Biomedical subjects

Yasuyuki Fujita

Publications and source records attributed to Yasuyuki Fujita.

At least 19 recordsLinked to original sources

PubMed2006

Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program.

The recognition of microbial components by Toll-like receptors (TLRs) initiates signal transduction pathways, which trigger the expression of a series of target genes. It has been reported that TLR signaling is enhanced by cytokines such as IFN-gamma, but the mechanisms underlying this enhancement remain unclear. The MyD88 adaptor, which is essential for signaling by many TLRs, recruits members of the IFN regulatory factor (IRF) family of transcription factors, such as IRF5 and IRF7, to evoke the activation of TLR target genes. In this study we demonstrate that IRF1, which is induced by IFN-gamma, also interacts with and is activated by MyD88 upon TLR activation. We provide evidence that MyD88-associated IRF1 migrates into the nucleus more efficiently than non-MyD88-associated IRF1 and that this IRF1 selectively participates in the TLR-dependent gene induction program. The critical role of MyD88-dependent "IRF1 licensing" is underscored by the observation that the induction of a specific gene subset downstream of the TLR-MyD88 pathway, such as IFN-beta, inducible NO synthase, and IL-12p35, are impaired in Irf1-deficient cells. Thus, our present study places IRF1 as an additional member participating in MyD88 signaling and provides a mechanistic insight into the enhancement of the TLR-dependent gene induction program by IFN-gamma.

Animals↗

PubMed2006

CTACK/CCL27 accelerates skin regeneration via accumulation of bone marrow-derived keratinocytes.

Recent studies have suggested that bone marrow (BM) cells transdifferentiate to regenerate a variety of cellular lineages. Due to the relatively small population of BM-derived cells in each organ, it is still controversial whether these BM-derived cells are really present in sufficient numbers for effective function. Conversely, it is speculated that chemokine/chemokine receptor interactions mediate this migration of the tissue-specific precursor cells from BM into the target tissue. Here, we show that cutaneous T-cell attracting chemokine (CTACK)/CCL27 is the major regulator involved in the migration of keratinocyte precursor cells from BM into skin. By screening various chemokine expression patterns, we demonstrated that CTACK is constitutively expressed in normal skin and upregulated in wounds and that approximately 20% of CD34(+) BM cells expressed CCR10, the ligand for CTACK. Intradermal injection of CTACK/CCL27 into the periphery of skin wounds significantly enhanced BM-derived keratinocyte (BMDK) migration, and CTACK/CCL27 neutralizing antibody inhibited this BMDK migration. Furthermore, increased BMDK migration caused by CTACK/CCL27 significantly accelerated the wound-healing process without any influence over either angiogenesis or keratinocyte proliferation. These results provide direct evidence that recruitment of BM keratinocyte precursor cells to the skin is regulated by specific chemokine/chemokine receptor interactions, making possible the development of new regenerative therapeutic strategies.

Animals↗

PubMed2006

Characteristics of dioxin emissions at startup and shutdown of MSW incinerators.

Dioxin concentrations from municipal waste incinerators in Japan and elsewhere often show low concentrations that comply with legal limits (in this paper, the term "dioxin" designates WHO-TEQ: PCDD/Fs+dioxin-like PCB). However, such data is usually generated under normal steady state operational conditions, and there has been little investigation of releases occurring during startup and shutdown. It is important, therefore, to ascertain quantitatively emissions in an unsteady state (startup and shutdown) in order to correctly evaluate the relationship between emissions from a facility and the surrounding environment. The present study aimed to examine dioxin emissions of a continuously operated incinerator at startup and shutdown, and estimating the time period of greatest emission, and the processes causing dioxin generation. The startup process was divided into five stages and the shutdown into two; at each stage, dioxins in the flue gas were measured at the boiler outlet and the stack. From the concentration of dioxins and the flue gas volume at each stage, the amount of dioxins at startup and shutdown were calculated, and these were compared with that under steady state conditions. Dioxin concentration at the stack under steady state conditions was a very low level, while those at startup and shutdown were higher. In the case where dioxin concentration under a steady state is a low level like in this study, it is indicated that the total annual dioxin emission from a facility could be attributed to the startup periods.

Air Pollution↗

PubMed2006

Noninvasive measurement of isovolumetric contraction time by Doppler cardiography can be substituted for fetal cardiac contractility: evaluation of a fetal lamb study.

OBJECTIVE: The objective of this study is to clarify whether the isovolumetric contraction time obtained from Doppler cardiography (Doppler ICT) can be an index substituted for fetal cardiac contractility. MATERIALS AND METHODS: In 10 pregnant ewes, fetal hypoxemia was induced by giving a variable mixture of gases. Through experiment, the Doppler ICT, pre-ejection period (PEP), and the maximum first derivative of the left ventricular pressure waveform (Max dp/dt) were simultaneously recorded every 10min. The relationship between both the Doppler ICT and PEP, and the Max dp/dt were analyzed. RESULTS: A significant negative linear regression was founded between the Doppler ICT and the Max dp/dt. A significant negative linear regression was also shown between PEP and the Max dp/dt. Moreover, the regression of Max dp/dt on ICT had significantly less residual variance than the regression of Max dp/dt on PEP (p=0.0004). CONCLUSION: In contrast to PEP, Doppler ICT is a reliable, and non-invasive index which can be substituted for fetal cardiac contractility.

Animals↗

PubMed2006

Presence of circulating CCR10+ T cells and elevated serum CTACK/CCL27 in the early stage of mycosis fungoides.

PURPOSE: Mycosis fungoides (MF), a common type of cutaneous T cell lymphoma with an indolent clinical course, has the characteristic that malignant T cell clones are recruited into the skin from the early disease stages. The mechanisms of recruitment have been suggested from our knowledge of various chemokine-chemokine receptor interactions. Recently, CCR10 and CTACK/CCL27 were proposed to play a role in the recruitment of other types of cutaneous T cell lymphoma. We examined the expression of CCR10 in peripheral blood and serum CTACK/CCL27 levels in patients with MF. EXPERIMENTAL DESIGN: Eighteen patients with MF, six patients with atopic dermatitis, and nine healthy volunteers were enrolled in our investigation. We investigated the differences in CCR10+ CD4+ expression in peripheral blood mononuclear cells by flow cytometry. Serum CTACK/CCL27 levels were determined using a CTACK/CCL27 ELISA assay kit. RESULTS: The number of circulating CCR10+ CD4+ cells was significantly higher in MF peripheral blood than in controls, even during the early stages. In lesional MF skin, infiltrating tumor cells also showed extensive expression of CCR10. The serum level of CTACK/CCL27 was higher in patients with MF than normal controls, but no statistical difference was found compared with atopic dermatitis patients. CONCLUSIONS: CCR10-CTACK/CCL27 interactions between circulating T cells and keratinocytes would seem to play an important role in the pathophysiology of MF from the early disease stages.

Adult↗

PubMed2006

Regulated and polarized PtdIns(3,4,5)P3 accumulation is essential for apical membrane morphogenesis in photoreceptor epithelial cells.

BACKGROUND: In a specialized epithelial cell such as the Drosophila photoreceptor, a conserved set of proteins is essential for the establishment of polarity, its maintenance, or both--in Drosophila, these proteins include the apical factors Bazooka, D-atypical protein kinase C, and D-Par6 together with D-Ecadherin. However, little is known about the mechanisms by which such apical factors might regulate the differentiation of the apical membrane into functional domains such as an apical-most stack of microvilli or more lateral sub-apical membrane. RESULTS: We show that in photoreceptors Bazooka (D-Par3) recruits the tumor suppressor lipid phosphatase PTEN to developing cell-cell junctions (Zonula Adherens, za). za-localized PTEN controls the spatially restricted accumulation of optimum levels of the lipid PtdIns(3,4,5)P3 within the apical membrane domain. This in turn finely tunes activation of Akt1, a process essential for proper morphogenesis of the light-gathering organelle, consisting of a stack of F-actin rich microvilli within the apical membrane. CONCLUSIONS: Spatially localized PtdIns(3,4,5)P3 mediates directional sensing during neutrophil and Dictyostelium chemotaxis. We conclude that a conserved mechanism also operates during photoreceptor epithelial cell morphogenesis in order to achieve normal differentiation of the apical membrane.

Adherens Junctions↗

PubMed2006

Nail dystrophy and blisters as sole manifestations in myeloma-associated amyloidosis.

We report the case of a 61-year-old Japanese man with IgG lambda-type multiple myeloma, who presented with nail dystrophy as the initial manifestation of systemic amyloidosis. Subsequently he developed bullous amyloidosis. This report documents these two rare signs of systemic amyloidosis and demonstrates the precise location of cutaneous blister formation and amyloid deposition by fluorescence antigen mapping and electron microscopy.

Amyloidosis↗

PubMed2006

Regulation of cell-cell adhesion by Rap1.

Rap1 has been implicated in the regulation of morphogenesis and cell-cell contacts in vivo (Asha et al., 1999; Hariharan et al., 1991; Knox and Brown, 2002) and in vitro (Hogan et al., 2004; Price et al., 2004). Among cell-cell adhesion molecules regulated by Rap1 is cadherin, a calcium-dependent adhesive receptor. Assembly of cadherin-mediated cell-cell contacts triggers Rap1 activation, and Rap function is necessary for the stability of cadherins at junctions (Hogan et al., 2004; Price et al., 2004). Here we describe assays to access the effects of Rap1 on cadherin-dependent adhesion in epithelia, in particular the method used for Rap1 localization, activation, and function modulation by microinjection. We focus on controls and culture conditions to determine the specificity of the phenotype with respect to cadherin receptors. This is important, because different receptors that accumulate at sites of cell-cell contacts are also able to activate Rap1 (Fukuyama et al., 2005; Mandell et al., 2005).

Animals↗

PubMed2006

Fetal aortic distension waveforms for evaluating cardiac function and changes in blood pressure: fetal lamb validation.

AIM: To investigate which part of the fetal aortic distension waveform is mainly influenced by changes in fetal cardiac contractility and aortic blood pressure. METHODS: In acute preparation, aortic distension waveforms were recorded using an echo-tracking system, and aortic and left ventricular pressure waveforms were obtained from six late-gestation catheterized fetal lambs. Dobutamine and angiotensin II were separately infused and the correlations between the maximum value in the first derivative of left ventricle pressure waveforms (Max dP/dt) and fetal blood pressure, and the parameters obtained from aortic distension waveforms were analyzed using linear regression analysis. RESULTS: With a change in cardiac contractility, the maximum value of first derivative of the systolic rising slope in the aortic distension waveform had a positive correlation with Max dP/dt (r = 0.93, P < 0.0001). With changes in fetal blood pressure, both the amplitude and the ratio of increase from the end diastolic diameter obtained from the aortic distension waveform had a significant positive correlation with aortic blood pressure amplitude (r = 0.60, P < 0.01; r = 0.61, P < 0.01, respectively). CONCLUSION: The maximum first derivative of the systolic rising slope in the aortic distension waveform and the amplitude in the aortic distension waveform enable us to non-invasively substitute for fetal cardiac contractility and aortic blood pressure amplitude, respectively.

Animals↗

PubMed2006

Investigation of the management of industrial safety and health at an educational research institution.

Following the incorporation of national universities, the Industrial Safety and Health Law became applicable to universities. A questionnaire survey was conducted on 93 national universities in order to ascertain the current management of industrial safety and health at incorporated national universities. The present findings indicate that each university has established a managerial organization in accordance with the Industrial Safety and Health Law; however, it is important for such organizations to maintain and improve safety management. Therefore, the implementation of a safety and health management system in conjunction with the managerial organization required by the Industrial Safety and Health Law is recommended as a method of enhancing safety management at university laboratories.

Environmental Health↗

PubMed2005

Noninvasive measurement of isovolumetric contraction time during hypoxemia and acidemia: Fetal lamb validation as an index of cardiac contractility.

OBJECTIVES: The objectives of this study are firstly to clarify how the Doppler isovolumetric contraction time (ICT) is influenced by arterial oxygen pressure (PaO2) or pH, and secondly to confirm the relationship between the Doppler ICT and myocardial contractility during hypoxemia and/or acidemia in the fetal lamb. MATERIAL AND METHODS: In 12 pregnant ewes, fetal hypoxemia and acidemia were induced by giving ewes a variable mixture of gases for 120 min. The chronological change of fetal PaO2, pH, Doppler ICT and maximum first derivative of the left ventricular pressure waveform (Max dp/dt) was recorded every 30 min. RESULTS: Doppler ICT and PaO2 had no significant regression. On the other hand, Doppler ICT and pH demonstrated a significant negative regression. Moreover, one critical given pH point was indicated with statistical significance at 7.20 and the prolongation of the Doppler ICT was found more markedly in the range below the pH of 7.20 compared with the range above 7.20. A significant negative linear regression was found between the Doppler ICT and the Max dp/dt. CONCLUSION: The measurement of Doppler ICT enables us to predict severe acidosis and a decrease of myocardial contractility in the fetus.

Acidosis↗

PubMed2005

Lysosomal targeting of E-cadherin: a unique mechanism for the down-regulation of cell-cell adhesion during epithelial to mesenchymal transitions.

A hallmark characteristic of epithelial tumor progression as well as some processes of normal development is the loss of the epithelial phenotype and acquisition of a motile or mesenchymal phenotype. Such epithelial to mesenchymal transitions are accompanied by the loss of E-cadherin function by either transcriptional or posttranscriptional mechanisms. Here we demonstrate that, upon v-Src expression, a potent trigger of epithelial to mesenchymal transitions, E-cadherin is internalized and then shuttled to the lysosome instead of being recycled back to the lateral membrane. Thus, while E-cadherin internalization facilitates the dissolution of adherens junctions, its subsequent traffic to the lysosome serves as a means to ensure that cells do not reform their cell-cell contacts and remain motile. We also show that ubiquitin tagging of E-cadherin is essential for its sorting to the lysosome. The lysosomal targeting of E-cadherin is mediated by hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and v-Src-induced activation of the Rab5 and Rab7 GTPases. Our studies reveal that the lysosomal targeting of E-cadherin is an important posttranscriptional mechanism to deplete cellular E-cadherin during Src-induced epithelial to mesenchymal transitions.

Animals↗

PubMed2005

Proteinuria is a prognostic marker for cardiovascular mortality: NIPPON DATA 80, 1980-1999.

BACKGROUND: Proteinuria has been considered to be a prognostic marker for persons with diabetes mellitus, but only a limited number of studies about the relationship between proteinuria and mortality among general population has been available. METHODS: The subjects were 10,897 individuals who participated in the National Cardiovascular Survey conducted in 1980 and who were aged 30 years or older living in 300 districts that had been randomly selected throughout Japan. The vital records were confirmed in 1999 and 7,203 subjects (3,180 males and 4,023 females) without a history of hypertension, stroke, heart disease, renal disease, or diabetes mellitus at the start of the study were investigated. RESULTS: There were 126,825 person-years of follow-up. During the observed period of time, 371 died of cardiovascular causes, including 171 stroke deaths and 74 coronary deaths. The risk of proteinuria for cardiovascular mortality was greater than unity for those with a normal serum creatinine level, after adjusting for age and other cardiovascular disease risk factors. CONCLUSIONS: When contrasted with other cardiovascular disease risk factors, urinary protein is an independent risk factor for cardiovascular death among the Japanese population.

Adult↗

PubMed2005

Epithelial cell shape and Rho small GTPases.

In epithelial cells, morphology is intrinsically related to function. Typically, polarization (i.e. acquisition of a cuboidal cell shape) must occur prior to terminal differentiation and functionality of epithelial sheets. Extensive work has been performed to understand the initial steps that drive cell-cell contact assembly, a process that is essential for polarization. However, not much is known about the subsequent steps that lead to remodelling of actin cytoskeleton and concomitant cell shape changes. Here we review what is known about actin organization during epithelial polarization, and discuss current models for junction assembly, actin reorganization and signalling pathways that may contribute to the generation of a polarized epithelial morphology.

Animals↗

PubMed2004

Rap1 regulates the formation of E-cadherin-based cell-cell contacts.

In epithelial tissues, cells are linked to their neighbors through specialized cell-cell adhesion proteins. E-cadherin is one of the most important membrane proteins for the establishment of intimate cell-cell contacts, but the molecular mechanism by which it is recruited to contact sites is largely unknown. We report here that the cytoplasmic domain of E-cadherin interacts with C3G, a guanine nucleotide exchange factor for Rap1. In epithelial cell cultures, ligation of the extracellular domain of E-cadherin enhances Rap1 activity, which in turn is necessary for the proper targeting of E-cadherin molecules to maturing cell-cell contacts. Furthermore, our data suggest that Cdc42 functions downstream of Rap1 in this process. We conclude that Rap1 plays a vital role in the establishment of E-cadherin-based cell-cell adhesion.

Animals↗

PubMed2004

Surveillance of mortality among atomic bomb survivors living in the United States using the National Death Index.

BACKGROUND: The National Death Index is a useful source to establish the death of an individual and to determine the cause of death. We identified deaths in atomic bomb survivors in the United States who were lost to follow-up through the National Death Index, and examined the completeness of mortality ascertainment in atomic bomb survivors in the US through the National Death Index. METHODS: Since 1977, biennial medical examinations of atomic bomb survivors in the US have been conducted. The 1,073 atomic bomb survivors in the US included 764 individuals who had medical examinations at least once in sixteen years from 1977 through 1993 and 309 individuals who reported atomic bomb survivorship to medical examination project themselves. Of the 1,073 survivors living in the US, 471 people who participated in the ninth health examinations of atomic bomb survivors living in the US in 1993 were removed, and two people among the remaining 602 individuals had no information about their birth dates and Social Security numbers. An investigation of those deceased between 1979 and 1993 was conducted among 600 of the atomic bomb survivors in the US. Death certificates for atomic bomb survivors in the US were requested from the National Death Index. A comparison was made between the information on the death certificates acquired through the National Death Index and the data ascertained from the medical examination project conducted from 1979 through 1993. RESULTS: Forty-nine death certificates were obtained using the National Death Index. By sex, the dominant cause of death in females was malignant neoplasm, accounting for 53%. In males, it was circulatory disease, accounting for 37%. The National Death Index and the medical examination project determined that 57 deaths had occurred between 1979 and 1993. The sensitivity and specificity of the National Death Index is 86% and 97% respectively. CONCLUSION: It is suggested that the National Death Index is useful to follow up mortality among atomic bomb survivors in the US.

Adult↗

PubMed2003

A novel interaction between kinesin and p120 modulates p120 localization and function.

p120-catenin exists in a membrane-associated cadherin-bound pool, a cytosolic pool that affects Rho GTPases, and a nuclear pool that is thought to associate with the methylation-relevant transcriptional repressor Kaiso. We show here that cytoplasmic p120 can also associate both directly and indirectly with the microtubule network, and that p120 traffics along microtubules toward their plus ends. The direct binding required most of the armadillo repeats and was mutually exclusive for interaction with E-cadherin. Perturbing the p120-microtubule interaction with nocodazole or taxol markedly affected both the tubulin interaction and the balance between cytoplasmic and nuclear p120. The indirect binding occurred via a novel interaction between a segment of the p120 N-terminal domain and conventional kinesin heavy chains. Selective uncoupling of the p120-kinesin interaction by overexpression of the respective p120 and kinesin-binding fragments promoted nuclear p120 accumulation. In addition, expression of full-length kinesin reduced the nuclear accumulation of p120 and blocked the branching phenotype associated with p120 overexpression. Taken together, the data suggest that kinesin affects both the targeting and activity of p120 at several cellular locations.

Animals↗

PubMed2003

beta-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system.

beta-Catenin is an essential component of the canonical Wnt signaling system that controls decisive steps in development. We employed here two conditional beta-catenin mutant alleles to alter beta-catenin signaling in the central nervous system of mice: one allele to ablate beta-catenin and the second allele to express a constitutively active beta-catenin. The tissue mass of the spinal cord and brain is reduced after ablation of beta-catenin, and the neuronal precursor population is not maintained. In contrast, the spinal cord and brain of mice that express activated beta-catenin is much enlarged in mass, and the neuronal precursor population is increased in size. beta-Catenin signals are thus essential for the maintenance of proliferation of neuronal progenitors, controlling the size of the progenitor pool, and impinging on the decision of neuronal progenitors to proliferate or to differentiate.

Alleles↗