全文获取类型
收费全文 | 14709篇 |
免费 | 1340篇 |
国内免费 | 1603篇 |
专业分类
17652篇 |
出版年
2024年 | 61篇 |
2023年 | 247篇 |
2022年 | 542篇 |
2021年 | 887篇 |
2020年 | 630篇 |
2019年 | 726篇 |
2018年 | 694篇 |
2017年 | 495篇 |
2016年 | 667篇 |
2015年 | 975篇 |
2014年 | 1102篇 |
2013年 | 1235篇 |
2012年 | 1346篇 |
2011年 | 1272篇 |
2010年 | 750篇 |
2009年 | 703篇 |
2008年 | 765篇 |
2007年 | 647篇 |
2006年 | 638篇 |
2005年 | 408篇 |
2004年 | 408篇 |
2003年 | 382篇 |
2002年 | 326篇 |
2001年 | 241篇 |
2000年 | 196篇 |
1999年 | 195篇 |
1998年 | 162篇 |
1997年 | 116篇 |
1996年 | 106篇 |
1995年 | 95篇 |
1994年 | 73篇 |
1993年 | 64篇 |
1992年 | 84篇 |
1991年 | 58篇 |
1990年 | 52篇 |
1989年 | 50篇 |
1988年 | 41篇 |
1987年 | 28篇 |
1986年 | 22篇 |
1985年 | 28篇 |
1984年 | 19篇 |
1983年 | 11篇 |
1982年 | 17篇 |
1981年 | 11篇 |
1980年 | 8篇 |
1979年 | 11篇 |
1978年 | 10篇 |
1977年 | 7篇 |
1975年 | 11篇 |
1973年 | 7篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
51.
为探究滇西北不同退化级别高寒草甸植物群落结构对外界干扰的响应敏感性,以香格里拉市的典型高寒草甸为研究对象,于2018-2020年在三个退化梯度上(严重退化,S1;中度退化,S2;轻度退化,S3)开展控制刈割实验,进而分析草甸植物物种丰富度、群落组成相似性、群落复杂度和关键种的变化规律。结果表明:(1)刈割后,S1的物种丰富度显著增加(P<0.05),S2和S3的物种丰富度未发生显著变化(P>0.05);(2)相较于S2和S3,S1梯度的植物群落组成变化最大;(3) S1、S2和S3的植物群落复杂度在刈割后均呈先下降后增加的趋势,但S1的植物群落复杂度变化幅度高于S2和S3;(4)刈割导致各退化草甸植物群落的关键种发生了变化,2018、2019和2020年S1梯度的关键种在豆科(Leguminsae)和蔷薇科(Rosaceae)之间变化,S2梯度的关键种在禾本科(Gramineae)和菊科(Compositae)之间变化,S3梯度的关键种在蔷薇科(Rosaceae)、菊科(Compositae)和禾本科(Gramineae)之间转变。研究表明,滇西北高寒草甸植物物种丰富度、群落组成和群落复杂度对外界干扰响应的敏感性可能随退化加剧而上升,但群落关键种的响应过程较复杂。 相似文献
52.
Yun Zhang Doudou Dong Xiaoting Xu Hui He Yuan Zhu Tingwen Lei Hailong Ou 《The Journal of biological chemistry》2022,298(6)
Oxidized high-density lipoprotein (oxHDL) reduces the ability of cells to mediate reverse cholesterol transport and also shows atherogenic properties. Palmitoylation of cluster of differentiation 36 (CD36), an important receptor mediating lipoprotein uptake, is required for fatty acid endocytosis. However, the relationship between oxHDL and CD36 has not been described in mechanistic detail. Here, we demonstrate using acyl-biotin exchange analysis that oxHDL activates CD36 by increasing CD36 palmitoylation, which promotes efficient uptake in macrophages. This modification increased CD36 incorporation into plasma lipid rafts and activated downstream signaling mediators, such as Lyn, Fyn, and c-Jun N-terminal kinase, which elicited enhanced oxHDL uptake and foam cell formation. Furthermore, blocking CD36 palmitoylation with the pharmacological inhibitor 2-bromopalmitate decreased cell surface translocation and lowered oxHDL uptake in oxHDL-treated macrophages. We verified these results by transfecting oxHDL-induced macrophages with vectors expressing wildtype or mutant CD36 (mCD36) in which the cytoplasmic palmitoylated cysteine residues were replaced. We show that cells containing mCD36 exhibited less palmitoylated CD36, disrupted plasma membrane trafficking, and reduced protein stability. Moreover, in ApoE−/−CD36−/− mice, lipid accumulation at the aortic root in mice receiving the mCD36 vector was decreased, suggesting that CD36 palmitoylation is responsible for lipid uptake in vivo. Finally, our data indicated that palmitoylation of CD36 was dependent on DHHC6 (Asp-His-His-Cys) acyltransferase and its cofactor selenoprotein K, which increased the CD36/caveolin-1 interaction and membrane targeting in cells exposed to oxHDL. Altogether, our study uncovers a causal link between oxHDL and CD36 palmitoylation and provides insight into foam cell formation and atherogenesis. 相似文献
53.
Yue Li Yuwei Du Zhengqing Xu Yuan He Ran Yao Huiran Jiang Wen Ju Jianlin Qiao Kailin Xu Tzu-Ming Liu Lingyu Zeng 《Journal of lipid research》2022,63(5)
Macrophages play pivotal roles in the maintenance of tissue homeostasis. However, the reactivation of macrophages toward proinflammatory states correlates with a plethora of inflammatory diseases, including atherosclerosis, obesity, neurodegeneration, and bone marrow (BM) failure syndromes. The lack of methods to reveal macrophage phenotype and function in vivo impedes the translational research of these diseases. Here, we found that proinflammatory macrophages accumulate intracellular lipid droplets (LDs) relative to resting or noninflammatory macrophages both in vitro and in vivo, indicating that LD accumulation serves as a structural biomarker for macrophage phenotyping. To realize the staining and imaging of macrophage LDs in vivo, we developed a fluorescent fatty acid analog-loaded poly(lactic-co-glycolic acid) nanoparticle to label macrophages in mice with high efficiency and specificity. Using these novel nanoparticles, we achieved in situ functional identification of single macrophages in BM, liver, lung, and adipose tissues under conditions of acute or chronic inflammation. Moreover, with this intravital imaging platform, we further realized in vivo phenotyping of individual macrophages in the calvarial BM of mice under systemic inflammation. In conclusion, we established an efficient in vivo LD labeling and imaging system for single macrophage phenotyping, which will aid in the development of diagnostics and therapeutic monitoring. Moreover, this method also provides new avenues for the study of lipid trafficking and dynamics in vivo.Supplementary key words: macrophage, inflammation, lipid droplet, nanoparticle delivery, in vivo imaging, fatty acid analog, bone marrow, systemic inflammation, lipid trafficking, biomarkerMacrophages, a type of immune cells, almost reside in all tissues of body, from the skin to the bone marrow (BM) (1). Macrophages have remarkable plasticity, and they can be activated into specific subtypes by modifying their physiology and functions in response to local environmental cues. Activated macrophages are commonly divided into proinflammatory killing subtype and anti-inflammatory repairing subtype. Proinflammatory macrophages responding to bacteria, IFN-γ, and lipopolysaccharide (LPS) are involved in host defense and inflammation, whereas anti-inflammatory macrophages responding to interleukin-4 (IL-4), IL-10, and IL-13 play a pivotal role in tissue homeostasis and remodeling (2). Increasing evidence indicates that the reactivation of macrophages toward proinflammatory states under diverse kinds of stress is correlated with a plethora of inflammatory diseases, such as atherosclerosis, diabetes, obesity, rheumatoid arthritis, neurodegeneration, and BM failure syndromes (3, 4). Thus, characterization of macrophage activation status and the underlying molecular mechanism in situ will help elucidate their functions in these diseases; however, in vivo analysis of the macrophage activation status in their native multicellular microenvironment is challenging.Although lipid droplets (LDs) have been initially described as intracellular fat storage organelles in adipocytes, increasing studies indicate that myeloid cells also form LDs under inflammation and stress (5, 6). Macrophages, as the effector cells of innate immunity, are found to form LDs to support their host defense when exposed to pathogens, such as parasites, bacteria, and viruses (7, 8, 9, 10, 11). However, abnormal LD accumulation in tissue-resident macrophages correlates with the pathogenesis of various inflammatory diseases. For instance, foam cells in atherosclerotic lesions can maintain the local inflammatory response by secreting proinflammatory cytokines (12, 13, 14). Moreover, LD-accumulating microglia contribute to neurodegeneration by producing high levels of reactive oxygen species (ROS) and secreting proinflammatory cytokines (15). These findings indicate that LD accumulation might be a hallmark of macrophages with proinflammatory functions.In this study, based on the typical activation of in vitro BM-derived macrophages, we find that proinflammatory M(LPS + IFN-γ) macrophages are characterized by LD accumulation, whereas resting macrophages and anti-inflammatory M(IL-4) and M(IL-10) macrophages do not contain any LDs. These features also hold for Matrigel plug-recruited macrophages and tissue-resident macrophages in mice. These findings demonstrate that LD accumulation could serve as a morphological index to distinguish proinflammatory macrophages from others.It is feasible to distinguish LD-containing cells using imaging techniques, which has translational potential for identification of proinflammatory macrophages in vivo. However, current techniques for LD visualization are traditional in vitro staining method, and in vivo staining and imaging of LD in individual macrophages remains a challenge. Through nanocarrier screening, we selected the poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) as nanocarrier to deliver the lipophilic carbocyanine dye (DiIC18(5) solid (1,1''-dioctadecyl-3,3,3'',3''-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt) [DiD]) and lipid staining dye (C1-BODIPY 500/510-C12) into macrophages. Using these dual fluorescence-labeled PLGA NPs, we achieved in situ and in vivo functional identification of single macrophages in various tissues under systemic or local inflammatory stress. Collectively, this study establishes an efficient in vivo labeling and imaging system of intracellular LDs for phenotyping the activation status and functions of individual macrophages in their dynamic niche, which is pivotal for disease diagnosis and preclinical research. 相似文献
54.
为促进城市可持续发展,在科学合理规划城市空间格局的基础上,应突出强调保护原有特色生态环境要素,保育生态系统服务功能和原住民人居环境。作为世界文化遗产,丽江城市面貌在过去数十年发生了深刻变化,城市用地显著扩张,同时严峻的环境问题对城市可持续发展提出挑战。以丽江市为例,选取对其发展影响深远的水系元素、噪声环境因子和森林火灾3个关键生态敏感因子,提出通过分析这类生态敏感区在城市规划过程中的避让方法、程度,区划城市规划基本空间格局,以避免城市未来因生态环境问题突出而制约其发展的规划用地思路。结果表明,丽江城区周边湖泊水系、古城内部及周边原住民人口密集区都是保障城市可持续发展的生态保护重点地区,在城市用地规划中必须予以避让;该区域面积为147.2 km2,占研究区面积的11.1%。同时,明确给出了规划用地的具体空间控制范围和相应的避让原则。 相似文献
55.
56.
Hong-Guang Zhang Bin Wang Yong Yang Xuan Liu Junjie Wang Ning Xin Shifeng Li Ying Miao Qiuyu Wu Tingting Guo Yukang Yuan Yibo Zuo Xiangjie Chen Tengfei Ren Chunsheng Dong Jun Wang Hang Ruan Miao Sun Xingshun Xu Hui Zheng 《Cell research》2022,32(10):897
Depression is a serious public-health issue. Recent reports have suggested higher susceptibility to viral infections in depressive patients. However, how depression affects antiviral innate immune signaling remains unknown. Here, we revealed a reduction in expression of Abelson helper integration site 1 (AHI1) in the peripheral blood mononuclear cells (PBMCs) and macrophages from the patients with major depressive disorder (MDD), which leads to attenuated antiviral immune response. We found that depression-related arginine vasopressin (AVP) induces reduction of AHI1 in macrophages. Further studies demonstrated that AHI1 is a critical stabilizer of basal type-I-interferon (IFN-I) signaling. Mechanistically, AHI1 recruits OTUD1 to deubiquitinate and stabilize Tyk2, while AHI1 reduction downregulates Tyk2 and IFN-I signaling activity in macrophages from both MDD patients and depression model mice. Interestingly, we identified a clinical analgesic meptazinol that effectively stimulates AHI1 expression, thus enhancing IFN-I antiviral defense in depression model mice. Our study promotes the understanding of the signaling mechanisms of depression-mediated antiviral immune dysfunction, and reveals meptazinol as an enhancer of antiviral innate immunity in depressive patients.Subject terms: Innate immunity, Ubiquitylation, Cell signalling 相似文献
57.
Jianping Hu Yiting Zhang Shenglan Yi Chaokui Wang Xinyue Huang Su Pan Jinglu Yang Gangxiang Yuan Sisi Tan Hong Li 《International journal of biological sciences》2022,18(11):4545
Dendritic cells (DCs) are the major antigen-presenting cells and play an important role in autoimmune uveitis. Emerging evidence suggests that bile acids (BAs) regulate DCs maturation. However, the underlying mechanisms by which BAs regulate the function of DCs still need to be clarified. Here, we demonstrate that lithocholic acid (LCA) inhibits the production of pro-inflammatory cytokines and the expression of surface molecules in bone marrow-derived dendritic cells (BMDCs). LCA attenuates the severity of EAU by modulating the maturation of splenic CD11C+MHCIIhigh DCs. Notably, Takeda G-protein coupled receptor 5 (TGR5) deficiency partially reverses the inhibitory effect of LCA on DCs in vitro and in vivo. TGR5 activation also downregulates the NF-κB and MAPK pathways by inhibiting glutathione production and inducing oxidative stress in DCs, which leads to apoptosis and autophagy in DCs. In addition, LCA or INT-777 treatment increases the TGR5 expression in monocyte-derived dendritic cells (MD-DCs) of patients with active BD, whereas both LCA and TGR5 agonists inhibit the activation of MD-DCs. These results suggest that LCA and TGR5 agonists might be potential therapeutic drugs for the treatment of autoimmune uveitis. 相似文献
58.
59.
60.
Weifeng He Yuan Gao Jing Zhou Yi Shi Dajing Xia Han-Ming Shen 《International journal of biological sciences》2022,18(12):4690
There is increasing amount of evidence indicating the close interplays between the replication cycle of SARS-CoV-2 and the autophagy-lysosome pathway in the host cells. While autophagy machinery is known to either assist or inhibit the viral replication process, the reciprocal effects of the SARS-CoV-2 on the autophagy-lysosome pathway have also been increasingly appreciated. More importantly, despite the disappointing results from the clinical trials of chloroquine and hydroxychloroquine in treatment of COVID-19, there is still ongoing effort in discovering new therapeutics targeting the autophagy-lysosome pathway. In this review, we provide an update-to-date summary of the interplays between the autophagy-lysosome pathway in the host cells and the pathogen SARS-CoV-2 at the molecular level, to highlight the prognostic value of autophagy markers in COVID-19 patients and to discuss the potential of developing novel therapeutic strategies for COVID-19 by targeting the autophagy-lysosome pathway. Thus, understanding the nature of such interactions between SARS-CoV-2 and the autophagy-lysosome pathway in the host cells is expected to provide novel strategies in battling against this global pandemic. 相似文献