28,581 research outputs found
Impaired neural development in a zebrafish model for lowe syndrome
Full text linkLowe syndrome, which is characterized by defects in the central nervous system, eyes and kidneys, is caused by mutation of the phosphoinositide 5-phosphatase OCRL1. The mechanisms by which loss of OCRL1 leads to the phenotypic manifestations of Lowe syndrome are currently unclear, in part, owing to the lack of an animal model that recapitulates the disease phenotype. Here, we describe a zebrafish model for Lowe syndrome using stable and transient suppression of OCRL1 expression. Deficiency of OCRL1, which is enriched in the brain, leads to neurological defects similar to those reported in Lowe syndrome patients, namely increased susceptibility to heat-induced seizures and cystic brain lesions. In OCRL1-deficient embryos, Akt signalling is reduced and there is both increased apoptosis and reduced proliferation, most strikingly in the neural tissue. Rescue experiments indicate that catalytic activity and binding to the vesicle coat protein clathrin are essential for OCRL1 function in these processes. Our results indicate a novel role for OCRL1 in neural development, and support a model whereby dysregulation of phosphoinositide metabolism and clathrin-mediated membrane traffic leads to the neurological symptoms of Lowe syndrome. © The Author 2011. Published by Oxford University Press. All rights reserved
Structure and function of the Lowe syndrome protein OCRL1
No full textOculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder with the hallmark features of congenital cataracts, mental retardation and Fanconi syndrome of the kidney proximal tubules. OCRL was first described in 1952, and exactly four decades later, the gene responsible was identified and found to encode a protein highly homologous to inositol polyphosphate 5-phosphatase. This suggested that Lowe syndrome may represent an inborn error of inositol phosphate metabolism, and subsequent studies confirmed that such metabolism is indeed perturbed in Lowe syndrome cells. However, the mechanism by which loss of function of the OCRL1 protein brings about Lowe syndrome remains ill defined. In this review, I will discuss our understanding of OCRL1, including where it is localized, what it interacts with and what its possible functions might be. I will then discuss possible mechanisms by which loss of OCRL1 may bring about cellular defects that manifest themselves in the pathology of Lowe syndrome. Copyright © Blackwell Munksgaard 2005
Modelling Lowe syndrome and Dent-2 disease using zebrafish
No full textLowe syndrome and Dent-2 disease are caused by mutations in the gene encoding OCRL, an inositol 5-phosphatase. The phenotype manifests in the eyes, brain and kidney, with the extra-renal features milder in the case of Dent-2 disease. Zebrafish has been used to study OCRL function in vivo and to successfully model these two rare genetic conditions. OCRL-deficient zebrafish have neurodevelopmental defects, which may lie downstream of disrupted endosomal trafficking or primary cilia function. OCRL-deficient zebrafish also have a renal tubular phenotype, with defective endocytosis, abnormal lysosomal function, and shortening of the renal tubule. These defects can account for the low molecular weight proteinuria seen in Lowe syndrome and Dent-2 disease and may explain the other renal features seen in both conditions. Chemical and genetic rescue experiments indicate that zebrafish can be used to test potential therapeutic approaches for Lowe syndrome and Dent-2 disease, raising the possibility of a phenotypic screen for these conditions in zebrafish. Alongside other models, zebrafish has proven its worth in studying Lowe syndrome and Dent-2 disease and should continue to serve as a valuable model going forwards.</p
Jogos Olímpicos de Paris (1924) - Douglas Lowe e Paul Martin
No full textOs Jogos Olímpicos de Paris foram realizados no período de 04 de maio à 27 de julho de 1924. A foto integra o acervo doado pela família de Frederico Guilherme Gaelzer que esteve no evento.Douglas Lowe e Paul Martin. Medalhistas de ouro e prata, respectivamente, na prova de 800 metros dos Jogos Olímpicos de Paris (1924).DoaçãoOlímpic
Study of the cell biological role of Lowe Syndrome protein OCRL1
No full textOculocerebrorenal syndrome of Lowe (OCRL) is caused by mutations in a
phosphatidylinositol 5-phosphatase, OCRL1, and is believed to lead to an
elevation of its preferred substrate, PI(4,5)P2. To date, much of the work on
OCRL1 has centred on its role at Golgi and endosomal membranes.
However, there is also evidence of plasma membrane activity for OCRL1,
where its PI(4,5)P2 substrate is known to be highly abundant. PI(4,5)P2
regulates a wide array of downstream cellular functions such as cytoskeletal
dynamics, membrane trafficking and signalling. The tight regulation of
PI(4,5)P2 levels and localisation, like other phosphoinositides, provides a
framework upon which many of these cellular processes work. In this thesis,
effects of OCRL1 loss have been tested through siRNA depletion of OCRL1,
focussing where possible on multiple PI(4,5)P2-dependent mechanisms, and
also focussing on cells forming polarised epithelia. Firstly, we have visualised
the localisation of PI(4,5)P2 in living HeLa cells lacking OCRL1 through
immunostaining for Annexin A2, which showed a marked translocation to the
plasma membrane. This change in distribution of Annexin A2 suggested that
OCRL1 depletion may have an effect on intracellular calcium dynamics as
well as PI(4,5)P2 localisation. We also used a GFP-chimera of the well
characterised PI(4,5)P2-binding pleckstrin homology domain of PLCδ1. This
showed no difference in localisation upon OCRL1 depletion. As OCRL1 is
highly enriched at the TGN, we fused the pleckstrin homology domain of
PLCδ1 to a mutated pleckstrin homology domain of OSBP known to bind ARF1 at the TGN, to act as a coincidence detector for PI(4,5)P2 at the TGN.
This construct also showed no reproducible effect of OCRL1 depletion.
Secondly we tested the effect of loss of OCRL1 on cytosolic calcium levels.
Using two phospholipase C (PLC) agonists, and a SERCA pump inhibitor, we
found no consistent differences in calcium handling upon depletion of OCRL1.
Thirdly, we have assessed the potential specialised role that OCRL1 has in
polarised epithelial cells, which might relate to the clinical picture in Lowe
Syndrome. We found that OCRL1 targets the tight junctions of immortalised
lines and primary cells. Through co-immunoprecipitation, we found OCRL1 in
complexes with the tight junction scaffold protein ZO-1. Most significantly, we
found that depletion of OCRL1 in human polarised epithelial cell lines
interfered with epithelial differentiation, reducing cell number and altering
morphology, to produce large flat cells. We attribute this phenotype, stronger
than any other so far described experimentally, to a defect in tight junction
maturation
The Cellular and Physiological Functions of the Lowe Syndrome Protein OCRL1.
No full textPhosphoinositide lipids play a key role in cellular physiology, participating in a wide array of cellular processes. Consequently, mutation of phosphoinositide-metabolizing enzymes is responsible for a growing number of diseases in humans. Two related disorders, oculocerebrorenal syndrome of Lowe (OCRL) and Dent-2 disease, are caused by mutation of the inositol 5-phosphatase OCRL1. Here, we review recent advances in our understanding of OCRL1 function. OCRL1 appears to regulate many processes within the cell, most of which depend upon coordination of membrane dynamics with remodeling of the actin cytoskeleton. Recently developed animal models have managed to recapitulate features of Lowe syndrome and Dent-2 disease, and revealed new insights into the underlying mechanisms of these disorders. The continued use of both cell-based approaches and animal models will be key to fully unraveling OCRL1 function, how its loss leads to disease and, importantly, the development of therapeutics to treat patients
Jack Alive / Martin Dead : The Location of the "Author" in Jack London\u27s Martin Eden
No full textThis essay is an attempt to read Martin Eden, Jack Londonʼs autobiographical novel, in terms of the inextricable relationship between the author and the protagonist. Critics have often taken the unbalanced plot and the lack of ironic distance between narrator and character in Martin Eden as the technical weakness of London, but this paper argues that the achievement of this novel owes a great deal to the attachment of London to Martin. The unbalanced structure is a necessary product of the severe struggle of the author to kill his romantic alter ego. // Martin, who aspires to win Ruth Morse, tries to cross class boundaries by making a career of a writer. Even after realizing the emptiness of Ruth, who turns out to be nothing but a typical figure of the bourgeoisie, he somehow persists in loving her. The notion underlying here is that, for Martin, love, career and art are fundamentally inseparable. He objects to the aestheteʼs view of Brissenden on account of his separation of art from career. Martinʼs identity and life consist only in the triunity of love/career/art; the alternative is the repudiation of life. Thus, the unnatural delay of his disappointment in love can be regarded as Londonʼs strategy to set the suicide of Martin as the necessary consequence of the story. // By finishing the story and killing Martin, London finally detaches himself from Martin, reconstructs his self, and, unlike Martin, survives as a professional writer. In this sense, Martin Eden is a story about “writerʼs self-reconstruction.
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Letter from Martin Chizzick
No full textCongratulations to Duane Pearsall for receiving the Enterpreneur of the Year award; note on the letter was written by Pearsall and it mentions that Martin, the author of the letter, died in a airplane accident
Robert Martin Tiffin's Mystery Man Newspaper Articles
No full textAdvertiser-Tribune newspaper clippings featuring a story about Robert Martin (written by Nancy Kleinhenz), a local author from Tiffin (Ohio) who wrote under the pseudonym of Lee Roberts, and two of his short stories. Martin wrote mystery novels in his spare time, creating more than 22 mystery novels. For more information about Robert Martin and a list of books go to http://www.mysteryfile.com/RMartin/JBennett.html
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