A 37 kb region upstream of brachyury comprising a notochord enhancer is essential for notochord and tail development

The node-streak border region comprising notochord progenitor cells (NPCs) at the posterior node and neuro-mesodermal progenitor cells (NMPs) in the adjacent epiblast is the prime organizing center for axial elongation in mouse embryos. The T-box transcription factor brachyury (T) is essential for both formation of the notochord and maintenance of NMPs, and thus is a key regulator of trunk and tail development. The T promoter controlling T expression in NMPs and nascent mesoderm has been characterized in detail; however, control elements for T expression in the notochord have not been identified yet. We have generated a series of deletion alleles by CRISPR/Cas9 genome editing in mESCs, and analyzed their effects in mutant mouse embryos. We identified a 37 kb region upstream of T that is essential for notochord function and tailbud outgrowth. Within that region, we discovered a T-binding enhancer required for notochord cell specification and differentiation. Our data reveal a complex regulatory landscape controlling cell type-specific expression and function of T in NMP/nascent mesoderm and node/notochord, allowing proper trunk and tail development

Regional CO2 Inversion Through Ensemble-Based Simultaneous State and Parameter Estimation: TRACE Framework and Controlled Experiments

Atmospheric inversions provide estimates of carbon dioxide (CO2) fluxes between the surface and atmosphere based on atmospheric CO2 concentration observations. The number of CO2 observations is projected to increase severalfold in the next decades from expanding in situ networks and next-generation CO2-observing satellites, providing both an opportunity and a challenge for inversions. This study introduces the TRACE Regional Atmosphere-Carbon Ensemble (TRACE) system, which employ an ensemble-based simultaneous state and parameter estimation (ESSPE) approach to enable the assimilation of large volumes of observations for constraining CO2 flux parameters. TRACE uses an online full-physics mesoscale atmospheric model and assimilates observations serially in a coupled atmosphere-carbon ensemble Kalman filter. The data assimilation system was tested in a series of observing system simulation experiments using in situ observations for a regional domain over North America in summer. Under ideal conditions with known prior flux parameter error covariances, TRACE reduced the error in domain-integrated monthly CO2 fluxes by about 97% relative to the prior flux errors. In a more realistic scenario with unknown prior flux error statistics, the corresponding relative error reductions ranged from 80.6% to 88.5% depending on the specification of prior flux parameter error correlations. For regionally integrated fluxes on a spatial scale of 10(6) km(2), the sum of absolute errors was reduced by 34.5%-50.9% relative to the prior flux errors. Moreover, TRACE produced posterior uncertainty estimates that were consistent with the true errors. These initial experiments show that the ESSPE approach in TRACE provides a promising method for advancing CO2 inversion techniques

Antagonistic Activities of Sox2 and Brachyury Control the Fate Choice of Neuro-Mesodermal Progenitors

The spinal cord and mesodermal tissues of the trunk such as the vertebral column and skeletal musculature derive from neuro-mesodermal progenitors (NMPs). Sox2, Brachyury (T), and Tbx6 have been correlated with NMP potency and lineage choice; however, their exact role and interaction in these processes have not yet been revealed. Here we present a global analysis of NMPs and their descending lineages performed on purified cells from embryonic day 8.5 wild-type and mutant embryos. We show that T, cooperatively with WNT signaling, controls the progenitor state and the switch toward the mesodermal fate. Sox2 acts antagonistically and promotes neural development. T is also involved in remodeling the chromatin for mesodermal development. Tbx6 reinforces the mesodermal fate choice, represses the progenitor state, and confers paraxial fate commitment. Our findings refine previous models and establish molecular principles underlying mammalian trunk development, comprising NMP maintenance, lineage choice, and mesoderm formation

Anti-anxiety drugs and fish behavior: Establishing the link between internal concentrations of oxazepam and behavioral effects

This is the final published version. Available from Wiley via the DOI in this record.Some of the chemistry data have been provided in the Supplemental Data. The raw data from the behavioral analysis can be provided on contact with the corresponding author ([email protected]).Psychoactive drugs are frequently detected in the aquatic environment. The evolutionary conservation of the molecular targets of these drugs in fish suggests that they may elicit mode of action–mediated effects in fish as they do in humans, and the key open question is at what exposure concentrations these effects might occur. In the present study, the authors investigated the uptake and tissue distribution of the benzodiazepine oxazepam in the fathead minnow (Pimephales promelas) after 28 d of waterborne exposure to 0.8 μg L −1 , 4.7 μg L −1 , and 30.6 μg L −1 . Successively, they explored the relationship between the internal concentrations of oxazepam and the effects on fish exploratory behavior quantified by performing 2 types of behavioral tests, the novel tank diving test and the shelter-seeking test. The highest internal concentrations of oxazepam were found in brain, followed by plasma and liver, whereas muscle presented the lowest values. Average concentrations measured in the plasma of fish from the 3 exposure groups were, respectively, 8.7 ± 5.7 μg L −1 , 30.3 ± 16.1 μg L −1 , and 98.8 ± 72.9 μg L −1 . Significant correlations between plasma and tissue concentrations of oxazepam were found in all 3 groups. Exposure of fish to 30.6 µg L −1 in water produced plasma concentrations within or just below the human therapeutic plasma concentration (H T PC) range in many individuals. Statistically significant behavioral effects in the novel tank diving test were observed in fish exposed to 4.7 μg L −1 . In this group, plasma concentrations of oxazepam were approximately one-third of the lowest H T PC value. No significant effects were observed in fish exposed to the lowest and highest concentrations. The significance of these results is discussed in the context of the species-specific behavior of fathead minnow and existing knowledge of oxazepam pharmacology. Environ Toxicol Chem 2016;35:2782–2790. © 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.Brunel University (London, UK)Spanish Ministry of Economy and CompetitivenessEconomy and Knowledge Department of the Catalan governmen

A Randomized Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder.

Objective: Selective serotonin reuptake inhibitors like sertraline have been shown in observational studies and anecdotal reports to improve language development in young children with fragile X syndrome (FXS). A previous controlled trial of sertraline in young children with FXS found significant improvement in expressive language development as measured by the Mullen Scales of Early Learning (MSEL) among those with comorbid autism spectrum disorder (ASD) in post hoc analysis, prompting the authors to probe whether sertraline is also indicated in nonsyndromic ASD. Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 58 children with ASD aged 24 to 72 months. Results: 179 subjects were screened for eligibility, and 58 were randomized to sertraline (32) or placebo (26). Eight subjects from the sertraline arm and five from the placebo arm discontinued. Intent-to-treat analysis showed no significant difference from placebo on the primary outcomes (MSEL expressive language raw score and age equivalent combined score) or secondary outcomes. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events possibly related to study treatment occurred. Conclusion: This randomized controlled trial of sertraline treatment showed no benefit with respect to primary or secondary outcome measures. For the 6-month period, treatment in young children with ASD appears safe, although the long-term side effects of low-dose sertraline in early childhood are unknown. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02385799

Scatterometry reference standards to improve tool matching and traceability in lithographical nanomanufacturing

High quality scatterometry standard samples have been developed to improve the tool matching between different scatterometry methods and tools as well as with high resolution microscopic methods such as scanning electron microscopy or atomic force microscopy and to support traceable and absolute scatterometric critical dimension metrology in lithographic nanomanufacturing. First samples based on one dimensional Si or on Si 3 N 4 grating targets have been manufactured and characterized for this purpose. The etched gratings have periods down to 50 nm and contain areas of reduced density to enable AFM measurements for comparison. Each sample contains additionally at least one large area scatterometry target suitable for grazing incidence small angle X ray scattering. We present the current design and the characterization of structure details and the grating quality based on AFM, optical, EUV and X Ray scatterometry as well as spectroscopic ellipsometry measurements. The final traceable calibration of these standards is currently performed by applying and combining different scatterometric as well as imaging calibration methods. We present first calibration results and discuss the final design and the aimed specifications of the standard samples to face the tough requirements for future technology nodes in lithography

(Meta-)stable reconstructions of the diamond(111) surface: interplay between diamond- and graphite-like bonding

Off-lattice Grand Canonical Monte Carlo simulations of the clean diamond (111) surface, based on the effective many-body Brenner potential, yield the $(2\times1)$ Pandey reconstruction in agreement with \emph{ab-initio} calculations and predict the existence of new meta-stable states, very near in energy, with all surface atoms in three-fold graphite-like bonding. We believe that the long-standing debate on the structural and electronic properties of this surface could be solved by considering this type of carbon-specific configurations.Comment: 4 pages + 4 figures, Phys. Rev. B Rapid Comm., in press (15Apr00). For many additional details (animations, xyz files) see electronic supplement to this paper at http://www.sci.kun.nl/tvs/carbon/meta.htm

Математична залежність точності верстатних пристроїв від їх ступеня гнучкості

Підвищення конкурентоспроможності продукції, що виробляється невеликими підприємствами, забезпечується шляхом скорочення витрат на проектування та виготовлення технологічної оснастки для свердлильно- фрезерно-розточувальних операцій. Це стає можливим за рахунок використання гнучких верстатних пристроїв (ВП), що мають можливість переналагодження у заданому діапазоні розмірів заготовки шляхом регулювання установлювально-затискних елементів

Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants

Reproduced with permission from Environmental Health PerspectivesNumerous chemicals are capable of disrupting androgen production, but the possibility that they might act together to produce effects greater than those of the most effective component in the mixture has not been studied directly in human tissues. Suppression of androgen synthesis in fetal life has been associated with testis maldescent, malformations of the genitalia at birth, and poor semen quality later in life.Our aim was to investigate whether chemicals can act together to disrupt androgen production in human fetal testis explants and to evaluate the importance of mixture effects when characterizing the hazard of individual chemicals.We used an organotypic culture system of human fetal testes explants called FEtal Gonad Assay (FEGA) with tissue obtained at 10 and 12 gestational wk (GW 10-12), to screen 27 chemicals individually for their possible anti-androgenic effect. Based on the results of the screen, we selected 11 compounds and tested them as mixtures.We evaluated mixtures composed of four and eight antiandrogens that contained the pharmaceuticals ketoconazole and theophylline and several previously untested chemicals, such as the pesticides imazalil and propiconazole. Mixtures of antiandrogens can suppress testosterone synthesis in human fetal testicular explants to an extent greater than that seen with individual chemicals. This revealed itself as a shift towards lower doses in the dose-response curves of individual antiandrogens that became more pronounced as the number of components increased from four to eight.Our results with the FEGA provide the foundations of a predictive human mixture risk assessment approach for anti-androgenic exposures in fetal life.We thank all the staff of the Department of Obstetrics and Gynecology and the Department of Pediatric Surgery of the Rennes Sud Hospital (Rennes, France) and the participating women, without whom this study would not have been possible. We acknowledge the financial supports from the Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (ANSES) ; CHEMIX-EST-12-171, ChemPSy- EST-13-081, Institut National de la Santé et de la Recherche Médicale (Inserm). P.Gaudriault is a recipient of a stipend of the Fondation pour la Recherche Médicale