全文获取类型
收费全文 | 19793篇 |
免费 | 1776篇 |
国内免费 | 1406篇 |
出版年
2023年 | 215篇 |
2022年 | 504篇 |
2021年 | 943篇 |
2020年 | 625篇 |
2019年 | 716篇 |
2018年 | 756篇 |
2017年 | 560篇 |
2016年 | 729篇 |
2015年 | 1211篇 |
2014年 | 1338篇 |
2013年 | 1444篇 |
2012年 | 1663篇 |
2011年 | 1583篇 |
2010年 | 1040篇 |
2009年 | 887篇 |
2008年 | 956篇 |
2007年 | 927篇 |
2006年 | 815篇 |
2005年 | 697篇 |
2004年 | 673篇 |
2003年 | 575篇 |
2002年 | 555篇 |
2001年 | 399篇 |
2000年 | 395篇 |
1999年 | 365篇 |
1998年 | 174篇 |
1997年 | 161篇 |
1996年 | 158篇 |
1995年 | 121篇 |
1994年 | 149篇 |
1993年 | 91篇 |
1992年 | 157篇 |
1991年 | 150篇 |
1990年 | 126篇 |
1989年 | 101篇 |
1988年 | 82篇 |
1987年 | 98篇 |
1986年 | 83篇 |
1985年 | 92篇 |
1984年 | 48篇 |
1983年 | 48篇 |
1982年 | 50篇 |
1981年 | 37篇 |
1980年 | 38篇 |
1979年 | 55篇 |
1978年 | 41篇 |
1977年 | 46篇 |
1976年 | 33篇 |
1975年 | 39篇 |
1974年 | 44篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Beiping Zhong Bing Cheng Xiaoming Huang Qian Xiao Zhitong Niu Yu-feng Chen Qiang Yu Wenyu Wang Xiao-Jian Wu 《Cell death & disease》2022,13(1)
Cancer-associated fibroblasts (CAFs) have been shown to play a strong role in colorectal cancer metastasis, yet the underlying mechanism remains to be fully elucidated. Using CRC clinical samples together with ex vivo CAFs-CRC co-culture models, we found that CAFs induce expression of Leucine Rich Alpha-2-Glycoprotein 1(LRG1) in CRC, where it shows markedly higher expression in metastatic CRC tissues compared to primary tumors. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. In addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. Mechanistically, we demonstrate that CAFs-secreted IL-6 (interleukin-6) is responsible for LRG1 up-regulation in CRC, which occurs through a direct transactivation by STAT3 following JAK2 activation. In clinical CRC tumor samples, LRG1 expression was positively correlated with CAFs-specific marker, α-SMA, and a higher LRG1 expression predicted poor clinical outcomes especially distant metastasis free survival, supporting the role of LRG1 in CRC progression. Collectively, this study provided a novel insight into CAFs-mediated metastasis in CRC and indicated that therapeutic targeting of CAFs-mediated IL-6-STAT3-LRG1 axis might be a potential strategy to mitigate metastasis in CRC.Subject terms: Colon cancer, Cancer microenvironment 相似文献
992.
993.
994.
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
995.
996.
997.
Zhen Wang Xiaoyan Du Daoyang Yu Yang Yang Gaoen Ma Xueli Jia Lulu Cheng 《European journal of histochemistry : EJH》2022,66(1)
Stroke is a brain system disease with a high fatality rate and disability rate. About 80% of strokes are ischemic strokes. Cerebral ischemia-reperfusion injury (CIRI) caused by ischemic stroke seriously affects the prognosis of stroke patients. The purpose of this study is to investigate the effect of sufentanil (SUF) on CIRI model rats. We used middle cerebral artery occlusion (MCAO) to make the CIRI model in rats and monitored region cerebral blood flow (rCBF) to ensure that blood flow was blocked and recanalized. We used ELISA and RT-PCR to detect the expression of inflammatory factors in rat serum and brain tissue. In addition, we detected the expression of metalloproteinase (MMP) 2, MMP9 and collagen IV in brain tissues and performed Evans blue (EB) assay to determine the permeability of the blood-brain barrier (BBB). Finally, we clarified the apoptosis of brain tissue through the TUNEL staining and the detection of caspase 3, Bcl2 and Bax. Various concentrations of SUF, especially 5, 10 and 25μg/kg of SUF, all alleviated the infarct size, neurological function and brain edema of MCAO rats. SUF pretreatment also effectively reduced the expression of inflammatory cytokines in MCAO rats, including interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α. In addition, SUF also inhibited MMP2 and MMP9 and promoted the expression of collagen IV, indicating that SUF attenuated the destruction of the BBB. SUF also inhibited caspase 3 and Bax rats and promoted Bcl2 in MCAO rats, thus inhibiting cell apoptosis. SUF pretreatment effectively improved the neurological function and cerebral infarction of MCAO rats, inhibited excessive inflammation in rats, protected the BBB, and inhibited cell apoptosis in brain tissue.Key words: Sufentanil, cerebral ischemia-reperfusion injury, inflammation, blood-brain barrier 相似文献
998.
999.
Choun-Sea Lin Chen-Tran Hsu Yu-Hsuan Yuan Po-Xing Zheng Fu-Hui Wu Qiao-Wei Cheng Yu-Lin Wu Ting-Li Wu Steven Lin Jin-Jun Yue Ying-Huey Cheng Shu-I Lin Ming-Che Shih Jen Sheen Yao-Cheng Lin 《Plant physiology》2022,188(4):1917
Wild tomatoes (Solanum peruvianum) are important genomic resources for tomato research and breeding. Development of a foreign DNA-free clustered regularly interspaced short palindromic repeat (CRISPR)-Cas delivery system has potential to mitigate public concern about genetically modified organisms. Here, we established a DNA-free CRISPR-Cas9 genome editing system based on an optimized protoplast regeneration protocol of S. peruvianum, an important resource for tomato introgression breeding. We generated mutants for genes involved in small interfering RNAs biogenesis, RNA-DEPENDENT RNA POLYMERASE 6 (SpRDR6), and SUPPRESSOR OF GENE SILENCING 3 (SpSGS3); pathogen-related peptide precursors, PATHOGENESIS-RELATED PROTEIN-1 (SpPR-1) and PROSYSTEMIN (SpProSys); and fungal resistance (MILDEW RESISTANT LOCUS O, SpMlo1) using diploid or tetraploid protoplasts derived from in vitro-grown shoots. The ploidy level of these regenerants was not affected by PEG-Ca2+-mediated transfection, CRISPR reagents, or the target genes. By karyotyping and whole genome sequencing analysis, we confirmed that CRISPR-Cas9 editing did not introduce chromosomal changes or unintended genome editing sites. All mutated genes in both diploid and tetraploid regenerants were heritable in the next generation. spsgs3 null T0 regenerants and sprdr6 null T1 progeny had wiry, sterile phenotypes in both diploid and tetraploid lines. The sterility of the spsgs3 null mutant was partially rescued, and fruits were obtained by grafting to wild-type (WT) stock and pollination with WT pollen. The resulting seeds contained the mutated alleles. Tomato yellow leaf curl virus proliferated at higher levels in spsgs3 and sprdr6 mutants than in the WT. Therefore, this protoplast regeneration technique should greatly facilitate tomato polyploidization and enable the use of CRISPR-Cas for S. peruvianum domestication and tomato breeding.A DNA-free CRISPR-Cas9 genome editing tool based on an optimized protoplast regeneration protocol of wild tomato creates stable and inheritable diploid and tetraploid regenerants. 相似文献
1000.
Jing Quan Can Cheng Yue Tan Nian Jiang Chaoliang Liao Weihua Liao Ya Cao Xiangjian Luo 《International journal of biological sciences》2022,18(6):2484
Cancer cells frequently undergo metabolic reprogramming to support tumorigenicity and malignancy, which is recognized as a hallmark of cancer. In addition to glycolysis and glutaminolysis, alterations in fatty acid (FA) metabolism have received increasing concerns in the past few years. Recently, accumulating evidence has shown that fatty acid β-oxidation (FAO) is abnormally activated in various tumors, which is associated with the machinery of proliferation, stemness, metastasis, and radiochemotherapeutic resistance of cancer cells. Acyl-CoA synthetases 3 (ACSL3) belongs to a family of enzymes responsible for converting free long-chain FAs into fatty acyl-CoA esters, which act as substrates both for lipid synthesis and FAO.Here, we demonstrate that transforming growth factor beta 1 (TGFβ1) induces the up-regulation of ACSL3 through sterol regulatory element-binding protein 1 (SREBP1) signaling to promote energy metabolic reprogramming in colorectal carcinoma (CRC) cells. ACSL3 mediates the epithelial mesenchymal transition (EMT) and metastasis of CRC cells by activation of FAO pathway to produce ATP and reduced nicotinamide adenine dinucleotide phosphate (NADPH), which sustain redox homeostasis and fuel cancer cells for invasion and distal metastasis. Thus, targeting ACSL3 and FAO metabolic pathways might be exploited for therapeutic gain for CRC and other FAs- addicted cancers. 相似文献