Major transcriptome re-organisation and abrupt changes in signalling, cell cycle and chromatin regulation at neural differentiation <em>in vivo</em>

Here, we exploit the spatial separation of temporal events of neural differentiation in the elongating chick body axis to provide the first analysis of transcriptome change in progressively more differentiated neural cell populations in vivo. Microarray data, validated against direct RNA sequencing, identified: (1) a gene cohort characteristic of the multi-potent stem zone epiblast, which contains neuro-mesodermal progenitors that progressively generate the spinal cord; (2) a major transcriptome reorganisation as cells then adopt a neural fate; and (3) increasing diversity as neural patterning and neuron production begin. Focussing on the transition from multi-potent to neural state cells, we capture changes in major signalling pathways, uncover novel Wnt and Notch signalling dynamics, and implicate new pathways (mevalonate pathway/steroid biogenesis and TGF beta). This analysis further predicts changes in cellular processes, cell cycle, RNA-processing and protein turnover as cells acquire neural fate. We show that these changes are conserved across species and provide biological evidence for reduced proteasome efficiency and a novel lengthening of S phase. This latter step may provide time for epigenetic events to mediate large-scale transcriptome re-organisation; consistent with this, we uncover simultaneous downregulation of major chromatin modifiers as the neural programme is established. We further demonstrate that transcription of one such gene, HDAC1, is dependent on FGF signalling, making a novel link between signals that control neural differentiation and transcription of a core regulator of chromatin organisation. Our work implicates new signalling pathways and dynamics, cellular processes and epigenetic modifiers in neural differentiation in vivo, identifying multiple new potential cellular and molecular mechanisms that direct differentiation

From segment to somite: segmentation to epithelialization analyzed within quantitative frameworks

One of the most visually striking patterns in the early developing embryo is somite segmentation. Somites form as repeated, periodic structures in pairs along nearly the entire caudal vertebrate axis. The morphological process involves short- and long-range signals that drive cell rearrangements and cell shaping to create discrete, epithelialized segments. Key to developing novel strategies to prevent somite birth defects that involve axial bone and skeletal muscle development is understanding how the molecular choreography is coordinated across multiple spatial scales and in a repeating temporal manner. Mathematical models have emerged as useful tools to integrate spatiotemporal data and simulate model mechanisms to provide unique insights into somite pattern formation. In this short review, we present two quantitative frameworks that address the morphogenesis from segment to somite and discuss recent data of segmentation and epithelialization

Cell Movement patterns during gastrulation in the chick are controlled by positive and negative chemotaxis mediated by FGF4 and FGF8

AbstractDuring gastrulation in amniotes, epiblast cells ingress through the primitive streak and migrate away to form endodermal, mesodermal, and extraembryonic structures. Here we analyze the detailed movement trajectories of cells emerging at different anterior-posterior positions from the primitive streak, using in vivo imaging of the movement of GFP-tagged streak cells. Cells emerging at different anterior-posterior positions from the streak show characteristic cell migration patterns, in response to guidance signals from neighboring tissues. Streak cells are attracted by sources of FGF4 and repelled by sources of FGF8. The observed movement patterns of anterior streak cells can be explained by an FGF8-mediated chemorepulsion of cells away from the streak followed by chemoattraction toward an FGF4 signal produced by the forming notochord

The Young Stellar Population of IC1613. I. A New Catalogue of OB Associations

Context: Determining the parameters of massive stars is crucial to understand many processes in galaxies and the Universe, since these objects are important sources of ionization, chemical enrichment and momentum. 10m class telescopes enable us to perform detailed quantitative spectroscopic analyses of massive stars in other galaxies, sampling areas of different metallicity. Relating the stars to their environment is crucial to understand the physical processes ruling their formation and evolution. Aims: In preparation for the GTC, our goal is to build a catalogue of massive star candidates in the metal-poor irregular galaxy IC1613 with high astrometric accuracy, apt for the current generation of multi-object spectrographs. A census of OB associations in this galaxy is also needed, to provide important additional information about age and environment of the candidate OB stars. Methods: From INT-WFC observations, we have built an astrometric and photometric catalogue of stars in IC1613. Candidate blue massive stars are preselected from their colors. A friends-of-friends algorithm is developed to find their clustering in the galaxy. While a common physical origin for all the members of the associations cannot be ensured, this is a necessary first step to place candidate OB stars in a population context. Results: We have produced a deep catalogue of targets in IC1613 that covers a large field of view. To achieve high astrometric accuracy a new astrometric procedure is developed for the INT-WFC data. We have also built a catalogue of OB associations in IC1613. We have found that they concentrate in the central regions, specially in the HII bubbles. The study of extinction confirms that it is patchy, with local values of color-excess above the foreground value.Comment: Accepted for publication in Astronomy and Astrophysics. 16 pages + appendix (14 pages); 20 figure

Coordination of Cell Differentiation and Migration in Mathematical Models of Caudal Embryonic Axis Extension

Vertebrate embryos display a predominant head-to-tail body axis whose formation is associated with the progressive development of post-cranial structures from a pool of caudal undifferentiated cells. This involves the maintenance of active FGF signaling in this caudal region as a consequence of the restricted production of the secreted factor FGF8. FGF8 is transcribed specifically in the caudal precursor region and is down-regulated as cells differentiate and the embryo extends caudally. We are interested in understanding the progressive down-regulation of FGF8 and its coordination with the caudal movement of cells which is also known to be FGF-signaling dependent. Our study is performed using mathematical modeling and computer simulations. We use an individual-based hybrid model as well as a caricature continuous model for the simulation of experimental observations (ours and those known from the literature) in order to examine possible mechanisms that drive differentiation and cell movement during the axis elongation. Using these models we have identified a possible gene regulatory network involving self-repression of a caudal morphogen coupled to directional domain movement that may account for progressive down-regulation of FGF8 and conservation of the FGF8 domain of expression. Furthermore, we have shown that chemotaxis driven by molecules, such as FGF8 secreted in the stem zone, could underlie the migration of the caudal precursor zone and, therefore, embryonic axis extension. These mechanisms may also be at play in other developmental processes displaying a similar mode of axis extension coupled to cell differentiation

Nonthermal Emission from Star-Forming Galaxies

The detections of high-energy gamma-ray emission from the nearby starburst galaxies M82 & NGC253, and other local group galaxies, broaden our knowledge of star-driven nonthermal processes and phenomena in non-AGN star-forming galaxies. We review basic aspects of the related processes and their modeling in starburst galaxies. Since these processes involve both energetic electrons and protons accelerated by SN shocks, their respective radiative yields can be used to explore the SN-particle-radiation connection. Specifically, the relation between SN activity, energetic particles, and their radiative yields, is assessed through respective measures of the particle energy density in several star-forming galaxies. The deduced energy densities range from O(0.1) eV/cm^3 in very quiet environments to O(100) eV/cm^3 in regions with very high star-formation rates.Comment: 17 pages, 5 figures, to be published in Astrophysics and Space Science Proceeding

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

Background: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. Purpose: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. Methods and Results: To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. Conclusions: The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease

SYNTHESIS OF 1H-BENZOXAZINE-2,4-DIONES FROM HETEROCYCLIC ANHYDRIDES: EVALUATION OF ANTIOXIDANT AND ANTIMICROBIAL ACTIVITIES

A facile one-step synthesis of 1H-benzoxazine-2,4-diones from heterocyclic anhydrides and TMSA was described. This paper determines their antimicrobial activity against nine human bacterial pathogens by the broth microdilution method; antioxidant activity by DPPH• inactivation and a ferric-reducing power assay; and toxicity by a brine shrimp, Artemia salina, assay. The 1H-benzoxazine-2,4-dione yields were in the range of 57 to 98%. The novel compound 1H-pyrazino[2,3-][1,3]oxazine-2,4-dione 4c showed the highest antioxidant capacity (DPPH 35.4% and FRAP 0.063 µmol TEs/µmol)