Peptidoglycan detection by mammals and flies

Peptidoglycan is an essential component of bacteria. The host exploits the peptidoglycan particular composition and uniqueness to bacteria for specific bacterial recognition. Insects and mammals accomplish this via receptors such as PGRP and Nod proteins.     

Using molecular and crowd-sourcing methods to assess breeding ground diet of a migratory brood parasite of conservation concern

Breeding ground food availability is critical to the survival and productivity of adult birds. The common cuckoo Cuculus canorus is a brood-parasitic Afro-Palearctic migrant bird exhibiting long-term (breeding) population declines in many European countries. Variation in population trend between regions and habitats suggests breeding ground drivers such as adult food supply. However, cuckoo diet has not been studied in detail since before the most significant population declines in Europe began in the mid-1980s. 20th century studies of cuckoo diet largely comprised field observations likely to carry bias towards larger prey taxa. Here we demonstrate the potential value of 1) using high-throughput DNA sequencing of invertebrate prey in faeces to determine cuckoo diet with minimal bias towards large prey taxa, and 2) using crowd-sourced digital photographs from across Britain to identify lepidopteran cuckoo prey taxa during recent years post-decline (2005–2016). DNA analysis found a high frequency of Lepidoptera, including moths of family Lasiocampidae, prominent within the past literature, but also grasshoppers (Orthoptera) and flies (Diptera) that may be overlooked by field observation methodologies. The range of larval lepidopteran prey identified from photographs largely agreed with those previously documented, with potential signs of reduced diversity, and identities of key adult prey taxa were supported by molecular results. Notably, many identified cuckoo prey taxa have shown severe declines due to agricultural intensification, suggesting this has driven spatial patterns of cuckoo loss. Landscape-scale, lowland rewilding interventions provide opportunities to understand the scale of reversal of previous agricultural intensification that may be necessary to restore prey populations sufficiently to permit recolonization by cuckoos.     

Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties

Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.     

Patterns of spontaneous activity in single rat olfactory receptor neurons are different in normally breathing and tracheotomized animals

Spontaneous firing of olfactory receptor neurons (ORNs) was recently shown to be required for the survival of ORNs and the maintenance of their appropriate synaptic connections with mitral cells in the olfactory bulb. ORN spontaneous activity has never been described or characterized quantitatively in mammals. To do so we have made extracellular single unit recordings from ORNs of freely breathing (FB) and tracheotomized (TT) rats. We show that the firing behavior of TT neurons was relatively simple: they tended to fire spikes at the same average frequency according to purely random (Poisson) or simple (Gamma or Weibull) statistical laws. A minority of them were bursting with relatively infrequent and short bursts. The activity of FB neurons was less simple: their firing rates were more diverse, some of them showed trends or were driven by breathing. Although more of them were regular, only a minority could be described by simple laws; the majority displayed random bursts with more spikes than the bursts of TT neurons. In both categories bursts and isolated spikes (outside bursts) occurred completely at random. The spontaneous activity of ORNs in rats resembles that of frogs, but is higher, which may be due to a difference in body temperature. These results suggest that, in addition to the intrinsic thermal noise, spontaneous activity is provoked in part by mechanical, thermal, or chemical (odorant molecules) effects of air movements due to respiration, this extrinsic part being naturally larger in FB neurons. It is suggested that spontaneous activity may be modulated by respiration. Because natural sampling of odors is synchronized with breathing, such modulation may prepare and keep olfactory bulb circuits tuned to process odor stimuli.     

Delivery of extraterrestrial amino acids to the primitive Earth. Exposure experiments in Earth orbit.

A large collection of micrometeorites has been recently extracted from Antarctic old blue ice. In the 50 to 100 micrometers size range, the carbonaceous micrometeorites represent 80% of the samples and contain 2% of carbon. They might have brought more carbon to the surface of the primitive Earth than that involved in the present surficial biomass. Amino acids such as "-amino isobutyric acid have been identified in these Antarctic micrometeorites. Enantiomeric excesses of L-amino acids have been detected in the Murchison meteorite. A large fraction of homochiral amino acids might have been delivered to the primitive Earth via meteorites and micrometeorites. Space technology in Earth orbit offers a unique opportunity to study the behaviour of amino acids required for the development of primitive life when they are exposed to space conditions, either free or associated with tiny mineral grains mimicking the micrometeorites. Our objectives are to demonstrate that porous mineral material protects amino acids in space from photolysis and racemization (the conversion of L-amino acids into a mixture of L- and D-molecules) and to test whether photosensitive amino acids derivatives can polymerize in mineral grains under space conditions. The results obtained in BIOPAN-1 and BIOPAN-2 exposure experiments on board unmanned satellite FOTON are presented.     

The first laminin G-like domain of protein S is essential for binding and activation of Tyro3 receptor and intracellular signalling

The homologous proteins Gas6 and protein S (ProS1) are both natural ligands for the TAM (Tyro3, Axl, MerTK) receptor tyrosine kinases. ProS1 selectively activates Tyro3; however, the precise molecular interface of the ProS1-Tyro3 contact has not been characterised. We used a set of chimeric proteins in which each of the C-terminal laminin G-like (LG) domains of ProS1 were swapped with those of Gas6, as well as a set of ProS1 mutants with novel added glycosylations within LG1. Alongside wildtype ProS1, only the chimera containing ProS1 LG1 domain stimulated Tyro3 and Erk phosphorylation in human cancer cells, as determined by Western blot. In contrast, Gas6 and chimeras containing minimally the Gas6 LG1 domain stimulated Axl and Akt phosphorylation. We performed in silico homology modelling and molecular docking analysis to construct and evaluate structural models of both ProS1-Tyro3 and Gas6-Axl ligand-receptor interactions. These analyses revealed a contact between the ProS1 LG1 domain and the first immunoglobulin domain of Tyro3, which was similar to the Gas6-Axl interaction, and involved long-range electrostatic interactions that were further stabilised by hydrophobic and polar contacts. The mutant ProS1 proteins, which had added glycosylations within LG1 but which were all outside of the modelled contact region, all activated Tyro3 in cells with no hindrance. In conclusion, we show that the LG1 domain of ProS1 is necessary for activation of the Tyro3 receptor, involving protein-protein interaction interfaces that are homologous to those of the Gas6-Axl interaction.