Crystallographic Education in the 21st Century

There are many methods that can be used to incorporate concepts of crystallography into the learning experiences of students, whether they are in elementary school, at university or part of the public at large. It is not always critical that those who teach crystallography have immediate access to diffraction equipment to be able to introduce the concepts of symmetry, packing or molecular structure in an age- and audience-appropriate manner. Crystallography can be used as a tool for teaching general chemistry concepts as well as general research techniques without ever having a student determine a crystal structure. Thus, methods for younger students to perform crystal growth experiments of simple inorganic salts, organic compounds and even metals are presented. For settings where crystallographic instrumentation is accessible (proximally or remotely), students can be involved in all steps of the process, from crystal growth, to data collection, through structure solution and refinement, to final publication. Several approaches based on the presentations in the MS92 Microsymposium at the IUCr 23rd Congress and General Assembly are reported. The topics cover methods for introducing crystallography to undergraduate students as part of a core chemistry curriculum; a successful short-course workshop intended to bootstrap researchers who rely on crystallography for their work; and efforts to bring crystallography to secondary school children and non-science majors. In addition to these workshops, demonstrations and long-format courses, open-format crystallographic databases and three-dimensional printed models as tools that can be used to excite target audiences and inspire them to pursue a deeper understanding of crystallography are described

Influence of Yb:YAG laser beam parameters on Haynes 188 weld fusion zone microstructure and mechanical properties

The weldability of 1.2 mm thick Haynes 188 alloy sheets by a disk Yb:YAG laser welding was examined. Butt joints were made, and the influence of parameters such as power, size, and shape of the spot, welding speed, and gas flow has been investigated. Based on an iconographic correlation approach, optimum process parameters were determined. Depending on the distribution of the power density (circular or annular), acceptable welds were obtained. Powers greater than 1700 W, welding speeds higher than 3.8 m mm1, and spot sizes between 160 and 320 lm were needed in the circular (small fiber) configuration. By comparison, the annular (large fiber) configuration required a power as high as 2500 W, and a welding speed less than 3.8 m min�1. The mechanical properties of the welds depended on their shape and microstructure, which in turn depended on the welding conditions. The content of carbides, the proportion of areas consisting of cellular and dendritic substructures, and the size of these substructures were used to explain the welded joint mechanical properties

Asgard/NOTT: L-band nulling interferometry at the VLTI I. Simulating the expected high-contrast performance

Context: NOTT (formerly Hi-5) is a new high-contrast L' band (3.5-4.0 \textmu m) beam combiner for the VLTI with the ambitious goal to be sensitive to young giant exoplanets down to 5 mas separation around nearby stars. The performance of nulling interferometers in these wavelengths is affected both by fundamental noise from the background and by the contributions of instrumental noises. This motivates the development of end-to-end simulations to optimize these instruments. Aims: To enable the performance evaluation and inform the design of such instruments on the current and future infrastructures, taking into account the different sources of noise, and their correlation. Methods: SCIFYsim is an end-to-end simulator for single mode filtered beam combiners, with an emphasis on nulling interferometers. It is used to compute a covariance matrix of the errors. Statistical detection tests based on likelihood ratios are then used to compute compound detection limits for the instrument. Results: With the current assumptions on the performance of the wavefront correction systems, the errors are dominated by correlated instrumental errors down to stars of magnitude 6-7 in the L band, beyond which thermal background from the telescopes and relay system becomes dominant. Conclusions: SCIFYsim is suited to anticipate some of the challenges of design, tuning, operation and signal processing for integrated optics beam combiners. The detection limits found for this early version of NOTT simulation with the unit telescopes are compatible with detections at contrasts up to $10^5$ in the L band at separations of 5 to 80 mas around bright stars

Spectral study of the diffuse synchrotron source in the galaxy cluster Abell 523

The galaxy cluster Abell 523 (A523) hosts an extended diffuse synchrotron source historically classified as a radio halo. Its radio power at 1.4 GHz makes it one of the most significant outliers in the scaling relations between observables derived from multiwavelength observations of galaxy clusters: it has a morphology that is different and offset from the thermal gas, and it has polarized emission at 1.4 GHz typically difficult to observe for this class of sources. A magnetic field fluctuating on large spatial scales (similar to 1 Mpc) can explain these peculiarities but the formation mechanism for this source is not yet completely clear. To investigate its formation mechanism, we present new observations obtained with the LOw Frequency ARray at 120-168 MHz and the Jansky Very Large Array at 1-2 GHz, which allow us to study the spectral index distribution of this source. According to our data the source is observed to be more extended at 144 MHz than previously inferred at 1.4 GHz, with a total size of about 1.8 Mpc and a flux density S-144 MHz = (1.52 +/- 0.31) Jy. The spectral index distribution of the source is patchy with an average spectral index alpha similar to 1.2 between 144 MHz and 1.410 GHz, while an integrated spectral index alpha similar to 2.1 has been obtained between 1.410 and 1.782 GHz. A previously unseen patch of steep spectrum emission is clearly detected at 144 MHz in the south of the cluster. Overall, our findings suggest that we are observing an overlapping of different structures, powered by the turbulence associated with the primary and a possible secondary merger.Peer reviewe

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency

Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway : a meta-analysis

Aims/hypothesis Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Methods Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. Results In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (beta +/- SE 0.014 +/- 0.004 [mmol/l], p = 1.5 x 10(-3)) and higher fasting insulin (0.030 +/- 0.005 [log(e) pmol/l], p = 2.0 x 10(-10)). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the beta-Klotho (KLB) locus on fasting insulin (0.030 +/- 0.011 log(e) pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. Conclusions/interpretation In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.Peer reviewe

Requirement of NOX2 and Reactive Oxygen Species for Efficient RIG-I-Mediated Antiviral Response through Regulation of MAVS Expression

The innate immune response is essential to the host defense against viruses, through restriction of virus replication and coordination of the adaptive immune response. Induction of antiviral genes is a tightly regulated process initiated mainly through sensing of invading virus nucleic acids in the cytoplasm by RIG-I like helicases, RIG-I or Mda5, which transmit the signal through a common mitochondria-associated adaptor, MAVS. Although major breakthroughs have recently been made, much remains unknown about the mechanisms that translate virus recognition into antiviral genes expression. Beside the reputed detrimental role, reactive oxygen species (ROS) act as modulators of cellular signaling and gene regulation. NADPH oxidase (NOX) enzymes are a main source of deliberate cellular ROS production. Here, we found that NOX2 and ROS are required for the host cell to trigger an efficient RIG-I-mediated IRF-3 activation and downstream antiviral IFNβ and IFIT1 gene expression. Additionally, we provide evidence that NOX2 is critical for the expression of the central mitochondria-associated adaptor MAVS. Taken together these data reveal a new facet to the regulation of the innate host defense against viruses through the identification of an unrecognized role of NOX2 and ROS

Analysis of Temperature-to-Polarization Leakage in BICEP3 and Keck CMB Data from 2016 to 2018

The Bicep/Keck Array experiment is a series of small-aperture refracting telescopes observing degree-scale Cosmic Microwave Background polarization from the South Pole in search of a primordial B-mode signature. As a pair differencing experiment, an important systematic that must be controlled is the differential beam response between the co-located, orthogonally polarized detectors. We use high-fidelity, in-situ measurements of the beam response to estimate the temperature-to-polarization (T → P) leakage in our latest data including observations from 2016 through 2018. This includes three years of Bicep3 observing at 95 GHz, and multifrequency data from Keck Array. Here we present band-averaged far-field beam maps, differential beam mismatch, and residual beam power (after filtering out the leading difference modes via deprojection) for these receivers. We show preliminary results of "beam map simulations," which use these beam maps to observe a simulated temperature (no Q/U) sky to estimate T → P leakage in our real data

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology