Structural Evaluation of EGFR Inhibition Mechanisms for Nanobodies/VHH Domains

SummaryThe epidermal growth factor receptor (EGFR) is implicated in human cancers and is the target of several classes of therapeutic agents, including antibody-based drugs. Here, we describe X-ray crystal structures of the extracellular region of EGFR in complex with three inhibitory nanobodies, the variable domains of heavy chain only antibodies (VHH). VHH domains, the smallest natural antigen-binding modules, are readily engineered for diagnostic and therapeutic applications. All three VHH domains prevent ligand-induced EGFR activation, but use two distinct mechanisms. 7D12 sterically blocks ligand binding to EGFR in a manner similar to that of cetuximab. EgA1 and 9G8 bind an epitope near the EGFR domain II/III junction, preventing receptor conformational changes required for high-affinity ligand binding and dimerization. This epitope is accessible to the convex VHH paratope but inaccessible to the flatter paratope of monoclonal antibodies. Appreciating the modes of binding and inhibition of these VHH domains will aid in developing them for tumor imaging and/or cancer therapy

Searching for z~7.7 Lyman Alpha Emitters in the COSMOS Field with NEWFIRM

The study of Ly-alpha emission in the high-redshift universe is a useful probe of the epoch of reionization, as the Ly-alpha line should be attenuated by the intergalactic medium (IGM) at low to moderate neutral hydrogen fractions. Here we present the results of a deep and wide imaging search for Ly-alpha emitters in the COSMOS field. We have used two ultra-narrowband filters (filter width of ~8-9 {\deg}A) on the NEWFIRM camera, installed on the Mayall 4m telescope at Kitt Peak National Observatory, in order to isolate Ly-alpha emitters at z = 7.7; such ultra-narrowband imaging searches have proved to be excellent at detecting Ly-alpha emitters. We found 5-sigma detections of four candidate Ly-alpha emitters in a survey volume of 2.8 x 10^4 Mpc^3 (total survey area ~760 arcmin^2). Each candidate has a line flux greater than 8 x 10^-18 erg s^-1 cm^-2. Using these results to construct a luminosity function and comparing to previously established Ly-alpha luminosity functions at z = 5.7 and z = 6.5, we find no conclusive evidence for evolution of the luminosity function between z = 5.7 and z = 7.7. Statistical Monte Carlo simulations suggest that half of these candidates are real z = 7.7 targets, and spectroscopic follow-up will be required to verify the redshift of these candidates. However, our results are consistent with no strong evolution in the neutral hydrogen fraction of the IGM between z = 5.7 and z = 7.7, even if only one or two of the z = 7.7 candidates are spectroscopically confirmed.Comment: 29 pages, 5 figures, accepted to ApJ (12/11

Sheep Updates 2009

This session covers seven papers from different authors: 1. Scouring Management and Worm Control, Brown Besier, Department of Agriculture and Food, Western Australia 2.Breeding sheep for resistance to breech strike:- Selection results in WA, LJE Karlsson, JC Greeff & AC Schlink, Department of Agriculture and Food, Western Australia 3.Future Ewe - matching genetics to the production system, Mark Ferguson, Department of Agriculture and Food, Western Australia 4. Within-flock selection of ewes: opportunities for gains in reproduction, Greg Leeand Sue Hatcher, NSW Department of Primary Industries & Australian CRCforSheep Industry Innovation (Orange) 5. Managing Merinos on Murrayfield, Bruce Michael, Murryfield, Bruny Island, Tasmania 6. Managing [breech] flystrike in [unmulesed] sheep, Rob Woodgate, Darren Michael, Mandy Curnow and Julia Smith, Department of Agriculture and Food, Western Australia 7. Value of Pregnancy Scanning and Differential Feeding of Dry, Single amd Twin Ewes, John Young, Farming Systems Analysis Service, Kojonup, WA, Andrew Thompson, Chris Oldham Department of Agriculture and Food, Western Australi

Effect of mental rotation skills training on ultrasound-guided regional anaesthesia task performance by novice operators: a rater-blinded, randomised, controlled study

© 2020 British Journal of Anaesthesia Background: The effect of mental rotation training on ultrasound-guided regional anaesthesia (UGRA) skill acquisition is currently unknown. In this study we aimed to examine whether mental rotation skill training can improve UGRA task performance by novice operators. Methods: We enrolled 94 volunteers with no prior experience of UGRA in this randomised controlled study. After a baseline mental rotation test, their performance in a standardised UGRA needling task was independently assessed by two raters using the composite error score (CES) and global rating scale (GRS). Volunteers with low baseline mental rotation ability were randomised to a mental rotation training group or a no training group, and the UGRA needling task was repeated to determine the impact of the training intervention on task performance. The study primary outcome measure was UGRA needling task CES measured before and after the training intervention. Results: Multivariate analyses controlling for age, gender, and previous performance showed that participants exposed to the training intervention made significantly fewer errors (CES B=-0.66 [standard error, SE=0.17];

Sources, behaviour and mitigation strategies influencing indoor air quality

The particulate impact on air quality of typical domestic behaviours (e.g. cleaning and cooking) and their potential mitigation strategies (e.g. increasing ventilation) was investigated in the DOMESTIC unit at University of Chester. A 'typical day' based on the UK Time Use Survey of 2014-15 and tested under 2 separate ventilation conditions for 2 days each. This clearly indicated the impacts of different activities and the reduction of particulate levels with higher ventilation

Investigation of a Neuronal Nitric Oxide Synthase Gene (NOS1) Polymorphism in a Multiple Sclerosis Population

Multiple Sclerosis (MS) is a chronic neurological disease characterized by demyelination associated with infiltrating white blood cells in the central nervous system (CNS). Nitric oxide synthases (NOS) are a family of enzymes that control the production of nitric oxide. It is possible that neuronal NOS could be involved in MS pathophysiology and hence the nNOS gene is a potential candidate for involvement in disease susceptibility. The aim of this study was to determine whether allelic variation at the nNOS gene locus is associated with MS in an Australian cohort. DNA samples obtained from a Caucasian Australian population affected with MS and an unaffected control population, matched for gender, age and ethnicity, were genotyped for a microsatellite polymorphism in the promoter region of the nNOS gene. Allele frequencies were compared using chi-squared based statistical analyses with significance tested by Monte Carlo simulation. Allelic analysis of MS cases and controls produced a chi-squared value of 5.63 with simulated P=0.96 (OR(max)=1.41, 95% CI: 0.926-2.15). Similarly, a Mann-Whitney U analysis gave a non-significant P-value of 0.377 for allele distribution. No differences in allele frequencies were observed for gender or clinical course subtype (P>0.05). Statistical analysis indicated that there is no association of this nNOS variant and MS and hence the gene does not appear to play a genetically significant role in disease susceptibility

A global outlook on increasing wildfire risk:current policy situation and future pathways

International audienc