全文获取类型
收费全文 | 21675篇 |
免费 | 1873篇 |
国内免费 | 1381篇 |
出版年
2024年 | 36篇 |
2023年 | 197篇 |
2022年 | 509篇 |
2021年 | 857篇 |
2020年 | 620篇 |
2019年 | 784篇 |
2018年 | 837篇 |
2017年 | 626篇 |
2016年 | 929篇 |
2015年 | 1402篇 |
2014年 | 1630篇 |
2013年 | 1703篇 |
2012年 | 2009篇 |
2011年 | 1925篇 |
2010年 | 1145篇 |
2009年 | 1090篇 |
2008年 | 1256篇 |
2007年 | 1148篇 |
2006年 | 1040篇 |
2005年 | 881篇 |
2004年 | 860篇 |
2003年 | 686篇 |
2002年 | 549篇 |
2001年 | 361篇 |
2000年 | 289篇 |
1999年 | 255篇 |
1998年 | 192篇 |
1997年 | 152篇 |
1996年 | 149篇 |
1995年 | 118篇 |
1994年 | 110篇 |
1993年 | 63篇 |
1992年 | 88篇 |
1991年 | 71篇 |
1990年 | 80篇 |
1989年 | 62篇 |
1988年 | 44篇 |
1987年 | 46篇 |
1986年 | 27篇 |
1985年 | 27篇 |
1984年 | 33篇 |
1983年 | 13篇 |
1982年 | 10篇 |
1981年 | 7篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1967年 | 2篇 |
1965年 | 1篇 |
1964年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 78 毫秒
971.
972.
Shuai Fan Guangxin Lv Xiao Feng Guangteng Wu Yuanyuan Jin Maocai Yan Zhaoyong Yang 《The Journal of biological chemistry》2022,298(2)
The potential antimicrobial compound Chuangxinmycin (CXM) targets the tryptophanyl-tRNA synthetase (TrpRS) of both Gram-negative and Gram-positive bacteria. However, the specific steric recognition mode and interaction mechanism between CXM and TrpRS is unclear. Here, we studied this interaction using recombinant GsTrpRS from Geobacillus stearothermophilus by X-ray crystallography and molecular dynamics (MD) simulations. The crystal structure of the recombinant GsTrpRS in complex with CXM was experimentally determined to a resolution at 2.06 Å. After analysis using a complex-structure probe, MD simulations, and site-directed mutation verification through isothermal titration calorimetry, the interaction between CXM and GsTrpRS was determined to involve the key residues M129, D132, I133, and V141 of GsTrpRS. We further evaluated binding affinities between GsTrpRS WT/mutants and CXM; GsTrpRS was found to bind CXM through hydrogen bonds with D132 and hydrophobic interactions between the lipophilic tricyclic ring of CXM and M129, I133, and V141 in the substrate-binding pockets. This study elucidates the precise interaction mechanism between CXM and its target GsTrpRS at the molecular level and provides a theoretical foundation and guidance for the screening and rational design of more effective CXM analogs against both Gram-negative and Gram-positive bacteria. 相似文献
973.
974.
975.
976.
977.
Jiaqi Wang Wenlong Zhang Zhao Jin Yue Ding Shilei Zhang Dianjun Wu Yongguo Cao 《PLoS neglected tropical diseases》2022,16(2)
Leptospirosis is a fatal zoonosis caused by contact between skin or a mucosal surface and contaminated soil or water. Hamsters were infected by intraperitoneal injection fto establish experimental leptospirosis, which is not a natural route of infection. There are no reports of nasal mucosal infection in hamsters. In this study, infection of the nasal mucosa was performed to establish a model of natural infection. Both methods of infection can cause lethal models with similar symptoms in the later stages of infection, such as weight loss, blood concentration, increased neutrophils (GRAN), and decreased lymphocytes (LYM) in the blood, severe organ damage and liver function obstruction. The burden of Leptospira in the organs and blood was lower in the mucosal inoculation groups at 1 day after infection. However, mucosal infection induced a higher Leptospira burden in urine than intraperitoneal infection in the late stages of infection. After nasal mucosal infection, antibody levels were higher and lasted longer. These results indicated that the route of nasal mucosal infection is a good choice for studying leptospirosis in hamsters. 相似文献
978.
Yu Ruan Jiaqiao Hu Yaping Che Yanyan Liu Zhenhuan Luo Jin Cheng Qi Han He He Qinghua Zhou 《Cell death & disease》2022,13(2)
Mitochondrial dysfunction is becoming one of the main pathology factors involved in the etiology of neurological disorders. Recently, mutations of the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) which encode two homologous proteins that belong to the mitochondrial CHCH domain protein family, are linked to Parkinson’s disease and amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), respectively. However, the physiological and pathological roles of these twin proteins have not been well elaborated. Here, we show that, in physiological conditions, CHCHD2 and CHCHD10 interact with OMA1 and suppress its enzyme activity, which not only restrains the initiation of the mitochondrial integrated response stress (mtISR), but also suppresses the processing of OPA1 for mitochondrial fusion. Further, during mitochondria stress-induced by carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment, CHCHD2 and CHCHD10 translocate to the cytosol and interacte with eIF2a, which attenuates mtISR overactivation by suppressing eIF2a phosphorylation and its downstream response. As such, knockdown of CHCHD2 and CHCHD10 triggers mitochondrial ISR, and such cellular response is enhanced by CCCP treatment. Therefore, our findings demonstrate the first “mtISR suppressor” localized in mitochondria for regulating stress responses in mammalian cells, which has a profound pathological impact on the CHCH2/CHCH10-linked neurodegenerative disorder.Subject terms: Stress signalling, Mitochondria 相似文献
979.
980.
Hye Won Lee Chanho Park Je-Gun Joung Minyong Kang Yun Shin Chung Won Joon Oh Seon-Yong Yeom Woong-Yang Park Tae Jin Kim Seong Il Seo 《Current issues in molecular biology》2021,43(1):226
Due to the highly immunogenic nature of renal cell carcinoma (RCC), the tumor microenvironment (TME) is enriched with various innate and adaptive immune subsets. In particular, gamma-delta (γδ) T cells can act as potent attractive mediators of adoptive cell transfer immunotherapy because of their unique properties such as non-reliance on major histocompatibility complex expression, their ability to infiltrate human tumors and recognize tumor antigens, relative insensitivity to immune checkpoint molecules, and broad tumor cytotoxicity. Therefore, it is now critical to better characterize human γδ T-cell subsets and their mechanisms in RCCs, especially the stage of differentiation. In this study, we aimed to identify γδ T cells that might have adaptive responses against RCC progression. We characterized γδ T cells in peripheral blood and tumor-infiltrating lymphocytes (TILs) in freshly resected tumor specimens from 20 RCC patients. Furthermore, we performed a gene set enrichment analysis on RNA-sequencing data from The Cancer Genome Atlas (TCGA) derived from normal kidneys and RCC tumors to ascertain the association between γδ T-cell infiltration and anti-cancer immune activity. Notably, RCC-infiltrating CD3low Vγ9Vδ1 T cells with a terminally differentiated effector memory phenotype with up-regulated activation/exhaustion molecules were newly detected as predominant TILs, and the cytotoxic activity of these cells against RCC was confirmed in vitro. In an additional analysis of the TCGA RCC dataset, γδ T-cell enrichment scores correlated strongly with those for CTLs, Th1 cells, “exhausted” T cells, and M1 macrophages, suggesting active involvement of γδ T cells in anti-tumor rather than pro-tumor activity, and Vδ1 cells were more abundant than Vδ2 or Vδ3 cells in RCC tumor samples. Thus, we posit that Vγ9Vδ1 T cells may represent an excellent candidate for adoptive immunotherapy in RCC patients with a high risk of relapse after surgery. 相似文献