Mouse genetics identifies unique and overlapping functions of fibroblast growth factor receptors in keratinocytes

Fibroblast growth factors (FGFs) are key regulators of tissue development, homeostasis and repair, and abnormal FGF signalling is associated with various human diseases. In human and murine epidermis, FGF receptor 3 (FGFR3) activation causes benign skin tumours, but the consequences of FGFR3 deficiency in this tissue have not been determined. Here, we show that FGFR3 in keratinocytes is dispensable for mouse skin development, homeostasis and wound repair. However, the defect in the epidermal barrier and the resulting inflammatory skin disease that develops in mice lacking FGFR1 and FGFR2 in keratinocytes were further aggravated upon additional loss of FGFR3. This caused fibroblast activation and fibrosis in the FGFR1/FGFR2 double-knockout mice and even more in mice lacking all three FGFRs, revealing functional redundancy of FGFR3 with FGFR1 and FGFR2 for maintaining the epidermal barrier. Taken together, our study demonstrates that FGFR1, FGFR2 and FGFR3 act together to maintain epidermal integrity and cutaneous homeostasis, with FGFR2 being the dominant receptor

Functional impairment outcomes in clinical trials of different ADHD medications:post hoc responder analyses and baseline subgroup analyses

Several recent phase 3 clinical trials of attention-deficit/hyperactivity disorder (ADHD) medications have used the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). Here, we assess WFIRS-P response in individual patients in two pivotal trials of lisdexamfetamine dimesylate (LDX) and guanfacine extended release (GXR). We also analysed pooled WFIRS-P data from seven phase 3 studies of ADHD medications to shed light on factors associated with baseline functional impairment. The proportion of patients with a change in WFIRS-P score that exceeded the minimal important difference (MID) criteria for response was greater for LDX than placebo in the Family, Learning and School, and Risky Activities domains, and was greater for GXR than placebo in the Social Activities, Learning and School, and Family domains. Responders had significantly worse baseline scores in all WFIRS-P domains (all p < 0.001) than non-responders. In the pooled analyses, baseline WFIRS-P scores in all domains were significantly worse in participants with oppositional defiant disorder (ODD) than in those without ODD. Having combined type or hyperactive-impulsive type ADHD, being enrolled into a study in Europe, being male and being younger also had modest negative effects on baseline WFIRS-P scores. The present analysis of WFIRS-P response shows that previously reported group-level improvements in WFIRS-P functional impairment score translated into clinically relevant improvements in many individual participants. Functional impairment is a diverse and subjective construct that is influenced by multiple factors. Optimal management of individuals with ADHD should involve monitoring improvements in functioning and quality of life, as well as symptomatic improvement

HST Imaging Polarimetry of the Gravitational Lens FSC10214+4724

We present imaging polarimetry of the extremely luminous, redshift 2.3 IRAS source FSC10214+4724. The observations were obtained with HST's Faint Object Camera in the F437M filter, which is free of strong emission lines. The 0.7 arcsec long arc is unresolved to 0.04 arcsec FWHM in the transverse direction, and has an integrated polarization of 28 +/- 3 percent, in good agreement with ground-based observations. The polarization position angle varies along the arc by up to 35 deg. The overall position angle is 62 +/- 3 deg east of north. No counterimage is detected to B = 27.5 mag ($3\sigma$), giving an observed arc to counterimage flux ratio greater than 250, considerably greater than the flux ratio of 100 measured previously in the I-band. This implies that the configuration of the object in the source plane at the B-band is different from that at I-band, and/or that the lensing galaxy is dusty.Comment: 17 pages, 3 figures. Accepted for publication in Astronomical Journal, February 199

Pseudo-prospective Evaluation of UCERF3-ETAS Forecasts During the 2019 Ridgecrest Sequence

The 2019 Ridgecrest sequence provides the first opportunity to evaluate Uniform California Earthquake Rupture Forecast v.3 with epidemic‐type aftershock sequences (UCERF3‐ETAS) in a pseudoprospective sense. For comparison, we include a version of the model without explicit faults more closely mimicking traditional ETAS models (UCERF3‐NoFaults). We evaluate the forecasts with new metrics developed within the Collaboratory for the Study of Earthquake Predictability (CSEP). The metrics consider synthetic catalogs simulated by the models rather than synoptic probability maps, thereby relaxing the Poisson assumption of previous CSEP tests. Our approach compares statistics from the synthetic catalogs directly against observations, providing a flexible approach that can account for dependencies and uncertainties encoded in the models. We find that, to the first order, both UCERF3‐ETAS and UCERF3‐NoFaults approximately capture the spatiotemporal evolution of the Ridgecrest sequence, adding to the growing body of evidence that ETAS models can be informative forecasting tools. However, we also find that both models mildly overpredict the seismicity rate, on average, aggregated over the evaluation period. More severe testing indicates the overpredictions occur too often for observations to be statistically indistinguishable from the model. Magnitude tests indicate that the models do not include enough variability in forecasted magnitude‐number distributions to match the data. Spatial tests highlight discrepancies between the forecasts and observations, but the greatest differences between the two models appear when aftershocks occur on modeled UCERF3‐ETAS faults. Therefore, any predictability associated with embedding earthquake triggering on the (modeled) fault network may only crystalize during the presumably rare sequences with aftershocks on these faults. Accounting for uncertainty in the model parameters could improve test results during future experiments.Maximilian J. Werner and Warner Marzocchi received funding from the European Union's Horizon 2020 research and innovation program (Number 821115, RISE: Real‐Time Earthquake Risk Reduction for a Resilient Europe). This research was supported by the Southern California Earthquake Center (SCEC; Contribution Number 10082). SCEC is funded by National Science Foundation (NSF) Cooperative Agreement EAR‐1600087 and the U.S. Geological Survey (USGS) Cooperative Agreement G17AC00047

Hubble Space Telescope Observations of the Luminous IRAS Source FSC 10214+4724: A Gravitationally Lensed Infrared Quasar

With a redshift of 2.3, the IRAS source FSC 10214+4724 is apparently one of the most luminous objects known in the universe. We present an image of FSC 10214+4724 at 0.8 pm obtained with the Hubble Space Telescope (HST) WFPC2 Planetary Camera. The source appears as an unresolved (less then 0.06) arc 0.7 long, with significant substructure along its length. The center of curvature of the arc is located near an elliptical galaxy 1.18 to the north. An unresolved component 100 times fainter than the arc is clearly detected on the opposite side of this galaxy. The most straightforward interpretation is that FSC 10214+4724 is gravitationally lensed by the foreground elliptical galaxy, with the faint component a counter-image of the IRAS source. The brightness of the arc in the HST image is then magnified by approx. 100, and the intrinsic source diameter is approx. 0.0l (80 pc) at 0.25 microns rest wavelength. The bolometric luminosity is probably amplified by a smaller factor (approx. 30) as a result of the larger extent expected for the source in the far-infrared. A detailed lensing model is presented that reproduces the observed morphology and relative flux of the arc and counterimage and correctly predicts the position angle of the lensing galaxy. The model also predicts reasonable values for the velocity dispersion, mass, and mass-to-light ratio of the lensing galaxy for a wide range of galaxy redshifts. A redshift for the lensing galaxy of -0.9 is consistent with the measured surface brightness profile from the image, as well as with the galaxy's spectral energy distribution. The background lensed source has an intrinsic luminosity approx. 2 x 10(exp 13) L(solar mass) and remains a highly luminous quasar with an extremely large ratio of infrared to optical/ultraviolet luminosity

Far Infrared Prperties of M Dwarfs

We report the mid- and far-infrared properties of nearby M dwarfs. Spitzer/MIPS measurements were obtained for a sample of 62 stars at 24 um, with subsamples of 41 and 20 stars observed at 70 um and 160 um respectively. We compare the results with current models of M star photospheres and look for indications of circumstellar dust in the form of significant deviations of K-[24 um] colors and 70 um / 24 um flux ratios from the average M star values. At 24 um, all 62 of the targets were detected; 70 um detections were achieved for 20 targets in the subsample observed; and no detections were seen in the 160 um subsample. No clear far-infrared excesses were detected in our sample. The average far infrared excess relative to the photospheric emission of the M stars is at least four times smaller than the similar average for a sample of solar-type stars. However, this limit allows the average fractional infrared luminosity in the M-star sample to be similar to that for more massive stars. We have also set low limits for the maximum mass of dust possible around our stars.Comment: 28 pages, 4 figures, to be published in The Astrophysical Journa

On-orbit performance of the Spitzer Space Telescope

The Spitzer Space Telescope (formally known as SIRTF) was successfully launched on August 25, 2003, and has completed its initial in-orbit checkout and science validation and calibration period. The measured performance of the observatory has met or exceeded all of its high-level requirements, it entered normal operations in January 2004, and is returning high-quality science data. A superfluid-helium cooled 85 cm diameter telescope provides extremely low infrared backgrounds and feeds three science instruments covering wavelengths ranging from 3.6 to 160 microns. The telescope optical quality is excellent, providing diffraction-limited performance down to wavelengths below 6.5 microns. Based on the first helium mass and boil-off rate measurements, a cryogenic lifetime in excess of 5 years is expected. This presentation will provide a summary of the overall performance of the observatory, with an emphasis on those performance parameters that have the greatest impact on its ultimate science return

Hyperspectral microarray scanning: impact on the accuracy and reliability of gene expression data

BACKGROUND: Commercial microarray scanners and software cannot distinguish between spectrally overlapping emission sources, and hence cannot accurately identify or correct for emissions not originating from the labeled cDNA. We employed our hyperspectral microarray scanner coupled with multivariate data analysis algorithms that independently identify and quantitate emissions from all sources to investigate three artifacts that reduce the accuracy and reliability of microarray data: skew toward the green channel, dye separation, and variable background emissions. RESULTS: Here we demonstrate that several common microarray artifacts resulted from the presence of emission sources other than the labeled cDNA that can dramatically alter the accuracy and reliability of the array data. The microarrays utilized in this study were representative of a wide cross-section of the microarrays currently employed in genomic research. These findings reinforce the need for careful attention to detail to recognize and subsequently eliminate or quantify the presence of extraneous emissions in microarray images. CONCLUSION: Hyperspectral scanning together with multivariate analysis offers a unique and detailed understanding of the sources of microarray emissions after hybridization. This opportunity to simultaneously identify and quantitate contaminant and background emissions in microarrays markedly improves the reliability and accuracy of the data and permits a level of quality control of microarray emissions previously unachievable. Using these tools, we can not only quantify the extent and contribution of extraneous emission sources to the signal, but also determine the consequences of failing to account for them and gain the insight necessary to adjust preparation protocols to prevent such problems from occurring