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排序方式: 共有913条查询结果,搜索用时 15 毫秒
831.
Benjamin Weber Steffen Schuster Daniel Zysset Silvia Rihs Nina Dickgreber Christian Schürch Carsten Riether Mark Siegrist Christoph Schneider Helga Pawelski Ursina Gurzeler Pascal Ziltener Vera Genitsch Fabienne Tacchini-Cottier Adrian Ochsenbein Willy Hofstetter Manfred Kopf Thomas Kaufmann Annette Oxenius Walter Reith Leslie Saurer Christoph Mueller 《PLoS pathogens》2014,10(1)
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions. While TREM-1-amplified responses likely aid an improved detection and elimination of pathogens, excessive production of cytokines and oxygen radicals can also severely harm the host. Studies addressing the pathogenic role of TREM-1 during endotoxin-induced shock or microbial sepsis have so far mostly relied on the administration of TREM-1 fusion proteins or peptides representing part of the extracellular domain of TREM-1. However, binding of these agents to the yet unidentified TREM-1 ligand could also impact signaling through alternative receptors. More importantly, controversial results have been obtained regarding the requirement of TREM-1 for microbial control. To unambiguously investigate the role of TREM-1 in homeostasis and disease, we have generated mice deficient in Trem1. Trem1−/− mice are viable, fertile and show no altered hematopoietic compartment. In CD4+ T cell- and dextran sodium sulfate-induced models of colitis, Trem1−/− mice displayed significantly attenuated disease that was associated with reduced inflammatory infiltrates and diminished expression of pro-inflammatory cytokines. Trem1−/− mice also exhibited reduced neutrophilic infiltration and decreased lesion size upon infection with Leishmania major. Furthermore, reduced morbidity was observed for influenza virus-infected Trem1−/− mice. Importantly, while immune-associated pathologies were significantly reduced, Trem1−/− mice were equally capable of controlling infections with L. major, influenza virus, but also Legionella pneumophila as Trem1+/+ controls. Our results not only demonstrate an unanticipated pathogenic impact of TREM-1 during a viral and parasitic infection, but also indicate that therapeutic blocking of TREM-1 in distinct inflammatory disorders holds considerable promise by blunting excessive inflammation while preserving the capacity for microbial control. 相似文献
832.
Anke Jaudszus Christian Degen Stephan W. Barth Martin Klempt Wiebke Schl?rmann Alexander Roth Carsten Rohrer Helga Sauerwein Konrad Sachse Gerhard Jahreis 《PloS one》2014,9(12)
Scope
Established epithelial cell lines equipped with pattern recognition receptors such as the Toll-like receptor (TLR)-2 are common tools for immune response studies on invading pathogens, e.g. the obligate intracellular species of Chlamydia. Moreover, such models are widely used to elucidate fatty acid-mediated immune effects. In several transformed cell lines, however, unusual loss of metabolic functions was described. The cell lines A549 and HeLa are poorly characterized in this respect. Therefore, we comparatively assessed the metabolic capacity of A549 and HeLa prior to proposed application as in vitro model for fatty acid effects on chlamydial infection.Methodology/Principal Findings
We incubated both cell lines either with substrates (C18∶2n−6 or C18∶3n−3) or products (C18∶3n−6, C18∶4n−3) of fatty acid desaturase-2 (FADS2), and analysed the fatty acid profiles after 24 h and 72 h by gas chromatography. Based on these data, we suspected that the complete discontinuation of normal biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFA) in HeLa was due to loss of FADS2 function. Consequently, prostaglandin E2 (PGE2) formation was less inducible by TLR2 stimulation in HeLa, likely as a result of not only insufficient supply of precursors but also weak cyclooxygenase-2 (COX-2) response. In accordance, Chlamydia infection rates were consistently lower in HeLa than in A549. Sequence analysis revealed no alteration within the FADS2 gene in HeLa. The FADS2 expression level, however, was significantly lower and, in contrast to A549, not regulated by C18∶2n−6. A549 exhibited regular fatty acid metabolism and enzyme functionality.Conclusions/Significance
Our data show that HeLa cells considerably differ from A549 at several stages of fatty acid metabolism. The poor metabolic potential of HeLa, mainly concerning FADS2 upstream of COX-2 function, calls into question whether these cells represent a good model to unveil fatty acid or downstream eicosanoid effects in the course of intracellular bacterial infection. 相似文献833.
Anke Schaffartzik Nina Eisenmenger Fridolin Krausmann Helga Weisz 《Journal of Industrial Ecology》2014,18(1):102-112
In 2007, imports accounted for approximately 34% of the material input (domestic extraction and imports) into the Austrian economy and almost 60% of the GDP stemmed from exports. Upstream material inputs into the production of traded goods, however, are not yet included in the standard framework of material flow accounting (MFA). We have reviewed different approaches accounting for these upstream material inputs, or raw material equivalents (RME), positioning them in a wider debate about consumption‐based perspectives in environmental accounting. For the period 1995–2007, we calculated annual RME of Austria's trade and consumption applying a hybrid approach. For exports and competitive imports, we used an environmentally extended input‐output model of the Austrian economy, based on annual supply and use tables and MFA data. For noncompetitive imports, coefficients for upstream material inputs were extracted from life cycle inventories. The RME of Austria's imports and exports were approximately three times larger than the trade flows themselves. In 2007, Austria's raw material consumption was 30 million tonnes or 15% higher than its domestic material consumption. We discuss the material composition of these flows and their temporal dynamics. Our results demonstrate the need for a consumption‐based perspective in MFA to provide robust indicators for dematerialization and resource efficiency analysis of open economies. 相似文献
834.
Potential Role of Elicitins in the Interaction between Phytophthora Species and Tobacco 总被引:7,自引:0,他引:7 下载免费PDF全文
Sophien Kamoun Mary Young Helga Frster Michael D. Coffey Brett M. Tyler 《Applied microbiology》1994,60(5):1593-1598
The potential role of extracellular elicitor proteins (elicitins) from Phytophthora species as avirulence factors in the interaction between Phytophthora and tobacco was examined. A survey of 85 Phytophthora isolates representing 14 species indicated that production of elicitin is almost ubiquitous except for isolates of Phytophthora parasitica from tobacco. The production of elicitins by isolates of P. parasitica correlated without exception with low or no virulence on tobacco. Genetic analysis was conducted by using a cross between two isolates of P. parasitica, segregating for production of elicitin and virulence on tobacco. Virulence assays of the progeny on tobacco confirmed the correlation between production of elicitin and low virulence. 相似文献
835.
836.
837.
Role of the Pseudomonas fluorescens alginate lyase (AlgL) in clearing the periplasm of alginates not exported to the extracellular environment 总被引:2,自引:0,他引:2 下载免费PDF全文
Bakkevig K Sletta H Gimmestad M Aune R Ertesvåg H Degnes K Christensen BE Ellingsen TE Valla S 《Journal of bacteriology》2005,187(24):8375-8384
Alginate is an industrially widely used polysaccharide produced by brown seaweeds and as an exopolysaccharide by bacteria belonging to the genera Pseudomonas and Azotobacter. The polymer is composed of the two sugar monomers mannuronic acid and guluronic acid (G), and in all these bacteria the genes encoding 12 of the proteins essential for synthesis of the polymer are clustered in the genome. Interestingly, 1 of the 12 proteins is an alginate lyase (AlgL), which is able to degrade the polymer down to short oligouronides. The reason why this lyase is associated with the biosynthetic complex is not clear, but in this paper we show that the complete lack of AlgL activity in Pseudomonas fluorescens in the presence of high levels of alginate synthesis is toxic to the cells. This toxicity increased with the level of alginate synthesis. Furthermore, alginate synthesis became reduced in the absence of AlgL, and the polymers contained much less G residues than in the wild-type polymer. To explain these results and other data previously reported in the literature, we propose that the main biological function of AlgL is to degrade alginates that fail to become exported out of the cell and thereby become stranded in the periplasmic space. At high levels of alginate synthesis in the absence of AlgL, such stranded polymers may accumulate in the periplasm to such an extent that the integrity of the cell is lost, leading to the observed toxic effects. 相似文献
838.
Debby Kruijsen Helga K. Einarsdottir Marcel A. Schijf Frank E. Coenjaerts Ellen C. van der Schoot Gestur Vidarsson Grada M. van Bleek 《Journal of virology》2013,87(13):7550-7557
Infants are protected from a severe respiratory syncytial virus (RSV) infection in the first months of life by maternal antibodies or by prophylactically administered neutralizing antibodies. Efforts are under way to produce RSV-specific antibodies with increased neutralizing capacity compared to the currently licensed palivizumab. While clearly beneficial during primary infections, preexisting antibodies might affect the onset of adaptive immune responses and the ability to resist subsequent RSV infections. Therefore, we addressed the question of how virus neutralizing antibodies influence the priming of subsequent adaptive immune responses. To test a possible role of the neonatal Fc receptor (FcRn) in this process, we compared the responses in C57BL/6 wild-type (WT) and FcRn−/− mice. We observed substantial virus-specific T-cell priming and B-cell responses in mice primed with RSV IgG immune complexes resulting in predominantly Th1-type CD4+ T-cell and IgG2c antibody responses upon live-virus challenge. RSV-specific CD8+ T cells were primed as well. Activation of these adaptive immune responses was independent of FcRn. Thus, neutralizing antibodies that localize to the airways and prevent infection-related routes of antigen processing can still facilitate antigen presentation of neutralized virus particles and initiate adaptive immune responses against RSV. 相似文献
839.
Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors—target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0–8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics. 相似文献
840.
Extensive epidemiological data indicate that inorganic arsenic is associated with several types of human cancer. Nevertheless,
the underlying mechanisms are poorly understood. Among its mode of action are the alterations on DNA methylation, which provoke
aberrant gene expression. However, beyond DNA methylation, little is known about arsenic’s effects on chromatin. In this study,
we investigated the effects of sodium arsenite (NaAsO2) on global histone modifications and nucleosome-associated proteins. Our findings revealed that NaAsO2 exposure significantly increases global histone acetylation. This effect was related to the inhibition of histone deacetylase
(HDAC) activity because NaAsO2 was able to inhibit HDACs comparable to the well-known HDAC inhibitor trichostatin A (TSA). Furthermore, analyses of the
dynamic properties of the nucleosome-associated high mobility group N proteins demonstrate that NaAsO2 elevates their mobility. Thus, our data suggest that NaAsO2 induces chromatin opening by histone hyperacetylation due to HDAC inhibition and increase of the mobility of nucleosome-associated
proteins. As the chromatin compaction is crucial for the regulation of gene expression as well as for genome stability, we
propose that chromatin opening by NaAsO2 may play a significant role to impart its genotoxic effects.
Tzutzuy Ramirez and Jan Brocher contributed equally. 相似文献