Chemical enrichment of the pre-solar cloud by supernova dust grains

The presence of short-lived radioisotopes (SLRs) in solar system meteorites has been interpreted as evidence that the solar system was exposed to a supernova shortly before or during its formation. Yet results from hydrodynamical models of SLR injection into the proto-solar cloud or disc suggest that gas-phase mixing may not be efficient enough to reproduce the observed abundances. As an alternative, we explore the injection of SLRs via dust grains as a way to overcome the mixing barrier. We numerically model the interaction of a supernova remnant containing SLR-rich dust grains with a nearby molecular cloud. The dust grains are subject to drag forces and both thermal and non-thermal sputtering. We confirm that the expanding gas shell stalls upon impact with the dense cloud and that gas-phase SLR injection occurs slowly due to hydrodynamical instabilities at the cloud surface. In contrast, dust grains of sufficient size (> 1 micron) decouple from the gas and penetrate into the cloud within 0.1 Myr. Once inside the cloud, the dust grains are destroyed by sputtering, releasing SLRs and rapidly enriching the dense (potentially star-forming) regions. Our results suggest that SLR transport on dust grains is a viable mechanism to explain SLR enrichment.Comment: 15 pages, 10 figures, Accepted for publication in MNRAS. Movies can be found here: http://user.physics.unc.edu/~mdgood86/research.htm

Gas Inflow and Star Formation near Supermassive Black Holes: The Role of Nuclear Activity

Numerical models of gas inflow towards a supermassive black hole (SMBH) show that star formation may occur in such an environment through the growth of a gravitationally unstable gas disc. We consider the effect of nuclear activity on such a scenario. We present the first three-dimensional grid-based radiative hydrodynamic simulations of direct collisions between infalling gas streams and a $4 \times 10^6~\text{M}_\odot$ SMBH, using ray-tracing to incorporate radiation consistent with an active galactic nucleus (AGN). We assume inflow masses of $\approx 10^5~\text{M}_\odot$ and explore radiation fields of 10% and 100% of the Eddington luminosity ($L_\text{edd}$). We follow our models to the point of central gas disc formation preceding star formation and use the Toomre Q parameter ($Q_T$) to test for gravitational instability. We find that radiation pressure from UV photons inhibits inflow. Yet, for weak radiation fields, a central disc forms on timescales similar to that of models without feedback. Average densities of $> 10^{8}~\text{cm}^{-3}$ limit photo-heating to the disc surface allowing for $Q_T\approx1$. For strong radiation fields, the disc forms more gradually resulting in lower surface densities and larger $Q_T$ values. Mass accretion rates in our models are consistent with 1%--60% of the Eddington limit, thus we conclude that it is unlikely that radiative feedback from AGN activity would inhibit circumnuclear star formation arising from a massive inflow event.Comment: 29 pages, 27 figures, accepted by MNRA

Constraints on UV Absorption in the Intracluster Medium of Abell 1030

We present results from an extensive HST spectroscopic search for UV absorption lines in the spectrum of the quasar B2~1028+313, which is associated with the central dominant galaxy in the cluster Abell~1030 ($z=0.178$). This is one of the brightest known UV continuum sources located in a cluster, and therefore provides an ideal opportunity to obtain stringent constraints on the column densities of any cool absorbing gas that may be associated with the intracluster medium (ICM). Our HST spectra were obtained with the FOS and GHRS, and provide continuous coverage at rest-frame wavelengths from $\sim 975$ to 4060~\AA, thereby allowing the investigation of many different elements and ionization levels. We utilize a new technique that involves simultaneous fitting of large numbers of different transitions for each species, thereby yielding more robust constraints on column densities than can be obtained from a single transition. This method yields upper limits of $\lesssim 10^{11} - 10^{13}$ cm$^{-2}$ on the column densities of a wide range of molecular, atomic and ionized species that may be associated with the ICM. We also discuss a possible \Lya and C IV absorption system associated with the quasar. We discuss the implications of the upper limits on cool intracluster gas in the context of the physical properties of the ICM and its relationship to the quasar.Comment: Astrophysical Journal, in press, 19 pages, includes 5 PostScript figures. Latex format, uses aas2pp4.sty and epsfig.sty file

Mutations in topoisomerase IIβ result in a B cell immunodeficiency.

B cell development is a highly regulated process involving multiple differentiation steps, yet many details regarding this pathway remain unknown. Sequencing of patients with B cell-restricted immunodeficiency reveals autosomal dominant mutations in TOP2B. TOP2B encodes a type II topoisomerase, an essential gene required to alleviate topological stress during DNA replication and gene transcription, with no previously known role in B cell development. We use Saccharomyces cerevisiae, and knockin and knockout murine models, to demonstrate that patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization

iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for 95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines

A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10-6) had not been highlighted in previous studies. While rs56137030was correlated at r2>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations

The Next PAGE in Understanding Complex Traits: Design for the Analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study

Genetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the “phenome-wide association study” approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser

An Open Access Database of Genome-wide Association Results

<p>Abstract</p> <p>Background</p> <p>The number of genome-wide association studies (GWAS) is growing rapidly leading to the discovery and replication of many new disease loci. Combining results from multiple GWAS datasets may potentially strengthen previous conclusions and suggest new disease loci, pathways or pleiotropic genes. However, no database or centralized resource currently exists that contains anywhere near the full scope of GWAS results.</p> <p>Methods</p> <p>We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS.</p> <p>Results</p> <p>Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e.g., MHC loci) were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e.g., <it>APOE</it>, <it>LPL</it>). At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (<it>SLC16A7, CSMD1, OAS1</it>), suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies) containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p < 4.6 × 10^-14), a finding which was not perturbed by a sensitivity analysis.</p> <p>Conclusion</p> <p>We provide access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information. We make a number of general observations. Of reported associated SNPs, 40% lie within the boundaries of a RefSeq gene and 68% are within 60 kb of one, indicating a bias toward gene-centricity in the findings. We found considerable heterogeneity in information available from GWAS suggesting the wider community could benefit from standardization and centralization of results reporting.</p

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin