Three-dimensional morphology and gene expression in the Drosophila blastoderm at cellular resolution II: dynamics.

BackgroundTo accurately describe gene expression and computationally model animal transcriptional networks, it is essential to determine the changing locations of cells in developing embryos.ResultsUsing automated image analysis methods, we provide the first quantitative description of temporal changes in morphology and gene expression at cellular resolution in whole embryos, using the Drosophila blastoderm as a model. Analyses based on both fixed and live embryos reveal complex, previously undetected three-dimensional changes in nuclear density patterns caused by nuclear movements prior to gastrulation. Gene expression patterns move, in part, with these changes in morphology, but additional spatial shifts in expression patterns are also seen, supporting a previously proposed model of pattern dynamics based on the induction and inhibition of gene expression. We show that mutations that disrupt either the anterior/posterior (a/p) or the dorsal/ventral (d/v) transcriptional cascades alter morphology and gene expression along both the a/p and d/v axes in a way suggesting that these two patterning systems interact via both transcriptional and morphological mechanisms.ConclusionOur work establishes a new strategy for measuring temporal changes in the locations of cells and gene expression patterns that uses fixed cell material and computational modeling. It also provides a coordinate framework for the blastoderm embryo that will allow increasingly accurate spatio-temporal modeling of both the transcriptional control network and morphogenesis

Detailed equilibrium and dynamical tides: impact on circularization and synchronization in open clusters

Binary stars evolve into chemically-peculiar objects and are a major driver of the Galactic enrichment of heavy elements. During their evolution they undergo interactions, including tides, that circularize orbits and synchronize stellar spins, impacting both individual systems and stellar populations. Using Zahn's tidal theory and MESA main-sequence model grids, we derive the governing parameters $\lambda_{lm}$ and $E_2$, and implement them in the new MINT library of the stellar population code BINARY_C. Our MINT equilibrium tides are 2 to 5 times more efficient than the ubiquitous BSE prescriptions while the radiative-tide efficiency drops sharply with increasing age. We also implement precise initial distributions based on bias-corrected observations. We assess the impact of tides and initial orbital-parameter distributions on circularization and synchronization in eight open clusters, comparing synthetic populations and observations through a bootstrapping method. We find that changing the tidal prescription yields no statistically-significant improvement as both calculations typically lie within 0.5$\sigma$. The initial distribution, especially the primordial concentration of systems at $\log_{10}(P/{\rm d}) \approx 0.8, e\approx 0.05$ dominates the statistics even when artificially increasing tidal strength. This confirms the inefficiency of tides on the main sequence and shows that constraining tidal-efficiency parameters using the $e-\log_{10}(P/{\rm d})$ distribution alone is difficult or impossible. Orbital synchronization carries a more striking age-dependent signature of tidal interactions. In M35 we find twice as many synchronized rotators in our MINT calculation as with BSE. This measure of tidal efficiency is verifiable with combined measurements of orbital parameters and stellar spins.Comment: 24 pages, 29 figures includings appendices. Accepted for publication in MNRA

Isabelle/PIDE as Platform for Educational Tools

The Isabelle/PIDE platform addresses the question whether proof assistants of the LCF family are suitable as technological basis for educational tools. The traditionally strong logical foundations of systems like HOL, Coq, or Isabelle have so far been counter-balanced by somewhat inaccessible interaction via the TTY (or minor variations like the well-known Proof General / Emacs interface). Thus the fundamental question of math education tools with fully-formal background theories has often been answered negatively due to accidental weaknesses of existing proof engines. The idea of "PIDE" (which means "Prover IDE") is to integrate existing provers like Isabelle into a larger environment, that facilitates access by end-users and other tools. We use Scala to expose the proof engine in ML to the JVM world, where many user-interfaces, editor frameworks, and educational tools already exist. This shall ultimately lead to combined mathematical assistants, where the logical engine is in the background, without obstructing the view on applications of formal methods, formalized mathematics, and math education in particular.Comment: In Proceedings THedu'11, arXiv:1202.453

Three-dimensional morphology and gene expression in the Drosophila blastoderm at cellular resolution I: data acquisition pipeline

BACKGROUND: To model and thoroughly understand animal transcription networks, it is essential to derive accurate spatial and temporal descriptions of developing gene expression patterns with cellular resolution. RESULTS: Here we describe a suite of methods that provide the first quantitative three-dimensional description of gene expression and morphology at cellular resolution in whole embryos. A database containing information derived from 1,282 embryos is released that describes the mRNA expression of 22 genes at multiple time points in the Drosophila blastoderm. We demonstrate that our methods are sufficiently accurate to detect previously undescribed features of morphology and gene expression. The cellular blastoderm is shown to have an intricate morphology of nuclear density patterns and apical/basal displacements that correlate with later well-known morphological features. Pair rule gene expression stripes, generally considered to specify patterning only along the anterior/posterior body axis, are shown to have complex changes in stripe location, stripe curvature, and expression level along the dorsal/ventral axis. Pair rule genes are also found to not always maintain the same register to each other. CONCLUSION: The application of these quantitative methods to other developmental systems will likely reveal many other previously unknown features and provide a more rigorous understanding of developmental regulatory networks

Three-dimensional morphology and gene expression in the Drosophila blastoderm at cellular resolution I: data acquisition pipeline

BACKGROUND: To model and thoroughly understand animal transcription networks, it is essential to derive accurate spatial and temporal descriptions of developing gene expression patterns with cellular resolution. RESULTS: Here we describe a suite of methods that provide the first quantitative three-dimensional description of gene expression and morphology at cellular resolution in whole embryos. A database containing information derived from 1,282 embryos is released that describes the mRNA expression of 22 genes at multiple time points in the Drosophila blastoderm. We demonstrate that our methods are sufficiently accurate to detect previously undescribed features of morphology and gene expression. The cellular blastoderm is shown to have an intricate morphology of nuclear density patterns and apical/basal displacements that correlate with later well-known morphological features. Pair rule gene expression stripes, generally considered to specify patterning only along the anterior/posterior body axis, are shown to have complex changes in stripe location, stripe curvature, and expression level along the dorsal/ventral axis. Pair rule genes are also found to not always maintain the same register to each other. CONCLUSION: The application of these quantitative methods to other developmental systems will likely reveal many other previously unknown features and provide a more rigorous understanding of developmental regulatory networks

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

A ‘quiet revolution’? The impact of Training Schools on initial teacher training partnerships

This paper discusses the impact on initial teacher training of a new policy initiative in England: the introduction of Training Schools. First, the Training School project is set in context by exploring the evolution of a partnership approach to initial teacher training in England. Ways in which Training Schools represent a break with established practice are considered together with their implications for the dominant mode of partnership led by higher education institutions (HEIs). The capacity of Training Schools to achieve their own policy objectives is examined, especially their efficacy as a strategy for managing innovation and the dissemination of innovation. The paper ends by focusing on a particular Training School project which has adopted an unusual approach to its work and enquires whether this alternative approach could offer a more profitable way forward. During the course of the paper, five different models of partnership are considered: collaborative, complementary, HEI-led, school-led and partnership within a partnership

Dutch healthcare reform: did it result in better patient experiences in hospitals? a comparison of the consumer quality index over time

<p>Abstract</p> <p>Background</p> <p>In 2006, the Dutch hospital market was reformed to create a more efficient delivery system through managed competition. To allow competition on quality, patient experiences were measured using the Consumer Quality index (CQI). We study whether public reporting and competition had an effect on the CQI between 2006 and 2009.</p> <p>Methods</p> <p>We analyzed 8,311 respondents covering 31 hospitals in 2006, 22,333 respondents covering 78 hospitals in 2007 and 24,246 respondents covering 94 hospitals in 2009. We describe CQI trends over the period 2006-2009. In addition we compare hospitals that varied in the level of competition they faced and hospitals that were forced to publish CQI results publicly and those that were not. We corrected for observable covariates between hospital respondents using a multi level linear regression. We used the Herfindahl Hirschman Index to indicate the level of competition.</p> <p>Results</p> <p>Between 2006 and 2009 hospitals showed a CQI improvement of 0.034 (p < 0.05) to 0.060 (p < 0.01) points on a scale between one and four. Hospitals that were forced to publish their scores showed a further improvement of 0.027 (p < 0.01) to 0.030 (p < 0.05). Furthermore, hospitals that faced more competition from geographically close competitors showed a more pronounced improvement of CQI-scores 0.004 to 0.05 than other hospitals (p < 0.001).</p> <p>Conclusion</p> <p>Our results show that patients reported improved experiences measured by the CQI between 2006 and 2009. CQI levels improve at a faster rate in areas with higher levels of competition. Hospitals confronted with forced public publication of their CQI responded by enhancing the experiences of their patients.</p

Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer

Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. We identified patients who were PD-(L)1-naïve with advanced non-small-cell lung cancer from two institutions-Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center-who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non-small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended

A Conserved Developmental Patterning Network Produces Quantitatively Different Output in Multiple Species of Drosophila

Differences in the level, timing, or location of gene expression can contribute to alternative phenotypes at the molecular and organismal level. Understanding the origins of expression differences is complicated by the fact that organismal morphology and gene regulatory networks could potentially vary even between closely related species. To assess the scope of such changes, we used high-resolution imaging methods to measure mRNA expression in blastoderm embryos of Drosophila yakuba and Drosophila pseudoobscura and assembled these data into cellular resolution atlases, where expression levels for 13 genes in the segmentation network are averaged into species-specific, cellular resolution morphological frameworks. We demonstrate that the blastoderm embryos of these species differ in their morphology in terms of size, shape, and number of nuclei. We present an approach to compare cellular gene expression patterns between species, while accounting for varying embryo morphology, and apply it to our data and an equivalent dataset for Drosophila melanogaster. Our analysis reveals that all individual genes differ quantitatively in their spatio-temporal expression patterns between these species, primarily in terms of their relative position and dynamics. Despite many small quantitative differences, cellular gene expression profiles for the whole set of genes examined are largely similar. This suggests that cell types at this stage of development are conserved, though they can differ in their relative position by up to 3–4 cell widths and in their relative proportion between species by as much as 5-fold. Quantitative differences in the dynamics and relative level of a subset of genes between corresponding cell types may reflect altered regulatory functions between species. Our results emphasize that transcriptional networks can diverge over short evolutionary timescales and that even small changes can lead to distinct output in terms of the placement and number of equivalent cells