Radio and Millimeter Monitoring of Sgr A*: Spectrum, Variability, and Constraints on the G2 Encounter

We report new observations with the Very Large Array, Atacama Large Millimeter Array, and Submillimeter Array at frequencies from 1.0 to 355 GHz of the Galactic Center black hole, Sagittarius A*. These observations were conducted between October 2012 and November 2014. While we see variability over the whole spectrum with an amplitude as large as a factor of 2 at millimeter wavelengths, we find no evidence for a change in the mean flux density or spectrum of Sgr A* that can be attributed to interaction with the G2 source. The absence of a bow shock at low frequencies is consistent with a cross-sectional area for G2 that is less than $2 \times 10^{29}$ cm$^2$. This result fits with several model predictions including a magnetically arrested cloud, a pressure-confined stellar wind, and a stellar photosphere of a binary merger. There is no evidence for enhanced accretion onto the black hole driving greater jet and/or accretion flow emission. Finally, we measure the millimeter wavelength spectral index of Sgr A* to be flat; combined with previous measurements, this suggests that there is no spectral break between 230 and 690 GHz. The emission region is thus likely in a transition between optically thick and thin at these frequencies and requires a mix of lepton distributions with varying temperatures consistent with stratification.Comment: Accepted for publication in Ap

Pan-Genomic Analysis of Clostridium botulinum Group II (Non-Proteolytic C. botulinum) Associated with Foodborne Botulism and Isolated from the Environment

The neurotoxin formed by Clostridium botulinum Group II is a major cause of foodborne botulism, a deadly intoxication. This study aims to understand the genetic diversity and spread of C. botulinum Group II strains and their neurotoxin genes. A comparative genomic study has been conducted with 208 highly diverse C. botulinum Group II strains (180 newly sequenced strains isolated from 16 countries over 80 years, 28 sequences from Genbank). Strains possessed a single type B, E, or F neurotoxin gene or were closely related strains with no neurotoxin gene. Botulinum neurotoxin subtype variants (including novel variants) with a unique amino acid sequence were identified. Core genome single-nucleotide polymorphism (SNP) analysis identified two major lineages—one with type E strains, and the second dominated by subtype B4 strains with subtype F6 strains. This study revealed novel details of population structure/diversity and established relationships between whole-genome lineage, botulinum neurotoxin subtype variant, association with foodborne botulism, epidemiology, and geographical source. Additionally, the genome sequences represent a valuable resource for the research community (e.g., understanding evolution of C. botulinum and its neurotoxin genes, dissecting key aspects of C. botulinum Group II biology). This may contribute to improved risk assessments and the prevention of foodborne botulism

Sampling Performance of Multiple Independent Molecular Dynamics Simulations of an RNA Aptamer

Using multiple independent simulations instead of one long simulation has been shown to improve the sampling performance attained with the molecular dynamics (MD) simulation method. However, it is generally not known how long each independent simulation should be, how many independent simulations should be used, or to what extent either of these factors affects the overall sampling performance achieved for a given system. The goal of the present study was to assess the sampling performance of multiple independent MD simulations, where each independent simulation begins from a different initial molecular conformation. For this purpose, we used an RNA aptamer that is 25 nucleotides long as a case study. The initial conformations of the aptamer are derived from six de novo predicted 3D structures. Each of the six de novo predicted structures is energy minimized in solution and equilibrated with MD simulations at high temperature. Ten conformations from these six high-temperature equilibration runs are selected as initial conformations for further simulations at ambient temperature. In total, we conducted 60 independent MD simulations, each with a duration of 100 ns, to study the conformation and dynamics of the aptamer. For each group of 10 independent simulations that originated from a particular de novo predicted structure, we evaluated the potential energy distribution of the RNA and used recurrence quantification analysis to examine the sampling of RNA conformational transitions. To assess the impact of starting from different de novo predicted structures, we computed the density of structure projection on principal components to compare the regions sampled by the different groups of ten independent simulations. The recurrence rate and dependence of initial conformation among the groups were also compared. We stress the necessity of using different initial configurations as simulation starting points by showing long simulations from different initial structures suffer from being trapped in different states. Finally, we summarized the sampling efficiency for the complete set of 60 independent simulations and determined regions of under-sampling on the potential energy landscape. The results suggest that conducting multiple independent simulations using a diverse set of de novo predicted structures is a promising approach to achieve sufficient sampling. This approach avoids undesirable outcomes, such as the problem of the RNA aptamer being trapped in a local minimum. For others wishing to conduct multiple independent simulations, the analysis protocol presented in this study is a guide for examining overall sampling and determining if more simulations are necessary for sufficient sampling

Forage fish interactions: A symposium on creating the tools for ecosystem-based management of marine resources

Forage fish (FF) have a unique position within marine foodwebs and the development of sustainable harvest strategies for FF will be a critical step in advancing and implementing the broader, ecosystem-based management of marine systems. In all, 70 scientists from 16 nations gathered for a symposium on 12–14 November 2012 that was designed to address three key questions regarding the effective management of FF and their ecosystems: (i) how do environmental factors and predator–prey interactions drive the productivity and distribution of FF stocks across ecosystems worldwide, (ii) what are the economic and ecological costs and benefits of different FF management strategies, and (iii) do commonalities exist across ecosystems in terms of the effective management of FF exploitation

Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10

Type I interferon (IFN) α/β is critical for host defense. During endotoxicosis or highly lethal bacterial infections where systemic inflammation predominates, mice deficient in IFN-α/β receptor (IFNAR) display decreased systemic inflammation and improved outcome. However, human sepsis mortality often occurs during a prolonged period of immunosuppression and not from exaggerated inflammation. We used a low lethality cecal ligation and puncture (CLP) model of sepsis to determine the role of type I IFNs in host defense during sepsis. Despite increased endotoxin resistance, IFNAR−/− and chimeric mice lacking IFNAR in hematopoietic cells display increased mortality to CLP. This was not associated with an altered early systemic inflammatory response, except for decreased CXCL10 production. IFNAR−/− mice display persistently elevated peritoneal bacterial counts compared with wild-type mice, reduced peritoneal neutrophil recruitment, and recruitment of neutrophils with poor phagocytic function despite normal to enhanced adaptive immune function during sepsis. Importantly, CXCL10 treatment of IFNAR−/− mice improves survival and decreases peritoneal bacterial loads, and CXCL10 increases mouse and human neutrophil phagocytosis. Using a low lethality sepsis model, we identify a critical role of type I IFN–dependent CXCL10 in host defense during polymicrobial sepsis by increasing neutrophil recruitment and function

Radio and Millimeter Monitoring of Sgr A*: Spectrum, Variability, and Constraints on the G2 Encounter

We report new observations with the Very Large Array, Atacama Large Millimeter Array, and Submillimeter Array at frequencies from 1.0 to 355 GHz of the Galactic Center black hole, Sagittarius A*. These observations were conducted between 2012 October and 2014 November. While we see variability over the whole spectrum with an amplitude as large as a factor of 2 at millimeter wavelengths, we find no evidence for a change in the mean flux density or spectrum of Sgr A* that can be attributed to interaction with the G2 source. The absence of a bow shock at low frequencies is consistent with a cross-sectional area for G2 that is less than 2 10 ´ 29 cm2. This result fits with several model predictions including a magnetically arrested cloud, a pressure-confined stellar wind, and a stellar photosphere of a binary merger. There is no evidence for enhanced accretion onto the black hole driving greater jet and/or accretion flow emission. Finally, we measure the millimeter wavelength spectral index of Sgr A* to be flat; combined with previous measurements, this suggests that there is no spectral break between 230 and 690 GHz. The emission region is thus likely in a transition between optically thick and thin at these frequencies and requires a mix of lepton distributions with varying temperatures consistent with stratification.Astronom

Precision Newborn Screening for Lysosomal Disorders

Purpose: The implementation of newborn screening for lysosomal disorders has uncovered overall poor specificity, psychosocial harm experienced by caregivers, and costly follow-up testing of false-positive cases. We report an informatics solution proven to minimize these issues. Methods: The Kentucky Department for Public Health outsourced testing for mucopolysaccharidosis type I (MPS I) and Pompe disease, conditions recently added to the recommended uniform screening panel, plus Krabbe disease, which was added by legislative mandate. A total of 55,161 specimens were collected from infants born over 1 year starting from February 2016. Testing by tandem mass spectrometry was integrated with multivariate pattern recognition software (Collaborative Laboratory Integrated Reports), which is freely available to newborn screening programs for selection of cases for which a biochemical second-tier test is needed. Results: Of five presumptive positive cases, one was affected with infantile Krabbe disease, two with Pompe disease, and one with MPS I. The remaining case was a heterozygote for the latter condition. The false-positive rate was 0.0018% and the positive predictive value was 80%. Conclusion: Postanalytical interpretive tools can drastically reduce false-positive outcomes, with preliminary evidence of no greater risk of false-negative events, still to be verified by long-term surveillance

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