Mosaicism and the genetic architecture of congenital heart disease

Congenital heart disease (CHD) is characterized by structural defects of the heart and great vessels. It is the most common birth defect, affecting an estimated 1% of live births, and is the leading cause of mortality among birth defects. Despite recent progress in genetic research, more than 50% of CHD cases remain unexplained. An estimated 23% are due to aneuploidies and copy number variants and up to 30% has been attributed to de novo variation, though that number ranges between 3-30% depending on CHD complexity. The contribution of somatic mosaicism, or de novo genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood due to limitations in sample size, detection method, and validation rate. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. We developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic accurately detected 309 mosaic mutations in blood, with 85 of 94 (90%) candidates tested independently confirmed. We found twenty-five likely damaging mosaics in plausible CHD-risk genes, affecting 1% of our cohort. Variants in these genes predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The frequency of protein-coding mosaic variants detectable in blood was 0.122 or roughly 1 in 8 individuals. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. CHD patients often present with comorbid cardiac and extracardiac anomalies that further their impact quality of life. Neurodevelopmental disorders (NDDs) are especially prevalent in CHD cases compared to the general population, yet the underlying genetic causes remain poorly explained. Further, patients with single ventricle defects undergoing surgery often later develop arrhythmias and experience worsening ventricular function. We used a statistical approach to dissect the association between de novo variation and these clinical outcomes and found that pleiotropic mutations contribute a large fraction of the risk of acquiring NDD and abnormal ventricular function phenotypes in CHD patients. We developed a proof-of-concept rare variant risk score that combines information from de novo, rare transmitted, and copy- number variants and show that prediction of outcomes such as NDD can be improved, especially in complex CHD cases

Ground-based PIV and numerical flow visualization results from the surface tension driven convection experiment

The Surface Tension Driven Convection Experiment (STDCE) is a Space Transportation System flight experiment to study both transient and steady thermocapillary fluid flows aboard the United States Microgravity Laboratory-1 (USML-1) Spacelab mission planned for June, 1992. One of the components of data collected during the experiment is a video record of the flow field. This qualitative data is then quantified using an all electric, two dimensional Particle Image Velocimetry (PIV) technique called Particle Displacement Tracking (PDT), which uses a simple space domain particle tracking algorithm. Results using the ground based STDCE hardware, with a radiant flux heating mode, and the PDT system are compared to numerical solutions obtained by solving the axisymmetric Navier Stokes equations with a deformable free surface. The PDT technique is successful in producing a velocity vector field and corresponding stream function from the raw video data which satisfactorily represents the physical flow. A numerical program is used to compute the velocity field and corresponding stream function under identical conditions. Both the PDT system and numerical results were compared to a streak photograph, used as a benchmark, with good correlation

Methods and systems for dynamic pitch helical scanning

Methods and systems for controlling x-ray exposure during a dynamic pitch helical scan using a translatable table are provided. The system includes a collimator positioned between an x-ray source and an object to be scanned configured to shutter an x-ray fan beam generated by the x-ray source to at least one of translate the x-ray fan beam along a z-axis of the scan and vary the width of the x-ray beam along the z-axis, and a collimator controller configured to dynamically position the collimator using at least one of predetermined trajectory of the translatable table and a current position of the translatable table

The rhenium isotope composition of Atlantic Ocean seawater

The concentrations and isotopic compositions of rhenium are presented from seawater samples obtained from the primary station for the Bermuda Atlantic Time Series Study in the North Atlantic Ocean and from the 40oS UK GEOTRACES expedition in the South Atlantic Ocean. Salinity-normalized Re concentrations in both locations range between ∼6.8–7.7 ppt between 50–5000 m depth, consistent with previously published concentration data from the North Atlantic and North Pacific Oceans. Rhenium isotope values (expressed as δ187/185Re relative to NIST 3143) exhibit minimal variation around an average value of −0.17 ± 0.12‰ (n = 12, 2 S.D.), irrespective of water depth or water mass. These results confirm that the isotopic composition of perrhenate (ReO4−) in seawater is uniform. The new data establish a baseline for evaluating the isotopic mass balance of Re, and for future assessments of whether this global cycle can be disturbed by changes in seafloor redox and/or global weathering rates

Deciphering the functions of O-GlcNAc glycosylation in the brain: The role of site-specific quantitative O-GlcNAcomics

The dynamic posttranslational modification O-linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) is present on thousands of intracellular proteins in the brain. Like phosphorylation, O-GlcNAcylation is inducible and plays important functional roles in both physiology and disease. Recent advances in mass spectrometry (MS) and bioconjugation methods are now enabling the mapping of O-GlcNAcylation events to individual sites in proteins. However, our understanding of which glycosylation events are necessary for regulating protein function and controlling specific processes, phenotypes, or diseases remains in its infancy. Given the sheer number of O-GlcNAc sites, methods for identifying promising sites and prioritizing them for time- and resource-intensive functional studies are greatly needed. Revealing sites that are dynamically altered by different stimuli or disease states will likely go a long way in this regard. Here, we describe advanced methods for identifying O-GlcNAc sites on individual proteins and across the proteome and for determining their stoichiometry in vivo. We also highlight emerging technologies for quantitative, site-specific MS-based O-GlcNAc proteomics (O-GlcNAcomics), which allow proteome-wide tracking of O-GlcNAcylation dynamics at individual sites. These cutting-edge technologies are beginning to bridge the gap between the high-throughput cataloguing of O-GlcNAcylated proteins and the relatively low-throughput study of individual proteins. By uncovering the O-GlcNAcylation events that change in specific physiological and disease contexts, these new approaches are providing key insights into the regulatory functions of O-GlcNAc in the brain, including their roles in neuroprotection, neuronal signaling, learning and memory, and neurodegenerative diseases

Phase field model of premelting of grain boundaries

We present a phase field model of solidification which includes the effects of the crystalline orientation in the solid phase. This model describes grain boundaries as well as solid-liquid boundaries within a unified framework. With an appropriate choice of coupling of the phase field variable to the gradient of the crystalline orientation variable in the free energy, we find that high angle boundaries undergo a premelting transition. As the melting temperature is approached from below, low angle grain boundaries remain narrow. The width of the liquid layer at high angle grain boundaries diverges logarithmically. In addition, for some choices of model coupling, there may be a discontinuous jump in the width of the fluid layer as function of temperature.Comment: 6 pages, 9 figures, RevTeX