全文获取类型
收费全文 | 7691篇 |
免费 | 544篇 |
国内免费 | 716篇 |
专业分类
8951篇 |
出版年
2024年 | 25篇 |
2023年 | 101篇 |
2022年 | 261篇 |
2021年 | 420篇 |
2020年 | 302篇 |
2019年 | 351篇 |
2018年 | 327篇 |
2017年 | 269篇 |
2016年 | 363篇 |
2015年 | 499篇 |
2014年 | 567篇 |
2013年 | 620篇 |
2012年 | 768篇 |
2011年 | 646篇 |
2010年 | 367篇 |
2009年 | 368篇 |
2008年 | 390篇 |
2007年 | 331篇 |
2006年 | 291篇 |
2005年 | 242篇 |
2004年 | 207篇 |
2003年 | 175篇 |
2002年 | 156篇 |
2001年 | 151篇 |
2000年 | 115篇 |
1999年 | 100篇 |
1998年 | 68篇 |
1997年 | 71篇 |
1996年 | 70篇 |
1995年 | 54篇 |
1994年 | 50篇 |
1993年 | 31篇 |
1992年 | 41篇 |
1991年 | 20篇 |
1990年 | 25篇 |
1989年 | 19篇 |
1988年 | 16篇 |
1987年 | 16篇 |
1986年 | 11篇 |
1985年 | 18篇 |
1984年 | 9篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1966年 | 1篇 |
1965年 | 2篇 |
排序方式: 共有8951条查询结果,搜索用时 0 毫秒
91.
Samuel J. Craven Samson G.F. Condon Gladys Díaz Vzquez Qiang Cui Alessandro Senes 《The Journal of biological chemistry》2022,298(1)
The FtsLB complex is a key regulator of bacterial cell division, existing in either an off state or an on state, which supports the activation of septal peptidoglycan synthesis. In Escherichia coli, residues known to be critical for this activation are located in a region near the C-terminal end of the periplasmic coiled-coil domain of FtsLB, raising questions about the precise role of this conserved domain in the activation mechanism. Here, we investigate an unusual cluster of polar amino acids found within the core of the FtsLB coiled coil. We hypothesized that these amino acids likely reduce the structural stability of the domain and thus may be important for governing conformational changes. We found that mutating these positions to hydrophobic residues increased the thermal stability of FtsLB but caused cell division defects, suggesting that the coiled-coil domain is a “detuned” structural element. In addition, we identified suppressor mutations within the polar cluster, indicating that the precise identity of the polar amino acids is important for fine-tuning the structural balance between the off and on states. We propose a revised structural model of the tetrameric FtsLB (named the “Y-model”) in which the periplasmic domain splits into a pair of coiled-coil branches. In this configuration, the hydrophilic terminal moieties of the polar amino acids remain more favorably exposed to water than in the original four-helix bundle model (“I-model”). We propose that a shift in this architecture, dependent on its marginal stability, is involved in activating the FtsLB complex and triggering septal cell wall reconstruction. 相似文献
92.
93.
Head and neck squamous cell carcinoma (HNSCC) remains a major health problem worldwide. We aimed to identify a robust microRNA (miRNA)-based signature for predicting HNSCC prognosis. The miRNA expression profiles of HNSCC were obtained from The Cancer Genome Atlas (TCGA) database. The TCGA HNSCC cohort was randomly divided into the discovery and validation cohort. A miRNA-based prognostic signature was built up based on TGCA discovery cohort, and then further validated. The downstream targets of prognostic miRNAs were subjected to functional enrichment analyses. The role of miR-1229-3p, a prognosis-related miRNA, in tumorigenesis of HNSCC was further evaluated. A total of 305 significantly differentially expressed miRNAs were found between HNSCC samples and normal tissues. A six-miRNA prognostic signature was constructed, which exhibited a strong association with overall survival (OS) in the TCGA discovery cohort. In addition, these findings were successfully confirmed in TCGA validation cohort and our own independent cohort. The miRNA-based signature was demonstrated as an independent prognostic indicator for HNSCC. A risk signature-based nomogram model was constructed and showed good performance for predicting the OS for HNSCC. The functional analyses revealed that the downstream targets of these prognostic miRNAs were closely linked to cancer progression. Mechanistically, in vitro analysis revealed that miR-1229-3p played a tumor promoting role in HNSCC. In conclusion, our study has developed a robust miRNA-based signature for predicting the prognosis of HNSCC with high accuracy, which will contribute to improve the therapeutic outcome. 相似文献
94.
Xingzhi Jing Ting Du Tao Li Xiaoxia Yang Guodong Wang Xiaoyang Liu Zhensong Jiang Xingang Cui 《Journal of cellular and molecular medicine》2021,25(12):5671-5680
Iron overload is common in elderly people which is implicated in the disease progression of osteoarthritis (OA), however, how iron homeostasis is regulated during the onset and progression of OA and how it contributes to the pathological transition of articular chondrocytes remain unknown. In the present study, we developed an in vitro approach to investigate the roles of iron homeostasis and iron overload mediated oxidative stress in chondrocytes under an inflammatory environment. We found that pro-inflammatory cytokines could disrupt chondrocytes iron homeostasis via upregulating iron influx transporter TfR1 and downregulating iron efflux transporter FPN, thus leading to chondrocytes iron overload. Iron overload would promote the expression of chondrocytes catabolic markers, MMP3 and MMP13 expression. In addition, we found that oxidative stress and mitochondrial dysfunction played important roles in iron overload-induced cartilage degeneration, reducing iron concentration using iron chelator or antioxidant drugs could inhibit iron overload-induced OA-related catabolic markers and mitochondrial dysfunction. Our results suggest that pro-inflammatory cytokines could disrupt chondrocytes iron homeostasis and promote iron influx, iron overload-induced oxidative stress and mitochondrial dysfunction play important roles in iron overload-induced cartilage degeneration. 相似文献
95.
Liszewski MK Leung M Cui W Subramanian VB Parkinson J Barlow PN Manchester M Atkinson JP 《The Journal of biological chemistry》2000,275(48):37692-37701
Membrane cofactor protein (MCP; CD46), a widely distributed regulator of complement activation, is a cofactor for the factor I-mediated degradation of C3b and C4b deposited on host cells. MCP possesses four extracellular, contiguous complement control protein modules (CCPs) important for this inhibitory activity. The goal of the present study was to delineate functional sites within these modules. We employed multiple approaches including mutagenesis, epitope mapping, and comparisons to primate MCP to make the following observations. First, functional sites were located to each of the four CCPs. Second, some residues were important for both C3b and C4b interactions while others were specific for one or the other. Third, while a reduction in ligand binding was invariably accompanied by a parallel reduction in cofactor activity (CA), other mutants lost or had reduced CA but retained ligand binding. Fourth, two C4b-regulatory domains overlapped measles virus interactive regions, indicating that the hemagglutinin docks to a site important for complement inhibition. Fifth, several MCP regulatory areas corresponded to functionally critical, homologous positions in other CCP-bearing C3b/C4b-binding proteins. Based on these data and the recently derived crystal structure of repeats one and two, computer modeling was employed to predict MCP structure and examine active sites. 相似文献
96.
Sang-Hwal Yoon Cui Li Young-Mi Lee Sook-Hee Lee Sung-Hee Kim Myung-Suk Choi Weon-Taek Seo Jae-Kyung Yang Jae-Yeon Kim Seon-Won Kim 《Biotechnology and Bioprocess Engineering》2005,10(4):378-384
Vanillin is one of the world's principal flavoring compounds, and is used extensively in the food industry. The potential
vanillin production of the bacteria was compared to select and clone genes which were appropriate for highly productive vanillin
production byE. coli. Thefcs (feruloyl-CoA synthetase) andech (enoyl-CoA hydratase/aldolase) genes cloned fromAmycolatopsis sp. strain HR104 andDelftia acidovorans were introduced to pBAD24 vector with PBAD promoter and were named pDAHEF and pDDAEF, respectively. We observed 160 mg/L vanillin production withE. coli harboring pDAHEF, whereas 10 mg/L of vanillin was observed with pDDAEF. Vanillin production was optimized withE. coli harboring pDAHEF. Induction of thefcs andech genes from pDAHEF was optimized with the addition of 13.3 mM arabinose at 18 h of culture, from which 450 mg/L of vanillin
was produced. The feeding time and concentration of ferulic acid were also optimized by the supplementation of 0.2% ferulic
acid at 18 h of culture, from which 500 mg/L of vanillin was obtained. Under the above optimized condition of arabinose induction
and ferulic acid supplementation, vanillin production was carried out with four different types of media, M9, LB, 2YT, and
TB. The highest vanillin production, 580 mg/L, was obtained with LB medium, a 3.6 fold increase in comparison to the 160 mg/L
obtained before the optimization of vanillin production. 相似文献
97.
Liu Zhensheng Wang Xiaoming Li Zhigang Cui Duoying Li Xinqing 《Frontiers of Biology in China》2007,2(1):100-107
The feeding habitat selection of blue sheep (Pseudois nayaur) was studied by direct observation method in the Helan Mountains, China during winter (from November to December) and spring
(from April to June) from 2003 to 2004. We established 25 line transects to collect information on feeding habitats used by
blue sheep. Blue sheep in the study area preferred mountain savanna forests, a habitat dominated by Ulmus glaucescens, with medium tree density (<4 individuals / 400 m2), moderate tree height (4–6 m), higher shrub density (> 5 individuals / 100 m2), higher shrub (> 1.3 m), higher food abundance (> 50 g), moderate distance to human disturbance (< 500 m), and mild distance
to bare rock (< 2 m). Such habitats characterized by 12 ecological factors were preferred as feeding areas by blue sheep during
winter. Similar to habitat selection by the species during winter, blue sheep also showed a preference for mountain savanna
with tree dominated by Ulmus glaucescens and medium tree density (< 4 individuals / 400 m2) during spring. Nevertheless, blue sheep preferred medium tree height (< 6 m), moderate tree density (5–10 individuals /
100 m2), medium shrub height (1.3–1.7 m), higher food abundance (> 100 g), moderate altitude (< 2 000 m), moderate distance to water
resource (< 500 m), and medium hiding cover (50%–75%) during spring. Selection of the feeding habitats by sheep showed a significant
difference in vegetation type, landform feature, dominant tree, tree height, shrub density, distance to the nearest shrub,
food abundance, slope direction, slope degree, distance to water resource, and hiding cover between winter and spring. Results
of principal components analysis indicated that the first principal component accounted for 24.493% of the total variance
among feeding habitat variance during winter, with higher loadings for vegetation type, dominant tree, tree height, distance
to the nearest tree, shrub density, shrub height, altitude, distance to water resource, and distance to human disturbance.
In spring, the first principal components explained 28.777% of the variance, with higher loadings for vegetation type, distance
to the nearest tree, shrub height, distance to the nearest shrub, food abundance, altitude, and distance to human disturbance.
Translated from Zoological Research, 2005, 26(6): 580–589 [译自: 动物学研究] 相似文献
98.
Wang B Zhang S Cui S Yang B Zhao Y Chen H Hao X Shen Q Zhou J 《Biotechnology letters》2012,34(1):19-28
Two new types of stable ternary complexes were formed by mixing chitosan with DOTAP/pDNA lipoplex and DOTAP with chitosan/pDNA
polyplex via non-covalent conjugation for the efficient delivery of plasmid DNA. They were characterized by atomic force microscopy,
gel retarding, and dynamic light scattering. The DOTAP/CTS/pDNA complexes were in compacted spheroids and irregular lump of
larger aggregates in structure, while the short rod- and toroid-like and donut shapes were found in CTS/DOTAP/pDNA complexes.
The transfection efficiency of the lipopolyplexes showed higher GFP gene expression than DOTAP/pDNA and CTS/pDNA controls
in Hep-2 and Hela cells, and luciferase gene expression 2–3-fold than DOTAP/pDNA control and 70–120-fold than CTS/pDNA control
in Hep-2 cells. The intracellular trafficking was examined by confocal laser scanning microscopy. Rapid pDNA delivery to the
nucleus enchanced by chitosan was achieved after 4 h transfection. 相似文献
99.
100.
Polycomb group (PcG) proteins are key chromatin regulators implicated in multiple processes including embryonic development, tissue homeostasis, genomic imprinting, X-chromosome inactivation, and germ cell differentiation. The PcG proteins recognize target genomic loci through cis DNA sequences known as Polycomb Response Elements (PREs), which are well characterized in Drosophila. However, mammalian PREs have been elusive until two groups reported putative mammalian PREs recently. Consistent with the existence of mammalian PREs, here we report the identification and characterization of a potential PRE from human T cells. The putative human PRE has enriched binding of PcG proteins, and such binding is dependent on a key PcG component SUZ12. We demonstrate that the putative human PRE carries both genetic and molecular features of Drosophila PRE in transgenic flies, implying that not only the trans PcG proteins but also certain features of the cis PREs are conserved between mammals and Drosophila. 相似文献