164 research outputs found
Crystal structure of nitrogen regulatory protein IIA(Ntr )from Neisseria meningitidis
BACKGROUND: The NMB0736 gene of Neisseria meningitidis serogroup B strain MC58 encodes the putative nitrogen regulatory protein, IIA(Ntr )(abbreviated to NM-IIA(Ntr)). The homologous protein present in Escherichia coli is implicated in the control of nitrogen assimilation. As part of a structural proteomics approach to the study of pathogenic Neisseria spp., we have selected this protein for structure determination by X-ray crystallography. RESULTS: The NM-IIA(Ntr )was over-expressed in E. coli and was shown to be partially mono-phosphorylated, as assessed by mass spectrometry of the purified protein. Crystals of un-phosphorylated protein were obtained and diffraction data collected to 2.5 Å resolution. The structure of NM-IIA(Ntr )was solved by molecular replacement using the coordinates of the E. coli nitrogen regulatory protein IIA(ntr )[PDB: 1A6J] as the starting model. The overall fold of the Neisseria enzyme shows a high degree of similarity to the IIA(Ntr )from E. coli, and the position of the phosphoryl acceptor histidine residue (H67) is conserved. The orientation of an adjacent arginine residue (R69) suggests that it may also be involved in coordinating the phosphate group. Comparison of the structure with that of E. coli IIA(mtl )complexed with HPr [PDB: 1J6T] indicates that NM-IIA(Ntr )binds in a similar way to the HPr-like enzyme in Neisseria. CONCLUSION: The structure of NM-IIA(Ntr )confirms its assignment as a homologue of the IIA(Ntr )proteins found in a range of other Gram-negative bacteria. We conclude that the NM- IIA(Ntr )protein functions as part of a phosphorylation cascade which, in contrast to E. coli, shares the upstream phosphotransfer protein with the sugar uptake phosphoenolpyruvate:sugar phosphotransferase system (PTS), but in common with E. coli has a distinct downstream effector mechanism
Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies
Zanamivir is a highly selective neuraminidase (NA) inhibitor with
demonstrated clinical efficacy against influenza A and B virus infections.
In phase II clinical efficacy trials (NAIB2005 and NAIB2008), virological
substudies showed mean reductions in virus shedding after 24 h of
treatment of 1.5 to 2.0 log(10) 50% tissue culture infective doses
compared to a placebo, with no reemergence of virus after the completion
of therapy. Paired isolates (n = 41) obtained before and during therapy
with zanamivir demonstrated no shifts in susceptibility to zanamivir when
measured by NA assays, although for a few isolates NA activity was too low
to evaluate. In plaque reduction assays in MDCK cells, the susceptibility
of isolates to zanamivir was extremely variable even at baseline and did
not correlate with the speed of resolution of virus shedding. Isolates
with apparent limited susceptibility to zanamivir by plaque reduction
proved highly susceptible in vivo in the ferret model. Further sequence
analysis of paired isolates revealed no changes in the hemagglutinin and
NA genes in the majority of isolates. The few changes observed were all
natural variants. No amino acid changes that had previously been
identified in vitro as being involved with reduced susceptibility to
zanamivir were observed. These studies highlighted problems associated
with monitoring susceptibility to NA inhibitors in the clinic, in that no
reliable cell-based assay is available. At present the NA assay is the
best available predictor of susceptibility to NA inhibitors in vivo, as
measured in the validated ferret model of infection
High-p_T pion and kaon production in relativistic nuclear collisions
High-p_T pion and kaon production is studied in relativistic proton-proton,
proton-nucleus, and nucleus-nucleus collisions in a wide energy range. Cross
sections are calculated based on perturbative QCD, augmented by a
phenomenological transverse momentum distribution of partons (``intrinsic
k_T''). An energy dependent width of the transverse momentum distribution is
extracted from pion and charged hadron production data in
proton-proton/proton-antiproton collisions. Effects of multiscattering and
shadowing in the strongly interacting medium are taken into account.
Enhancement of the transverse momentum width is introduced and parameterized to
explain the Cronin effect. In collisions between heavy nuclei, the model
over-predicts central pion production cross sections (more significantly at
higher energies), hinting at the presence of jet quenching. Predictions are
made for proton-nucleus and nucleus-nucleus collisions at RHIC energies.Comment: 26 pages in Latex, 19 EPS figure
Solar Wind Turbulence and the Role of Ion Instabilities
International audienc
Photoproduction of mesons associated with a leading neutron
The photoproduction of mesons associated with a leading
neutron has been observed with the ZEUS detector in collisions at HERA
using an integrated luminosity of 80 pb. The neutron carries a large
fraction, {}, of the incoming proton beam energy and is detected at
very small production angles, { mrad}, an indication of
peripheral scattering. The meson is centrally produced with
pseudorapidity {
GeV}, which is large compared to the average transverse momentum of the neutron
of 0.22 GeV. The ratio of neutron-tagged to inclusive production is
in the photon-proton
center-of-mass energy range { GeV}. The data suggest that the
presence of a hard scale enhances the fraction of events with a leading neutron
in the final state.Comment: 28 pages, 4 figures, 2 table
Measurement of the Isolated Photon Cross Section in p-pbar Collisions at sqrt{s}=1.96 TeV
The cross section for the inclusive production of isolated photons has been
measured in p anti-p collisions at sqrt{s}=1.96 TeV with the D0 detector at the
Fermilab Tevatron Collider. The photons span transverse momenta 23 to 300 GeV
and have pseudorapidity |eta|<0.9. The cross section is compared with the
results from two next-to-leading order perturbative QCD calculations. The
theoretical predictions agree with the measurement within uncertainties.Comment: 7 pages, 5 figures, submitted to Phys.Lett.
Origins of the Ambient Solar Wind: Implications for Space Weather
The Sun's outer atmosphere is heated to temperatures of millions of degrees,
and solar plasma flows out into interplanetary space at supersonic speeds. This
paper reviews our current understanding of these interrelated problems: coronal
heating and the acceleration of the ambient solar wind. We also discuss where
the community stands in its ability to forecast how variations in the solar
wind (i.e., fast and slow wind streams) impact the Earth. Although the last few
decades have seen significant progress in observations and modeling, we still
do not have a complete understanding of the relevant physical processes, nor do
we have a quantitatively precise census of which coronal structures contribute
to specific types of solar wind. Fast streams are known to be connected to the
central regions of large coronal holes. Slow streams, however, appear to come
from a wide range of sources, including streamers, pseudostreamers, coronal
loops, active regions, and coronal hole boundaries. Complicating our
understanding even more is the fact that processes such as turbulence,
stream-stream interactions, and Coulomb collisions can make it difficult to
unambiguously map a parcel measured at 1 AU back down to its coronal source. We
also review recent progress -- in theoretical modeling, observational data
analysis, and forecasting techniques that sit at the interface between data and
theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue
connected with a 2016 ISSI workshop on "The Scientific Foundations of Space
Weather." 44 pages, 9 figure
Crowdsourcing the General Public for Large Scale Molecular Pathology Studies in Cancer
Background: Citizen science, scientific research conducted by non-specialists, has the potential to facilitate biomedical research using available large-scale data, however validating the results is challenging. The Cell Slider is a citizen science project that intends to share images from tumors with the general public, enabling them to score tumor markers independently through an internet-based interface.
Methods: From October 2012 to June 2014, 98,293 Citizen Scientists accessed the Cell Slider web page and scored 180,172 sub-images derived from images of 12,326 tissue microarray cores labeled for estrogen receptor (ER). We evaluated the accuracy of Citizen Scientist's ER classification, and the association between ER status and prognosis by comparing their test performance against trained pathologists.
Findings: The area under ROC curve was 0.95 (95% CI 0.94 to 0.96) for cancer cell identification and 0.97 (95% CI 0.96 to 0.97) for ER status. ER positive tumors scored by Citizen Scientists were associated with survival in a similar way to that scored by trained pathologists. Survival probability at 15 years were 0.78 (95% CI 0.76 to 0.80) for ER-positive and 0.72 (95% CI 0.68 to 0.77) for ER-negative tumors based on Citizen Scientists classification. Based on pathologist classification, survival probability was 0.79 (95% CI 0.77 to 0.81) for ER-positive and 0.71 (95% CI 0.67 to 0.74) for ER-negative tumors. The hazard ratio for death was 0.26 (95% CI 0.18 to 0.37) at diagnosis and became greater than one after 6.5 years of follow-up for ER scored by Citizen Scientists, and 0.24 (95% CI 0.18 to 0.33) at diagnosis increasing thereafter to one after 6.7 (95% CI 4.1 to 10.9) years of follow-up for ER scored by pathologists.
Interpretation: Crowdsourcing of the general public to classify cancer pathology data for research is viable, engages the public and provides accurate ER data. Crowdsourced classification of research data may offer a valid solution to problems of throughput requiring human input
Emerging role of insulin with incretin therapies for management of type 2 diabetes
Type 2 diabetes mellitus (T2DM) is a progressive disease warranting intensification of treatment, as beta-cell function declines over time. Current treatment algorithms recommend metformin as the first-line agent, while advocating the addition of either basal-bolus or premixed insulin as the final level of intervention. Incretin therapy, including incretin mimetics or enhancers, are the latest group of drugs available for treatment of T2DM. These agents act through the incretin axis, are currently recommended as add-on agents either as second-or third-line treatment, without concurrent use of insulin. Given the novel role of incretin therapy in terms of reducing postprandial hyperglycemia, and favorable effects on weight with reduced incidence of hypoglycemia, we explore alternative options for incretin therapy in T2DM management. Furthermore, as some evidence alludes to incretins potentially increasing betacell mass and altering disease progression, we propose introducing these agents earlier in the treatment algorithm. In addition, we suggest the concurrent use of incretins with insulin, given the favorable effects especially in relation to weight gain
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