When it Pays to Rush: Interpreting Morphogen Gradients Prior to Steady-State

During development, morphogen gradients precisely determine the position of gene expression boundaries despite the inevitable presence of fluctuations. Recent experiments suggest that some morphogen gradients may be interpreted prior to reaching steady-state. Theoretical work has predicted that such systems will be more robust to embryo-to-embryo fluctuations. By analysing two experimentally motivated models of morphogen gradient formation, we investigate the positional precision of gene expression boundaries determined by pre-steady-state morphogen gradients in the presence of embryo-to-embryo fluctuations, internal biochemical noise and variations in the timing of morphogen measurement. Morphogens that are direct transcription factors are found to be particularly sensitive to internal noise when interpreted prior to steady-state, disadvantaging early measurement, even in the presence of large embryo-to-embryo fluctuations. Morphogens interpreted by cell-surface receptors can be measured prior to steady-state without significant decrease in positional precision provided fluctuations in the timing of measurement are small. Applying our results to experiment, we predict that Bicoid, a transcription factor morphogen in Drosophila, is unlikely to be interpreted prior to reaching steady-state. We also predict that Activin in Xenopus and Nodal in zebrafish, morphogens interpreted by cell-surface receptors, can be decoded in pre-steady-state.Comment: 18 pages, 3 figure

Solar Magnetic Tracking. IV. The Death of Magnetic Features

The removal of magnetic flux from the quiet-sun photosphere is important for maintaining the statistical steady-state of the magnetic field there, for determining the magnetic flux budget of the Sun, and for estimating the rate of energy injected into the upper solar atmosphere. Magnetic feature death is a measurable proxy for the removal of detectable flux. We used the SWAMIS feature tracking code to understand how nearly 20000 detected magnetic features die in an hour-long sequence of Hinode/SOT/NFI magnetograms of a region of quiet Sun. Of the feature deaths that remove visible magnetic flux from the photosphere, the vast majority do so by a process that merely disperses the previously-detected flux so that it is too small and too weak to be detected. The behavior of the ensemble average of these dispersals is not consistent with a model of simple planar diffusion, suggesting that the dispersal is constrained by the evolving photospheric velocity field. We introduce the concept of the partial lifetime of magnetic features, and show that the partial lifetime due to Cancellation of magnetic flux, 22 h, is 3 times slower than previous measurements of the flux turnover time. This indicates that prior feature-based estimates of the flux replacement time may be too short, in contrast with the tendency for this quantity to decrease as resolution and instrumentation have improved. This suggests that dispersal of flux to smaller scales is more important for the replacement of magnetic fields in the quiet Sun than observed bipolar cancellation. We conclude that processes on spatial scales smaller than those visible to Hinode dominate the processes of flux emergence and cancellation, and therefore also the quantity of magnetic flux that threads the photosphere.Comment: Accepted by Ap

Aerodynamic Forces on Flight Crew Helmets

Wind tunnel tests were conducted to deter- mine the aerodynamic forces generated on aircrew flight helmets. Three helmets were tested: two used by aircrews flying ejection seat aircraft in the U.S. military, the Navy HGU-33/P and the Air Force HGU-53/P; and one prototype helmet of significantly different shape and volume. Axial and normal forces were measured through a range of pitch and yaw angles. It was found that large forces exist tending to promote helmet loss during ejection, and that simple modifications to the current helmet configurations can reduce those forces by as much as 40%. It is demonstrated that the proper design of future helmet external geometry can contribute to the increased safety and survivability of aircrews in the ejection environment

The California-Kepler Survey. IV. Metal-rich Stars Host a Greater Diversity of Planets

Probing the connection between a star's metallicity and the presence and properties of any associated planets offers an observational link between conditions during the epoch of planet formation and mature planetary systems. We explore this connection by analyzing the metallicities of Kepler target stars and the subset of stars found to host transiting planets. After correcting for survey incompleteness, we measure planet occurrence: the number of planets per 100 stars with a given metallicity $M$. Planet occurrence correlates with metallicity for some, but not all, planet sizes and orbital periods. For warm super-Earths having $P = 10-100$ days and $R_P = 1.0-1.7~R_E$, planet occurrence is nearly constant over metallicities spanning $-$0.4 dex to +0.4 dex. We find 20 warm super-Earths per 100 stars, regardless of metallicity. In contrast, the occurrence of warm sub-Neptunes ($R_P = 1.7-4.0~R_E$) doubles over that same metallicity interval, from 20 to 40 planets per 100 stars. We model the distribution of planets as $d f \propto 10^{\beta M} d M$, where $\beta$ characterizes the strength of any metallicity correlation. This correlation steepens with decreasing orbital period and increasing planet size. For warm super-Earths $\beta = -0.3^{+0.2}_{-0.2}$, while for hot Jupiters $\beta = +3.4^{+0.9}_{-0.8}$. High metallicities in protoplanetary disks may increase the mass of the largest rocky cores or the speed at which they are assembled, enhancing the production of planets larger than 1.7 $R_E$. The association between high metallicity and short-period planets may reflect disk density profiles that facilitate the inward migration of solids or higher rates of planet-planet scattering.Comment: 32 pages, 15 figures, 9 tables, accepted for publication in The Astronomical Journa

Low-Dose Continuous 5-Fluorouracil Combined with Leucovorin, nab-Paclitaxel, Oxaliplatin, and Bevacizumab for Patients with Advanced Pancreatic Cancer: A Retrospective Analysis.

BackgroundContinuous-infusion 5-fluorouracil (5FU) and calcium leucovorin plus nab-paclitaxel and oxaliplatin have been shown to be active in patients with pancreatic cancer. As a protracted low-dose infusion, 5FU is antiangiogenic, and has synergy with bevacizumab. As shown in the treatment of breast cancer, bevacizumab and nab-paclitaxel are also synergetic.ObjectiveIn this paper we retrospectively analyze the survival of 65 patients with advanced pancreatic cancer who were treated with low-dose continuous (metronomic) chemotherapy given in conjunction with conventional anti-VEGF therapy.Patients and methodsSince July of 2008, we have treated 65 patients with 5FU (180 mg/m2/day × 14 days) via an ambulatory pump. Calcium leucovorin (20 mg/m2 IV), nab-paclitaxel (60 mg/m2) IV as a 30-min infusion, and oxaliplatin (50 mg/m2) IV as a 60-min infusion were given on days 1, 8, and 15. Bevacizumab (5 mg/kg) IV over 30 min was administered on days 1 and 15. Cycles were repeated every 28-35 days. There were 42 women and 23 men, and the median age was 59 years. Forty-six patients had stage IV disease.ResultsThe median survival was 19 months, with 82% of patients surviving 12 months or longer. The overall response rate was 49%. There were 28 patients who had received prior treatment, 15 of whom responded to therapy. Fifty-two patients had elevated CA 19-9 prior to treatment. Of these, 21 patients had 90% or greater reduction in CA 19-9 levels. This cohort had an objective response rate of 71% and a median survival of 27 months. Thirty patients stopped treatment due to disease progression, and an additional 22 stopped because of toxicity. One patient died while on therapy.ConclusionsThis non-gemcitabine-based regimen resulted in higher response rates and better survival than what is commonly observed with therapy given at conventional dosing schedules. Low-dose continuous (metronomic therapy) cytotoxic chemotherapy combined with antiangiogenic therapy is safe and effective

Performance of mixed effects models in the analysis of mediated longitudinal data

Backgroun: Linear mixed effects models (LMMs) are a common approach for analyzing longitudinal data in a variety of settings. Although LMMs may be applied to complex data structures, such as settings where mediators are present, it is unclear whether they perform well relative to methods for mediational analyses such as structural equation models (SEMs), which have obvious appeal in such settings. For some researchers, SEMs may be more difficult than LMMs to implement, e.g. due to lack of training in the methodology or the need for specialized SEM software. It therefore is of interest to evaluate whether the LMM performs sufficiently in a scenario particularly suitable for SEMs. We focus on evaluation of the total effect (i.e. direct and indirect) of an exposure on an outcome of interest when a mediating factor is present. Our aim is to explore whether the LMM performs as well as the SEM in a setting that is conducive to using the SEM.Methods We simulated mediated longitudinal data from an SEM where a binary, main independent variable has both direct and indirect effects on a continuous outcome. We conducted analyses with both the LMM and SEM to evaluate the performance of the LMM in a setting where the SEM is expected to be preferable. Models were evaluated with respect to bias, coverage probability and power. Sample size, effect size and error distribution of the simulated data were varied. Results: Both models performed well in a range of settings. Marginal increases in power estimates were observed for the SEM, although generally there were no major differences in performance. Power for both models was good with a sample of size of 250 and a small to medium effect size. Bias did not substantially increase for either model when data were generated from distributions that were both skewed and kurtotic. Conclusions: In settings where the goal is to evaluate the overall effects, the LMM excluding mediating variables appears to have good performance with respect to power, bias and coverage probability relative to the SEM. The major benefit of SEMs is that it simultaneously and efficiently models both the direct and indirect effects of the mediation process

Constraints on the Obliquities of Kepler Planet-Hosting Stars

Stars with hot Jupiters have obliquities ranging from 0-180 degrees, but relatively little is known about the obliquities of stars with smaller planets. Using data from the California-Kepler Survey, we investigate the obliquities of stars with planets spanning a wide range of sizes, most of which are smaller than Neptune. First, we identify 156 planet hosts for which measurements of the projected rotation velocity (vsini) and rotation period are both available. By combining estimates of v and vsini, we find nearly all the stars to be compatible with high inclination, and hence, low obliquity (less than about 20 degrees). Second, we focus on a sample of 159 hot stars (> 6000K) for which vsini is available but not necessarily the rotation period. We find 6 stars for which vsini is anomalously low, an indicator of high obliquity. Half of these have hot Jupiters, even though only 3% of the stars that were searched have hot Jupiters. We also compare the vsini distribution of the hot stars with planets to that of 83 control stars selected without prior knowledge of planets. The mean vsini of the control stars is lower than that of the planet hosts by a factor of approximately pi/4, as one would expect if the planet hosts have low obliquities. All these findings suggest that the Kepler planet-hosting stars generally have low obliquities, with the exception of hot stars with hot Jupiters.Comment: AJ, in pres

The California-Kepler Survey. III. A Gap in the Radius Distribution of Small Planets

The size of a planet is an observable property directly connected to the physics of its formation and evolution. We used precise radius measurements from the California-Kepler Survey (CKS) to study the size distribution of 2025 $\textit{Kepler}$ planets in fine detail. We detect a factor of $\geq$2 deficit in the occurrence rate distribution at 1.5-2.0 R$_{\oplus}$. This gap splits the population of close-in ($P$ < 100 d) small planets into two size regimes: R$_P$ < 1.5 R$_{\oplus}$ and R$_P$ = 2.0-3.0 R$_{\oplus}$, with few planets in between. Planets in these two regimes have nearly the same intrinsic frequency based on occurrence measurements that account for planet detection efficiencies. The paucity of planets between 1.5 and 2.0 R$_{\oplus}$ supports the emerging picture that close-in planets smaller than Neptune are composed of rocky cores measuring 1.5 R$_{\oplus}$ or smaller with varying amounts of low-density gas that determine their total sizes.Comment: Paper III in the California-Kepler Survey series, accepted to the Astronomical Journa