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851.
Guillem Prats-Ejarque Jose A. Blanco Vivian A. Salazar Victòria M. Nogués Mohammed Moussaoui Ester Boix 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(1):105-117
Background
Human RNase6 is a small cationic antimicrobial protein that belongs to the vertebrate RNaseA superfamily. All members share a common catalytic mechanism, which involves a conserved catalytic triad, constituted by two histidines and a lysine (His15/His122/Lys38 in RNase6 corresponding to His12/His119/Lys41 in RNaseA). Recently, our first crystal structure of human RNase6 identified an additional His pair (His36/His39) and suggested the presence of a secondary active site.Methods
In this work we have explored RNase6 and RNaseA subsite architecture by X-ray crystallography, site-directed mutagenesis and kinetic characterization.Results
The analysis of two novel crystal structures of RNase6 in complex with phosphate anions at atomic resolution locates a total of nine binding sites and reveals the contribution of Lys87 to phosphate-binding at the secondary active center. Contribution of the second catalytic triad residues to the enzyme activity is confirmed by mutagenesis. RNase6 catalytic site architecture has been compared with an RNaseA engineered variant where a phosphate-binding subsite is converted into a secondary catalytic center (RNaseA-K7H/R10H).Conclusions
We have identified the residues that participate in RNase6 second catalytic triad (His36/His39/Lys87) and secondary phosphate-binding sites. To note, residues His39 and Lys87 are unique within higher primates. The RNaseA/RNase6 side-by-side comparison correlates the presence of a dual active site in RNase6 with a favored endonuclease-type cleavage pattern.General significance
An RNase dual catalytic and extended binding site arrangement facilitates the cleavage of polymeric substrates. This is the first report of the presence of two catalytic centers in a single monomer within the RNaseA superfamily. 相似文献852.
The chemokine receptor CXCR2 and its ligands are implicated in the progression of tumours and various inflammatory diseases. Activation of the CXCLs/CXCR2 axis activates multiple signalling pathways, including the PI3K, p38/ERK, and JAK pathways, and regulates cell survival and migration. The CXCLs/CXCR2 axis plays a vital role in the tumour microenvironment and in recruiting neutrophils to inflammatory sites. Extensive infiltration of neutrophils during chronic inflammation is one of the most important pathogenic factors in various inflammatory diseases. Chronic inflammation is considered to be closely correlated with initiation of cancer. In addition, immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) against T cells attenuate the anti-tumour effects of T cells and promote tumour invasion and metastasis. Over the last several decades, many therapeutic strategies targeting CXCR2 have shown promising results and entered clinical trials. In this review, we focus on the features and functions of the CXCLs/CXCR2 axis and highlight its role in cancer and inflammatory diseases. We also discuss its potential use in targeted therapies. 相似文献
853.
Ronnie J.M. Lubbers Adiphol Dilokpimol Jaap Visser Miia R. Mäkelä Kristiina S. Hildén Ronald P. de Vries 《Biotechnology advances》2019,37(7):107396
Aromatic compounds derived from lignin are of great interest for renewable biotechnical applications. They can serve in many industries e.g. as biochemical building blocks for bioplastics or biofuels, or as antioxidants, flavor agents or food preservatives. In nature, lignin is degraded by microorganisms, which results in the release of homocyclic aromatic compounds. Homocyclic aromatic compounds can also be linked to polysaccharides, tannins and even found freely in plant biomass. As these compounds are often toxic to microbes already at low concentrations, they need to be degraded or converted to less toxic forms. Prior to ring cleavage, the plant- and lignin-derived aromatic compounds are converted to seven central ring-fission intermediates, i.e. catechol, protocatechuic acid, hydroxyquinol, hydroquinone, gentisic acid, gallic acid and pyrogallol through complex aromatic metabolic pathways and used as energy source in the tricarboxylic acid cycle. Over the decades, bacterial aromatic metabolism has been described in great detail. However, the studies on fungal aromatic pathways are scattered over different pathways and species, complicating a comprehensive view of fungal aromatic metabolism. In this review, we depicted the similarities and differences of the reported aromatic metabolic pathways in fungi and bacteria. Although both microorganisms share the main conversion routes, many alternative pathways are observed in fungi. Understanding the microbial aromatic metabolic pathways could lead to metabolic engineering for strain improvement and promote valorization of lignin and related aromatic compounds. 相似文献
854.
Actinomycetes are one of the most valuable sources of natural products with industrial and medicinal importance. After more than half a century of exploitation, it has become increasingly challenging to find novel natural products with useful properties as the same known compounds are often repeatedly re-discovered when using traditional approaches. Modern genome mining approaches have led to the discovery of new biosynthetic gene clusters, thus indicating that actinomycetes still harbor a huge unexploited potential to produce novel natural products. In recent years, innovative synthetic biology and metabolic engineering tools have greatly accelerated the discovery of new natural products and the engineering of actinomycetes. In the first part of this review, we outline the successful application of metabolic engineering to optimize natural product production, focusing on the use of multi-omics data, genome-scale metabolic models, rational approaches to balance precursor pools, and the engineering of regulatory genes and regulatory elements. In the second part, we summarize the recent advances of synthetic biology for actinomycetal metabolic engineering including cluster assembly, cloning and expression, CRISPR/Cas9 technologies, and chassis strain development for natural product overproduction and discovery. Finally, we describe new advances in reprogramming biosynthetic pathways through polyketide synthase and non-ribosomal peptide synthetase engineering. These new developments are expected to revitalize discovery and development of new natural products with medicinal and other industrial applications. 相似文献
855.
Vipin Chandra Kalia Sanjay K.S. Patel Yun Chan Kang Jung-Kul Lee 《Biotechnology advances》2019,37(1):68-90
The mechanisms through which microbes communicate using signal molecules has inspired a great deal of research. Microbes use this exchange of information, known as quorum sensing (QS), to initiate and perpetuate infectious diseases in eukaryotic organisms, evading the eukaryotic defense system by multiplying and expressing their pathogenicity through QS regulation. The major issue to arise from such networks is increased bacterial resistance to antibiotics, resulting from QS-dependent mediation of the formation of biofilm, the induction of efflux pumps, and the production of antibiotics. QS inhibitors (QSIs) of diverse origins have been shown to act as potential antipathogens. In this review, we focus on the use of QSIs to counter diseases in humans as well as plants and animals of economic importance. We also discuss the challenges encountered in the potential applications of QSIs. 相似文献
856.
Amyotrophic lateral sclerosis (ALS), a progressive motor-neurone disease, affects individuals usually aged between 50 and 70 years. C21orf2, recently identified as the new ALS susceptibility gene, harbours rare missense mutations that cause this fatal disease. We used bioinformatics and molecular modelling approaches to study specific ALS-associated mutations in C21orf2. Both native and mutant structures of the protein obtained from homology modelling were analysed in detail to gain insights into the potential impact of these mutations on the protein structure and its function. Our analyses reveal that more than 75% of the mutations are likely to be deleterious. These effects seem to carry through to mouse C21orf2 as well, indicating that mouse would make a viable animal model to study this ALS gene in detail. 相似文献
857.
Hao Hu Lingling Peng Haiyan Jiang Haijun Shen Ping Zhou Yunming Gao 《Journal of cellular biochemistry》2019,120(8):12595-12603
858.
859.
Xiaoguang Chen Xuemin Zhu Zhiguo Wei Qiongxia Lv 《Journal of cellular biochemistry》2019,120(12):19878-19890
Our previous study has discovered the positive effect of phospholipase Cγ 2 (PLCγ2) on the growth of hepatocarcinoma cells; however, the underlying mechanism is far from being understood. For this reason, this study attempts to identify the differently expressed microRNAs (miRNAs) and messenger RNAs (mRNAs) in PLCγ2-overexpressing hepatocarcinoma cells. The results showed that totally 596 differently-expressed genes (DEGs) were identified in PLCγ2-expressed cells, including 314 upregulated and 282 downregulated ones; according to gene ontology analysis, these DEGs were involved in different cellular processes. Concurrently, 34 differently-expressed miRNAs (DEMs) were also detected in PLCγ2-expressing hepatocarcinoma cells. Moreover, the integrative analysis of miRNA and mRNA expression profiles identified the potential regulatory network linked to hepatocarcinoma-related biological processes, including metabolic activity, gene expression, cell cycle, cell migration, and so on. To our knowledge, it is the first study on the effect of PLCγ2 on miRNA and mRNA expressions in hepatocarcinoma cells, and the findings provide new insights into the mechanism supporting the growth-promoting effect of PLCγ2 in hepatocarcinoma cells. 相似文献
860.