Three-dimensional full-field X-ray orientation microscopy

International audienceA previously introduced mathematical framework for full-field X-ray orientation microscopy is for the first time applied to experimental near-field diffraction data acquired from a polycrystalline sample. Grain by grain tomographic reconstructions using convex optimization and prior knowledge are carried out in a six-dimensional representation of position-orientation space, used for modelling the inverse problem of X-ray orientation imaging. From the 6D reconstruction output we derive 3D orientation maps, which are then assembled into a common sample volume. The obtained 3D orientation map is compared to an EBSD surface map and local misorientations, as well as remaining discrepancies in grain boundary positions are quantified. The new approach replaces the single orientation reconstruction scheme behind X-ray diffraction contrast tomography and extends the applicability of this diffraction imaging technique to material micro-structures exhibiting sub-grains and/or intra-granular orientation spreads of up to a few degrees. As demonstrated on textured sub-regions of the sample, the new framework can be extended to operate on experimental raw data, thereby bypassing the concept of orientation indexation based on diffraction spot peak positions. This new method enables fast, three-dimensional characterization with isotropic spatial resolution, suitable for time-lapse observations of grain microstructures evolving as a function of applied strain or temperature

High-Resolution Modeling of the Dust and Water Cycles with the NASA Ames Mars Global Climate Model

NASAs Mars Climate Modeling Center at Ames Research Center is currently undergoing an exciting period of growth in personnel, modeling capabilities, and science productivity. We are transitioning from our legacy Arakawa C-grid finite-difference dynamical core to the NOAA/GFDL cubed-sphere finite-volume dynamical core for simulating the climate of Mars in a global framework. This highly parallelized core is scalable and flexible, which allows for significant improvements in the horizontal and vertical resolutions of our simulations. We have implemented the Ames water ice cloud microphysics package described in Haberle et al. (2018) into this new dynamical core. We will present high-resolution simulations of the dust and water cycles that show that sub-degree horizontal resolution improves the agreement between the vertical distribution of dust and water ice and observations. In particular, both water ice clouds and dust are transported to higher altitudes due to stronger topographic circulations at high resolution. Preliminary results suggest that high-resolution global modeling is needed to properly capture critical features of the dust and water cycles, and thus the current Mars climate

Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier

Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

MICROSCOPE mission: first results of a space test of the equivalence principle

According to the weak equivalence principle, all bodies should fall at the same rate in a gravitational field. The MICROSCOPE satellite, launched in April 2016, aims to test its validity at the 10−15 precision level, by measuring the force required to maintain two test masses (of titanium and platinum alloys) exactly in the same orbit. A nonvanishing result would correspond to a violation of the equivalence principle, or to the discovery of a new long-range force. Analysis of the first data gives δ(Ti,Pt)=[−1±9(stat)±9(syst)]×10−15 (1σ statistical uncertainty) for the titanium-platinum Eötvös parameter characterizing the relative difference in their free-fall accelerations

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Deformation of aluminum in situ SEM and full field measurements by digital image correlation: evidence of concomitant crystal slip and grain boundary sliding

Mechanical testing in situ scanning electron microscopy (SEM) has become a standard technique for multiscale micromechanical investigation of polycrystalline materials. Direct observation of developing strain heterogeneities allows identification of the active mechanisms and quantification of their respective contributions to the overall strain. We developed a novel experimental setup for thermomechanical testing in situ SEM, especially suited to full strain field measurements. These are based on digital image correlation (DIC), from the sample scale to the scales of the aggregate and the single grain. We present results obtained during simple compression, at controlled displacement rates and at temperatures up to 400°C, of nearly pure polycrystalline aluminum exhibiting randomly oriented coarse grains (ca. 300 m in size). Electron microlithography was applied to produce specific surface marking patterns appropriate for the different scales of interest. Full surface strain fields were obtained by digital image correlation (DIC) analysis. The localization patterns evidenced dominant crystal slip plasticity, but also substantial simultaneous and continuous activity of grain boundary sliding (GBS), the contribution of which increased with temperature. We therefore advocate that experiments such as these here presented are necessary to go beyond a description in terms of deformation mechanism maps, which attribute deformation to a single mechanism

Deformation of aluminum in situ SEM and full field measurements by digital image correlation: evidence of concomitant crystal slip and grain boundary sliding

International audienceMechanical testing in situ scanning electron microscopy (SEM) has become a standard technique for multiscale micromechanical investigation of polycrystalline materials. Direct observation of developing strain heterogeneities allows identification of the active mechanisms and quantification of their respective contributions to the overall strain. We developed a novel experimental setup for thermomechanical testing in situ SEM, especially suited to full strain field measurements. These are based on digital image correlation (DIC), from the sample scale to the scales of the aggregate and the single grain. We present results obtained during simple compression, at controlled displacement rates and at temperatures up to 400°C, of nearly pure polycrystalline aluminum exhibiting randomly oriented coarse grains (ca. 300 m in size). Electron microlithography was applied to produce specific surface marking patterns appropriate for the different scales of interest. Full surface strain fields were obtained by digital image correlation (DIC) analysis. The localization patterns evidenced dominant crystal slip plasticity, but also substantial simultaneous and continuous activity of grain boundary sliding (GBS), the contribution of which increased with temperature. We therefore advocate that experiments such as these here presented are necessary to go beyond a description in terms of deformation mechanism maps, which attribute deformation to a single mechanism