全文获取类型
收费全文 | 1407篇 |
免费 | 115篇 |
国内免费 | 1篇 |
出版年
2022年 | 14篇 |
2021年 | 32篇 |
2020年 | 13篇 |
2019年 | 20篇 |
2018年 | 22篇 |
2017年 | 23篇 |
2016年 | 44篇 |
2015年 | 70篇 |
2014年 | 68篇 |
2013年 | 87篇 |
2012年 | 123篇 |
2011年 | 123篇 |
2010年 | 67篇 |
2009年 | 60篇 |
2008年 | 77篇 |
2007年 | 88篇 |
2006年 | 84篇 |
2005年 | 76篇 |
2004年 | 61篇 |
2003年 | 70篇 |
2002年 | 68篇 |
2001年 | 17篇 |
2000年 | 9篇 |
1999年 | 16篇 |
1998年 | 11篇 |
1997年 | 11篇 |
1996年 | 13篇 |
1994年 | 7篇 |
1993年 | 8篇 |
1992年 | 8篇 |
1991年 | 3篇 |
1990年 | 9篇 |
1989年 | 9篇 |
1988年 | 8篇 |
1987年 | 6篇 |
1986年 | 5篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 11篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 7篇 |
1977年 | 8篇 |
1975年 | 6篇 |
1974年 | 5篇 |
1973年 | 3篇 |
1972年 | 3篇 |
1971年 | 4篇 |
1969年 | 3篇 |
1967年 | 3篇 |
排序方式: 共有1523条查询结果,搜索用时 31 毫秒
111.
112.
Bovine viral diarrhea virus: prevention of persistent fetal infection by a combination of two mutations affecting Erns RNase and Npro protease
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Meyers G Ege A Fetzer C von Freyburg M Elbers K Carr V Prentice H Charleston B Schürmann EM 《Journal of virology》2007,81(7):3327-3338
Different genetically engineered mutants of bovine viral diarrhea virus (BVDV) were analyzed for the ability to establish infection in the fetuses of pregnant heifers. The virus mutants exhibited either a deletion of the overwhelming part of the genomic region coding for the N-terminal protease N(pro), a deletion of codon 349, which abrogates the RNase activity of the structural glycoprotein E(rns), or a combination of both mutations. Two months after infection of pregnant cattle with wild-type virus or either of the single mutants, the majority of the fetuses contained virus or were aborted or found dead in the uterus. In contrast, the double mutant was not recovered from fetal tissues after a similar challenge, and no dead fetuses were found. This result was verified with a nonrelated BVDV containing similar mutations. After intrauterine challenge with wild-type virus, mutated viruses, and cytopathogenic BVDV, all viruses could be detected in fetal tissue after 5, 7, and 14 days. Type 1 interferon (IFN) could be detected in fetal serum after challenge, except with wild-type noncytopathogenic BVDV. On days 7 and 14 after challenge, the largest quantities of IFN in fetal serum were induced by the N(pro) and RNase-negative double mutant virus. The longer duration of fetal infection with the double mutant resulted in abortion. Therefore, for the first time, we have demonstrated the essential role of both N(pro) and E(rns) RNase in blocking interferon induction and establishing persistent infection by a pestivirus in the natural host. 相似文献
113.
Pickhardt M Larbig G Khlistunova I Coksezen A Meyer B Mandelkow EM Schmidt B Mandelkow E 《Biochemistry》2007,46(35):10016-10023
One of the key pathological features of Alzheimer's disease is the aggregation of tau protein. We are therefore searching for compounds capable of inhibiting this reaction. On the basis of an initial screen of 200000 compounds [Pickhardt, M., Gazova, Z., von Bergen, M., Khlistunova, I., Wang, Y., Hascher, A., Mandelkow, E. M., Biernat, J., and Mandelkow, E. (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells, J. Biol. Chem. 280, 3628-3635], we performed an in silico screen and predicted a new phenylthiazolyl-hydrazide (PTH) compound as a possible hit [Larbig, G., Pickhardt, M., Lloyd, D. G., Schmidt, B., and Mandelkow, E. (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res. 4 (3), 315-323.]. Synthesis of this compound showed that it was indeed active in terms of inhibiting de novo tau aggregation and disassembling preformed aggregates (IC50 = 7.7 microM and DC50 = 10.8 microM). We have now synthesized 49 similar structures and identified the core of the PTHs to be crucial for activity, thus representing a lead structure. Analysis of the binding epitope by saturation transfer difference NMR shows strong interactions between the tau protein and the ligand in the aromatic regions of the inhibitor. By chemical variation of the core, we improved the inhibitory potency five-fold. The compounds showed a low toxicity as judged by an N2A cell model of tau aggregation and lend themselves for further development. 相似文献
114.
The transporter RcnA has previously been implicated in Ni(II) and Co(II) detoxification in E. coli probably through efflux. Here we demonstrate that the divergently described rcnA and rcnR gene products constitute a link between nickel, cobalt and iron homeostasis. Deletion of the rcnA gene resulted in increased cellular nickel, cobalt and iron concentrations. Expression of rcnA was induced by Ni(II) or Co(II). Overproduction of rcnR inhibited induction of rcnA by metal cations but RcnR did not bind to the rcnA promoter in vitro. When rcnR or fur, the gene of the global repressor of iron homeostasis, was deleted, expression of rcnA was also induced by iron. The promoter region of rcnA was positive in a Fur titration (FURTA) in vivo assay indicative of Fur binding. Thus, rcnA is part of the Fur regulon of E.␣coli. The implications of a connection between the homoeostasis of closely related transition metals are discussed. 相似文献
115.
Beaulieu F Ouellet C Ruediger EH Belema M Qiu Y Yang X Banville J Burke JR Gregor KR MacMaster JF Martel A McIntyre KW Pattoli MA Zusi FC Vyas D 《Bioorganic & medicinal chemistry letters》2007,17(5):1233-1237
We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 microM), which however was considerably less potent against IKK-1 (IC50 = 4.0 microM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described. 相似文献
116.
Wang CI Guncar G Forwood JK Teh T Catanzariti AM Lawrence GJ Loughlin FE Mackay JP Schirra HJ Anderson PA Ellis JG Dodds PN Kobe B 《The Plant cell》2007,19(9):2898-2912
The gene-for-gene mechanism of plant disease resistance involves direct or indirect recognition of pathogen avirulence (Avr) proteins by plant resistance (R) proteins. Flax rust (Melampsora lini) AvrL567 avirulence proteins and the corresponding flax (Linum usitatissimum) L5, L6, and L7 resistance proteins interact directly. We determined the three-dimensional structures of two members of the AvrL567 family, AvrL567-A and AvrL567-D, at 1.4- and 2.3-A resolution, respectively. The structures of both proteins are very similar and reveal a beta-sandwich fold with no close known structural homologs. The polymorphic residues in the AvrL567 family map to the surface of the protein, and polymorphisms in residues associated with recognition differences for the R proteins lead to significant changes in surface chemical properties. Analysis of single amino acid substitutions in AvrL567 proteins confirm the role of individual residues in conferring differences in recognition and suggest that the specificity results from the cumulative effects of multiple amino acid contacts. The structures also provide insights into possible pathogen-associated functions of AvrL567 proteins, with nucleic acid binding activity demonstrated in vitro. Our studies provide some of the first structural information on avirulence proteins that bind directly to the corresponding resistance proteins, allowing an examination of the molecular basis of the interaction with the resistance proteins as a step toward designing new resistance specificities. 相似文献
117.
Heather J. Robinson Gregor M. Cailliet David A. Ebert 《Environmental Biology of Fishes》2007,80(2-3):165-179
Feeding studies can provide researchers with important insights towards understanding potential fishery impacts on marine
systems. Raja rhina is one of the most common elasmobranch species landed in central and northern California demersal fisheries, yet life history
information is extremely limited for this species and aspects of its diet are unknown. Specimens of R. rhina were collected between September, 2002 and August, 2003 from fisheries-independent trawl surveys. Percent Index of Relative
Importance values indicated that the five most important prey items in 618 stomachs of R. rhina were unidentified teleosts (31.6% IRI), unidentified shrimps (19.6% IRI), unidentified euphausiids (10.9% IRI), Crangonidae
(7.4% IRI), and Neocrangon resima (6.0% IRI). There were significant dietary shifts with increasing skate total length and with increasing depths. Smaller
skates ate small crustaceans and larger skates ate larger fishes and cephalopods. With increasing depths, diet included bentho-pelagic
teleosts and more cephalopods and euphausiids. The findings of this study are consistent with previous researchers that report
similar diet shifts in skate species with size and depth. 相似文献
118.
119.
Agu CA Klein R Lengler J Schilcher F Gregor W Peterbauer T Bläsi U Salmons B Günzburg WH Hohenadl C 《Cellular microbiology》2007,9(7):1753-1765
The bacteriophage-encoded holin proteins are known to promote bacterial cell lysis by forming lesions within the cytoplasmic membrane. Recently, we have shown that the bacteriophage lambda-holin protein exerts cytotoxic activity also in eukaryotic cells accounting for a reduced tumour growth in vivo. In order to elucidate the mechanisms of lambda-holin-induced mammalian cell death, detailed biochemical and morphological analyses were performed. Colocalization analyses by subcellular fractionation and organelle-specific fluorescence immunocytochemistry indicated the presence of the lambda-holin protein in the endoplasmic reticulum and in mitochondria. Functional studies using the mitochondria-specific fluorochrome JC-1 demonstrated a loss of mitochondrial transmembrane potential in response to lambda-holin expression. Morphologically, these cells exhibited unfragmented nuclei but severe cytoplasmic vacuolization representing signs of oncosis/necrosis rather than apoptosis. Consistently, Western blot analyses indicated neither an activation of effector caspases 3 and 7 nor cleavage of the respective substrate poly(ADP-ribose) polymerase (PARP) in an apoptosis-specific manner. These findings suggest that the lambda-holin protein mediates a caspase-independent non-apoptotic mode of cell death. 相似文献
120.
Gregor J Zeller T Balzer A Haberzettl K Klug G 《Journal of molecular microbiology and biotechnology》2007,13(1-3):126-139
The formation of photosynthetic complexes in facultatively photosynthetic bacteria is controlled by the oxygen tension in the environment. In Rhodobacter capsulatus the two-component system RegB/RegA plays a major role in the redox control of photosynthesis genes but also controls other redox-dependent systems. The response regulator RegA is phosphorylated under low oxygen tension and activates the puf and puc operons, which encode pigment binding proteins, by binding to their promoter regions. Data from a yeast two-hybrid analysis as well as an in vitroanalysis indicate that RegA interacts with the NtrX protein, the response regulator of the NtrY/NtrX two-component system which is believed to be involved in regulation of nitrogen fixation genes. Our further analysis revealed that NtrX is indeed involved in the regulation of the puf and puc operons. Furthermore, we showed that an altered NtrX protein, which is predicted to adopt the conformation of phosphorylated NtrX protein, binds within the puf promoter region close to the RegA binding sites. We conclude that a direct interaction of two response regulators connects the regulatory systems for redox control and nitrogen control. 相似文献