全文获取类型
收费全文 | 245篇 |
免费 | 22篇 |
专业分类
267篇 |
出版年
2022年 | 2篇 |
2018年 | 3篇 |
2016年 | 3篇 |
2015年 | 8篇 |
2014年 | 7篇 |
2013年 | 5篇 |
2012年 | 8篇 |
2011年 | 10篇 |
2010年 | 4篇 |
2009年 | 6篇 |
2008年 | 13篇 |
2007年 | 13篇 |
2006年 | 7篇 |
2005年 | 16篇 |
2004年 | 8篇 |
2003年 | 11篇 |
2002年 | 12篇 |
2001年 | 11篇 |
2000年 | 14篇 |
1999年 | 9篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1996年 | 3篇 |
1995年 | 2篇 |
1993年 | 3篇 |
1992年 | 9篇 |
1991年 | 12篇 |
1990年 | 11篇 |
1989年 | 8篇 |
1988年 | 8篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1983年 | 5篇 |
1982年 | 3篇 |
1981年 | 7篇 |
1980年 | 1篇 |
1978年 | 5篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1972年 | 1篇 |
排序方式: 共有267条查询结果,搜索用时 0 毫秒
71.
Serum amyloid A (SAA)-induced remodeling of CSF-HDL 总被引:2,自引:0,他引:2
Miida T Yamada T Seino U Ito M Fueki Y Takahashi A Kosuge K Soda S Hanyu O Obayashi K Miyazaki O Okada M 《Biochimica et biophysica acta》2006,1761(4):424-433
Inflammation is a risk factor for Alzheimer's disease. Serum amyloid A (SAA) is an acute phase protein that dissociates apolipoprotein AI (apoAI) from plasma HDL. In cerebrospinal fluid (CSF), the SAA concentration is much higher in subjects with Alzheimer's disease than in controls. CSF-HDL is rich in apoE, which plays an important role as a ligand for lipoprotein receptors in the central nervous system (CNS). To clarify whether SAA dissociates apoE from CSF-HDL, we added recombinant SAA to CSF and determined the apoE distribution in the CSF using native two-dimensional gel electrophoresis. We found that SAA dissociated apoE from CSF-HDL in a dose-dependent manner. This effect was more evident in apoE4 carriers than in apoE3 or apoE2 carriers. After a 24-h incubation at 37 degrees C, SAA continuously dissociated apoE from CSF-HDL. Amyloid beta (Abeta) fragments (1-42) were bound to large CSF-HDL but not to apoE dissociated by SAA. In conclusion, SAA dissociates apoE from CSF-HDL. We postulate that inflammation in the CNS may impair Abeta clearance due to the loss of apoE from CSF-HDL. 相似文献
72.
Torsten Kleffmann Seino A. K. Jongkees Graham Fairweather Sigurd M. Wilbanks Guy N. L. Jameson 《Journal of biological inorganic chemistry》2009,14(6):913-921
Recent crystal structures of cysteine dioxygenase (CDO) suggest the presence of two posttranslational modifications adjacent
to the catalytic iron center: a thioether cross-link between Cys93 and Tyr157 and extra electron density at Cys164 which was
variously explained as cystine or cysteine sulfinic acid. Purification of recombinant rat CDO yields “mature” and “immature”
forms with distinct electrophoretic mobilities. We have positively identified and characterized the two modifications in the
products of three sequential proteolytic digestions using liquid chromatography coupled with tandem mass spectrometry. The
cross-link is unique to the mature form and was identified in an ion of m/z 3,225.403, consistent with a Tyr-Cys cross-link of peptides Gly80-Phe94 with His155-Phe167. The cross-link is liable to cleavage
by in-source decay and the resulting separate peptides were sequenced by collision-induced dissociation tandem mass spectrometry.
Mass-spectrometric analysis of these same and overlapping peptides in the presence or absence of reductants and alkylating
agents identified the second modification to be a cystine formed between Cys164 and exogenous cysteine as proposed earlier.
Both modifications have been shown to form in the presence of high levels of cysteine and iron. This and the presence of small
amounts of an apparently off-pathway cystine at position Cys93 suggest that although these conditions promote CDO maturation,
they may actually arise via nonenzymatic, nonphysiological processes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
73.
Zvi Granot Avital Swisa Judith Magenheim Miri Stolovich-Rain Wakako Fujimoto Elisabetta Manduchi Takashi Miki Jochen K. Lennerz Christian J. Stoeckert Jr. Oded Meyuhas Susumu Seino M. Alan Permutt Helen Piwnica-Worms Nabeel Bardeesy Yuval Dor 《Cell metabolism》2009,10(4):285-308
Pancreatic β cells, organized in the islets of Langerhans, sense glucose and secrete appropriate amounts of insulin. We have studied the roles of LKB1, a conserved kinase implicated in the control of cell polarity and energy metabolism, in adult β cells. LKB1-deficient β cells show a dramatic increase in insulin secretion in vivo. Histologically, LKB1-deficient β cells have striking alterations in the localization of the nucleus and cilia relative to blood vessels, suggesting a shift from hepatocyte-like to columnar polarity. Additionally, LKB1 deficiency causes a 65% increase in β cell volume. We show that distinct targets of LKB1 mediate these effects. LKB1 controls β cell size, but not polarity, via the mTOR pathway. Conversely, the precise position of the β cell nucleus, but not cell size, is controlled by the LKB1 target Par1b. Insulin secretion and content are restricted by LKB1, at least in part, via AMPK. These results expose a molecular mechanism, orchestrated by LKB1, for the coordinated maintenance of β cell size, form, and function. 相似文献
74.
Scott B. Widenmaier Su-Jin Kim Gary K. Yang Thomas De Los Reyes Cuilan Nian Ali Asadi Yutaka Seino Timothy J. Kieffer Yin Nam Kwok Christopher H. S. McIntosh 《PloS one》2010,5(3)
Aims
The gastrointestinal hormone GIP promotes pancreatic islet function and exerts pro-survival actions on cultured β-cells. However, GIP also promotes lipogenesis, thus potentially restricting its therapeutic use. The current studies evaluated the effects of a truncated GIP analog, D-Ala2-GIP1–30 (D-GIP1–30), on glucose homeostasis and β-cell mass in rat models of diabetes.Materials and Methods
The insulinotropic and pro-survival potency of D-GIP1–30 was evaluated in perfused pancreas preparations and cultured INS-1 β-cells, respectively, and receptor selectivity evaluated using wild type and GIP receptor knockout mice. Effects of D-GIP1–30 on β-cell function and glucose homeostasis, in vivo, were determined using Lean Zucker rats, obese Vancouver diabetic fatty rats, streptozotocin treated rats, and obese Zucker diabetic fatty rats, with effects on β-cell mass determined in histological studies of pancreatic tissue. Lipogenic effects of D-GIP1–30 were evaluated on cultured 3T3-L1 adipocytes.Results
Acutely, D-GIP1–30 improved glucose tolerance and insulin secretion. Chronic treatment with D-GIP1–30 reduced levels of islet pro-apoptotic proteins in Vancouver diabetic fatty rats and preserved β-cell mass in streptozotocin treated rats and Zucker diabetic fatty rats, resulting in improved insulin responses and glycemic control in each animal model, with no change in body weight. In in vitro studies, D-GIP1–30 exhibited equivalent potency to GIP1–42 on β-cell function and survival, but greatly reduced action on lipoprotein lipase activity in 3T3-L1 adipocytes.Conclusions
These findings demonstrate that truncated forms of GIP exhibit potent anti-diabetic actions, without pro-obesity effects, and that the C-terminus contributes to the lipogenic actions of GIP. 相似文献75.
76.
Saito T Sato T Miki T Seino S Nakaya H 《American journal of physiology. Heart and circulatory physiology》2005,288(1):H352-H357
The role of cardiac ATP-sensitive K(+) (K(ATP)) channels in ischemia-induced electrophysiological alterations has not been thoroughly established. Using mice with homozygous knockout (KO) of Kir6.2 (a pore-forming subunit of cardiac K(ATP) channel) gene, we investigated the potential contribution of K(ATP) channels to electrophysiological alterations and extracellular K(+) accumulation during myocardial ischemia. Coronary-perfused mouse left ventricular muscles were stimulated at 5 Hz and subjected to no-flow ischemia. Transmembrane potential and extracellular K(+) concentration ([K(+)](o)) were measured by using conventional and K(+)-selective microelectrodes, respectively. In wild-type (WT) hearts, action potential duration (APD) at 90% repolarization (APD(90)) was significantly decreased by 70.1 +/- 5.2% after 10 min of ischemia (n = 6, P < 0.05). Such ischemia-induced shortening of APD(90) did not occur in Kir6.2-deficient (Kir6.2 KO) hearts. Resting membrane potential in WT and Kir6.2 KO hearts similarly decreased by 16.8 +/- 5.6 (n = 7, P < 0.05) and 15.0 +/- 1.7 (n = 6, P < 0.05) mV, respectively. The [K(+)](o) in WT hearts increased within the first 5 min of ischemia by 6.9 +/- 2.5 mM (n = 6, P < 0.05) and then reached a plateau. However, the extracellular K(+) accumulation similarly occurred in Kir6.2 KO hearts and the degree of [K(+)](o) increase was comparable to that in WT hearts (by 7.0 +/- 1.7 mM, n = 6, P < 0.05). In Kir6.2 KO hearts, time-dependent slowing of conduction was more pronounced compared with WT hearts. In conclusion, the present study using Kir6.2 KO hearts provides evidence that the activation of K(ATP) channels contributes to the shortening of APD, whereas it is not the primary cause of extracellular K(+) accumulation during early myocardial ischemia. 相似文献
77.
78.
Y Yamada Y Seino J Takeda H Fukumoto H Yano N Inagaki Y Fukuda S Seino H Imura 《Biochemical and biophysical research communications》1990,168(3):1274-1279
Gene expression of liver facilitated glucose transporter was rapidly induced during the liver regenerating process in rats. It reached maximum of 2.7 times at 8 hr of the regenerating course and returned to normal by 48 hr. The protein synthesis inhibitor, cycloheximide, did not interfere with the increased gene expression of liver facilitated glucose transporter. By contrast, erythrocyte/brain-type glucose transporter mRNA could not be detected in the livers of partially hepatectomized rats and sham-operated rats. The plasma glucose levels were transiently increased within 2 hr of the regenerative course and then decreased to a nadir at 4 hr. These results suggest that the increased gene expression of liver facilitated glucose transporter contributes to the decrease in plasma glucose levels. 相似文献
79.
Minami K Yokokura M Ishizuka N Seino S 《The Journal of biological chemistry》2002,277(28):25277-25282
Although intracellular Ca(2+) in pancreatic beta-cells is the principal signal for insulin secretion, the effect of chronic elevation of the intracellular Ca(2+) concentration ([Ca(2+)](i)) on insulin secretion is poorly understood. We recently established two pancreatic beta-cell MIN6 cell lines that are glucose-responsive (MIN6-m9) and glucose-unresponsive (MIN6-m14). In the present study we have determined the cause of the glucose unresponsiveness in MIN6-m14. Initially, elevated [Ca(2+)](i) was observed in MIN6-m14, but normalization of the [Ca(2+)](i) by nifedipine, a Ca(2+) channel blocker, markedly improved the intracellular Ca(2+) response to glucose and the glucose-induced insulin secretion. The expression of subunits of ATP-sensitive K(+) channels and voltage-dependent Ca(2+) channels were increased at both mRNA and protein levels in MIN6-m14 treated with nifedipine. As a consequence, the functional expression of these channels at the cell surface, both of which are decreased in MIN6-m14 without nifedipine treatment, were increased significantly. Contrariwise, Bay K8644, a Ca(2+) channel agonist, caused severe impairment of glucose-induced insulin secretion in glucose-responsive MIN6-m9 due to decreased expression of the channel subunits. Chronically elevated [Ca(2+)](i), therefore, is responsible for the glucose unresponsiveness of MIN6-m14. The present study also suggests normalization of [Ca(2+)](i) in pancreatic beta-cells as a therapeutic strategy in treatment of impaired insulin secretion. 相似文献
80.
Kinsuke Tsuda Yutaka Seino Kouzaburo Mori Susumo Seino Jiro Takemura Hideshi Kuzuya Takehira Yamamura Yoshinao Kotoura Nobuyoshi Ito Hiroo Imura 《Regulatory peptides》1981,1(5):347-352
Intravenous glucose infusion was performed in six dogs with and without truncal vagotomy, and plasma pancreatic polypeptide (PP) responses were compared before and after truncal vagotomy. Following truncal vagotomy, basal PP levels decreased significantly from 286 ± 64 pg/ml (mean ± S.E.) to 94 ± 14 pg/ml (P < 0.05). Basal plasma insulin and blood glucose levels also tended to be lower, but not significantly. During the influsion of glucose, blood glucose concentrations rose rapidly in both groups and after 15 min reached peak values which were not significantly different from each other. In the vagotomized group the plasma insulin response to intravenous glucose infusion was significantly lower than in the control group. Following intravenous glucose loading, plasma PP concentrations decreased rapidly in both groups, but the PP level in the vagotomized group was suppressed only to 77 ± 4% of the basal level whereas in the control group it decreased to 45 ± 8%, significantly lower than in the vagotomized group (P < 0.01).These results suggest that basal PP is regulated by vagal tonus and that vagus controls, at least in part, suppression by intravenous glucose administration. 相似文献