全文获取类型
收费全文 | 16728篇 |
免费 | 944篇 |
国内免费 | 834篇 |
出版年
2024年 | 31篇 |
2023年 | 328篇 |
2022年 | 610篇 |
2021年 | 946篇 |
2020年 | 648篇 |
2019年 | 705篇 |
2018年 | 584篇 |
2017年 | 365篇 |
2016年 | 387篇 |
2015年 | 506篇 |
2014年 | 993篇 |
2013年 | 1218篇 |
2012年 | 746篇 |
2011年 | 1043篇 |
2010年 | 725篇 |
2009年 | 753篇 |
2008年 | 804篇 |
2007年 | 825篇 |
2006年 | 718篇 |
2005年 | 670篇 |
2004年 | 575篇 |
2003年 | 530篇 |
2002年 | 452篇 |
2001年 | 289篇 |
2000年 | 256篇 |
1999年 | 236篇 |
1998年 | 210篇 |
1997年 | 161篇 |
1996年 | 154篇 |
1995年 | 139篇 |
1994年 | 157篇 |
1993年 | 121篇 |
1992年 | 129篇 |
1991年 | 128篇 |
1990年 | 88篇 |
1989年 | 82篇 |
1988年 | 72篇 |
1987年 | 77篇 |
1986年 | 71篇 |
1985年 | 127篇 |
1984年 | 126篇 |
1983年 | 86篇 |
1982年 | 102篇 |
1981年 | 108篇 |
1980年 | 103篇 |
1979年 | 68篇 |
1978年 | 65篇 |
1977年 | 53篇 |
1976年 | 51篇 |
1974年 | 29篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
921.
Compared with other SARS-related coronaviruses (SARSr-CoVs), SARS-CoV-2 possesses a unique furin cleavage site (FCS) in its spike. This has stimulated discussion pertaining to the origin of SARS-CoV-2 because the FCS has been observed to be under strong selective pressure in humans and confers the enhanced ability to infect some cell types and induce cell–cell fusion. Furthermore, scientists have demonstrated interest in studying novel cleavage sites by introducing them into SARSr-CoVs. We review what is known about the SARS-CoV-2 FCS in the context of its pathogenesis, origin, and how future wildlife coronavirus sampling may alter the interpretation of existing data. 相似文献
922.
Fernanda Medeiros Sebastio Kristiane Michelin-Tirelli Fernanda Bender Franciele Ftima Lopes Inamara Moraes Francyne Kubaski Roberto Giugliani Maira Burin 《Genetics and molecular biology》2022,45(1)
The COVID-19 pandemic led to the reorganization of health care in several countries, including Brazil. Inborn Errors of Metabolism (IEM) are a group of rare and difficult to diagnose genetic diseases caused by pathogenic variants in genes that code for enzymes, cofactors, or structural proteins affecting different metabolic pathways. The aim of this study was to evaluate how COVID-19 affected the diagnosis of patients with IEM during the first year of the pandemic in Brazil comparing two distinct periods: from March 1st, 2019 to February 29th, 2020 (TIME A) and from March 1st, 2020 to February 28th, 2021 (TIME B), by the analysis of the number of tests and diagnoses performed in a Reference Center in South of Brazil. In the comparison TIME A with TIME B, we observe a reduction in the total number of tests performed (46%) and in the number of diagnoses (34%). In both periods analyzed, mucopolysaccharidoses (all subtypes combined) was the most frequent LD suspected and/or confirmed. Our data indicates a large reduction in the number of tests requested for the investigation of IEM and consequently a large reduction in the number of diagnoses caused by the COVID-19 pandemic leading to a significant underdiagnosis of IEM. 相似文献
923.
Calvin J. Gordon Hery W. Lee Egor P. Tchesnokov Jason K. Perry Joy Y. Feng John P. Bilello Danielle P. Porter Matthias Gtte 《The Journal of biological chemistry》2022,298(2)
Remdesivir (RDV) is a direct-acting antiviral agent that is approved in several countries for the treatment of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2. RDV exhibits broad-spectrum antiviral activity against positive-sense RNA viruses, for example, severe acute respiratory syndrome coronavirus and hepatitis C virus, and nonsegmented negative-sense RNA viruses, for example, Nipah virus, whereas segmented negative-sense RNA viruses such as influenza virus or Crimean-Congo hemorrhagic fever virus are not sensitive to the drug. The reasons for this apparent efficacy pattern are unknown. Here, we expressed and purified representative RNA-dependent RNA polymerases and studied three biochemical parameters that have been associated with the inhibitory effects of RDV-triphosphate (TP): (i) selective incorporation of the nucleotide substrate RDV-TP, (ii) the effect of the incorporated RDV-monophosphate (MP) on primer extension, and (iii) the effect of RDV-MP in the template during incorporation of the complementary UTP. We found a strong correlation between antiviral effects and efficient incorporation of RDV-TP. Inhibition in primer extension reactions was heterogeneous and usually inefficient at higher NTP concentrations. In contrast, template-dependent inhibition of UTP incorporation opposite the embedded RDV-MP was seen with all polymerases. Molecular modeling suggests a steric conflict between the 1′-cyano group of the inhibitor and residues of the structurally conserved RNA-dependent RNA polymerase motif F. We conclude that future efforts in the development of nucleotide analogs with a broader spectrum of antiviral activities should focus on improving rates of incorporation while capitalizing on the inhibitory effects of a bulky 1′-modification. 相似文献
924.
925.
Andrew E Rosselot Miri Park Mari Kim Toru MatsuUra Gang Wu Danilo E Flores Krithika R Subramanian Suengwon Lee Nambirajan Sundaram Taylor R Broda Heather A McCauley Jennifer A Hawkins Kashish Chetal Nathan Salomonis Noah F Shroyer Michael A Helmrath James M Wells John B Hogenesch Sean R Moore Christian I Hong 《The EMBO journal》2022,41(2)
926.
927.
The coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe COVID-19 exhibit hyper-inflammatory responses characterized by excessive activation of myeloid cells, including monocytes, macrophages, and neutrophils, and a plethora of pro-inflammatory cytokines and chemokines. Accumulating evidence also indicates that hyper-inflammation is a driving factor for severe progression of the disease, which has prompted the development of anti-inflammatory therapies for the treatment of patients with COVID-19. Corticosteroids, IL-6R inhibitors, and JAK inhibitors have demonstrated promising results in treating patients with severe disease. In addition, diverse forms of exosomes that exert anti-inflammatory functions have been tested experimentally for the treatment of COVID-19. Here, we briefly describe the immunological mechanisms of the hyper-inflammatory responses in patients with severe COVID-19. We also summarize current anti-inflammatory therapies for the treatment of severe COVID-19 and novel exosome-based therapeutics that are in experimental stages. 相似文献
928.
Xiaoman Li Liang Wang Jialin Hao Qingfeng Zhu Min Guo Changjing Wu Sihui Li Qiqiang Guo Qiuhong Ren Ning Bai Fei Yi Bo Jiang Wenyu Zhang Yanling Feng Hongde Xu Han Jiang Xiaoyue Zhai Guohua Zhang Hong-long Ji Xuesong Yang Dan Zhang Jianhua Fu Jianjun Chang Xiaoyu Song Liu Cao 《International journal of biological sciences》2022,18(3):1107
The lamellar body (LB), a concentric structure loaded with surfactant proteins and phospholipids, is an organelle specific to type 2 alveolar epithelial cells (AT2). However, the origin of LBs has not been fully elucidated. We have previously reported that autophagy regulates Weibel-Palade bodies (WPBs) formation, and here we demonstrated that autophagy is involved in LB maturation, another lysosome-related organelle. We found that during development, LBs were transformed from autophagic vacuoles containing cytoplasmic contents such as glycogen. Fusion between LBs and autophagosomes was observed in wild-type neonate mice. Moreover, the markers of autophagic activity, microtubule-associated protein 1 light chain 3B (LC3B), largely co-localized on the limiting membrane of the LB. Both autophagy-related gene 7 (Atg7) global knockout and conditional Atg7 knockdown in AT2 cells in mice led to defects in LB maturation and surfactant protein B production. Additionally, changes in autophagic activity altered LB formation and surfactant protein B production. Taken together, these results suggest that autophagy plays a critical role in the regulation of LB formation during development and the maintenance of LB homeostasis during adulthood. 相似文献
929.
Dong Chen Xi Su Haibo Chen Siyan Chen Yongsheng Zhao Wei Wei 《International journal of biological sciences》2022,18(3):901
The coronavirus disease 2019 (COVID-19) global pandemic evoked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a major public health problem with significant morbidity and mortality. Understanding the pathogenesis and molecular mechanisms underlying this novel virus is crucial for both fundamental research and clinical trials in order to devise effective therapies and vaccination regimens. Basic research on SARS-CoV-2 largely depends on ex vivo models that allow viral invasion and replication. Organoid models are now emerging as a valuable tool to investigate viral biology and disease progression, serving as an efficient platform to investigate potential therapies for COVID-19. Here, we summarize various human stem cell-derived organoid types employed in SARS-CoV-2 studies. We highlight key findings from these models, including cell tropisms and molecular mechanisms in viral infection. We also describe their use in identifying potential therapeutic agents against SARS-CoV-2. As more and more advanced organoids emerge, they will facilitate the understanding of disease pathogenesis for drug development in this dreaded pandemic. 相似文献
930.