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141.
Saito A Ariki S Sohma H Nishitani C Inoue K Ebata N Takahashi M Hasegawa Y Kuronuma K Takahashi H Kuroki Y 《The Journal of biological chemistry》2012,287(18):15034-15043
Defensins are important molecules in the innate immune system that eliminate infectious microbes. They also exhibit cytotoxicity against host cells in higher concentrations. The mechanisms by which hosts protect their own cells from cytotoxicity of defensins have been poorly understood. We found that the cytotoxicity of human β-defensin 3 (hBD3) against lung epithelial cells was dose-dependently attenuated by pulmonary surfactant protein A (SP-A), a collectin implicated in host defense and regulation of inflammatory responses in the lung. The direct interaction between SP-A and hBD3 may be an important factor in decreasing this cytotoxicity because preincubation of epithelial cells with SP-A did not affect the cytotoxicity. Consistent with in vitro analysis, intratracheal administration of hBD3 to SP-A(-/-) mice resulted in more severe tissue damage compared with that in WT mice. These data indicate that SP-A protects lung epithelium from tissue injury caused by hBD3. Furthermore, we found that the functional region of SP-A lies within Tyr(161)-Lys(201). Synthetic peptide corresponding to this region, tentatively called SP-A Y161-G200, also inhibited cytotoxicity of hBD3 in a dose-dependent manner. The SP-A Y161-G200 is a candidate as a therapeutic reagent that prevents tissue injury during inflammation. 相似文献
142.
Yamada C Sano H Shimizu T Mitsuzawa H Nishitani C Himi T Kuroki Y 《The Journal of biological chemistry》2006,281(31):21771-21780
The purpose of the current study was to examine the binding of pulmonary surfactant protein A (SP-A) to TLR4 and MD-2, which are critical signaling receptors for lipopolysaccharides (LPSs). The direct binding of SP-A to the recombinant soluble form of extracellular TLR4 domain (sTLR4) and MD-2 was detected using solid-phase binding, immunoprecipitation, and BIAcore. SP-A bound to sTLR4 and MD-2 in a Ca2+-dependent manner, and an anti-SP-A monoclonal antibody whose epitope lies in the region Thr184-Gly194 blocked the SP-A binding to sTLR4 and MD-2, indicating the involvement of the carbohydrate recognition domain (CRD) in the binding. SP-A avidly bound to the deglycosylated forms of sTLR4 and MD-2, suggesting a protein/protein interaction. In addition, SP-A attenuated cell surface binding of smooth LPS and smooth LPS-induced NF-kappaB activation in TLR4/MD-2-expressing cells. To know the role of oligomerization in the interaction of SP-A with TLR4 and MD-2, the collagenase-resistant fragment (CRF), which consisted of CRD plus neck domain of SP-A, was isolated. CRF assembled as a trimer, whereas SP-A assembled as a higher order oligomer. Although CRD was suggested to be involved in the binding, CRF exhibited approximately 600- and 155-fold higher KD for the binding to TLR4 and MD-2, respectively, when compared with SP-A. Consistently significantly higher molar concentrations of CRF were required to inhibit smooth LPS-induced NF-kappaB activation and tumor necrosis factor-alpha secretion. These results demonstrate for the first time the direct interaction between SP-A and TLR4/MD-2 and suggest the importance of supratrimeric oligomerization in the immunomodulatory function of SP-A. 相似文献
143.
Nishitani C Mitsuzawa H Sano H Shimizu T Matsushima N Kuroki Y 《The Journal of biological chemistry》2006,281(50):38322-38329
Toll-like receptor 4 (TLR4) is a signaling receptor for lipopolysaccharide (LPS), but its interaction with MD-2 is required for efficient responses to LPS. Previous studies with deletion mutants indicate a critical role of the amino-terminal TLR4 region in interaction with MD-2. However, it is uncertain which region in the TLR4 molecule directly binds to MD-2. The purpose of this study was to determine a critical stretch of primary sequence in the TLR4 region that directly binds MD-2 and is critical for LPS signaling. The synthetic TLR4 peptide corresponding to the TLR4 region Glu(24)-Lys(47) directly binds to recombinant soluble MD-2 (sMD-2). The TLR4 peptide inhibited the binding of a recombinant soluble form of the extracellular TLR4 domain (sTLR4) to sMD-2 and significantly attenuated LPS-induced NF-kappaB activation and IL-8 secretion in wild type TLR4-transfected cells. Reduction and S-carboxymethylation of sTLR4 abrogated its association with sMD-2. The TLR4 mutants, TLR4(C29A), TLR4(C40A), and TLR4(C29A,C40A), were neither co-precipitated with MD-2 nor expressed on the cell surface and failed to transmit LPS signaling. These results demonstrate that the TLR4 region Glu(24)-Lys(47) is a site for MD-2 binding and that Cys(29) and Cys(40) within this region are critical residues for MD-2 binding and LPS signaling. 相似文献
144.
145.
High phosphorylation of HBV core protein by two alpha-type CK2-activated cAMP-dependent protein kinases in vitro 总被引:2,自引:0,他引:2
Two alpha-type CK2-activated PKAs (CK2-aPKAIalpha and CK2-aPKAIIalpha) were biochemically characterized in vitro using GST-HBV core fusion protein (GST-Hcore) and GST-Hcore157B as phosphate acceptors. It was found that (i), in the absence of cAMP, these two CK2-aPKAs phosphorylated both Ser-170 and Ser-178 on GST-Hcore and Hcore157B; (ii) this phosphorylation was approx. 4-fold higher than their phosphorylation by cAMP-activated PKAs; and (iii) suramin effectively inhibited the phosphorylation of Hcore157B by CK2-aPKAIIalpha through its direct binding to Hcore157B in vitro. These results suggest that high phosphorylation of HBV-CP by two CK2-aPKAs, in the absence of cAMP, may be involved in the pregenomic RNA (pgRNA) encapsidation and DNA-replication in HBV-infected cells. 相似文献
146.
Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress
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Misao Kuroki Yasuo Ariumi Masanori Ikeda Hiromichi Dansako Takaji Wakita Nobuyuki Kato 《Journal of virology》2009,83(5):2338-2348
Arsenic trioxide (ATO), a therapeutic reagent used for the treatment of acute promyelocytic leukemia, has recently been reported to increase human immunodeficiency virus type 1 infectivity. However, in this study, we have demonstrated that replication of genome-length hepatitis C virus (HCV) RNA (O strain of genotype 1b) was notably inhibited by ATO at submicromolar concentrations without cell toxicity. RNA replication of HCV-JFH1 (genotype 2a) and the release of core protein into the culture supernatants were also inhibited by ATO after the HCV infection. To clarify the mechanism of the anti-HCV activity of ATO, we examined whether or not PML is associated with this anti-HCV activity, since PML is known to be a target of ATO. Interestingly, we observed the cytoplasmic translocation of PML after treatment with ATO. However, ATO still inhibited the HCV RNA replication even in the PML knockdown cells, suggesting that PML is dispensable for the anti-HCV activity of ATO. In contrast, we found that N-acetyl-cysteine, an antioxidant and glutathione precursor, completely and partially eliminated the anti-HCV activity of ATO after 24 h and 72 h of treatment, respectively. In this context, it is worth noting that we found an elevation of intracellular superoxide anion radical, but not hydrogen peroxide, and the depletion of intracellular glutathione in the ATO-treated cells. Taken together, these findings suggest that ATO inhibits the HCV RNA replication through modulation of the glutathione redox system and oxidative stress.Hepatitis C virus (HCV) is the causative agent of chronic hepatitis, which progresses to liver cirrhosis and hepatocellular carcinoma. HCV is an enveloped virus with a positive single-stranded 9.6-kb RNA genome, which encodes a large polyprotein precursor of approximately 3,000 amino acid residues. This polyprotein is cleaved by a combination of the host and viral proteases into at least 10 proteins in the following order: core, envelope 1 (E1), E2, p7, nonstructural 2 (NS2), NS3, NS4A, NS4B, NS5A, and NS5B (30).Alpha interferon has been used as an effective anti-HCV reagent in clinical therapy for patients with chronic hepatitis C. The current combination treatment with pegylated alpha interferon and ribavirin, a nucleoside analogue, has been shown to improve the sustained virological response rate to more than 50% (15). However, the adverse effects of the combination therapy and the limited efficacy against genotype 1b warrant the development of new anti-HCV reagents.Arsenic trioxide (ATO) (As2O3, arsenite) has been used as a therapeutic reagent in acute promyelocytic leukemia, which bears an oncogenic PML-retinoic acid receptor alpha fusion protein resulting from chromosomal translocation (51, 52, 68, 70). The ATO treatment induces complete remission through degradation of the aberrant PML-retinoic acid receptor α (70). The PML tumor suppressor protein is required for formation of the PML nuclear body (PML-NB), also known as nuclear dot 10 or the PML oncogenic domain, which is often disrupted by infection with DNA viruses, such as herpes simplex virus type 1, human cytomegalovirus, and Epstein-Barr virus (17). The treatment with ATO results in degradation of the PML protein and disruption of the PML-NB (70). Therefore, ATO has been become a useful probe for investigating the functions of the PML-NB, including cell growth, apoptosis, stress response, and viral infection. Indeed, ATO has been shown to increase retroviral infectivity, such as human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus infectivity, but the mechanisms of this change are not well understood (5, 6, 32, 44, 47, 50, 57). In contrast, ATO was recently reported to inhibit the replication of HCV subgenomic replicon RNA (24). However, it also remains unclear how ATO inhibits the HCV RNA replication. In this study, using genome-length HCV RNA replication systems, we investigated the molecular mechanism(s) of the anti-HCV activity of ATO, and we provide evidence that ATO inhibits HCV RNA replication through modulation of the glutathione redox system and oxidative stress. 相似文献
147.
Hiroshi Yao Tatsuo Nakahara Nobuaki Nakagawa Kijiro Hashimoto Toshihide Kuroki 《Neurochemical research》2009,34(11):1999-2007
Although DNA microarray studies showed up-regulation of various genes, failures of translation of many genes are expected
to occur under ischemic conditions even in the penumbra with mild reduction in cerebral blood flow. We applied surface enhanced
laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS) technology to study proteomic profile at 6, 12,
and 24 h after photothrombotic middle cerebral artery (MCA) occlusion with or without YAG laser-induced reperfusion in adult
male spontaneously hypertensive rats. Of the 43 protein peaks that differed from the sham-operation group with a criterion
(no overlap of peak intensities between the two groups), 36 peaks (84%) were down-regulated, and seven were up-regulated.
All increased peaks showed greater than twofold increases (up to 8.1 fold) compared with those in the sham-operation group.
Effects of reperfusion were observed mainly at 24 h after 1 h of MCA occlusion only in the penumbra, where 23 of 32 peaks
returned toward the control values, whereas none of 33 peaks showed such attenuation in the ischemic core. Major ischemia-induced
changes in protein peaks detected with SELDI-TOF-MS were down-regulations. The present study showed that dynamic changes of
protein profile were associated with progression and recovery of the ischemic core and penumbra. 相似文献
148.
Yukiko Inoue Ken Yoda Hidenori Fujii Hirofumi Kuroki Yasuaki Niizuma 《Journal of Ethology》2010,28(2):221-230
Infanticide, the killing of young animals by conspecifics, has been observed in diverse taxa. The function of infanticide
has been classified as exploitation, sexual selection, parental manipulation or resource competition. We observed infanticidal
behavior and its reproductive results at five breeding colonies of great cormorants from January to August 2008. Eighteen
cases of nest intrusions and/or attacks toward a chick by conspecific non-nest-owners were observed, and two of them were
filmed. In both attacks, perpetrators pecked the necks of chicks several times with display. The chicks bent their necks down
onto the nest and remained stationary. Our data did not support the exploitation hypothesis because adult cormorants did not
use chicks as food. In addition, the perpetrators were not true parents and did not mate with the female nest owner, indicating
that parental manipulation and sexual selection hypotheses were unlikely explanations. On the other hand, concurrent presence
of adults during prelaying and chick-rearing periods at a particular colony affected the occurrence of nest takeovers and
intrusions and/or attacks, suggesting that some conflicts over nests arise between individuals that are at different stages
of the breeding cycle. Digital videos relating to this article are available at and . 相似文献
149.
Transgenerational mass marking of viviparous fish larvae in vivo was validated by intra‐muscular injection of elemental strontium chloride (SrCl2) in gestating females and detection of the Sr in the otoliths of developing larvae. All otoliths of brown rockfish Sebastes auriculatus larvae produced from SrCl2‐injected females showed enriched Sr:Ca ratios near the otolith edges, and the signatures did not appear to be affected by the anterior, centre and posterior positions of larvae within the ovary. Results from the present study indicate that transgenerational marking is a highly reliable technique for marking large numbers of extremely small viviparous fish larvae. 相似文献
150.
Sawada H Oeda T Kuno S Nomoto M Yamamoto K Yamamoto M Hisanaga K Kawamura T;Amantadine Study Group 《PloS one》2010,5(12):e15298