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Biomedical subjects

Joan E B Fox

Publications and source records attributed to Joan E B Fox.

7 recordsLinked to original sources
PubMed2006

Integrative medicine: implementation and evaluation of a professional development program using experiential learning and conceptual change teaching approaches.

OBJECTIVE: To meet the increasing patient interest in complementary and alternative medicine (CAM), conventional physicians need to understand CAM, be willing to talk with their patients about CAM, and be open to recommending selected patients to appropriate CAM modalities. We aimed to raise physicians' awareness of, and initiate attitudinal changes towards CAM in the context of integrative medical practice. We developed and implemented a professional development program involving experiential learning and conceptual change teaching approaches. METHODS: A randomized controlled study with a pre-post design in a large academic medical center. The 8-hour intervention used experiential and conceptual change educational approaches. Forty-eight cardiologists were randomized to participant and control groups. A questionnaire measured physicians' conceptions of, and attitudes to CAM, the likelihood of changing practice patterns, and the factors most important in influencing such changes. The questionnaire included an embedded control question on a topic that was not the focus of this program. We administered the questionnaire before (pretest) and after (posttest) the intervention. We compared differences in pre- and post-intervention scores between the participant (N = 20) and control (N = 16) groups. We used both groups to identify factors that influenced their practice patterns. The study was NIH-funded and IRB-exempt. RESULTS: Both groups initially had little knowledge about, and negative attitudes to CAM. The participant group had significant positive changes in their conceptions about, and attitudes to CAM after the program, and significant improvements when compared with the control group. Participant physicians significantly increased in their willingness to integrate CAM in their practices. Physicians (combined groups) rated research evidence as the most important factor influencing their willingness to integrate CAM. They requested more research evidence for CAM efficacy, and more information on non-conventional pharmacology. Participants reflected enthusiasm for the experiential program. CONCLUSIONS: The participants were able to experience the positive effects of selected CAM modalities. It is possible to increase physician knowledge and change attitudes towards integrative medicine with an eight-hour intervention using experiential and conceptual change teaching approaches. PRACTICE IMPLICATIONS: Professional development on integrative medicine can be offered to medical practitioners using experiential learning and conceptual change teaching approaches, with the help of local CAM practitioners.

Attitude of Health Personnel↗
PubMed2005

SH3 domain of spectrin participates in the activation of Rac in specialized calpain-induced integrin signaling complexes.

In this study, we used cultured cells spreading on beta3 integrin substrates to examine the possibility that spectrin is involved in signal transduction. Spectrin clustered with specialized calpain-induced beta3 integrin signaling complexes that mediate the initial attachment of cells and initiate Rac activation and lamellipodia extension. It was absent from focal complexes and focal adhesions, the integrin complexes that mediate adhesion in lamellipodia and fully spread cells. Spectrin contains a Src homology (SH3) domain of unknown function. Cells overexpressing this domain adhered and calpain-induced integrin signaling complexes formed. However, Rac activation, lamellipodia extension and cell spreading were inhibited. Spreading was restored by overexpression of constitutively active Rac. These studies point to a previously unrecognized role for spectrin and its SH3 domain in initiating Rac activation in the specialized integrin clusters that initiate cell adhesion and spreading. Thus, spectrin may have a pivotal role in initiating integrin-induced physiological and pathological events such as development, proliferation, cell survival, wound healing, metastasis and atherosclerosis.

Animals↗
PubMed2004

Megakaryocyte proliferation and ploidy regulated by the cytoplasmic tail of glycoprotein Ibalpha.

We have investigated the ability of glycoprotein (GP) Ibalpha, a megakaryocytic gene product, to sequester the signal transduction protein 14-3-3xi and to influence megakaryocytopoiesis. Using a Gp1ba(-/-) mouse colony, we compared the rescued phenotypes produced by a wild-type human GP Ibalpha allele or a similar allele containing a 6-residue cytoplasmic tail truncation that abrogates binding to 14-3-3xi. The observed phenotypes illustrate an involvement for GP Ibalpha in thrombopoietin-mediated events of megakaryocyte proliferation, polyploidization, and the expression of apoptotic markers in maturing megakaryocytes. We developed a hypothesis for the involvement of a GP Ibalpha/14-3-3xi/PI-3 kinase complex in regulating thrombopoietin-mediated responses. An observed increase in thrombopoietin-mediated Akt phosphorylation in the truncated variant supported the hypothesis and led to the development of a model in which the GP Ibalpha cytoplasmic tail sequestered signaling proteins during megakaryocytopoiesis and, as such, became a critical regulator in the temporal sequence of events that led to normal megakaryocyte maturation.

14-3-3 Proteins↗
PubMed2003

14-3-3 zeta mediates integrin-induced activation of Cdc42 and Rac. Platelet glycoprotein Ib-IX regulates integrin-induced signaling by sequestering 14-3-3 zeta.

Integrin-induced cytoskeletal reorganizations are initiated by Cdc42 and Rac1 but little is known about mechanisms by which integrins activate these Rho GTPases. 14-3-3 proteins are adaptors implicated in binding and regulating the function and subcellular location of numerous signaling molecules. In platelets, the 14-3-3 zeta isoform interacts with the glycoprotein (GP) Ibalpha subunit of the adhesion receptor GP Ib-IX. In this study, we show that integrin-induced activation of Cdc42, activation of Rac, cytoskeletal reorganizations, and cell spreading were inhibited in Chinese hamster ovary cells expressing full-length GP Ibalpha compared with GP Ibalpha lacking the 14-3-3 zeta binding site. Activation of Rho GTPases and cytoskeletal reorganizations were restored by expression of 14-3-3 zeta. Spreading in cells expressing truncated GP Ibalpha was inhibited by co-expressing a chimeric receptor containing interleukin 2 receptor alpha and GP Ibalpha cytoplasmic domain. These results identify a previously unrecognized function of 14-3-3 zeta, that of mediating integrin-induced signaling. They show that 14-3-3 zeta mediates Cdc42 and Rac activation. They also reveal a novel function of platelet GP Ib-IX, that of regulating integrin-induced cytoskeletal reorganizations by sequestering 14-3-3 zeta. Signaling across integrins initiates changes in cell behavior such as spreading, migration, differentiation, apoptosis, or cell division. Thus, introduction of the 14-3-3 zeta binding domain of GP Ibalpha into target cells might provide a method for regulating integrin-induced pathways in a variety of pathological conditions.

14-3-3 Proteins↗
PubMed2002

Identification of Dp71 isoforms in the platelet membrane cytoskeleton. Potential role in thrombin-mediated platelet adhesion.

Utrophin is a component of the platelet membrane cytoskeleton and participates in cytoskeletal reorganization (Earnest, J. P., Santos, G. F., Zuerbig, S., and Fox, J. E. B. (1995) J. Biol. Chem. 270, 27259-27265). Although platelets do not contain dystrophin, the identification of smaller C-terminal isoforms of dystrophin, including Dp71, which are expressed in a wide range of nonmuscle tissues and cell lines, has not been investigated. In this report, we have identified Dp71 protein variants of 55-60 kDa (designated Dp71Delta(110)) in the membrane cytoskeleton of human platelets. Both Dp71Delta(110) and utrophin sediment from lysed platelets along with the high speed detergent-insoluble pellet, which contains components of the membrane cytoskeleton. Like the membrane cytoskeletal proteins vinculin and spectrin, Dp71Delta(110) and utrophin redistributed from the high speed detergent-insoluble pellet to the integrin-rich low speed pellet of thrombin-stimulated platelets. Immunoelectron microscopy provided further evidence that Dp71Delta(110) was localized to the submembranous cytoskeleton. In addition to Dp71Delta(110), platelets contained several components of the dystrophin-associated protein complex, including beta-dystroglycan and syntrophin. To better understand the potential function of Dp71Delta(110), collagen adhesion assays were performed on platelets isolated from wild-type or Dp71-deficient (mdx(3cv)) mice. Adhesion to collagen in response to thrombin was significantly decreased in platelets isolated from mdx(3cv) mice, compared with wild-type platelets. Collectively, our results provide evidence that Dp71Delta(110) is a component of the platelet membrane cytoskeleton, is involved in cytoskeletal reorganization and/or signaling, and plays a role in thrombin-mediated platelet adhesion.

Animals↗
PubMed2002

Calpain cleaves RhoA generating a dominant-negative form that inhibits integrin-induced actin filament assembly and cell spreading.

Integrin-induced cell adhesion results in transmission of signals that induce cytoskeletal reorganizations and resulting changes in cell behavior. The cytoskeletal reorganizations are regulated by transient activation and inactivation of Rho GTPases. Previously, we identified mu-calpain as an enzyme that is activated by signaling across beta1 and beta3 integrins. We showed that it mediates cytoskeletal reorganizations in bovine aortic endothelial (BAE) and Chinese hamster ovary (CHO) cells and does so by acting upstream of Rac1 activation. Here we show that mu-calpain is also involved in inactivating RhoA during integrin-induced signaling. Cleavage of RhoA was detectable in BAE cells plated on an integrin substrate; it did not occur in cells plated on poly-l-lysine. Cleavage was inhibited by calpain inhibitors. In vitro, mu-calpain cleaved RhoA generating a fragment of the same size as in intact cells. The cleavage site was identified, an HA-tagged construct expressing calpain-cleaved RhoA generated, and the construct expressed in BAE and CHO cells. Calpain-cleaved RhoA inhibited integrin-induced stress fiber assembly and decreased cell spreading. Together, our data show that calpain cleaves RhoA and generates a form that inhibits integrin-induced stress fiber assembly and cell spreading.

Actins↗