250 research outputs found
Macromolecular crowding modulates folding mechanism of alpha/beta protein apoflavodoxin
Protein dynamics in cells may be different from that in dilute solutions in
vitro since the environment in cells is highly concentrated with other
macromolecules. This volume exclusion due to macromolecular crowding is
predicted to affect both equilibrium and kinetic processes involving protein
conformational changes. To quantify macromolecular crowding effects on protein
folding mechanisms, here we have investigated the folding energy landscape of
an alpha/beta protein, apoflavodoxin, in the presence of inert macromolecular
crowding agents using in silico and in vitro approaches. By coarse-grained
molecular simulations and topology-based potential interactions, we probed the
effects of increased volume fraction of crowding agents (phi_c) as well as of
crowding agent geometry (sphere or spherocylinder) at high phi_c. Parallel
kinetic folding experiments with purified Desulfovibro desulfuricans
apoflavodoxin in vitro were performed in the presence of Ficoll (sphere) and
Dextran (spherocylinder) synthetic crowding agents. In conclusion, we have
identified in silico crowding conditions that best enhance protein stability
and discovered that upon manipulation of the crowding conditions, folding
routes experiencing topological frustrations can be either enhanced or
relieved. The test-tube experiments confirmed that apoflavodoxin's
time-resolved folding path is modulated by crowding agent geometry. We propose
that macromolecular crowding effects may be a tool for manipulation of protein
folding and function in living cells.Comment: to appear in Biophysical Journal (2009). to appear in Biophysical
Journal (2009
A Strategy to Measure the Dark Energy Equation of State using the HII galaxy Hubble Relation & X-ray AGN Clustering: Preliminary Results
We explore the possibility of setting stringent constraints to the Dark
Energy equation of state using alternative cosmic tracers like: (a) the Hubble
relation using HII galaxies, which can be observed at much higher redshifts
(z~3.5) than those currently traced by SNIa samples, and (b) the large-scale
structure using the clustering of X-ray selected AGN,which have a redshift
distribution peaking at z~1.
We use extensive Monte-Carlo simulations to define the optimal strategy for
the recovery of the dark-energy equation of state using the high redshift (z~2)
Hubble relation, but accounting also for the effects of gravitational lensing,
which for such high redshifts can significantly affect the derived cosmological
constraints. Based on a "Figure of Merit" analysis, we provide estimates for
the number of 2<z<3.5 tracers needed to reduce the cosmological solution space,
presently provided by the Constitution SNIa set, by a desired factor. We find
that it is much more efficient to increase the number of tracers than to reduce
their individual uncertainties.
Finally, we propose a framework to put constraints on the dark energy
equation of state by using the joint likelihood of the X-ray AGN clustering and
of the Hubble relation cosmological analyses. A preliminary joint analysis
using the X-ray AGN clustering of the 2XMM survey and the Hubble relation of
the Constitution SNIa set provide: Omega_m= 0.31+-0.01 and w=-1.06+-0.05. We
also find that the joint SNIa-2XMM analysis provides significantly more
stringent cosmological constraints, increasing the Figure of Merit by a factor
~2, with respect to that of the joint SNIa-BAO analysis.Comment: MNRAS in press, 12 colour figure
Toll-like receptor 9 polymorphisms are associated with severity variables in a cohort of meningococcal meningitis survivors
BACKGROUND: Genetic variation in immune response genes is associated with susceptibility and severity of infectious diseases. Toll-like receptor (TLR) 9 polymorphisms are associated with susceptibility to develop meningococcal meningitis (MM). The aim of this study is to compare genotype distributions of two TLR9 polymorphisms between clinical severity variables in MM survivors. METHODS: We used DNA samples of a cohort of 390 children who survived MM. Next, we determined the genotype frequencies of TLR9 -1237 and TLR9 +2848 polymorphisms and compared these between thirteen clinical variables associated with prognostic factors predicting adverse outcome of bacterial meningitis in children. RESULTS: The TLR9 -1237 TC and CC genotypes were associated with a decreased incidence of a positive blood culture for Neisseria (N.) meningitidis (p = 0.014, odds ratio (OR) 0.5. 95% confidence interval (CI) 0.3 – 0.9). The TLR9 +2848 AA mutant was associated with a decreased incidence of a positive blood culture for N. meningitidis (p = 0.017, OR 0.6, 95% CI 0.3 – 0.9). Cerebrospinal fluid (CSF) leukocytes per μL were higher in patients carrying the TLR9 -1237 TC or CC genotypes compared to carriers of the TT wild type (WT) (p = 0.024, medians: 2117, interquartile range (IQR) 4987 versus 955, IQR 3938). CSF blood/glucose ratios were lower in TLR9 -1237 TC or CC carriers than in carriers of the TT WT (p = 0.017, medians: 0.20, IQR 0.4 versus 0.35, IQR 0.5). CSF leukocytes/μL were higher in patients carrying the TLR9 +2848 AA mutant compared to carriers of GG or GA (p = 0.0067, medians: 1907, IQR 5221 versus 891, IQR 3952). CONCLUSIONS: We identified TLR9 genotypes associated with protection against meningococcemia and enhanced local inflammatory responses inside the central nervous system, important steps in MM pathogenesis and defense
A search for point sources of EeV photons
Measurements of air showers made using the hybrid technique developed with
the fluorescence and surface detectors of the Pierre Auger Observatory allow a
sensitive search for point sources of EeV photons anywhere in the exposed sky.
A multivariate analysis reduces the background of hadronic cosmic rays. The
search is sensitive to a declination band from -85{\deg} to +20{\deg}, in an
energy range from 10^17.3 eV to 10^18.5 eV. No photon point source has been
detected. An upper limit on the photon flux has been derived for every
direction. The mean value of the energy flux limit that results from this,
assuming a photon spectral index of -2, is 0.06 eV cm^-2 s^-1, and no celestial
direction exceeds 0.25 eV cm^-2 s^-1. These upper limits constrain scenarios in
which EeV cosmic ray protons are emitted by non-transient sources in the
Galaxy.Comment: 28 pages, 10 figures, accepted for publication in The Astrophysical
Journa
Respiratory Syncytial Virus (RSV) RNA loads in peripheral blood correlates with disease severity in mice
<p>Abstract</p> <p>Background</p> <p>Respiratory Syncytial Virus (RSV) infection is usually restricted to the respiratory epithelium. Few studies have documented the presence of RSV in the systemic circulation, however there is no consistent information whether virus detection in the blood correlates with disease severity.</p> <p>Methods</p> <p>Balb/c mice were inoculated with live RSV, heat-inactivated RSV or medium. A subset of RSV-infected mice was treated with anti-RSV antibody 72 h post-inoculation. RSV RNA loads were measured by PCR in peripheral blood from day 1-21 post-inoculation and were correlated with upper and lower respiratory tract viral loads, the systemic cytokine response, lung inflammation and pulmonary function. Immunohistochemical staining was used to define the localization of RSV antigens in the respiratory tract and peripheral blood.</p> <p>Results</p> <p>RSV RNA loads were detected in peripheral blood from day 1 to 14 post-inoculation, peaked on day 5 and significantly correlated with nasal and lung RSV loads, airway obstruction, and blood CCL2 and CXCL1 expression. Treatment with anti-RSV antibody reduced blood RSV RNA loads and improved airway obstruction. Immunostaining identified RSV antigens in alveolar macrophages and peripheral blood monocytes.</p> <p>Conclusions</p> <p>RSV RNA was detected in peripheral blood upon infection with live RSV, followed a time-course parallel to viral loads assessed in the respiratory tract and was significantly correlated with RSV-induced airway disease.</p
Reconstruction of inclined air showers detected with the Pierre Auger Observatory
We describe the method devised to reconstruct inclined cosmic-ray air showers
with zenith angles greater than detected with the surface array of
the Pierre Auger Observatory. The measured signals at the ground level are
fitted to muon density distributions predicted with atmospheric cascade models
to obtain the relative shower size as an overall normalization parameter. The
method is evaluated using simulated showers to test its performance. The energy
of the cosmic rays is calibrated using a sub-sample of events reconstructed
with both the fluorescence and surface array techniques. The reconstruction
method described here provides the basis of complementary analyses including an
independent measurement of the energy spectrum of ultra-high energy cosmic rays
using very inclined events collected by the Pierre Auger Observatory.Comment: 27 pages, 19 figures, accepted for publication in Journal of
Cosmology and Astroparticle Physics (JCAP
Ultrahigh-energy neutrino follow-up of Gravitational Wave events GW150914 and GW151226 with the Pierre Auger Observatory
On September 14, 2015 the Advanced LIGO detectors observed their first
gravitational-wave (GW) transient GW150914. This was followed by a second GW
event observed on December 26, 2015. Both events were inferred to have arisen
from the merger of black holes in binary systems. Such a system may emit
neutrinos if there are magnetic fields and disk debris remaining from the
formation of the two black holes. With the surface detector array of the Pierre
Auger Observatory we can search for neutrinos with energy above 100 PeV from
point-like sources across the sky with equatorial declination from about -65
deg. to +60 deg., and in particular from a fraction of the 90% confidence-level
(CL) inferred positions in the sky of GW150914 and GW151226. A targeted search
for highly-inclined extensive air showers, produced either by interactions of
downward-going neutrinos of all flavors in the atmosphere or by the decays of
tau leptons originating from tau-neutrino interactions in the Earth's crust
(Earth-skimming neutrinos), yielded no candidates in the Auger data collected
within s around or 1 day after the coordinated universal time (UTC)
of GW150914 and GW151226, as well as in the same search periods relative to the
UTC time of the GW candidate event LVT151012. From the non-observation we
constrain the amount of energy radiated in ultrahigh-energy neutrinos from such
remarkable events.Comment: Published version. Added journal reference and DOI. Added Report
Numbe
Azimuthal asymmetry in the risetime of the surface detector signals of the Pierre Auger Observatory
The azimuthal asymmetry in the risetime of signals in Auger surface detector
stations is a source of information on shower development. The azimuthal
asymmetry is due to a combination of the longitudinal evolution of the shower
and geometrical effects related to the angles of incidence of the particles
into the detectors. The magnitude of the effect depends upon the zenith angle
and state of development of the shower and thus provides a novel observable,
, sensitive to the mass composition of cosmic rays
above eV. By comparing measurements with predictions from
shower simulations, we find for both of our adopted models of hadronic physics
(QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass
increases slowly with energy, as has been inferred from other studies. However,
the mass estimates are dependent on the shower model and on the range of
distance from the shower core selected. Thus the method has uncovered further
deficiencies in our understanding of shower modelling that must be resolved
before the mass composition can be inferred from .Comment: Replaced with published version. Added journal reference and DO
The Pierre Auger Observatory: Contributions to the 34th International Cosmic Ray Conference (ICRC 2015)
Contributions of the Pierre Auger Collaboration to the 34th International
Cosmic Ray Conference, 30 July - 6 August 2015, The Hague, The NetherlandsComment: 24 proceedings, the 34th International Cosmic Ray Conference, 30 July
- 6 August 2015, The Hague, The Netherlands; will appear in PoS(ICRC2015
- …