A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing
to explore ...protein-altering variants and their consequences in 454,787 participants in the UK Biobank study
. We identified 12 million coding variants, including around 1 million loss-of-function and around 1.8 million deleterious missense variants. When these were tested for association with 3,994 health-related traits, we found 564 genes with trait associations at P ≤ 2.18 × 10
. Rare variant associations were enriched in loci from genome-wide association studies (GWAS), but most (91%) were independent of common variant signals. We discovered several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3). Six genes were associated with brain imaging phenotypes, including two involved in neural development (GBE1, PLD1). Of the signals available and powered for replication in an independent cohort, 81% were confirmed; furthermore, association signals were generally consistent across individuals of European, Asian and African ancestry. We illustrate the ability of exome sequencing to identify gene-trait associations, elucidate gene function and pinpoint effector genes that underlie GWAS signals at scale.
Abstract
Tough and impact-resistant ceramic systems offer a wide range of remarkable opportunities beyond those offered by the conventional brittle ceramics. However, despite their promise, the ...availability of traditional manufacturing technique for fabricating such advanced ceramic structures in a highly controllable and scalable manner poses a significant manufacturing bottleneck. In this study, a precise and programmable laser manufacturing system was used to manufacture topologically interlocking ceramics. This manufacturing strategy offers feasible mechanisms for a precise material architecture and quantitative process control, particularly when scalability is considered. An optimized material removal method that approaches near-net shaping was employed to fabricate topologically interlocking ceramic systems (load-carrying assemblies of building blocks interacting by contact and friction) with different architectures (i.e., interlocking angles and building block sizes) subjected to low-velocity impact conditions. These impacts were evaluated using 3D digital image correlation. The optimal interlocked ceramics exhibited a higher deformation (up to 310%) than the other interlocked ones advantageous for flexible protections. Their performance was tuned by controlling the interlocking angle and block size, adjusting the frictional sliding, and minimizing damage to the building blocks. In addition, the developed subtractive manufacturing technique leads to the fabrication of tough, impact-resistant, damage-tolerant ceramic systems with excellent versatility and scalability.
Combining high strength and high toughness still remains a challenge in engineered materials. With the aim of improving the toughness of high-strength ceramics, multilayered architectured ceramic ...panels were developed inspired by natural materials such as nacre and conch shell. These panels were manufactured by stacking laser-engraved architectured ceramic tiles and commercial monomer Surlyn or Ethylene-vinyl acetate (EVA) resins. The mechanics of the multilayered architectured ceramics was investigated both numerically and experimentally by subjecting them to out-of-plane quasi-static and impact loads. Digital image correlation (DIC), computed radiography technique, micro-CT scanning and 3D laser scanning microscopy were used for multiscale damage assessment during and after loading. The finite element analysis was performed using ANSYS LS-DYNA to model the quasi-static and impact responses and to investigate the effects of architectural parameters on the energy absorption and multi-hit capabilities of architectured ceramic panels. It was found that the multilayered ceramic panels with optimized architectures showed up to 20% and 48% improvements in energy absorption performance in quasi-static testing and impact loading, respectively, with only a 5–10% stiffness reduction compared to plain ceramics. The deformation analysis showed localized failure in the architectured ceramics (opposed to the plain ones) and improved impact resistance of architectured ceramics originating mostly from the energy dissipation due to the plastic deformation in adhesives (up to 35%) as well as the frictional energy dissipation (up to 55%) upon sliding of the tiles, mechanisms that are absent in plain ceramics.
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•Developing a fast and industry viable fabrication technique based on laser engraving for large scale nacre-like ceramics.•Revealing novel structure-performance relationships in architectured ceramics through combined static and impact testing.•Investigating multi-hit capability as well as extending design space of bio-inspired ceramics by tuning architectures.•Enriching geometry in multilayered ceramics to improve energy absorption by 20% in quasi-static and 48% in impact loads.
We report the discovery of T dwarf companions to the nearby stars HN Peg (G0 V, 18.4 pc, t 6 0.3 Gyr) and HD 3651 (K0 V, 11.1 pc, t 6 7 Gyr). During an ongoing survey of 5' x 5' fields surrounding ...stars in the solar neighborhood with the Infrared Array Camera aboard the Spitzer Space Telescope, we identified these companions as candidate T dwarfs based on their mid-infrared colors. Using near-infrared spectra obtained with SpeX at the NASA Infrared Telescope Facility, we confirm the presence of methane absorption that characterizes T dwarfs and measure spectral types of T2.5 c 0.5 and T7.5 c 0.5 for HN Peg B and HD 3651B, respectively. By comparing our Spitzer data to images from the Two Micron All Sky Survey obtained several years earlier, we find that the proper motions of HN Peg B and HD 3651B are consistent with those of the primaries, confirming their companionship. A comparison of their luminosities to the values predicted by theoretical evolutionary models implies masses of 0.021 c 0.009 and 0.051 c 0.014 M sub( )for HN Peg B and HD 3651B, respectively. In addition, the models imply an effective temperature for HN Peg B that is significantly lower than the values derived for other T dwarfs at similar spectral types, which is the same behavior reported by Metchev & Hillenbrand for the young late L dwarf HD 203030B. Thus, the temperature of the L/T transition appears to depend on surface gravity. Meanwhile, HD 3651B is the first substellar companion directly imaged around a star that is known to harbor a close-in planet from radial velocity surveys. The discovery of this companion supports the notion that the high eccentricities of close-in planets like that near HD 3651 may be the result of perturbations by low-mass companions at wide separations.
We report observations from the Spitzer Space Telescope regarding the frequency of 24 mu m excess emission toward Sun-like stars. Our unbiased sample is composed of 309 stars with masses 0.7-2.2 M ...unk and ages from <3 Myr to >3 Gyr that lack excess emission at wavelengths less than or equal to 8 mu m. We identify 30 stars that exhibit clear evidence of excess emission from the observed 24 mu m/8 mu m flux ratio. The implied 24 mu m excesses of these candidate debris disk systems range from 13% (the minimum detectable) to more than 100% compared to the expected photospheric emission. The frequency of systems with evidence for dust debris emitting at 24 mu m ranges from 8.5%-19% at ages <300 Myr to <4% for older stars. The results suggest that many, perhaps most, Sun-like stars might form terrestrial planets.
Ceramics offer many attractive properties including low-density, high compressive strength, remarkable thermal stability, and high oxidation/corrosion resistance. However, these materials suffer from ...brittleness, which substantially limits the range of their applications, where high toughness is required. This investigation draws inspiration from a concept of architectures with three-dimensional (3D) networks of weak interfaces targeting high toughness ceramics. In this study, a comprehensive method combining an advanced computational model with 3D digital image correlation (DIC) was developed to engineer bioinspired multilayered architectured ceramics and assesses their toughening and deformation mechanisms when subjected to a low-velocity impact load regime. A complete finite element (FE) analysis was conducted to precisely evaluate the crack growth and displacement field of the architectured ceramics and is compared to those of plain ceramics. The damage and displacement evolution results from FE analysis and experimental testing revealed that the primary source of toughening of the architectured ceramic systems is extrinsic, resulting from extensive crack deflection and delamination. Crack propagation along an irregular long path at the weak interfaces of architectured layers increased the toughness of the plain ceramics by two orders of magnitude. Based on the DIC data, both extrinsic and intrinsic toughening mechanisms were captured: sliding of the tiles in the architectured ceramics and channel plastic deformation in adhesive interlayers, respectively.
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•Developing a comprehensive model to design a new class of architectured ceramics.•Developing industrially scalable fabrication technique based on a laser system.•Exploring dynamic toughening mechanisms of bioinspired ceramics.•The primary toughening mechanisms is extensive crack deflection and delamination.
Spitzer and Caltech Submillimeter Observatory images and spectrophotometry of Eridani at wavelengths from 3.5 to 350 mm reveal new details of its bright debris disk. The 350 mm map confirms the ...presence of a ring at r = 11''-28''(35-90 AU), observed previously at longer sub-mm wavelengths. The Spitzer mid-IR and far-IR images do not show the ring, but rather a featureless disk extending from within a few arcsec of the star across the ring to r~ 34'' (110 AU). The spectral energy distribution (SED) of the debris system implies a complex structure. A model constrained by the surface brightness profiles and the SED indicates that the sub-mm ring emission is primarily from large (a~ 135 mm) grains, with smaller (a~ 15 mm) grains also present in and beyond the ring. The Spitzer Infrared Spectrograph and Multiband Imaging Photometer for Spitzer SED-mode spectrophotometry data clearly show the presence of spatially compact excess emission at l 15 mm that requires the presence of two additional narrow belts of dust within the sub-mm ring's central void. The innermost belt at r~ 3 AU is composed of silicate dust. A simple dynamical model suggests that dust produced collisionally by a population of about 11 M {circled plus} of planetesimals in the sub-mm ring could be the source of the emission from both in and beyond the sub-mm ring. Maintaining the inner belts and the inner edge to the sub-mm ring may require the presence of three planets in this system including the candidate radial velocity object.
The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world
. Here we describe the release ...of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
We present data obtained with the Infrared Array Camera (IRAC) aboard the Spitzer Space Telescope (Spitzer) for a sample of 74 young (t < 30 Myr old) Sun-like (0.7 < M sub(*)/M sub( )< 1.5) stars. ...These are a subset of the observations that comprise the Spitzer Legacy science program entitled the Formation and Evolution of Planetary Systems (FEPS). Using IRAC, we study the fraction of young stars that exhibit 3.6-8.0 km infrared emission in excess of that expected from the stellar photosphere, as a function of age from 3 to 30 Myr. The most straightforward interpretation of such excess emission is the presence of hot (300-1000 K) dust in the inner regions (<3 AU) of a circumstellar disk. Five out of the 74 young stars show a strong infrared excess, four of which have estimated ages of 3-10 Myr. While we detect excesses from five optically thick disks and photospheric emission from the remainder of our sample, we do not detect any excess emission from optically thin disks at these wavelengths. We compare our results with accretion disk fractions detected in previous studies and use the ensemble results to place additional constraints on the dissipation timescales for optically thick, primordial disks.
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