494 research outputs found
Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro.
A key aspect of nervous system development, including that of the cerebral cortex, is the formation of higher-order neural networks. Developing neural networks undergo several phases with distinct activity patterns in vivo, which are thought to prune and fine-tune network connectivity. We report here that human pluripotent stem cell (hPSC)-derived cerebral cortex neurons form large-scale networks that reflect those found in the developing cerebral cortex in vivo. Synchronised oscillatory networks develop in a highly stereotyped pattern over several weeks in culture. An initial phase of increasing frequency of oscillations is followed by a phase of decreasing frequency, before giving rise to non-synchronous, ordered activity patterns. hPSC-derived cortical neural networks are excitatory, driven by activation of AMPA- and NMDA-type glutamate receptors, and can undergo NMDA-receptor-mediated plasticity. Investigating single neuron connectivity within PSC-derived cultures, using rabies-based trans-synaptic tracing, we found two broad classes of neuronal connectivity: most neurons have small numbers (40). These data demonstrate that the formation of hPSC-derived cortical networks mimics in vivo cortical network development and function, demonstrating the utility of in vitro systems for mechanistic studies of human forebrain neural network biology.This is the final version of the article. It first appeared from The Company of Biologists via http://dx.doi.org/10.1242/dev.12385
Exaggerated renal fibrosis in P2X4 receptor-deficient mice following unilateral ureteric obstruction
Background The ATP-sensitive P2X7 receptor (P2X7R) has been shown to contribute to renal injury in nephrotoxic nephritis, a rodent model of acute glomerulonephritis, and in unilateral ureteric obstruction (UUO), a rodent model of chronic interstitial inflammation and fibrosis. Renal tubular cells, endothelial cells and macrophages also express the closely related P2X4 receptor (P2X4R), which is chromosomally co-located with P2X7R and has 40% homology; it is also pro-inflammatory and has been shown to interact with P2X7R to modulate its pro-apoptotic and pro-inflammatory effects. Therefore, we chose to explore the function of P2X4R in the UUO model of renal injury using knockout mice. We hypothesized that UUO-induced tubulointerstitial damage and fibrosis would also be attenuated in P2X4R−/− mice. Method P2X4R−/− and wild-type (WT) mice were subjected to either UUO or sham operation. Kidney samples taken on Days 7 and 14 were evaluated for renal inflammation and fibrosis, and expression of pro-fibrotic factors. Results To our surprise, the obstructed kidney in P2X4R−/− mice showed more severe renal injury, more collagen deposition (picrosirius red staining, increase of 53%; P < 0.05) and more type I collagen staining (increase of 107%; P < 0.01), as well as increased mRNA for TGF-β (increase of 102%, P < 0.0005) and CTGF (increase of 157%; P < 0.05) by Day 14, compared with the UUO WT mice. Conclusion These findings showed that lack of P2X4R expression leads to increased renal fibrosis, and increased expression of TGF-β and CTGF in the UUO mode
The Ionized Gas and Nuclear Environment in NGC 3783 V. Variability and Modeling of the Intrinsic Ultraviolet Absorption
We present results on the location, physical conditions, and geometry of the
outflow in the Seyfert 1 galaxy NGC 3783 from a study of the variable intrinsic
UV absorption. Based on 18 observations with HST/STIS and 6 observations with
FUSE, we find: 1) The absorption from the lowest-ionization species in each of
the three strong kinematic components varied inversely with the continuum flux,
indicating the ionization structure responded to changes in the photoionizing
flux over the weekly timescales sampled by our observations. 2) A multi-
component model with an unocculted NLR and separate BLR and continuum
line-of-sight covering factors predicts saturation in several lines, consistent
with the lack of observed variability. 3) Column densities for the individual
metastable levels are measured from the resolved C III *1175 absorption complex
observed in one component. Based on our computed metastable level populations,
the electron density of this absorber is ~3x10^4 cm^-3. Photoionization
modeling results place it at ~25 pc from the central source. 4) Using
time-dependent calculations, we are able to reproduce the detailed variability
observed in this absorber, and derive upper limits on the distances for the
other components of 25-50 pc. 5) The ionization parameters derived for the
higher ionization UV absorbers are consistent with the modeling results for the
lowest-ionization X-ray component, but with smaller total column density. They
have similar pressures as the three X-ray ionization components. These results
are consistent with an inhomogeneous wind model for the outflow in NGC 3783. 6)
Based on the predicted emission-line luminosities, global covering factor
constraints, and distances derived for the UV absorbers, they may be identified
with emission- line gas observed in the inner NLR of AGNs. (abridged)Comment: 30 pages, 18 figures (7 color), emulateapj, accepted for publication
in The Astrophysical Journa
Self-Reported Sleep Apnea and Dementia Risk: Findings from the Prevention of Alzheimer\u27s Disease with Vitamin E and Selenium Trial
OBJECTIVES: To investigate the association between baseline sleep apnea and risk of incident dementia in the Prevention of Alzheimer\u27s Disease with Vitamin E and Selenium (PREADViSE) study and to explore whether the association depends on apolipoprotein E (APOE) ɛ4 allele status.
DESIGN: Secondary analysis based on data collected during PREADViSE.
SETTING: Participants were assessed at 128 local clinical study sites during the clinical trial phase and later were followed by telephone from a centralized location.
PARTICIPANTS: Men enrolled in PREADViSE (without dementia or other active neurological conditions that affect cognition such as major psychiatric disorders, including depression; N = 7,547).
MEASUREMENTS: Participants were interviewed at baseline for sleep apnea. The Memory Impairment Screen (MIS) was administered to each participant annually. Subjects who failed this initial screen were tested with secondary screening tests. Medical history and medication use were determined, and the AD8 dementia screening instrument was used.
RESULTS: The effect of self-reported sleep apnea on dementia risk depended on APOE ɛ4 status. When the allele was absent, baseline self-reported sleep apnea was associated with a 66% higher risk of developing dementia (95% confidence interval = 2-170%), whereas self-reported sleep apnea conferred no additional risk for participants with an ɛ4 allele.
CONCLUSION: Sleep apnea may increase risk of dementia in the absence of APOE ɛ4. This may help inform prevention strategies for dementia or AD in older men with sleep apnea.
Registration: PREADViSE is registered at ClinicalTrials.gov: NCT00040378
CSI 2264: Characterizing Accretion-Burst Dominated Light Curves for Young Stars in NGC 2264
Based on more than four weeks of continuous high cadence photometric
monitoring of several hundred members of the young cluster NGC 2264 with two
space telescopes, NASA's Spitzer and the CNES CoRoT (Convection, Rotation, and
planetary Transits), we provide high quality, multi-wavelength light curves for
young stellar objects (YSOs) whose optical variability is dominated by short
duration flux bursts, which we infer are due to enhanced mass accretion rates.
These light curves show many brief -- several hour to one day -- brightenings
at optical and near-infrared (IR) wavelengths with amplitudes generally in the
range 5-50% of the quiescent value. Typically, a dozen or more of these bursts
occur in a thirty day period. We demonstrate that stars exhibiting this type of
variability have large ultraviolet (UV) excesses and dominate the portion of
the u-g vs. g-r color-color diagram with the largest UV excesses. These stars
also have large Halpha equivalent widths, and either centrally peaked, lumpy
Halpha emission profiles or profiles with blue-shifted absorption dips
associated with disk or stellar winds. Light curves of this type have been
predicted for stars whose accretion is dominated by Rayleigh-Taylor
instabilities at the boundary between their magnetosphere and inner
circumstellar disk, or where magneto-rotational instabilities modulate the
accretion rate from the inner disk. Amongst the stars with the largest UV
excesses or largest Halpha equivalent widths, light curves with this type of
variability greatly outnumber light curves with relatively smooth sinusoidal
variations associated with long-lived hot spots. We provide quantitative
statistics for the average duration and strength of the accretion bursts and
for the fraction of the accretion luminosity associated with these bursts.Comment: Accepted for publication in AJ. 39 pages; 6 tables; 25 figures, many
of which are highly degraded to meet size limits. Please download the regular
resolution version at
http://web.ipac.caltech.edu/staff/amc/staufferetal2014.pd
Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways
P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved
The Ionized Gas and Nuclear Environment in NGC 3783. I. Time-Averaged 900 ks Chandra Grating Spectroscopy
We present results from a 900 ks exposure of NGC 3783 with the High-Energy
Transmission Grating Spectrometer on board the Chandra X-ray Observatory. The
resulting X-ray spectrum has the best combination of signal-to-noise and
resolution ever obtained for an AGN. This spectrum reveals absorption lines
from H-like and He-like ions of N, O, Ne, Mg, Al, Si, and S. There are also
possible absorption lines from H-like and He-like Ar and Ca. We also identify
inner-shell absorption from lower-ionization ions such as Si_VII-Si_XII and
S_XII-S_XIV. The iron absorption spectrum is very rich; L-shell lines of
Fe_XVII-Fe_XXIV are detected, strong complex of M-shell lines, and probable
resonance lines from Fe_XXV. The absorption lines are blueshifted relative to
the systemic velocity by a mean velocity of -590+-150 km/s. We resolve many of
the absorption lines, and their mean FWHM is 820+-280 km/s. We do not find
correlations between the velocity shifts or the FWHMs with the ionization
potentials of the ions. Most absorption lines show asymmetry, having more
extended blue wings than red wings. In O_VII we have resolved this asymmetry to
be from an additional absorption system at ~ -1300 km/s. The two X-ray
absorption systems are consistent in velocity shift and FWHM with the ones
identified in the UV lines of C IV, N V, and H I. Equivalent width measurements
for all lines are given and column densities are calculated for several ions.
We resolve the narrow Fe_K\alpha line at 6398.2+-3.3 eV to have a FWHM of
1720+-360 km/s, which suggests that this narrow line may be emitted from the
outer part of the broad line region or the inner part of the torus. We also
detect a `Compton shoulder' redward of the narrow Fe_K\alpha line which
indicates that it arises in cold, Compton-thick gas.Comment: 19 pages, 12 figures (2 in color), emulateapj5, accepted for
publication in The Astrophysical Journal Supplement
Structural Requirements for Dihydrobenzoxazepinone Anthelmintics:Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni
Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here, we report a systematic investigation of the structure–activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics
Chandra Observations of Associates of Car: I. Luminosities
The region around the Car nebula has three OB associations, which
contain a Wolf-Rayet star and several massive O3 stars. An early Chandra ACIS-I
image was centered on Car and includes Trumpler 16 and part of Trumpler
14. The Chandra image confirms the well-known result that O and very early B
stars are X-ray sources with L 10 L over an
X-ray luminosity range of about 100. Two new anomalously strong X-ray sources
have been found among the hot star population, Tr 16-244, a heavily-reddened O3
I star, and Tr 16-22, a heavily-reddened O8.5 V star. Two stars have an
unusually large L/L: HD 93162, a Wolf-Rayet star (and possible
binary), and Tr 16-22, a possible colliding wind binary In addition, a
population of sources associated with cool stars is detected. In the
color-magnitude diagram, these X-ray sources sit above the sequence of field
stars in the Carina arm. The OB stars are on average more X-ray luminous than
the cool star X-ray sources. X-ray sources among A stars have similar X-ray
luminosities to cooler stars, and may be due to cooler companions. Upper limits
are presented for B stars which are not detected in X-rays. These upper limits
are also the upper limits for any cool companions which the hot stars may have.
Hardness ratios are presented for the most luminous sources in bands 0.5 to 0.9
keV, 0.9 to 1.5 keV, and 1.5 to 2.04 kev. The available information on the
binary nature of the hot stars is discussed, but binarity does not correlate
with X-ray strength in a simple way.Comment: accepted by Ap
- …