全文获取类型
收费全文 | 1441篇 |
免费 | 125篇 |
专业分类
1566篇 |
出版年
2023年 | 6篇 |
2022年 | 21篇 |
2021年 | 54篇 |
2020年 | 21篇 |
2019年 | 30篇 |
2018年 | 37篇 |
2017年 | 28篇 |
2016年 | 55篇 |
2015年 | 87篇 |
2014年 | 83篇 |
2013年 | 96篇 |
2012年 | 114篇 |
2011年 | 114篇 |
2010年 | 61篇 |
2009年 | 55篇 |
2008年 | 71篇 |
2007年 | 74篇 |
2006年 | 77篇 |
2005年 | 70篇 |
2004年 | 54篇 |
2003年 | 45篇 |
2002年 | 51篇 |
2001年 | 20篇 |
2000年 | 11篇 |
1999年 | 11篇 |
1998年 | 14篇 |
1997年 | 11篇 |
1996年 | 4篇 |
1995年 | 8篇 |
1994年 | 8篇 |
1993年 | 5篇 |
1992年 | 13篇 |
1991年 | 16篇 |
1990年 | 10篇 |
1989年 | 11篇 |
1988年 | 13篇 |
1987年 | 8篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1984年 | 9篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1980年 | 6篇 |
1978年 | 4篇 |
1976年 | 5篇 |
1974年 | 5篇 |
1967年 | 4篇 |
1966年 | 3篇 |
1965年 | 4篇 |
1963年 | 6篇 |
排序方式: 共有1566条查询结果,搜索用时 13 毫秒
61.
Yalitza Lopez Corcino Shekina Gonzalez Ferrer Luz Eliana Mantilla Sophia Trikeriotis Jin‐Sang Yu Steven Kim Samuel Hansen Jose‐Andres C. Portillo Carlos S. Subauste 《Cellular microbiology》2019,21(10)
Toxoplasma gondii causes retinitis and encephalitis. Avoiding targeting by autophagosomes is key for its survival because T. gondii cannot withstand lysosomal degradation. During invasion of host cells, T. gondii triggers epidermal growth factor receptor (EGFR) signalling enabling the parasite to avoid initial autophagic targeting. However, autophagy is a constitutive process indicating that the parasite may also use a strategy operative beyond invasion to maintain blockade of autophagic targeting. Finding that such a strategy exists would be important because it could lead to inhibition of host cell signalling as a novel approach to kill the parasite in previously infected cells and treat toxoplasmosis. We report that T. gondii induced prolonged EGFR autophosphorylation. This effect was mediated by PKCα/PKCβ ? Src because T. gondii caused prolonged activation of these molecules and their knockdown or incubation with inhibitors of PKCα/PKCβ or Src after host cell invasion impaired sustained EGFR autophosphorylation. Addition of EGFR tyrosine kinase inhibitor (TKI) to previously infected cells led to parasite entrapment by LC3 and LAMP‐1 and pathogen killing dependent on the autophagy proteins ULK1 and Beclin 1 as well as lysosomal enzymes. Administration of gefitinib (EGFR TKI) to mice with ocular and cerebral toxoplasmosis resulted in disease control that was dependent on Beclin 1. Thus, T. gondii promotes its survival through sustained EGFR signalling driven by PKCα/β ? Src, and inhibition of EGFR controls pre‐established toxoplasmosis. 相似文献
62.
63.
64.
Several bacterial species carry in their genomes a so-called "mutagenesis" gene cluster encoding ImuB which is similar to Y-family DNA polymerases, and DnaE2 related to the catalytic subunit DnaE of Pol III. Y-family DNA polymerases are known to be involved in stationary-phase mutagenesis and DnaE2 homologues characterized so far have expressed a mutator phenotype. In this study, we raised a question about the involvement of ImuB and DnaE2 in stationary-phase mutagenesis. Here, we show that Pseudomonas putida ImuB and DnaE2 have antagonistic effects on stationary-phase mutagenesis. ImuB facilitated accumulation of stationary-phase mutants up to two-fold. In contrast to that, DnaE2 had no significant effect on emergence of 1-bp deletion mutants and moreover, it acted as an anti-mutator in accumulation of base substitution mutants in starving bacteria. Similar antagonistic effects of DnaE2 and ImuB on mutagenesis appeared also in UV-mutagenesis study. This data distinguishes the DnaE2 of P. putida from its homologues studied in other organisms. 相似文献
65.
Max Wisshak Neele Meyer Piotr Kuklinski Andres Rüggeberg Andr Freiwald 《Geobiology》2022,20(1):112-136
Rhodolith beds and bioherms formed by ecosystem engineering crustose coralline algae support the northernmost centres of carbonate production, referred to as polar cold-water carbonate factories. Yet, little is known about biodiversity and recruitment of these hard-bottom communities or the bioeroders degrading them, and there is a demand for carbonate budgets to include respective rates of polar carbonate build-up and bioerosion. To address these issues, a 10-year settlement and bioerosion experiment was carried out at the Arctic Svalbard archipelago in and downslope of a rhodolith bed. The calcifiers recorded on experimental settlement tiles (56 taxa) were dominated by bryozoans, serpulids and foraminiferans. The majority of the bioerosion traces (30 ichnotaxa) were microborings, followed by attachment etchings and grazing traces. Biodiversity metrics show that calcifier diversity and bioerosion ichnodiversity are both elevated in the rhodolith bed, if compared to adjacent aphotic waters, but these differences are statistically insignificant. Accordingly, there were only low to moderate dissimilarities in the calcifier community structure and bioerosion trace assemblages between the two depth stations (46 and 127 m), substrate orientations (up- and down-facing) and substrate types (PVC and limestone), in that order of relevance. In contrast, surface coverage as well as the carbonate accretion and bioerosion rates were all significantly elevated in the rhodolith bed, reflecting higher abundance or size of calcifiers and bioerosion traces. All three measures were highest for up-facing substrates at 46 m, with a mean coverage of 78.2% (on PVC substrates), a mean accretion rate of 24.6 g m?2 year?1 (PVC), and a mean bioerosion rate of ?35.1 g m?2 year?1 (limestone). Differences in these metrics depend on the same order of factors than the community structure. Considering all limestone substrates of the two platforms, carbonate accretion and bioerosion were nearly in balance at a net rate of ?2.5 g m?2 year?1. A latitudinal comparison with previous settlement studies in the North Atlantic suggests that despite the harsh polar environment there is neither a depletion in the diversity of hard-bottom calcifier communities nor in the ichnodiversity of grazing traces, attachment etchings and microborings formed by organotrophs. In contrast, microborings produced by phototrophs are strongly depleted because of limitations in the availability of light (condensed photic zonation, polar night, shading by sea ice). Also, macroborings were almost absent, surprisingly. With respect to carbonate production, the Svalbard carbonate factory marks the low end of a latitudinal gradient while bioerosion rates are similar or even higher than at comparable depth or photic regime at lower latitudes, although this might not apply to shallow euphotic waters (not covered in our experiment), given the observed depletion in bioeroding microphytes and macroborers. While echinoid grazing is particularly relevant for the bioerosion in the rhodolith bed, respective rates are far lower than those reported from tropical shallow-water coral reefs. The slow pace of carbonate production but relatively high rates of bioerosion (both promoted by low carbonate supersaturation states in Arctic waters), in concert with high retention of skeletal carbonates on the seafloor and no calcite cements forming in open pore space created by microborers, suggest a low fossilisation potential for polar carbonates, such as those formed in the Mosselbukta rhodolith beds. 相似文献
66.
Norbertas Noreika Aveliina Helm Maarja
pik Teele Jairus Martti Vasar Ülle Reier Ene Kook Kersti Riibak Liis Kasari Hardi Tullus Tea Tullus Reimo Lutter Ede Oja Andres Saag Tiina Randlane Meelis Prtel 《Oikos》2019,128(11):1653-1665
Ecosystem biomass, soil conditions and the diversity of different taxa are often interrelated. These relationships could originate from biogeographic affinity (varying species pools) or from direct ecological effects within local communities. Disentangling regional and local causes is challenging as the former might mask the latter in natural ecosystems with varying habitat conditions. However, when the species pool contribution is considered in statistics, local ecological effects might be detected. In this study we disentangle the indirect effects of the species pool and direct ecological effects on the complex relationships among wood volume, soil conditions and diversities of different plant and fungal groups in 100 old‐growth forest sites (10 × 10 m) at the border of boreal and nemoral zones in northern Europe. We recorded all species for different vegetation groups: woody and herbaceous vascular plants, terricolous and epiphytic bryophytes and lichens. Fungal communities were detected by DNA‐based analyses from soil samples. Above‐ground wood volume was used as a proxy of biomass. We measured soil pH and nutrient content and obtained modelled climate parameters for each site. Species pool effect was considered by dividing sites into boreal and nemoral groups based on community composition. In order to disentangle direct and indirect effects, we applied variation partitioning, and raw and partial correlations. We found many significant positive relationships among studied variables. Many of these relationships were associated to boreal and nemoral species pools, thus indicating that biogeographic affinity of interacting plants and fungi largely defines forest diversity and functioning. At the same time, several relationships were significant also after considering biogeography: woody plant and ectomycorrhizal fungi diversities with wood volume, many plant and fungal groups with each other, or with soil conditions. These direct ecological interactions could be considered in forestry practices to achieve both economic gain and maintenance of biodiversity. 相似文献
67.
Vicki Waetzig Wiebke Haeusgen Cordula Andres Sonja Frehse Kirstin Reinecke Henrike Bruckmueller Ruwen Boehm Thomas Herdegen Ingolf Cascorbi 《Journal of cellular biochemistry》2019,120(4):5974-5986
Neuroblastoma is a malignant childhood cancer arising from the embryonic sympathoadrenal lineage of the neural crest. Retinoic acid (RA) is included in the multimodal therapy of patients with high-risk neuroblastoma to eliminate minimal residual disease. However, the formation of RA-resistant cells substantially lowers 5-year overall survival rates. To examine mechanisms that lead to treatment failure, we chose human SH-SY5Y cells, which are known to tolerate incubation with RA by activating the survival kinases Akt and extracellular signal-regulated kinase 1/2. Characterization of downstream pathways showed that both kinases increased the phosphorylation of the ubiquitin ligase mouse double minute homolog 2 (Mdm2) and thereby enhanced p53 degradation. When p53 signaling was sustained by blocking complex formation with Mdm2 or enhancing c-Jun N-terminal kinase (JNK) activation, cell viability was significantly reduced. In addition, Akt-mediated phosphorylation of the cell-cycle regulator p21 stimulated complex formation with caspase-3, which also contributed to cell protection. Thus, treatment with RA augmented survival signaling and attenuated basal apoptotic pathways in SH-SY5Y cells, which increased cell viability. 相似文献
68.
69.
RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer 总被引:5,自引:0,他引:5
Finlin BS Gau CL Murphy GA Shao H Kimel T Seitz RS Chiu YF Botstein D Brown PO Der CJ Tamanoi F Andres DA Perou CM 《The Journal of biological chemistry》2001,276(45):42259-42267
Using microarray analysis, we identified a unique ras superfamily gene, termed RERG (ras-related and estrogen-regulated growth inhibitor), whose expression was decreased or lost in a significant percentage of primary human breast tumors that show a poor clinical prognosis. Importantly, high RERG expression correlated with expression of a set of genes that define a breast tumor subtype that is estrogen receptor-positive and associated with a slow rate of tumor cell proliferation and a favorable prognosis for these cancer patients. RERG mRNA expression was induced rapidly in MCF-7 cells stimulated by beta-estradiol and repressed by tamoxifen treatment. Like Ras, RERG protein exhibited intrinsic GDP/GTP binding and GTP hydrolysis activity. Unlike Ras proteins, RERG lacks a known recognition signal for COOH-terminal prenylation and was localized primarily in the cytoplasm. Expression of RERG protein in MCF-7 breast carcinoma cells resulted in a significant inhibition of both anchorage-dependent and anchorage-independent growth in vitro and inhibited tumor formation in nude mice. These features of RERG are strikingly different from most Ras superfamily GTP-binding pro-teins and suggest that the loss of RERG expression may contribute to breast tumorigenesis. 相似文献
70.
Farnesylation is a posttranslational lipid modification in which a 15-carbon farnesyl isoprenoid is linked via a thioether bond to specific cysteine residues of proteins in a reaction catalyzed by protein farnesyltransferase (FTase). We synthesized the benzyloxyisoprenyl pyrophosphate (BnPP) series of transferable farnesyl pyrophosphate (FPP) analogues (1a-e) to test the length dependence of the isoprenoid substrate on the FTase-catalyzed transfer of lipid to protein substrate. Kinetic analyses show that pyrophosphates 1a-e and geranyl pyrophosphate (GPP) transfer with a lower efficiency than FPP whereas geranylgeranyl pyrophosphate (GGPP) does not transfer at all. While a correlation was found between K(m) and analogue hydrophobicity and length, there was no correlation between k(cat) and these properties. Potential binding geometries of FPP, GPP, GGPP, and analogues 1a-e were examined by modeling the molecules into the active site of the FTase crystal structure. We found that analogue 1d displaces approximately the same volume of the active site as does FPP, whereas GPP and analogues 1a-c occupy lesser volumes and 1e occupies a slightly larger volume. Modeling also indicated that GGPP adopts a different conformation than the farnesyl chain of FPP, partially occluding the space occupied by the Ca(1)a(2)X peptide in the ternary X-ray crystal structure. Within the confines of the FTase pocket, the double bonds and branched methyl groups of the geranylgeranyl chain significantly restrict the number of possible conformations relative to the more flexible lipid chain of analogues 1a-e. The modeling results also provide a molecular explanation for the observation that an aromatic ring is a good isostere for the terminal isoprene of FPP. 相似文献