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Biomedical subjects

T Yagi

Publications and source records attributed to T Yagi.

At least 271 records · Page 15Linked to original sources
PubMed1997

Fyn-kinase as a determinant of ethanol sensitivity: relation to NMDA-receptor function.

Animals vary in their sensitivity to ethanol, a trait at least partly determined by genetic factors. In order to identify possible responsible genes, mice lacking Fyn, a non-receptor type tyrosine kinase, were investigated. These mice were hypersensitive to the hypnotic effect of ethanol. The administration of ethanol enhanced tyrosine phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) in the hippocampus of control mice but not in Fyn-deficient mice. An acute tolerance to ethanol inhibition of NMDAR-mediated excitatory postsynaptic potentials in hippocampal slices developed in control mice but not in Fyn-deficient mice. These results indicate that Fyn affects behavioral, biochemical, and physiological responses to ethanol.

Animals↗
PubMed1997

Biologically inactive growth hormone caused by an amino acid substitution.

Short stature caused by biologically inactive growth hormone (GH) is characterized by lack of GH action despite high immunoassayable GH levels in serum and marked catch-up growth to exogenous GH administration. We found a heterozygous single-base substitution (A-->G) in exon 4 of the GH-1 gene of a girl with short stature, clinically suspected to indicate the presence of bioinactive GH and resulting in the substitution of glycine for aspartic acid at codon 112. We confirmed the presence of mutant GH in the serum using isoelectric focusing analysis. The locus of mutation D112G was found within site 2 of the GH molecule in binding with GH receptor (GHR)/GH binding protein (GHBP). The expressed recombinant mutant GH tended to form a 1:1 instead of the 1:2 GH-GHBP complex normally produced by wild-type GH. The formation of a 1:2 GH-GHBP complex is compatible with the dimerization of GHRs by GH, a crucial step in GH signal transduction. Mutant GH was less potent than wild-type GH not only in phosphorylation of tyrosine residues in GHR, janus kinase 2 (JAK2), and signal transducers and activators of transcription 5 (STAT5) in IM-9 cells, but also in metabolic responses of BaF/GM cells, a stable clone transfected with cDNA of the chimera of the extracellular domain of human GHR, the transmembrane and the cytoplasmic domain of the human thrombopoietin receptor. These results indicate that the D112G mutation in the GH-1 gene causes production of bioinactive GH, which prevents dimerization of GHR and is therefore responsible for the patient's short stature.

Child, Preschool↗
PubMed1997

Suppression of autoimmune disease and of massive lymphadenopathy in MRL/Mp-lpr/lpr mice lacking tyrosine kinase Fyn (p59fyn).

MRL/Mp-lpr/lpr (MRL/lpr) mice suffer from a generalized autoimmune disease that includes autoantibody production and glomerulonephritis and develop massive lymphadenopathy characterized by an expanded population of CD4- CD8- B220+ T cells that is derived from autoreactive T cells in the periphery. Some of us previously reported that these atypical T cells overexpressed a gene for tyrosine kinase p59fyn (Fyn). To define the role of Fyn in the renal disease and lymphadenopathy in MRL/lpr mice, we have generated Fyn-deficient MRL/lpr mice whose fyn gene is replaced by the gene for beta-galactosidase. Fyn-deficient MRL/lpr mice developed markedly limited disease and lived more than twice as long as the conventional MRL/lpr mice. In the mutant mice, the production of IgG3 anti-DNA autoantibody was significantly (p < 0.005%) reduced, and glomerular deposits of IgG3 and C3 were remarkably diminished. Ag receptor-mediated proliferative responses of Fyn-deficient splenic T cells were markedly impaired. The mutant mice showed delayed accumulation of the atypical CD4- CD8- B220+ T cells that exhibited a significantly lower activity of ZAP-70 compared with those in the conventional MRL/lpr mice. These data demonstrated that Fyn is involved as a positive regulator in the disease of MRL/lpr mice. Fyn provides a signal for both the expansion of autoreactive T cells and the production of IgG3 anti-DNA autoantibody by B cells. Thus, manipulation of Fyn may improve systemic autoimmune disease in humans.

Animals↗
PubMed1997

Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase.

In addition to its role as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system. GABA is synthesized by glutamic acid decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined. The selective elimination of each GAD isoform by gene targeting is expected to clarify these issues. Recently we have produced GAD65 -/- mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures. Here we report the production of GAD67 -/- mice. These mice were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67 -/- mice. Their brain, however, did not show any discernible defects. Previous pharmacological and genetic investigations have suggested the involvement of GABA in palate formation, but this is the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.

Aging↗
PubMed1997

Molecular cloning of Fyn-associated molecules in the mouse central nervous system.

Fyn tyrosine kinase is expressed extensively in the central nervous system (CNS) of mammals, and its genetic disruption in mouse displays several behavioral abnormalities with morphological and electrophysiological defects in the brain. To understand the signaling pathways in which Fyn is involved in the CNS, we screened molecules that directly associate with Fyn in neonatal mouse brain by using a two-hybrid yeast system. We isolated five cDNA clones with strong and reproducible Fyn-binding activity. Sequence analyses revealed that three of them are previously reported molecules, SON, tctex-1, and hnRNP K, and that two clones encode novel sequences. The hnRNP K has been shown to associate with Fyn, so our yeast system is appropriate to isolate Fyn-binding molecules. Northern hybridization analyses indicated that all isolated clones are expressed in the mouse brain and that the mRNA levels of the two molecules (tctex-1 and clone 82) change during development in the brain. A full-length cDNA of clone 82 was obtained and its deduced amino acid sequence was homologous to the RNA-binding proteins. Isolation of many Fyn-binding molecules suggest that, in the mouse CNS, Fyn mediates multiple signaling pathways by binding to multiple molecules and that some of these pathways play critical roles in determining a certain type of behavior.

Age Factors↗
PubMed1997

Successful long-term xenoperfusion of the pig liver: continuous administration of prostaglandin E1 and insulin.

For clinical utilization of extracorporeal liver perfusion as an artificial liver assist device, we examined the possibility of long-term xenoperfusion of the pig liver by the continuous administration of prostaglandin E1 (PGE1) and insulin. After a 3-hr perfusion period, pig livers that were xenoperfused with human blood exhibited a drastic decrease in the perfusate volume, a progressive elevation of the hepatic artery pressure, a gradual deterioration of bile production, and a marked increase in the release of creatine kinase-BB component. The continuous administration of PGE1 (25 microg/hr) and insulin (1 U/hr) significantly improved these derangements (P<0.05) and allowed stable perfusion for up to 9 hr. This manipulation also inhibited leukocyte aggregation in the graft, the characteristic perfusate hemolysis, and acceleration of ketogenesis. Histological examination revealed that the interlobular edema and hemorrhage, characteristics of tissue injuries in xenogeneic hyperacute rejection, were markedly alleviated in the PGE1 and insulin-treated group. This study clarifies the finding that the combined administration of PGE1 and insulin is effective for long-term xenogeneic extracorporeal liver perfusion, with the graft viability well maintained.

Alprostadil↗
PubMed1997

The proton-translocating NADH-quinone oxidoreductase (NDH-1) of thermophilic bacterium Thermus thermophilus HB-8. Complete DNA sequence of the gene cluster and thermostable properties of the expressed NQO2 subunit.

The genes encoding the proton-translocating NADH-quinone oxidoreductase (NDH-1) of a thermophilic bacterium Thermus thermophilus HB-8 were cloned and sequenced. They constitute a cluster that is composed of 14 structural genes and contains no unidentified reading frames. All of the 14 structural genes, which are designated NQO1-14, encode subunits homologous to those of Paracoccus denitrificans NDH-1, respectively, and are arranged in the same order as other bacterial NDH-1 genes. T. thermophilus NDH-1 contains at most nine putative iron-sulfur cluster binding sites, eight of which are commonly found in other organisms. The T. thermophilus NQO2 subunit was expressed in Escherichia coli. The expressed subunit bears a single [2Fe-2S] cluster whose optical and EPR properties are very similar to those of N1a cluster in the P. denitrificans NQO2 subunit (Yano, T., Sled', V.D., Ohnishi, T., and Yagi, T. (1994) Biochemistry 33, 494-499). These results strongly suggest that the T. thermophilus NDH-1 is similar to other NDH-1 enzyme complexes in terms of subunit and cofactor composition. The T. thermophilus NQO2 subunit displayed much higher stability than the mesophilic equivalent and its iron-sulfur cluster remained intact even after incubation for 3 h at 65 degrees C under anaerobic conditions. With the advantage of thermostability, the T. thermophilus NDH-1 provides a great model system to investigate the structure-function relationship of the NDH-1 enzyme complexes.

Amino Acid Sequence↗
PubMed1997

Transformation in Garnet from Orthorhombic Perovskite to LiNbO3 Phase on Release of Pressure

High-pressure in situ x-ray diffraction and transmission electron microscopy on quenched samples show that natural garnet transforms to orthorhombic perovskite (and minor coexisting phases) containing increasing amounts of aluminum with increasing pressure. This suggests that the perovskite is the dominant host mineral for aluminum in Earth's lower mantle. Orthorhombic perovskite is quenched from approximately 35 gigapascals but, because of the increased aluminum content, transforms to the LiNbO3 structure upon quenching from approximately 60 gigapascals.

Journal Article↗
PubMed1997

Ca2+-dependent waveform conversion in the flagellar axoneme of Chlamydomonas mutants lacking the central-pair/radial spoke system.

Chlamydomonas flagella undergo a striking waveform conversion from an asymmetrical ciliary type to a symmetrical flagellar type when the cell is stimulated by intense light and the Ca2+ concentration within the flagellum is increased above approximately 10(-6) M. To see whether the central-pair/radial spoke system is needed for this conversion as suggested by previous studies, we examined the effect of Ca2+ on the reactivated axonemes of the mutants lacking the central pair (pf18) or the radial spokes (pf14). Although the flagella of these mutants are paralyzed in vivo, demembranated axonemes can be reactivated to beat under certain nucleotide conditions such as in the presence of low concentrations (< 100 microM) of ATP. We examined the waveform of the axonemes reactivated at 20 microM ATP in the presence of 10(-8)-10(-4) M Ca2+ and found that these axonemes, as well as the wild-type axonemes, undergo a waveform conversion over a Ca2+ concentration range of 10(-7)-10(-5) M: a highly asymmetrical waveform at <10(-6) M Ca2+ and a symmetrical waveform at >=10(-5) M Ca2+. Although the waveform is different between the mutants and the wild type, the Ca2+ concentration at which the waveform conversion occurred was similar. These results indicate that the central pair/radial spoke system is not essential for the waveform conversion.

Adenosine Triphosphate↗
PubMed1997

Accumulation of somatic hypermutation and antigen-driven selection in rapidly cycling surface Ig+ germinal center (GC) B cells which occupy GC at a high frequency during the primary anti-hapten response in mice.

Well-developed germinal centers (GC) contain rapidly dividing surface immunoglobulin-negative (sIg-) B cells (centroblasts), and most of their progeny are sIg+ B cells (centrocytes) in a resting state. It has been predicted that somatic hypermutation occurs in centroblasts, whereas antigen-driven selection takes place in centrocytes. The present analysis indicates that murine GC B cells bearing sIg with specificity for an immunizing antigen are in a rapidly cycling state and increase exponentially in number to occupy spleen GC at high frequency during the 1st week after primary immunization; however, the number of these cells is significantly reduced in the 2nd week of immunization. During that period, these proliferating sIg+ GC B cells accumulate somatic hypermutations with nucleotide exchanges indicative of affinity maturation. These sIg+ GC B cells co-express B7-2, ICAM-1, and LFA-1, and have potent antigen-presenting activity which results in T cell activation in vitro. These observations indicate that the sIg+ GC B cells accumulate somatic hypermutations and undergo antigen-driven selection through proliferation, probably upon activation by T cells. This sIg+ GC B cell population may represent cell cycling centrocytes; however, the possibility that these may represent centroblasts undergoing re-expression of sIg could not be excluded.

Amino Acid Sequence↗
PubMed1997

The protective effects of prostaglandin E1 on sinusoidal endothelial cells in xenogeneic pig liver perfusion.

The effects of prostaglandin E1 (PGE1) on hepatic sinusoidal endothelial cells (SEC) in the xenogeneic immunoreaction were investigated. Porcine livers were perfused with fresh human blood via the portal vein (PV) and the hepatic artery (HA) either with the administration of PGE1 (Group PG) or without PGE1 (Group C). The creatine kinase-BB component (CK-BB) in the perfusate was measured to assess SEC damage. SEC activation and complement activation were evaluated immunohistochemically by the expression of von Willebrand factor (vWF) and by the deposition of membrane attack complex (MAC), respectively. Xenoperfusion in Group C was discontinued between 4 and 6 hr due to the rapid elevation of HA pressures and the massive loss of perfusate. In Group PG, both PV and HA pressures were kept stable for up to 9 hr. In Group C, severe interlobular bleeding and diffuse extrasinusoidal hemorrhage were observed at 4 hr histologically, while in Group PG, the hepatic architecture was maintained without hemorrhage at 6 hr. MAC was markedly deposited on SEC and parenchymal cells at 3 hr in both groups. The amount of vWF, however, was expressed on SEC in large amounts at 1 hr in Group C, while small amounts were expressed at 1 hr in Group PG. In Group PG, CK-BB release was significantly lower than in Group C (P < 0.01). These results suggest that PGE1 suppressed SEC activation and protected the impairment of hepatic SEC during xenoperfusion without suppressing complement activation, resulting in the prolongation of xenogeneic liver perfusion.

Alprostadil↗
PubMed1997

Intramedullary spinal cord tumour associated with neurofibromatosis type 1.

We investigated the characteristic features of intramedullary spinal cord tumour associated with neurofibromatosis type 1 (NF-1). We have experienced 44 cases of pathologically confirmed intramedullary spinal cord tumour. Diagnosis of NF-1 was done according to the criteria set by the National Institute of Health Consensus Development Conference. Within the described population NF-1 was diagnosed in two patients. Both the patients were male and histopathologically the tumours were anaplastic astrocytoma and glioblastoma multiforme respectively. 6 cases of NF-1 associated with intramedullary spinal cord tumour based on the above diagnostic criteria have so far been reported, including our 2 cases. Of these 6 cases, 5 were male and in one sex was not described. The tumour was an astrocytoma in all 6 cases. This finding suggested that intramedullary spinal cord tumour associated with NF-1 tends to occur predominantly in males and that histopathologically the tumour is likely to be an astrocytoma. We conclude that the criteria proposed by the National Institute of Health Consensus Development Conference are contributory in making an accurate pre-operative pathological diagnosis of intramedullary spinal cord tumour associated with NF-1.

Adolescent↗
PubMed1997

Antiperistaltic transverse colostomy for massive bowel necrosis following surgery for an abdominal aortic aneurysm: report of a case.

We herein report the findings of a 72-year-old man with gangrenous multivisceral necrosis following an operation for abdominal aortic aneurysm. The region of necrosis, which accompanied infarction of the left kidney, included the entire ileum and the ascending, descending, and sigmoid colon. An end ileostomy and transverse colostomy were performed subsequent to massive bowel resection in a second operation. After the second operation, he was managed with total parenteral nutrition and recovered uneventfully except for end-jejunostomy syndrome. A third operation was performed to reconstruct the interrupted bowel. To minimize abandoned bowel, antiperistaltic transverse colostomy was used for jejunocolonal reconstruction. The antiperistaltic colostomy improved the symptoms of end-jejunostomy syndrome and normalized the patient's vitamin B12 and bile acid levels. An antiperistaltic colostomy is thus considered to be useful for preventing short bowel syndrome after a massive bowel resection.

Aged↗
PubMed1997

The role of retinal bipolar cell in early vision: an implication with analogue networks and regularization theory.

A linear analogue network model is proposed to describe the neuronal circuit of the outer retina consisting of cones, horizontal cells, and bipolar cells. The model reflects previous physiological findings on the spatial response properties of these neurons to dim illumination and is expressed by physiological mechanisms, i.e., membrane conductances, gap-junctional conductances, and strengths of chemical synaptic interactions. Using the model, we characterized the spatial filtering properties of the bipolar cell receptive field with the standard regularization theory, in which the early vision problems are attributed to minimization of a cost function. The cost function accompanying the present characterization is derived from the linear analogue network model, and one can gain intuitive insights on how physiological mechanisms contribute to the spatial filtering properties of the bipolar cell receptive field. We also elucidated a quantitative relation between the Laplacian of Gaussian operator and the bipolar cell receptive field. From the computational point of view, the dopaminergic modulation of the gap-junctional conductance between horizontal cells is inferred to be a suitable neural adaptation mechanism for transition between photopic and mesopic vision.

Animals↗
PubMed1997

Failure of aged rats to accumulate eosinophils in allergic inflammation of the airway.

To investigate the effect of aging on the allergic airway response, we examined the bronchoconstrictive responses and cellular inflammatory changes in a rat model of bronchial asthma by evaluating young and old animals. Two different age groups of Brown-Norway rats, actively sensitized by injection of ovalbumin into the foot pads, were used: 7 to 8 weeks old (young group) and 100 to 120 weeks old (aged group). Both the aged and young rats produced on ovalbumin-specific IgE antibody and exhibited an immediate asthmatic response after exposure to ovalbumin, but the degree of specific IgE antibody was significantly higher in young rats. The young group showed a marked increase in the number of eosinophils and neutrophils in bronchoalveolar lavage fluid 2 days after exposure to ovalbumin, whereas no eosinophilia was seen in the aged group. To evaluate the mechanism of the decreased accumulation of eosinophils in aged rats, cells from popliteal lymph nodes from ovalbumin-sensitized rats were incubated with ovalbumin for 48 hours. Although eosinophil chemotactic activity, determined by a modified Boyden chamber method, was present in the supernatant of cultured lymph node cells from young rats, it was absent from those of aged rats. In vivo administration of anti-IL-5 monoclonal antibody revealed that one of the factors of eosinophil chemotactic activity was IL-5. Lymph node cells from aged rats tended to produce greater amounts of interferon-gamma than did those from young animals. Findings indicate that aged rats have a defect in eosinophil accumulation in sites exposed to antigen, probably because of an age-dependent alteration in T cells.

Aging↗
PubMed1997

Therapeutic doses of theophylline exert proconvulsant effects in developing mice.

We studied the effect of therapeutic doses of theophylline on electrically-induced convulsions in developing mice. A theophylline dose as small as 3 mg/kg increased seizure susceptibility of 21-day-old mice, but not of 42-day-old mice. These findings were consistent with clinical reports that theophylline at the therapeutic blood concentrations occasionally induced convulsions in children. The age-dependent proconvulsant effect of theophylline was well inhibited by phenobarbital (PB), dose-dependently, but not by other well-established antiepileptic drugs (AEDs). PB may be a good choice of AED in patients with bronchial asthma and seizure disorders, if PB is indicative for their seizure types. The proconvulsant effect of theophylline in 21-day-old mice was counteracted by not only an adenosine A1 agonist, but also an NMDA antagonist and a histamine H3 antagonist. Several studies have established that the proconvulsant effect of theophylline intoxication is mainly due to the blockade of adenosine A1 receptors. The present findings suggested that the proconvulsant properties of therapeutic doses of theophylline in developing period were different from those of theophylline intoxication. Combination of therapeutic doses of theophylline and centrally-acting histamine H1 antagonists showed proconvulsant effects even in 42-day-old mice, suggesting that peripherally acting histamine H1 antagonists, such as astemizole, evastine and epinastine, were much safer than centrally acting histamine H1 antagonists for patients with both allergy and seizure history.

Aging↗