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PubMed1985

An enzymatic assay reveals that proteins destined for the apical or basolateral domains of an epithelial cell line share the same late Golgi compartments.

The expression of viral envelope proteins on the plasma membrane domains of the epithelial cell line, MDCK, is polar. Influenza virus infection of these cells leads to expression of the viral haemagglutinin and neuraminidase glycoproteins on the apical domain of the plasma membrane while vesicular stomatitis virus (VSV) infection yields basolateral expression of the sialic acid-bearing G protein. We have exploited the ability of the influenza neuraminidase to desialate the G protein of VSV to test for contact between these proteins during their intracellular transport to separate plasma membrane domains. We were able to select for VSV-G protein expression in doubly-infected cells because VSV protein production was accelerated in cells pre-infected with influenza virus. During double infection the envelope proteins of both viruses displayed the same polar localization as during single infection but the VSG-G protein was undersialated due to the action of the influenza neuraminidase. Incubation of singly-infected cells at 20 degrees C blocked the transport of VSV-G protein to the cell surface and resulted in increased sialation of the protein over that seen at 37 degrees C. This suggests that G protein is held in contact with the sialyl transferase at this temperature. 20 degrees C incubations of doubly-infected cells also produced the undersialated G protein characteristic of interaction with the neuraminidase. We conclude that most of the newly synthesised basolaterally-directed G protein is in physical contact with the majority of the neuraminidase through the terminal steps of Golgi processing.

Animals↗
PubMed1995

A novel periplasmic carrier protein involved in the sorting and transport of Escherichia coli lipoproteins destined for the outer membrane.

Lipoproteins are localized in the outer or inner membrane of Escherichia coli, depending on the species of amino acid located next to the N-terminal fatty acylated Cys. The major outer membrane lipoprotein (Lpp) expressed in spheroplasts was, however, retained in the inner membrane as a mature form. A novel protein that is essential for the release of Lpp from the inner membrane was discovered in the periplasm and purified. The partial amino acid sequence of this 20 kDa protein (p20) was determined and used to clone a gene for p20. Sequencing of the gene revealed that p20 is synthesized as a precursor with a signal sequence. p20 formed a soluble complex only with outer membrane-directed lipoproteins such as Lpp, indicating that p20 plays a critical role in the sorting of lipoproteins. Lpp released from the inner membrane in the presence of p20 was specifically assembled into the outer membrane in vitro. These results indicate that p20 is a periplasmic carrier protein involved in the translocation of lipoproteins from the inner to the outer membrane.

Amino Acid Sequence↗
PubMed2006

Plasma membrane destination of the classical Xenopus laevis progesterone receptor accelerates progesterone-induced oocyte maturation.

Xenopus laevis oocyte maturation is induced by the steroid hormone progesterone through a non-genomic mechanism initiated at the cell membrane. Recently, two Xenopus oocyte progesterone receptors have been cloned; one is the classical progesterone receptor (xPR-1) involved in genomic actions and the other a putative seven-transmembrane-G-protein-couple receptor. Both receptors are postulated to be mediating the steroid-induced maturation process in the frog oocyte. In this study, we tested the hypothesis that the classical progesterone receptor, associated to the oocyte plasma membrane, is participating in the reinitiation of the cell cycle. Addition of a myristoilation and palmytoilation signal at the amino terminus of xPR-1 (mp xPR-1), increased the amount of receptor associated to the oocyte plasma membrane and most importantly, significantly potentiated progesterone-induced oocyte maturation sensitivity. These findings suggest that the classical xPR-1, located at the plasma membrane, is mediating through a non-genomic mechanism, the reinitiation of the meiotic cell cycle in the X. laevis oocyte.

Animals↗
PubMed2005

The destination of the aged, nonreleasable neurohypophyseal peptides stored in the neural lobe is associated to the remodeling of the neurosecretory axon.

The present investigation was designed to investigate the fate of the large pool of neurohypophyseal hormones that is never released into the blood. Normal Sprague-Dawley and taiep mutant rats were investigated under normal water balance, after dehydration and after dehydration-rehydration. Lectin histochemistry and light- and electron-microscopic immunocytochemistry using antibodies against vasopressin, oxytocin, and neurophysins used at low (1:1,000) and high (1:15,000) dilutions allowed to distinguish (1) recently packed immature granules, as those located in the perikaryon; (2) mature; and (3) aged granules. The distribution of these granules within the different domains of the neurosecretory axons located in the neural lobe, namely, undilated segments, swellings, terminals, and Herring bodies, and the response of these compartments to dehydration and dehydration-rehydration allowed to roughly follow the routing of the granules through such axonal domains. It is suggested that granules may move backward and forward between the terminals and the swellings. At variance, aged granules located in Herring body are retained in this compartment and would finally become degraded. Herring bodies displayed distinct lectin binding and immunocytochemical properties, allowing to distinguish them from axonal swellings. After a dehydration-rehydration cycle, immunocytochemistry and electron microscopy revealed that Herring bodies were no longer present in the neural lobe and that several terminals had degenerated. It is concluded that (1) the neurophysin axons may undergo remodeling under appropriate stimuli and (2) Herring bodies are a specialized and plastic domain of the magnocellular neurosecretory neuron involved in the disposal of aged neurosecretory granules. No differences were detected at the neural lobe level between normal and mutant rats subjected to the same experimental conditions.

Aging↗
PubMedDate not supplied

Destination 'lysosome': a target organelle for tumour cell killing?

Lysosomes and lysosome-related organelles constitute a system of acid compartments that interconnect the inside of the cell with the extracellular environment via endocytosis, phagocytosis and exocytosis. In recent decades it has been recognized that lysosomes are not just wastebaskets for disposal of unused cellular constituents, but that they are involved in several cellular processes such as post-translational maturation of proteins, degradation of receptors and extracellular release of active enzymes. By complementing the autophagic process, lysosomes actively contribute to the maintenance of cellular homeostasis. Proteolysis by lysosomal cathepsins has been shown to mediate the death signal of cytotoxic drugs and cytokines, as well as the activation of pro-survival factors. Secreted lysosomal cathepsins have been shown to degrade protein components of the extracellular matrix, thus contributing actively to its re-modelling in physiological and pathological processes. The malfunction of lysosomes can, therefore, impact on cell behaviour and fate. Here we review the role of lysosomal hydrolases in several aspects of the malignant phenotype including loss of cell growth control, altered regulation of cell death, acquisition of chemoresistance and of metastatic potential. Based on these observations, the lysosome is proposed as a potential target organelle for the chemotherapy of tumours. We will also present some recent data concerning the technologies for delivering chemotherapeutic drugs to the endosomal-lysosomal compartment and the strategies to improve their efficacy.

Animals↗
PubMed1996

A comparison of the patterns of migration and the destinations of homotopically transplanted neonatal subventricular zone cells and heterotopically transplanted telencephalic ventricular zone cells.

The cells arising in the anterior part of the subventricular zone (SVZa) migrate along a well-demarcated pathway which lacks radial glial fibers to the olfactory bulb where they differentiate into interneurons of the granule cell layer or glomerular layer (Luskin, 1993, Neuron 11, 173). To analyze the mechanisms underlying this highly directed migration, we have compared the migratory behavior of unmanipulated SVZa-derived cells to that of homotopically transplanted SVZa cells and of heterotopically transplanted telencephalic ventricular zone (VZ) cells that ordinarily migrate in association with radial glial fibers. To identify the phenotype of the SVZa progenitor cells prior to their transplantation, we characterized them in vitro using cell type-specific markers. After 1 day in culture nearly all the SVZa cells were stained with TuJ1, a neuron-specific marker; only an occasional cell exhibited a glial phenotype as judged by the presence of GFAP-immunoreactivity. This indicates that SVZa cells express a neuronal phenotype. To reveal the spatiotemporal distribution of homotopically transplanted neonatal SVZa cells in a host brain, dissociated SVZa cells from Postnatal Day 0 (P0)-P2 animals were labeled with the lipophilic dye PKH26 or the cell proliferation marker BrdU and implanted into the SVZa of host animals of the same age. Within the first week after transplantation there were vast numbers of labeled cells throughout the pathway. Over the next 2 weeks the labeled cells migrated into the overlying cellular layer of the olfactory bulb and began to differentiate, and within 4 weeks the transplanted cells had reached their final positions in the granule cell and glomerular layers of the olfactory bulb in the same proportions as for unmanipulated SVZa-derived cells. While en route to the olfactory bulb the homotopically transplanted cells never strayed from the migratory pathway. In contrast, heterotopically transplanted VZ cells from the embryonic telencephalon did not undergo migration although they did differentiate. These results demonstrate that the homotopically transplanted SVZa-derived cells adopt a mode of migration indistinguishable from that ordinarily utilized by SVZa-derived neurons and that the VZ cells are unable to decipher the same set of guidance cues.

Animals↗
PubMed1997

Neuroglian is expressed on cells destined to form the prothoracic glands of Manduca embryos as they segregate from surrounding cells and rearrange during morphogenesis.

A cell surface protein (3B11) is differentially expressed in the embryonic labial segment of Manduca as two circular monolayers of epithelial cells invaginate and segregate from surrounding epithelial cells. The cells that invaginate and preferentially express 3B11 represent the presumptive prothoracic glands. These cells continue to express protein 3B11 as they rearrange to form first a three-dimensional aggregate and later anastomosing filaments of cells. In the differentiated prothoracic gland, expression of 3B11 is restricted to sites of cell-cell contact. Cloning and sequencing of the cDNA for protein 3B11 revealed that this protein is the Manduca counterpart of Drosophila neuroglian and mouse L1. These surface proteins are known to function as adhesion/recognition molecules during development. Manduca neuroglian shares 58 and 31% identity respectively with the Drosophila and mouse proteins and has a cytoplasmic domain of over 100 amino acids.

Amino Acid Sequence↗
PubMed1977

Origin, destination and mapping of tritocerebral neurons of locust.

The connectivities of the tritocerebrum of locust (Locusta migratoria L., Schistocerca gregaria (Forsk.)) were studied histologically and by means of cobalt chloride infusion. Its neuropil consists partly of fibers which traverse the tritocerebrum and areas consisting of neuropilar agglomerizations ("glomeruli"). The following direct connections between the tritocerebrum and other regions were observed: connections to 1) dorsal and lateral brain regions (mushroom body, optic lobe), 2) the ventral nerve cord, 3) the stomatogastric nervous system (here the protocerebrum and the subesophageal ganglion are also involved in these connections), 4) the retro-cerebral glands (corpora cardiaca, corpora allata), and 5) muscles of the foregut.

Animals↗
PubMed1990

Fate of highly expressed proteins destined to peroxisomes in Saccharomyces cerevisiae.

Import of proteins into organelles usually requires a cis-acting targeting signal. Analysis of various hybrid proteins, consisting of mouse DHFR and parts of catalase A from Saccharomyces cerevisiae, revealed that fusion proteins containing the N-terminal 126 amino acids, or less, of catalase A remain in the cytosol whereas fusion proteins containing 140, or more, N-terminal amino acids of catalase A form large aggregates inside the cell. These protein bodies, which lack a surrounding membrane, copurified with peroxisomes on cell fractionation. The peroxisomal targeting signal of catalase A does not reside at the C-terminus or at the N-terminus.

Amino Acid Sequence↗
PubMed1997

Altered distribution of collagen type I and hyaluronic acid in the cardiac outflow tract of mouse embryos destined to develop transposition of the great arteries.

Complete transposition of the great arteries (TGA) is inducible by treatment with all-trans retinoic acid in the ICR mouse. In this model, hypoplasia and dysplasia of the proximal outflow tract cushion tissue lead to non-spiral septation. In order to evaluate the effect of retinoic acid on the extracellular matrix of the cardiac outflow tract, we examined the distribution of collagen type I and hyaluronic acid, immunohistochemically, on days 8-9 of gestation. In controls, collagen type I fibrils ran mainly in a radial direction, extending towards the endocardium in the cardiac jelly of the proximal outflow tract. Also, a pair of longitudinal fiber bundles were formed stretching to the distal outflow tract. As for hyaluronic acid, intense staining was observed in the submyocardial and intermyocardial space of the outer curvature of the heart. On the other hand, in retinoic acid-treated embryos, the submyocardial radial fibrils or longitudinal fiber bundles of collagen type I were diminished, and irregular and dense deposits of collagen type I were observed along the endocardium. Furthermore, hyaluronic acid showed a loss of differential localization between the outer and inner curvature. Instead, irregular and intense staining was observed uniformly along the outflow myocardium. Thus, retinoic acid appeared to have perturbed the differentiation in the proximal outflow tract causing an altered organization of multiple extracellular matrix molecules, including collagen type I and hyaluronic acid, which led to an abnormal molecular network of the cardiac jelly in the cardiac outflow tract, abnormal septation and, further, to TGA or TGA-type anomalies.

Animals↗
PubMed2005

[Impact of rescue method and the destination clinic on mortality in polytrauma. A status report].

BACKGROUND: The aim of this study was to document the present knowledge from the medical literature on (1) efficacy of aeromedical evacuation (helicopter emergency medical service, HEMS) and (2) influence of the level of the first receiving hospital on mortality of patients. METHODS: Systematic review of the literature between 1970 and 2003; identification of studies with an evidence level of at least III and included control group; own results. RESULTS: (1) 17 studies concerning the efficacy of HEMS were included into the review. No single study yielded shorter rescue times with the use of HEMS. 11 of 17 studies showed a significantly higher survival rate (8.2 to 52%) with the employment of HEMS especially with mid-degree polytrauma. (2) All 6 relevant studies dealing with hospital level found a considerable lower mortality rate (19 to 42%) for patients treated primarily at a level 1 trauma center or comparable institution. CONCLUSIONS: The analyzed studies showed a trend toward decreased mortality rates with the employment of HEMS. Considering the comparable hospital level and even longer rescue times with HEMS, these differences can be explained with higher quality of initial diagnosis and treatment of the HEMS rescue team. Furthermore, mortality rates can be lowered significantly through primary treatment at a level 1 trauma center. Thus, the more flexible choice of the first receiving hospital represents a specific, clinically relevant advantage of HEMS in emergency medicine.

Air Ambulances↗
PubMed2000

Aggregate formation and degradation of overexpressed wild-type and mutant urate oxidase proteins. Quality control of organelle-destined proteins by the endoplasmic reticulum.

To analyze the cellular response caused by the overexpression of proteins in subcellular compartments, we constructed four expression clones encoding wild-type peroxisomal urate oxidase (UO), truncated UO lacking the peroxisomal targeting signal (UOdC), and chimeric UOs with a mitochondrial targeting signal (MTS) at the N-terminus of UOdC (MUOdC) or UO (MUO). After transfection, we examined COS-1 and HEK293 cells by immunofluorescence and immunoelectron microscopy, transmission electron microscopy, and pulse-chase experiments. The overexpressed UO and UOdC formed large electron-dense aggregates with no limiting membrane in both the cytoplasm and the nucleus. The UO aggregates exhibited the crystalloid structure quite similar to that of rat liver peroxisomal cores, whereas the UOdC aggregates formed a loose mass consisting of small dense substructures. The overexpressed MUOdC and MUO, on the other hand, formed other types of aggregates which were distributed in the cytoplasm. They consisted of tubular and circular membrane structures, which were morphologically confirmed to be derived from the endoplasmic reticulum (ER). No immunolabeling signals for MUOdC and MUO were present free in the cytoplasm and most of them were associated with membrane structures, suggesting that overexpressed UO containing the MTS attached to the ER membranes soon after synthesis and segregated from the cytosolic compartment. All the UO aggregates were stained for ubiquitin antigen. Pulse-chase experiments in combination with proteasome inhibitors suggested that proteasomes did not contribute to the degradation of these products.

Animals↗
PubMed2006

An implantable aortic valvo-pump for destination therapy.

To investigate the possibility of a long-term applicable left ventricular assist device, a 23 mm outer diameter and 31 g weight implantable aortic valvo-pump was developed. It consists of a rotor and a stator; the rotor has a driven magnets assemble and an impeller, the stator has a motor coil with iron core and a outflow guide vane. The device locates the position of aortic valve, delivers the blood directly from left ventricle to aorta. Neither connecting conduits nor "bypass" circuits are necessary. Therefore, the device has promisingly better antithrombogenicity than other heart pumps. In hemodynamic testing, the pump can produce a blood flow of 7 l/min volume with 50 mmHg pressure increase at 15,000 rpm rotating speed, and at zero flow rate the pump can maintain a diastolic pressure over 80 mmHg at same rotating speed. For further studies the blood compatibility and the durability of the device are of most importance.

Aorta↗
PubMed2004

Left Ventricular Assist Devices as Destination Therapy for End-stage Heart Failure.

In the therapy of advanced heart failure, left ventricular assist devices represent an exciting new option. The role of mechanical circulatory support is currently limited predominantly by factors related to device durability. The population for whom mechanical circulatory support can be considered as permanent therapy is defined by those for whom improvement in survival and clinical function is expected from current devices. Reported device survival in the range of 50% at 1 year limits the present candidate population to those with greater than 50% mortality at 1 year, who are not eligible for cardiac transplantation, after which survival is 50% at 10 years. Even as we learn to identify these patients who are "sick enough" to warrant device placement and yet "well enough" to survive surgery, the devices and surgical techniques are evolving so that the outcomes are improving and the candidate population is expanding.

Journal Article↗