全文获取类型
收费全文 | 717篇 |
免费 | 39篇 |
出版年
2023年 | 5篇 |
2022年 | 8篇 |
2021年 | 20篇 |
2020年 | 16篇 |
2019年 | 14篇 |
2018年 | 16篇 |
2017年 | 6篇 |
2016年 | 22篇 |
2015年 | 49篇 |
2014年 | 34篇 |
2013年 | 51篇 |
2012年 | 57篇 |
2011年 | 59篇 |
2010年 | 31篇 |
2009年 | 29篇 |
2008年 | 35篇 |
2007年 | 40篇 |
2006年 | 40篇 |
2005年 | 36篇 |
2004年 | 51篇 |
2003年 | 20篇 |
2002年 | 18篇 |
2001年 | 5篇 |
2000年 | 5篇 |
1999年 | 1篇 |
1998年 | 8篇 |
1997年 | 12篇 |
1996年 | 4篇 |
1995年 | 7篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 4篇 |
1990年 | 3篇 |
1989年 | 9篇 |
1988年 | 1篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1980年 | 4篇 |
1979年 | 1篇 |
1976年 | 1篇 |
1973年 | 4篇 |
1971年 | 2篇 |
1965年 | 2篇 |
1955年 | 1篇 |
排序方式: 共有756条查询结果,搜索用时 15 毫秒
81.
Morton MF Liu PQ Reik A de la Rosa R Mendel M Li XY Case C Pabo C Moreno V Pyati J Shankley NP 《Regulatory peptides》2005,129(1-3):227-232
Designed zinc finger proteins (ZFPs) regulate expression of target genes when coupled to activator or repressor domains. Transfection of ZFPs into cell lines can create expression systems where the targeted endogenous gene is transcribed and the protein of interest can be investigated in its own cellular context. Here we describe the pharmacological investigation of an expression system generated using CCK2 receptor-selective ZFPs transfected into human embryonic kidney cells (HEKZFP system). The receptors expressed in this system, in response to ZFP expression, were functional in calcium mobilization studies and the potency of the agonists investigated was consistent with their action at CCK2 receptors (CCK-8S pA50 = 9.05+/-0.11, pentagastrin pA50 = 9.11+/-0.13). In addition, binding studies were conducted using [125I]-BH-CCK-8S as radioligand. The saturation binding analysis of this radioligand was consistent with a single population of high affinity CCK receptors (pK(D) = 10.24). Competition studies were also conducted using a number of previously well-characterized CCK-receptor selective ligands; JB93182, YF476, PD-134,308, SR27897, dexloxiglumide, L-365,260 and L-364,718. Overall, the estimated affinity values for these ligands were consistent with their interaction at CCK2 receptors. Therefore, CCK2 receptors up-regulated using zinc finger protein technology can provide an alternative to standard transfection techniques for the pharmacological analysis of compounds. 相似文献
82.
Chrysina ED Kosmopoulou MN Kardakaris R Bischler N Leonidas DD Kannan T Loganathan D Oikonomakos NG 《Bioorganic & medicinal chemistry》2005,13(3):765-772
In an attempt to identify a new lead molecule that would enable the design of inhibitors with enhanced affinity for glycogen phosphorylase (GP), beta-D-glucopyranosyl bismethoxyphosphoramidate (phosphoramidate), a glucosyl phosphate analogue, was tested for inhibition of the enzyme. Kinetic experiments showed that the compound was a weak competitive inhibitor of rabbit muscle GPb (with respect to alpha-D-glucose-1-phosphate (Glc-1-P)) with a Ki value of 5.9 (+/-0.1) mM. In order to elucidate the structural basis of inhibition, we determined the structure of GPb complexed with the phosphoramidate at 1.83 A resolution. The complex structure reveals that the inhibitor binds at the catalytic site and induces significant conformational changes in the vicinity of this site. In particular, the 280s loop (residues 282-287) shifts 0.4-4.3 A (main-chain atoms) to accommodate the phosphoramidate, but these conformational changes do not lead to increased contacts between the inhibitor and the protein that would improve ligand binding. 相似文献
83.
Gagliano N Torri C Donetti E Grizzi F Costa F Bertelli AA Migliori M Filippi C Bedoni M Panichi V Giovannini L Gioia M 《Molecular medicine (Cambridge, Mass.)》2005,11(1-12):30-38
We characterized the effect of chronic ochratoxin A (OTA) on rat kidney cortex, analyzing collagen content and collagen turnover and the major markers of epithelial-to-mesenchymal transition (EMT), such as alpha-smooth muscle actin (alphaSMA), cadherins, and MMP-9. Because OTA nephrotoxicity is mediated by free radicals, we also investigated whether antioxidants in red wine provided protection for the kidney and attenuated OTA-induced EMT. Collagen content, determined by computerized analysis of Sirius red-stained kidney sections, increased in OTA, OTA-wine, and OTA-EtOH treated rats. In kidney cortex homogenates, COL-I and COL-III mRNA levels tended to rise in OTA treated rats, but were similar to CT after OTA-wine and OTA-EtOH administration. TIMP-1 gene expression was up-regulated in OTA, OTA-wine, and OTA-EtOH treated rats. LH2b mRNA/COL-I mRNA was significantly up-regulated in OTA-wine and OTA-EtOH treated rats, compared with CT and OTA alone. TGF-beta1 signaling tended to dominate after OTA, OTA-wine, and OTA-EtOH. MMP-1 protein levels were not affected. OTA induced proMMP-9 and alphaSMA overexpression, decreases of E-cadherin and N-cadherin, and DSC-2 up-regulation. OTA-wine caused a further, unexpected decrease of E- and N-cadherins and further up-regulation of OTA-induced DSC-2, while strongly reducing the OTA-induced increases of alphaSMA and proMMP-9. Posttranslational collagen modifications, such as decreased collagen degradation through MMP inhibition and increased collagen cross-links, seem to be key mechanisms leading to OTA-induced kidney cortex fibrosis. This mechanism was not affected by red wine in these conditions. Red wine seems to have some protective role against OTA-induced EMT, although without completely blocking the process and determining a condition in which abundant cells display an intermediate translational phenotype, but there are no alphaSMA or epithelial markers. 相似文献
84.
Masson N Appelhoff RJ Tuckerman JR Tian YM Demol H Puype M Vandekerckhove J Ratcliffe PJ Pugh CW 《FEBS letters》2004,570(1-3):166-170
Hypoxia-inducible factor-1 (HIF) is regulated by oxygen-dependent prolyl hydroxylation. Of the three HIF prolyl hydroxylases (PHD1, 2 and 3) identified, PHD3 exhibits restricted substrate specificity in vitro and is induced in different cell types by diverse stimuli. PHD3 may therefore provide an interface between oxygen sensing and other signalling pathways. We have used co-purification and mass spectrometry to identify proteins that interact with PHD3. The cytosolic chaperonin TRiC was found to copurify with PHD3 in extracts from several cell types. Our results indicate that PHD3 is a TRiC substrate, providing another step at which PHD3 activity may be regulated. 相似文献
85.
Background
Assisting mothers to breastfeed is not easy when babies experience difficulties. In a neonatal intensive care unit (NICU), nurses often help mothers by using hands-on-breast without their permission. Little is known about how mothers feel about this unusual body touching. To gain more knowledge from mothers who lived through this experience, this hands-on practice was studied in a NICU in Sweden.Methods
Between January and June 2001, in-depth interviews were conducted with ten mothers of preterm or sick term infants and all of them experienced the hands-on approach. In this research, Radnitzky's seven principles of hermeneutic interpretation were applied in order to interpret the meaning of mothers' responses. This article presents results related to the period of initiation of breastfeeding. This qualitative study was based on a combination of the models of Gustafsson, Orem, and Aarts' Marte Meo.Results
Five main themes were identified: Insult to integrity, Manipulating the baby, Understanding and adjustment, Breasts as objects, Alternatives to this practice. Hands-on help in the breastfeeding situation was experienced as unpleasant and the women experienced their breasts as objectified. The mothers accepted the hands-on help given by nursing staff, even though they considered it unpleasant. Most mothers expressed a need for assistance when starting breastfeeding, but could not suggest any alternative to hands-on help such as demonstrating with an artificial breast and a doll.Conclusion
The study provides information about how mothers experience unexpected hands-on help with breastfeeding in a NICU, which has not been described previously. Since most mothers in this study regarded this behavior as unpleasant and not helpful mostly because it was unexpected and unexplained, it would be important to either explain beforehand to mothers what type of physical approach could be attempted on their body or better, to avoid this type of approach completely. 相似文献86.
Héctor Flores-Villase?or Adrian Canizalez-Román Magda Reyes-Lopez Kamram Nazmi Mireya de la Garza Jorge Zazueta-Beltrán Nidia León-Sicairos Jan G. M. Bolscher 《Biometals》2010,23(3):569-578
Increased prevalence of antibiotic-resistant bacteria has become a major threat to the health sector worldwide due to their
virulence, limited therapeutic options and distribution in both hospital and community settings. Discovery and development
of new agents to combat antibiotic-resistant bacteria is thus needed. This study therefore aimed to evaluate the ability of
bovine lactoferrin (LF), peptides from two antimicrobial domains lactoferricin B (LFcin17-30) and lactoferrampin (LFampin265-284)
and a chimeric construct (LFchimera) containing both peptides, as potential bactericidal agents against clinical isolates
of antibiotic-resistant Staphylococcus aureus and Escherichia coli. Results in kinetics of growth show that LF chimera and peptides inhibited the growth of both bacterial species. By confocal
microscopy and flow cytometry it was observed that LF and FITC-labeled peptides are able to interact with these bacteria and
cause membrane permeabilization, as monitored by propidium iodide staining, these effects were decreased by preincubation
with lipopolysaccharide in E. coli. By electron microscopy, a clear cellular damage was observed in bacteria after treatments with LFchimera and peptides, suggesting
that interaction and membrane disruption are probably involved as a mechanism of action. In conclusion, results show that
LFchimera, LF and peptides have potential as bactericidal agents in the antibiotic-resistant strains of S.
aureus and E. coli and also the work strongly suggest that LFcin17-30 and LFampin265-284 acts synergistically with antibiotics against multidrug
resistant EPEC and MRSA in vitro. 相似文献
87.
Nadia Hanafy Metwally Magda Ahmed Abdalla Mosselhi Abdel Nabi Mosselhi Ebrahim Adel El-Desoky 《Carbohydrate research》2010,345(9):1135-2837
5-Arylidene-2-thioxo-4-thiazolidinones 3a-f react with each of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl and α-d-galactopyranosyl bromides 4a,b in acetone in the presence of aqueous potassium hydroxide at room temperature to afford N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl) or N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl) 2-thioxo-4-thiazolidinone derivatives 5a-f. Similarly, the reaction of 5-cycloalkylidene-2-thioxo-4-thiazolidinones 7a,b with 4a gave the corresponding N-glucosides 8a,b. Also, 5-pyrazolidene rhodanines 10a-e react with 4a to afford the new N-glucosides 11a-e. Treatment of compounds 15 and 16 with 4a in the presence of few drops of triethylamine or in KOH solution accomplished the mono- and bis-nucleosides 17 and 18, respectively. Some selected products were tested for their antimicrobial activities. 相似文献
88.
89.
Tettamanti G Malagoli D Marchesini E Congiu T de Eguileor M Ottaviani E 《Cell and tissue research》2006,326(1):179-186
Functional and morphological modifications in the IPLB-LdFB insect cell line were examined following a short treatment with a reversible inhibitor of mitochondrial ATP synthase, oligomycin A, and subsequent incubation for various times in oligomycin-A-free medium. Oncosis, apoptosis and autophagy at variable percentages were observed under the various experimental conditions. Together with oncotic and apoptotic pathways that lead directly to cell death, the insect cells responded to ATP depletion with autophagy. Our results revealed that, in most cases, autophagy failed to restore cellular homeostasis, probably because of a massive sequestration of mitochondria in autophagic vacuoles. This critical event was a “point of no return” and ultimately resulted in cell necrosis. However, cells with a misshapen body and nucleus resembling “resistant forms” were observed at the end of the experiments. Our findings indicate that oligomycin-A-induced autophagy can promote cell protection or cell destruction and is an open-ended process that can lead to survival or death depending on a combination of concomitant factors.This work was supported by MIUR (Italy) grants to M.deE. and E.O. and by the Centro Grandi Attrezzature (University of Insubria, Varese, Italy).Gianluca Tettamanti and Davide Malagoli contributed equally to this work. 相似文献
90.
Budny B Chen W Omran H Fliegauf M Tzschach A Wisniewska M Jensen LR Raynaud M Shoichet SA Badura M Lenzner S Latos-Bielenska A Ropers HH 《Human genetics》2006,120(2):171-178
We report on a large family in which a novel X-linked recessive mental retardation (XLMR) syndrome comprising macrocephaly and ciliary dysfunction co-segregates with a frameshift mutation in the OFD1 gene. Mutations of OFD1 have been associated with oral–facial–digital type 1 syndrome (OFD1S) that is characterized by X-chromosomal dominant inheritance and lethality in males. In contrast, the carrier females of our family were clinically inconspicuous, and the affected males suffered from severe mental retardation, recurrent respiratory tract infections and macrocephaly. All but one of the affected males died from respiratory problems in infancy; and impaired ciliary motility was confirmed in the index patient by high-speed video microscopy examination of nasal epithelium. This family broadens the phenotypic spectrum of OFD1 mutations in an unexpected way and sheds light on the complexity of the underlying disease mechanisms.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at . 相似文献