Protoplanetary Disk Structures in Ophiuchus II: Extension to Fainter Sources

We present new results from a significant extension of our previous high angular resolution (0.3" = 40 AU) Submillimeter Array survey of the 880 um continuum emission from dusty circumstellar disks in the ~1 Myr-old Ophiuchus star-forming region. An expanded sample is constructed to probe disk structures that emit significantly lower millimeter luminosities (hence dust masses), down to the median value for T Tauri stars. Using a Monte Carlo radiative transfer code, the millimeter visibilities and broadband spectral energy distribution for each disk are simultaneously reproduced with a two-dimensional parametric model for a viscous accretion disk. We find wide ranges of characteristic radii (14-198 AU) and disk masses (0.004-0.143 M_sun), but a narrow distribution of surface density gradients (0.4-1.1) that is consistent with a uniform value $\gamma$ = 0.9 +/- 0.2 and independent of mass (or millimeter luminosity). In this sample, we find a correlation between the disk luminosity/mass and characteristic radius, such that fainter disks are both smaller and less massive. We suggest that this relationship is an imprint of the initial conditions inherited by the disks at their formation epoch, compare their angular momenta with those of molecular cloud cores, and speculate on how future observations can help constrain the distribution of viscous evolution timescales. No other correlations between disk and star properties are found. The inferred disk structures are briefly compared with theoretical models for giant planet formation, although resolution limitations do not permit us to directly comment on material inside R = 20 AU. However, there is some compelling evidence for dust evolution in the planet formation region: 4/17 disks in the sample show resolved regions of significantly reduced optical depths within ~20-40 AU of their central stars.Comment: accepted in ApJ, 39 pages, 10 figure

Loss-of-Function Genomic Variants Highlight Potential Therapeutic Targets for Cardiovascular Disease

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Characterization of the two nonallelic genes encoding mouse preproinsulin

We have cloned and sequenced the two mouse preproinsulin genes. The deduced amino acid sequences of the mature mouse insulins are identical to the published protein sequences. However, the nucleotide sequence indicates that the mouse I C-peptide has a deletion of two amino acids compared with the mouse II C-peptide. We used an S1 nuclease assay to confirm the presence of the deletion and to measure the ratio of transcripts from gene I to transcripts from gene II. The mouse preproinsulin I gene, like the rat gene I, is missing the second intervening sequence that normally interrupts the C-peptide region in other insulin genes. Comparison of the 5\u27 flanking sequences of the mouse and rat genes II indicates that they are homologous for at least 1000 base pairs. The preproinsulin I genes also share homology in their 5\u27 flanking DNAs; however, their homology to the preproinsulin II genes extends for only about 500 base pairs