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S Scott

Publications and source records attributed to S Scott.

At least 217 records · Page 12Linked to original sources
PubMed1988

Lovastatin, an inhibitor of cholesterol synthesis, induces hydroxymethylglutaryl-coenzyme A reductase directly on membranes of expanded smooth endoplasmic reticulum in rat hepatocytes.

Lovastatin is a potent competitive inhibitor of the rate-limiting enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (NADPH) [HMG-CoA reductase; (S)-mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]. We determined the subcellular distribution of HMG-CoA reductase at high resolution by means of immunoelectron microscopy on ultrathin frozen liver sections of rats treated with lovastatin and cholestyramine. High concentrations of reductase were located on the outer (cytoplasmic) surfaces of smooth endoplasmic reticulum (SER) membranes induced in hepatocytes by acute drug administration. The enzyme was specifically localized over the whorled SER membranes and was absent from nonwhorled SER, rough endoplasmic reticulum, and peroxisomes. Intense HMG-CoA reductase labeling was only observed in hepatocytes containing high levels of HMG-CoA reductase activity; no staining was detected in untreated livers. These observations show that HMG-CoA reductase is induced as an integral component of the SER membranes that form in rat hepatocytes subsequent to lovastatin treatment and suggest that the formation of SER whorls in rat hepatocytes is due to mechanism-based effects of lovastatin.

Animals↗
PubMed1988

Cell surface distribution of fibronectin and vitronectin receptors depends on substrate composition and extracellular matrix accumulation.

We used antibodies against the alpha subunits of the human fibronectin receptor (FNR) and vitronectin receptor (VNR) to localize simultaneously FNR and VNR at major substrate adhesion sites of fibroblasts and melanoma cells with double-label immunofluorescence microscopy. In early (2-6-h) serum-containing cultures, both FNR and VNR coaccumulated in focal contacts detected by interference reflection microscopy. Under higher resolution immunoscanning electron microscopy, FNR and VNR were also observed to be distributed randomly on the dorsal cell surface. As fibronectin-containing extracellular matrix fibers accumulated beneath the cells at 24 h, FNR became concentrated at contacts with these fibers and was no longer detected at focal contacts. VNR was not observed at matrix contacts but remained strikingly localized in focal contacts of the 24-h cells. Since focal contacts represent the sites of strongest cell-to-substrate adhesion, these results suggest that FNR and VNR together play critical roles in the maintenance of stable contacts between the cell and its substrate. In addition, the accumulation of FNR at extracellular matrix contacts implies that this receptor might also function in the process of cellular migration along fibronectin-containing matrix cables. To define the factors governing accumulation of FNR and VNR at focal contacts, fibroblasts in serum-free media were plated on substrates coated with purified ligands. Fibronectin-coated surfaces fostered accumulation of FNR but not VNR at focal contacts. On vitronectin-coated surfaces, or substrata derivatized with a tridecapeptide containing the cell attachment sequence Arg-Gly-Asp, both FNR and VNR became concentrated at focal contacts. These observations suggest that the availability of ligand is critical to the accumulation of FNR and VNR at focal contacts, and that FNR might also recognize substrate-bound vitronectin.

Cell Adhesion↗
PubMed1987

Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse.

Genetic analysis of the development of diabetes and insulitis has been performed in the nonobese diabetic (NOD) mouse strain, a model of insulin-dependent (type I) diabetes mellitus. (NOD X C57BL/10)F1, F2, and (F1 X NOD) first-, second-, and third-backcross generations were studied. The data obtained were consistent with the hypothesis that diabetes is controlled by at least three functionally recessive diabetogenic genes, or gene complexes, one of which is linked to the MHC of the NOD. In contrast, pancreatic inflammation leading to insulitis was found to be controlled by a single incompletely dominant gene. One of the two diabetogenic loci that is not linked to the MHC appears to be essential for the development of severe insulitis. This diabetogenic gene may be identical to the gene that controls the initiation of the autoimmune response that progresses to insulitis. Although this gene appears to be functionally recessive in its control of diabetes, it is incompletely dominant in its control of insulitis. The MHC-linked diabetogenic gene, although not required for the development of insulitis, apparently influences the progression of the autoimmune response since NOD MHC homozygotes in the backcross generations displayed the highest incidence and most severe cases of insulitis. Interestingly, we have found two MHC heterozygous backcross females that have become diabetic, suggesting that either the MHC-linked diabetogenic gene is not strictly recessive or that a recombination event has occurred between the diabetogenic gene and the K or I-A regions of the MHC. The third diabetogenic locus appears to influence the progression of severe insulitis to overt diabetes. In animals homozygous at this locus, diabetes may result from a decreased ability to develop a protective suppressor response to the autoimmune process.

Animals↗
PubMed1987

Extracellular matrix fibers containing fibronectin and basement membrane heparan sulfate proteoglycan coalign with focal contacts and microfilament bundles in stationary fibroblasts.

Double-label immunofluorescence microscopy and immunoelectron microscopy were performed on stationary cultures of Nil 8 fibroblasts to determine if fibronectin and basement membrane heparan sulfate proteoglycans play coordinated roles in cell-to-substrate adhesion. Relationships between subcellular matrix fibers containing fibronectin plus proteoglycan, and focal contacts associated with microfilament bundles, were studied simultaneously using interference reflection microscopy, differential interference contrast microscopy, and immunofluorescence microscopy. Cells maintained in 0.3% FBS were doubly stained with monospecific anti-fibronectin IgG and antibodies against a basement membrane proteoglycan purified from the EHS (Engelbreth-Holm-Swarm) tumor. Coincident patterns of fibronectin and proteoglycan-containing fibers were found to codistribute with focal contacts and microfilament bundles in both early (6-h) and late (24-h) cultures. The early cells showed doubly-stained fibers colinear with substrate adhesion sites in 43% of the sample, while 100% of the later cells exhibited these coaligned matrix-cytoskeletal attachment complexes. Immunoelectron microscopy showed that both of these antigens were situated in the same type of extracellular matrix fiber that appeared to be loosely associated with the cell surface membrane. We hypothesize that the appearance of proteoglycan in subcellular matrix fibers of these fibroblasts might stabilize fibronectin-containing cell-to-substrate contacts.

Actin Cytoskeleton↗
PubMed1987

The fibronectin cell attachment sequence Arg-Gly-Asp-Ser promotes focal contact formation during early fibroblast attachment and spreading.

Cultured fibroblasts form focal contacts (FCs) associated with actin microfilament bundles (MFBs) during attachment and spreading on serum- or fibronectin (FN)-coated substrates. To determine if the minimum cellular adhesion receptor recognition signal Arg-Gly-Asp-Ser (RGDS) is sufficient to promote FC and MFB formation, rat (NRK), hamster (Nil 8), and mouse (Balb/c 3T3) fibroblasts in serum-free media were plated on substrates derivatized with small synthetic peptides containing RGDS. These cultures were studied with interference reflection microscopy to detect FCs, Normarski optics to identify MFBs, and immunofluorescence microscopy to observe endogenous FN fiber formation. By 1 h, 72-78% of the NRK and Nil 8 cells plated on RGDS-containing peptide had focal contacts without accompanying FN fibers, while these fibroblasts lacked FCs on control peptide. This early FC formation was followed by the appearance of coincident MFBs and colinear FN fibers forming fibronexuses at 4 h. NRK and Nil 8 cultures on substrates coated with native FN or 75,000-D FN-cell binding fragment showed similar kinetics of FC and MFB formation. In contrast, the Balb/c 3T3 mouse fibroblasts plated on Gly-Arg-Gly-Asp-Ser peptide-derivatized substrates, or on coverslips coated with 75,000-D FN cell-binding fragment, were defective in FC formation. These results demonstrate that the apparent binding of substrate-linked RGDS sequences to cell surface adhesion receptors is sufficient to promote early focal contact formation followed by the appearance of fibronexuses in some, but not all, fibroblast lines.

Amino Acid Sequence↗
PubMed1987

Lead on MacDuff.

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Health Facility Administrators↗
PubMed1987

Potential role of Epstein-Barr virus in Sjögren's syndrome.

Sjögren's syndrome is an autoimmune disease characterized by lymphocytic infiltration and destruction of salivary and lacrimal glands. This condition may occur as a primary condition or may be associated with other autoimmune disorders such as rheumatoid arthritis or systemic lupus. Because the environmental factors that initiate SS are unknown, we have investigated the potential role of EBV, CMV, and other viruses. We observed that epithelial cells in salivary gland biopsies of patients with SS contained antigens reactive with monoclonal antibodies against EBV-associated antigens. These antigens were not found in other tissues of patients with SS and were not detectable in salivary gland biopsies from normal persons and patients with other autoimmune diseases lacking SS. The molecular weight of the antigens present in the SS salivary gland extracts was similar to that expressed in cells containing reactivated EBV. Also, the content of EBV DNA in the saliva of patients with SS was significantly greater than in age-, sex-matched controls or persons with other autoimmune disorders. These studies provide one of the first examples where a specific viral agent may be implicated in perpetuating a chronic autoimmune disease. These results also may provide insight into other autoimmune diseases where the target organ is less accessible to biopsy.

Antigens, Viral↗
PubMed1986

Epidermal growth factor receptor ontogeny in mice with congenital hypothyroidism.

To assess the effect of endogenous thyroid hormone on hepatic EGF receptors in developing mice we measured EGF binding to plasma membrane receptors in liver and brain of mice with congenital hypothyroidism and in euthyroid controls at 20, 30 and 40 days of age. At 20 days hepatic EGF receptor binding was low in both hypothyroid and control animals. Between 20 and 30 days the hepatic binding increased dramatically in the euthyroid animals, an increase that was greater in males than females. The increase in binding was due to an increase in the high affinity receptor population. Among hypothyroid animals there were no changes in hepatic EGF receptor binding with increasing age. In cerebral cortex EGF binding was similar in euthyroid and hypothyroid animals at all ages. These results suggest that thyroxine has regulatory effects on the postnatal ontogeny of hepatic EGF receptors.

Age Factors↗
PubMed1984

Lipid organization in erythrocyte membrane microvesicles.

The aminophospholipids of microvesicles released from human erythrocytes on storage or prepared from erythrocyte ghosts by shearing under pressure are susceptible to the action of 2,4,6-trinitrobenzenesulphonic acid. The aminophospholipids of the former vesicles are also susceptible to attack by phospholipase A2. Under the same conditions, the aminophospholipids of erythrocytes undergo little reaction. This suggests that the phospholipids in microvesicle membranes are more randomly distributed than those in erythrocyte membranes. Measurements have also been made of the ability of filipin to react with the cholesterol of sealed and unsealed erythrocyte ghosts and of microvesicles prepared from them. From the initial rates of reaction, it was concluded that there is no preferential transfer of cholesterol molecules from one side of the bilayer to the other during the formation of the microvesicles.

Cholesterol↗