440 research outputs found
Complete reversal of epithelial to mesenchymal transition requires inhibition of both ZEB expression and the Rho pathway
<p>Abstract</p> <p>Background</p> <p>Epithelial to Mesenchymal Transition (EMT) induced by Transforming Growth Factor-β (TGF-β) is an important cellular event in organogenesis, cancer, and organ fibrosis. The process to reverse EMT is not well established. Our purpose is to define signaling pathways and transcription factors that maintain the TGF-β-induced mesenchymal state.</p> <p>Results</p> <p>Inhibitors of five kinases implicated in EMT, TGF-β Type I receptor kinase (TβRI), p38 mitogen-activated protein kinase (p38 MAPK), MAP kinase kinase/extracellular signal-regulated kinase activator kinase (MEK1), c-Jun NH-terminal kinase (JNK), and Rho kinase (ROCK), were evaluated for reversal of the mesenchymal state induced in renal tubular epithelial cells. Single agents did not fully reverse EMT as determined by cellular morphology and gene expression. However, exposure to the TβRI inhibitor SB431542, combined with the ROCK inhibitor Y27632, eliminated detectable actin stress fibers and mesenchymal gene expression while restoring epithelial E-cadherin and Kidney-specific cadherin (Ksp-cadherin) expression. A second combination, the TβRI inhibitor SB431542 together with the p38 MAPK inhibitor SB203580, was partially effective in reversing EMT. Furthermore, JNK inhibitor SP600125 inhibits the effectiveness of the TβRI inhibitor SB431542 to reverse EMT. To explore the molecular basis underlying EMT reversal, we also targeted the transcriptional repressors ZEB1 and ZEB2/SIP1. Decreasing ZEB1 and ZEB2 expression in mouse mammary gland cells with shRNAs was sufficient to up-regulate expression of epithelial proteins such as E-cadherin and to re-establish epithelial features. However, complete restoration of cortical F-actin required incubation with the ROCK inhibitor Y27632 in combination with ZEB1/2 knockdown.</p> <p>Conclusions</p> <p>We demonstrate that reversal of EMT requires re-establishing both epithelial transcription and structural components by sustained and independent signaling through TβRI and ROCK. These findings indicate that combination small molecule therapy targeting multiple kinases may be necessary to reverse disease conditions.</p
Creatinine-Based Estimations of Kidney Function Are Unreliable in Obese Kidney Donors
Accurate assessment of kidney function by measurement of glomerular filtration rate (GFR) is essential to the risk assessment of prospective living kidney donors. We evaluated the performance of various estimating equations for creatinine clearance (Cockcroft-Gault), GFR (Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration), and 24-hour urine collections for creatinine clearance in obese potential kidney donors. We evaluated 164 potential kidney donors including 49 with a BMI of 30–35 and 32 with a BMI >35 that have completed a routine living donor evaluation with a measured GFR. All the estimating equations performed poorly in obese donors. While 24-hour urine collections performed better, only 15% had an adequate 24-hour urine collection. Since obese kidney donors may be at higher than average risk for kidney failure, accurate assessment of kidney function in these donors is crucial to ensure their long-term health postdonation
Design of 280 GHz feedhorn-coupled TES arrays for the balloon-borne polarimeter SPIDER
We describe 280 GHz bolometric detector arrays that instrument the
balloon-borne polarimeter SPIDER. A primary science goal of SPIDER is to
measure the large-scale B-mode polarization of the cosmic microwave background
in search of the cosmic-inflation, gravitational-wave signature. 280 GHz
channels aid this science goal by constraining the level of B-mode
contamination from galactic dust emission. We present the focal plane unit
design, which consists of a 1616 array of conical, corrugated feedhorns
coupled to a monolithic detector array fabricated on a 150 mm diameter silicon
wafer. Detector arrays are capable of polarimetric sensing via waveguide
probe-coupling to a multiplexed array of transition-edge-sensor (TES)
bolometers. The SPIDER receiver has three focal plane units at 280 GHz, which
in total contains 765 spatial pixels and 1,530 polarization sensitive
bolometers. By fabrication and measurement of single feedhorns, we demonstrate
14.7 FHWM Gaussian-shaped beams with 1% ellipticity in a 30%
fractional bandwidth centered at 280 GHz. We present electromagnetic
simulations of the detection circuit, which show 94% band-averaged,
single-polarization coupling efficiency, 3% reflection and 3% radiative loss.
Lastly, we demonstrate a low thermal conductance bolometer, which is
well-described by a simple TES model and exhibits an electrical noise
equivalent power (NEP) = 2.6 10 W/,
consistent with the phonon noise prediction.Comment: Proceedings of SPIE Astronomical Telescopes + Instrumentation 201
Foreground simulations for the LOFAR - Epoch of Reionization Experiment
Future high redshift 21-cm experiments will suffer from a high degree of
contamination, due both to astrophysical foregrounds and to non-astrophysical
and instrumental effects. In order to reliably extract the cosmological signal
from the observed data, it is essential to understand very well all data
components and their influence on the extracted signal. Here we present
simulated astrophysical foregrounds datacubes and discuss their possible
statistical effects on the data. The foreground maps are produced assuming 5
deg x 5 deg windows that match those expected to be observed by the LOFAR
Epoch-of-Reionization (EoR) key science project. We show that with the expected
LOFAR-EoR sky and receiver noise levels, which amount to ~52 mK at 150 MHz
after 300 hours of total observing time, a simple polynomial fit allows a
statistical reconstruction of the signal. We also show that the polynomial
fitting will work for maps with realistic yet idealised instrument response,
i.e., a response that includes only a uniform uv coverage as a function of
frequency and ignores many other uncertainties. Polarized galactic synchrotron
maps that include internal polarization and a number of Faraday screens along
the line of sight are also simulated. The importance of these stems from the
fact that the LOFAR instrument, in common with all current interferometric EoR
experiments has an instrumentally polarized response.Comment: 18 figures, 3 tables, accepted to be published in MNRA
Affordances, constraints and information flows as ‘leverage points’ in design for sustainable behaviour
Copyright @ 2012 Social Science Electronic PublishingTwo of Donella Meadows' 'leverage points' for intervening in systems (1999) seem particularly pertinent to design for sustainable behaviour, in the sense that designers may have the scope to implement them in (re-)designing everyday products and services. The 'rules of the system' -- interpreted here to refer to affordances and constraints -- and the structure of information flows both offer a range of opportunities for design interventions to in fluence behaviour change, and in this paper, some of the implications and possibilities are discussed with reference to parallel concepts from within design, HCI and relevant areas of psychology
280 GHz Focal Plane Unit Design and Characterization for the SPIDER-2 Suborbital Polarimeter
We describe the construction and characterization of the 280 GHz bolometric
focal plane units (FPUs) to be deployed on the second flight of the
balloon-borne SPIDER instrument. These FPUs are vital to SPIDER's primary
science goal of detecting or placing an upper limit on the amplitude of the
primordial gravitational wave signature in the cosmic microwave background
(CMB) by constraining the B-mode contamination in the CMB from Galactic dust
emission. Each 280 GHz focal plane contains a 16 x 16 grid of corrugated
silicon feedhorns coupled to an array of aluminum-manganese transition-edge
sensor (TES) bolometers fabricated on 150 mm diameter substrates. In total, the
three 280 GHz FPUs contain 1,530 polarization sensitive bolometers (765 spatial
pixels) optimized for the low loading environment in flight and read out by
time-division SQUID multiplexing. In this paper we describe the mechanical,
thermal, and magnetic shielding architecture of the focal planes and present
cryogenic measurements which characterize yield and the uniformity of several
bolometer parameters. The assembled FPUs have high yields, with one array as
high as 95% including defects from wiring and readout. We demonstrate high
uniformity in device parameters, finding the median saturation power for each
TES array to be ~3 pW at 300 mK with a less than 6% variation across each array
at one standard deviation. These focal planes will be deployed alongside the 95
and 150 GHz telescopes in the SPIDER-2 instrument, slated to fly from McMurdo
Station in Antarctica in December 2018
Relation of exaggerated cytokine responses of CF airway epithelial cells to PAO1 adherence
In many model systems, cystic fibrosis (CF) phenotype airway epithelial cells in culture respond to P. aeruginosa with greater interleukin (IL)-8 and IL-6 secretion than matched controls. In order to test whether this excess inflammatory response results from the reported increased adherence of P. aeruginosa to the CF cells, we compared the inflammatory response of matched pairs of CF and non CF airway epithelial cell lines to the binding of GFP-PAO1, a strain of pseudomonas labeled with green fluorescent protein. There was no clear relation between GFP-PAO1 binding and cytokine production in response to PAO1. Treatment with exogenous aGM1 resulted in greater GFP-PAO1 binding to the normal phenotype compared to CF phenotype cells, but cytokine production remained greater from the CF cell lines. When cells were treated with neuraminidase, PAO1 adherence was equalized between CF and nonCF phenotype cell lines, but IL-8 production in response to inflammatory stimuli was still greater in CF phenotype cells. The polarized cell lines 16HBEo-Sense (normal phenotype) and Antisense (CF phenotype) cells were used to test the effect of disrupting tight junctions, which allows access of PAO1 to basolateral binding sites in both cell lines. IL-8 production increased from CF, but not normal, cells. These data indicate that increased bacterial binding to CF phenotype cells cannot by itself account for excess cytokine production in CF airway epithelial cells, encourage investigation of alternative hypotheses, and signal caution for therapeutic strategies proposed for CF that include disruption of tight junctions in the face of pseudomonas infection
Observing the First Stars and Black Holes
The high sensitivity of JWST will open a new window on the end of the
cosmological dark ages. Small stellar clusters, with a stellar mass of several
10^6 M_sun, and low-mass black holes (BHs), with a mass of several 10^5 M_sun
should be directly detectable out to redshift z=10, and individual supernovae
(SNe) and gamma ray burst (GRB) afterglows are bright enough to be visible
beyond this redshift. Dense primordial gas, in the process of collapsing from
large scales to form protogalaxies, may also be possible to image through
diffuse recombination line emission, possibly even before stars or BHs are
formed. In this article, I discuss the key physical processes that are expected
to have determined the sizes of the first star-clusters and black holes, and
the prospect of studying these objects by direct detections with JWST and with
other instruments. The direct light emitted by the very first stellar clusters
and intermediate-mass black holes at z>10 will likely fall below JWST's
detection threshold. However, JWST could reveal a decline at the faint-end of
the high-redshift luminosity function, and thereby shed light on radiative and
other feedback effects that operate at these early epochs. JWST will also have
the sensitivity to detect individual SNe from beyond z=10. In a dedicated
survey lasting for several weeks, thousands of SNe could be detected at z>6,
with a redshift distribution extending to the formation of the very first stars
at z>15. Using these SNe as tracers may be the only method to map out the
earliest stages of the cosmic star-formation history. Finally, we point out
that studying the earliest objects at high redshift will also offer a new
window on the primordial power spectrum, on 100 times smaller scales than
probed by current large-scale structure data.Comment: Invited contribution to "Astrophysics in the Next Decade: JWST and
Concurrent Facilities", Astrophysics & Space Science Library, Eds. H.
Thronson, A. Tielens, M. Stiavelli, Springer: Dordrecht (2008
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