全文获取类型
收费全文 | 3634篇 |
免费 | 204篇 |
国内免费 | 1篇 |
专业分类
3839篇 |
出版年
2022年 | 15篇 |
2021年 | 35篇 |
2020年 | 20篇 |
2019年 | 27篇 |
2018年 | 49篇 |
2017年 | 42篇 |
2016年 | 82篇 |
2015年 | 115篇 |
2014年 | 113篇 |
2013年 | 402篇 |
2012年 | 225篇 |
2011年 | 234篇 |
2010年 | 136篇 |
2009年 | 141篇 |
2008年 | 243篇 |
2007年 | 244篇 |
2006年 | 255篇 |
2005年 | 209篇 |
2004年 | 195篇 |
2003年 | 206篇 |
2002年 | 197篇 |
2001年 | 38篇 |
2000年 | 32篇 |
1999年 | 35篇 |
1998年 | 44篇 |
1997年 | 39篇 |
1996年 | 36篇 |
1995年 | 40篇 |
1994年 | 27篇 |
1993年 | 30篇 |
1992年 | 19篇 |
1991年 | 24篇 |
1990年 | 21篇 |
1989年 | 19篇 |
1988年 | 13篇 |
1987年 | 14篇 |
1986年 | 11篇 |
1985年 | 8篇 |
1984年 | 20篇 |
1983年 | 15篇 |
1982年 | 15篇 |
1981年 | 25篇 |
1980年 | 10篇 |
1979年 | 18篇 |
1978年 | 16篇 |
1977年 | 7篇 |
1976年 | 14篇 |
1975年 | 10篇 |
1974年 | 9篇 |
1973年 | 8篇 |
排序方式: 共有3839条查询结果,搜索用时 15 毫秒
71.
Minami M Shimizu K Okamoto Y Folco E Ilasaca ML Feinberg MW Aikawa M Libby P 《The Journal of biological chemistry》2008,283(15):9692-9703
Macrophage activation participates pivotally in the pathophysiology of chronic inflammatory diseases, including atherosclerosis. Through the receptor EP4, prostaglandin E(2) (PGE(2)) exerts an anti-inflammatory action in macrophages, suppressing stimulus-induced expression of certain proinflammatory genes, including chemokines. We recently identified a novel EP4 receptor-associated protein (EPRAP), whose function in PGE(2)-mediated anti-inflammation remains undefined. Here we demonstrate that PGE(2) pretreatment selectively inhibits lipopolysaccharide (LPS)-induced nuclear factor kappaB1 (NF-kappaB1) p105 phosphorylation and degradation in mouse bone marrow-derived macrophages through EP4-dependent mechanisms. Similarly, directed EPRAP expression in RAW264.7 cells suppresses LPS-induced p105 phosphorylation and degradation, and subsequent activation of mitogen-activated protein kinase kinase 1/2. Forced expression of EPRAP also inhibits NF-kappaB activation induced by various proinflammatory stimuli in a concentration-dependent manner. In co-transfected cells, EPRAP, which contains multiple ankyrin repeat motifs, directly interacts with NF-kappaB1 p105/p50 and forms a complex with EP4. In EP4-overexpressing cells, PGE(2) enhances the protective action of EPRAP against stimulus-induced p105 phosphorylation, whereas EPRAP silencing in RAW264.7 cells impairs the inhibitory effect of PGE(2)-EP4 signaling on LPS-induced p105 phosphorylation. Additionally, EPRAP knockdown as well as deficiency of NF-kappaB1 in macrophages attenuates the inhibitory effect of PGE(2) on LPS-induced MIP-1beta production. Thus, PGE(2)-EP4 signaling augments NF-kappaB1 p105 protein stability through EPRAP after proinflammatory stimulation, limiting macrophage activation. 相似文献
72.
Tsuboi S Sutoh M Hatakeyama S Hiraoka N Habuchi T Horikawa Y Hashimoto Y Yoneyama T Mori K Koie T Nakamura T Saitoh H Yamaya K Funyu T Fukuda M Ohyama C 《The EMBO journal》2011,30(15):3173-3185
The O-glycan branching enzyme, core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT), forms O-glycans containing an N-acetylglucosamine branch connected to N-acetylgalactosamine (core2 O-glycans) on cell-surface glycoproteins. Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT-expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT-expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression. Engagement of an NK-activating receptor, NKG2D, by its tumour-associated ligand, Major histocompatibility complex class I-related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT-expressing bladder tumour cells, poly-N-acetyllactosamine was present on core2 O-glycans on MICA, and galectin-3 bound the NKG2D-binding site of MICA through this poly-N-acetyllactosamine. Galectin-3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells. This new mode of NK cell silencing promotes immune evasion of C2GnT-expressing bladder tumour cells, resulting in tumour metastasis. 相似文献
73.
Koichi Chikuni Yutaka Mori Toshiyuki Tabata Masayoshi Saito Michiko Monma Motoaki Kosugiyama 《Journal of molecular evolution》1995,41(6):859-866
Nucleotide sequences for the -casein precursor proteins have been determined from the genomic DNAs or hair roots of the Ruminantia. The coding regions, exons 2, 3, and 4, were amplified separately via the three kinds of PCRs and then directly sequenced. The primers were designed from the sequence of bovine -casein gene; they were applicable for the amplification of the -casein genes from the 13 species in the Ruminantia except exon 2 of the lesser mouse deer. These results permitted an easy phylogenetic analysis based on the sequences of an autosomal gene. A phylogenetic tree was constructed from the mature K-casein sequences and compared with the tree of the cytochrome b genes which were sequenced from the same individuals. The Cervidae (sika deer, Cervus nippon) were separated from the branch of the Bovidae on the tree of -casein genes with a relatively high confidence level of the bootstrap analysis, but included in the branch of the Bovidae on the tree of cytochrome b genes. The -casein tree indicated a monophyly of the subfamily Caprinae, although the internal branches were uncertain in the Caprinae. The tree based on the nucleotide sequences of cytochrome b genes clearly showed the relationships of the closely related species in the genus Capricornis consisting of serow (C. smatorensis), Japanese serow (C. crispus), and Formosan serow (C. swinhoei). These results would be explained by the difference of resolving power between the -casein and the cytochrome b sequences.
Correspondence to: K. Chikuni 相似文献
74.
Jesús Olivero John E. Fa Miguel A. Farfán Jerome Lewis Barry Hewlett Thomas Breuer Giuseppe M. Carpaneto María Fernández Francesco Germi Shiho Hattori Josephine Head Mitsuo Ichikawa Koichi Kitanaishi Jessica Knights Naoki Matsuura Andrea Migliano Barbara Nese Andrew Noss Dieudonné Ongbwa Ekoumou Pascale Paulin Raimundo Real Mike Riddell Edward G. J. Stevenson Mikako Toda J. Mario Vargas Hirokazu Yasuoka Robert Nasi 《PloS one》2016,11(1)
Pygmy populations occupy a vast territory extending west-to-east along the central African belt from the Congo Basin to Lake Victoria. However, their numbers and actual distribution is not known precisely. Here, we undertake this task by using locational data and population sizes for an unprecedented number of known Pygmy camps and settlements (n = 654) in five of the nine countries where currently distributed. With these data we develop spatial distribution models based on the favourability function, which distinguish areas with favourable environmental conditions from those less suitable for Pygmy presence. Highly favourable areas were significantly explained by presence of tropical forests, and by lower human pressure variables. For documented Pygmy settlements, we use the relationship between observed population sizes and predicted favourability values to estimate the total Pygmy population throughout Central Africa. We estimate that around 920,000 Pygmies (over 60% in DRC) is possible within favourable forest areas in Central Africa. We argue that fragmentation of the existing Pygmy populations, alongside pressure from extractive industries and sometimes conflict with conservation areas, endanger their future. There is an urgent need to inform policies that can mitigate against future external threats to these indigenous peoples’ culture and lifestyles. 相似文献
75.
Because we found that WTC rats might be resistant to streptozotocin (STZ), we have elucidated the mechanisms of resistant to the diabetogenic effects of STZ in the WTC rats. Dose response to STZ was evaluated with glucose levels. No significant changes in glucose level to STZ administration were observed in WTC rats. Insulin secretion by suppling glucose was preserved in WTC rats even after STZ administration. Although there was no significant difference in gene expression of both GLUT2 and Kir6.2, which were involved in STZ resistance, between WTC rats and Wistar rats, the expression of metallothionein 2a in pancreas and liver to STZ administration of WTC rats was significantly higher than that of Wistar rats. Moreover, alloxan did not induce diabetes in WTC rats as same as STZ. These results suggest that WTC rats might have powerful antioxidant property to protect β cells in pancreas. Because the STZ-resistant property is very close characteristics to human beings, WTC rats will become a useful animal model in diabetic researches. 相似文献
76.
Mitsutaka Ogawa Naosuke Nakamura Yoshiaki Nakayama Akira Kurosaka Hiroshi Manya Motoi Kanagawa Tamao Endo Koichi Furukawa Tetsuya Okajima 《Biochemical and biophysical research communications》2013
Hypoglycosylation is a common characteristic of dystroglycanopathy, which is a group of congenital muscular dystrophies. More than ten genes have been implicated in α-dystroglycanopathies that are associated with the defect in the O-mannosylation pathway. One such gene is GTDC2, which was recently reported to encode O-mannose β-1,4-N-acetylglucosaminyltransferase. Here we show that GTDC2 generates CTD110.6 antibody-reactive N-acetylglucosamine (GlcNAc) epitopes on the O-mannosylated α-dystroglycan (α-DG). Using the antibody, we show that mutations of GTDC2 identified in Walker–Warburg syndrome and alanine-substitution of conserved residues between GTDC2 and EGF domain O-GlcNAc transferase resulted in decreased glycosylation. Moreover, GTDC2-modified GlcNAc epitopes are localized in the endoplasmic reticulum (ER). These data suggested that GTDC2 is a novel glycosyltransferase catalyzing GlcNAcylation of O-mannosylated α-DG in the ER. CTD110.6 antibody may be useful to detect a specific form of GlcNAcylated O-mannose and to analyze defective O-glycosylation in α-dystroglycanopathies. 相似文献
77.
Toru Nakayashiki Koichi Nishimura Ryouichi Tanaka Hachiro Inokuchi 《Molecular genetics and genomics : MGG》1995,249(2):139-146
Mutants of Escherichia coli defective in the HemA protein grow extremely poorly as the result of heme deficiency. A novel hemA mutant was identified whose rate of growth was dramatically enhanced by addition to the medium of low concentrations of translational inhibitors, such as chloramphenicol and tetracycline. This mutant (H110) carries mutation at position 314 in the hemA gene, which resulted in diminished activity of the encoded protein. Restoration of growth of H110 upon addition of the drugs mentioned above was due to activation of the synthesis of porphyrin. However, this activation was not characteristic exclusively of cells with this mutant hemA gene since it was also observed in a heme-deficient strain bearing the wild-type hemA gene. The activation did not depend on the promoter activity of the hemA gene, as indicated by studies with fusion genes. It appears that partial inhibition of protein synthesis via inhibition of peptidyltransferase can promote the synthesis of porphyrin by providing an increased supply of Guamyl-tRNA for porphyrin synthesis. Glutamyl-tRNA is the common substrate for peptidyltransferase and HemA. 相似文献
78.
中国脊髓灰质炎Ⅱ型疫苗相关分离株病毒性状的观察 总被引:7,自引:1,他引:7
对1994年中国分离的13株脊髓灰质炎Ⅱ型疫苗相关株进行了PCR-RFLP分析,发现7株为重组病毒,毒力较疫苗株有回复,在Ⅱ型脊髓灰质炎病毒基因序列上,对于神经毒力有重要影响的第481位核苷酸发生突变,另一个被视为重要位点的2908位核苷酸无一发生变化,反而在2909位核苷发生了高频率的点突变,意味着2909位点在中国Ⅱ型疫苗相关株的自然变异中可能起着重要作用。 相似文献
79.
Teppei Ikeya David Ban Donghan Lee Yutaka Ito Koichi Kato Christian Griesinger 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(2):287-306
Background
To understand the mechanisms related to the ‘dynamical ordering’ of macromolecules and biological systems, it is crucial to monitor, in detail, molecular interactions and their dynamics across multiple timescales. Solution nuclear magnetic resonance (NMR) spectroscopy is an ideal tool that can investigate biophysical events at the atomic level, in near-physiological buffer solutions, or even inside cells.Scope of review
In the past several decades, progress in solution NMR has significantly contributed to the elucidation of three-dimensional structures, the understanding of conformational motions, and the underlying thermodynamic and kinetic properties of biomacromolecules. This review discusses recent methodological development of NMR, their applications and some of the remaining challenges.Major conclusions
Although a major drawback of NMR is its difficulty in studying the dynamical ordering of larger biomolecular systems, current technologies have achieved considerable success in the structural analysis of substantially large proteins and biomolecular complexes over 1 MDa and have characterised a wide range of timescales across which biomolecular motion exists. While NMR is well suited to obtain local structure information in detail, it contributes valuable and unique information within hybrid approaches that combine complementary methodologies, including solution scattering and microscopic techniques.General significance
For living systems, the dynamic assembly and disassembly of macromolecular complexes is of utmost importance for cellular homeostasis and, if dysregulated, implied in human disease. It is thus instructive for the advancement of the study of the dynamical ordering to discuss the potential possibilities of solution NMR spectroscopy and its applications. This article is part of a Special Issue entitled “Biophysical Exploration of Dynamical Ordering of Biomolecular Systems” edited by Dr. Koichi Kato. 相似文献80.