[Mechanical property of high strength nickel-free stainless steel produced through mechanical alloying].
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Alloys↗
Biomedical subjects
S Takaki
Publications and source records attributed to S Takaki.
Atomic-level observation of disclination dipoles in mechanically milled, nanocrystalline Fe.
Plastic deformation of materials occurs by the motion of defects known as dislocations and disclinations. High-resolution transmission electron microscopy was used to directly reveal the individual dislocations that constitute partial disclination dipoles in nanocrystalline, body-centered cubic iron that had undergone severe plastic deformation by mechanical milling. The mechanisms by which the formation and migration of such partial disclination dipoles during deformation allow crystalline solids to fragment and rotate at the nanometer level are described. Such rearrangements are important basic phenomena that occur during material deformation, and hence, they may be critical in the formation of nanocrystalline metals by mechanical milling and other deformation processes.
Journal Article↗
Identification and characterization of a transcriptional regulator for the lck proximal promoter.
The lck gene encodes a protein-tyrosine kinase that plays a key role in signaling mediated through T cell receptor (TCR) and pre-TCR complexes. Transcription of the lck gene is regulated by two independent promoter elements: the proximal and distal promoters. Previous studies employing transgenic mice demonstrated that the sequence between -584 and -240 from the transcription start site in the mouse lck proximal promoter is required for its tissue-specific expression in the thymus. In this study, we demonstrate that a Krüppel-like zinc finger protein, mtbeta (BFCOL1, BERF-1, ZBP-89, ZNF148), previously cloned as a protein that binds to the CD3delta gene enhancer, binds to the -365 to -328 region of the lck proximal promoter. mtbeta is ubiquitously expressed in various cell lines and mouse tissues. Overexpressed mtbeta is more active in T-lineage cells than B-lineage cells for transactivating an artificial promoter consisting of the mtbeta binding site and a TATA box. Activity of the lck proximal promoter was significantly impaired by mutating the mtbeta binding site or by reducing mtbeta protein expression level by using antisense mRNA. Our results indicate that mtbeta activity is regulated in a tissue-specific manner and that mtbeta is a critical transactivator for the lck proximal promoter.
Animals↗
Functional dissection of the cytoplasmic subregions of the interleukin-5 receptor alpha chain in growth and immunoglobulin G1 switch recombination of B cells.
The interleukin-5 receptor alpha chain (IL-5Ralpha) is known to regulate the development and function of B cells and eosinophils. Although the functions of IL-5Ralpha cytoplasmic domain subregions have been studied extensively using cultured cell lines, this approach has limitations when studying the functions of distinct primary B-cell subpopulations and their responsiveness to IL-5. In the present study, we generated mice on an IL-5Ralpha null background, each expressing a mutant form of an IL-5Ralpha transgene ligated to a mu enhancer and VH promoter, either lacking the cytoplasmic DC3 region or substituting two proline residues for alanine (ApvA) in the membrane-proximal ppvp motif of the cytoplasmic domain. The ppvp motif, which mediates activation of JAK2/STAT5 and Btk, also contributes to c-fos, c-jun and c-myc expression. IL-5Ralpha null mutant mice showed impaired B-1-cell development, reduced serum immunoglobulin G3 (IgG3) and IgM, no IL-5-induced enhancement of B-cell proliferation and IL-5-induced switch recombination from the mu gene to gamma1 gene; these were not recovered following the expression of the ApvA mutant. In contrast, absence of the DC3 region affected the IL-5-induced switch recombination from the mu to the gamma1 gene and B-1-cell development, while IL-5-induced proliferation and IgM production were at levels similar to those of B cells expressing wild-type IL-5Ralpha transgene. The results clearly indicated that the ppvp motif and the DC3 region of IL-5Ralpha played distinct roles in B-cell proliferation and differentiation. Thus, this present approach offers new insights into the functions of the cytoplasmic subregions of IL-5Ralpha, in particular its carboxy-terminal region.
Amino Acid Sequence↗
Bruton's tyrosine kinase is required for signaling the CD79b-mediated pro-B to pre-B cell transition.
Formation of the pre-BCR complex is a critical check point during B cell development and induces the transition of pro-B to pre-B cells. CD79b (Igbeta) is a signaling component in the pre-BCR complex, since differentiation to the pre-B phenotype is induced by cross-linking the CD79b expressed on developmentally arrested pro-B cells from recombination-activating gene (RAG)-2-deficient mice. Bruton's tyrosine kinase (BTK) plays important roles in B cell development. However, its molecular mechanisms in early B cell development are not fully understood. To examine whether BTK functions in CD79b-mediated signaling for the pro-B/pre-B transition, we utilized RAG2/BTK double-knockout (DKO) mice. Pro-B cells from RAG2/BTK-DKO mice did not differentiate into pre-B cells following CD79b cross-linking, although tyrosine phosphorylation of cellular proteins including Erk1/2 and phospholipase C-gamma2 was induced in the same manner as RAG2-KO mice. BTK is phosphorylated after cross-linking of CD79b on RAG2-deficient pro-B cells. These findings suggest that BTK-dependent pathways downstream of CD79b are critical for the pro-B/pre-B transition and BTK-independent signaling pathways are also activated via the pre-BCR complex.
Agammaglobulinaemia Tyrosine Kinase↗
Molecular cloning of the mouse APS as a member of the Lnk family adaptor proteins.
Engagement of cell-surface receptors leads to activation of protein tyrosine kinases, which in turn phosphorylate various downstream enzymes and adaptor proteins. Lnk is an adaptor protein that appears to be involved in signal transduction in lymphocytes, and forms an adaptor protein family with SH2-B. We tried to identify another member of the adaptor protein family and isolated the mouse APS (adaptor molecule containing PH and SH2 domains). APS contains a proline-rich region, PH and SH2 domains, and a putative tyrosine phosphorylation site at the C-terminal, and the overall structure resembles those of Lnk and SH2-B. APS is expressed in brain, kidney, muscle, and mature B cells in spleen. Mouse APS gene consists of 8 coding exons and is deduced to map to chromosome 5. APS is tyrosine phosphorylated at the C-terminal phosphorylation site conserved among the Lnk family adaptor proteins by stimulation of IL-5 or IL-3 as well as by crosslinking of B cell receptor complex. These results suggest that APS is a member of the Lnk family adaptor protein and likely plays a role in signaling in B cells.
Adaptor Proteins, Signal Transducing↗
Strategy for finding new materials for ESR dosimeters
The right strategy for finding a new ESR dosimetric material sensitive to radiation is to follow the orthodox procedures used in the development of thermoluminescence dosimeters (TLD) and phosphorescence studies. Modern procedures used in materials sciences, such as computer calculation of molecular orbitals (MO), should be employed to estimate the ESR and optical properties of prospective materials. Radiation effects in lithium and magnesium sulfates and metal salts of organic acids, such as lithium and magnesium lactates, have been investigated in search for tissue-equivalent dosimeter with a large G value.
Journal Article↗
Control of B cell production by the adaptor protein lnk. Definition Of a conserved family of signal-modulating proteins.
Lnk is an SH2 domain-containing adaptor protein expressed preferentially in lymphocytes. To illuminate the importance of Lnk, we generated lnk(-/-) mice. Whereas T cell development was unaffected, pre-B and immature B cells accumulated in the spleens. In the bone marrow, B-lineage cells were proportionately increased, reflecting enhanced production of pro-B cells that resulted in part from hypersensitivity of precursors to SCF, the ligand for c-kit. Hence, Lnk ordinarily acts to regulate B cell production. Further characterization of lnk(-/-) mice also revealed that full-length Lnk is a 68 kDa protein containing a conserved proline-rich region and a PH domain. Lnk is a representative of a multigene adaptor protein family whose members act, by analogy with Lnk, to modulate intracellular signaling.
Adaptor Proteins, Signal Transducing↗
Multiple cerebral arteriovenous malformations (AVMs) associated with spinal AVM.
The co-existence of multiple cerebral arteriovenous malformations (AVMs) and a spinal AVM is extremely rare. A 22-year-old man suddenly developed severe headache. Computed tomography (CT) scan showed intracerebral haemorrhage in the left occipital lobe. Cerebral angiography revealed eight AVMs; four were in the right frontal lobe and two each were in the right temporal and left occipital lobe, respectively. A huge high-flow spinal AVM was found incidentally. He had no other vascular lesions such as hereditary haemorrhagic telangiectasia. A left occipital craniotomy was performed and the ruptured left occipital AVMs were removed. Further therapeutic treatment was refused. To our knowledge, except for one autopsy case, this is the first reported patient with multiple cerebral AVMs with a spinal AVM. We discuss the characteristics of this case and review reported cases with cerebral and spinal AVMs.
Adult↗
Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice.
BACKGROUND: TRAF6, a member of the tumour necrosis factor receptor-associated factor family, was first identified as a transducer of CD40 and interleukin-1 receptor (IL-1R) signals based on the interaction of TRAF6 with the cytoplasmic tail of CD40 and with the IL-1R associated kinase in vitro. However, the functions of TRAF6 in vivo remain unidentified. RESULTS: We show that TRAF6-/- mice exhibit severe osteopetrosis and are defective in osteoclast formation. In vitro culture experiments revealed that osteoclast precursor cells derived from TRAF6-/- mice are unable to differentiate to functional osteoclasts in response to osteoclast differentiation factor (ODF). In bone marrow of TRAF6-/- mice, the number of sIgM+B220+ immature B cells is markedly reduced while the ratio of proB to preB cells is not affected. In contrast, development of thymocytes is not affected. Furthermore, TRAF6-/- mice are defective in lymph node organogenesis and IL-1 signalling in thymocytes. CONCLUSIONS: The results identify TRAF6 as an essential component of ODF signalling pathway, and also show that TRAF6 plays pivotal roles in immune and inflammatory systems in vivo.
Animals↗
[Intra-arterial infusion chemotherapy for unresectable or recurrent breast cancer].
Epirubicin and 5-FU were administered through an indwelling catheter inserted into the internal mammary artery and/or subclavian artery employing an implantable infusion port system for the treatment of unresectable advanced breast cancer and recurrent breast cancer. Intraarterial infusion chemotherapy proved to be an effective treatment modality for unresectable advanced breast cancer and recurrent breast cancer.
Antineoplastic Combined Chemotherapy Protocols↗
Characterization of Lnk. An adaptor protein expressed in lymphocytes.
Stimulation of the T cell antigen receptor (TCR) activates a set of non-receptor protein tyrosine kinases that assist in delivering signals to the cell interior. Among the presumed substrates for these kinases, adaptor proteins, which juxtapose effector enzyme systems with the antigen receptor complex, figure prominently. Previous studies suggested that Lnk, a 38-kDa protein consisting of a single SH2 domain and a region containing potential tyrosine phosphorylation sites, might serve to join Grb2, phospholipase C-gamma1, and phosphatidylinositol 3-kinase to the TCR. To elucidate the physiological roles of Lnk in T cell signal transduction, we isolated the mouse Lnk cDNA, characterized the structure of the mouse Lnk gene, and generated transgenic mice that overproduce Lnk in thymocytes. Here we report that although Lnk becomes phosphorylated during T cell activation, it plays no limiting role in the TCR signaling process. Moreover, we have distinguished p38(Lnk) from the more prominent 36-kDa tyrosine phosphoproteins that appear in activated T cells. Together these studies suggest that Lnk participates in signaling from receptors other than antigen receptors in lymphocytes.
Adaptor Proteins, Signal Transducing↗
Differential signaling by lymphocyte antigen receptors.
Studies performed during the past several years make plain that ligand occupancy of antigen receptors need not necessarily provoke identical responses in all instances. For example, ligation of antigen receptors may stimulate a proliferative response, induce a state of unresponsiveness to subsequent stimulation (anergy), or induce apoptosis. How does a single type of transmembrane receptor induce these very heterogeneous cellular responses? In the following pages, we outline evidence supporting the view that the nature of the ligand/receptor interaction directs the physical recruitment of signaling pathways differentially inside the lymphocyte and hence defines the nature of the subsequent immune response. We begin by providing a functional categorization of antigen receptor components, considering the ways in which these components interact with the known set of signal transduction pathways, and then review the evidence suggesting that differential signaling through the TCR is achieved by qualitative differences in the effector pathways recruited by TCR, perhaps reflecting the time required to bring complicated signal transduction elements into proximity within the cell. The time-constant of the interaction between antigen and receptor in this way determines, at least in part, the nature of the resulting response. Finally, although our review focuses substantially on T cell receptor signaling, we have included a less detailed description of B cell receptor signaling as well, simply to emphasize the parallels that exist in these two closely related systems.
Animals↗
Defective B-1 cell development and impaired immunity against Angiostrongylus cantonensis in IL-5R alpha-deficient mice.
We generated interleukin-5 receptor alpha chain (IL-5R alpha)-deficient (IL-5R alpha-/-) mice by gene targeting. The IL-5R alpha-/- mice showed decreased numbers of B-1 cells concomitant with low serum concentrations of IgM and IgG3. They showed no IL-5-induced enhancement of B cell responses to T-independent antigens. The number of alpha beta T cell receptor-positive thymocytes tended to decrease in 3-week-old IL-5R alpha-/- mice, returning to normal by 6 weeks of age. The IL-5R alpha-/- mice produced basal levels of eosinophils, while their bone marrow cells failed to form eosinophilic colonies in response to IL-5. Impaired eosinophilopoiesis in IL-5R alpha-/-mice enhanced the survival of Angiostrongylus cantonensis. These results indicate that IL-5-induced eosinophils serve as potent effector cells in the killing of Angiostrongylus cantonensis in mice.
Angiostrongylus cantonensis↗
Critical proline residues of the cytoplasmic domain of the IL-5 receptor alpha chain and its function in IL-5-mediated activation of JAK kinase and STAT5.
The high-affinity receptor (R) for IL-5 consists of a unique alpha chain (IL-5R alpha) and a beta chain (beta c) that is shared with the receptors for IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF). We defined two regions of IL-5R alpha for the IL-5-induced proliferative response, the expression of nuclear proto-oncogenes, and the tyrosine phosphorylation of cellular proteins including beta c, SH2/SH3-containing proteins and JAK2 kinase. In the studies described here, we demonstrate that IL-5, IL-3 or GM-CSF stimulation induces the tyrosine phosphorylation of JAK2, and to a lesser extent JAK1, and of STAT5. Mutational analysis revealed that one of the proline residues, particularly Pro352 and Pro355, in the membrane-proximal proline-rich sequence (Pro352-Pro353-X-Pro355) of the cytoplasmic domain of IL-5R alpha is required for cell proliferation, and for both JAK1 and JAK2 activation. In addition, transfectants expressing chimeric receptors which consist of the extracellular domain of IL-5R alpha and the cytoplasmic domain of beta c responded to IL-5 for proliferation and tyrosine phosphorylation of JAK1. Intriguingly, electrophoretic mobility shift assay analysis revealed that STAT5 was activated in cells showing either JAK1 or JAK2 tyrosine phosphorylation. These results indicate that activation of JAK1, JAK2 and STAT5 is critical to coupling IL-5-induced tyrosine phosphorylation and ultimately mitogenesis, and that Pro352 and Pro355 in the proline-rich sequence appear to play more essential roles in cell growth and in both JAK1/STAT5 and JAK2/STAT5 activation than Pro353 does.
Animals↗
Demonstration of a cross-talk between IL-2 and IL-5 in phosphorylation of IL-2 and IL-5 receptor beta chains.
We have examined phosphorylation mediated by cross-talk between growth signal pathways induced by IL-2 and IL-5. To analyze the phosphorylation process in the same cells, we established two sublines, T88-Mbeta1, which is a subline of a murine IL-5-dependent cell line, T88-M, by introduction of the human IL-2 receptor beta chain (IL-2Rbeta), and secondly CTLL-5Ralphabeta, which is a subline of a murine IL-2-dependent cell line, CTLL-2, by introduction of the murine IL-5 receptor alpha chain (IL-5Ralpha) and IL-5 receptor beta chain (IL-5Rbeta, betac) genes. Both T88-Mbeta1 and CTLL-5Ralphabeta expressed high-affinity receptors for IL-2 and IL-5, and proliferated in response to both factors. Tyrosine phosphorylation of IL-2Rbeta was induced by stimulation of T88-Mbeta1 with not only IL-2 but also IL-5. Anti-IL-2Rbeta-directed immune complexes from T88-Mbeta1 stimulated with IL-5 as well as with IL-2 contained an activated tyrosine kinase. However, stimulation with IL-5 but not IL-2 induced the tyrosine phosphorylation of IL-5Rbeta, betac, suggesting that IL-2 does not activate a tyrosine kinase which efficiently catalyzes the IL-5Rbeta molecule in response to IL-5. On the other hand, the detection of JAK1 and the other common set of phosphotyrosine-containing proteins after stimulation with either IL-5 or IL-2 suggests the existence of the same tyrosine phosphorylation pathways.
Animals↗
Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce differentiation of chronic B cell leukemia expressing the alpha subunit of IL-3 and GM-CSF receptor.
Interleukin-5 (IL-5), IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) exhibit similar functions on eosinophils, and these common functions are believed to be mediated by the shared beta chain of receptors. IL-5 shows activity on the murine chronic B cell leukemia cell line BCL1-B20, inducing differentiation into IgM-secreting cells, but IL-3 and GM-CSF do not have such activity. To elucidate whether the lineage specificity of IL-5 is due to restricted expression of the IL-5 receptor alpha chain (IL-5R alpha), transfectants of BCL1-B20 were established that express IL-3 receptor alpha (BCL1-3R) or GM-CSF receptor alpha (BCL1-GMR). BCL1-3R and BCL1-GMR acquired responsiveness to IL-3 and GM-CSF, respectively, to an extent similar to IL-5 stimulation, resulting in IgM-secreting cells. Thus, the differentiation of BCL1-B20 into IgM-secreting cells can be equally supported by either IL-3 or GM-CSF, suggesting that intracellular signaling through IL-5R can be replaced by signaling from IL-3R and GM-CSFR. These results support the notion that the lineage specificity of IL-5 is mainly due to the restricted expression of IL-5R alpha. Regulation of IL-5R alpha, IL-3R alpha and GM-CSFR alpha expression in the developmental stage appears to be important for understanding the unique function of these cytokines on a particular cell type.
Animals↗
[Intra-arterial infusion chemotherapy for breast cancer].
In order to reduce toxic effects while attaining maximal therapeutic effects, epirubicin 10 mg/day, cyclophosphamide 100 mg/day and prednisolone 10 mg/day were administered through in indwelling catheter inserted into the internal mammary artery and/or subclavian artery for 3-4 weeks, employing the implantable port system for the treatment of unresectable breast cancer and recurrent cancer. Ten out of 11 patients (91%) with unresectable breast cancer showed a response (CR 3, PR 7, NC 1) to this modality of intra-arterial infusion chemotherapy. Seven out of 11 patients (64%) with recurrent cancer of the breast showed a response (CR 1, PR 6, NC 4). Intraarterial infusion chemotherapy for the unresectable advanced breast cancer and recurrent breast cancer proved to be an effective modality of treatment.
Antineoplastic Combined Chemotherapy Protocols↗