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241.
Diaz JA Wrobleski SK Hawley AE Lucchesi BR Wakefield TW Myers DD 《Journal of visualized experiments : JoVE》2011,(53):e2737
Animal models serve a vital role in deep venous thrombosis (DVT) research in order to study thrombus formation, thrombus resolution and to test potential therapeutic compounds. New compounds to be utilized in the treatment and prevention of DVT are currently being developed. The delivery of potential therapeutic antagonist compounds to an affected thrombosed vein has been problematic. In the context of therapeutic applications, a model that uses partial stasis and consistently generates thrombi within a major vein has been recently established. The Electrolytic Inferior vena cava Model (EIM) is mouse model of DVT that permits thrombus formation in the presence of continuous blood flow. This model allows therapeutic agents to be in contact with the thrombus in a dynamic fashion, and is more sensitive than other models of DVT. In addition, this thrombosis model closely simulates clinical situations of thrombus formation and is ideal to study venous endothelial cell activation, leukocyte migration, venous thrombogenesis, and to test therapeutic applications. The EIM model is technically simple, easily reproducible, creates consistent thrombi sizes and allows for a large sample (i.e. thrombus and vein wall) which is required for analytical purposes. 相似文献
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243.
Anthony Shock Linda Burkly Ian Wakefield Christopher Peters Ellen Garber Janine Ferrant Frederick R. Taylor Lihe Su Yen-Ming Hsu David Hutto Ali Amirkhosravi Todd Meyer John Francis Sarah Malcolm Martyn Robinson Derek Brown Stevan Shaw Roland Foulkes Alastair Lawson Olivier Harari Timothy Bourne Alison Maloney Neil Weir 《Arthritis research & therapy》2015,17(1)
IntroductionCD40 ligand (CD40L) blockade has demonstrated efficacy in experimental autoimmune models. However, clinical trials of hu5c8, an anti-human CD40L IgG1 antibody, in systemic lupus erythematosus (SLE) were halted due to an increased incidence of thrombotic events. This study evaluated CDP7657, a high affinity PEGylated monovalent Fab'' anti-CD40L antibody fragment, to assess whether an Fc-deficient molecule retains efficacy while avoiding the increased risk of thrombotic events observed with hu5c8.MethodsThe potency and cross-reactivity of CDP7657 was assessed in in vitro assays employing human and non-human primate leukocytes, and the capacity of different antibody formats to activate platelets in vitro was assessed using aggregometry and dense granule release assays. Given the important role CD40L plays in regulating humoral immunity, in vivo efficacy was assessed by investigating the capacity of Cynomolgus monkeys to generate immune responses to the tetanus toxoid antigen while the potential to induce thrombotic events in vivo was evaluated after repeat dosing of antibodies to Rhesus monkeys. A PEGylated anti-mouse CD40L was generated to assess efficacy in the New Zealand Black/White (NZB/W) mouse model of SLE.ResultsCDP7657 dose-dependently inhibited antigen-specific immune responses to tetanus toxoid in Cynomolgus monkeys, and in contrast to hu5c8, there was no evidence of pulmonary thrombovasculopathy in Rhesus monkeys. Aglycosyl hu5c8, which lacks Fc receptor binding function, also failed to induce thrombotic events in Rhesus monkeys. In vitro experiments confirmed that antibody constructs lacking an Fc, including CDP7657, did not induce human or monkey platelet activation. A PEGylated monovalent Fab'' anti-mouse CD40L antibody also inhibited disease activity in the NZB/W mouse model of SLE after administration using a therapeutic dosing regimen where mice received antibodies only after they had displayed severe proteinuria.ConclusionsThese findings demonstrate for the first time that anti-CD40L antibodies lacking a functional Fc region do not induce thrombotic events in Rhesus monkeys and fail to activate platelets in vitro but, nevertheless retain pharmacological activity and support the investigation of CDP7657 as a potential therapy for systemic lupus erythematosus and other autoimmune diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0757-4) contains supplementary material, which is available to authorized users. 相似文献244.
Calvin T. Wakefield James A. Martin Patrick H. Wightman Bobby T. Bond D. Kevin Lowrey Bradley S. Cohen Bret A. Collier Michael J. Chamberlain 《The Journal of wildlife management》2020,84(3):458-467
Roosting is an important component of wild turkey (Meleagris gallopavo; turkey) ecology as roosts provide security from predators and inclement weather. Males call (gobble) from roosts during the reproductive season, and roost locations are important for maximizing access to females and transmission of calls across the landscape, while also minimizing predation risk. Spring hunting of male turkeys occurs during the reproductive season, and hunting activity influences male behaviors and calling. Because roost sites are important for wild turkey ecology, we evaluated roost site selection and fidelity of male turkeys relative to land cover types, vegetative characteristics, and the presence of hunting activity during 2017–2018 in Georgia, USA. Prior to onset of hunting, males selected roosts nearest to hardwood and pine (Pinus spp.) forests. Roost site fidelity was low and distances between roosts were large. After onset of hunting, males selected pine forests less and exhibited greater plasticity in roost selection while fidelity remained minimal, suggesting that males may have altered selection to mitigate risk from hunting while maintaining the strategy of moving about their ranges and roosting at different sites on consecutive nights. Future research should examine potential effects of hunting-induced shifts in resource selection on other aspects of male turkey behavior and ecology. © 2019 The Wildlife Society. 相似文献
245.
The dark staining of human sperm heads by Diff Quik is significantly correlated with abnormal sperm head morphology (r=0.51, p<0.0001), but is not associated with changes in sperm chromatin detected by a sperm chromatin structure assay (SCSA; r=0.18, p>0.09). Whilst valuable in the assessment of head morphology, it is concluded that Diff Quik staining is not a useful substitute for the SCSA to assess human sperm chromatin. 相似文献
246.
Tsutomu Matsubara Naoki Tanaka Misako Sato Dong Wook Kang Kristopher W. Krausz Kathleen C. Flanders Kazuo Ikeda Hans Luecke Lalage M. Wakefield Frank J. Gonzalez 《Journal of lipid research》2012,53(12):2698-2707
Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFβ expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter β (OSTβ) expression were markedly decreased in Smad3-null mice, whereas TGFβ induced LPCAT4 and OSTβ expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFβ-induced LPCAT4 and OSTβ expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFβ-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury. 相似文献
247.
黄檗丛枝菌根真菌鉴定 总被引:1,自引:0,他引:1
目的:利用形态学特征与Nested-PCR技术鉴定黄檗丛枝菌根真菌。方法:采用酸性品红染色法挑选黄檗丛枝菌根。同时,利用湿筛法获得AM真菌孢子,进行形态学鉴定。运用Nested-PCR技术,对黄檗粗提DNA进行特异性扩增,采用blastn进行序列相似性比较。并构建系统进化树,确定侵染黄檗根系的AM真菌。结果:编号为HDAM-1的AM真菌孢子,形态特征与G.intraradices的特征描述一致。Nested-PCR检测到约455bp的目的片段,其序列与G.intraradices(DQ469118)相似性最高,达97.8%,有11个碱基的差异。系统进化树显示该序列在基于25S rDNA的进化树中与G.intraradices(DQ469118.1)处于同一分支,确定G.intraradices侵染黄檗根系。结论:将形态学特征与Nested-PCR技术相结合鉴定AM真菌,不仅简易、经济,而且能够提高研究结果的可靠性。 相似文献
248.
Li J Wakefield BD Ruble JC Stiff CM Romero DL Marotti KR Sweeney MT Zurenko GE Rohrer DC Thorarensen A 《Bioorganic & medicinal chemistry letters》2007,17(8):2347-2350
Discovery of novel antibacterial agents is a significant challenge. We have recently reported on our discovery of novel antibacterial agents in which we have rapidly optimized potency utilizing a parallel chemistry approach. These advanced leads suffer from high affinity for human serum albumin (HSA). In an effort to decrease the affinity for HSA we have prepared a series of heterocyclic analogs, which retained antibacterial activity and demonstrated reduced affinity for HSA. 相似文献
249.
Thorarensen A Wakefield BD Romero DL Marotti KR Sweeney MT Zurenko GE Rohrer DC Han F Bryant GL 《Bioorganic & medicinal chemistry letters》2007,17(10):2823-2827
In the past few years, a significant effort has been devoted by Pharmacia toward the discovery of novel antibiotics. We have recently described the identification of an anthranilic acid lead 1 and the optimization resulting in the advanced lead 2. In this report, we describe the preparation of several selected amide bioisosteres connecting the A- and the B-rings. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element rather acts as an appropriate spatial linker of the two important aryl A and B rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity. 相似文献
250.
Marjolijn CE Bragt Jogchum Plat Marco Mensink Patrick Schrauwen Ronald P Mensink 《BMC endocrine disorders》2009,9(1):1-9