1,176 research outputs found
E2F4 actively promotes the initiation and maintenance of nerve growth factor-induced cell differentiation
E2F transcription factors play a critical role in cell cycle progression through the regulation of genes required for G(1)/S transition. They are also thought to be important for growth arrest; however, their potential role in the cell differentiation process has not been previously examined. Here, we demonstrate that E2F4 is highly upregulated following the neuronal differentiation of PC12 cells with nerve growth factor (NGF), while E2F1, E2F3, and E2F5 are downregulated. Immunoprecipitation and subcellular fractionation studies demonstrated that both the nuclear localization of E2F4 and its association with the Rb family member p130 increased following neuronal differentiation. The forced expression of E2F4 markedly enhanced the rate of PC12 cell differentiation induced by NGF and also greatly lowered the rate at which cells lost their neuronal phenotype following NGF removal. Importantly, this effect occurred in the absence of any significant change in the growth regulation of PC12 cells by NGF. Further, the downregulation of E2F4 expression with antisense oligodeoxynucleotides inhibited NGF-induced neurite outgrowth, indicating an important role for this factor during PC12 cell differentiation. Finally, E2F4 expression was found to increase dramatically in the developing rat cerebral cortex and cerebellum, as neuroblasts became postmitotic and initiated terminal differentiation. These findings demonstrate that, in addition to its effects on cell proliferation, E2F4 actively promotes the neuronal differentiation of PC12 cells as well as the retention of this state. Further, this effect is independent of alterations in cell growth and may involve interactions between E2F4 and the neuronal differentiation program itself. E2F4 may be an important participant in the terminal differentiation of neuroblasts
Nuclear factor I coordinates multiple phases of cerebellar granule cell development via regulation of cell adhesion molecules
A central question is how various stages of neuronal development are integrated as a differentiation program. Here we show that the nuclear factor I (NFI) family of transcriptional regulators is expressed and functions throughout the postmitotic development of cerebellar granule neurons (CGNs). Expression of an NFI dominant repressor in CGN cultures blocked axon outgrowth and dendrite formation and decreased CGN migration. Inhibition of NFI transactivation also disrupted extension and fasciculation of parallel fibers as well as CGN migration to the internal granule cell layer in cerebellar slices. In postnatal day 17 Nfia-deficient mice, parallel fibers were greatly diminished and disoriented, CGN dendrite formation was dramatically impaired, and migration from the external germinal layer (EGL) was retarded. Axonal marker expression also was disrupted within the EGL of embryonic day 18 Nfib-null mice. NFI regulation of axon extension was observed under conditions of homotypic cell contact, implicating cell surface proteins as downstream mediators of its actions in CGNs. Consistent with this, the cell adhesion molecules ephrin B1 and N-cadherin were identified as NFI gene targets in CGNs using inhibitor and Nfi mutant analysis as well as chromatin immunoprecipitation. Functional inhibition of ephrin B1 or N-cadherin interfered with CGN axon extension and guidance, migration, and dendritogenesis in cell culture as well as in situ. These studies define NFI as a key regulator of postmitotic CGN development, in particular of axon formation, dendritogenesis, and migratory behavior. Furthermore, they reveal how a single transcription factor family can control and integrate multiple aspects of neuronal differentiation through the regulation of cell adhesion molecules
Temporal regulation of nuclear factor one occupancy by calcineurin/NFAT governs a voltage-sensitive developmental switch in late maturing neurons
Dendrite and synapse development are critical for establishing appropriate neuronal circuits, and disrupted timing of these events can alter neural connectivity. Using microarrays, we have identified a nuclear factor I (NFI)-regulated temporal switch program linked to dendrite formation in developing mouse cerebellar granule neurons (CGNs). NFI function was required for upregulation of many synapse-related genes as well as downregulation of genes expressed in immature CGNs. Chromatin immunoprecipitation analysis revealed that a central feature of this program was temporally regulated NFI occupancy of late-expressed gene promoters. Developing CGNs undergo a hyperpolarizing shift in membrane potential, and depolarization inhibits their dendritic and synaptic maturation via activation of calcineurin (CaN) (Okazawa et al., 2009). Maintaining immature CGNs in a depolarized state blocked NFI temporal occupancy of late-expressed genes and the NFI switch program via activation of the CaN/nuclear factor of activated T-cells, cytoplasmic (NFATc) pathway and promotion of late-gene occupancy by NFATc4, and these mechanisms inhibited dendritogenesis. Conversely, inhibition of the CaN/NFATc pathway in CGNs maturing under physiological nondepolarizing conditions upregulated the NFI switch program, NFI temporal occupancy, and dendrite formation. NFATc4 occupied the promoters of late-expressed NFI program genes in immature mouse cerebellum, and its binding was temporally downregulated with development. Further, NFI temporal binding and switch gene expression were upregulated in the developing cerebellum of Nfatc4 (-/-) mice. These findings define a novel NFI switch and temporal occupancy program that forms a critical link between membrane potential/CaN and dendritic maturation in CGNs. CaN inhibits the program and NFI occupancy in immature CGNs by promoting NFATc4 binding to late-expressed genes. As maturing CGNs become more hyperpolarized, NFATc4 binding declines leading to onset of NFI temporal binding and the NFI switch program
A Neutron Star Binary Merger Model for GW170817/GRB170817a/SSS17a
The merging neutron star gravitational wave event GW170817 has been observed
throughout the entire electromagnetic spectrum from radio waves to
-rays. The resulting energetics, variability, and light curves are
shown to be consistent with GW170817 originating from the merger of two neutron
stars, in all likelihood followed by the prompt gravitational collapse of the
massive remnant. The available -ray, X-ray and radio data provide a
clear probe for the nature of the relativistic ejecta and the non-thermal
processes occurring within, while the ultraviolet, optical and infrared
emission are shown to probe material torn during the merger and subsequently
heated by the decay of freshly synthesized -process material. The simplest
hypothesis that the non-thermal emission is due to a low-luminosity short
-ray burst (sGRB) seems to agree with the present data. While low
luminosity sGRBs might be common, we show here that the collective prompt and
multi-wavelength observations are also consistent with a typical, powerful sGRB
seen off-axis. Detailed follow-up observations are thus essential before we can
place stringent constraints on the nature of the relativistic ejecta in
GW170817.Comment: 9 pages, 5 figures, accepted to ApJ Letter
Electromagnetic Evidence that SSS17a is the Result of a Binary Neutron Star Merger
11 hours after the detection of gravitational wave source GW170817 by the
Laser Interferometer Gravitational-Wave Observatory and Virgo Interferometers,
an associated optical transient SSS17a was discovered in the galaxy NGC 4993.
While the gravitational wave data indicate GW170817 is consistent with the
merger of two compact objects, the electromagnetic observations provide
independent constraints of the nature of that system. Here we synthesize all
optical and near-infrared photometry and spectroscopy of SSS17a collected by
the One-Meter Two-Hemisphere collaboration. We find that SSS17a is unlike other
known transients. The source is best described by theoretical models of a
kilonova consisting of radioactive elements produced by rapid neutron capture
(the r-process). We find that SSS17a was the result of a binary neutron star
merger, reinforcing the gravitational wave result.Comment: 21 pages, 4 figures, accepted to Scienc
Moving Beyond Too Little, Too Late: Managing Emerging Infectious Diseases in Wild Populations Requires International Policy and Partnerships
No Full Tex
Transiting Exoplanet Studies and Community Targets for JWST's Early Release Science Program
The James Webb Space Telescope will revolutionize transiting exoplanet
atmospheric science due to its capability for continuous, long-duration
observations and its larger collecting area, spectral coverage, and spectral
resolution compared to existing space-based facilities. However, it is unclear
precisely how well JWST will perform and which of its myriad instruments and
observing modes will be best suited for transiting exoplanet studies. In this
article, we describe a prefatory JWST Early Release Science (ERS) program that
focuses on testing specific observing modes to quickly give the community the
data and experience it needs to plan more efficient and successful future
transiting exoplanet characterization programs. We propose a multi-pronged
approach wherein one aspect of the program focuses on observing transits of a
single target with all of the recommended observing modes to identify and
understand potential systematics, compare transmission spectra at overlapping
and neighboring wavelength regions, confirm throughputs, and determine overall
performances. In our search for transiting exoplanets that are well suited to
achieving these goals, we identify 12 objects (dubbed "community targets") that
meet our defined criteria. Currently, the most favorable target is WASP-62b
because of its large predicted signal size, relatively bright host star, and
location in JWST's continuous viewing zone. Since most of the community targets
do not have well-characterized atmospheres, we recommend initiating preparatory
observing programs to determine the presence of obscuring clouds/hazes within
their atmospheres. Measurable spectroscopic features are needed to establish
the optimal resolution and wavelength regions for exoplanet characterization.
Other initiatives from our proposed ERS program include testing the instrument
brightness limits and performing phase-curve observations.(Abridged)Comment: This is a white paper that originated from an open discussion at the
Enabling Transiting Exoplanet Science with JWST workshop held November 16 -
18, 2015 at STScI (http://www.stsci.edu/jwst/science/exoplanets). Accepted
for publication in PAS
Context-dependent conservation responses to emerging wildlife diseases
Emerging infectious diseases pose an important threat to wildlife. While established protocols exist for combating outbreaks of human and agricultural pathogens, appropriate management actions before, during, and after the invasion of wildlife pathogens have not been developed. We describe stage-specific goals and management actions that minimize disease impacts on wildlife, and the research required to implement them. Before pathogen arrival, reducing the probability of introduction through quarantine and trade restrictions is key because prevention is more cost effective than subsequent responses. On the invasion front, the main goals are limiting pathogen spread and preventing establishment. In locations experiencing an epidemic, management should focus on reducing transmission and disease, and promoting the development of resistance or tolerance. Finally, if pathogen and host populations reach a stable stage, then recovery of host populations in the face of new threats is paramount. Successful management of wildlife disease requires risk-taking, rapid implementation, and an adaptive approach."Funding was provided by the US National Science Foundation (grants EF-0914866, DGE-0741448, DEB-1115069, DEB-1336290) and the National Institutes of Health (grant 1R010AI090159)."https://esajournals.onlinelibrary.wiley.com/doi/abs/10.1890/14024
Multi-Messenger Astronomy with Extremely Large Telescopes
The field of time-domain astrophysics has entered the era of Multi-messenger
Astronomy (MMA). One key science goal for the next decade (and beyond) will be
to characterize gravitational wave (GW) and neutrino sources using the next
generation of Extremely Large Telescopes (ELTs). These studies will have a
broad impact across astrophysics, informing our knowledge of the production and
enrichment history of the heaviest chemical elements, constrain the dense
matter equation of state, provide independent constraints on cosmology,
increase our understanding of particle acceleration in shocks and jets, and
study the lives of black holes in the universe. Future GW detectors will
greatly improve their sensitivity during the coming decade, as will
near-infrared telescopes capable of independently finding kilonovae from
neutron star mergers. However, the electromagnetic counterparts to
high-frequency (LIGO/Virgo band) GW sources will be distant and faint and thus
demand ELT capabilities for characterization. ELTs will be important and
necessary contributors to an advanced and complete multi-messenger network.Comment: White paper submitted to the Astro2020 Decadal Surve
Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status
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