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41.
Naoko Kubo Birukawa Kazuyuki Murase Yasushi Sato Akemi Kosaka Akihiro Yoneda Hiroki Nishita Ryosuke Fujita Miyuki Nishimura Takafumi Ninomiya Keiko Kajiwara Miyono Miyazaki Yusuke Nakashima Sigenori Ota Yuya Murakami Yasunobu Tanaka Kenjiro Minomi Yasuaki Tamura Yoshiro Niitsu 《The Journal of biological chemistry》2014,289(29):20209-20221
Stellate cells are distributed throughout organs, where, upon chronic damage, they become activated and proliferate to secrete collagen, which results in organ fibrosis. An intriguing property of hepatic stellate cells (HSCs) is that they undergo apoptosis when collagen is resolved by stopping tissue damage or by treatment, even though the mechanisms are unknown. Here we disclose the fact that HSCs, normal diploid cells, acquired dependence on collagen for their growth during the transition from quiescent to active states. The intramolecular RGD motifs of collagen were exposed by cleavage with their own membrane type 1 matrix metalloproteinase (MT1-MMP). The following evidence supports this conclusion. When rat activated HSCs (aHSCs) were transduced with siRNA against the collagen-specific chaperone gp46 to inhibit collagen secretion, the cells underwent autophagy followed by apoptosis. Concomitantly, the growth of aHSCs was suppressed, whereas that of quiescent HSCs was not. These in vitro results are compatible with the in vivo observation that apoptosis of aHSCs was induced in cirrhotic livers of rats treated with siRNAgp46. siRNA against MT1-MMP and addition of tissue inhibitor of metalloproteinase 2 (TIMP-2), which mainly inhibits MT1-MMP, also significantly suppressed the growth of aHSCs in vitro. The RGD inhibitors echistatin and GRGDS peptide and siRNA against the RGD receptor αVβ1 resulted in the inhibition of aHSCs growth. Transduction of siRNAs against gp46, αVβ1, and MT1-MMP to aHSCs inhibited the survival signal of PI3K/AKT/IκB. These results could provide novel antifibrosis strategies. 相似文献
42.
The Broad-Complex gene encodes one of the key regulators of the ecdysone signal cascade. We previously isolated part of the genomic DNA and cDNAs of Broad-Complex in Bombyx mori (BmBR-C). Here, we report structures of the entire genomic DNA and 5' untranslated region (5'-UTR) of the cDNAs. BmBR-C was found to span about 158 kbp including 13 exons. In the 5'-UTR, additional alternatively spliced exons were identified. The 5' ends of the cDNAs were mapped to two different positions, the distal promoter (P(dist)) and proximal promoter (P(prox)), separated by 86 kbp. Expression from these promoters was controlled differentially. Semi-quantitative PCR using cDNAs from the carcass, silk glands and fat body revealed that expression from P(prox) was changed moderately and expression from P(dist) was weak and constant during the fourth ecdysis. At the onset of pupation, expression from P(prox) was suppressed in all tissues, but that from P(dist) was induced in the carcass and ASG. In the fat body, expression from both promoters increased in the prepupal stage. A combination of promoters differing in responsiveness to an ecdysone signal may serve to achieve a complex regulation of downstream genes in reply to a simple hormonal signal. 相似文献
43.
Nakatani S Ikura M Yamamoto S Nishita Y Itadani S Habashita H Sugiura T Ogawa K Ohno H Takahashi K Nakai H Toda M 《Bioorganic & medicinal chemistry》2006,14(15):5402-5422
A series of N-benzoyl 4-aminobutyric acid hydroxamate analogs were synthesized and evaluated as matrix metalloproteinase inhibitors. Synthetic work was focused on the chemical modification of the 4-aminobutyric acid part using easily available starting materials. As such, chemical modification was carried out using commercially available starting materials such as 4-aminobutyric acid, (+)- and (-)-malic acid, and D- and L-glutamic acid derivatives. Among the compounds tested, N-[4-(benzofuran-2-yl)benzoyl] 4-amino-4S-hydroxymethylbutyric acid hydroxamates derived from L-glutamic acid demonstrated more potent inhibitory activity against MMP-2 and MMP-9 compared with the corresponding 2S-hydroxy analogs or 3S-hydroxy analogs, respectively, which were derived from (-)-malic acid. Structure-activity relationship study is presented. 相似文献
44.
Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis 总被引:2,自引:0,他引:2
Maeda K Kobayashi Y Udagawa N Uehara S Ishihara A Mizoguchi T Kikuchi Y Takada I Kato S Kani S Nishita M Marumo K Martin TJ Minami Y Takahashi N 《Nature medicine》2012,18(3):405-412
The signaling molecule Wnt regulates bone homeostasis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-κB (RANK) expression in osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis. 相似文献
45.
Nomachi A Nishita M Inaba D Enomoto M Hamasaki M Minami Y 《The Journal of biological chemistry》2008,283(41):27973-27981
The receptor tyrosine kinase Ror2 has recently been shown to act as an alternative receptor or coreceptor for Wnt5a and to mediate Wnt5a-induced migration of cultured cells. However, little is known about the molecular mechanism underlying this migratory process. Here we show by wound-healing assays that Ror2 plays critical roles in Wnt5a-induced cell migration by regulating formation of lamellipodia and reorientation of microtubule-organizing center (MTOC). Wnt5a stimulation induces activation of the c-Jun N-terminal kinase JNK at the wound edge in a Ror2-dependent manner, and inhibiting JNK activity abrogates Wnt5a-induced lamellipodia formation and MTOC reorientation. Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. We further show that Wnt5a-induced JNK activation and MTOC reorientation can be suppressed by inhibiting PKCzeta. Taken together, our findings indicate that Wnt5a/Ror2 activates JNK, through a process involving filamin A and PKCzeta, to regulate polarized cell migration. 相似文献
46.
Changgong Li Hongyan Chen Lingyan Hu Yiming Xing Tomoyo Sasaki Maria F Villosis John Li Michiru Nishita Yasuhiro Minami Parviz Minoo 《BMC molecular biology》2008,9(1):11
Background
Wnt signaling is mediated through 1) the beta-catenin dependent canonical pathway and, 2) the beta-catenin independent pathways. Multiple receptors, including Fzds, Lrps, Ror2 and Ryk, are involved in Wnt signaling. Ror2 is a single-span transmembrane receptor-tyrosine kinase (RTK). The functions of Ror2 in mediating the non-canonical Wnt signaling have been well established. The role of Ror2 in canonical Wnt signaling is not fully understood. 相似文献47.
Kitade K Takahashi K Yonekura S Katsumata N Furukawa G Ohsuga S Nishita T Katoh K Obara Y 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2002,172(5):379-385
Thirty-two male Holstein calves were used to investigate the effects of nutritional conditions around weaning and aging on carbonic anhydrase (CA) activity in the parotid gland and epithelium from the rumen and abomasum. We fed calf starter and lucerne hay as well as milk replacer (group N) or fed milk replacer either with (group S) or without (group M) administration of short-chain fatty acids (SCFA) through polypropylene tubing into the forestomach until 13 weeks of age. The diets were fed at 1000 hours and 1600 hours, and SCFA were administrated after milk replacer feeding at 1600 hours. Slaughter and tissue sampling were carried out between 1300 hours and 1430 hours at 1, 3, 7, 13, and 18 weeks of age. Tissue samples from five adult (1.5-2.0 years-old) Holstein steers were obtained from a local abattoir. In group N, CA activity in the parotid gland gradually and significantly increased toward the adult value, whilst in the epithelium from the rumen and abomasum, adult values were reached at 3 and 7 weeks of age, respectively. At 13 weeks, the activity for group N was significantly higher than that for the other two groups in the parotid gland, but there was no significant difference in the epithelium from the rumen and abomasum. The concentration of the carbonic isozyme VI in the parotid gland also changed with age but, in contrast to CA activity, had not reached adult levels by 13 weeks of age. In groups M and S, parotid saliva did not show any change toward an alkaline pH or toward a reciprocal change in the concentrations between Cl(-) and HCO(3)(-), even at 13 weeks of age. From these results we conclude that a concentrate-hay based diet around weaning has a crucial role in CA development in the parotid gland, but not in the epithelium of the rumen and abomasum. 相似文献
48.
The sequence of equine muscle carbonic anhydrase 总被引:2,自引:0,他引:2
K M Wendorff T Nishita J R Jabusch H F Deutsch 《The Journal of biological chemistry》1985,260(10):6129-6132
The sequence of equine muscle carbonic anhydrase (CA-III) has been determined. The 2 reactive cysteines of the 5 such residues have been localized. A strong sequence homology to other mammalian carbonic anhydrases exists, and 91% of the residues in the equine and bovine muscle forms are identical. 相似文献
49.
In a previous report (J. Biochem. 89, 1333-1335, 1981) we showed that 30 degrees C-treatment (pCa less than 6 and 2 mM MgCl2), like EDTA-treatment, caused a reversible removal of regulatory light-chains from Akazara adductor myosin. Utilizing the heat-treatment, we now show (a) that not half but the total removal of regulatory light-chains from Akazara myosin is required for a complete loss of calcium sensitivity of myosin-ATPase, and (b) that recombination of not 1 but 2 mol of regulatory light-chains is required for a full recovery of calcium sensitivity of both myosin-ATPase and actomyosin-superprecipitation. These (a, b) are what we showed previously with EDTA-treatment (J. Biochem. 85, 1543-1546, 1979 and 86, 663-673, 1979), thus establishing that in all respects we tested, the heat-treatment is as good as EDTA-treatment for reversible removal of regulatory light-chains. We also show that the presence of actin during heat-treatment of myosin prevented regulatory light-chains from being released (at pCa 7) and that how well the release was prevented depended on the MgCl2 concentration during the heat-treatment. 相似文献
50.
Toshiaki Matsui Takashi Kondo Yoshitaka Nishita Satoshi Itadani Hiroshi Tsuruta Setsuko Fujita Nagashige Omawari Masaru Sakai Shuichi Nakazawa Akihito Ogata Hideaki Mori Wataru Kamoshima Kouichiro Terai Hiroyuki Ohno Takaaki Obata Hisao Nakai Masaaki Toda 《Bioorganic & medicinal chemistry》2002,10(12):136-3805
Design and synthesis of metabolically stabilized inhibitors of TNF-alpha production, which could be new drug candidates, are reported. Conformational analysis of an active diastereoisomer was performed based on biological evaluations of the conformationally fixed indane derivatives 17 and 18. Structure-activity relationships (SARs) based on biological evaluations of the optically active derivatives are also discussed. Full details including chemistry are reported. 相似文献