A genomic perspective on the potential of Actinobacillus succinogenes for industrial succinate production

<p>Abstract</p> <p>Background</p> <p>Succinate is produced petrochemically from maleic anhydride to satisfy a small specialty chemical market. If succinate could be produced fermentatively at a price competitive with that of maleic anhydride, though, it could replace maleic anhydride as the precursor of many bulk chemicals, transforming a multi-billion dollar petrochemical market into one based on renewable resources. <it>Actinobacillus succinogenes </it>naturally converts sugars and CO₂into high concentrations of succinic acid as part of a mixed-acid fermentation. Efforts are ongoing to maximize carbon flux to succinate to achieve an industrial process.</p> <p>Results</p> <p>Described here is the 2.3 Mb <it>A. succinogenes </it>genome sequence with emphasis on <it>A. succinogenes</it>'s potential for genetic engineering, its metabolic attributes and capabilities, and its lack of pathogenicity. The genome sequence contains 1,690 DNA uptake signal sequence repeats and a nearly complete set of natural competence proteins, suggesting that <it>A. succinogenes </it>is capable of natural transformation. <it>A. succinogenes </it>lacks a complete tricarboxylic acid cycle as well as a glyoxylate pathway, and it appears to be able to transport and degrade about twenty different carbohydrates. The genomes of <it>A. succinogenes </it>and its closest known relative, <it>Mannheimia succiniciproducens</it>, were compared for the presence of known Pasteurellaceae virulence factors. Both species appear to lack the virulence traits of toxin production, sialic acid and choline incorporation into lipopolysaccharide, and utilization of hemoglobin and transferrin as iron sources. Perspectives are also given on the conservation of <it>A. succinogenes </it>genomic features in other sequenced Pasteurellaceae.</p> <p>Conclusions</p> <p>Both <it>A. succinogenes </it>and <it>M. succiniciproducens </it>genome sequences lack many of the virulence genes used by their pathogenic Pasteurellaceae relatives. The lack of pathogenicity of these two succinogens is an exciting prospect, because comparisons with pathogenic Pasteurellaceae could lead to a better understanding of Pasteurellaceae virulence. The fact that the <it>A. succinogenes </it>genome encodes uptake and degradation pathways for a variety of carbohydrates reflects the variety of carbohydrate substrates available in the rumen, <it>A. succinogenes</it>'s natural habitat. It also suggests that many different carbon sources can be used as feedstock for succinate production by <it>A. succinogenes</it>.</p

The XMM–NEWTON Ω Project: I. The X-ray luminosity – temperature relation at z>0.4

We describe XMM-Newton Guaranteed Time observations of a sample of eight high redshift (0.45 < z < rvirial) bolometric luminosities, performed β-model fits to the radial surface profiles and made spectral fits to a single temperature isothermal model. We describe data analysis techniques that pay particular attention to background mitigation. We have also estimated temperatures and luminosities for two known clusters (Abell 2246 and RXJ1325.0-3814), and one new high redshift cluste r candidate (XMMU J084701.8 +345117), that were detected o ff-axis. Characterizing the L x − Tx relation as L x = L 6 ( T 6keV ) α , we find L 6 = 15 . 9 + 7 . 6 − 5 . 2 × 1044erg s − 1 and α =2.7 ±0.4 for an Ω Λ = 0 . 0 , Ω M = 1 .0, H0 = 50 km s − 1 Mpc − 1 cosmology at a typical redshift z ∼ 0 .55. Comparing with the low redshift study by Markevitch, 1998, we find α to be in agreement, and assuming L x − Tx to evolve as (1 + z ) A , we find A =0.68 ±0.26 for the same cosmology and A = 1 .52 + 0 .26 − 0 .27 for an Ω Λ = 0 . 7 , Ω M = 0 . 3 cosmology. Our A values are very similar to those found previously by Vikhlinin et al., 2002 using a compilation of Chandra observations of 0 .39 < z < 1 .26 clusters. We conclude that there is now evidence from both XMM-Newton and Chandra for an evolutionary trend in the L x − Tx relation. This evolution is significantly below the level expected from the predictions of the self-similar model for an Ω Λ = 0 . 0 , Ω M = 1 .0, cosmology, but consistent with self-similar model in an Ω Λ = 0 . 7 , Ω M = 0 . 3 cosmology. Our observations lend support to the robustness and completeness of the SHARC and 160SD surveys

Simulation techniques for cosmological simulations

Modern cosmological observations allow us to study in great detail the evolution and history of the large scale structure hierarchy. The fundamental problem of accurate constraints on the cosmological parameters, within a given cosmological model, requires precise modelling of the observed structure. In this paper we briefly review the current most effective techniques of large scale structure simulations, emphasising both their advantages and shortcomings. Starting with basics of the direct N-body simulations appropriate to modelling cold dark matter evolution, we then discuss the direct-sum technique GRAPE, particle-mesh (PM) and hybrid methods, combining the PM and the tree algorithms. Simulations of baryonic matter in the Universe often use hydrodynamic codes based on both particle methods that discretise mass, and grid-based methods. We briefly describe Eulerian grid methods, and also some variants of Lagrangian smoothed particle hydrodynamics (SPH) methods.Comment: 42 pages, 16 figures, accepted for publication in Space Science Reviews, special issue "Clusters of galaxies: beyond the thermal view", Editor J.S. Kaastra, Chapter 12; work done by an international team at the International Space Science Institute (ISSI), Bern, organised by J.S. Kaastra, A.M. Bykov, S. Schindler & J.A.M. Bleeke

Action Without Awareness: Reaching to an Object You Do Not Remember Seeing

BACKGROUND: Previous work by our group has shown that the scaling of reach trajectories to target size is independent of obligatory awareness of that target property and that "action without awareness" can persist for up to 2000 ms of visual delay. In the present investigation we sought to determine if the ability to scale reaching trajectories to target size following a delay is related to the pre-computing of movement parameters during initial stimulus presentation or the maintenance of a sensory (i.e., visual) representation for on-demand response parameterization. METHODOLOGY/PRINCIPAL FINDINGS: Participants completed immediate or delayed (i.e., 2000 ms) perceptual reports and reaching responses to different sized targets under non-masked and masked target conditions. For the reaching task, the limb associated with a trial (i.e., left or right) was not specified until the time of response cuing: a manipulation that prevented participants from pre-computing the effector-related parameters of their response. In terms of the immediate and delayed perceptual tasks, target size was accurately reported during non-masked trials; however, for masked trials only a chance level of accuracy was observed. For the immediate and delayed reaching tasks, movement time as well as other temporal kinematic measures (e.g., times to peak acceleration, velocity and deceleration) increased in relation to decreasing target size across non-masked and masked trials. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that speed-accuracy relations were observed regardless of whether participants were aware (i.e., non-masked trials) or unaware (i.e., masked trials) of target size. Moreover, the equivalent scaling of immediate and delayed reaches during masked trials indicates that a persistent sensory-based representation supports the unconscious and metrical scaling of memory-guided reaching

Clusters of galaxies: setting the stage

Clusters of galaxies are self-gravitating systems of mass ~10^14-10^15 Msun. They consist of dark matter (~80 %), hot diffuse intracluster plasma (< 20 %) and a small fraction of stars, dust, and cold gas, mostly locked in galaxies. In most clusters, scaling relations between their properties testify that the cluster components are in approximate dynamical equilibrium within the cluster gravitational potential well. However, spatially inhomogeneous thermal and non-thermal emission of the intracluster medium (ICM), observed in some clusters in the X-ray and radio bands, and the kinematic and morphological segregation of galaxies are a signature of non-gravitational processes, ongoing cluster merging and interactions. In the current bottom-up scenario for the formation of cosmic structure, clusters are the most massive nodes of the filamentary large-scale structure of the cosmic web and form by anisotropic and episodic accretion of mass. In this model of the universe dominated by cold dark matter, at the present time most baryons are expected to be in a diffuse component rather than in stars and galaxies; moreover, ~50 % of this diffuse component has temperature ~0.01-1 keV and permeates the filamentary distribution of the dark matter. The temperature of this Warm-Hot Intergalactic Medium (WHIM) increases with the local density and its search in the outer regions of clusters and lower density regions has been the quest of much recent observational effort. Over the last thirty years, an impressive coherent picture of the formation and evolution of cosmic structures has emerged from the intense interplay between observations, theory and numerical experiments. Future efforts will continue to test whether this picture keeps being valid, needs corrections or suffers dramatic failures in its predictive power.Comment: 20 pages, 8 figures, accepted for publication in Space Science Reviews, special issue "Clusters of galaxies: beyond the thermal view", Editor J.S. Kaastra, Chapter 2; work done by an international team at the International Space Science Institute (ISSI), Bern, organised by J.S. Kaastra, A.M. Bykov, S. Schindler & J.A.M. Bleeke

Baryon content in a sample of 91 galaxy clusters selected by the South Pole Telescope at 0.2 <z < 1.25

We estimate total mass (M500), intracluster medium (ICM) mass (MICM), and stellar mass (M) in a Sunyaev–Zel’dovich effect (SZE) selected sample of 91 galaxy clusters with masses M500 2.5 × 1014 M and redshift 0.2 < z < 1.25 from the 2500 deg2 South Pole Telescope SPT-SZ survey. The total masses M500 are estimated from the SZE observable, the ICM masses MICM are obtained from the analysis of Chandra X-ray observations, and the stellar masses M are derived by fitting spectral energy distribution templates to Dark Energy Survey griz optical photometry and WISE or Spitzer near-infrared photometry. We study trends in the stellar mass, the ICM mass, the total baryonic mass, and the cold baryonic fraction with cluster halo mass and redshift. We find significant departures from self-similarity in the mass scaling for all quantities, while the redshift trends are all statistically consistent with zero, indicating that the baryon content of clusters at fixed mass has changed remarkably little over the past ≈9 Gyr. We compare our results to the mean baryon fraction (and the stellar mass fraction) in the field, finding that these values lie above (below) those in cluster virial regions in all but the most massive clusters at low redshift. Using a simple model of the matter assembly of clusters from infalling groups with lower masses and from infalling material from the low-density environment or field surrounding the parent haloes, we show that the measured mass trends without strong redshift trends in the stellar mass scaling relation could be explained by a mass and redshift dependent fractional contribution from field material. Similar analyses of the ICM and baryon mass scaling relations provide evidence for the so-called ‘missing baryons’ outside cluster virial regions

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa.

The progression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in Africa has so far been heterogeneous, and the full impact is not yet well understood. In this study, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations predominantly from Europe, which diminished after the early introduction of international travel restrictions. As the pandemic progressed, ongoing transmission in many countries and increasing mobility led to the emergence and spread within the continent of many variants of concern and interest, such as B.1.351, B.1.525, A.23.1, and C.1.1. Although distorted by low sampling numbers and blind spots, the findings highlight that Africa must not be left behind in the global pandemic response, otherwise it could become a source for new variants