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61.
N-haloacetylimino neonicotinoids: potency and molecular recognition at the insect nicotinic receptor
Tomizawa M Durkin KA Ohno I Nagura K Manabe M Kumazawa S Kagabu S 《Bioorganic & medicinal chemistry letters》2011,21(12):3583-3586
This structure-activity relationship study for neonicotinoids with an N-haloacetylimino pharmacophore identifies several candidate compounds showing outstanding insecticidal potency and consequently leads to establishing their molecular recognition at an insect nicotinic receptor structural model, wherein the neonicotinoid halogen atoms (fluorine, chlorine, bromine, and iodine) variously interact with the receptor loops C-D interfacial niche via H-bonding and/or hydrophobic interactions. 相似文献
62.
Some cytotoxic immunoconjugates have been approved for malignant lymphoma, a representative of hypervascular and stroma-poor tumors. However, many human solid tumors possess abundant intercellular stromata that prevent diffusion of cancer cell-specific monoclonal antibodies (mAb) and become a barrier preventing immunoconjugates from directly attacking cancer cells. Here we show the successful development of a new strategy that overcomes this drawback and achieves a highly localized concentration of a topoisomerase I inhibitor, SN 38, by conjugating it via an ester bond to a mAb targeted against collagen 4, a plentiful component of the tumor stroma. Poly(ethylene glycol) (PEG) was utilized as a spacer, close to each bond, to maintain stability in the blood. Immunoconjugates selectively extravasated from leaky tumor vessels and minimally from normal vessels because the immunoconjugates are too large to pass through normal vessel walls. Stroma-targeting immunoconjugates bound to the stroma to create a scaffold, from which sustained release of cytotoxic agent occurred and the agent subsequently diffused throughout the tumor tissue to damage both tumor cells and vessels. Cancer-stroma-targeting immunoconjugate therapy was thus validated as a new modality of oncological therapy, especially for refractory, stromal-rich cancers. 相似文献
63.
Kida H Miyoshi T Manabe K Takahashi N Konno T Ueda S Chiba T Shimizu T Okada Y Morishima S 《The Journal of membrane biology》2005,208(1):55-64
Membrane water transport is an essential event not only in the osmotic cell volume change but also in the subsequent cell
volume regulation. Here we investigated the route of water transport involved in the regulatory volume decrease (RVD) that
occurs after osmotic swelling in human epithelial Intestine 407 cells. The diffusion water permeability coefficient (Pd) measured by NMR under isotonic conditions was much smaller than the osmotic water permeability coefficient (Pf) measured under an osmotic gradient. Temperature dependence of Pf showed the Arrhenius activation energy (Ea) of a low value (1.6 kcal/mol). These results indicate an involvement of a facilitated diffusion mechanism in osmotic water
transport. A mercurial water channel blocker (HgCl2) diminished the Pf value. A non-mercurial sulfhydryl reagent (MMTS) was also effective. These blockers of water channels suppressed the RVD.
RT-PCR and immunocytochemistry demonstrated predominant expression of AQP3 water channel in this cell line. Downregulation
of AQP3 expression induced by treatment with antisense oligodeoxynucleotides was found to suppress the RVD response. Thus,
it is concluded that AQP3 water channels serve as an essential pathway for volume-regulatory water transport in, human epithelial
cells. 相似文献
64.
65.
OCA4: evidence for a founder effect for the p.D157N mutation of the MATP gene in Japanese and Korean
Inagaki K Suzuki T Ito S Suzuki N Fukai K Horiuchi T Tanaka T Manabe E Tomita Y 《Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society》2005,18(5):385-388
Oculocutaneous albinism type 4 (OCA4) was identified as a rare form of human OCA among a group of autosomal recessive hypopigmentary disorders. Little is known about the prevailing distribution of patients of OCA4 with mutations of the MATP gene, although one Turkish, five German, one Korean, and 18 Japanese patients have been reported so far. The p.D157N mutation was previously reported to be the most frequent (0.389; 14/36) in Japanese patients and was also found in a Korean patient. On the other hand, this mutation has not been found in Turkish and German patients. We therefore investigated haplotypes of the patients who have the p.D157N mutation. The results showed that OCA4 is prevalent in East Asia including Japan and Korea likely as a result of a founder effect for the p.D157N mutation. Furthermore, it is suspected that the p.D157N mutation might have occurred on an ancestral chromosome after the divergence of Orientals and Caucasians. 相似文献
66.
Kazunori Fujimoto Hiroyuki Kishino Takashi Yamoto Sunao Manabe Atsushi Sanbuissho 《Chemico-biological interactions》2010,188(3):404-411
Glutathione plays an important role as not only a scavenger of reactive oxygen species but also in the conjugation or detoxification of electrophilic reactive metabolites, which has been thought to be one of the causes for idiosyncratic drug toxicity (IDT). Therefore, toxic responses to the reactive metabolites have been expected to be expressed more strongly in a glutathione-depleted condition. In the present study, we attempted to establish an in vitro cytotoxicity assay method to evaluate the toxicity of the reactive metabolite using rat primary cultured hepatocytes with cellular glutathione depletion by l-buthionine-S,R-sulfoximine. Also, we investigated whether the IDT risk is predictable by comparing the cytotoxic sensitivity between glutathione-depleted hepatocytes and untreated hepatocytes. Consequently, 10 drugs of 42 approved drugs, which were classified into 4 IDT categories (Withdrawn, Black box warning, Warning, and Safe), demonstrated higher cytotoxic sensitivity in the glutathione-depleted hepatocytes. Furthermore, a correlation was observed between the incidence of drugs with higher cytotoxic sensitivity in the glutathione-depleted hepatocytes and the IDT risk. The incidence was 50% in the Withdrawn category, 38% in the Black box warning category, 22% in the Warning category, and 8% in the Safe category. These results suggest that the IDT risk of some drugs may be predicted by comparing the cytotoxic sensitivity between them. Additionally, this method may be useful as a screening in the early stage of drug development where leads/candidates are optimized. 相似文献
67.
Izu H Shobayashi M Manabe Y Goto K Iefuji H 《Bioscience, biotechnology, and biochemistry》2006,70(12):2982-2989
The suppressive effects on acute alcoholic liver injury of S-adenosylmethionine (SAM) and the sake yeast, Saccharomyces cerevisiae Kyokai No. 9, have been shown previously. To enhance the suppression of acute alcoholic liver injury by sake yeast, we prepared SAM-accumulating sake yeast (SAM yeast). Male C57BL/6 mice that had been fed on a diet containing 0.25% SAM yeast or sake yeast for two weeks received three doses of ethanol (5 g/kg BW). In the mice fed on the SAM yeast, the ethanol-induced increases in both triglyceride (TG) and alanine aminotransferase (ALT) were significantly repressed. In addition, the SAM yeast-fed mice did not show an ethanol-induced decrease in hepatic SAM level, suggesting that a disorder of methionine metabolism in the liver caused by ethanol was relieved by the SAM yeast. These results suggest that the SAM yeast had a stronger effect suppressing acute alcoholic liver injury in mice than the sake yeast. 相似文献
68.
69.
Kamei N Tobe K Suzuki R Ohsugi M Watanabe T Kubota N Ohtsuka-Kowatari N Kumagai K Sakamoto K Kobayashi M Yamauchi T Ueki K Oishi Y Nishimura S Manabe I Hashimoto H Ohnishi Y Ogata H Tokuyama K Tsunoda M Ide T Murakami K Nagai R Kadowaki T 《The Journal of biological chemistry》2006,281(36):26602-26614
Adipose tissue expression and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) correlate positively with adiposity. To ascertain the roles of MCP-1 overexpression in adipose, we generated transgenic mice by utilizing the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice). These mice had higher plasma MCP-1 concentrations and increased macrophage accumulation in adipose tissues, as confirmed by immunochemical, flow cytometric, and gene expression analyses. Tumor necrosis factor-alpha and interleukin-6 mRNA levels in white adipose tissue and plasma non-esterified fatty acid levels were increased in transgenic mice. aP2-MCP-1 mice showed insulin resistance, suggesting that inflammatory changes in adipose tissues may be involved in the development of insulin resistance. Insulin resistance in aP2-MCP-1 mice was confirmed by hyperinsulinemic euglycemic clamp studies showing that transgenic mice had lower rates of glucose disappearance and higher endogenous glucose production than wild-type mice. Consistent with this, insulin-induced phosphorylations of Akt were significantly decreased in both skeletal muscles and livers of aP2-MCP-1 mice. MCP-1 pretreatment of isolated skeletal muscle blunted insulin-stimulated glucose uptake, which was partially restored by treatment with the MEK inhibitor U0126, suggesting that circulating MCP-1 may contribute to insulin resistance in aP2-MCP-1 mice. We concluded that both paracrine and endocrine effects of MCP-1 may contribute to the development of insulin resistance in aP2-MCP-1 mice. 相似文献
70.
Miso (fermented soybean paste), shoyu (soy sauce) and sake (rice wine) are traditional moldfermented foods in Japan and have
been consumed throughout much of its history. These have long been considered safe foods. In this contribution we review and
summarize long-term studies to investigate potential problems with mycotoxin contamination of these products. The fungal cultures
used for fermentation of these products are called “koji-molds” and mainly consist of strains ofAspergillus oryzae. A. oryzae belongs to theA. flavus group taxonomically, which is generally known to be a main producer of aflatoxins. Therefore, we studied the productivity
of aflatoxins by various koji-molds, as well as the possibility of aflatoxin contamination of rice (which is used in the production
of fermented foods), miso, shoyu and sake. Rice was found to be free from aflatoxins. Furthermore, none of the tested koji-molds
produced any detectable levels of aflatoxins, consequently no aflatoxins were found in miso, shoyu, or sake. However, some
koji-molds are known to produce cyclopiazonic acid (CPA) and kojic acid (KA). We studied the production of CPA and KA by various
commercial koji-molds and identified some strains that produce relatively high amounts of CPA or KA. Consequently, we advised
food industry not to use these strains. Although mycotoxin contamination of these products is therefore presently very low,
further attempts should be made to completely eliminate CPA and KA from fermented foods. 相似文献