2,239 research outputs found
A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes
Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties
Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-depleted Murine Embryonic Stem Cells
Embryonic stem cells (ESC) have the potential to self-renew indefinitely and
to differentiate into any of the three germ layers. The molecular mechanisms
for self-renewal, maintenance of pluripotency and lineage specification are
poorly understood, but recent results point to a key role for epigenetic
mechanisms. In this study, we focus on quantifying the impact of histone 3
acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We
analyze genome-wide histone acetylation patterns and gene expression profiles
measured over the first five days of cell differentiation triggered by
silencing Nanog, a key transcription factor in ESC regulation. We explore the
temporal and spatial dynamics of histone acetylation data and its correlation
with gene expression using supervised and unsupervised statistical models. On a
genome-wide scale, changes in acetylation are significantly correlated to
changes in mRNA expression and, surprisingly, this coherence increases over
time. We quantify the predictive power of histone acetylation for gene
expression changes in a balanced cross-validation procedure. In an in-depth
study we focus on genes central to the regulatory network of Mouse ESC,
including those identified in a recent genome-wide RNAi screen and in the
PluriNet, a computationally derived stem cell signature. We find that compared
to the rest of the genome, ESC-specific genes show significantly more
acetylation signal and a much stronger decrease in acetylation over time, which
is often not reflected in an concordant expression change. These results shed
light on the complexity of the relationship between histone acetylation and
gene expression and are a step forward to dissect the multilayer regulatory
mechanisms that determine stem cell fate.Comment: accepted at PLoS Computational Biolog
Search for transient optical counterparts to high-energy IceCube neutrinos with Pan-STARRS1
In order to identify the sources of the observed diffuse high-energy neutrino
flux, it is crucial to discover their electromagnetic counterparts. IceCube
began releasing alerts for single high-energy ( TeV) neutrino
detections with sky localisation regions of order 1 deg radius in 2016. We used
Pan-STARRS1 to follow-up five of these alerts during 2016-2017 to search for
any optical transients that may be related to the neutrinos. Typically 10-20
faint ( mag) extragalactic transients are found within the
Pan-STARRS1 footprints and are generally consistent with being unrelated field
supernovae (SNe) and AGN. We looked for unusual properties of the detected
transients, such as temporal coincidence of explosion epoch with the IceCube
timestamp. We found only one transient that had properties worthy of a specific
follow-up. In the Pan-STARRS1 imaging for IceCube-160427A (probability to be of
astrophysical origin of 50 %), we found a SN PS16cgx, located at 10.0'
from the nominal IceCube direction. Spectroscopic observations of PS16cgx
showed that it was an H-poor SN at z = 0.2895. The spectra and light curve
resemble some high-energy Type Ic SNe, raising the possibility of a jet driven
SN with an explosion epoch temporally coincident with the neutrino detection.
However, distinguishing Type Ia and Type Ic SNe at this redshift is notoriously
difficult. Based on all available data we conclude that the transient is more
likely to be a Type Ia with relatively weak SiII absorption and a fairly normal
rest-frame r-band light curve. If, as predicted, there is no high-energy
neutrino emission from Type Ia SNe, then PS16cgx must be a random coincidence,
and unrelated to the IceCube-160427A. We find no other plausible optical
transient for any of the five IceCube events observed down to a 5
limiting magnitude of mag, between 1 day and 25 days after
detection.Comment: 20 pages, 6 figures, accepted to A&
Search for astrophysical sources of neutrinos using cascade events in IceCube
The IceCube neutrino observatory has established the existence of a flux of
high-energy astrophysical neutrinos inconsistent with the expectation from
atmospheric backgrounds at a significance greater than . This flux has
been observed in analyses of both track events from muon neutrino interactions
and cascade events from interactions of all neutrino flavors. Searches for
astrophysical neutrino sources have focused on track events due to the
significantly better angular resolution of track reconstructions. To date, no
such sources have been confirmed. Here we present the first search for
astrophysical neutrino sources using cascades interacting in IceCube with
deposited energies as small as 1 TeV. No significant clustering was observed in
a selection of 263 cascades collected from May 2010 to May 2012. We show that
compared to the classic approach using tracks, this statistically-independent
search offers improved sensitivity to sources in the southern sky, especially
if the emission is spatially extended or follows a soft energy spectrum. This
enhancement is due to the low background from atmospheric neutrinos forming
cascade events and the additional veto of atmospheric neutrinos at declinations
.Comment: 14 pages, 9 figures, 1 tabl
Measurement of the multi-TeV neutrino cross section with IceCube using Earth absorption
Neutrinos interact only very weakly, so they are extremely penetrating.
However, the theoretical neutrino-nucleon interaction cross section rises with
energy such that, at energies above 40 TeV, neutrinos are expected to be
absorbed as they pass through the Earth. Experimentally, the cross section has
been measured only at the relatively low energies (below 400 GeV) available at
neutrino beams from accelerators \cite{Agashe:2014kda, Formaggio:2013kya}. Here
we report the first measurement of neutrino absorption in the Earth, using a
sample of 10,784 energetic upward-going neutrino-induced muons observed with
the IceCube Neutrino Observatory. The flux of high-energy neutrinos transiting
long paths through the Earth is attenuated compared to a reference sample that
follows shorter trajectories through the Earth. Using a fit to the
two-dimensional distribution of muon energy and zenith angle, we determine the
cross section for neutrino energies between 6.3 TeV and 980 TeV, more than an
order of magnitude higher in energy than previous measurements. The measured
cross section is (stat.) (syst.)
times the prediction of the Standard Model \cite{CooperSarkar:2011pa},
consistent with the expectation for charged and neutral current interactions.
We do not observe a dramatic increase in the cross section, expected in some
speculative models, including those invoking new compact dimensions
\cite{AlvarezMuniz:2002ga} or the production of leptoquarks
\cite{Romero:2009vu}.Comment: Preprint version of Nature paper 10.1038/nature2445
Search for astrophysical sources of neutrinos using cascade events in IceCube
The IceCube neutrino observatory has established the existence of a flux of
high-energy astrophysical neutrinos inconsistent with the expectation from
atmospheric backgrounds at a significance greater than . This flux has
been observed in analyses of both track events from muon neutrino interactions
and cascade events from interactions of all neutrino flavors. Searches for
astrophysical neutrino sources have focused on track events due to the
significantly better angular resolution of track reconstructions. To date, no
such sources have been confirmed. Here we present the first search for
astrophysical neutrino sources using cascades interacting in IceCube with
deposited energies as small as 1 TeV. No significant clustering was observed in
a selection of 263 cascades collected from May 2010 to May 2012. We show that
compared to the classic approach using tracks, this statistically-independent
search offers improved sensitivity to sources in the southern sky, especially
if the emission is spatially extended or follows a soft energy spectrum. This
enhancement is due to the low background from atmospheric neutrinos forming
cascade events and the additional veto of atmospheric neutrinos at declinations
.Comment: 14 pages, 9 figures, 1 tabl
Book Reviews
With the observation of high-energy astrophysical neutrinos by the IceCube Neutrino Observatory, interest has risen in models of PeV-mass decaying dark matter particles to explain the observed flux. We present two dedicated experimental analyses to test this hypothesis. One analysis uses 6 years of IceCube data focusing on muon neutrino âtrackâ events from the Northern Hemisphere, while the second analysis uses 2 years of âcascadeâ events from the full sky. Known background components and the hypothetical flux from unstable dark matter are fitted to the experimental data. Since no significant excess is observed in either analysis, lower limits on the lifetime of dark matter particles are derived: we obtain the strongest constraint to date, excluding lifetimes shorter than s at 90% CL for dark matter masses above 10 TeV
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