59 research outputs found
High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.
Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo
Evidence for a Population of High-Redshift Submillimeter Galaxies from Interferometric Imaging
We have used the Submillimeter Array to image a flux-limited sample of seven submillimeter galaxies, selected by the AzTEC camera on the JCMT at 1.1 mm, in the COSMOS field at 890 μm with ∼2″ resolution. All of the sources - two radio-bright and five radio-dim - are detected as single point sources at high significance (\u3e6 σ), with positions accurate to ∼0.2″ that enable counterpart identification at other wavelengths observed with similarly high angular resolution. All seven have IRAC counterparts, but only two have secure counterparts in deep HST ACS imaging. As compared to the two radio-bright sources in the sample, and those in previous studies, the five radio-dim sources in the sample (1) have systematically higher submillimeter-to-radio flux ratios, (2) have lower IRAC 3.6-8.0 μm fluxes, and (3) are not detected at 24 μm. These properties, combined with size constraints at 890 μm (θ ≲ 1.2″), suggest that the radio-dim submillimeter galaxies represent a population of very dusty starbursts, with physical scales similar to local ultraluminous infrared galaxies, with an average redshift higher than radio-bright sources
The physical scale of the far-infrared emission in the most luminous submillimetre galaxies II: evidence for merger-driven star formation
We present high-resolution 345 GHz interferometric observations of two
extreme luminous (L_{IR}>10^{13} L_sun), submillimetre-selected galaxies (SMGs)
in the COSMOS field with the Submillimeter Array (SMA). Both targets were
previously detected as unresolved point-sources by the SMA in its compact
configuration, also at 345 GHz. These new data, which provide a factor of ~3
improvement in resolution, allow us to measure the physical scale of the
far-infrared in the submillimetre directly. The visibility functions of both
targets show significant evidence for structure on 0.5-1 arcsec scales, which
at z=1.5 translates into a physical scale of 5-8 kpc. Our results are
consistent with the angular and physical scales of two comparably luminous
objects with high-resolution SMA followup, as well as radio continuum and CO
sizes. These relatively compact sizes (<5-10 kpc) argue strongly for
merger-driven starbursts, rather than extended gas-rich disks, as the preferred
channel for forming SMGs. For the most luminous objects, the derived sizes may
also have important physical consequences; under a series of simplifying
assumptions, we find that these two objects in particular are forming stars
close to or at the Eddington limit for a starburst.Comment: 9 pages, 3 Figures, submitted to MNRA
Genome modeling system: A knowledge management platform for genomics
In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformatics development, allowing a large team to collaborate on data analysis, or an individual researcher to leverage the work of others effectively within its data management system. Rather than separating ad-hoc analysis from rigorous, reproducible pipelines, the GMS promotes systematic integration between the two. As a demonstration of the GMS, we performed an integrated analysis of whole genome, exome and transcriptome sequencing data from a breast cancer cell line (HCC1395) and matched lymphoblastoid line (HCC1395BL). These data are available for users to test the software, complete tutorials and develop novel GMS pipeline configurations. The GMS is available at https://github.com/genome/gms
The Nucleocapsid Region of HIV-1 Gag Cooperates with the PTAP and LYPXnL Late Domains to Recruit the Cellular Machinery Necessary for Viral Budding
HIV-1 release is mediated through two motifs in the p6 region of Gag, PTAP and LYPXnL, which recruit cellular proteins Tsg101 and Alix, respectively. The Nucleocapsid region of Gag (NC), which binds the Bro1 domain of Alix, also plays an important role in HIV-1 release, but the underlying mechanism remains unclear. Here we show that the first 202 residues of the Bro1 domain (Broi) are sufficient to bind Gag. Broi interferes with HIV-1 release in an NC–dependent manner and arrests viral budding at the plasma membrane. Similar interrupted budding structures are seen following over-expression of a fragment containing Bro1 with the adjacent V domain (Bro1-V). Although only Bro1-V contains binding determinants for CHMP4, both Broi and Bro1-V inhibited release via both the PTAP/Tsg101 and the LYPXnL/Alix pathways, suggesting that they interfere with a key step in HIV-1 release. Remarkably, we found that over-expression of Bro1 rescued the release of HIV-1 lacking both L domains. This rescue required the N-terminal region of the NC domain in Gag and the CHMP4 binding site in Bro1. Interestingly, release defects due to mutations in NC that prevented Bro1 mediated rescue of virus egress were rescued by providing a link to the ESCRT machinery via Nedd4.2s over-expression. Our data support a model in which NC cooperates with PTAP in the recruitment of cellular proteins necessary for its L domain activity and binds the Bro1–CHMP4 complex required for LYPXnL–mediated budding
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Genome remodelling in a basal-like breast cancer metastasis and xenograft
Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour
1694 Endoscopic Ultrasonography With Fine-Needle Aspiration in the Diagnosis of Metastatic Rectal Adenocarcinoma in Left Atrium
1695 Removal of a Retained Biliary Stent in a Liver Transplant Patient Secondary to Biliary Cast Syndrome Using Digital Cholangioscopy and Electrohydraulic Lithotripsy
Glial cell line-derived neurotrophic factor administration in postnatal life results in motor unit enlargement and continuous synaptic remodeling at the neuromuscular junction
Overexpression of glial cell line-derived neurotrophic factor (GDNF) in embryonic muscle fibers causes dramatic hyperinnervation of neuromuscular junctions. However, it is not known whether GDNF induces the extra innervation by regulation of axonal branching and/or synaptic maintenance. To address this issue, high levels of circulating GDNF were established by administering subcutaneous injections starting either at birth or later and continuing for up to 40 d. Treatment with exogenous GDNF beginning in the first week, but not later, increased the number of axons converging at neuromuscular junctions. The effect of GDNF on the branching pattern of individual motor axons was determined by reconstructing labeled axonal arbors from transgenic mice expressing yellow fluorescent protein in subsets of motor neurons. Whereas, at postnatal day 8 (P8) individual axons in control animals branched to sporadicall
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