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Biomedical subjects

F Simpson

Publications and source records attributed to F Simpson.

At least 19 recordsLinked to original sources
PubMed2003

Host choice promotes reproductive isolation between host races of the larch budmoth Zeiraphera diniana.

The chances for sympatric speciation are improved if ecological divergence leads to assortative mating as a by-product. This effect is known in parasites that find mates using host cues, but studies of larch- and pine-feeding races of the larch budmoth (Zeiraphera diniana, Lepidoptera: Tortricidae) suggest it may also occur when mate attraction is via sex pheromones that are independent of habitat. We have previously shown that females releasing pheromones on or near their own host attract more males of their own race than if placed on the alternative host. This host effect would enhance assortative mating provided adults preferentially alight on their native hosts. Here we investigate alighting preferences in natural mixed forest using a novel likelihood analysis of genotypic clusters based on three semidiagnostic allozyme loci. Both larch and pine females show a realized alighting preference for their own host of 86%. The equivalent preferences of males were 79% for the larch race and 85% for the pine race. These preferences are also detectable in small-scale laboratory experiments, where alighting preferences of larch and pine races towards their own hosts were, respectively, 67 and 66% in females and 69 and 63% in males. Pure larch race moths reared in the laboratory had alighting choice similar to moths from natural populations, while hybrids were intermediate, showing that alighting preferences were heritable and approximately additive. The field estimates of alighting preference, coupled with earlier work on mate choice, yield an estimated rate of natural hybridization between sympatric host races of 2.2-3.8% per generation. Divergent alighting choice enhances pheromone-mediated assortative mating today, and is likely to have been an important cause of assortative mating during initial divergence in host use. Because resources are normally 'coarse-grained' in space and time, assortative mating due to ecological divergence may be a more important catalyst of sympatric speciation than generally realized.

Animals↗
PubMed2001

Resistance to mantle flow inferred from the electromagnetic strike of the Australian upper mantle.

Seismic anisotropy is thought to result from the strain-induced lattice-preferred orientation of mantle minerals, especially olivine, owing to shear waves propagating faster along the a-axis of olivine crystals than along the other axes. This anisotropy results in birefringence, or 'shear-wave splitting', which has been investigated in numerous studies. Although olivine is also anisotropic with respect to electrical conductivity (with the a-axis being most conductive), few studies of the electrical anisotropy of the upper mantle have been undertaken, and these have been limited to relatively shallow depths in the lithospheric upper mantle. Theoretical models of mantle flow have been used to infer that, for progressive simple shear imparted by the motion of an overriding tectonic plate, the a-axes of olivine crystals should align themselves parallel to the direction of plate motion. Here, however, we show that a significant discrepancy exists between the electromagnetic strike of the mantle below Australia and the direction of present-day absolute plate motion. We infer from this discrepancy that the a-axes of olivine crystals are not aligned with the direction of the present-day plate motion of Australia, indicating resistance to deformation of the mantle by plate motion.

Journal Article↗
PubMed2001

GLUT4--at the cross roads between membrane trafficking and signal transduction.

GLUT4 is a mammalian facilitative glucose transporter that is highly expressed in adipose tissue and striated muscle. In response to insulin, GLUT4 moves from intracellular storage areas to the plasma membrane, thus increasing cellular glucose uptake. While the verification of this 'translocation hypothesis' (Cushman SW, Wardzala LJ. J Biol Chem 1980;255: 4758-4762 and Suzuki K, Kono T. Proc Natl Acad Sci 1980;77: 2542-2545) has increased our understanding of insulin-regulated glucose transport, a number of fundamental questions remain unanswered. Where is GLUT4 stored within the basal cell? How does GLUT4 move to the cell surface and what mechanism does insulin employ to accelerate this process? Ultimately we require a convergence of trafficking studies with research in signal transduction. However, despite more than 30 years of intensive research we have still not reached this point. The problem is complex, involving at least two separate signal transduction pathways which feed into what appears to be a very dynamic sorting process. Below we discuss some of these complexities and highlight new data that are bringing us closer to the resolution of these questions.

Adipocytes↗
PubMed1999

Casein kinase II activity is required for transferrin receptor endocytosis.

The effect of protein kinase inhibitors on transferrin receptor (TR) internalization was examined in HeLa, A431, 3T3-L1 cells, and primary chicken embryo fibroblasts. We show that TR endocytosis is not affected by tyrosine kinase or protein kinase C inhibitors, but is inhibited by one serine/threonine kinase inhibitor, H-89. Inhibition occurred within 15 min, was completely reversible after H-89 withdrawal, and was specific for endocytosis rather than pinocytosis since a TR mutant lacking an internalization signal was not affected. Interestingly, H-89 also inhibited the internalization of a TR chimera containing the major histocompatibility complex class II invariant chain cytoplasmic tail, indicating that the effect was not specific for the TR. Since H-89 inhibits a number of kinases, we employed a permeabilized cell endocytosis assay to further characterize the kinase. In permeabilized 3T3-L1 cells, addition of pseudosubstrate inhibitor peptides of casein kinase II (CKII) blocked TR internalization by more than 50%, whereas pseudosubstrates of cyclic AMP-dependent kinase A, protein kinase C, and casein kinase I had no effect. Furthermore, addition of purified CKII to the cell-free reactions containing CKII pseudosubstrates reversed the endocytosis block, suggesting that CKII or a CKII-like activity is required for constitutive endocytosis.

3T3 Cells↗
PubMed1999

SH3-domain-containing proteins function at distinct steps in clathrin-coated vesicle formation.

Several SH3-domain-containing proteins have been implicated in endocytosis by virtue of their interactions with dynamin; however, their functions remain undefined. Here we report the efficient reconstitution of ATP-, GTP-, cytosol- and dynamin-dependent formation of clathrin-coated vesicles in permeabilized 3T3-L1 cells. The SH3 domains of intersectin, endophilin I, syndapin I and amphiphysin II inhibit coated-vesicle formation in vitro through interactions with membrane-associated proteins. Most of the SH3 domains tested selectively inhibit late events involving membrane fission, but the SH3A domain of intersectin uniquely inhibits intermediate events leading to the formation of constricted coated pits. These results suggest that interactions between SH3 domains and their partners function sequentially in endocytic coated-vesicle formation.

3T3 Cells↗
PubMed1997

Characterization of the adaptor-related protein complex, AP-3.

We have recently shown that two proteins related to two of the adaptor subunits of clathrincoated vesicles, p47 (mu3) and beta-NAP (beta3B), are part of an adaptor-like complex not associated with clathrin (Simpson, F., N.A. Bright, M.A. West, L.S. Newman, R.B. Darnell, and M.S. Robinson, 1996. J. Cell Biol. 133:749-760). In the present study we have searched the EST database and have identified, cloned, and sequenced a ubiquitously expressed homologue of beta-NAP, beta3A, as well as homologues of the alpha/gamma and sigma adaptor subunits, delta and sigma3, which are also ubiquitously expressed. Antibodies raised against recombinant delta and sigma3 show that they are the other two subunits of the adaptor-like complex. We are calling this complex AP-3, a name that has also been used for the neuronalspecific phosphoprotein AP180, but we feel that it is a more appropriate designation for an adaptor-related heterotetramer. Immunofluorescence using anti-delta antibodies reveals that the AP-3 complex is associated with the Golgi region of the cell as well as with more peripheral structures. These peripheral structures show only limited colocalization with endosomal markers and may correspond to a postTGN biosynthetic compartment. The delta subunit is closely related to the protein product of the Drosophila garnet gene, which when mutated results in reduced pigmentation of the eyes and other tissues. Because pigment granules are believed to be similar to lysosomes, this suggests either that the AP-3 complex may be directly involved in trafficking to lysosomes or alternatively that it may be involved in another pathway, but that missorting in that pathway may indirectly lead to defects in pigment granules.

Adaptor Protein Complex 3↗
PubMed1996

A novel adaptor-related protein complex.

Coat proteins are required for the budding of the transport vesicles that mediate membrane traffic pathways, but for many pathways such proteins pathways, but for many pathways such proteins have not yet been identified. We have raised antibodies against p47, a homologue of the medium chains of the adaptor complexes of clathrin-coated vesicles (Pevsner, J., W. Volknandt, B.R. Wong, and R.H. Scheller. 1994. Gene (Amst.). 146:279-283), to determine whether this protein might be a component of a new type of coat. p47 coimmunoprecipitates with three other proteins: two unknown proteins of 160 and 25 kD, and beta-NAP, a homologue of the beta/beta'-adaptins, indicating that it is a subunit of an adaptor-like heterotetrameric complex. However, p47 is not enriched in preparations of clathrin-coated vesicles. Recruitment of the p47-containing complex onto cell membranes is stimulated by GTP gamma S and blocked by brefeldin A, indicating that, like other coat proteins, its membrane association is regulated by an ARF. The newly recruited complex is localized to non-clathrin-coated buds and vesicles associated with the TGN. Endogenous complex in primary cultures of neuronal cells is also localized to the TGN, and in addition, some complex is associated with the plasma membrane. These results indicate that the complex is a component of a novel type of coat that facilitates the budding of vesicles from the TGN, possibly for transporting newly synthesized proteins to the plasma membrane.

Adaptor Protein Complex 3↗
PubMed1995

Isolation of endothelial-like stromal cells that express Kit ligand and support in vitro hematopoiesis.

Although macrophages account for 70-90% of the adherent cells in mouse long-term bone marrow cultures (LTBMC) and CFU-F colonies, the predominant nonhematopoietic stromal cell is endothelial-like (EL), expressing cytoplasmic collagen IV, laminin, and an antigen recognized by the monoclonal antibody MECA-10. We report the isolation of this stromal cell lineage from primary LTBMC by immunomagnetic cell selection using MECA-10. More than 95% of the cells in the MECA-10-positive fraction are EL cells as judged by morphology, surface staining for MECA-10, cytoplasmic staining for collagen IV, and electrophoretic analysis of MECA-10-positive cells isolated from radiation chimeras. When plated under LTBMC conditions, EL cell monolayers recharged with either wild-type or Sl/Sld marrow support an increased density and number of clonogenic and mature hematopoietic cells in short-term cultures. In accord with this finding, Northern blots of mRNA from unstimulated EL cells demonstrate constitutive expression of Kit ligand (KL). Moreover, in situ two-color immunofluorescence staining for cytoplasmic collagen IV and surface KL suggests that EL cells are the exclusive source of membrane-bound KL in mouse cultures. The ability to isolate EL cells from primary cultures without the need for repeated cell passage or immortalization provides a novel approach to dissecting the molecular basis of stem cell-stromal cell interactions.

Animals↗
PubMed1979

Aldehyde dehydrogenase of the Mongolian gerbil, Meriones unguiculatus.

The aldehyde dehydrogenase (Aldehyde:NAD(P) oxidoreductase E.C. 1.2.1.3. and 1.2.1.5) phenotype in several tissues of the Mongolian gerbil, Meriones unguiculatus, has been established. The tissue distribution of gerbil aldehyde dehydrogenase is similar to that of the rat, with liver possessing the majority of the aldehyde dehydrognease activity. Male kidney and testis possess significantly more activity than female kidney and ovary. The substrate and co-enzyme specificity of gerbil liver aldehyde dehydrogenase is also similar to that of rat and mouse liver. Gel isoelectric focusing resolves one major gerbil liver aldehyde dehydrogenase isozyme at pI 5.3. Mouse liver is resolved into two major isozymes at pIs 5.3 and 5.6 and rat liver aldehyde dehydrogenase into one major isozyme at pI 5.4. Gerbil liver aldehyde dehydrogenase is functional over a broad pH range with an optima at pH 9.0. Rat and mouse liver aldehyde dehydrogenase possess sharp pH optima at pH 8.5.

Aldehyde Oxidoreductases↗
PubMed1978

Schedule induced self injections of nicotine with recovered body weight.

In a recent series of experiments we have shown that high rates of self injection of nicotine were acquired when rats are at 80% body weight on an FT-1 min food delivery schedule. This rate was significantly higher than that of rats at reduced or normal body weight without food delivery schedules or that of rats injecting saline under three parallel control conditions. In the present experiment naive rats were trained to acquire nicotine self injection at 80% body weight with an FT-1 min food delivery schedule. These rats maintained their self injection rates after they were allowed to regain free feeding body weight. The data indicate that once nicotine intake behavior is established it can be maintained with changing nutritional factors.

Animals↗