Molecular Mechanistic Explanation for the Spectrum of Cholestatic Disease Caused by the S320F Variant of ABCB4

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.26970E.J.A. was funded by Barts and the London Charity award 458/1495. M.N. was funded by a Medical Research Council centenary award. M.R.R. was supported by funding from the Spanish Ministry of Science (Grant SAF2010-15517). The groups of K.J.L. and C.W. are supported by the Medical Research Council, UK (MC_U120088463) and Imperial College Healthcare NHS trust biomedical research centre, respectively

Charged Scalar-Tensor Boson Stars: Equilibrium, Stability and Evolution

We study charged boson stars in scalar-tensor (ST) gravitational theories. We analyse the weak field limit of the solutions and analytically show that there is a maximum charge to mass ratio for the bosons above which the weak field solutions are not stable. This charge limit can be greater than the GR limit for a wide class of ST theories. We numerically investigate strong field solutions in both the Brans Dicke and power law ST theories. We find that the charge limit decreases with increasing central boson density. We discuss the gravitational evolution of charged and uncharged boson stars in a cosmological setting and show how, at any point in its evolution, the physical properties of the star may be calculated by a rescaling of a solution whose asymptotic value of the scalar field is equal to its initial asymptotic value. We focus on evolution in which the particle number of the star is conserved and we find that the energy and central density of the star decreases as the cosmological time increases. We also analyse the appearance of the scalarization phenomenon recently discovered for neutron stars configurations and, finally, we give a short discussion on how making the correct choice of mass influences the argument over which conformal frame, the Einstein frame or the Jordan frame, is physical.Comment: RevTeX, 27 pages, 9 postscript figures. Minor revisions and updated references. Accepted for publication in Phys. Rev.

Shutting down or powering up a (U)LIRG? Merger components in distinctly different evolutionary states in IRAS 19115-2124 (the Bird)

We present new SINFONI near-infrared (NIR) integral field unit (IFU) spectroscopy and Southern African Large Telescope (SALT) optical long-slit spectroscopy characterizing the history of a nearby merging luminous infrared galaxy, dubbed the Bird (IRAS19115-2124). TheNIR line-ratio maps of the IFU data cubes and stellar population fitting of the SALT spectra now allow dating of the star formation (SF) over the triple system uncovered from our previous adaptive optics data. The distinct components separate clearly in line-ratio diagnostic diagrams, both thermal and non-thermal excitation is present. An off-nuclear starburst dominates the current SF of the Bird with 60-70 per cent of the total, with a 4-7 Myr age. The most massive nucleus, in contrast, is quenched with a starburst age of >40 Myr and shows hints of budding active galactic nucleus (AGN) activity. The secondary massive nucleus is at an intermediate stage. The two major components have signs of an older stellar population, consistent with a starburst triggered 1 Gyr ago in a first encounter. The simplest explanation of the history is that of a triple merger, where the strongly star-forming component has joined later. We detect multiple gas flows. The Bird offers an opportunity to witness multiple stages of galaxy evolution in the same system; triggering as well as very recent quenching of SF, and, perhaps, an early appearance of AGN activity. It also serves as a cautionary note on interpretations of observations with lower spatial resolution and/or without infrared data. At high redshift the system would look like a clumpy starburst with crucial pieces of its puzzle hidden in danger of misinterpretations

β1 Integrin-Mediated Adhesion Signalling Is Essential for Epidermal Progenitor Cell Expansion

Background: There is a major discrepancy between the in vitro and in vivo results regarding the role of b1 integrins in the maintenance of epidermal stem/progenitor cells. Studies of mice with skin-specific ablation of b1 integrins suggested that epidermis can form and be maintained in their absence, while in vitro data have shown a fundamental role for these adhesion receptors in stem/progenitor cell expansion and differentiation. Methodology/Principal Findings: To elucidate this discrepancy we generated hypomorphic mice expressing reduced b1 integrin levels on keratinocytes that developed similar, but less severe defects than mice with b1-deficient keratinocytes. Surprisingly we found that upon aging these abnormalities attenuated due to a rapid expansion of cells, which escaped or compensated for the down-regulation of b1 integrin expression. A similar phenomenon was observed in aged mice with a complete, skin-specific ablation of the b1 integrin gene, where cells that escaped Cre-mediated recombination repopulated the mutant skin in a very short time period. The expansion of b1 integrin expressing keratinocytes was even further accelerated in situations of increased keratinocyte proliferation such as wound healing. Conclusions/Significance: These data demonstrate that expression of b1 integrins is critically important for the expansion of epidermal progenitor cells to maintain epidermal homeostasis

Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury

Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients

Translational Medicine is developing in China: A new venue for collaboration

Translational Medicine is an emerging area comprising multidisciplinary Research from basic sciences to medical applications well summarized by the Bench-to-Beside concept; this entails close collaboration between clinicians and basic scientists across institutes. We further clarified that Translational Medicine should be regarded as a two-way road: Bench-to-Bedside and Bedside-to-Bench, to complement testing of novel therapeutic strategies in humans with feedback understanding of how they respond to them. It is, therefore, critical and important to define and promote Translational Medicine among clinicians, basic Researchers, biotechnologists, politicians, ethicists, sociologists, investors and coordinate these efforts among different Countries, fostering aspects germane only to this type of Research such as, as recently discussed, biotechnology entrepreneurship. Translational Medicine as an inter-disciplinary science is developing rapidly and widely and, in this article, we will place a special emphasis on China

Drosophila Genome-Wide RNAi Screen Identifies Multiple Regulators of HIF–Dependent Transcription in Hypoxia

Hypoxia-inducible factors (HIFs) are a family of evolutionary conserved alpha-beta heterodimeric transcription factors that induce a wide range of genes in response to low oxygen tension. Molecular mechanisms that mediate oxygen-dependent HIF regulation operate at the level of the alpha subunit, controlling protein stability, subcellular localization, and transcriptional coactivator recruitment. We have conducted an unbiased genome-wide RNA interference (RNAi) screen in Drosophila cells aimed to the identification of genes required for HIF activity. After 3 rounds of selection, 30 genes emerged as critical HIF regulators in hypoxia, most of which had not been previously associated with HIF biology. The list of genes includes components of chromatin remodeling complexes, transcription elongation factors, and translational regulators. One remarkable hit was the argonaute 1 (ago1) gene, a central element of the microRNA (miRNA) translational silencing machinery. Further studies confirmed the physiological role of the miRNA machinery in HIF–dependent transcription. This study reveals the occurrence of novel mechanisms of HIF regulation, which might contribute to developing novel strategies for therapeutic intervention of HIF–related pathologies, including heart attack, cancer, and stroke

Study of Inclusive J/psi Production in Two-Photon Collisions at LEP II with the DELPHI Detector

Inclusive J/psi production in photon-photon collisions has been observed at LEP II beam energies. A clear signal from the reaction gamma gamma -> J/psi+X is seen. The number of observed N(J/psi -> mu+mu-) events is 36 +/- 7 for an integrated luminosity of 617 pb^{-1}, yielding a cross-section of sigma(J/psi+X) = 45 +/- 9 (stat) +/- 17 (syst) pb. Based on a study of the event shapes of different types of gamma gamma processes in the PYTHIA program, we conclude that (74 +/- 22)% of the observed J/psi events are due to `resolved' photons, the dominant contribution of which is most probably due to the gluon content of the photon.Comment: 13 pages, 8 figures, Accepted by Phys. Lett.