Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians

OBJECTIVE— Recent genome-wide association studies have identified six novel genes for type 2 diabetes and obesity and confirmed TCF7L2 as the major type 2 diabetes gene to date in Europeans. However, the implications of these genes in Asians are unclear

On the dispersion of solid particles in a liquid agitated by a bubble swarm

This article deals with the dispersion of solid particles in a liquid agitated by a homogeneous swarm of bubbles. The scale of interest lies between the plant scale (of the order of the tank) and the microscale (less than the bubble diameter). The strategy consists in simulating both the twophase flow of deforming bubbles and the motion of solid particles. The evolution of the spatial distribution of particles together with the encounter and entrainment phenomena is studied as a function of the void fraction and the relative size and mass of particles. The influence of the shape of the bubble and of the model of forces that govern the motion of particles is also considered

Proteogenomic integration reveals therapeutic targets in breast cancer xenografts

Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities

2022 Upgrade and Improved Low Frequency Camera Sensitivity for CMB Observation at the South Pole

Constraining the Galactic foregrounds with multi-frequency Cosmic Microwave Background (CMB) observations is an essential step towards ultimately reaching the sensitivity to measure primordial gravitational waves (PGWs), the sign of inflation after the Big-Bang that would be imprinted on the CMB. The BICEP Array telescope is a set of multi-frequency cameras designed to constrain the energy scale of inflation through CMB B-mode searches while also controlling the polarized galactic foregrounds. The lowest frequency BICEP Array receiver (BA1) has been observing from the South Pole since 2020 and provides 30 GHz and 40 GHz data to characterize the Galactic synchrotron in our CMB maps. In this paper, we present the design of the BA1 detectors and the full optical characterization of the camera including the on-sky performance at the South Pole. The paper also introduces the design challenges during the first observing season including the effect of out-of-band photons on detectors performance. It also describes the tests done to diagnose that effect and the new upgrade to minimize these photons, as well as installing more dichroic detectors during the 2022 deployment season to improve the BA1 sensitivity. We finally report background noise measurements of the detectors with the goal of having photon noise dominated detectors in both optical channels. BA1 achieves an improvement in mapping speed compared to the previous deployment season.Comment: Proceedings of SPIE Astronomical Telescopes + Instrumentation 2022 (AS22

A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF < 1 %), compared to imputation using the SNP chip alone. Also, we investigated the systematic effect of reference panels on imputation quality using five reference panels and three genotype panels. The best performing approach was the combination of the study specific reference panel and the genotype panel of combined data. Conclusions: Our study demonstrates that combined datasets, including SNP chips and exome chips, enhances both the imputation quality and genomic coverage of rare variants

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Measurement of the W+W- Production Cross Section in ppbar Collisions at sqrt(s)=1.96 TeV using Dilepton Events

We present a measurement of the W+W- production cross section using 184/pb of ppbar collisions at a center-of-mass energy of 1.96 TeV collected with the Collider Detector at Fermilab. Using the dilepton decay channel W+W- -> l+l-vvbar, where the charged leptons can be either electrons or muons, we find 17 candidate events compared to an expected background of 5.0+2.2-0.8 events. The resulting W+W- production cross section measurement of sigma(ppbar -> W+W-) = 14.6 +5.8 -5.1 (stat) +1.8 -3.0 (syst) +-0.9 (lum) pb agrees well with the Standard Model expectation.Comment: 8 pages, 2 figures, 2 tables. To be submitted to Physical Review Letter

ϒ production in p–Pb collisions at √sNN=8.16 TeV

ϒ production in p–Pb interactions is studied at the centre-of-mass energy per nucleon–nucleon collision √sNN = 8.16 TeV with the ALICE detector at the CERN LHC. The measurement is performed reconstructing bottomonium resonances via their dimuon decay channel, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and −4.46 < ycms < −2.96, down to zero transverse momentum. In this work, results on the ϒ(1S) production cross section as a function of rapidity and transverse momentum are presented. The corresponding nuclear modification factor shows a suppression of the ϒ(1S) yields with respect to pp collisions, both at forward and backward rapidity. This suppression is stronger in the low transverse momentum region and shows no significant dependence on the centrality of the interactions. Furthermore, the ϒ(2S) nuclear modification factor is evaluated, suggesting a suppression similar to that of the ϒ(1S). A first measurement of the ϒ(3S) has also been performed. Finally, results are compared with previous ALICE measurements in p–Pb collisions at √sNN = 5.02 TeV and with theoretical calculations.publishedVersio