GRB 060605: multi-wavelength analysis of the first GRB observed using integral field spectroscopy

The long and relatively faint gamma-ray burst GRB 060605 detected by \emph{Swift}/BAT lasted about 20 sec. Its afterglow could be observed with \emph{Swift}/XRT for nearly 1 day, while \emph{Swift}/UVOT could detect the afterglow during the first 6 hours after the event. Here, we report on integral field spectroscopy of its afterglow performed with PMAS/PPak mounted at the Calar Alto 3.5 m telescope. In addition, we report on a detailed analysis of XRT and UVOT data and on the results of deep late-time VLT observations that reveal the GRB host galaxy. We find that the burst occurred at a redshift of $z$=3.773, possibly associated with a faint, $R_C=26.4 \pm 0.3$ host. Based on the optical and X-ray data, we deduce information on the SED of the afterglow, the position of the cooling frequency in the SED, the nature of the circumburst environment, its collimation factor, and its energetics. We find that the GRB fireball was expanding into a constant-density medium and that the explosion was collimated with a narrow half-opening angle of about 2.4 degrees. The initial Lorentz factor of the fireball was about 250; however, its beaming-corrected energy release in the gamma-ray band was comparably low. The optical, X-ray afterglow, on the other hand, was rather luminous. Finally, we find that the data are consistent within the error bars with an achromatic evolution of the afterglow during the suspected jet break time at about 0.27 days after the burst.Comment: accepted in A&A; changed title, major reviews after referee's report; 15 pages and 14 figure

Pairing in two-dimensional boson-fermion mixtures

The possibilities of pairing in two-dimensional boson-fermion mixtures are carefully analyzed. It is shown that the boson-induced attraction between two identical fermions dominates the p-wave pairing at low density. For a given fermion density, the pairing gap becomes maximal at a certain optimal boson concentration. The conditions for observing pairing in current experiments are discussedComment: 10 pages, 5 figs, revtex

One-loop weak corrections to hadronic production of Z bosons at large transverse momenta

To match the precision of present and future measurements of Z-boson production at hadron colliders, electroweak radiative corrections must be included in the theory predictions. In this paper we consider their effect on the transverse momentum ($p_T$) distribution of Z bosons, with emphasis on large $p_T$. We evaluate, analytically and numerically, the full one-loop corrections for the parton scattering reaction $q\bar q \to Z g$ and its crossed variants. In addition we derive compact approximate expressions which are valid in the high-energy region, where the weak corrections are strongly enhanced by logarithms of $\hat s/M_W^2$. These expressions include quadratic and single logarithms as well as those terms that are not logarithmically enhanced. This approximation, which confirms and extends earlier results obtained to next-to-leading logarithmic accuracy, permits to reproduce the exact one-loop corrections with high precision. Numerical results are presented for proton-proton and proton-antiproton collisions. The corrections are negative and their size increases with $p_T$. For the Tevatron they amount up to -7% at 300 GeV. For the LHC, where transverse momenta of 2 TeV or more can be reached, corrections up to -40% are observed. We also include the dominant two-loop effects of up to 8% in our final LHC predictions.Comment: 32 pages, 7 figure

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID)

ObjectiveThe objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. MethodsThe GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. ResultsData from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.67.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. ConclusionWith the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID)

ObjectiveThe objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. MethodsThe GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. ResultsData from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.67.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. ConclusionWith the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE

Conserved phosphoryl transfer mechanisms within kinase families and the role of the C8 proton of ATP in the activation of phosphoryl transfer

<p>Abstract</p> <p>Background</p> <p>The kinome is made up of a large number of functionally diverse enzymes, with the classification indicating very little about the extent of the conserved kinetic mechanisms associated with phosphoryl transfer. It has been demonstrated that C8-H of ATP plays a critical role in the activity of a range of kinase and synthetase enzymes.</p> <p>Results</p> <p>A number of conserved mechanisms within the prescribed kinase fold families have been identified directly utilizing the C8-H of ATP in the initiation of phosphoryl transfer. These mechanisms are based on structurally conserved amino acid residues that are within hydrogen bonding distance of a co-crystallized nucleotide. On the basis of these conserved mechanisms, the role of the nucleotide C8-H in initiating the formation of a pentavalent intermediate between the γ-phosphate of the ATP and the substrate nucleophile is defined. All reactions can be clustered into two mechanisms by which the C8-H is induced to be labile via the coordination of a backbone carbonyl to C6-NH₂of the adenyl moiety, namely a "push" mechanism, and a "pull" mechanism, based on the protonation of N7. Associated with the "push" mechanism and "pull" mechanisms are a series of proton transfer cascades, initiated from C8-H, via the tri-phosphate backbone, culminating in the formation of the pentavalent transition state between the γ-phosphate of the ATP and the substrate nucleophile.</p> <p>Conclusions</p> <p>The "push" mechanism and a "pull" mechanism are responsible for inducing the C8-H of adenyl moiety to become more labile. These mechanisms and the associated proton transfer cascades achieve the proton transfer via different family-specific conserved sets of amino acids. Each of these mechanisms would allow for the regulation of the rate of formation of the pentavalent intermediate between the ATP and the substrate nucleophile. Phosphoryl transfer within kinases is therefore a specific event mediated and regulated via the coordination of the adenyl moiety of ATP and the C8-H of the adenyl moiety.</p

Influence of fecal collection conditions and 16S rRNA gene sequencing at two centers on human gut microbiota analysis

Published online: 12 March 2018To optimise fecal sampling for reproducible analysis of the gut microbiome, we compared different methods of sample collection and sequencing of 16S rRNA genes at two centers. Samples collected from six individuals on three consecutive days were placed in commercial collection tubes (OMNIgeneGut OMR-200) or in sterile screw-top tubes in a home fridge or home freezer for 6-24 h, before transfer and storage at -80 °C. Replicate samples were shipped to centers in Australia and the USA for DNA extraction and sequencing by their respective PCR protocols, and analysed with the same bioinformatic pipeline. Variation in gut microbiome was dominated by differences between individuals. Minor differences in the abundance of taxa were found between collection-processing methods and day of collection, and between the two centers. We conclude that collection with storage and transport at 4 °C within 24 h is adequate for 16S rRNA analysis of the gut microbiome. Other factors including differences in PCR and sequencing methods account for relatively minor variation compared to differences between individuals.Jocelyn Sietsma Penington, Megan A. S. Penno, Katrina M. Ngui, Nadim J. Ajami, Alexandra J. Roth-Schulze, Stephen A. Wilcox, Esther Bandala-Sanchez, John M. Wentworth, Simon C. Barry, Cheryl Y. Brown, Jennifer J. Couper, Joseph F. Petrosino, Anthony T. Papenfuss, Leonard C. Harrison and ENDIA Study Group (Lynne Giles and Rebecca L. Thomson

New constraints on atmospheric CO2 concentration for the Phanerozoic

Earth's atmospheric CO2 concentration (ca) for the Phanerozoic Eon is estimated from proxies and geochemical carbon cycle models. Most estimates come with large, sometimes unbounded uncertainty. Here, we calculate tightly constrained estimates of ca using a universal equation for leaf gas exchange, with key variables obtained directly from the carbon isotope composition and stomatal anatomy of fossil leaves. Our new estimates, validated against ice cores and direct measurements of ca, are less than 1000 ppm for most of the Phanerozoic, from the Devonian to the present, coincident with the appearance and global proliferation of forests. Uncertainties, obtained from Monte Carlo simulations, are typically less than for ca estimates from other approaches. These results provide critical new empirical support for the emerging view that large (~2000-3000 ppm), long-term swings in ca do not characterize the post-Devonian and that Earth's long-term climate sensitivity to ca is greater than originally thought. Key Points A novel CO2 proxy calculates past atmospheric CO2 with improved certainty CO2 is unlikely to have exceeded ~1000 ppm for extended periods post Devonian Earth's long-term climate sensitivity to CO2 is greater than originally thought

NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Hepatocellular carcinoma (HCC) can have viral or non-viral causes(1-5). Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need(6,7). Here we report the progressive accumulation of exhausted, unconventionally activated CD8(+)PD1(+) T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8(+)PD1(+) T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8(+)PD1(+)CXCR6(+), TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8(+) T cells or TNF neutralization, suggesting that CD8(+) T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8(+)PD1(+) T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment