A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing

RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize and activate RET stimulating its cytoplasmic kinase function. The principles for RET ligand-co-receptor recognition are incompletely understood. Here, we report a crystal structure of the cadherin-like module (CLD1-4) from zebrafish RET revealing interdomain flexibility between CLD2 and CLD3. Comparison with a cryo-electron microscopy structure of a ligand-engaged zebrafish RETECD-GDNF-GFRα1a complex indicates conformational changes within a clade-specific CLD3 loop adjacent to the co-receptor. Our observations indicate that RET is a molecular clamp with a flexible calcium-dependent arm that adapts to different GFRα co-receptors, while its rigid arm recognizes a GFL dimer to align both membrane-proximal cysteine-rich domains. We also visualize linear arrays of RETECD-GDNF-GFRα1a suggesting that a conserved contact stabilizes higher-order species. Our study reveals that ligand-co-receptor recognition by RET involves both receptor plasticity and strict spacing of receptor dimers by GFL ligands

Characterization of large area avalanche photodiodes in X-ray and VUV-light detection

The present manuscript summarizes novel studies on the application of large area avalanche photodiodes (LAAPDs) to the detection of X-rays and vacuum ultraviolet (VUV) light. The operational characteristics of four different LAAPDs manufactured by Advanced Photonix Inc., with active areas of 80 and 200 mm^2 were investigated for X-ray detection at room temperature. The best energy resolution was found to be in the 10-18% range for 5.9 keV X-rays. The LAAPD, being compact, simple to operate and with high counting rate capability (up to about 10^5/s), proved to be useful in several applications, such as low-energy X-ray detection, where they can reach better performance than proportional counters. Since X-rays are used as reference in light measurements, the gain non-linearity between 5.9 keV X-rays and light pulses was investigated. The gain ratio between X-rays and VUV light decreases with gain, reaching 10 and 6% variations for VUV light produced in argon (~128 nm) and xenon (~172 nm), respectively, for a gain 200, while for visible light (~635 nm) the variation is lower than 1%. The effect of temperature on the LAAPD performance was investigated. Relative gain variations of about -5% per Celsius degree were observed for the highest gains. The excess noise factor was found to be independent on temperature, being between 1.8 and 2.3 for gains from 50 to 300. The energy resolution is better for decreasing temperatures due mainly to the dark current. LAAPDs were tested under intense magnetic fields up to 5 T, being insensitive when used in X-ray and visible-light detection, while for VUV light a significant amplitude reduction was observed at 5 T.Comment: 25 pages, 40 figures, submitted to JINS

Characterization of large area avalanche photodiodes in X-ray and VUV-light detection

The present manuscript summarizes novel studies on the application of large area avalanche photodiodes (LAAPDs) to the detection of X-rays and vacuum ultraviolet (VUV) light. The operational characteristics of four different LAAPDs manufactured by Advanced Photonix Inc., with active areas of 80 and 200 mm^2 were investigated for X-ray detection at room temperature. The best energy resolution was found to be in the 10-18% range for 5.9 keV X-rays. The LAAPD, being compact, simple to operate and with high counting rate capability (up to about 10^5/s), proved to be useful in several applications, such as low-energy X-ray detection, where they can reach better performance than proportional counters. Since X-rays are used as reference in light measurements, the gain non-linearity between 5.9 keV X-rays and light pulses was investigated. The gain ratio between X-rays and VUV light decreases with gain, reaching 10 and 6% variations for VUV light produced in argon (~128 nm) and xenon (~172 nm), respectively, for a gain 200, while for visible light (~635 nm) the variation is lower than 1%. The effect of temperature on the LAAPD performance was investigated. Relative gain variations of about -5% per Celsius degree were observed for the highest gains. The excess noise factor was found to be independent on temperature, being between 1.8 and 2.3 for gains from 50 to 300. The energy resolution is better for decreasing temperatures due mainly to the dark current. LAAPDs were tested under intense magnetic fields up to 5 T, being insensitive when used in X-ray and visible-light detection, while for VUV light a significant amplitude reduction was observed at 5 T.Comment: 25 pages, 40 figures, submitted to JINS

Characterization of large area avalanche photodiodes in X-ray and VUV-light detection

The present manuscript summarizes novel studies on the application of large area avalanche photodiodes (LAAPDs) to the detection of X-rays and vacuum ultraviolet (VUV) light. The operational characteristics of four different LAAPDs manufactured by Advanced Photonix Inc., with active areas of 80 and 200 mm^2 were investigated for X-ray detection at room temperature. The best energy resolution was found to be in the 10-18% range for 5.9 keV X-rays. The LAAPD, being compact, simple to operate and with high counting rate capability (up to about 10^5/s), proved to be useful in several applications, such as low-energy X-ray detection, where they can reach better performance than proportional counters. Since X-rays are used as reference in light measurements, the gain non-linearity between 5.9 keV X-rays and light pulses was investigated. The gain ratio between X-rays and VUV light decreases with gain, reaching 10 and 6% variations for VUV light produced in argon (~128 nm) and xenon (~172 nm), respectively, for a gain 200, while for visible light (~635 nm) the variation is lower than 1%. The effect of temperature on the LAAPD performance was investigated. Relative gain variations of about -5% per Celsius degree were observed for the highest gains. The excess noise factor was found to be independent on temperature, being between 1.8 and 2.3 for gains from 50 to 300. The energy resolution is better for decreasing temperatures due mainly to the dark current. LAAPDs were tested under intense magnetic fields up to 5 T, being insensitive when used in X-ray and visible-light detection, while for VUV light a significant amplitude reduction was observed at 5 T.Comment: 25 pages, 40 figures, submitted to JINS

The Atacama Cosmology Telescope: A Catalog of >4000 Sunyaev–Zel’dovich Galaxy Clusters

We present a catalog of 4195 optically confirmed Sunyaev–Zel'dovich (SZ) selected galaxy clusters detected with signal-to-noise ratio >4 in 13,211 deg2 of sky surveyed by the Atacama Cosmology Telescope (ACT). Cluster candidates were selected by applying a multifrequency matched filter to 98 and 150 GHz maps constructed from ACT observations obtained from 2008 to 2018 and confirmed using deep, wide-area optical surveys. The clusters span the redshift range 0.04 1 clusters, and a total of 868 systems are new discoveries. Assuming an SZ signal versus mass-scaling relation calibrated from X-ray observations, the sample has a 90% completeness mass limit of M500c > 3.8 × 1014 M⊙, evaluated at z = 0.5, for clusters detected at signal-to-noise ratio >5 in maps filtered at an angular scale of 2farcm4. The survey has a large overlap with deep optical weak-lensing surveys that are being used to calibrate the SZ signal mass-scaling relation, such as the Dark Energy Survey (4566 deg2), the Hyper Suprime-Cam Subaru Strategic Program (469 deg2), and the Kilo Degree Survey (825 deg2). We highlight some noteworthy objects in the sample, including potentially projected systems, clusters with strong lensing features, clusters with active central galaxies or star formation, and systems of multiple clusters that may be physically associated. The cluster catalog will be a useful resource for future cosmological analyses and studying the evolution of the intracluster medium and galaxies in massive clusters over the past 10 Gyr

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Strong detection of the CMB lensing and galaxy weak lensing cross-correlation from ACT-DR4, Planck Legacy, and KiDS-1000

Large scale structure and cosmolog

Strong detection of the CMB lensing and galaxy weak lensing cross-correlation from ACT-DR4, Planck Legacy, and KiDS-1000

Large scale structure and cosmolog