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Articles by K Takeda
Total Records ( 7 ) for K Takeda
  Y Watanabe , K Takeda and S. Funahashi
 

To understand functional roles of the thalamic mediodorsal nucleus (MD) in sensory-to-motor information transformation during spatial working memory performance and compare with those of the dorsolateral prefrontal cortex (DLPFC), we calculated population vectors using a population of MD activities recorded during 2 tasks. In the oculomotor delayed-response (ODR) task, monkeys needed to make a memory-guided saccade to the cue location, whereas in the rotatory oculomotor delayed-response (R-ODR) task, they needed to make a memory-guided saccade 90o clockwise from the cue direction. The directions of population vectors calculated from populations of cue- and response-period activities were similar to the cue and saccade target directions, respectively, which confirmed that population vectors represent information regarding the directions of the visual cue and the saccade target. We then calculated population vectors of delay-period activity using a sliding 250-ms time window. In the ODR task, population vectors were directed toward the cue direction throughout the delay. However, in the R-ODR task, they gradually rotated from the cue direction to the saccade target direction. Based on a comparison with the results obtained from DLPFC neurons, the rotation of population vectors started earlier in the MD than in the DLPFC, suggesting that the motor information regarding forthcoming saccade is provided from the MD.

  X Ma , K Takeda , A Singh , Z. X Yu , P Zerfas , A Blount , C Liu , J. A Towbin , M. D Schneider , R. S Adelstein and Q. Wei
 

Rationale: Germline ablation of the cytoskeletal protein nonmuscle myosin II (NMII)-B results in embryonic lethality, with defects in both the brain and heart. Tissue-specific ablation of NMII-B by a Cre recombinase strategy should prevent embryonic lethality and permit study of the function of NMII-B in adult hearts.

Objective: We sought to understand the function of NMII-B in adult mouse hearts and to see whether the brain defects found in germline-ablated mice influence cardiac development.

Methods and Results: We used a loxP/Cre recombinase strategy to specifically ablate NMII-B in the brains or hearts of mice. Mice ablated for NMII-B in neural tissues die between postnatal day 12 and 22 without showing cardiac defects. Mice deficient in NMII-B only in cardiac myocytes (BMHC/BMHC mice) do not show brain defects. However, BMHC/BMHC mice display novel cardiac defects not seen in NMII-B germline-ablated mice. Most of the BMHC/BMHC mice are born with enlarged cardiac myocytes, some of which are multinucleated, reflecting a defect in cytokinesis. Between 6 to 10 months, they develop a cardiomyopathy that includes interstitial fibrosis and infiltration of the myocardium and pericardium with inflammatory cells. Four of 5 BMHC/BMHC hearts develop marked widening of intercalated discs.

Conclusions: By avoiding the embryonic lethality found in germline-ablated mice, we were able to study the function of NMII-B in adult mice and show that absence of NMII-B in cardiac myocytes results in cardiomyopathy in the adult heart. We also define a role for NMII-B in maintaining the integrity of intercalated discs.

  T Ito , C Nishiyama , N Nakano , M Nishiyama , Y Usui , K Takeda , S Kanada , K Fukuyama , H Akiba , T Tokura , M Hara , R Tsuboi , H Ogawa and K. Okumura
 

Over-expression of PU.1, a myeloid- and lymphoid-specific transcription factor belonging to the Ets family, induces monocyte-specific gene expression in mast cells. However, the effects of PU.1 on each target gene and the involvement of cytokine signaling in PU.1-mediated gene expression are largely unknown. In the present study, PU.1 was over-expressed in two different types of bone marrow-derived cultured mast cells (BMMCs): BMMCs cultured with IL-3 plus stem cell factor (SCF) and BMMCs cultured with pokeweed mitogen-stimulated spleen-conditioned medium (PWM-SCM). PU.1 over-expression induced expression of MHC class II, CD11b, CD11c and F4/80 on PWM-SCM-cultured BMMCs, whereas IL-3/SCF-cultured BMMCs expressed CD11b and F4/80, but not MHC class II or CD11c. When IFN- was added to the IL-3/SCF-based medium, PU.1 transfectant acquired MHC class II expression, which was abolished by antibody neutralization or in Ifngr–/– BMMCs, through the induction of expression of the MHC class II transactivator, CIITA. Real-time PCR detected CIITA mRNA driven by the fourth promoter, pIV, and chromatin immunoprecipitation indicated direct binding of PU.1 to pIV in PU.1-over-expressing BMMCs. PU.1-over-expressing cells showed a marked increase in IL-6 production in response to LPS stimulation in both IL-3/SCF and PWM-SCM cultures. These results suggest that PU.1 overproduction alone is sufficient for both expression of CD11b and F4/80 and for amplification of LPS-induced IL-6 production. However, IFN- stimulation is essential for PU.1-mediated transactivation of CIITA pIV. Reduced expression of mast cell-related molecules and transcription factors GATA-1/2 and up-regulation of C/EBP in PU.1 transfectants indicate that enforced PU.1 suppresses mast cell-specific gene expression through these transcription factors.

  T Kurata , N Yamamoto , T Komiya , J Tsurutani , M Miyazaki , K Tamura , K Takeda , K Nakagawa and M. Fukuoka
 

A combination Phase I study of gemcitabine and irinotecan in patients with previously untreated advanced non-small-cell lung cancer was conducted. Patients received gemcitabine and irinotecan on Days 1 and 8 every 3 weeks. A total of 11 patients were enrolled. Three of six patients who received the starting dose (gemcitabine, 800 mg/m2; irinotecan, 80 mg/m2) experienced dose-limiting toxicities (Grade 4 neutropenia, Grade 3 elevation of transaminase and Grade 5 interstitial pneumonia). At the reduced dose level (gemcitabine, 800 mg/m2; irinotecan, 60 mg/m2), all two assessable patients could not meet the administration criteria of Day 8 (one, Grade 2 elevation of transaminase; the other, Grade 1 diarrhea). No objective response was observed in eight evaluable patients. We could not determine the recommended dose of this combination because of intolerable toxicities and no efficacy. Therefore, it is difficult to forward this combination chemotherapy toward further studies.

  H Yoshida , K Takeda , K Izumori and S. Kamitori
 

Pseudomonas stutzeri l-rhamnose isomerase (l-RhI) is capable of catalyzing the isomerization between various aldoses and ketoses, showing high catalytic activity with broad substrate-specificity compared with Escherichia coli l-RhI. In a previous study, the crystal structure of P. stutzeri l-RhI revealed an active site comparable with that of E. coli l-RhI and d-xylose isomerases (d-XIs) with structurally conserved amino acids, but also with a different residue seemingly responsible for the specificity of P. stutzeri l-RhI, though the residue itself does not interact with the bound substrate. This residue, Ser329, corresponds to Phe336 in E. coli l-RhI and Lys294 in Actinoplanes missouriensis d-XI. To elucidate the role of Ser329 in P. stutzeri l-RhI, we constructed mutants, S329F (E. coli l-RhI type), S329K (A. missouriensis d-XI type), S329L and S329A. Analyses of the catalytic activity and crystal structure of the mutants revealed a hydroxyl group of Ser329 to be crucial for catalytic activity via interaction with a water molecule. In addition, in complexes with substrate, the mutants S329F and S329L exhibited significant electron density in the C-terminal region not observed in the wild-type P. stutzeri l-RhI. The C-terminal region of P. stutzeri l-RhI has flexibility and shows a flip-flop movement at the inter-molecular surface of the dimeric form.

  F Han , K Takeda , M Ono , F Date , K Ishikawa , S Yokoyama , Y Shinozawa , K Furuyama and S. Shibahara
 

Heme oxygenase (HO) catalyzes oxidative breakdown of heme, and constitutes two isozymes, HO-1 and HO-2. Here, we explored the tissue-specific regulation of expression of HO-1 and HO-2 under hypoxemia. There was no significant change in the overall expression levels of HO-1 and HO-2 mRNAs and proteins in the lung during adaptation of C57BL/6 mice to normobaric hypoxia (10% O2). However, immunohistochemical analysis revealed the increased expression of HO-1 and HO-2 proteins after 28 days of normobaric hypoxia in the pulmonary venous myocardium that is the extension of the left atrial myocardium into pulmonary venous walls. Moreover, the expression of HO-2 protein was increased in the sub-endocardial myocardium of ventricles under hypoxia, while HO-1 protein level was increased in the full-thickness walls. Thus, hypoxemia induces expression of both HO-1 and HO-2 proteins in the myocardium. Using C57BL/6 mice lacking HO-2 (HO-2–/–), which manifest chronic hypoxemia, we also showed that the HO-1 protein level in the lung was similar between HO-2–/– mice and wild-type mice. Unexpectedly, HO-1 protein level was lower by 35% in the HO-2–/– mouse liver than the wild-type liver. These results indicate that the expression of HO-1 protein is regulated in a tissue-specific manner under hypoxemia.

  K Takeda , N. H Takahashi , M Yoshizawa and S. Shibahara
 

Lipocalin-type prostaglandin D synthase (L-PGDS) catalyses the formation of prostaglandin D2 (PGD2) and also functions as a transporter for lipophilic ligands, including all-trans retinoic acid (RA). Here, we show that human epidermal melanocytes produce and secrete L-PGDS and PGD2 in culture medium, whereas L-PGDS is not expressed in human melanoma cell lines, HMV-II, SK-MEL-28, 624 mel and G361. Treatment with RA (1 or 10 µM) for 4 days decreased the proliferation of melanocytes (30% decrease), but not melanoma cells. We therefore isolated L-PGDS-expressing cell lines from 624 mel cells. Treatment with RA decreased the proliferation of L-PGDS-expressing cells by 20%, but not mock-transfected cell lines lacking L-PGDS expression. RA induced expression of a cyclin-dependent kinase inhibitor p21Cip1 in L-PGDS-expressing cells, but not mock-transfected cells. Moreover, RA increased the transient expression of a reporter gene carrying the RA-responsive elements in L-PGDS-expressing cell lines (at least 5-fold activation), compared to the 2-fold activation in mock-transfected cell lines, suggesting that L-PGDS may increase the sensitivity to RA. Lastly, the knockdown of L-PGDS expression by RNA interference was associated with the restoration of the RA-mediated decrease in proliferation of human and mouse melanocytes. In conclusion, L-PGDS may fine-tune the RA signalling in melanocytes.

 
 
 
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