242 research outputs found
Characterization and Structure of a Zn2+ and [2Fe-2S]-containing Copper Chaperone from Archaeoglobus Fulgidus
Bacterial CopZ proteins deliver copper to P1B-type Cu+-ATPases that are homologous to the human Wilson and Menkes disease proteins. The genome of the hyperthermophile Archaeoglobus fulgidus encodes a putative CopZ copper chaperone that contains an unusual cysteine rich N-terminal domain of 130 amino acids in addition to a C-terminal copper-binding domain with a conserved CXXC motif. The N-terminal domain (CopZ-NT) is homologous to proteins found only in extremophiles and is the only such protein that is fused to a copper chaperone. Surprisingly, optical, electron paramagnetic resonance, and X-ray absorption spectroscopic data indicate the presence of a [2Fe-2S] cluster in CopZ-NT. The intact CopZ protein binds two copper ions, one in each domain. The 1.8 Å resolution crystal structure of CopZ-NT reveals that the [2Fe-2S] cluster is housed within a novel fold and that the protein also binds a zinc ion at a four cysteine site. CopZ can deliver Cu+ to the A. fulgidus CopA N-terminal metal binding domain and is capable of reducing Cu2+ to Cu+. This unique fusion of a redox-active domain with a CXXC-containing copper chaperone domain is relevant to the evolution of copper homeostatic mechanisms and suggests new models for copper trafficking
Letter: liver disease and COVID-19 - not the perfect storm
This article is linked to Garrido et al papers. To view these articles, visit https://doi.org/10.1111/apt.15813 and https://doi.org/10.1111/apt.15886
Oxford SWIFT IFS and multi-wavelength observations of the Eagle galaxy at z=0.77
The `Eagle' galaxy at a redshift of 0.77 is studied with the Oxford Short
Wavelength Integral Field Spectrograph (SWIFT) and multi-wavelength data from
the All-wavelength Extended Groth strip International Survey (AEGIS). It was
chosen from AEGIS because of the bright and extended emission in its slit
spectrum. Three dimensional kinematic maps of the Eagle reveal a gradient in
velocity dispersion which spans 35-75 +/- 10 km/s and a rotation velocity of 25
+/- 5 km/s uncorrected for inclination. Hubble Space Telescope images suggest
it is close to face-on. In comparison with galaxies from AEGIS at similar
redshifts, the Eagle is extremely bright and blue in the rest-frame optical,
highly star-forming, dominated by unobscured star-formation, and has a low
metallicity for its size. This is consistent with its selection. The Eagle is
likely undergoing a major merger and is caught in the early stage of a
star-burst when it has not yet experienced metal enrichment or formed the mass
of dust typically found in star-forming galaxies.Comment: accepted for publication in MNRA
The rovibrational spectrum of BeH, MgH and CaH at high temperatures in the state: a theoretical study
Accurate line lists for three molecules, BeH, MgH and CaH, in their ground
electronic states are presented. These line lists are suitable for temperatures
relevant to exoplanetary atmospheres and cool stars (up to 2000K). A
combination of empirical and \textit{ab initio} methods is used. The
rovibrational energy levels of BeH, MgH and CaH are computed using the programs
Level and DPotFit in conjunction with `spectroscopic' potential energy curves
(PECs). The PEC of BeH is taken from the literature, while the PECs of CaH and
MgH are generated by fitting to the experimental transition energy levels. Both
spin-rotation interactions (except for BeH, for which it is negligible) and
non-adiabatic corrections are explicitly taken into account. Accurate line
intensities are generated using newly computed \textit{ab initio} dipole moment
curves for each molecule using high levels of theory. Full line lists of
rotation-vibration transitions for BeH, MgH, MgH, MgH
and CaH are made available in an electronic form as supplementary data
to this article and at \url{www.exomol.com}.Comment: MNRAS (in press
A joint spectro-imaging analysis of the XMM-Newton and HESS observations of the supernova remnant RX J1713.7-3946
The supernova remnant (SNR) RX J1713.7-3946 (also known as G347.3-0.5) is
part of the class of remnants dominated by synchrotron emission in X-rays. It
is also one of the few shell-type SNRs observed at TeV energies allowing to
investigate particle acceleration at SNRs shock.
Our goal is to compare spatial and spectral properties of the remnant in X-
and gamma-rays to understand the nature of the TeV emission. This requires to
study the remnant at the same spatial scale at both energies. To complement the
non-thermal spectrum of the remnant, we attempt to provide a reliable estimate
for the radio flux density. In radio, we revisited ATCA data and used HI and
mid-infrared observations to disentangle the thermal from the non-thermal
emission. In X-rays, we produced a new mosaic of the remnant and degraded the
spatial resolution of the X-ray data to the resolution of the HESS instrument
to perform spatially resolved spectroscopy at the same spatial scale in X- and
gamma-rays. Radial profiles were obtained to investigate the extension of the
emission at both energies.
We found that part of the radio emission within the SNR contours is thermal
in nature. Taking this into account, we provide new lower and upper limits for
the integrated synchrotron flux of the remnant at 1.4 GHz of 22 Jy and 26 Jy
respectively. In X-rays, we obtained the first full coverage of RX J1713.7-3946
with XMM-Newton. The spatial variation of the photon index seen at small scale
in X-rays is smeared out at HESS resolution. A non-linear correlation between
the X- and gamma-ray fluxes of the type Fx \propto Fg^2.41 is found.Comment: 13 pages, 10 figures, accepted for publication in A&A. An image of
the remnant with higher definition will be distributed through the XMM-Newton
image gallery (http://xmm.esac.esa.int/external/xmm_science/gallery/public/
Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients.
International audienceBackground: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p<0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p<0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit
Targeted proteomics links virulence factor expression with clinical severity in staphylococcal pneumonia
IntroductionThe bacterial pathogen Staphylococcus aureus harbors numerous virulence factors that impact infection severity. Beyond virulence gene presence or absence, the expression level of virulence proteins is known to vary across S. aureus lineages and isolates. However, the impact of expression level on severity is poorly understood due to the lack of high-throughput quantification methods of virulence proteins.MethodsWe present a targeted proteomic approach able to monitor 42 staphylococcal proteins in a single experiment. Using this approach, we compared the quantitative virulomes of 136 S. aureus isolates from a nationwide cohort of French patients with severe community-acquired staphylococcal pneumonia, all requiring intensive care. We used multivariable regression models adjusted for patient baseline health (Charlson comorbidity score) to identify the virulence factors whose in vitro expression level predicted pneumonia severity markers, namely leukopenia and hemoptysis, as well as patient survival.ResultsWe found that leukopenia was predicted by higher expression of HlgB, Nuc, and Tsst-1 and lower expression of BlaI and HlgC, while hemoptysis was predicted by higher expression of BlaZ and HlgB and lower expression of HlgC. Strikingly, mortality was independently predicted in a dose-dependent fashion by a single phage-encoded virulence factor, the Panton-Valentine leucocidin (PVL), both in logistic (OR 1.28; 95%CI[1.02;1.60]) and survival (HR 1.15; 95%CI[1.02;1.30]) regression models.DiscussionThese findings demonstrate that the in vitro expression level of virulence factors can be correlated with infection severity using targeted proteomics, a method that may be adapted to other bacterial pathogens
Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set
We report a measurement of the bottom-strange meson mixing phase \beta_s
using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays
in which the quark-flavor content of the bottom-strange meson is identified at
production. This measurement uses the full data set of proton-antiproton
collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment
at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity.
We report confidence regions in the two-dimensional space of \beta_s and the
B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2,
-1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in
agreement with the standard model expectation. Assuming the standard model
value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +-
0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +-
0.009 (syst) ps, which are consistent and competitive with determinations by
other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012
GENESIS: Co-location of Geodetic Techniques in Space
Improving and homogenizing time and space reference systems on Earth and,
more directly, realizing the Terrestrial Reference Frame (TRF) with an accuracy
of 1mm and a long-term stability of 0.1mm/year are relevant for many scientific
and societal endeavors. The knowledge of the TRF is fundamental for Earth and
navigation sciences. For instance, quantifying sea level change strongly
depends on an accurate determination of the geocenter motion but also of the
positions of continental and island reference stations, as well as the ground
stations of tracking networks. Also, numerous applications in geophysics
require absolute millimeter precision from the reference frame, as for example
monitoring tectonic motion or crustal deformation for predicting natural
hazards. The TRF accuracy to be achieved represents the consensus of various
authorities which has enunciated geodesy requirements for Earth sciences.
Today we are still far from these ambitious accuracy and stability goals for
the realization of the TRF. However, a combination and co-location of all four
space geodetic techniques on one satellite platform can significantly
contribute to achieving these goals. This is the purpose of the GENESIS
mission, proposed as a component of the FutureNAV program of the European Space
Agency. The GENESIS platform will be a dynamic space geodetic observatory
carrying all the geodetic instruments referenced to one another through
carefully calibrated space ties. The co-location of the techniques in space
will solve the inconsistencies and biases between the different geodetic
techniques in order to reach the TRF accuracy and stability goals endorsed by
the various international authorities and the scientific community. The purpose
of this white paper is to review the state-of-the-art and explain the benefits
of the GENESIS mission in Earth sciences, navigation sciences and metrology.Comment: 31 pages, 9 figures, submitted to Earth, Planets and Space (EPS
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