全文获取类型
收费全文 | 24848篇 |
免费 | 1980篇 |
国内免费 | 1879篇 |
专业分类
28707篇 |
出版年
2024年 | 55篇 |
2023年 | 309篇 |
2022年 | 817篇 |
2021年 | 1309篇 |
2020年 | 896篇 |
2019年 | 1052篇 |
2018年 | 1050篇 |
2017年 | 759篇 |
2016年 | 1089篇 |
2015年 | 1491篇 |
2014年 | 1773篇 |
2013年 | 1922篇 |
2012年 | 2304篇 |
2011年 | 1963篇 |
2010年 | 1196篇 |
2009年 | 1041篇 |
2008年 | 1223篇 |
2007年 | 1083篇 |
2006年 | 945篇 |
2005年 | 826篇 |
2004年 | 701篇 |
2003年 | 640篇 |
2002年 | 558篇 |
2001年 | 481篇 |
2000年 | 423篇 |
1999年 | 404篇 |
1998年 | 256篇 |
1997年 | 272篇 |
1996年 | 258篇 |
1995年 | 243篇 |
1994年 | 223篇 |
1993年 | 140篇 |
1992年 | 206篇 |
1991年 | 145篇 |
1990年 | 130篇 |
1989年 | 109篇 |
1988年 | 73篇 |
1987年 | 94篇 |
1986年 | 56篇 |
1985年 | 56篇 |
1984年 | 43篇 |
1983年 | 30篇 |
1982年 | 30篇 |
1981年 | 19篇 |
1980年 | 8篇 |
1979年 | 6篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Yuping Chen Ni Jiao Ming Jiang Liping Liu Yihui Zhu Hongyan Wu Jing Chen Yingxue Fu Qiu Du Huiqin Xu Jihu Sun 《Journal of cellular and molecular medicine》2020,24(11):6083-6095
Diabetes mellitus (DM) damages male reproduction at multiple levels, such as endocrine secretion, spermatogenesis and penile erection. We herein investigated the protective effects and mechanism of loganin targeting the advanced glycation end products (AGEs)/receptor for AGEs (RAGE)/p38 mitogen-activated protein kinase (p38MAPK)/NF-κB signalling pathway. Loganin relieved the general DM symptoms and decreased the blood glucose level of KK-Ay DM mice. Haematoxylin-eosin staining demonstrated that loganin ameliorated testicular histology and function and enhanced the activities of testis-specific markers lactate dehydrogenase (LDH), acid phosphatase (ACP) and gamma-glutamyl transferase (γ-GT). Loganin also showed evident anti-oxidative stress, anti-apoptotic and anti-inflammatory effects on DM-induced reproductive damage by restoring glutathione (GSH) level and superoxide dismutase (SOD) activity, as well as reducing reactive oxygen species (ROS) level and Bax/Bcl-2 ratio in vivo and in vitro. Western blotting exhibited that loganin significantly inhibited the AGEs/RAGE/p38MAPK/NF-κB signalling pathway. Acridine orange and ethidium bromide staining (AOEB) and Western blotting showed that loganin in combination with inhibitors of RAGE, p38MAPK and NF-κB exerted stronger anti-apoptotic effects on AGE-induced GC-2 cell damage compared with loganin alone. In conclusion, loganin can protect against DM-induced reproductive damage, probably by suppressing the AGEs/RAGE/p38MAPK/NF-κB pathway. 相似文献
992.
Mengmeng Han Jialun Li Yaqiang Cao Yuanyong Huang Wen Li Haijun Zhu Qian Zhao Jing-Dong Jackie Han Qihan Wu Jiwen Li Jing Feng Jiemin Wong 《Nucleic acids research》2020,48(21):12116
LSH, a SNF2 family DNA helicase, is a key regulator of DNA methylation in mammals. How LSH facilitates DNA methylation is not well defined. While previous studies with mouse embryonic stem cells (mESc) and fibroblasts (MEFs) derived from Lsh knockout mice have revealed a role of Lsh in de novo DNA methylation by Dnmt3a/3b, here we report that LSH contributes to DNA methylation in various cell lines primarily by promoting DNA methylation by DNMT1. We show that loss of LSH has a much bigger effect in DNA methylation than loss of DNMT3A and DNMT3B. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association and UHRF1-catalyzed histone H3 ubiquitination in an ATPase activity-dependent manner, which in turn promotes DNMT1 recruitment to replication fork and DNA methylation. Notably, UHRF1 also enhances LSH association with the replication fork. Thus, our study identifies LSH as an essential factor for DNA methylation by DNMT1 and provides novel insight into how a feed-forward loop between LSH and UHRF1 facilitates DNMT1-mediated maintenance of DNA methylation in chromatin. 相似文献
993.
Xudong Zhang Cailin Xue Xiaohan Cui Zhao Zhou Yue Fu Xu Yin Siyuan Wu Yu Gong Yi Liu Chunfu Zhu Xihu Qin 《Journal of cellular and molecular medicine》2020,24(24):14596
Pancreatic cancer (PC) is a leading cause of cancer‐related mortality globally. Though increasing evidence has demonstrated that circular RNAs (circRNAs) are linked to the development and progression of cancers, the biological functions of circRNAs in PC remain largely unexplored so far. Based on previous studies, Hsc_circ_0075829 (circ_0075829) was screened out and then further identified in PC clinical specimens and cell lines by real‐time PCR. After the stability tests, a series of in vitro and in vivo functional experiments were performed to investigate the role of circ_0075829 in PC development. Furthermore, fluorescent in situ hybridization (FISH), bioinformatics tools, dual‐luciferase assays and rescue experiments were conducted to clarify the regulatory mechanisms of circ_0075829 in SW1990 and BxPC‐3 cells. Compared with paracancerous tissues, the expression of circ_0075829 was increased in PC tissues, which was positively correlated with the clinical features of PC. Knockdown of circ_0075829 significantly suppressed the proliferative, migratory and invasive rates of SW1990 and BxPC‐3 cells both in vitro and in vivo. Bioinformatics analysis and dual‐luciferase reporter gene assay indicated that circ_0075829 could bind to miR‐1287‐5p. Mechanism research and rescue experiments demonstrated that circ_0075829 could regulate the LAMTOR3/p‐ERK signalling pathway via sponging miR‐1287‐5p in PC cell lines. Our data reveal that the circ_0075829 could facilitate the proliferation and metastasis of PC through circ_0075829/miR‐1287‐5p/LAMTOR3 axis. 相似文献
994.
Identification of novel susceptibility loci for non‐syndromic cleft lip with or without cleft palate
Lan Ma Shu Lou Ziyue Miao Siyue Yao Xin Yu Shiyi Kan Guirong Zhu Fan Yang Chi Zhang Weibing Zhang Meilin Wang Lin Wang Yongchu Pan 《Journal of cellular and molecular medicine》2020,24(23):13669
Although several genome‐wide association studies (GWAS) of non‐syndromic cleft lip with or without cleft palate (NSCL/P) have been reported, more novel association signals are remained to be exploited. Here, we performed an in‐depth analysis of our previously published Chinese GWAS cohort study with replication in an extra dbGaP case‐parent trios and another in‐house Nanjing cohort, and finally identified five novel significant association signals (rs11119445: 3’ of SERTAD4, P = 6.44 × 10−14; rs227227 and rs12561877: intron of SYT14, P = 5.02 × 10−13 and 2.80 × 10−11, respectively; rs643118: intron of TRAF3IP3, P = 4.45 × 10−6; rs2095293: intron of NR6A1, P = 2.98 × 10−5). The mean (standard deviation) of the weighted genetic risk score (wGRS) from these SNPs was 1.83 (0.65) for NSCL/P cases and 1.58 (0.68) for controls, respectively (P = 2.67 × 10−16). Rs643118 was identified as a shared susceptible factor of NSCL/P among Asians and Europeans, while rs227227 may contribute to the risk of NSCL/P as well as NSCPO. In addition, sertad4 knockdown zebrafish models resulted in down‐regulation of sox2 and caused oedema around the heart and mandibular deficiency, compared with control embryos. Taken together, this study has improved our understanding of the genetic susceptibility to NSCL/P and provided further clues to its aetiology in the Chinese population. 相似文献
995.
Sun Weifeng Wu Yuanming Ding Wenwu Wang Li Wu Lunjie Lin Lu Che Zhenming Zhu Longbao Liu Yi Chen Xiaohua 《Bioprocess and biosystems engineering》2020,43(4):701-710
Bioprocess and Biosystems Engineering - Currently, some cases about the expression of flavor peptides with microorganisms were reported owing to the obvious advantages of biological expression over... 相似文献
996.
Li Guo-Si Zhu Fu-Cheng Wei Pei-Pei Gu Fang-Li Xu Qi-Ling Ma Meng-Hua 《Biotechnology letters》2022,44(9):1073-1080
Biotechnology Letters - To produce high concentrations of hyperoside from quercetin using recombinant Escherichia coli with in situ regeneration of UDP-galactose. Sucrose synthase from Glycine max... 相似文献
997.
Li Huanhuan Wu Xueqiang Bu Dingfang Wang Lihua Xu Xueju Wang Yingchao Liu Yufeng Zhu Ping 《Journal of molecular histology》2022,53(4):741-751
Journal of Molecular Histology - High Mobility Group Chromosomal Protein N2 (HMGN2) can recognize tumor cells and enhance the anti-tumor effect of immune cells. This study aimed to establish a... 相似文献
998.
Q Zhu X Zhang L Zhang W Li H Wu X Yuan F Mao M Wang W Zhu H Qian W Xu 《Cell death & disease》2014,5(6):e1295
Emerging evidence indicate that mesenchymal stem cells (MSCs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are essential component of the tumor microenvironment and are critically involved in cancer progression. Whether the phenotype and function of neutrophils is influenced by MSCs is not well understood. Herein, we investigated the interaction between neutrophils and gastric cancer-derived MSCs (GC-MSCs) and explored the biological role of this interaction. We found that GC-MSCs induced the chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from GC-MSCs with increased expression of IL-8, TNFα, CCL2, and oncostatin M (OSM). GC-MSCs-primed neutrophils augmented the migration of gastric cancer cells in a cell contact-dependent manner but had minimal effect on gastric cancer cell proliferation. In addition, GC-MSCs-primed neutrophils prompted endothelial cells to form tube-like structure in vitro. We demonstrated that GC-MSCs stimulated the activation of STAT3 and ERK1/2 pathways in neutrophils, which was essential for the functions of activated neutrophils. We further revealed that GC-MSCs-derived IL-6 was responsible for the protection and activation of neutrophils. In turn, GC-MSCs-primed neutrophils induced the differentiation of normal MSCs into cancer-associated fibroblasts (CAFs). Collectively, our results suggest that GC-MSCs regulate the chemotaxis, survival, activation, and function of neutrophils in gastric cancer via an IL-6–STAT3–ERK1/2 signaling cascade. The reciprocal interaction between GC-MSCs and neutrophils presents a novel mechanism for the role of MSCs in remodeling cancer niche and provides a potential target for gastric cancer therapy.Accumulating evidence suggest that neutrophils are critical for cancer initiation and progression.1, 2 The increased presence of intratumoral neutrophils has been linked to a poorer prognosis for patients with renal cancer, hepatocellular carcinoma (HCC), melanoma, head and neck squamous cell carcinoma (HNSCC), pancreatic cancer, colorectal carcinoma, and gastric adenocarcinoma.3 Recent studies using murine tumor models or involving cancer patients have suggested an important functional role of neutrophils during tumor progression.4, 5, 6, 7 Neutrophils-derived factors promote genetic mutations leading to tumorigenesis or promote tumor cell proliferation,8 migration, and invasion.9, 10 Neutrophils have also been demonstrated to induce tumor vascularization by the production of pro-angiogenic factors11, 12The infiltration of neutrophils into tumors has been shown to be mediated by factors produced by both tumor and stromal cells. Recent reports suggest that tumor cells actively modulate the functions of neutrophils. Tumor-derived CXCL5 modulates the chemotaxis of neutrophils, which in turn enhances the migration and invasion of human HCC cells.13 HNSCC cells-derived MIF induces the recruitment and activation of neutrophils through a p38-dependent manner.14, 15 Neutrophils respond to hyaluronan fragments in tumor supernatants via PI3K/Akt signaling, leading to prolonged survival and stimulating effect on HCC cell motility.16 Kuang et al.17 suggest that IL-17 promotes the migration of neutrophils into HCC through epithelial cell-derived CXC chemokines, resulting in increased MMP-9 production and angiogenesis at invading tumor edge However, much less is known about the role of stromal cells in modulating the phenotype and function of neutrophils in cancer thus far.Cancer-associated fibroblasts (CAFs) have a key role in cancer mainly through secretion of soluble factors, as growth factors or inflammatory mediators, as well as production of extracellular matrix proteins and their proteases. These activated fibroblasts are involved in creating a niche for cancer cells, promoting their proliferation, motility and chemoresistance. Activated fibroblasts express several mesenchymal markers such as α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), and vimentin. CAFs actively participate in reciprocal interaction with tumor cells and with other cell types in the microenvironment, contributing to a tumor-permissive niche and promoting tumor progression.Mesenchymal stem cells (MSCs) are adult stromal cells with self-renewal and pluripotent differentiation abilities. MSCs can be mobilized from bone marrow to the site of damage, respond to the local microenvironment, and exert wound repair and tissue regeneration functions upon injury and inflammation conditions.18 MSCs have been considered as one of the major components of the tumor stroma and are believed to be the precursors of CAFs.19, 20 We have previously demonstrated that human bone marrow MSCs prompt tumor growth in vivo.21 In addition, we have recently isolated MSCs-like cells from the gastric cancer tissues (GC) and the adjacent normal tissues (GCN) and shown that the gastric cancer-derived MSCs (GC-MSCs) possess the properties of CAFs.22, 23 As tumor-derived MSCs are often exposed to distinct inflammatory cells and factors in the tumor microenvironment, they may acquire novel functions that are not present in normal MSCs, and these unique functions may have a role in reshaping the tumor microenvironment and ultimately affect tumor progression. As neutrophils are key mediators of tumor progression and tumor angiogenesis, it is likely that an intense interaction may exist between the tumor-derived MSCs and tumor-infiltrating neutrophils.The emerging roles of CAFs in cancer immunoeditting led us to investigate whether GC-MSCs are able to regulate the phenotype and function of neutrophils in gastric cancer. We have shown that there is a reciprocal interaction between GC-MSCs and neutrophils. GC-MSCs enhanced the chemotaxis of peripheral blood-derived neutrophils and protected them from spontaneous apoptosis. GC-MSCs induced the activation of neutrophils to highly express IL-8, CCL2, TNFα, and oncostatin M (OSM), leading to the increase of gastric cancer cell migration and angiogenesis in vitro. GC-MSCs exerted this effect through the IL-6–STAT3–ERK1/2 signaling axis, and blockade of the IL-6–IL-6R interaction or pharmacological inhibition of STAT3 and ERK1/2 activation abrogated this role. In turn, GC-MSCs-activated neutrophils could trigger the CAF differentiation of normal MSCs. Therefore, these results establish a bi-directional interaction between GC-MSCs and neutrophils that may be critically involved in the progression of gastric cancer. 相似文献
999.
1000.