Hox proteins drive cell segregation and non-autonomous apical remodelling during hindbrain segmentation

Hox genes encode a conserved family of homeodomain transcription factors regulating development along the major body axis. During embryogenesis, Hox proteins are expressed in segment-specific patterns and control numerous different segment-specific cell fates. It has been unclear, however, whether Hox proteins drive the epithelial cell segregation mechanism that is thought to initiate the segmentation process. Here, we investigate the role of vertebrate Hox proteins during the partitioning of the developing hindbrain into lineage-restricted units called rhombomeres. Loss-of-function mutants and ectopic expression assays reveal that Hoxb4 and its paralogue Hoxd4 are necessary and sufficient for cell segregation, and for the most caudal rhombomere boundary (r6/r7). Hox4 proteins regulate Eph/ephrins and other cell-surface proteins, and can function in a non-cell-autonomous manner to induce apical cell enlargement on both sides of their expression border. Similarly, other Hox proteins expressed at more rostral rhombomere interfaces can also regulate Eph/ephrins, induce apical remodelling and drive cell segregation in ectopic expression assays. However, Krox20, a key segmentation factor expressed in odd rhombomeres (r3 and r5), can largely override Hox proteins at the level of regulation of a cell surface target, Epha4. This study suggests that most, if not all, Hox proteins share a common potential to induce cell segregation but in some contexts this is masked or modulated by other transcription factors

Anaplastic Lymphoma Kinase Spares Organ Growth during Nutrient Restriction in Drosophila

SummaryDeveloping animals survive periods of starvation by protecting the growth of critical organs at the expense of other tissues. Here, we use Drosophila to explore the as yet unknown mechanisms regulating this privileged tissue growth. As in mammals, we observe in Drosophila that the CNS is more highly spared than other tissues during nutrient restriction (NR). We demonstrate that anaplastic lymphoma kinase (Alk) efficiently protects neural progenitor (neuroblast) growth against reductions in amino acids and insulin-like peptides during NR via two mechanisms. First, Alk suppresses the growth requirement for amino acid sensing via Slimfast/Rheb/TOR complex 1. And second, Alk, rather than insulin-like receptor, primarily activates PI3-kinase. Alk maintains PI3-kinase signaling during NR as its ligand, Jelly belly (Jeb), is constitutively expressed from a glial cell niche surrounding neuroblasts. Together, these findings identify a brain-sparing mechanism that shares some regulatory features with the starvation-resistant growth programs of mammalian tumors.PaperCli

Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila

SummaryStem cells reside in specialized microenvironments known as niches. During Drosophila development, glial cells provide a niche that sustains the proliferation of neural stem cells (neuroblasts) during starvation. We now find that the glial cell niche also preserves neuroblast proliferation under conditions of hypoxia and oxidative stress. Lipid droplets that form in niche glia during oxidative stress limit the levels of reactive oxygen species (ROS) and inhibit the oxidation of polyunsaturated fatty acids (PUFAs). These droplets protect glia and also neuroblasts from peroxidation chain reactions that can damage many types of macromolecules. The underlying antioxidant mechanism involves diverting PUFAs, including diet-derived linoleic acid, away from membranes to the core of lipid droplets, where they are less vulnerable to peroxidation. This study reveals an antioxidant role for lipid droplets that could be relevant in many different biological contexts

Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear. Here, we show that p53 maintains quiescence by inducing fatty-acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention

A Planetary Microlensing Event with an Unusually Red Source Star: MOA-2011-BLG-291

We present the analysis of planetary microlensing event MOA-2011-BLG-291, which has a mass ratio of $q=(3.8\pm0.7)\times10^{-4}$ and a source star that is redder (or brighter) than the bulge main sequence. This event is located at a low Galactic latitude in the survey area that is currently planned for NASA's WFIRST exoplanet microlensing survey. This unusual color for a microlensed source star implies that we cannot assume that the source star is in the Galactic bulge. The favored interpretation is that the source star is a lower main sequence star at a distance of $D_S=4.9\pm1.3\,$kpc in the Galactic disk. However, the source could also be a turn-off star on the far side of the bulge or a sub-giant in the far side of the Galactic disk if it experiences significantly more reddening than the bulge red clump stars. However, these possibilities have only a small effect on our mass estimates for the host star and planet. We find host star and planet masses of $M_{\rm host} =0.15^{+0.27}_{-0.10}M_\odot$ and $m_p=18^{+34}_{-12}M_\oplus$ from a Bayesian analysis with a standard Galactic model under the assumption that the planet hosting probability does not depend on the host mass or distance. However, if we attempt to measure the host and planet masses with host star brightness measurements from high angular resolution follow-up imaging, the implied masses will be sensitive to the host star distance. The WFIRST exoplanet microlensing survey is expected to use this method to determine the masses for many of the planetary systems that it discovers, so this issue has important design implications for the WFIRST exoplanet microlensing survey

Early In-Hospital Mortality following Trainee Doctors' First Day at Work

BACKGROUND:There is a commonly held assumption that early August is an unsafe period to be admitted to hospital in England, as newly qualified doctors start work in NHS hospitals on the first Wednesday of August. We investigate whether in-hospital mortality is higher in the week following the first Wednesday in August than in the previous week. METHODOLOGY:A retrospective study in England using administrative hospital admissions data. Two retrospective cohorts of all emergency patients admitted on the last Wednesday in July and the first Wednesday in August for 2000 to 2008, each followed up for one week. PRINCIPAL FINDINGS:The odds of death for patients admitted on the first Wednesday in August was 6% higher (OR 1.06, 95% CI 1.00 to 1.15, p=0.05) after controlling for year, gender, age, socio-economic deprivation and co-morbidity. When subdivided into medical, surgical and neoplasm admissions, medical admissions admitted on the first Wednesday in August had an 8% (OR 1.08, 95% CI 1.01 to 1.16, p=0.03) higher odds of death. In 2007 and 2008, when the system for junior doctors' job applications changed, patients admitted on Wednesday August 1(st) had 8% higher adjusted odds of death than those admitted the previous Wednesday, but this was not statistically significant (OR 1.08, 95% CI 0.95 to 1.23, p=0.24). CONCLUSIONS:We found evidence that patients admitted on the first Wednesday in August have a higher early death rate in English hospitals compared with patients admitted on the previous Wednesday. This was higher for patients admitted with a medical primary diagnosis

Preventing “a virological Hiroshima”: Cold War press coverage of biological weapons disarmament

This article examines representations of biological weapons during a crucial period in the recent history of this form of warfare. The study draws on a corpus of newspaper articles from the US New York Times and the UK Times and Guardian written around the time of the negotiation period of the 1972 Biological Weapons Convention, the international treaty banning this form of warfare. We argue that a conventional discourse can be found wherein biological weapons are portrayed as morally offensive, yet highly effective and militarily attractive. Interwoven with this discourse, however, is a secondary register which depicts biological weapons as ineffective, unpredictable and of questionable value for the military. We finish with a somewhat more speculative consideration of the significance of these discourses by asking what might have been at stake when journalists and other writers deployed such differing representations of biological warfare

Spectroscopic Mass and Host-star Metallicity Measurements for Newly Discovered Microlensing Planet OGLE-2018-BLG-0740Lb

We report the discovery of the microlensing planet OGLE-2018-BLG-0740Lb. The planet is detected with a very strong signal of $\Delta\chi^2\sim 4630$, but the interpretation of the signal suffers from two types of degeneracies. One type is caused by the previously known close/wide degeneracy, and the other is caused by an ambiguity between two solutions, in which one solution requires to incorporate finite-source effects, while the other solution is consistent with a point-source interpretation. Although difficult to be firmly resolved based on only the photometric data, the degeneracy is resolved in strong favor of the point-source solution with the additional external information obtained from astrometric and spectroscopic observations. The small astrometric offset between the source and baseline object supports that the blend is the lens and this interpretation is further secured by the consistency of the spectroscopic distance estimate of the blend with the lensing parameters of the point-source solution. The estimated mass of the host is $1.0\pm 0.1~M_\odot$ and the mass of the planet is $4.5\pm 0.6~M_{\rm J}$ (close solution) or $4.8\pm 0.6~M_{\rm J}$ (wide solution) and the lens is located at a distance of $3.2\pm 0.5$~kpc. The bright nature of the lens, with $I\sim 17.1$ ($V\sim 18.2$), combined with its dominance of the observed flux suggest that radial-velocity (RV) follow-up observations of the lens can be done using high-resolution spectrometers mounted on large telescopes, e.g., VLT/ESPRESSO, and this can potentially not only measure the period and eccentricity of the planet but also probe for close-in planets. We estimate that the expected RV amplitude would be $\sim 60\sin i ~{\rm m~s}^{-1}$.Comment: 12 pages, 11 figures, 4 table