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71.
Kawato M Shirakawa R Kondo H Higashi T Ikeda T Okawa K Fukai S Nureki O Kita T Horiuchi H 《The Journal of biological chemistry》2008,283(1):166-174
Non-hydrolyzable GTP analogues, such as guanosine 5'-(beta, gamma-imido)triphosphate (GppNHp), induce granule secretion from permeabilized platelets in the absence of increased intracellular Ca(2+). Here, we show that the GppNHp-induced dense granule secretion from permeabilized platelets occurred concomitantly with the activation of small GTPase Ral. This secretion was inhibited by the addition of GTP-Ral-binding domain (RBD) of Sec5, which is a component of the exocyst complex known to function as a tethering factor at the plasma membrane for vesicles. We generated an antibody against Sec5-RBD, which abolished the interaction between GTP-Ral and the exocyst complex in vitro. The addition of this antibody inhibited the GppNHp-induced secretion. These data indicate that Ral mediates the GppNHp-induced dense granule secretion from permeabilized platelets through interaction with its effector, the exocyst complex. Furthermore, GppNHp enhanced the Ca(2+) sensitivity of dense granule secretion from permeabilized platelets, and this enhancement was inhibited by Sec5-RBD. In intact platelets, the association between Ral and the exocyst complex was induced by thrombin stimulation with a time course similar to that of dense granule secretion and Ral activation. Taken together, our results suggest that the Ral-exocyst pathway participates in the regulation of platelet dense granule secretion by enhancing the Ca(2+) sensitivity of the secretion. 相似文献
72.
Tomohito Mizuno Nobuhiko Satoh Shoko Horita Hiroyuki Tsukada Mayuko Takagi Yusuke Sato Haruki Kume Masaomi Nangaku Motonobu Nakamura 《The Journal of biological chemistry》2022,298(3)
Oxidized phospholipids have been shown to exhibit pleiotropic effects in numerous biological contexts. For example, 1-O-hexadecyl-2-azelaoyl-sn-glycero-3-phosphocholine (azPC), an oxidized phospholipid formed from alkyl phosphatidylcholines, is a peroxisome proliferator–activated receptor gamma (PPARγ) nuclear receptor agonist. Although it has been reported that PPARγ agonists including thiazolidinediones can induce plasma volume expansion by enhancing renal sodium and water retention, the role of azPC in renal transport functions is unknown. In the present study, we investigated the effect of azPC on renal proximal tubule (PT) transport using isolated PTs and kidney cortex tissues and also investigated the effect of azPC on renal sodium handling in vivo. We showed using a microperfusion technique that azPC rapidly stimulated Na+/HCO3− cotransporter 1 (NBCe1) and luminal Na+/H+ exchanger (NHE) activities in a dose-dependent manner at submicromolar concentrations in isolated PTs from rats and humans. The rapid effects (within a few minutes) suggest that azPC activates NBCe1 and NHE via nongenomic signaling. The stimulatory effects were completely blocked by specific PPARγ antagonist GW9662, ERK kinase inhibitor PD98059, and CD36 inhibitor sulfosuccinimidyl oleate. Treatment with an siRNA against PPAR gamma completely blocked the stimulation of both NBCe1 and NHE by azPC. Moreover, azPC induced ERK phosphorylation in rat and human kidney cortex tissues, which were completely suppressed by GW9662 and PD98059 treatments. These results suggest that azPC stimulates renal PT sodium-coupled bicarbonate transport via a CD36/PPARγ/mitogen-activated protein/ERK kinase/ERK pathway. We conclude that the stimulatory effects of azPC on PT transport may be partially involved in volume expansion. 相似文献
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Morita M Takahashi I Kanai M Okafuji F Iwashima M Hayashi T Watanabe S Hamazaki T Shimozawa N Suzuki Y Furuya H Yamada T Imanaka T 《FEBS letters》2005,579(2):409-414
The purpose of the present study is to identify bioactive compounds with potential for X-linked adrenoleukodystrophy (X-ALD) pharmacological therapy. Various plant natural products including flavonoids were tested for their ability to ameliorate the abnormality of very long chain fatty acid (VLCFA) metabolism in cultured skin-fibroblasts from X-ALD patients. Of the compounds tested, baicalein 5,6,7-trimethyl ether (baicalein-tri-Me) was found to significantly stimulate the VLCFA beta-oxidation activity. Furthermore, the incorporation of [1-(14)C]lignoceric acid into cholesteryl esters was markedly reduced towards the normal level and the VLCFA (C24:0 and C26:0) content was decreased. These results make baicalein-tri-Me a candidate for the therapeutic compound for X-ALD. 相似文献
76.
Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene 总被引:3,自引:0,他引:3
Miguel Viribay Tomohito Hayashi Dolores Tellería Toshio Mochizuki David M. Reynolds Rafael Alonso Xose M. Lens Felipe Moreno Peter C. Harris Stefan Somlo José L. San Millán 《Human genetics》1997,101(2):229-234
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent inherited disorders. The majority of cases
are due to mutation of the PKD1 gene, on 16p13.3, while in most of the remainder the disease maps to the PKD2 locus, at chromosome
4q21-q23. Recently, the PKD2 gene has been positionally cloned and three nonsense mutations within the coding sequence of
the gene identified. Here we report a systematic mutation screening of all 15 exons of the PKD2 gene in chromosome 4-linked
ADPKD families, using heteroduplex and SSCP analyses. We have identified and characterized seven novel mutations, with a detection
rate of approximately 90% in the population studied. All of the mutations result in the premature stop of translation: four
nonsense changes and three deletions. The deletions are all frameshifting, of four T nucleotides in one case and one G nucleotide
in the other two. All mutations are unique and are distributed throughout the gene without evidence of clustering. Comparison
of specific mutations with the clinical profile in ADPKD2 families shows no clear correlation.
Received: 5 April 1997 / Accepted: 31 July 1997 相似文献
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Machiko Kanzaki Yoshihiro Asano Hatsue Ishibashi-Ueda Eiji Oiki Tomoki Nishida Hiroshi Asanuma Hisakazu Kato Toru Oka Tomohito Ohtani Osamu Tsukamoto Shuichiro Higo Hidetaka Kioka Ken Matsuoka Yoshiki Sawa Issei Komuro Masafumi Kitakaze Seiji Takashima Yasushi Sakata 《PloS one》2016,11(2)
Background
Accurate prediction of both mortality and morbidity is of significant importance, but it is challenging in patients with severe heart failure. It is especially difficult to detect the optimal time for implanting mechanical circulatory support devices in such patients. We aimed to analyze the morphometric ultrastructure of nuclear chromatin in cardiomyocytes by developing an original clinical histopathological method. Using this method, we developed a biomarker to predict poor outcome in patients with dilated cardiomyopathy (DCM).Methods and Results
As a part of their diagnostic evaluation, 171 patients underwent endomyocardial biopsy (EMB). Of these, 63 patients diagnosed with DCM were included in this study. We used electron microscopic imaging of cardiomyocyte nuclei and an automated image analysis software program to assess whether it was possible to detect discontinuity of the nuclear periphery. Twelve months after EMB, all patients with a discontinuous nuclear periphery (Group A, n = 11) died from heart failure or underwent left ventricular assist device (VAD) implantation. In contrast, in patients with a continuous nuclear periphery (Group N, n = 52) only 7 patients (13%) underwent VAD implantation and there were no deaths (p<0.01). We then evaluated chromatin particle density (Nuc-CS) and chromatin thickness in the nuclear periphery (Per-CS) in Group N patients; these new parameters were able to identify patients with poor prognosis.Conclusions
We developed novel morphometric methods based on cardiomyocyte nuclear chromatin that may provide pivotal information for early prediction of poor prognosis in patients with DCM. 相似文献80.