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191.
192.
Tumor targeting with a selective gelatinase inhibitor. 总被引:29,自引:0,他引:29
E Koivunen W Arap H Valtanen A Rainisalo O P Medina P Heikkil? C Kantor C G Gahmberg T Salo Y T Konttinen T Sorsa E Ruoslahti R Pasqualini 《Nature biotechnology》1999,17(8):768-774
Several lines of evidence suggest that tumor growth, angiogenesis, and metastasis are dependent on matrix metalloproteinase (MMP) activity. However, the lack of inhibitors specific for the type IV collagenase/gelatinase family of MMPs has thus far prevented the selective targeting of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) for therapeutic intervention in cancer. Here, we describe the isolation of specific gelatinase inhibitors from phage display peptide libraries. We show that cyclic peptides containing the sequence HWGF are potent and selective inhibitors of MMP-2 and MMP-9 but not of several other MMP family members. Our prototype synthetic peptide, CTTHWGFTLC, inhibits the migration of human endothelial cells and tumor cells. Moreover, it prevents tumor growth and invasion in animal models and improves survival of mice bearing human tumors. Finally, we show that CTTHWGFTLC-displaying phage specifically target angiogenic blood vessels in vivo. Selective gelatinase inhibitors may prove useful in tumor targeting and anticancer therapies. 相似文献
193.
Juha Kokkonen Antti Leinonen Jari Tuominen Timo Seppl 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1999,734(2):2149
In doping control laboratories the misuse of anabolic androgenic steroids is commonly investigated in urine by gas chromatography–low-resolution mass spectrometry with selected ion monitoring (GC–LRMS–SIM). By using high-resolution mass spectrometry (HRMS) detection sensitivity is improved due to reduction of biological background. In our study HRMS and LRMS methods were compared to each other. Two different sets were measured both with HRMS and LRMS. In the first set metandienone (I) metabolites 17α-methyl-5β-androstan-3α,17β-diol (II), 17-epimetandienone (III), 17β-methyl-5β-androst-1-ene-3α,17α-diol (IV) and 6β-hydroxymetandienone (V) were spiked in urine extract prepared by solid-phase extraction, hydrolysis with β-glucuronidase from Escherichia coli and liquid–liquid extraction. In the second set the metabolites were first spiked in blank urine samples of four male persons before pretreatment. Concentration range of the spiked metabolites was 0.1–10 ng/ml in both sets. With HRMS (resolution of 5000) detection limits were 2–10 times lower than with LRMS. However, also with the HRMS method the biological background hampered detection and compounds from matrix were coeluted with some metabolites. For this reason the S/N values of the metabolites spiked had to be first compared to S/N values of coeluted matrix compounds to get any idea of detection limits. At trace concentrations selective isolation procedures should be implemented in order to confirm a positive result. The results suggest that metandienone misuse can be detected by HRMS for a prolonged period after stopping the intake of metandienone. 相似文献
194.
Marc AquinoBaleyt Vianey LeosBarajas Timo Adam Mauricio HoyosPadilla Omar SantanaMorales Felipe GalvnMagaa Rogelio GonzlezArmas Christopher G. Lowe James T. Ketchum Hctor Villalobos 《Ecology and evolution》2021,11(21):14932
- Fine‐scale movement patterns are driven by both biotic (hunting, physiological needs) and abiotic (environmental conditions) factors. The energy balance governs all movement‐related strategic decisions.
- Marine environments can be better understood by considering the vertical component. From 24 acoustic trackings of 10 white sharks in Guadalupe Island, this study linked, for the first time, horizontal and vertical movement data and inferred six different behavioral states along with movement states, through the use of hidden Markov models, which allowed to draw a comprehensive picture of white shark behavior.
- Traveling was the most frequent state of behavior for white sharks, carried out mainly at night and twilight. In contrast, area‐restricted searching was the least used, occurring primarily in daylight hours.
- Time of day, distance to shore, total shark length, and, to a lesser extent, tide phase affected behavioral states. Chumming activity reversed, in the short term and in a nonpermanent way, the behavioral pattern to a general diel vertical pattern.
195.
Timo Heinrich Hans-Peter Buchstaller Bertram Cezanne Felix Rohdich Jörg Bomke Manja Friese-Hamim Mireille Krier Thorsten Knöchel Djordje Musil Birgitta Leuthner Frank Zenke 《Bioorganic & medicinal chemistry letters》2017,27(3):551-556
The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC50: 1 μM) led to the most potent compound 27 (IC50: 0.038 μM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side-chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180° flip for the triazolo[1,5-a]pyrimdine bicyclic template. 相似文献
196.
Carbon accrual rates,vegetation and nutrient dynamics in a regularly burned coppice woodland in Germany 下载免费PDF全文
Nils Borchard Timo Adolphs Friederike Beulshausen Brenton Ladd Urs C. Gießelmann Dominik Hegenberg Bodo M. Möseler Wulf Amelung 《Global Change Biology Bioenergy》2017,9(6):1140-1150
Historically, large areas of forest in Europe were managed as coppice woodland to produce wood‐based fuel for the smelting industry. We hypothesized that this practice produced a legacy effect on current forest ecosystem properties. Specifically, we hypothesized that the historical form of coppicing may have produced a legacy of elevated stocks of soil organic carbon (SOC), nutrients and black carbon (BC) in soil as fire was routinely used in coppiced woodland to clear land. We further hypothesized that these changes in soil properties would result in increased biodiversity. To test these hypotheses, we sampled the surface soil (0–5, 5–10 and 10–20 cm) from a chronosequence of forest sites found in the Siegerland (Germany) that had been coppiced and burned 1, 2, 3.5, 6, 8, 11 and 17 years before present. Mature beech and spruce forests (i.e., >60 years) were also sampled as reference sites: to provide a hint of what might occur in the absence of human intervention. We measured stocks of SOC, BC, NO3‐N, P, K, Mg, as well as cation exchange and water‐holding capacity, and we mapped plant composition to calculate species richness and evenness. The results showed that coppicing in combination with burning soil and litter improved soil nutrient availability, enhanced biodiversity and increased SOC stocks. The SOC stocks and biodiversity were increased by a factor of three relative to those in the mature beech and spruce forests. This study shows that traditional coppicing practice may facilitate net C accrual rates of 20 t ha?1 yr?1 and maintain high biodiversity, indicating that aspects of traditional practice could be applied in current forest management to foster biodiversity and to mitigate climate change. 相似文献
197.
Timo Maran 《Biosemiotics》2017,10(3):355-368
Environmental signs as physically manifested signs that we and other animals perceive and interpret in the natural environment are seldom focused on in contemporary semiotics. The aim of the present paper is to highlight the diversity of environmental signs and to propose a typology for analysing them. Combining ecosemiotics and the pragmatist semiotics of C. Peirce and C. Morris, the proposed typology draws its criteria from the properties of the object and the representamen of the sign, and of their relationships. The analysis distinguishes eight basic types of environmental signs and provides examples of these from the natural environment. The typology also integrates existing concepts of environmental affordances, ecofields, phonetic syntax, sign fields, ecological codes, meta-signs and others. In addition to basic types of environmental signs, compound environmental signs are discussed with three types of these distinguished: (1) environmental meta-signs; (2) ecological codes; and (3) environmental-cultural hybrid signs. Further study of compound environmental signs could lead to reconceptualising relations between linguistic and pre-linguistic semiosis. 相似文献
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