Cooperation between MEF2 and PPARγ in human intestinal β,β-carotene 15,15'-monooxygenase gene expression

BACKGROUND: Vitamin A and its derivatives, the retinoids, are essential for normal embryonic development and maintenance of cell differentiation. β, β-carotene 15,15'-monooxygenase 1 (BCMO1) catalyzes the central cleavage of β-carotene to all-trans retinal and is the key enzyme in the intestinal metabolism of carotenes to vitamin A. However, human and various rodent species show markedly different efficiencies in intestinal BCMO1-mediated carotene to retinoid conversion. The aim of this study is to identify potentially human-specific regulatory control mechanisms of BCMO1 gene expression. RESULTS: We identified and functionally characterized the human BCMO1 promoter sequence and determined the transcriptional regulation of the BCMO1 gene in a BCMO1 expressing human intestinal cell line, TC-7. Several functional transcription factor-binding sites were identified in the human promoter that are absent in the mouse BCMO1 promoter. We demonstrate that the proximal promoter sequence, nt -190 to +35, confers basal transcriptional activity of the human BCMO1 gene. Site-directed mutagenesis of the myocyte enhancer factor 2 (MEF2) and peroxisome proliferator-activated receptor (PPAR) binding elements resulted in decreased basal promoter activity. Mutation of both promoter elements abrogated the expression of intestinal cell BCMO1. Electrophoretic mobility shift and supershift assays and transcription factor co-expression in TC-7 cells showed MEF2C and PPARγ bind to their respective DNA elements and synergistically transactivate BCMO1 expression. CONCLUSION: We demonstrate that human intestinal cell BCMO1 expression is dependent on the functional cooperation between PPARγ and MEF2 isoforms. The findings suggest that the interaction between MEF2 and PPAR factors may provide a molecular basis for interspecies differences in the transcriptional regulation of the BCMO1 gene

Clinical trials and basic research: defining mechanisms and improving treatment in connective tissue disease

Despite advances in elucidating the pathogenic factors responsible for its development, systemic sclerosis remains complex and poorly understood, and treatment options are limited. Multidisciplinary collaborative efforts are needed to better characterize clinical and prognostic parameters and to design and implement large-scale clinical trials in well defined populations with therapies that target potential disease modulators

Systemic sclerosis and related connective tissue diseases: present and future

Greece, to discuss systemic sclerosis (SSc) and related connective tissue diseases (CTDs). SSc is a clinically heterogeneous and complex disease that is characterized by vascular dysfunction, vascular and extravascular fibrosis, and characteristic immune derangements, and for which few treatment options are available. The aims of the CTD International Scientific Advisory Board were threefold: to define the role of local mediators in CTDs, in particular to identify the nature of the initial insult in CTDs and to consider the role of genetic perturbations in CTDs; to translate what has been learned from clinical trials into clinical practice and to evaluate current treatment options for CTDs and their complications; and to address future directions for the management of CTDs and associated rare diseases, based on the biologic mechanisms elucidated. This supplemen

Response to comment on "Human-specific gain of function in a developmental enhancer"

Duret and Galtier argue that human-specific sequence divergence and gain of function in the HACNS1 enhancer result from deleterious biased gene conversion (BGC) with no contribution from positive selection. We reinforce our previous conclusion by analyzing hypothesized BGC events genomewide and assessing the effect of recombination rates on human-accelerated conserved noncoding sequence ascertainment. We also provide evidence that AT → GC substitution bias can coexist with positive selection

Sulfate-rich eolian and wet interdune deposits, Erebus crater, Meridiani Planum, Mars

This study investigates three bedrock exposures at Erebus crater, an ~ 300 m diameter crater approximately 4 km south of Endurance crater on Mars. These outcrops, called Olympia, Payson, and Yavapai, provide additional evidence in support of the dune–interdune model proposed for the formation of the deposits at the Opportunity landing site in Meridiani Planum. There is evidence for greater involvement of liquid water in the Olympia outcrop exposures than was observed in Eagle or Endurance craters. The Olympia outcrop likely formed in a wet interdune and sand sheet environment. The facies observed within the Payson outcrop, which is likely stratigraphically above the Olympia outcrop, indicate that it was deposited in a damp-wet interdune, sand sheet, and eolian dune environment. The Yavapai outcrop, which likely stratigraphically overlies the Payson outcrop, indicates that it was deposited in primarily a sand sheet environment and also potentially in an eolian dune environment. These three outcrop exposures may indicate an overall drying-upward trend spanning the stratigraphic section from its base at the Olympia outcrop to its top at the Yavapai outcrop. This contrasts with the wetting-upward trend seen in Endurance and Eagle craters. Thus, the series of outcrops seen at Meridiani by Opportunity may constitute a full climatic cycle, evolving from dry to wet to dry conditions

Depoliticisation, Resilience and the Herceptin Post-code Lottery Crisis: Holding Back the Tide

This article: Covers new empirical terrain in the study of depoliticisation, with an in-depth case study of health technology regulation; Analyses depoliticisation from a novel analytical perspective, examining how depoliticised institutions are resilient to external pressure for politicisation; Posits a distinctive framework for analysing resilience, drawing on cognate literatures on policy networks and agencification; Raises interesting and distinctive questions about the nature of depoliticisation in advanced liberal democracies, arguing it is more contested than commonly acknowledged. Depoliticisation as a concept offers distinctive insights into how governments attempt to relieve political pressures in liberal democracies. Analysis has examined the effects of depoliticisation tactics on the public, but not how those tactics are sustained during moments of political tension. Drawing on policy networks and agencification literatures, this article examines how these tactics are resilient against pressure for politicisation. Using an in-depth case study of the controversial appraisal of cancer drug Herceptin in 2005/6 by the National Institute for Health and Clinical Excellence (NICE), the article examines how ‘resilient’ NICE was to external politicisation. It is argued that NICE was resilient because it was effectively ‘insulated’ by formal procedures and informal norms of deference to scientific expertise. This mechanism is termed ‘institutional double glazing’. The conclusion suggests developments to the conceptual and methodological framework of depoliticisation, and highlights theoretical insights into the nature of ‘anti-politics’ in contemporary democracies

Origin and trends in NH4+ observed in the coma of 67P

The European Space Agency/Rosetta mission escorted comet 67P/Churyumov–Gerasimenko and witnessed the evolution of its coma from low activity (∼2.5–3.8 au) to rich ion-neutral chemistry (∼1.2–2.0 au). We present an analysis of the ion composition in the coma, focusing on the presence of protonated high proton affinity (HPA) species, in particular NH4+ ⁠. This ion is produced through the protonation of NH3 and is an indicator of the level of ion-neutral chemistry in the coma. We aim to assess the importance of this process compared with other NH4+ sources, such as the dissociation of ammonium salts embedded in dust grains. The analysis of NH4+ has been possible thanks to the high mass resolution of the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis/Double Focusing Mass Spectrometer (ROSINA/DFMS). In this work, we examine the NH4+ data set alongside data from the Rosetta Plasma Consortium instruments, and against outputs from our in-house ionospheric model. We show that increased comet outgassing around perihelion yields more detections of NH4+ and other protonated HPA species, which results from more complex ion-neutral chemistry occurring in the coma. We also reveal a link between the low magnetic field strength associated with the diamagnetic cavity and higher NH4+ counts. This suggests that transport inside and outside the diamagnetic cavity is very different, which is consistent with 3D hybrid simulations of the coma: non-radial plasma dynamics outside the diamagnetic cavity is an important factor affecting the ion composition

The Stratigraphy of Central and Western Butte and the Greenheugh Pediment Contact

The Greenheugh pediment at the base of Aeolis Mons (Mt. Sharp), which may truncate units in the Murray formation and is capped by a thin sandstone unit, appears to represent a major shift in climate history within Gale crater. The pediment appears to be an erosional remnant of potentially a much more extensive feature. Curiositys traverse through the southern extent of Glen Torridon (south of Vera Rubin ridge) has brought the rover in contact with several new stratigraphic units that lie beneath the pediment. These strata were visited at two outcrop-forming buttes (Central and Western butte- both remnants of the retreating pediment) south of an orbitally defined boundary marking the transition from the Fractured Clay-bearing Unit (fCU) and the fractured Intermediate Unit (fIU). Here we present preliminary interpretations of the stratigraphy within Central and Western buttes and propose the Western butte cap rocks do not match the pediment capping unit

HI in the Outskirts of Nearby Galaxies

The HI in disk galaxies frequently extends beyond the optical image, and can trace the dark matter there. I briefly highlight the history of high spatial resolution HI imaging, the contribution it made to the dark matter problem, and the current tension between several dynamical methods to break the disk-halo degeneracy. I then turn to the flaring problem, which could in principle probe the shape of the dark halo. Instead, however, a lot of attention is now devoted to understanding the role of gas accretion via galactic fountains. The current $\rm \Lambda$ cold dark matter theory has problems on galactic scales, such as the core-cusp problem, which can be addressed with HI observations of dwarf galaxies. For a similar range in rotation velocities, galaxies of type Sd have thin disks, while those of type Im are much thicker. After a few comments on modified Newtonian dynamics and on irregular galaxies, I close with statistics on the HI extent of galaxies.Comment: 38 pages, 17 figures, invited review, book chapter in "Outskirts of Galaxies", Eds. J. H. Knapen, J. C. Lee and A. Gil de Paz, Astrophysics and Space Science Library, Springer, in pres