The Deuterium to Hydrogen Abundance Ratio Towards the QSO SDSS1558-0031

We present a measurement of the D/H abundance ratio in a metal-poor damped Lyman alpha (DLA) system along the sightline of QSO SDSS1558-0031. The DLA system is at redshift z = 2.70262, has a neutral column density of log(NHI)=20.67+/-0.05 cm^2, and a gas-phase metallicity [O/H]= -1.49 which indicates that deuterium astration is negligible. Deuterium absorption is observed in multiple Lyman series with a column density of log(NDI)=16.19+/-0.04 cm^2, best constrained by the deuterium Lyman-11 line. We measure log(D/H) = -4.48+/-0.06, which when combined with previous measurements along QSO sightlines gives a best estimate of log(D/H) = -4.55+/-0.04, where the 1-sigma error estimate comes from a jackknife analysis of the weighted means. Using the framework of standard big bang nucleosynthesis, this value of D/H translates into a baryon density of Omega_b h^2 = 0.0213 +/- 0.0013 +/- 0.0004 where the error terms represent the 1-sigma errors from D/H and the uncertainties in the nuclear reaction rates respectively. Combining our new measurement with previous measurements of D/H, we no longer find compelling evidence for a trend of D/H with NHI.Comment: 13 pages, 3 figures, 1 table. Accepted to the Astrophysical Journal Letter

Poxvirus Exploitation of the Ubiquitin-Proteasome System

Ubiquitination plays a critical role in many cellular processes. A growing number of viruses have evolved strategies to exploit the ubiquitin-proteasome system, including members of the Poxviridae family. Members of the poxvirus family have recently been shown to encode BTB/kelch and ankyrin/F-box proteins that interact with cullin-3 and cullin-1 based ubiquitin ligases, respectively. Multiple members of the poxvirus family also encode ubiquitin ligases with intrinsic activity. This review describes the numerous mechanisms that poxviruses employ to manipulate the ubiquitin-proteasome system

The Keck+Magellan Survey for Lyman Limit Absorption I: The Frequency Distribution of Super Lyman Limit Systems

We present the results of a survey for super Lyman limit systems (SLLS; defined to be absorbers with 19.0 <= log(NHI) <= 20.3 cm^-2) from a large sample of high resolution spectra acquired using the Keck and Magellan telescopes. Specifically, we present 47 new SLLS from 113 QSO sightlines. We focus on the neutral hydrogen frequency distribution f(N,X) of the SLLS and its moments, and compare these results with the Lyman-alpha forest and the damped Lyman alpha systems (DLA; absorbers with log(NHI) >= 20.3 cm^-2). We find that that f(N,X) of the SLLS can be reasonably described with a power-law of index alpha = -1.43^{+0.15}_{-0.16} or alpha = -1.19^{+0.20}_{-0.21} depending on whether we set the lower N(HI) bound for the analysis at 10^{19.0} cm^-2 or 10^{19.3}$ cm^-2, respectively. The results indicate a flattening in the slope of f(N,X) between the SLLS and DLA. We find little evidence for redshift evolution in the shape of f(N,X) for the SLLS over the redshift range of the sample 1.68 < z < 4.47 and only tentative evidence for evolution in the zeroth moment of f(N,X), the line density l_lls(X). We introduce the observable distribution function O(N,X) and its moment, which elucidates comparisons of HI absorbers from the Lyman-alpha through to the DLA. We find that a simple three parameter function can fit O(N,X) over the range 17.0 <= log(NHI) <=22.0. We use these results to predict that f(N,X) must show two additional inflections below the SLLS regime to match the observed f(N,X) distribution of the Lyman-alpha forest. Finally, we demonstrate that SLLS contribute a minor fraction (~15%) of the universe's hydrogen atoms and, therefore, an even small fraction of the mass in predominantly neutral gas.Comment: 15 pages, 10 figures, accepted to the Astrophysical Journal. Revision includes updated reference

Limitations of pulmonary embolism ICD-10 codes in emergency department administrative data: let the buyer beware

Abstract Background Administrative data is a useful tool for research and quality improvement; however, validity of research findings based on these data depends on their reliability. Diagnoses assigned by physicians are subsequently converted by nosologists to ICD-10 codes (International Statistical Classification of Diseases and Related Health Problems, 10th Revision). Several groups have reported ICD-9 coding errors in inpatient data that have implications for research, quality improvement, and policymaking, but few have assessed ICD-10 code validity in ambulatory care databases. Our objective was to evaluate pulmonary embolism (PE) ICD-10 code accuracy in our large, integrated hospital system, and the validity of using these codes for operational and health services research using ED ambulatory care databases. Methods Ambulatory care data for patients (age ≥ 18 years) with a PE ICD-10 code (I26.0 and I26.9) were obtained from the records of four urban EDs between July 2013 to January 2015. PE diagnoses were confirmed by reviewing medical records and imaging reports. In cases where chart diagnosis and ICD-10 code were discrepant, chart review was considered correct. Physicians’ written discharge diagnoses were also searched using ‘pulmonary embolism’ and ‘PE’, and patients who were diagnosed with PE but not coded as PE were identified. Coding discrepancies were quantified and described. Results One thousand, four hundred and fifty-three ED patients had a PE ICD-10 code. Of these, 257 (17.7%) were false positive, with an incorrectly assigned PE code. Among the 257 false positives, 193 cases had ambiguous ED diagnoses such as ‘rule out PE’ or ‘query PE’, while 64 cases should have had non-PE codes. An additional 117 patients (8.90%) with a PE discharge diagnosis were incorrectly assigned a non-PE ICD-10 code (false negative group). The sensitivity of PE ICD-10 codes in this dataset was 91.1% (95%CI, 89.4–92.6) with a specificity of 99.9% (95%CI, 99.9–99.9). The positive and negative predictive values were 82.3% (95%CI, 80.3–84.2) and 99.9% (95%CI, 99.9–99.9), respectively. Conclusions Ambulatory care data, like inpatient data, are subject to coding errors. This confirms the importance of ICD-10 code validation prior to use. The largest proportion of coding errors arises from ambiguous physician documentation; therefore, physicians and data custodians must ensure that quality improvement processes are in place to promote ICD-10 coding accuracy

EVM005: An Ectromelia-Encoded Protein with Dual Roles in NF-κB Inhibition and Virulence

<div><p>Poxviruses contain large dsDNA genomes encoding numerous open reading frames that manipulate cellular signalling pathways and interfere with the host immune response. The NF-κB signalling cascade is an important mediator of innate immunity and inflammation, and is tightly regulated by ubiquitination at several key points. A critical step in NF-κB activation is the ubiquitination and degradation of the inhibitor of kappaB (IκBα), by the cellular SCF^β-TRCP ubiquitin ligase complex. We show here that upon stimulation with TNFα or IL-1β, <i>Orthopoxvirus</i>-infected cells displayed an accumulation of phosphorylated IκBα, indicating that NF-κB activation was inhibited during poxvirus infection. Ectromelia virus is the causative agent of lethal mousepox, a natural disease that is fatal in mice. Previously, we identified a family of four ectromelia virus genes (EVM002, EVM005, EVM154 and EVM165) that contain N-terminal ankyrin repeats and C-terminal F-box domains that interact with the cellular SCF ubiquitin ligase complex. Since degradation of IκBα is catalyzed by the SCF^β-TRCP ubiquitin ligase, we investigated the role of the ectromelia virus ankyrin/F-box protein, EVM005, in the regulation of NF-κB. Expression of Flag-EVM005 inhibited both TNFα- and IL-1β-stimulated IκBα degradation and p65 nuclear translocation. Inhibition of the NF-κB pathway by EVM005 was dependent on the F-box domain, and interaction with the SCF complex. Additionally, ectromelia virus devoid of EVM005 was shown to inhibit NF-κB activation, despite lacking the EVM005 open reading frame. Finally, ectromelia virus devoid of EVM005 was attenuated in both A/NCR and C57BL/6 mouse models, indicating that EVM005 is required for virulence and immune regulation <i>in vivo</i>.</p></div

EVM005 is required for virulence during ECTV infection of C57BL/6 and A/NCR mice.

<p>(A and B) Female C57BL/6 mice were mock-infected or infected with 10,000 pfu of ECTV, ECTV pfu of ECTV, ECTV-Δ005, ECTV-005-rev or ECTV-005(1-593)-rev via intranasal inoculation. Mice were monitored daily for mortality, day of death (A), and body weight (B). (C and D) Alternatively, female A/NCR mice were mock-infected or infected with 10,000 pfu of ECTV, ECTV pfu of ECTV, ECTV-Δ005, ECTV-005-rev or ECTV-005(1-593)-rev via footpad injection. Mice were monitored daily for day of death and mortality (C) as well as body weight (D). Morality curves were statistically analyzed using a Log-rank (Mantel-Cox) test.</p

ECTV and ECTV-Δ005 inhibit production of NF-κB regulated transcripts.

<p>HeLa cells were mock-infected or infected with ECTV or ECTV-Δ005 at a MOI of 5. At 12 hours post infection cells were stimulated with TNF hours post infection cells were stimulated with TNFα. RNA samples were collected at the indicated time points post-TNFα treatment. Samples were reverse transcribed, followed by real time PCR analysis for relative levels of (A) TNFα, (B) IL-1β, and (C) IL-6 transcripts, as compared to GAPDH. Time courses were performed in triplicate and plotted as the average with standard error.</p

EVM005 inhibits activation of the immune response.

<p>C57BL/6 mice were infected with 10,000 pfu of ECTV or ECTV pfu of ECTV or ECTV-Δ005 via intranasal inoculation. Tissues and whole blood were collected at 2, 3, 4 and 7 days post infection. (A and B) Spleen, liver, lung and kidney tissues were homogenized and plated onto BSC-1 cells to measure viral titers at day 4 (A) and 7 (B) post infection. Cell suspensions were prepared from infected spleens (C and D) or peripheral blood (E and F) on day 3 and 7 and analyzed by flow cytometry. (C and E) NK cells are identified as CD45+, CD3−, and NK1.1+. We gated 50,000 CD45+ cells, and presented the total number of NK1.1+ cells within this lymphocyte population (D and F) Virus-specific CD8+ T-cells were identified as CD8+, CD45+, and tetramer+, and presented as the ratio of tetramer+ cells to total CD8+ T-cells within each sample. (G and H) RNA was purified from spleen (G) and liver (H) and subjected to qRT-PCR to quantify transcriptional upregulation of TNFα, IL-1β and IL-6 at 7 days post infection. Data are normalized against GAPDH.</p

ECTV-Δ005, ECTV-Δ002 and ECTV-Δ002-005 inhibit TNFα induced IκBα degradation.

<p>(A) HeLa cells were mock-infected or infected with ECTV, ECTV-Δ005 or ECTV-005-rev at a MOI of 5. (C) Alternatively, HeLa cells were mock-infected or infected with ECTV, ECTV-Δ002, ECTV-Δ005 or ECTV-Δ002-005 at a MOI of 5. (A and C) At 12 hours post hours post-infection, cells were stimulated with 10 µM MG132 for 1 hour and hour and/or 10 ng ng/ml TNFα for 20 minutes. Cells were harvested, fixed and permeablized, followed by staining with anti minutes. Cells were harvested, fixed and permeablized, followed by staining with anti-IκBα and anti-I3L. Samples were subjected to flow cytometry, IκBα (A panels a–d, and C panels i–m) or I3L (A panels e–h and C panels n–r) are measured along the x-axis. (B and D) The percentage of cells expressing IκBα were measured and plotted as the average of three independent experiments with SEM.</p