Finding and Characterising Active Slip Systems: A Short Review and Tutorial with Automation Tools.

The behaviour of many materials is strongly influenced by the mechanical properties of hard phases, present either from deliberate introduction for reinforcement or as deleterious precipitates. While it is, therefore, self-evident that these phases should be studied, the ability to do so-particularly their plasticity-is hindered by their small sizes and lack of bulk ductility at room temperature. Many researchers have, therefore, turned to small-scale testing in order to suppress brittle fracture and study the deformation mechanisms of complex crystal structures. To characterise the plasticity of a hard and potentially anisotropic crystal, several steps and different nanomechanical testing techniques are involved, in particular nanoindentation and microcompression. The mechanical data can only be interpreted based on imaging and orientation measurements by electron microscopy. Here, we provide a tutorial to guide the collection, analysis, and interpretation of data on plasticity in hard crystals. We provide code collated in our group to help new researchers to analyse their data efficiently from the start. As part of the tutorial, we show how the slip systems and deformation mechanisms in intermetallics such as the Fe7Mo6 µ-phase are discovered, where the large and complex crystal structure precludes determining a priori even the slip planes in these phases. By comparison with other works in the literature, we also aim to identify "best practises" for researchers throughout to aid in the application of the methods to other materials systems.

Data on measurement of the strain partitioning in a multiphase Zn-Al eutectic alloy.

This paper presents original data related to the research article "Local mechanical properties and plasticity mechanisms in a Zn-Al eutectic alloy" (Wu et al., 2018). The raw data provided here was used for in-situ digital image correlation on the microstructural level using a new method described in the related study. The data includes sample preparation details, image acquisition and data processing. The described approach provides an approach to quantify the local strain distribution and strain partitioning in multiphase microstructures.

Non-Newtonian Flow to the Theoretical Strength of Glasses via Impact Nanoindentation at Room Temperature.

In many daily applications glasses are indispensable and novel applications demanding improved strength and crack resistance are appearing continuously. Up to now, the fundamental mechanical processes in glasses subjected to high strain rates at room temperature are largely unknown and thus guidelines for one of the major failure conditions of glass components are non-existent. Here, we elucidate this important regime for the first time using glasses ranging from a dense metallic glass to open fused silica by impact as well as quasi-static nanoindentation. We show that towards high strain rates, shear deformation becomes the dominant mechanism in all glasses accompanied by Non-Newtonian behaviour evident in a drop of viscosity with increasing rate covering eight orders of magnitude. All glasses converge to the same limit stress determined by the theoretical hardness, thus giving the first experimental and quantitative evidence that Non-Newtonian shear flow occurs at the theoretical strength at room temperature.

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. METHODS: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. FINDINGS: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. INTERPRETATION: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials. FUNDING: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation.

BACKGROUND: Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures. AIM: To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy. METHODS: A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers. RESULTS: Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31). DISCUSSION: We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.