Is there a primary care tool to detect aberrant drug-related behaviors in patients on opioids?

Of the several screening instruments developed and originally validated in patients in a pain center population (TABLE), one also has been validated in primary care. The Current Opioid Misuse Measure (COMM) predicts aberrant drug-related behaviors in primary care patients who have been prescribed opioids within the past 12 months with a sensitivity of 77% and specificity of 77% (strength of recommendation [SOR]: B, cohort studies). Although not validated in primary care populations, 3 other instruments (the Addiction Behaviors Checklist [ABC], Prescription Opioid Misuse Index [POMI], and prescription Drug Use Questionnaire [PDUQ]) detect aberrant drug-related behaviors in pain center patients with chronic pain with sensitivities of 82% to 87.5% and specificities of 86.14% to 92.3% (SOR: B, cohort studies)

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

Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy.

IL-2 has been used to treat diseases ranging from cancer to autoimmune disorders, but its concurrent immunostimulatory and immunosuppressive effects hinder efficacy. IL-2 orchestrates immune cell function through activation of a high-affinity heterotrimeric receptor (composed of IL-2Rα, IL-2Rβ, and common γ [γc]). IL-2Rα, which is highly expressed on regulatory T (TReg) cells, regulates IL-2 sensitivity. Previous studies have shown that complexation of IL-2 with the JES6-1 Ab preferentially biases cytokine activity toward TReg cells through a unique mechanism whereby IL-2 is exchanged from the Ab to IL-2Rα. However, clinical adoption of a mixed Ab/cytokine complex regimen is limited by stoichiometry and stability concerns. In this study, through structure-guided design, we engineered a single agent fusion of the IL-2 cytokine and JES6-1 Ab that, despite being covalently linked, preserves IL-2 exchange, selectively stimulating TReg expansion and exhibiting superior disease control to the mixed IL-2/JES6-1 complex in a mouse colitis model. These studies provide an engineering blueprint for resolving a major barrier to the implementation of functionally similar IL-2/Ab complexes for treatment of human disease