From z>6 to z~2: Unearthing Galaxies at the Edge of the Dark Ages

Galaxies undergoing formation and evolution can now be observed over a time baseline of some 12 Gyr. An inherent difficulty with high-redshift observations is that the objects are very faint and the best resolution (HST) is only ~0.5 kpc. Such studies thereby combine in a highly synergistic way with the great detail that can be obtained for nearby galaxies. 3 new developments are highlighted. First is the derivation of stellar masses for galaxies from SEDs using HST and now Spitzer data, and dynamical masses from both sub-mm observations of CO lines and near-IR observations of optical lines like Halpha. A major step has been taken with evidence that points to the z~2-3 LBGs having masses that are a few x 10^10 Msolar. Second is the discovery of a population of evolved red galaxies at z~2-3 which appear to be the progenitors of the more massive early-type galaxies of today, with dynamical masses around a few x 10^11 Msolar. Third are the remarkable advances that have occurred in characterizing dropout galaxies to z~6 and beyond, < 1 Gyr from recombination. The HST ACS has played a key role here, with the dropout technique being applied to i & z images in several deep ACS fields, yielding large samples of these objects. This has allowed a detailed determination of their properties and meaningful comparisons against lower-z samples. The use of cloning techniques has overcome many of the strong selection biases affecting the study of these objects. A clear trend of size with redshift has been identified, and its impact on the luminosity density and SFR estimated. There is a significant though modest decrease in the SFR from z~2.5 to z~6. The latest data also allow for the first robust determination of the LF at z~6. Finally, the latest UDF ACS and NICMOS data has resulted in the detection of some galaxies at z~7-8.Comment: 18 pages, 8 figures. To appear in Penetrating Bars through Masks of Cosmic Dust: The Hubble Tuning Fork Strikes a New Note, eds. D. Block, K. Freeman, R. Groess, I. Puerari, & E.K. Block (Dordrecht: Kluwer), in pres

Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense interest; however, covalent PROTACs with a broad protein of interest (POI) scope have proven challenging to discover by design. Here, we report the structure-guided design and optimization of Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides which covalently bind Ser110 in the HIF1α binding site. We demonstrate that their incorporation in bifunctional degraders induces targeted protein degradation of BRD4 or the androgen receptor without further linker optimization. Our study discloses the first covalent VHL ligands which can be implemented directly in bifunctional degrader design, expanding the substrate scope of covalent E3 ligase PROTACs

A life cycle stakeholder management framework for enhanced collaboration between stakeholders with competing interests

This is a postprint version of the Book Chapter. Information regarding the official publication is available from the link below - Copyright @ 2011 SpringerImplementation of a Life Cycle Sustainability Management (LCSM) strategy can involve significant challenges because of competing or conflicting objectives between stakeholders. These differences may, if not identified and managed, hinder successful adoption of sustainability initiatives. This article proposes a conceptual framework for stakeholder management in a LCSM context. The framework identifies the key sustainability stakeholder groups and suggests strategic ambiguity as a management tool to harness dysfunctional conflict into constructive collaboration. The framework is of practical value as it can be used as a guideline by managers who wish to improve collaboration with stakeholders along the supply chain. The article also fills a gap in the academic literature where there is only limited research on sustainability stakeholder management through strategic ambiguity

The Complete Star Formation History of the Universe

The determination of the star-formation history of the Universe is a key goal of modern cosmology, as it is crucial to our understanding of how structure in the Universe forms and evolves. A picture has built up over recent years, piece-by-piece, by observing young stars in distant galaxies at different times in the past. These studies indicated that the stellar birthrate peaked some 8 billion years ago, and then declined by a factor of around ten to its present value. Here we report on a new study which obtains the complete star formation history by analysing the fossil record of the stellar populations of 96545 nearby galaxies. Broadly, our results support those derived from high-redshift galaxies elsewhere in the Universe. We find, however, that the peak of star formation was more recent - around 5 billion years ago. Our study also shows that the bigger the stellar mass of the galaxy, the earlier the stars were formed. This striking result indicates a very different formation history for high- and low-mass formation.Comment: Accepted by Nature. Press embargo until publishe

Compounds from Silicones Alter Enzyme Activity in Curing Barnacle Glue and Model Enzymes

Background: Attachment strength of fouling organisms on silicone coatings is low. We hypothesized that low attachment strength on silicones is, in part, due to the interaction of surface available components with natural glues. Components could alter curing of glues through bulk changes or specifically through altered enzyme activity. Methodology/Principal Findings: GC-MS analysis of silicone coatings showed surface-available siloxanes when the coatings were gently rubbed with a cotton swab for 15 seconds or given a 30 second rinse with methanol. Mixtures of compounds were found on 2 commercial and 8 model silicone coatings. The hypothesis that silicone components alter glue curing enzymes was tested with curing barnacle glue and with commercial enzymes. In our model, barnacle glue curing involves trypsin-like serine protease(s), which activate enzymes and structural proteins, and a transglutaminase which cross-links glue proteins. Transglutaminase activity was significantly altered upon exposure of curing glue from individual barnacles to silicone eluates. Activity of purified trypsin and, to a greater extent, transglutaminase was significantly altered by relevant concentrations of silicone polymer constituents. Conclusions/Significance: Surface-associated silicone compounds can disrupt glue curing and alter enzyme properties

Rapid Evolution in the Most Luminous Galaxies During the First 900 Million Years

The first 900 million years (Myr) to redshift z~6 (the first seven per cent of the age of the Universe) remains largely unexplored for the formation of galaxies. Large samples of galaxies have been found at z~6, but detections at earlier times are uncertain and unreliable. It is not at all clear how galaxies built up from the first stars when the Universe was ~300 Myr old (z~12-15) to z~6, just 600 Myr later. Here we report the results of a search for galaxies at z~7-8, about 700 Myr after the Big Bang, using the deepest near-infrared and optical images ever taken. Under conservative selection criteria we find only one candidate galaxy at z~7-8, where ten would be expected if there were no evolution in the galaxy population between z~7-8 and z~6. Using less conservative criteria, there are four candidates, where 17 would be expected with no evolution. This demonstrates that very luminous galaxies are quite rare 700 Myr after the Big Bang. The simplest explanation is that the Universe is just too young to have built up many luminous galaxies at z~7-8 by the hierarchical merging of small galaxies.Comment: Accepted for publication in Nature, 20 pages, 5 figures, 2 tables (includes Supplementary Information), replaced to match version in pres

Why do women invest in pre-pregnancy health and care? A qualitative investigation with women attending maternity services

Background Despite the importance attributed to good pre-pregnancy care and its potential to improve pregnancy and child health outcomes, relatively little is known about why women invest in pre-pregnancy health and care. We sought to gain insight into why women invested in pre-pregnancy health and care. Methods We carried out 20 qualitative in-depth interviews with pregnant or recently pregnant women who were drawn from a survey of antenatal clinic attendees in London, UK. Interviewees were purposively sampled to include high and low investors in pre-pregnancy health and care, with variation in age, partnership status, ethnicity and pre-existing medical conditions. Data analysis was conducted using the Framework method. Results We identified three groups in relation to pre-pregnancy health and care: 1) The “prepared” group, who had high levels of pregnancy planning and mostly positive attitudes to micronutrient supplementation outside of pregnancy, carried out pre-pregnancy activities such as taking folic acid and making changes to diet and lifestyle. 2) The “poor knowledge” group, who also had high levels of pregnancy planning, did not carry out pre-pregnancy activities and described themselves as having poor knowledge. Elsewhere in their interviews they expressed a strong dislike of micronutrient supplementation. 3) The “absent pre-pregnancy period” group, had the lowest levels of pregnancy planning and also expressed anti-supplement views. Even discussing the pre-pregnancy period with this group was difficult as responses to questions quickly shifted to focus on pregnancy itself. Knowledge of folic acid was poor in all groups. Conclusion Different pre-pregnancy care approaches are likely to be needed for each of the groups. Among the “prepared” group, who were proactive and receptive to health messages, greater availability of information and better response from health professionals could improve the range of pre-pregnancy activities carried out. Among the “poor knowledge” group, better response from health professionals might yield greater uptake of pre-pregnancy information. A different, general health strategy might be more appropriate for the “absent pre-pregnancy period” group. The fact that general attitudes to micronutrient supplementation were closely related to whether or not women invested in pre-pregnancy health and care was an unanticipated finding and warrants further investigation.This report is independent research commissioned and funded by the Department of Health Policy Research Programme Pre-Pregnancy Health and Care in England: Exploring Implementation and Public Health Impact, 006/0068

The Proteolipid Protein Promoter Drives Expression outside of the Oligodendrocyte Lineage during Embryonic and Early Postnatal Development

The proteolipid protein (Plp) gene promoter is responsible for driving expression of one of the major components of myelin – PLP and its splice variant DM-20. Both products are classically thought to express predominantly in oligodendrocytes. However, accumulating evidence suggests Plp expression is more widespread than previously thought. In an attempt to create a mouse model for inducing oligodendrocyte-specific gene deletions, we have generated transgenic mice expressing a Cre recombinase cDNA under control of the mouse Plp promoter. We demonstrate Plp promoter driven Cre expression is restricted predominantly to mature oligodendrocytes of the central nervous system (CNS) at postnatal day 28. However, crosses into the Rosa26LacZ and mT/mG reporter mouse lines reveal robust and widespread Cre activity in neuronal tissues at E15.5 and E10.5 that is not strictly oligodendrocyte lineage specific. By P28, all CNS tissues examined displayed high levels of reporter gene expression well outside of defined white matter zones. Importantly, our study reinforces the emerging idea that Plp promoter activity is not restricted to the myelinating cell lineage, but rather, has widespread activity both during embryonic and early postnatal development in the CNS. Specificity of the promoter to the oligodendrocyte cell lineage, as shown through the use of a tamoxifen inducible Plp-CreERt line, occurs only at later postnatal stages. Understanding the temporal shift in Plp driven expression is of consequence when designing experimental models to study oligodendrocyte biology