全文获取类型
收费全文 | 1081篇 |
免费 | 84篇 |
出版年
2023年 | 8篇 |
2022年 | 28篇 |
2021年 | 52篇 |
2020年 | 20篇 |
2019年 | 19篇 |
2018年 | 42篇 |
2017年 | 19篇 |
2016年 | 17篇 |
2015年 | 40篇 |
2014年 | 40篇 |
2013年 | 74篇 |
2012年 | 70篇 |
2011年 | 69篇 |
2010年 | 36篇 |
2009年 | 40篇 |
2008年 | 31篇 |
2007年 | 44篇 |
2006年 | 29篇 |
2005年 | 35篇 |
2004年 | 49篇 |
2003年 | 29篇 |
2002年 | 27篇 |
2001年 | 25篇 |
2000年 | 35篇 |
1999年 | 23篇 |
1997年 | 13篇 |
1995年 | 11篇 |
1994年 | 7篇 |
1993年 | 7篇 |
1992年 | 22篇 |
1991年 | 9篇 |
1990年 | 13篇 |
1989年 | 17篇 |
1988年 | 8篇 |
1987年 | 12篇 |
1986年 | 7篇 |
1985年 | 9篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 6篇 |
1981年 | 6篇 |
1980年 | 7篇 |
1979年 | 17篇 |
1978年 | 5篇 |
1977年 | 5篇 |
1975年 | 10篇 |
1973年 | 8篇 |
1972年 | 6篇 |
1971年 | 12篇 |
1970年 | 8篇 |
排序方式: 共有1165条查询结果,搜索用时 62 毫秒
131.
Siddiqui N Tempel W Nedyalkova L Volpon L Wernimont AK Osborne MJ Park HW Borden KL 《Journal of molecular biology》2012,415(5):781-792
The eukaryotic translation initiation factor eIF4E plays key roles in cap-dependent translation and mRNA export. These functions rely on binding the 7-methyl-guanosine moiety (5'cap) on the 5'-end of all mRNAs. eIF4E is regulated by proteins such as eIF4G and eIF4E binding proteins (4EBPs) that bind the dorsal surface of eIF4E, distal to the cap binding site, and modulate cap binding activity. Both proteins increase the affinity of eIF4E for 5'cap. Our understanding of the allosteric effects and structural underpinnings of 4EBP1 or eIF4G binding can be advanced by obtaining structural data on cap-free eIF4E bound to one of these proteins. Here, we report the crystal structure of apo-eIF4E and cap-free eIF4E in complex with a 4EBP1 peptide. We also monitored 4EBP1 binding to cap-free eIF4E in solution using NMR. Together, these studies suggest that 4EBP1 transforms eIF4E into a cap-receptive state. NMR methods were also used to compare the allosteric routes activated by 4EBP1, eIF4G, and the arenavirus Z protein, a negative regulator of cap binding. We observed chemical shift perturbation at the dorsal binding site leading to alterations in the core of the protein, which were ultimately communicated to the unoccupied cap binding site of eIF4E. There were notable similarities between the routes taken by 4EBP1 and eIF4G and differences from the negative regulator Z. Thus, binding of 4EBP1 or eIF4G allosterically drives alterations throughout the protein that increase the affinity of eIF4E for the 5'cap. 相似文献
132.
Vaibhav K Shrivastava P Javed H Khan A Ahmed ME Tabassum R Khan MM Khuwaja G Islam F Siddiqui MS Safhi MM Islam F 《Molecular and cellular biochemistry》2012,367(1-2):73-84
The pathophysiological mechanisms leading to neuronal injury in middle cerebral artery occlusion (MCAO) model of cerebral stroke are complex and multifactorial that form the bases of behavioral deficits and inflammation mediated damage. The present study demonstrates the effect of piperine pretreatment (10 mg/kg b wt, once daily p.o. for 15 days) on cerebral ischemia-induced inflammation in male Wistar rats. The right middle cerebral artery was occluded for 2 h followed by reperfusion for 22 h. A maximum infarct volume (57.80 %) was observed in ischemic MCAO group. However, piperine administration prior to ischemia showed a significant reduction in infarct volume (28.29 %; p < 0.05) and neuronal loss (12.72 %; p < 0.01). As a result of piperine pretreatment, a significant improvement in behavioral outputs of MCAO rats (p < 0.05-0.01) was observed. Piperine successfully reduced the level of proinflammatory cytokines IL-1β, IL-6 and TNF-α, in ischemic group (p < 0.01). Ischemic group brain has shown edematous morphology with vacuolated architecture and pyknotic nuclei in H & E staining which was successfully ameliorated by piperine administration. Moreover, piperine also succeeded in lowering the expression of COX-2, NOS-2, and NF-κB (p < 0.01). Both cytosolic and nuclear NF-κB were down-regulated in ischemic group pre-administered with piperine (p < 0.01). The present study suggests that piperine is able to salvage the ischemic penumbral zone neurons by virtue of its anti-inflammatory property, thereby limiting ischemic cell death. 相似文献
133.
The precise characterization of post translational modifications (PTMs) is important for the understanding of protein regulatory
mechanisms and their role in disease. However, experimental studies on PTMs, especially with multifunctional proteins are
difficult to follow and investigate. Bioinformatic tools are therefore helpful in predicting key protein modifications. To
study the role of PTMs in claudin proteins, specifically claudin-1, -3 and -4 in the onset or progression of human cancers,
we performed an in silico study of various PTMs and investigated their interplay. Given that the activity of claudins is known
to be influenced by two types of PTMs, specifically palmitoylation and kinase- dependent phosphorylation, we predicted two
conserved regions in the topological domains of claudin-1, -3 and -4 as potential palmitoylation sites. Furthermore, conserved
phosphorylation residues, which may be targets for kinases and can alter claudin’s ability to maintain the integrity of tight
junctions, were identified. To our knowledge, this is the first report to suggest O-glycosylation of claudin proteins, as well as a potential novel interplay between phosphorylation and O-glycosylation at Yin Yang sites. Thus, our findings may facilitate the production of anti-cancer drugs, and suggest that
novel therapeutic strategies should target post translational events. 相似文献
134.
135.
136.
Interactive role of nitric oxide and calcium chloride in enhancing tolerance to salt stress 总被引:2,自引:0,他引:2
Nitric oxide (NO), a small diffusible, ubiquitous bioactive molecule, acts as prooxidant as well as antioxidant, and also regulates remarkable spectrum of plant cellular mechanisms. The present work was undertaken to investigate the role of nitric oxide donor sodium nitroprusside (SNP) and/or calcium chloride (CaCl(2)) in the tolerance of excised mustard leaves to salt stress. After 24h, salt stressed leaves treated with SNP and/or CaCl(2), showed an improvement in the activities of carbonic anhydrase (CA) and nitrate reductase (NR), and leaf chlorophyll (Chl) content, leaf relative water content (LRWC) and leaf ion concentration as compared with the leaves treated with NaCl only. Salinity stress caused a significant increase in H(2)O(2) content and membrane damage which is witnessed by enhanced levels of thiobarbituric acid reactive substances (TBARS) and electrolyte leakage. By contrast, such increases were blocked by the application of 0.2mM SNP and 10mM CaCl(2) to salt stressed leaves. Application of SNP and/or CaCl(2) alleviated NaCl stress by enhancing the activities of antioxidative enzymes viz. superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), ascorbate peroxidase (APX) and glutathione reductase (GR) and by enhancing proline (Pro) and glycinebetaine (GB) accumulation with a concomitant decrease in H(2)O(2) content, TBARS and electrolyte leakage, which is manifested in the tolerance of plants to salinity stress. Moreover, application of SNP with CaCl(2) was more effective to reduce the detrimental effects of NaCl stress on excised mustard leaves. In addition to this, ameliorating effect of SNP was not effective in presence of NO scavenger cPTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide]. To put all these in a nut shell, the results advocate that SNP in association with CaCl(2) plays a role in enhancing the tolerance of plants to salt stress by improving antioxidative defence system, osmolyte accumulation and ionic homeostasis. 相似文献
137.
Kataoka R Siddiqui ZA Kikuchi J Ando M Sriwati R Nozaki A Futai K 《Journal of microbiology (Seoul, Korea)》2012,50(2):199-206
The fungus Tricholoma matsutake forms an ectomycorrhizal relationship with pine trees. Its sporocarps often develop in a circle, which is commonly known
as a fairy ring. The fungus produces a solid, compact, white aggregate of mycelia and mycorrhizae beneath the fairy ring,
which in Japanese is called a ’shiro’. In the present study, we used soil dilution plating and molecular techniques to analyze
the bacterial communities within, beneath, and outside the T. matsutake fairy ring. Soil dilution plating confirmed previous reports that bacteria and actinomycetes are seldom present in the soil
of the active mycorrhizal zone of the T. matsutake shiro. In addition, the results showed that the absence of bacteria was strongly correlated with the presence of T. matsutake mycorrhizae. The results demonstrate that bacteria, especially aerobic and heterotrophic forms, and actinomycetes, are strongly
inhibited by T. matsutake. Indeed, neither bacteria nor actinomycetes were detected in 11.3% of 213 soil samples from the entire shiro area by culture-dependent
methods. However, molecular techniques demonstrated that some bacteria, such as individual genera of Sphingomonas and Acidobacterium, were present in the active mycorrhizal zone, even though they were not detected in soil assays using the dilution plating
technique. 相似文献
138.
U Bashir Aamir N Badar MR Mehmood N Nisar RM Suleman S Shaukat S Sharif J Kamran SS Zaidi BM Kazi L Gubareva X Xu R Garten A Klimov 《PloS one》2012,7(8):e41866
Background
In early 2009, a novel influenza A(H1N1) virus that emerged in Mexico and United States rapidly disseminated worldwide. The spread of this virus caused considerable morbidity with over 18000 recorded deaths. The new virus was found to be a reassortant containing gene segments from human, avian and swine influenza viruses.Methods/Results
The first case of human infection with A(H1N1)pdm09 in Pakistan was detected on 18th June 2009. Since then, 262 laboratory-confirmed cases have been detected during various outbreaks with 29 deaths (as of 31st August 2010). The peak of the epidemic was observed in December with over 51% of total respiratory cases positive for influenza. Representative isolates from Pakistan viruses were sequenced and analyzed antigenically. Sequence analysis of genes coding for surface glycoproteins HA and NA showed high degree of high levels of sequence identity with corresponding genes of regional viruses circulating South East Asia. All tested viruses were sensitive to Oseltamivir in the Neuraminidase Inhibition assays.Conclusions
Influenza A(H1N1)pdm09 viruses from Pakistan form a homogenous group of viruses. Their HA genes belong to clade 7 and show antigenic profile similar to the vaccine strain A/California/07/2009. These isolates do not show any amino acid changes indicative of high pathogenicity and virulence. It is imperative to continue monitoring of these viruses for identification of potential variants of high virulence or drug resistance. 相似文献139.
Xiaowen He Michael Knepper Cheng Ding Jun Li Suita Castro Maham Siddiqui Melitta Schachner 《PloS one》2012,7(9)
The L1 cell adhesion molecule promotes neurite outgrowth and neuronal survival in homophilic and heterophilic interactions and enhances neurite outgrowth and neuronal survival homophilically, i.e. by self binding. We investigated whether exploitation of homophilic and possibly also heterophilic mechanisms of neural stem cells overexpressing the full-length transmembrane L1 and a secreted trimer engineered to express its extracellular domain would be more beneficial for functional recovery of the compression injured spinal cord of adult mice than stem cells overexpressing only full-length L1 or the parental, non-engineered cells. Here we report that stem cells expressing trimeric and full-length L1 are indeed more efficient in promoting locomotor recovery when compared to stem cells overexpressing only full-length L1 or the parental stem cells. The trimer expressing stem cells were also more efficient in reducing glial scar volume and expression of chondroitin sulfates and the chondroitin sulfate proteoglycan NG2. They were also more efficient in enhancing regrowth/sprouting and/or preservation of serotonergic axons, and remyelination and/or myelin sparing. Moreover, degeneration/dying back of corticospinal cord axons was prevented more by the trimer expressing stem cells. These results encourage the view that stem cells engineered to drive the beneficial functions of L1 via homophilic and heterophilic interactions are functionally optimized and may thus be of therapeutic value. 相似文献
140.