164 research outputs found
Dissecting cell identity via network inference and in silico gene perturbation
Cell identity is governed by the complex regulation of gene expression, represented as gene-regulatory network
Gene regulatory network reconfiguration in direct lineage reprogramming
In direct lineage conversion, transcription factor (TF) overexpression reconfigures gene regulatory networks (GRNs) to reprogram cell identity. We previously developed CellOracle, a computational method to infer GRNs from single-cell transcriptome and epigenome data. Using inferred GRNs, CellOracle simulates gene expression changes in response to TF perturbation, enabling in silico interrogation of network reconfiguration. Here, we combine CellOracle analysis with lineage tracing of fibroblast to induced endoderm progenitor (iEP) conversion, a prototypical direct reprogramming paradigm. By linking early network state to reprogramming outcome, we reveal distinct network configurations underlying successful and failed fate conversion. Via in silico simulation of TF perturbation, we identify new factors to coax cells into successfully converting their identity, uncovering a central role for the AP-1 subunit Fos with the Hippo signaling effector, Yap1. Together, these results demonstrate the efficacy of CellOracle to infer and interpret cell-type-specific GRN configurations, providing new mechanistic insights into lineage reprogramming
Transcriptional profiling reveals extraordinary diversity among skeletal muscle tissues
Skeletal muscle comprises a family of diverse tissues with highly specialized functions. Many acquired diseases, including HIV and COPD, affect specific muscles while sparing others. Even monogenic muscular dystrophies selectively affect certain muscle groups. These observations suggest that factors intrinsic to muscle tissues influence their resistance to disease. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use RNAseq to profile mRNA expression in skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. We detect mRNA expression of hundreds of putative myokines that may underlie the endocrine functions of skeletal muscle. We identify candidate genes that may drive tissue specialization, including Smarca4, Vegfa, and Myostatin. By demonstrating the intrinsic diversity of skeletal muscles, these data provide a resource for studying the mechanisms of tissue specialization
Basal epithelial stem cells cross an alarmin checkpoint for postviral lung disease
Epithelial cells are charged with protection at barrier sites, but whether this normally beneficial response might sometimes become dysfunctional still needs definition. Here, we recognized a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaced normal airspaces in a mouse model of progressive postviral lung disease due to the Sendai virus. Single-cell and lineage-tracing technologies identified a distinct subset of basal epithelial stem cells (basal ESCs) that extended into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset was selectively expanded by crossing a cell-growth and survival checkpoint linked to the nuclear-localized alarmin IL-33 that was independent of IL-33 receptor signaling and instead connected to autocrine chromatin accessibility. This mechanism creates an activated stem-progenitor cell lineage with potential for physiological or pathological function. Thus, conditional loss of Il33 gene function in basal epithelial cells disrupted the homeostasis of the epithelial barrier at skin and gut sites but also markedly attenuated postviral disease in the lung based on the downregulation of remodeling and inflammation. Thus, we define a basal ESC strategy to deploy innate immune machinery that appears to overshoot the primordial goal of self-defense. Our findings reveal new targets to stratify and correct chronic and often deadly postviral disease
Search for non-relativistic Magnetic Monopoles with IceCube
The IceCube Neutrino Observatory is a large Cherenkov detector instrumenting
of Antarctic ice. The detector can be used to search for
signatures of particle physics beyond the Standard Model. Here, we describe the
search for non-relativistic, magnetic monopoles as remnants of the GUT (Grand
Unified Theory) era shortly after the Big Bang. These monopoles may catalyze
the decay of nucleons via the Rubakov-Callan effect with a cross section
suggested to be in the range of to
. In IceCube, the Cherenkov light from nucleon decays
along the monopole trajectory would produce a characteristic hit pattern. This
paper presents the results of an analysis of first data taken from May 2011
until May 2012 with a dedicated slow-particle trigger for DeepCore, a
subdetector of IceCube. A second analysis provides better sensitivity for the
brightest non-relativistic monopoles using data taken from May 2009 until May
2010. In both analyses no monopole signal was observed. For catalysis cross
sections of the flux of non-relativistic
GUT monopoles is constrained up to a level of at a 90% confidence level,
which is three orders of magnitude below the Parker bound. The limits assume a
dominant decay of the proton into a positron and a neutral pion. These results
improve the current best experimental limits by one to two orders of magnitude,
for a wide range of assumed speeds and catalysis cross sections.Comment: 20 pages, 20 figure
A combined maximum-likelihood analysis of the high-energy astrophysical neutrino flux measured with IceCube
Evidence for an extraterrestrial flux of high-energy neutrinos has now been
found in multiple searches with the IceCube detector. The first solid evidence
was provided by a search for neutrino events with deposited energies
TeV and interaction vertices inside the instrumented volume. Recent
analyses suggest that the extraterrestrial flux extends to lower energies and
is also visible with throughgoing, -induced tracks from the Northern
hemisphere. Here, we combine the results from six different IceCube searches
for astrophysical neutrinos in a maximum-likelihood analysis. The combined
event sample features high-statistics samples of shower-like and track-like
events. The data are fit in up to three observables: energy, zenith angle and
event topology. Assuming the astrophysical neutrino flux to be isotropic and to
consist of equal flavors at Earth, the all-flavor spectrum with neutrino
energies between 25 TeV and 2.8 PeV is well described by an unbroken power law
with best-fit spectral index and a flux at 100 TeV of
.
Under the same assumptions, an unbroken power law with index is disfavored
with a significance of 3.8 () with respect to the best
fit. This significance is reduced to 2.1 () if instead we
compare the best fit to a spectrum with index that has an exponential
cut-off at high energies. Allowing the electron neutrino flux to deviate from
the other two flavors, we find a fraction of at Earth.
The sole production of electron neutrinos, which would be characteristic of
neutron-decay dominated sources, is rejected with a significance of 3.6
().Comment: 16 pages, 10 figures; accepted for publication in The Astrophysical
Journal; updated one referenc
Measurement of the Atmospheric Spectrum with IceCube
We present a measurement of the atmospheric spectrum at energies
between 0.1 TeV and 100 TeV using data from the first year of the complete
IceCube detector. Atmospheric originate mainly from the decays of kaons
produced in cosmic-ray air showers. This analysis selects 1078 fully contained
events in 332 days of livetime, then identifies those consistent with particle
showers. A likelihood analysis with improved event selection extends our
previous measurement of the conventional fluxes to higher energies. The
data constrain the conventional flux to be times a
baseline prediction from a Honda's calculation, including the knee of the
cosmic-ray spectrum. A fit to the kaon contribution () to the neutrino
flux finds a kaon component that is times the baseline
value. The fitted/measured prompt neutrino flux from charmed hadron decays
strongly depends on the assumed astrophysical flux and shape. If the
astrophysical component follows a power law, the result for the prompt flux is
times a calculated flux based on the work by Enberg, Reno
and Sarcevic.Comment: PRD accepted versio
Characterization of the Atmospheric Muon Flux in IceCube
Muons produced in atmospheric cosmic ray showers account for the by far
dominant part of the event yield in large-volume underground particle
detectors. The IceCube detector, with an instrumented volume of about a cubic
kilometer, has the potential to conduct unique investigations on atmospheric
muons by exploiting the large collection area and the possibility to track
particles over a long distance. Through detailed reconstruction of energy
deposition along the tracks, the characteristics of muon bundles can be
quantified, and individual particles of exceptionally high energy identified.
The data can then be used to constrain the cosmic ray primary flux and the
contribution to atmospheric lepton fluxes from prompt decays of short-lived
hadrons.
In this paper, techniques for the extraction of physical measurements from
atmospheric muon events are described and first results are presented. The
multiplicity spectrum of TeV muons in cosmic ray air showers for primaries in
the energy range from the knee to the ankle is derived and found to be
consistent with recent results from surface detectors. The single muon energy
spectrum is determined up to PeV energies and shows a clear indication for the
emergence of a distinct spectral component from prompt decays of short-lived
hadrons. The magnitude of the prompt flux, which should include a substantial
contribution from light vector meson di-muon decays, is consistent with current
theoretical predictions.Comment: 36 pages, 39 figure
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