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991.
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Charlotte B. Spliid Alejandro Gomez Toledo Patience Sanderson Yang Mao Francesco Gatto Tobias Gustavsson Swati Choudhary Ana L. Saldanha Rasmus P. Vogelsang Ismail Ggenur Thor G. Theander Franklin E. Leach rd I. Jonathan Amster Jeffrey D. Esko Ali Salanti Thomas Mandel Clausen 《The Journal of biological chemistry》2021,297(6)
Placental malaria infection is mediated by the binding of the malarial VAR2CSA protein to the placental glycosaminoglycan, chondroitin sulfate. Recombinant subfragments of VAR2CSA (rVAR2) have also been shown to bind specifically and with high affinity to cancer cells and tissues, suggesting the presence of a shared type of oncofetal chondroitin sulfate (ofCS) in the placenta and in tumors. However, the exact structure of ofCS and what determines the selective tropism of VAR2CSA remains poorly understood. In this study, ofCS was purified by affinity chromatography using rVAR2 and subjected to detailed structural analysis. We found high levels of N-acetylgalactosamine 4-O-sulfation (∼80–85%) in placenta- and tumor-derived ofCS. This level of 4-O-sulfation was also found in other tissues that do not support parasite sequestration, suggesting that VAR2CSA tropism is not exclusively determined by placenta- and tumor-specific sulfation. Here, we show that both placenta and tumors contain significantly more chondroitin sulfate moieties of higher molecular weight than other tissues. In line with this, CHPF and CHPF2, which encode proteins required for chondroitin polymerization, are significantly upregulated in most cancer types. CRISPR/Cas9 targeting of CHPF and CHPF2 in tumor cells reduced the average molecular weight of cell-surface chondroitin sulfate and resulted in a marked reduction of rVAR2 binding. Finally, utilizing a cell-based glycocalyx model, we showed that rVAR2 binding correlates with the length of the chondroitin sulfate chains in the cellular glycocalyx. These data demonstrate that the total amount and cellular accessibility of chondroitin sulfate chains impact rVAR2 binding and thus malaria infection. 相似文献
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Daniel P. Mould Ulf Bremberg Allan M. Jordan Matthis Geitmann Alba Maiques-Diaz Alison E. McGonagle Helen F. Small Tim C.P. Somervaille Donald Ogilvie 《Bioorganic & medicinal chemistry letters》2017,27(14):3190-3195
A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23 µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10 nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound. 相似文献
996.
Daniel P. Mould Ulf Bremberg Allan M. Jordan Matthis Geitmann Alison E. McGonagle Tim C.P. Somervaille Gary J. Spencer Donald J. Ogilvie 《Bioorganic & medicinal chemistry letters》2017,27(20):4755-4759
As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22 nM and a biochemical IC50 of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1. 相似文献
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Kamil J. Kuder Dorota Łażewska Maria Kaleta Gniewomir Latacz Tim Kottke Agnieszka Olejarz Tadeusz Karcz Andrzej Fruziński Katarzyna Szczepańska Janina Karolak-Wojciechowska Holger Stark Katarzyna Kieć-Kononowicz 《Bioorganic & medicinal chemistry》2017,25(10):2701-2712
As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2–21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6–8 (Ki = 8.8–23.4 nM range) and among them piperidine derivative 6 with Ki = 8.8 nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50 = 157 and 164 nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2–4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30 mg/kg at 0.5 h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300 mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate “drug-likeness” of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed. 相似文献
999.
The global growth of farmed shellfish production has resulted in considerable research investigating how biofouling compromises farm productivity. Shellfish fitness can be compared between fouled stock and stock which has undergone treatment. As treatment options are often harsh, they may deleteriously affect stock. The projected impact of biofouling may therefore be confounded by the impact of treatments. Given the substantial cost of fouling removal, some have questioned the necessity of biofouling mitigation strategies. Meta-analysis revealed that biofouling typically reduces shellfish fitness. However, the fitness of treated stock was often lower or equal to fouled control stock, indicating that many common antifouling (AF) strategies are ineffective at enhancing farm productivity. Overall, caution and diligence are required to successfully implement biofouling mitigation strategies. The need remains for increased passive prevention approaches and novel AF strategies suitable for shellfish culture, such as strategic siting of bivalve farms in areas of low biofouling larval supply. 相似文献
1000.
Anthony Ricciardi Tim M. Blackburn James T. Carlton Jaimie T.A. Dick Philip E. Hulme Josephine C. Iacarella Jonathan M. Jeschke Andrew M. Liebhold Julie L. Lockwood Hugh J. MacIsaac Petr Pyšek David M. Richardson Gregory M. Ruiz Daniel Simberloff William J. Sutherland David A. Wardle David C. Aldridge 《Trends in ecology & evolution》2017,32(6):464-474