全文获取类型
收费全文 | 10849篇 |
免费 | 931篇 |
国内免费 | 908篇 |
专业分类
12688篇 |
出版年
2024年 | 33篇 |
2023年 | 146篇 |
2022年 | 282篇 |
2021年 | 482篇 |
2020年 | 356篇 |
2019年 | 439篇 |
2018年 | 502篇 |
2017年 | 345篇 |
2016年 | 491篇 |
2015年 | 692篇 |
2014年 | 822篇 |
2013年 | 898篇 |
2012年 | 1033篇 |
2011年 | 904篇 |
2010年 | 592篇 |
2009年 | 417篇 |
2008年 | 555篇 |
2007年 | 458篇 |
2006年 | 406篇 |
2005年 | 372篇 |
2004年 | 357篇 |
2003年 | 361篇 |
2002年 | 281篇 |
2001年 | 181篇 |
2000年 | 148篇 |
1999年 | 172篇 |
1998年 | 95篇 |
1997年 | 68篇 |
1996年 | 55篇 |
1995年 | 68篇 |
1994年 | 61篇 |
1993年 | 42篇 |
1992年 | 59篇 |
1991年 | 51篇 |
1990年 | 34篇 |
1989年 | 32篇 |
1988年 | 36篇 |
1987年 | 19篇 |
1986年 | 27篇 |
1985年 | 23篇 |
1984年 | 25篇 |
1983年 | 15篇 |
1982年 | 14篇 |
1981年 | 14篇 |
1979年 | 12篇 |
1974年 | 12篇 |
1973年 | 21篇 |
1972年 | 12篇 |
1966年 | 12篇 |
1958年 | 13篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
81.
82.
Roniel Cabrera Miguel Ararat Yiling Xu Todd Brusko Clive Wasserfall Mark A. Atkinson Lung Ji Chang Chen Liu David R. Nelson 《Cancer immunology, immunotherapy : CII》2013,62(4):737-746
Hepatocellular carcinoma (HCC) is a difficult to treat cancer characterized by poor tumor immunity with only one approved systemic drug, sorafenib. If novel combination treatments are to be developed with immunological agents, the effects of sorafenib on tumor immunity are important to understand. In this study, we investigate the impact of sorafenib on the CD4+CD25? effector T cells (Teff) and CD4+CD25+ regulatory T cells (Tregs) from patients with HCC. We isolated Teff and Treg from peripheral mononuclear cells of HCC patients to determine immune reactivity by thymidine incorporation, ELISA and flow cytometry. Teff cultured alone or with Treg were supplemented with different concentrations of sorafenib. The effects of sorafenib on Teff responses were dose-dependent. Pharmacologic doses of sorafenib decreased Teff activation by down regulating CD25 surface expression. In contrast, sub-pharmacologic concentrations of sorafenib resulted in Teff activation. These low doses of sorafenib in the Teff cultures led to a significant increase in Teff proliferation, IL2 secretion and up-regulation of CD25 expression on the cell surface. In addition, low doses of sorafenib in the suppression Teff/Treg cocultures restored Teff responses by eliminating Treg suppression. The loss of Treg suppressive function correlated with an increase in IL2 and IL6 secretion. Our findings show that sub-pharmacologic doses of sorafenib impact subsets of T cells differently, selectively increasing Teff activation while blocking Treg function. In conclusion, this study describes novel immune activating properties of low doses of sorafenib by promoting immune responsiveness in patients with HCC. 相似文献
83.
Wang Ning Gao Qing Shi Jie Yulan Chen Ji Weimeng Sheng Xiumei Zhang Rui 《Molecular biology reports》2022,49(9):8727-8740
Molecular Biology Reports - During the pathogenesis and progression of diabetes, lipotoxicity is a major threat to the function and survival of pancreatic β-cells. To battle against the... 相似文献
84.
目的 探究组织蛋白酶B(CTSB)介导NLRP3小体在砷致小胶质细胞(BV-2)炎症激活中的作用。方法 取处于对数生长期的BV-2细胞,分别暴露于终浓度为0、2、4、8 μmol/L亚砷酸钠(NaAsO2)溶液培养24 h,检测细胞活性,测定各组细胞内CTSB和细胞焦亡相关蛋白NLRP3、Caspase-1、IL-18、IL-1β的表达水平。流式细胞仪检测胞内溶酶体膜稳定性。基于实验结果,增设CTSB抑制剂组(5 μmol/L CA074-Me +8 μmol/L NaAsO2、10 μmol/L CA074-Me+8 μmol/L NaAsO2),检测两组细胞内炎症相关蛋白NLRP3、Caspase-1和IL-1β、IL-18的表达水平。结果 与对照组比较,各染砷组细胞抑制率增高,呈现剂量效应关系,溶酶体膜稳定性下降,差异有统计学意义(P<0.01),胞内CTSB、NLRP3、IL-1β、IL-18、Caspase-1表达增高,差异有统计学意义(P<0.01);与对照组(8 μmol/L NaAsO2)比较,抑制剂组BV-2细胞胞内CTSB、NLRP3、IL-1β、IL-18、Caspase-1水平均降低,差异有统计学差异(P<0.01)。结论 NaAsO2通过诱导小胶质细胞内CTSB水平的上升,介导NLRP3炎症小体激活小胶质细胞,促其释放炎性因子,致神经系统损伤。 相似文献
85.
Irina Vaseva Dessislava Todorova Jiří Malbeck Alena Trávníčková Ivana Macháčková 《Acta Physiologiae Plantarum》2008,30(2):151-155
Changes in cytokinin pool and cytokinin oxidase/dehydrogenase activity (CKX EC: 1.5.99.12) in response to increasing abscisic
acid (ABA) concentrations (0.5–10 μM) were assessed in the last fully expanded leaves and secondary roots of two pea (Pisum sativum) varieties with different vegetation periods. Certain organ diversity in CKX response to exogenous ABA was observed. Treatment
provoked altered cytokinin pool in the aboveground parts of both studied cultivars. Specific CKX activity was influenced significantly
basically in roots of the treated plants. Results suggest that ABA-mediated cytokinin pool changes are leaf-specific and involve
certain root signals in which CKX activity presents an important link. This enzymatic activity most probably regulates vascular
transport of active cytokinins from roots to shoots. 相似文献
86.
Yu Q Ji R Gao X Fu J Guo W Song X Zhao X Burnstock G Shi X He C Xiang Z 《Cell and tissue research》2011,344(2):227-237
Single- and double-immunostaining techniques were used systematically to study the distribution pattern and neurochemical density of oxytocin-immunoreactive (-ir) neurons in the digestive tract of the guinea pig. Oxytocin immunoreactivity was distributed widely in the guinea pig gastrointestinal tract; 3%, 13%, 17%, 15%, and 10% of ganglion neurons were immunoreactive for oxytocin in the myenteric plexuses of the gastric corpus, jejunum, ileum, proximal colon, and distal colon, respectively, and 36%, 40%, 52%, and 56% of ganglion neurons were immunoreactive for oxytocin in the submucosal plexuses of the jejunum, ileum, proximal colon, and distal colon, respectively. In the myenteric plexus, oxytocin was expressed exclusively in the intrinsic enteric afferent neurons, as identified by calbindin 28 K. In the submucosal plexuses, oxytocin was expressed in non-cholinergic secretomotor neurons, as identified by vasoactive intestinal polypeptide. Oxytocin-ir nerve fibers in the inner circular muscle layer possibly arose from the myenteric oxytocin-ir neurons, and oxytocin-ir nerve fibers in the mucosa possibly arose from both the myenteric and submucosal oxytocin-ir neurons. Thus, oxytocin in the digestive tract might be involved in gastrointestinal tract motility mainly via the regulation of the inner circular muscle and the balance of the absorption and secretion of water and electrolytes. 相似文献
87.
Huo X Qi X Tang F Zu R Li L Wu B Qin Y Ji H Fu J Wang S Tian H Hu Z Yang H Zhou M Wang H Zhu F 《PloS one》2011,6(3):e17995
Background
We investigated the seropositive rates and persistence of antibody against pandemic (H1N1) 2009 virus (pH1N1) in pregnant women and voluntary blood donors after the second wave of the pandemic in Nanjing, China.Methodology/Principal Findings
Serum samples of unvaccinated pregnant women (n = 720) and voluntary blood donors (n = 320) were collected after the second wave of 2009 pandemic in Nanjing. All samples were tested against pH1N1 strain (A/California/7/2009) with hemagglutination inhibition assay. A significant decline in seropositive rates, from above 50% to about 20%, was observed in pregnant women and voluntary blood donors fifteen weeks after the second wave of the pandemic. A quarter of the samples were tested against a seasonal H1N1 strain (A/Brisbane/59/2007). The antibody titers against pH1N1 strain were found to correlate positively with those against seasonal H1N1 strain. The correlation was modest but statistically significant.Conclusions and Significance
The high seropositive rates in both pregnant women and voluntary blood donors suggested that the pH1N1 virus had widely spread in these two populations. Immunity derived from natural infection seemed not to be persistent well. 相似文献88.
89.
Ahmed H.E. Hassan Min Chang Cho Hye In Kim Ji Seul Yang Kyung Tae Park Ji Young Hwang Choon-Gon Jang Ki Duk Park Yong Sup Lee 《Bioorganic & medicinal chemistry》2018,26(18):5069-5078
CRA13; a peripheral dual CB1R/CB2R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB1R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB1R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB1R and CB2R activity revealed the alcohol metabolite 8c as a more potent and more effective CB2R ligand with attenuated CB1R affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CB2R affinity and reduced CB1R affinity. The CB2R binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds. 相似文献
90.
Cheon H Rho YH Choi SJ Lee YH Song GG Sohn J Won NH Ji JD 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(2):1092-1100
In inflamed joints of rheumatoid arthritis, PGE(2) is highly expressed, and IL-10 and IL-6 are also abundant. PGE(2) is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE(2) on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE(2) significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE(2) suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE(2)-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change IL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect. H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE(2)-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE(2) selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE(2) may modulate immune responses by alteration of cytokine signaling in THP-1 cells. 相似文献