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991.
Increases in the environmental osmolarity are key determinants for the growth of microorganisms. To ensure a physiologically acceptable level of cellular hydration and turgor at high osmolarity, many bacteria accumulate compatible solutes. Osmotically controlled uptake systems allow the scavenging of these compounds from scarce environmental sources as effective osmoprotectants. A number of these systems belong to the BCCT family (betaine-choline-carnitine-transporter), sodium- or proton-coupled transporters (e.g. BetP and BetT respectively) that are ubiquitous in microorganisms. The BCCT family also contains CaiT, an L-carnitine/γ-butyrobetaine antiporter that is not involved in osmotic stress responses. The glycine betaine transporter BetP from Corynebacterium glutamicum is a representative for osmoregulated symporters of the BCCT family and functions both as an osmosensor and osmoregulator. The crystal structure of BetP in an occluded conformation in complex with its substrate glycine betaine and two crystal structures of CaiT in an inward-facing open conformation in complex with L-carnitine and γ-butyrobetaine were reported recently. These structures and the wealth of biochemical data on the activity control of BetP in response to osmotic stress enable a correlation between the sensing of osmotic stress by a transporter protein with the ensuing regulation of transport activity. Molecular determinants governing the high-affinity binding of the compatible solutes by BetP and CaiT, the coupling in symporters and antiporters, and the osmoregulatory properties are discussed in detail for BetP and various BCCT carriers. 相似文献
992.
C. Engohan‐Aloghe N. Hottat J. Cosaert R. Boutemy I. Fayt J.‐C. Noël 《Cytopathology》2010,21(3):161-163
C. Engohan‐Aloghe, N. Hottat, J. Cosaert, R. Boutemy, I. Fayt and J.‐C. Noël Evaluation of accuracy of fine needle aspiration cytology in BI‐RADS3 category breast lesions: cytohistological correlation in 337 cases Objective: To evaluate the accuracy of fine needle aspiration cytology (FNAC) in BI‐RADS3 breast lesions. Methods: Between January 2004 and December 2007, 337 cases from BI‐RADS3 lesions underwent FNAC. Three to six needle passes were made on each patient. In 67 cases (20%) a histological biopsy was performed. Cytological and histological interpretations were performed by the same pathologist. Results: The histological diagnosis showed that 88% (59/67) of BI‐RADS3 breast lesions were benign. Only 6% (4/67) were malignant, consisting of ductal carcinoma in situ and infiltrating ductal carcinoma. Conclusion: BI‐RADS3 lesions remain disruptive in their management. However, the correlation between cytology and histology showed that most of these lesions were benign and that finally FNAC remains a useful and accurate test in the management of these lesions. 相似文献
993.
Potter A Oldfield V Nunns C Fromont C Ray S Northfield CJ Bryant CJ Scrace SF Robinson D Matossova N Baker L Dokurno P Surgenor AE Davis B Richardson CM Murray JB Moore JD 《Bioorganic & medicinal chemistry letters》2010,20(22):6483-6488
Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-μM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential. 相似文献
994.
Christine E. Brotherton-Pleiss Michael P. Dillon Anthony P.D.W. Ford Joel R. Gever David S. Carter Shelley K. Gleason Clara J. Lin Amy G. Moore Anthony W. Thompson Marzia Villa Yansheng Zhai 《Bioorganic & medicinal chemistry letters》2010,20(3):1031-1036
Despite the extensive literature describing the role of the ATP-gated P2X3 receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X3 antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85. 相似文献
995.
Laszlo Revesz Achim Schlapbach Reiner Aichholz Janet Dawson Roland Feifel Stuart Hawtin Amanda Littlewood-Evans Guido Koch Markus Kroemer Henrik Möbitz Clemens Scheufler Juraj Velcicky Christine Huppertz 《Bioorganic & medicinal chemistry letters》2010,20(15):4719-4723
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D–E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC50 <3 nM and inhibit the release of TNFα (IC50<0.3 μM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50 = 0.05–0.23 μM), less potent in cells (IC50 <1.1 μM), but show good oral absorption. Compound 13E (100 mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score. 相似文献
996.
Wu TY Juteau H Ducharme Y Friesen RW Guiral S Dufresne L Poirier H Salem M Riendeau D Mancini J Brideau C 《Bioorganic & medicinal chemistry letters》2010,20(23):6978-6982
Microsomal prostaglandin E(2) synthase (mPGES-1) represents a potential target for novel analgesic and anti-inflammatory agents. High-throughput screening identified several leads of mPGES-1 inhibitors which were further optimized for potency and selectivity. A series of inhibitors bearing a biaryl imidazole scaffold exhibits excellent inhibition of PGE(2) production in enzymatic and cell-based assays. The synthesis of these molecules and their activities will be discussed. 相似文献
997.
Emily M. Stocking Leah Aluisio John R. Atack Pascal Bonaventure Nicholas I. Carruthers Christine Dugovic Anita Everson Ian Fraser Xiaohui Jiang Perry Leung Brian Lord Kiev S. Ly Kirsten L. Morton Diane Nepomuceno Chandravadan R. Shah Jonathan Shelton Akinola Soyode-Johnson Michael A. Letavic 《Bioorganic & medicinal chemistry letters》2010,20(9):2755-2760
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H3 receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H3 receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate. 相似文献
998.
Jehun Choi Sung Jin Bae Young Mi Ha Jae Kyung No Eun Kyeong Lee Jun Sik Lee Suhee Song Hyojin Lee Hongsuk Suh Byung Pal Yu Hae Young Chung 《Bioorganic & medicinal chemistry letters》2010,20(16):4882-4884
In searching for new agents with a depigmenting effect, we synthesized a derivative of resveratrol, 5-(6-hydroxy-2-naphthyl)-1,2,3-benzenetriol (5HNB) with a potent tyrosinase inhibitory activity. 5HNB inhibited mushroom tyrosinase with an IC50 value of 2.95 μM, which is more potent than the well-known anti-tyrosinase activity of kojic acid (IC50 = 38.24). The results of the enzymatic inhibition kinetics by Lineweaver–Burk analysis indicated 5HNB inhibits tyrosinase non-competitively when l-tyrosine was used as the substrate. Based on the strong inhibitory action of 5HNB, it is expected that 5HNB can suppress melanin production in which tyrosinase plays the essential role. Our expectation was confirmed by the experimentations with B16 melanoma cells in which 5HNB inhibited melanin production. We propose that 5HNB might have skin-whitening effects as well as therapeutic potential for treating skin pigmentation disorders. 相似文献
999.
Robert R. Singhaus Ronald C. Bernotas Robert Steffan Edward Matelan Elaine Quinet Ponnal Nambi Irene Feingold Christine Huselton Anna Wilhelmsson Annika Goos-Nilsson Jay Wrobel 《Bioorganic & medicinal chemistry letters》2010,20(2):521-525
Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs. 相似文献
1000.
Kristen L.G. Jones M. Katharine Holloway Hua-Poo Su Steven S. Carroll Christine Burlein Sinoeun Touch Daniel J. DiStefano Rosa I. Sanchez Theresa M. Williams Joseph P. Vacca Craig A. Coburn 《Bioorganic & medicinal chemistry letters》2010,20(14):4065-4068
A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-l-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket. 相似文献