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      Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure

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          Abstract

          Mutations of the human CLCN5 gene, which encodes the CLC-5 Cl /H + exchanger, lead to Dent's disease. Mutations result in functional defects that range from moderate reductions to complete loss of whole cell currents, although the severity of the functional defect rarely correlates with the severity of the disease. To further elucidate the basis of CLC-5 mutations causing Dent's disease, we examined the functional and cell biological consequences of seven previously reported missense mutants, utilizing electrophysiological and cell biological techniques. This revealed three classes of Dent's disease-causing CLC-5 mutations. Class 1 mutations lead to endoplasmic reticulum retention and degradation of CLC-5. Class 2 mutations appear to have little effect on subcellular distribution of CLC-5 but cause defective function resulting in severe defects in endosomal acidification. Class 3 mutations lead to alterations in the endosomal distribution of CLC-5 but are otherwise able to support endosomal acidification. Molecular modeling demonstrates a structural basis that may underlie the nature of the defect resulting from each mutation with each class occupying discrete regions of the protein quaternary structure. Thus these results demonstrate that the cell biological consequences of CLC-5 mutations are heterogeneous and can be classified into three major groups and that a correlation between the nature of the defect and the location of the mutation in the structure may be drawn. This model may prove to be useful as a tool to aid in the diagnosis and future therapeutic intervention of the disease.

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          Most cited references 61

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          Rapid planetesimal formation in turbulent circumstellar discs

          The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.
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            The Dicke Quantum Phase Transition with a Superfluid Gas in an Optical Cavity

            A phase transition describes the sudden change of state in a physical system, such as the transition between a fluid and a solid. Quantum gases provide the opportunity to establish a direct link between experiment and generic models which capture the underlying physics. A fundamental concept to describe the collective matter-light interaction is the Dicke model which has been predicted to show an intriguing quantum phase transition. Here we realize the Dicke quantum phase transition in an open system formed by a Bose-Einstein condensate coupled to an optical cavity, and observe the emergence of a self-organized supersolid phase. The phase transition is driven by infinitely long-ranged interactions between the condensed atoms. These are induced by two-photon processes involving the cavity mode and a pump field. We show that the phase transition is described by the Dicke Hamiltonian, including counter-rotating coupling terms, and that the supersolid phase is associated with a spontaneously broken spatial symmetry. The boundary of the phase transition is mapped out in quantitative agreement with the Dicke model. The work opens the field of quantum gases with long-ranged interactions, and provides access to novel quantum phases.
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              Self-assembled organic monolayers: model systems for studying adsorption of proteins at surfaces

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                Author and article information

                Journal
                Am J Physiol Renal Physiol
                ajprenal
                American Journal of Physiology - Renal Physiology
                American Physiological Society
                0363-6127
                1522-1466
                February 2009
                19 November 2008
                1 February 2010
                : 296
                : 2
                : F390-F397
                Affiliations
                [1 ]Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds; and [2 ]Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, United Kingdom
                Author notes

                Address for reprint requests and other correspondence: J. D. Lippiat, Institute of Membrane & Systems Biology, Faculty of Biological Sciences, Univ. of Leeds, Leeds, LS2 9JT, UK (e-mail: j.d.lippiat@ 123456leeds.ac.uk )

                Article
                F-90526-2008
                10.1152/ajprenal.90526.2008
                2643861
                19019917
                Copyright © 2009, American Physiological Society

                This document may be redistributed and reused, subject to www.the-aps.org/publications/journals/funding_addendum_policy.htm.

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                Nephrology

                endosomal acidification, proteinuria, endocytosis, chloride channel

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