全文获取类型
收费全文 | 17693篇 |
免费 | 1814篇 |
国内免费 | 6篇 |
出版年
2022年 | 123篇 |
2021年 | 271篇 |
2020年 | 177篇 |
2019年 | 236篇 |
2018年 | 355篇 |
2017年 | 282篇 |
2016年 | 499篇 |
2015年 | 780篇 |
2014年 | 854篇 |
2013年 | 1059篇 |
2012年 | 1282篇 |
2011年 | 1189篇 |
2010年 | 835篇 |
2009年 | 690篇 |
2008年 | 978篇 |
2007年 | 929篇 |
2006年 | 849篇 |
2005年 | 784篇 |
2004年 | 811篇 |
2003年 | 668篇 |
2002年 | 639篇 |
2001年 | 335篇 |
2000年 | 298篇 |
1999年 | 264篇 |
1998年 | 176篇 |
1997年 | 162篇 |
1996年 | 120篇 |
1995年 | 124篇 |
1994年 | 144篇 |
1993年 | 125篇 |
1992年 | 193篇 |
1991年 | 201篇 |
1990年 | 194篇 |
1989年 | 207篇 |
1988年 | 178篇 |
1987年 | 166篇 |
1986年 | 160篇 |
1985年 | 150篇 |
1984年 | 128篇 |
1983年 | 107篇 |
1982年 | 102篇 |
1981年 | 109篇 |
1980年 | 97篇 |
1979年 | 111篇 |
1978年 | 111篇 |
1977年 | 73篇 |
1976年 | 91篇 |
1975年 | 99篇 |
1974年 | 102篇 |
1973年 | 90篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Mason LH Willette-Brown J Anderson SK Alvord WG Klabansky RL Young HA Ortaldo JR 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(8):4235-4242
Murine NK cells express the Ly-49 family of class I MHC-binding receptors that control their ability to lyse tumor or virally infected host target cells. X-ray crystallography studies have identified two predominant contact sites (sites 1 and 2) that are involved in the binding of the inhibitory receptor, Ly-49A, to H-2D(d). Ly-49G2 (inhibitory) and Ly-49D (activating) are highly homologous to Ly-49A and also recognize H-2D(d). However, the binding of Ly-49D and G(2) to H-2D(d) is of lower affinity than Ly-49A. All Ly-49s contain N-glycosylation motifs; however, the importance of receptor glycosylation in Ly-49-class I interactions has not been determined. Ly-49D and G(2) contain a glycosylation motif (NTT (221-223)), absent in Ly-49A, adjacent to one of the proposed binding sites for H-2D(d) (site 2). The presence of a complex carbohydrate group at this critical site could interfere with class I binding. In this study, we are able to demonstrate for the first time that Ly-49D binds H-2D(d) in the presence of mouse beta(2)-microglobulin. We also demonstrate that glycosylation of the NTT (221-23) motif of Ly-49D inteferes with recognition of H-2D(d). Alteration of the Ly-49D-NTT (221-23) motif to abolish glycosylation at this site resulted in enhanced H-2D(d) binding and receptor activation. Furthermore, glycosylation of Ly-49G2 at NTT (221-23) also reduces receptor binding to H-2D(d) tetramers. Therefore, the addition of complex carbohydrates to the Ly-49 family of receptors may represent a mechanism by which NK cells regulate affinity for host class I ligands. 相似文献
992.
IL-21 induces the apoptosis of resting and activated primary B cells 总被引:16,自引:0,他引:16
Mehta DS Wurster AL Whitters MJ Young DA Collins M Grusby MJ 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(8):4111-4118
Cytokines play an important role in regulating the development and homeostasis of B cells by controlling their viability. In this study, we show that the recently described T cell-derived cytokine IL-21 induces the apoptosis of resting primary murine B cells. In addition, the activation of primary B cells with IL-4, LPS, or anti-CD40 Ab does not prevent IL-21-mediated apoptosis. The induction of apoptosis by IL-21 correlates with a down-regulation in the expression of Bcl-2 and Bcl-x(L), two antiapoptotic members of the Bcl-2 family. Furthermore, the reconstitution of Bcl-x(L) or Bcl-2 expression protects primary B cells from IL-21-induced apoptosis. In addition, a short-term preactivation of B cells with anti-CD40 Ab confers protection from IL-21-mediated apoptosis through the up-regulation of Bcl-x(L). These studies reveal a novel pathway that mediates B cell apoptosis via the IL-21R and suggest that IL-21 may play a role in regulating B cell homeostasis. 相似文献
993.
Optimal induction of T-cell responses against hepatitis C virus E2 by antigen engineering in DNA immunization 总被引:3,自引:0,他引:3
Although DNA immunization is a safe and efficient method for inducing cellular immune responses, it generates relatively weak and slow immune responses. Here, we investigated the effect of hepatitis C virus (HCV) antigen modifications on the induction of T-cell responses in DNA immunization. It is likely that the strength of T-cell responses has an inverse relationship with the length of the insert DNA. Interestingly, a mixture of several plasmids carrying each gene induced a higher level of T-cell responses than a single plasmid expressing a long polyprotein. Moreover, the presence of a transmembrane domain in HCV E2 resulted in stronger T-cell responses against E2 protein than its absence. Taken together, our results indicate that the tailored modifications of DNA-encoded antigens are capable of optimizing the induction of T-cell responses which is required for eliminating the cells chronically infected with highly variable viruses such as HCV and human immunodeficiency virus. 相似文献
994.
Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility 总被引:10,自引:0,他引:10
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Transmissible spongiform encephalopathies (TSEs) may be acquired peripherally, in which case infectivity usually accumulates in lymphoid tissues before dissemination to the nervous system. Studies of mouse scrapie models have shown that mature follicular dendritic cells (FDCs), expressing the host prion protein (PrP(c)), are critical for replication of infection in lymphoid tissues and subsequent neuroinvasion. Since FDCs require lymphotoxin signals from B lymphocytes to maintain their differentiated state, blockade of this stimulation with a lymphotoxin beta receptor-immunoglobulin fusion protein (LT beta R-Ig) leads to their temporary dedifferentiation. Here, a single treatment with LT beta R-Ig before intraperitoneal scrapie inoculation blocked the early accumulation of infectivity and disease-specific PrP (PrP(Sc)) within the spleen and substantially reduced disease susceptibility. These effects coincided with an absence of FDCs in the spleen for ca. 28 days after treatment. Although the period of FDC dedifferentiation was extended to at least 49 days by consecutive LT beta R-Ig treatments, this had little added protective benefit after injection with a moderate dose of scrapie. We also demonstrate that mature FDCs are critical for the transmission of scrapie from the gastrointestinal tract. Treatment with LT beta R-Ig before oral scrapie inoculation blocked PrP(Sc) accumulation in Peyer's patches and mesenteric lymph nodes and prevented neuroinvasion. However, treatment 14 days after oral inoculation did not affect survival time or susceptibility, suggesting that infectivity may have already spread to the peripheral nervous system. Although manipulation of FDCs may offer a potential approach for early intervention in peripherally acquired TSEs, these data suggest that the duration of the treatment window may vary widely depending on the route of exposure. 相似文献
995.
Acute gastric anisakiasis with multiple anisakid larvae infection is reported. A 68-year-old woman residing in Busan, Korea, had epigastric pain with severe vomiting about 5 hours after eating raw anchovies. Four nematode larvae penetrating the gastric mucosae in the great curvature of the middle body and fundus were found and removed during gastro-endoscopic examination. Another one thread-like moving larva was found in the great curvature of upper body on the following day. On the basis of their morphology, the worms were identified as the 3rd stage larvae of Anisakis simplex. This case is acute gastric anisakiasis provoking severe clinical problems by the multiple infection and the greatest number of anisakid larvae found in a patient in Korea. 相似文献
996.
Binding of anthrax toxin to its receptor is similar to alpha integrin-ligand interactions 总被引:6,自引:0,他引:6
Bradley KA Mogridge J Jonah G Rainey A Batty S Young JA 《The Journal of biological chemistry》2003,278(49):49342-49347
The secreted protein toxin produced by Bacillus anthracis contributes to virulence of this pathogen and can cause many of the symptoms seen during an anthrax infection, including shock and sudden death. The cell-binding component of anthrax toxin, protective antigen, mediates entry of the toxin into cells by first binding directly to the extracellular integrin-like inserted (I) domain of the cellular anthrax toxin receptor, ATR. Here we report that this interaction requires an intact metal ion-dependent adhesion site (MIDAS) in the receptor as well as the presence of specific divalent cations. Also, we demonstrate that the toxin-receptor interaction is critically dependent on the Asp-683 carboxylate group of protective antigen, which projects from the receptor binding surface. We propose that this carboxylate group completes the coordination of the MIDAS metal of ATR, mimicking integrin-ligand interactions. 相似文献
997.
998.
Yan Z Choi S Liu X Zhang M Schageman JJ Lee SY Hart R Lin L Thurmond FA Williams RS 《The Journal of biological chemistry》2003,278(10):8826-8836
999.
Jutabha P Kanai Y Hosoyamada M Chairoungdua A Kim DK Iribe Y Babu E Kim JY Anzai N Chatsudthipong V Endou H 《The Journal of biological chemistry》2003,278(30):27930-27938
A novel transport protein with the properties of voltage-driven organic anion transport was isolated from pig kidney cortex by expression cloning in Xenopus laevis oocytes. A cDNA library was constructed from size-fractionated poly(A)+ RNA and screened for p-aminohippurate (PAH) transport in high potassium medium. A 1856-base pair cDNA encoding a 467-amino acid peptide designated as OATV1 (voltage-driven organic anion transporter 1) was isolated. The predicted amino acid sequence of OATV1 exhibited 60-65% identity to those of human, rat, rabbit, and mouse sodium-dependent phosphate cotransporter type 1 (NPT1), although OATV1 did not transport phosphate. The homology of this transporter to known members of the organic anion transporter family (OAT family) was about 25-30%. OATV1-mediated PAH transport was affected by the changes in membrane potential. The transport was Na+-independent and enhanced at high concentrations of extracellular potassium and low concentrations of extracellular chloride. Under the voltage clamp condition, extracellularly applied PAH induced outward currents in oocytes expressing OATV1. The current showed steep voltage dependence, consistent with the voltage-driven transport of PAH by OATV1. The PAH transport was inhibited by various organic anions but not by organic cations, indicating the multispecific nature of OATV1 for anionic compounds. This transport protein is localized at the apical membrane of renal proximal tubule, consistent with the proposed localization of a voltage-driven organic anion transporter. Therefore, it is proposed that OATV1 plays an important role to excrete drugs, xenobiotics, and their metabolites driven by membrane voltage through the apical membrane of the tubular epithelial cells into the urine. 相似文献
1000.
Ko YH Delannoy M Hullihen J Chiu W Pedersen PL 《The Journal of biological chemistry》2003,278(14):12305-12309
The terminal step of ATP synthesis in intact mitochondria is catalyzed by the ATP synthase (F(0)F(1)) that works in close synchrony with the P(i) and ADP/ATP carriers. Each carrier consists of only a single polypeptide chain in dimeric form, while the ATP synthase is highly complex consisting in animals of 17 known subunit types and more than 30 total subunits. Although structures at high resolution have been obtained for the water-soluble F(1) part of the ATP synthase consisting of only five subunit types, such structures have not been obtained for either the complete ATP synthase or the P(i) and ADP/ATP carriers. Here, we report that all three proteins are localized in highly purified cristae-like vesicles obtained by extensive subfractionation of the mitochondrial inner membrane. Moreover, using a multiwell detergent screening assay, 4 nonionic detergents out of 80 tested were found to disperse these cristae-like vesicles into single soluble complexes or "ATP synthasomes" that contain the ATP synthase in association with the P(i) and ADP/ATP carriers. These studies offer new mechanistic insights into the terminal steps of oxidative phosphorylation in mitochondria and set the stage for future structural efforts designed to visualize in atomic detail the entire complex involved. They also provide evidence that the cristae are a subcompartment of the inner membrane. 相似文献