Stem and/or progenitor cells often generate distinct cell types in a stereotyped birth order and over time lose competence to specify earlier-born fates by unknown mechanisms. In Drosophila, the ...Hunchback transcription factor acts in neural progenitors (neuroblasts) to specify early-born neurons, in part by indirectly inducing the neuronal transcription of its target genes, including the hunchback gene. We used in vivo immuno-DNA FISH and found that the hunchback gene moves to the neuroblast nuclear periphery, a repressive subnuclear compartment, precisely when competence to specify early-born fate is lost and several hours and cell divisions after termination of its transcription. hunchback movement to the lamina correlated with downregulation of the neuroblast nuclear protein, Distal antenna (Dan). Either prolonging Dan expression or disrupting lamina interfered with hunchback repositioning and extended neuroblast competence. We propose that neuroblasts undergo a developmentally regulated subnuclear genome reorganization to permanently silence Hunchback target genes that results in loss of progenitor competence.
Display omitted
► Drosophila neuroblasts can make Hb+ neurons only during the early competence window ► hb gene repositioning to the nuclear periphery ends the early competence window ► Repositioning of the hb locus occurs 3 cell divisions after end of hb transcription ► Dan and laminB regulate hb subnuclear positioning and neuroblast competence
Nuclear repositioning of a key developmental gene is shown to underlie the closing of a window in which neuroblasts can be specified to a particular cell fate.
There is increasing concern that climate change poses an existential risk to humanity. Understanding these worst-case scenarios is essential for good risk management. However, our knowledge of the ...causal pathways through which climate change could cause societal collapse is underdeveloped. This paper aims to identify and structure an empirical evidence base of the climate change, food insecurity and societal collapse pathway. We first review the societal collapse and existential risk literature and define a set of determinants of societal collapse. We develop an original methodology, using these determinants as societal collapse proxies, to identify an empirical evidence base of climate change, food insecurity and societal collapse in contemporary society and then structure it using a novel-format causal loop diagram (CLD) defined at global scale and national granularity. The resulting evidence base varies in temporal and spatial distribution of study and in the type of data-driven methods used. The resulting CLD documents the spread of the evidence base, using line thickness and colour to depict density and type of data-driven method respectively. It enables exploration of how the effects of climate change may undermine agricultural systems and disrupt food supply, which can lead to economic shocks, socio-political instability as well as starvation, migration and conflict. Suggestions are made for future work that could build on this paper to further develop our qualitative understanding of, and quantitative complex systems modelling capabilities for analysing, the causal pathways between climate change and societal collapse.
Abstract
The Pan-STARRS1 (PS1) Science Consortium has carried out a set of imaging surveys using the 1.4 gigapixel GPC1 camera on the PS1 telescope. As this camera is composed of many individual ...electronic readouts and covers a very large field of view, great care was taken to ensure that the many instrumental effects were corrected to produce the most uniform detector response possible. We present the image-detrending steps used as part of the processing of the data contained within the public release of Pan-STARRS1 Data Release 1 (DR1). In addition to the single image processing, the methods used to transform the 375,573 individual exposures into a common sky-oriented grid are discussed, as well as those used to produce both the image stack and difference combination products.
All dietary fiber, by definition, escapes digestion in the small intestine and thus arrives relatively intact in the large intestine. Its fate in the large intestine depends upon the type of fiber ...and the colonic microflora. Highly fermentable fibers result in short chain fatty acids including butyrate, which is thought by some to be protective against colon cancer. However, not all studies support a chemopreventive effect for butyrate and the lack of agreement (particularly between in vivo and in vitro studies) on butyrate and colon cancer has been termed the “butyrate paradox.” There are a number of reasons for this discrepant effect including differences between the in vitro and in vivo environments, the timing of butyrate administration, the amount of butyrate administered, the source of butyrate (usually dietary fiber) as a potential confounder, and an interaction with dietary fat. Collectively, the studies suggest that the chemopreventive benefits of butyrate depend in part on amount, time of exposure with respect to the tumorigenic process, and the type of fat in the diet.
Glutathione (γ-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from ...glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, γ-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by γ-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.
BACKGROUND:Antiarrhythmic drugs have not proven to significantly improve overall survival after out-of-hospital cardiac arrest from shock-refractory ventricular fibrillation/pulseless ventricular ...tachycardia. How this might be influenced by the route of drug administration is not known.
METHODS:In this prespecified analysis of a randomized, placebo-controlled clinical trial, we compared the differences in survival to hospital discharge in adults with shock-refractory ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest who were randomly assigned by emergency medical services personnel to an antiarrhythmic drug versus placebo in the ALPS trial (Resuscitation Outcomes Consortium Amiodarone, Lidocaine or Placebo Study), when stratified by the intravenous versus intraosseous route of administration.
RESULTS:Of 3019 randomly assigned patients with a known vascular access site, 2358 received ALPS drugs intravenously and 661 patients by the intraosseous route. Intraosseous and intravenous groups differed in sex, time-to-emergency medical services arrival, and some cardiopulmonary resuscitation characteristics, but were similar in others, including time-to-intravenous/intrasosseous drug receipt. Overall hospital discharge survival was 23%. In comparison with placebo, discharge survival was significantly higher in recipients of intravenous amiodarone (adjusted risk ratio, 1.26 95% CI, 1.06–1.50; adjusted absolute survival difference, 5.5% 95% CI, 1.5–9.5) and intravenous lidocaine (adjusted risk ratio, 1.21 95% CI, 1.02–1.45; adjusted absolute survival difference, 4.7% 95% CI, 0.7–8.8); but not in recipients of intraosseous amiodarone (adjusted risk ratio, 0.94 95% CI, 0.66–1.32) or intraosseous lidocaine (adjusted risk ratio, 1.03 95% CI, 0.74–1.44). Survival to hospital admission also increased significantly when drugs were given intravenously but not intraosseously, and favored improved neurological outcome at discharge. There were no outcome differences between intravenous and intraosseous placebo, indicating that the access route itself did not demarcate patients with poor prognosis. The study was underpowered to assess intravenous/intraosseous drug interactions, which were not statistically significant.
CONCLUSIONS:We found no significant effect modification by drug administration route for amiodarone or lidocaine in comparison with placebo during out-of-hospital cardiac arrest. However, point estimates for the effects of both drugs in comparison with placebo were significantly greater for the intravenous than for the intraosseous route across virtually all outcomes and beneficial only for the intravenous route. Given that the study was underpowered to statistically assess interactions, these findings signal the potential importance of the drug administration route during resuscitation that merits further investigation.
Abstract The inflammatory response is designed to help fight and clear infection, remove harmful chemicals, and repair damaged tissue and organ systems. Although this process, in general, is ...protective, the failure to resolve the inflammation and return the target tissue to homeostasis can result in disease, including the promotion of cancer. A plethora of published literature supports the contention that dietary n-3 polyunsaturated fatty acids (PUFA), and eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) in particular, are important modulators of a host's inflammatory/immune responses. The following review describes a mechanistic model that may explain, in part, the pleiotropic anti-inflammatory and immunosuppressive properties of EPA and DHA. In this review, we focus on salient studies that address three overarching mechanisms of n-3 PUFA action: (i) modulation of nuclear receptor activation, i.e., nuclear factor-κB (NF-κB) suppression; (ii) suppression of arachidonic acid–cyclooxygenase-derived eicosanoids, primarily prostaglandin E2 -dependent signaling; and (iii) alteration of the plasma membrane micro-organization (lipid rafts), particularly as it relates to the function of Toll-like receptors (TLRs), and T-lymphocyte signaling molecule recruitment to the immunological synapse (IS). We propose that lipid rafts may be targets for the development of n-3 PUFA-containing dietary bioactive agents to down-modulate inflammatory and immune responses and for the treatment of autoimmune and chronic inflammatory diseases.
Weak lensing is emerging as a powerful observational tool to constrain cosmological models, but is at present limited by an incomplete understanding of many sources of systematic error. Many of these ...errors are multiplicative and depend on the population of background galaxies. We show how the commonly cited geometric test, which is rather insensitive to cosmology, can be used as a ratio test of systematics in the lensing signal at the 1 per cent level. We apply this test to the galaxy-galaxy lensing analysis of the Sloan Digital Sky Survey (SDSS), which at present is the sample with the highest weak lensing signal-to-noise ratio and has the additional advantage of spectroscopic redshifts for lenses. This allows one to perform meaningful geometric tests of systematics for different subsamples of galaxies at different mean redshifts, such as brighter galaxies, fainter galaxies and high-redshift luminous red galaxies, both with and without photometric redshift estimates. We use overlapping objects between SDSS and the DEEP2 and 2df-Sloan LRG and Quasar (2SLAQ) spectroscopic surveys to establish accurate calibration of photometric redshifts and to determine the redshift distributions for SDSS. We use these redshift results to compute the projected surface density contrast Δσ around 259 609 spectroscopic galaxies in the SDSS; by measuring Δσ with different source samples we establish consistency of the results at the 10 per cent level (1σ). We also use the ratio test to constrain shear calibration biases and other systematics in the SDSS survey data to determine the overall galaxy-galaxy weak lensing signal calibration uncertainty. We find no evidence of any inconsistency among many subsamples of the data.
We use Sloan Digital Sky Survey (SDSS) Data Release 5 (DR5) u, g, r, i, z photometry to study Milky Way halo substructure in the area around the north Galactic cap. A simple color cut (g - r < 0.4) ...reveals the tidal stream of the Sagittarius dwarf spheroidal galaxy, as well as a number of other stellar structures in the field. Two branches (A and B) of the Sagittarius stream are clearly visible in an RGB composite image created from three magnitude slices, and there is also evidence for a still more distant wrap behind the A branch. A comparison of these data with numerical models suggests that the shape of the Galactic dark halo is close to spherical.
We present the source separation framework scarlet for multi-band images, which is based on a generalization of the Non-negative Matrix Factorization to alternative and several simultaneous ...constraints. Our approach describes the observed scene as a mixture of components with compact spatial support and uniform spectra over their support. We present the algorithm to perform the matrix factorization and introduce constraints that are useful for optical images of stars and distinct stellar populations in galaxies, in particular symmetry and monotonicity with respect to the source peak position. We also derive the treatment of correlated noise and convolutions with band-dependent point spread functions, rendering our approach applicable to coadded images observed under variable seeing conditions. scarlet thus yields a PSF-matched photometry measurement with an optimally chosen weight function given by the mean morphology in all available bands. We demonstrate the performance of scarlet for deblending crowded extragalactic scenes and on an AGN jet–host galaxy separation problem in deep 5-band imaging from the Hyper Suprime-Cam Strategic Survey Program. Using simulations with prominent crowding we show that scarlet yields superior results to the HSC-SDSS deblender for the recovery of total fluxes, colors, and morphologies. Due to its non-parametric nature, a conceptual limitation of scarlet is its sensitivity to undetected sources or multiple stellar population within detected sources, but an iterative strategy that adds components at the location of significant residuals appears promising. The code is implemented in Python with C++ extensions and is available at https://github.com/fred3m/scarlet.