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31.
CD3 Ligation on Immature Thymocytes Generates Antagonist-like Signals Appropriate for CD8 Lineage Commitment, Independently of T Cell Receptor Specificity
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M. Albert Basson Ursula Bommhardt Michael S. Cole J. Yun Tso Rose Zamoyska 《The Journal of experimental medicine》1998,187(8):1249-1260
The signals that direct differentiation of T cells to the CD4 or CD8 lineages in the thymus remain poorly understood. Although it has been relatively easy to direct differentiation of CD4 single positive (CD4+) cells using combinations of antibodies and pharmacological agents that mimic receptor engagements, equivalent stimuli do not induce efficient maturation of CD8+ cells. Here we report that, irrespective of the MHC-restriction specificity of the TCR, differentiation of mature CD8+ thymocytes can be induced by ligation of CD3 polypeptides on immature thymocytes with a F(ab′)2 reagent (CD3fos-F(ab′)2). The tyrosine phosphorylation patterns stimulated by CD3fos-F(ab′)2 have been shown to resemble those delivered to mature T cells by antagonist peptides, which are known to direct positive selection of CD8+ cells, and we can show that this reagent exhibits potent antagonistic-like activity for primary T cell responses. Our results suggest a distinction in the signals that specify lineage commitment in the thymus. We present a model of thymocyte differentiation that proposes that the relative balance of signals delivered by TCR engagement and by p56lck activation is responsible for directing commitment to the CD8 or CD4 lineages. 相似文献
32.
Gordon E Panaghie G Deng L Bee KJ Roepke TK Krogh-Madsen T Christini DJ Ostrer H Basson CT Chung W Abbott GW 《Cardiovascular research》2008,77(1):98-106
AIMS: Auditory stimulus-induced long QT syndrome (LQTS) is almost exclusively linked to mutations in the hERG potassium channel, which generates the I Kr ventricular repolarization current. Here, a young woman with prior episodes of auditory stimulus-induced syncope presented with LQTS and ventricular fibrillation (VF) with hypomagnesaemia and hypocalcaemia after completing a marathon, followed by subsequent VF with hypokalaemia. The patient was found to harbour a KCNE2 gene mutation encoding a T10M amino acid substitution in MiRP1, an ancillary subunit that co-assembles with and functionally modulates hERG. Other family members with the mutation were asymptomatic, and the proband had no mutations in hERG or other LQTS-linked cardiac ion channel genes. The T10M mutation was absent from 578 unrelated, ethnically matched control chromosomes analysed here and was previously described only once-in an LQTS patient-but not functionally characterized. METHODS AND RESULTS: T10M-MiRP1-hERG currents were assessed using whole-cell voltage clamp of transfected Chinese Hamster ovary cells. T10M-MiRP1-hERG channels showed 相似文献
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Sean Bhalla Hiroe Shiratsuchi David H. Craig Marc D. Basson 《American journal of surgery》2009,198(5):611-616
Background
Extracellular pressure alterations in infection, inflammation, or positive pressure ventilation may influence macrophage phagocytosis. We hypothesized that pressure modulates β1-integrins to stimulate phagocytosis.Methods
We assayed fibroblast phagocytosis of fluorescent latex beads at ambient or 20 mm Hg increased pressure, and macrophage integrin phosphorylation by Western blot.Results
Pressure did not alter phagocytosis in β1-integrin null GD25 fibroblasts, but stimulated phagocytosis in fibroblasts expressing wild-type β1-integrin. In phorbol myristate acetate-differentiated THP-1 macrophages, pressure stimulated β1-integrin T788/789 phosphorylation, but not S785 phosphorylation. Furthermore, pressure stimulated phagocytosis in cells expressing an inactivating S785A point mutation or a T788D substitution to mimic a constitutively phosphorylated threonine, but not in cells expressing an inactivating TT788/9AA mutation.Conclusions
The effects of pressure on phagocytosis are not limited to macrophages but generalize to other phagocytic cells. These results suggest that pressure stimulates phagocytosis via increasing β1-integrin T789 phosphorylation. Interventions that target β1-integrin threonine 789 phosphorylation may modulate phagocytic function. 相似文献35.
Yuichiro Yaguchi Tian Yu Mohi U. Ahmed Mary Berry Ivor Mason M. Albert Basson 《Developmental dynamics》2009,238(8):2058-2072
The cerebellum is derived from the anterior‐most segment of the embryonic hindbrain, rhombomere 1 (r1). Previous studies have shown that the early development and patterning of r1 requires fibroblast growth factor (FGF) signaling. However, many of the developmental processes that shape cerebellar morphogenesis take place later in embryonic development and during the first 2 weeks of postnatal life in the mouse. Here, we present a more comprehensive analysis of the expression patterns of genes encoding FGF receptors and secreted FGF ligands during these later stages of cerebellar development. We show that these genes are expressed in multiple cell types in the developing cerebellum, in an astonishing array of distinct patterns. These data suggest that FGF signaling functions throughout cerebellar development to regulate many processes that shape the formation of a functional cerebellum. Developmental Dynamics, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
36.
Treatment goals for the management of lipids and inflammation for patients with coronary artery disease 总被引:2,自引:0,他引:2
Opinion statement Appropriate management of lipids is a central component of risk reduction in patients with coronary artery disease (CAD).
According to the most recent guidelines, low-density lipoprotein cholesterol (LDLC) is the principal target of lipid-lowering
therapy and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the mainstay of this therapy. The actual
target level of LDL lowering is being reassessed in light of recent clinical trials. Once appropriate LDL lowering has been
achieved, treatment of other targets such as high-density lipoprotein cholesterol (HDLC), triglycerides, and non-HDLC should
be considered. In addition to dyslipidemia, multiple observational studies suggest that inflammatory markers such as C-reactive
protein (CRP) are associated with risk of cardiovascular events and that treatment with statins may lower CRP levels. However,
there are insufficient data at this time supporting treatment of CRP as a principal target in CAD. 相似文献
37.
That sexual symptoms can signal serious underlying disease confirms the importance of sexual enquiry as an integral component of medical assessment. Data on sexual function are sparse in some medical specialties. However, increased scientific understanding of the central and peripheral physiology of sexual response could help to identify the pathophysiology of sexual dysfunction from disease and medical interventions, and also to ameliorate or prevent some dysfunctions. Many common general medical disorders have negative effects on desire, arousal, orgasm, ejaculation, and freedom from pain during sex. Chronic disease also interferes indirectly with sexual function, by altering relationships and self-image and causing fatigue, pain, disfigurement, and dependency. Current approaches to assessment of sexual dysfunction are based on models that combine psychological and biological aspects. 相似文献
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40.
Colchicine inhibits pressure-induced tumor cell implantation within surgical wounds and enhances tumor-free survival in mice
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Craig DH Owen CR Conway WC Walsh MF Downey C Basson MD 《The Journal of clinical investigation》2008,118(9):3170-3180
Iatrogenic tumor cell implantation within surgical wounds can compromise curative cancer surgery. Adhesion of cancer cells, in particular colon cancer cells, is stimulated by exposure to increased extracellular pressure through a cytoskeleton-dependent signaling mechanism requiring FAK, Src, Akt, and paxillin. Mechanical stimuli during tumor resection may therefore negatively impact patient outcome. We hypothesized that perioperative administration of colchicine, which prevents microtubule polymerization, could disrupt pressure-stimulated tumor cell adhesion to surgical wounds and enhance tumor-free survival. Ex vivo treatment of Co26 and Co51 colon cancer cells with colchicine inhibited pressure-stimulated cell adhesion to murine surgical wounds and blocked pressure-induced FAK and Akt phosphorylation. Surgical wound contamination with pressure-activated Co26 and Co51 cells significantly reduced tumor-free survival compared with contamination with tumor cells under ambient pressure. Mice treated with pressure-activated Co26 and Co51 cells from tumors preoperatively treated with colchicine in vivo displayed reduced surgical site implantation and significantly increased tumor-free survival compared with mice exposed to pressure-activated cells from tumors not pretreated with colchicine. Our data suggest that pressure activation of malignant cells promotes tumor development and impairs tumor-free survival and that perioperative colchicine administration or similar interventions may inhibit this effect. 相似文献