139 research outputs found
Cultures of human tracheal gland cells of mucous or serous phenotype
There are two main epithelial cell types in the secretory tubules of mammalian glands: serous and mucous. The former is believed to secrete predominantly water and antimicrobials, the latter mucins. Primary cultures of human airway gland epithelium have been available for almost 20Â yr, but they are poorly differentiated and lack clear features of either serous or mucous cells. In this study, by varying growth supports and media, we have produced cultures from human airway glands that in terms of their ultrastructure and secretory products resemble either mucous or serous cells. Of four types of porous-bottomed insert tested, polycarbonate filters (Transwells) most strongly promoted the mucous phenotype. Coupled with the addition of epidermal growth factor (EGF), this growth support produced âmucousâ cells that contained the large electron-lucent granules characteristic of native mucous cells, but lacked the small electron-dense granules characteristic of serous cells. Furthermore, they showed high levels of mucin secretion and low levels of release of lactoferrin and lysozyme (markers of native serous cells). By contrast, growth on polyethylene terephthalate filters (Cyclopore) in medium lacking EGF produced âserousâ cells in which small electron-dense granules replaced the electron-lucent ones, and the cells had high levels of lactoferrin and lysozyme but low levels of mucins. Measurements of transepithelial resistance and short-circuit current showed that both âserousâ and âmucousâ cell cultures possessed tight junctions, had become polarized, and were actively secreting Cl
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Nanomolar-potency 'co-potentiator' therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants.
Available CFTR modulators provide no therapeutic benefit for cystic fibrosis (CF) caused by many loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, including N1303K. We previously introduced the concept of 'co-potentiators' (combination-potentiators) to rescue CFTR function in some minimal function CFTR mutants. Herein, a screen of ~120,000 drug-like synthetic small molecules identified active co-potentiators of pyrazoloquinoline, piperidine-pyridoindole, tetrahydroquinoline and phenylazepine classes, with EC50 down to ~300ânM following initial structure-activity studies. Increased CFTR chloride conductance by up to 8-fold was observed when a co-potentiator (termed 'Class II potentiator') was used with a classical potentiator ('Class I potentiator') such as VX-770 or GLPG1837. To investigate the range of CFTR mutations benefitted by co-potentiators, 14 CF-associated CFTR mutations were studied in transfected cell models. Co-potentiator efficacy was found for CFTR missense, deletion and nonsense mutations in nucleotide binding domain-2 (NBD2), including W1282X, N1303K, c.3700Aâ>âG and Q1313X (with corrector for some mutations). In contrast, CFTR mutations G85E, R334W, R347P, V520F, R560T, A561E, M1101K and R1162X showed no co-potentiator activity, even with corrector. Co-potentiator efficacy was confirmed in primary human bronchial epithelial cell cultures generated from a N1303K homozygous CF subject. The Class II potentiators identified here may have clinical benefit for CF caused by mutations in the NBD2 domain of CFTR
Some gating potentiators, including VX-770, diminish ÎF508-CFTR functional expression.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ÎF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ÎF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ÎF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ÎF508-CFTR density and function. VX-770-induced destabilization of ÎF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ÎF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF
Herschel Far-Infrared and Sub-millimeter Photometry for the KINGFISH Sample of Nearby Galaxies
New far-infrared and sub-millimeter photometry from the Herschel Space
Observatory is presented for 61 nearby galaxies from the Key Insights on Nearby
Galaxies: A Far-Infrared Survey with Herschel (KINGFISH) sample. The
spatially-integrated fluxes are largely consistent with expectations based on
Spitzer far-infrared photometry and extrapolations to longer wavelengths using
popular dust emission models. Dwarf irregular galaxies are notable exceptions,
as already noted by other authors, as their 500um emission shows evidence for a
sub-millimeter excess. In addition, the fraction of dust heating attributed to
intense radiation fields associated with photo-dissociation regions is found to
be (21+/-4)% larger when Herschel data are included in the analysis. Dust
masses obtained from the dust emission models of Draine & Li are found to be on
average nearly a factor of two higher than those based on single-temperature
modified blackbodies, as single blackbody curves do not capture the full range
of dust temperatures inherent to any galaxy. The discrepancy is largest for
galaxies exhibiting the coolest far-infrared colors.Comment: Accepted for publication in Ap
Modeling Dust and Starlight in Galaxies Observed by Spitzer and Herschel: NGC 628 and NGC 6946
We characterize the dust in NGC628 and NGC6946, two nearby spiral galaxies in
the KINGFISH sample. With data from 3.6um to 500um, dust models are strongly
constrained. Using the Draine & Li (2007) dust model, (amorphous silicate and
carbonaceous grains), for each pixel in each galaxy we estimate (1) dust mass
surface density, (2) dust mass fraction contributed by polycyclic aromatic
hydrocarbons (PAH)s, (3) distribution of starlight intensities heating the
dust, (4) total infrared (IR) luminosity emitted by the dust, and (5) IR
luminosity originating in regions with high starlight intensity. We obtain maps
for the dust properties, which trace the spiral structure of the galaxies. The
dust models successfully reproduce the observed global and resolved spectral
energy distributions (SEDs). The overall dust/H mass ratio is estimated to be
0.0082+/-0.0017 for NGC628, and 0.0063+/-0.0009 for NGC6946, consistent with
what is expected for galaxies of near-solar metallicity. Our derived dust
masses are larger (by up to a factor 3) than estimates based on
single-temperature modified blackbody fits. We show that the SED fits are
significantly improved if the starlight intensity distribution includes a
(single intensity) "delta function" component. We find no evidence for
significant masses of cold dust T<12K. Discrepancies between PACS and MIPS
photometry in both low and high surface brightness areas result in large
uncertainties when the modeling is done at PACS resolutions, in which case
SPIRE, MIPS70 and MIPS160 data cannot be used. We recommend against attempting
to model dust at the angular resolution of PACS.Comment: To be published in Apj, September 2012. See the full version at
http://www.astro.princeton.edu/~ganiano/Papers
Colors of 2625 Quasars at 0<z<5 Measured in the Sloan Digital Sky Survey Photometric System
We present an empirical investigation of the colors of quasars in the Sloan
Digital Sky Survey (SDSS) photometric system. The sample studied includes 2625
quasars with SDSS photometry. The quasars are distributed in a 2.5 degree wide
stripe centered on the Celestial Equator covering square degrees.
Positions and SDSS magnitudes are given for the 898 quasars known prior to SDSS
spectroscopic commissioning. New SDSS quasars represent an increase of over
200% in the number of known quasars in this area of the sky. The ensemble
average of the observed colors of quasars in the SDSS passbands are well
represented by a power-law continuum with (). However, the contributions of the bump
and other strong emission lines have a significant effect upon the colors. The
color-redshift relation exhibits considerable structure, which may be of use in
determining photometric redshifts for quasars. The range of colors can be
accounted for by a range in the optical spectral index with a distribution
(95% confidence), but there is a red tail in the
distribution. This tail may be a sign of internal reddening. Finally, we show
that there is a continuum of properties between quasars and Seyfert galaxies
and we test the validity of the traditional division between the two classes of
AGN.Comment: 66 pages, 15 figures (3 color), accepted by A
Galaxy Clustering in Early SDSS Redshift Data
We present the first measurements of clustering in the Sloan Digital Sky
Survey (SDSS) galaxy redshift survey. Our sample consists of 29,300 galaxies
with redshifts 5,700 km/s < cz < 39,000 km/s, distributed in several long but
narrow (2.5-5 degree) segments, covering 690 square degrees. For the full,
flux-limited sample, the redshift-space correlation length is approximately 8
Mpc/h. The two-dimensional correlation function \xi(r_p,\pi) shows clear
signatures of both the small-scale, ``fingers-of-God'' distortion caused by
velocity dispersions in collapsed objects and the large-scale compression
caused by coherent flows, though the latter cannot be measured with high
precision in the present sample. The inferred real-space correlation function
is well described by a power law, \xi(r)=(r/6.1+/-0.2 Mpc/h)^{-1.75+/-0.03},
for 0.1 Mpc/h < r < 16 Mpc/h. The galaxy pairwise velocity dispersion is
\sigma_{12} ~ 600+/-100 km/s for projected separations 0.15 Mpc/h < r_p < 5
Mpc/h. When we divide the sample by color, the red galaxies exhibit a stronger
and steeper real-space correlation function and a higher pairwise velocity
dispersion than do the blue galaxies. The relative behavior of subsamples
defined by high/low profile concentration or high/low surface brightness is
qualitatively similar to that of the red/blue subsamples. Our most striking
result is a clear measurement of scale-independent luminosity bias at r < 10
Mpc/h: subsamples with absolute magnitude ranges centered on M_*-1.5, M_*, and
M_*+1.5 have real-space correlation functions that are parallel power laws of
slope ~ -1.8 with correlation lengths of approximately 7.4 Mpc/h, 6.3 Mpc/h,
and 4.7 Mpc/h, respectively.Comment: 51 pages, 18 figures. Replaced to match accepted ApJ versio
Sloan Digital Sky Survey Imaging of Low Galactic Latitude Fields: Technical Summary and Data Release
The Sloan Digital Sky Survey (SDSS) mosaic camera and telescope have obtained
five-band optical-wavelength imaging near the Galactic plane outside of the
nominal survey boundaries. These additional data were obtained during
commissioning and subsequent testing of the SDSS observing system, and they
provide unique wide-area imaging data in regions of high obscuration and star
formation, including numerous young stellar objects, Herbig-Haro objects and
young star clusters. Because these data are outside the Survey regions in the
Galactic caps, they are not part of the standard SDSS data releases. This paper
presents imaging data for 832 square degrees of sky (including repeats), in the
star-forming regions of Orion, Taurus, and Cygnus. About 470 square degrees are
now released to the public, with the remainder to follow at the time of SDSS
Data Release 4. The public data in Orion include the star-forming region NGC
2068/NGC 2071/HH24 and a large part of Barnard's loop.Comment: 31 pages, 9 figures (3 missing to save space), accepted by AJ, in
press, see http://photo.astro.princeton.edu/oriondatarelease for data and
paper with all figure
Non-cognate translation priming in masked priming lexical decision experiments: a meta-analysis
The masked translation priming paradigm has been widely used in the last 25 years to investigate word processing in bilinguals. Motivated by studies reporting mixed findings, in particular for second language (L2) to first language (L1) translation priming, we conducted, for the first time in the literature, a meta-analysis of 64 lexical decision experiments across 24 studies to assess the effect sizes of L1-L2 and L2-L1 non-cognate translation priming effects in bilinguals. Our meta-analysis also investigated the influence of potential moderators of translation priming effects. The results provided clear evidence of significant translation priming effects for both directions, with L1-L2 translation priming significantly larger than L2-L1 translation priming (i.e., effect size of 0.86 vs. 0.31). The analyses also revealed that L1-L2 translation effect sizes were moderated by the interval between prime and target (ISI), whereas L2-L1 translation effect sizes were modulated by the number of items per cell. Theoretical and methodological implications of this meta-analysis are discussed and recommendations for future studies are provided
Molecular characterization of partial-open reading frames 1a and 2 of the human astroviruses in South Korea
Human astroviruses (HAstVs) are among the major causes of gastroenteritis in South Korea. In this study, the partial regions of the open reading frame (ORF) 1a and ORF2 genes of HAstVs from gastroenteritis patients in nine hospitals were sequenced, and the molecular characterization of the viruses was revealed. 89 partial nucleotide sequences of ORF1a and 88 partial nucleotide sequences of ORF2 were amplified from 120 stool specimens. Phylogenetic analysis showed that most of the nucleotide sequences of ORF1a and ORF2 were grouped with HAstV type 1 but had evolutionary genetic distance compared with the reference sequences, such as the HAstV-1 prototype, Dresden strain, and Oxford strain. According to the phylogenetic analysis, some nucleotide sequences including SE0506041, SE0506043, and SE0506058, showed the discrepancy of the genotypes, but there was no proof of recombination among the HAstV types. In conclusion, this study showed that the dominant HAstV isolated from the Seoul metropolitan area in 2004-2005 was HAstV type 1, and that Korean HAstV-1 had the genetic distance in evolution compared with the reference sequences of HAstVs. Lots of nucleotide sequences of the ORF1a and ORF2 genes of HAstV will be useful for studying for the control and prevention of HAstV gastroenteritis in South Korea
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