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971.
972.
973.
An X-Ray diffraction study on mouse cardiac cross-bridge function in vivo: effects of adrenergic {beta}-stimulation
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Toh R Shinohara M Takaya T Yamashita T Masuda S Kawashima S Yokoyama M Yagi N 《Biophysical journal》2006,90(5):1723-1728
To investigate how beta-stimulation affects the contractility of cardiac muscle, x-ray diffraction from cardiac muscle in the left ventricular free wall of a mouse heart was recorded in vivo. To our knowledge, this is the first x-ray diffraction study on a heart in a living body. After the R wave in electrocardiograms, the ratio of the intensities of the equatorial (1,0) and (1,1) reflections decreased for approximately 50 ms from a diastolic value of 2.1 to a minimum of 0.8, and then recovered. The spacing of the (1,0) lattice planes increased for approximately 90 ms from a diastolic value of 37.2 nm to a maximum of 39.1 nm, and then returned to the diastolic level, corresponding to approximately 10% stretch of sarcomere. Stimulation of beta-adrenergic receptor by dobutamine (20 microg/kg/min) accelerated both the decrease in the intensity ratio, which reached a smaller systolic value, and the increase in the lattice spacing. However, the intensity ratio and spacing at the end-diastole were unchanged. The recovery of the lattice spacing during relaxation was also accelerated. The mass transfer to the thin filaments at systole in a beta-stimulated heart was close to the peak value in twitch of frog skeletal muscle at 4 degrees C, showing that the majority of cross-bridges have been recruited with few in reserve. 相似文献
974.
By using published experimental values of the standard oxygen (O2) equilibrium curve and the in vivo arterial and venous O2 pressure (PO2) of fetal and maternal blood in five mammalian species (human, cow, pig, sheep, and horse), we investigated the relationship between the efficiency of O2 delivery and the effectiveness of the Bohr shift, and discussed the significance of cooperativity for mammalian Hb. The O2 delivery of fetal blood was more efficient than that of maternal blood, and the effectiveness of the Bohr shift at both O2 loading and release sites of fetal blood was high. A linear relationship was observed between the efficiency of O2 delivery and the effectiveness of the Bohr shift at O2 loading sites of the five mammalian species. In both fetal and maternal blood, the theoretically obtained optimal P50 value for O2 delivery (optP50(OD)) was nearly equal to the optimal P50 value for the effectiveness of the Bohr shift at the O2 loading site (optP50(BS)(loading)). This phenomenon was favorable for fetal blood to uptake O2 from maternal blood with the aid of the Bohr shift and to deliver a large amount of O2 to the tissues. The optP50s for the effectiveness of the Bohr shift at given arterial PO2 (PaO2) and venous PO2 (PvO2) were derived as follows: optP50(BS)(loading) = PaO2((n+1)/(n-1))(1/n), and optP50(BS)(release) = PvO2((n+1)/(n-1))(1/n). The relationship between in vivo PO2s and n, PaO2/PvO2 = ((n+1)/(n-1))(2/n), was derived by letting optP50 for the efficiency of O2 delivery be equal to that for the effectiveness of the Bohr shift. 相似文献
975.
Kazunori Matsumura Kazuki Orita Yuichi Wakamoto Kenji Yasuda 《Journal of nanobiotechnology》2006,4(1):7-6
To understand the control mechanism of innate immune response in macrophages, a series of phagocytic responses to plural stimulation
of antigens on identical cells was observed. Two zymosan particles, which were used as antigens, were put on different surfaces
of a macrophage using optical tweezers in an on-chip single-cell cultivation system, which maintains isolated conditions of
each macrophage during their cultivation. When the two zymosan particles were attached to the macrophage simultaneously, the
macrophage responded and phagocytosed both of the antigens simultaneously. In contrast, when the second antigen was attached
to the surface after the first phagocytosis had started, the macrophage did not respond to the second stimulation during the
first phagocytosis; the second phagocytosis started only after the first process had finished. These results indicate that
(i) phagocytosis in a macrophage is not an independent process when there are plural stimulations; (ii) the response of the
macrophage to the second stimulation is related to the time" delay from the first stimulation. Stimulations that occur at
short time intervals resulted in simultaneous phagocytosis, while a second stimulation that is delayed long enough might be
neglected until the completion of the first phagocytic process. 相似文献
976.
Yamamoto T Yamada A Watanabe M Yoshimura Y Yamazaki N Yoshimura Y Yamauchi T Kataoka M Nagata T Terada H Shinohara Y 《Journal of proteome research》2006,5(12):3336-3344
The voltage-dependent anion channel (VDAC) is a pore-forming protein expressed in the outer membrane of eukaryotic mitochondria. Three isoforms of it, i.e., VDAC1, VDAC2, and VDAC3, are known to be expressed in mammals; however, the question as to which is the main isoform in mitochondria is still unanswered. To address this question, we first prepared standard VDACs by using a bacterial expression system and raised various antibodies against them by using synthetic peptides as immunogens. Of the three bacterially expressed VDAC isoforms, VDAC3 showed faster migration in SDS-polyacrylamide gels than VDAC1 and VDAC2, although VDAC2 is longer than VDAC1 and VDAC3, due to a 12-amino acid extension of its N-terminal region. Even with careful structural characterization of the expressed VDACs by LC-MS/MS analysis, serious structural modifications of VDACs causing changes in their migration in SDS-polyacrylamide gels were not detected. Next, immunoreactivities of the raised antibodies toward these bacterially expressed VDAC isoforms were evaluated. Trials to prepare specific antibodies against the three individual VDAC isoforms were not successful except in the case of VDAC1. However, using a synthetic peptide corresponding to the highly conserved region among the three VDACs, we were successful in preparing an antibody showing essentially equal immunoreactivities toward all three VDACs. When mitochondrial outer membrane proteins of various rat tissues were subjected to 2-dimensional electrophoresis followed by immunoblotting with this antibody, six immunoreactive protein spots were detected. These spots were characterized by LC-MS/MS analysis, and the signal intensities among the spots were compared. As a result, the signal intensity of the spot representing VDAC1 was the highest, and thus, VDAC1 was concluded to be the most abundantly expressed of the three VDAC isoforms in mammalian mitochondria. 相似文献
977.
978.
Design and synthesis of potent beta-secretase (BACE1) inhibitors with P1' carboxylic acid bioisosteres 总被引:2,自引:0,他引:2
Kimura T Hamada Y Stochaj M Ikari H Nagamine A Abdel-Rahman H Igawa N Hidaka K Nguyen JT Saito K Hayashi Y Kiso Y 《Bioorganic & medicinal chemistry letters》2006,16(9):2380-2386
Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P4 position of KMI-260 and KMI-360, respectively, with a 1H-tetrazole-5-carbonyl DAP (L-alpha,beta-diaminopropionic acid) residue. At the P1' position, these compounds contain one or two carboxylic acid groups, which are unfavorable for crossing the blood-brain barrier. Herein, we report BACE1 inhibitors with P1' carboxylic acid bioisosteres in order to develop practical anti-Alzheimer's disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50=4.8 nM) and KMI-684 (IC50=1.2 nM), exhibited significantly potent BACE1 inhibitory activities. 相似文献
979.
Design, synthesis, and structure-activity relationships of 3,4-dihydro-2(1H)-quinazolinone derivatives as sodium/calcium (Na+/Ca2+) exchanger inhibitors are described. In these studies, optimization of the substituents at the 3-position of this series of compounds was carried out and dramatic effects of the substituent on the activities were observed. Based on these SAR studies, a highly potent inhibitor of the Na+/Ca2+ exchanger, which showed single-digit-nanomolar activity, was discovered. 相似文献
980.
Ikeda K Sato K Kitani S Suzuki T Maki N Suzuki Y Sato M 《Bioorganic & medicinal chemistry》2006,14(23):7893-7897
To explore the influence of binding to human parainfluenza virus type 1 (hPIV-1), a series of 4-O-substituted Neu5Ac2en derivatives 6a-e was synthesized and tested for their ability to inhibit hPIV-1 sialidase. Among compounds 6a-e, the 4-O-ethyl-Neu5Ac2en derivative 6b showed the most potent inhibitory activity (IC50 6.3 microM) against hPIV-1 sialidase. 相似文献