing of puberty. To investigate the timing of the critical window for this programming of the HPG axis, neonatal female rats were injected with lipopolysaccharide (LPS; 50 μg/kg i.p.) or saline on postnatal days 3 + 5, 7 + 9, or 14 + 16 and monitored for vaginal opening and first vaginal oestrus as markers of puberty. We also investigated the effects of neonatal programming on the development of the expression patterns of kisspeptin (Kiss1) and its receptor (Kiss1r) in hypothalamic sites known to contain kisspeptin-expressing neuronal populations critical to reproductive function: the medial preoptic area (mPOA) and the arcuate nucleus in neonatally-stressed animals. We determined that the critical period for a significant delay in puberty as a result of neonatal LPS exposure is before 7 days of age in the female rat, and demonstrated that Kiss1, but not Kiss1r mRNA, expression in the mPOA is down-regulated in pre-pubertal females. These data suggest that the mPOA population of kisspeptin neurones play a pivotal role in controlling the onset of puberty, and that their function can be affected by neonatal stress

A six-parameter space to describe galaxy diversification

Galaxy diversification proceeds by transforming events like accretion, interaction or mergers. These explain the formation and evolution of galaxies that can now be described with many observables. Multivariate analyses are the obvious tools to tackle the datasets and understand the differences between different kinds of objects. However, depending on the method used, redundancies, incompatibilities or subjective choices of the parameters can void the usefulness of such analyses. The behaviour of the available parameters should be analysed before an objective reduction of dimensionality and subsequent clustering analyses can be undertaken, especially in an evolutionary context. We study a sample of 424 early-type galaxies described by 25 parameters, ten of which are Lick indices, to identify the most structuring parameters and determine an evolutionary classification of these objects. Four independent statistical methods are used to investigate the discriminant properties of the observables and the partitioning of the 424 galaxies: Principal Component Analysis, K-means cluster analysis, Minimum Contradiction Analysis and Cladistics. (abridged)Comment: Accepted for publicationin A\&