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| 3. |
- Blokzijl, A, et al.
(författare)
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Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3
- 2003
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Ingår i: The Journal of cell biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 163:4, s. 723-728
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Tidskriftsartikel (refereegranskat)abstract
- The Notch and transforming growth factor-β (TGF-β) signaling pathways play critical roles in the control of cell fate during metazoan development. However, mechanisms of cross-talk and signal integration between the two systems are unknown. Here, we demonstrate a functional synergism between Notch and TGF-β signaling in the regulation of Hes-1, a direct target of the Notch pathway. Activation of TGF-β signaling up-regulated Hes-1 expression in vitro and in vivo. This effect was abrogated in myogenic cells by a dominant-negative form of CSL, an essential DNA-binding component of the Notch pathway. TGF-β regulated transcription from the Hes-1 promoter in a Notch-dependent manner, and the intracellular domain of Notch1 (NICD) cooperated synergistically with Smad3, an intracellular transducer of TGF-β signals, to induce the activation of synthetic promoters containing multimerized CSL- or Smad3-binding sites. NICD and Smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and Smad3 could be recruited to CSL-binding sites on DNA in the presence of CSL and NICD. These findings indicate that Notch and TGF-β signals are integrated by direct protein–protein interactions between the signal-transducing intracellular elements from both pathways.
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| 9. |
- Dahlqvist, C, et al.
(författare)
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Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation
- 2003
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Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 130:24, s. 6089-6099
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Tidskriftsartikel (refereegranskat)abstract
- The bone morphogenetic protein (BMP) and Notch signaling pathways are crucial for cellular differentiation. In many cases, the two pathways act similarly; for example, to inhibit myogenic differentiation. It is not known whether this inhibition is caused by distinct mechanisms or by an interplay between Notch and BMP signaling. Here we demonstrate that functional Notch signaling is required for BMP4-mediated block of differentiation of muscle stem cells, i.e. satellite cells and the myogenic cell line C2C12. Addition of BMP4 during induction of differentiation dramatically reduced the number of differentiated satellite and C2C12 cells. Differentiation was substantially restored in BMP4-treated cultures by blocking Notch signaling using either theγ-secretase inhibitor L-685,458 or by introduction of a dominant-negative version of the Notch signal mediator CSL. BMP4 addition to C2C12 cells increased transcription of two immediate Notch responsive genes, Hes1 and Hey1, an effect that was abrogated by L-685,458. A 3 kb Hey1-promoter reporter construct was synergistically activated by the Notch 1 intracellular domain (Notch 1 ICD) and BMP4. The BMP4 mediator SMAD1 mimicked BMP activation of the Hey1 promoter. A synthetic Notch-responsive promoter containing no SMAD1 binding sites responded to SMAD1, indicating that DNA-binding activity of SMAD1 is not required for activation. Accordingly, Notch 1 ICD and SMAD1 interacted in binding experiments in vitro. Thus, the data presented here provide evidence for a direct interaction between the Notch and BMP signaling pathways, and indicate that Notch has a crucial role in the execution of certain aspects of BMP-mediated differentiation control.
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| 14. |
- Chew, M, et al.
(författare)
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Thalidomide inhibits early atherogenesis in apoE-deficient mice
- 2003
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Ingår i: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - 1600-0463. ; 111:Suppl., s. 113-116
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is present in all stages of atherosclerosis, from fatty streaks to rupture of mature plaques. Tumour necrosis factor (TNF)-alpha is expressed in atherosclerotic lesions but its role in atherogenesis has not been defined. To clarify the role of this cytokine, we administered thalidomide, a compound known to inhibit TNF-alpha production, to homozygous apolipoprotein E-deficient (apoE(-/-)) mice in order to examine the effect of thalidomide on the development of early atherosclerotic lesions. Twelve apoE(-/-) mice were randomized to receive either sustained-release thalidomide or placebo pellets implanted subcutaneously, and the amount of atherosclerosis was quantified six weeks later. Thalidomide was well tolerated and did not result in any changes in body weight. Mice treated with thalidomide had significantly smaller mean (7986+/-5189 vs 19607+/-10353 mum(2), p=0.05) and maximum (15800 [12777-23675] vs 37169 [28000-41351] mum(2), p=0.03) lesion sizes than those treated with placebo. Thus, thalidomide is capable of inhibiting the early development of atherosclerosis, presumably by inhibition of TNF-alpha secretion.
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- Falk, A, et al.
(författare)
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Gene delivery to adult neural stem cells
- 2002
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 279:1, s. 34-39
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Tidskriftsartikel (refereegranskat)abstract
- Neural stem cells may present an ideal route for gene therapy as well as offer new possibilities for the replacement of neurons lost to injury or disease. However, it has proved difficult to express ectopic genes in stem cells. We report methods to introduce genes into adult neural stem cells using viral and nonviral vectors in vitro and in vivo. Adenoviral and VSV-G-pseudotyped retroviral vectors are more efficient than plasmid transfection or VSV-G lentiviral transduction in vitro. We further show that adult neural stem cells can be directed to a neuronal fate by ectopic expression of neurogenin 2 in vitro. Plasmids can be delivered in vivo when complexed with linear polyethyleneimine, and gene expression can be targeted specifically to neural stem or progenitor cells by the use of specific promoters. These techniques may be utilized both to study the function of various genes in the differentiation of neural stem cells to specific cell fates and, ultimately, for gene therapy or to generate specific differentiated progeny for cell transplantation. (C) 2002 Elsevier Science (USA).
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- Mattheos, N, et al.
(författare)
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The interactive examination: assessing students' self-assessment ability
- 2004
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Ingår i: Medical Education. - : Wiley. - 0308-0110 .- 1365-2923. ; 38:4, s. 378-389
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The ability to self-assess one's competence is a crucial skill for all health professionals. The interactive examination is an assessment model aiming to evaluate not only students' clinical skills and competence, but also their ability to self-assess their proficiency. METHODS The methodology utilised students' own self-assessment, an answer to a written essay question and a group discussion. Students' self-assessment was matched to the judgement of their instructors. As a final task, students compared their own essay to one written by an 'expert'. The differences pointed by students in their comparison documents and the accompanying arguments were analysed and categorised. Students received individual feedback on their performance and learning needs. The model was tested on 1 cohort of undergraduate dental students (year 2001, n = 52) in their third semester of studies, replacing an older form of examination in the discipline of clinical periodontology. RESULTS Students' acceptance of the methodology was very positive. Students tended to overestimate their competence in relation to the judgement of their instructors in diagnostic skills, but not in skills relevant to treatment. No gender differences were observed, although females performed better than males in the examination. Three categories of differences were observed in the students' comparison documents. The accompanying arguments may reveal students' understanding and methods of prioritising. CONCLUSIONS Students tended to overestimate their competence in diagnostic rather than treatment skills. The interactive examination appeared to be a convenient tool for providing deeper insight into students' ability to prioritise, self-assess and steer their own learning.
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| 23. |
- Rajnavolgyi, E, et al.
(författare)
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A repetitive sequence of Epstein-Barr virus nuclear antigen 6 comprises overlapping T cell epitopes which induce HLA-DR-restricted CD4(+) T lymphocytes
- 2000
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377 .- 0953-8178. ; 12:3, s. 281-293
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Tidskriftsartikel (refereegranskat)abstract
- Most human adults carry the Epstein-Barr virus (EBV) and develop immunological memory against the structural and the virus-encoded cellular proteins. The EBV nuclear antigen 6 (EBNA6) elicits cytotoxic T cell responses and it also maintains a persistent antibody response. The majority of sera from EBV-seropositive individuals reacts with a synthetic peptide, p63, comprising 21 amino acids of a repetitive region of EBNA6. CD4(+) T lymphocytes, with specificity for p63, could be recalled from the T cell repertoire of EBV carriers that expressed certain HLA-DR allotypes which were identified as good binders of p63 by an in vitro flow cytometric assay. Analysis of the HLA-DR/p63 interaction by molecular mechanics calculations indicated the presence of multiple overlapping epitopes which were predicted to bind in a HLA-DRB1 allo- and subtype-specific manner. Specific activation of p63-selected long-term CD4(+) T cell cultures resulted in a proliferative response, in the production of IL-2 and in the secretion of high levels of tumor necrosis factor as measured by bioassays. Proliferation and cytokine production of p63-specific T cells could be induced by p63-loaded HLA-DR-matched antigen-presenting cells and by B cells co-expressing relevant HLA-DR molecules and EBNA6. Our results show that peptides of an EBNA6 repeat region induce CD4(+) T cells which can react with EBNA6-carrying cells in many individuals. We suggest that these T(h) cells may be important in conditioning dendritic cells for initiation potent virus-specific immune responses, provide help for EBV-specific B cells, drive IgG isotype switch and support the sustained effector function of memory cytotoxic T lymphocytes.
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| 24. |
- Schiessling, Joachim, et al.
(författare)
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Synchrotron radiation study of the electronic structure of multiwalled carbon nanotubes
- 2003
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Ingår i: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 15:38, s. 6563-
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Tidskriftsartikel (refereegranskat)abstract
- We present photoelectron (PE) and x-ray absorption spectra (XAS) of macroscopically aligned multiwalled carbon nanotubes. We identify the peaks in the valence PE spectra with regions of high density of states through comparison to calculations for graphite. Finally, we outline and illustrate a simple method for using XAS to determine the average alignment of a nanotube sample.
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| 28. |
- Yang, Jia Jin, et al.
(författare)
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Internalization of proteinase 3 is concomitant with endothelial cell apoptosis and internalization of myeloperoxidase with generation of intracellular oxidants
- 2001
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Ingår i: American Journal of Pathology. - 1525-2191. ; 158:2, s. 581-592
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Tidskriftsartikel (refereegranskat)abstract
- The important issue addressed by the studies presented here is the mechanism of neutrophil-mediated damage to endothelial and epithelial cells during inflammation. Binding of neutrophil-released granule proteins to endothelial cells may be involved in vascular damage in patients with inflammatory vascular diseases. We have determined whether granule proteins proteinase 3(PR3) and/or myeloperoxidase (MPO) are internalized into endothelial cells, as examined by UV light, confocal, and electron microscopy. Coincident induction of apoptosis and/or the generation of intracellular oxidants were monitored. The results indicate that human endothelial cells (human umbilical vein endothelial cells, human umbilical arterial endothelial cells, human lung microvascular endothelial cells) internalize both PR3 and MPO, which are detected on the cell surface, in the cytoplasm, and possibly nuclear. Epithelial cells (small airway epithelial cells) internalized MPO but not PR3, implying that the mechanism of PR3 internalization may be cell-type specific and different from that of MPO. Internalization of PR3, but not MPO, correlated with activation of apoptosis. Internalization of MPO correlated with an increase in intracellular oxidant radicals. The requirement for the proteolytic activity of PR3 for the induction of apoptosis was examined by generating PR3-truncated fragments that did not contain the components of the catalytic triad. An apoptotic function was localized to the C-terminal portion of PR3. These studies reveal novel mechanisms by which the neutrophil granule proteins PR3 and MPO contribute to tissue injury at sites of inflammation.
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| 29. |
- Yao, Yiming, 1957, et al.
(författare)
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Synthesis of carbon nanotube films by thermal CVD in the presence of supported catalyst particles. Part I: The silicon substrate/nanotube film interface
- 2004
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Ingår i: Journal of Materials Science: Materials in Electronics. ; 15:8, s. 533-543
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The interface between the silicon substrate and a carbon nanotube film grown by thermal CVD with acetylene (C2H2) and hydrogen at 750 or 900 °C has been characterized by high resolution and analytical transmission electron microscopy, including electron spectroscopic imaging. Silicon (0 0 2) substrates coated with a thin (2.8 nm) iron film were heat treated in the CVD furnace at the deposition temperature in a mixture of flowing argon and hydrogen whereby nanosized particles of (Fe,Si)3O4 formed. These particles were reduced to catalytic iron silicides with the α–(Fe, Si), α2–Fe2Si and α1–Fe2Si structures during CVD at 900 °C, and multi-wall carbon nanotubes grew from supported particles via a base-growth mechanism. A limited number of intermediate iron carbides, hexagonal and orthorhombic Fe7C3, were also present on the substrate surface after CVD at 900 °C. The reduction of the preformed (Fe, Si)3O4 particles during thermal CVD at 750 °C was accompanied by disintegration leading to the formation of a number of smaller (
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| 31. |
- Yao, Yiming, 1957, et al.
(författare)
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Synthesis of carbon nanotube films by thermal CVD in the presence of supported catalyst particles. Part II: the nanotube film
- 2004
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Ingår i: Journal of Materials Science: Materials in Electronics. ; 15:9, s. 583-594
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Carbon nanotube films have been grown at 750° and 900 °C by thermal chemical vapor deposition (CVD) with acetylene (C2H2) and hydrogen on silicon (0 0 2) wafers supporting preformed (Fe,Si)3O4 particles. The reduction of the (Fe,Si)3O4 particles during CVD at 750 °C was accompanied by a disintegration leading to the formation of a high density of smaller (predominantly 5–15 nm) iron silicide (α1-Fe2Si) particles that catalyzed the growth of a dense and aligned multi-wall carbon nanotube film. The tubes did not contain any inclusions apart from the catalytic particles present in the bottom part of the film, and it was concluded that the nanotubes grew via a “base-growth” mechanism. CVD at 900 °C resulted in a random growth of predominantly multi-wall carbon nanotubes. The film contained an increased number of amorphous carbon, or graphite, clusters containing particles that had been carbonized, the larger ones to cementite, θ-Fe3C. Nanotubes were observed to grow from some of these clusters. Multi-wall carbon nanotube tips contained after CVD at 900 °C encapsulated θ-Fe3C, or in a few cases α- or γ-Fe, particles.
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