全文获取类型
收费全文 | 576篇 |
免费 | 50篇 |
出版年
2023年 | 1篇 |
2022年 | 8篇 |
2021年 | 9篇 |
2020年 | 9篇 |
2019年 | 12篇 |
2018年 | 20篇 |
2017年 | 17篇 |
2016年 | 14篇 |
2015年 | 29篇 |
2014年 | 33篇 |
2013年 | 46篇 |
2012年 | 46篇 |
2011年 | 33篇 |
2010年 | 39篇 |
2009年 | 18篇 |
2008年 | 32篇 |
2007年 | 45篇 |
2006年 | 30篇 |
2005年 | 24篇 |
2004年 | 27篇 |
2003年 | 30篇 |
2002年 | 27篇 |
2001年 | 7篇 |
2000年 | 3篇 |
1999年 | 4篇 |
1998年 | 8篇 |
1997年 | 6篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 5篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1983年 | 4篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1978年 | 2篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1973年 | 2篇 |
1969年 | 2篇 |
1931年 | 1篇 |
排序方式: 共有626条查询结果,搜索用时 31 毫秒
101.
Microtubule defects in mesenchymal stromal cells distinguish patients with Progressive Supranuclear Palsy
下载免费PDF全文
![点击此处可从《Journal of cellular and molecular medicine》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Alessandra Maria Calogero Mariele Viganò Silvia Budelli Daniela Galimberti Chiara Fenoglio Daniele Cartelli Lorenza Lazzari Petri Lehenkari Margherita Canesi Rosaria Giordano Graziella Cappelletti Gianni Pezzoli 《Journal of cellular and molecular medicine》2018,22(5):2670-2679
Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease whose etiopathogenesis remains elusive. The intraneuronal accumulation of hyperphosphorylated Tau, a pivotal protein in regulating microtubules (MT), leads to include PSP into tauopathies. Pathological hallmarks are well known in neural cells but no word yet if PSP‐linked dysfunctions occur also in other cell types. We focused on bone marrow mesenchymal stromal cells (MSCs) that have recently gained attention for therapeutic interventions due to their anti‐inflammatory, antiapoptotic and trophic properties. Here, we aimed to investigate MSCs biology and to disclose if any disease‐linked defect occurs in this non‐neuronal compartment. First, we found that cells obtained from patients showed altered morphology and growth. Next, Western blotting analysis unravelled the imbalance in α‐tubulin post‐translational modifications and in MT stability. Interestingly, MT mass is significantly decreased in patient cells at baseline and differently changes overtime compared to controls, suggesting their inability to efficiently remodel MT cytoskeleton during ageing in culture. Thus, our results provide the first evidence that defects in MT regulation and stability occur and are detectable in a non‐neuronal compartment in patients with PSP. We suggest that MSCs could be a novel model system for unravelling cellular processes implicated in this neurodegenerative disorder. 相似文献
102.
103.
104.
Alessandro Chiarolini Maria Teresa Donato Maria Jose Gomez Lechon Mauro Pala Federico Valerio Margherita Ferro 《Biomarkers》1997,2(5):279-285
Cytochrome P450 1A1 CYP1A1 enzymatic activity was evaluated in cultured liver cells, and taken as a biological indicator of the presence of inducers of this isoform in urban airborne particulate matter fraction samples. It is known that CYP1A1 inducers can play an important role in the risk of mutagenesis and carcinogenesis by environmental pollution. A romatic polycyclic hydrocarbons PAH from urban air were collected in the city of Genoa Italy at two sites on two different days of the year. The objective of the study was to compare the inducibility of cultured rat hepatocytes with that of MH1C1 and FaO rat hepatoma cell lines after exposure to a PAH mixture and to a standard compound, such as benzo b fluoranthene B b F . Cytotoxic effects of the tested concentrations were evaluated by means of 3 4,5, dimenthylthyazol 2 yl 2,5 diphenyltetrazolium bromide MTT and lactate dehydrogenase release LDH tests, the potency of inducers by ethoxyresorufin O deethylase EROD assay. The results were in agreement in the three cellular systems: after exposure to the PAH mixture, an induction at low concentrations was observed; whereas no induction, but rather a decrease in activity was shown at higher concentrations; instead, the exposure to pure B b F showed a dose-response relationship in all cells, even at the highest doses. Such a difference between the toxicity of the complex mixture and that of the pure compound could be ascribed to the presence of drug metabolism inhibitors in the mixture, or to interactions between the original components and their metabolites. The finding that the cell lines responded to the CYP1A1 induction in a very efficient way gives further proof of the applicability of this system to environmental biomonitoring. 相似文献
105.
106.
This study presents an experimental approach, based on the change of Trp fluorescence between native and denatured states of proteins, which permits to monitor unfolding equilibria and the thermodynamic stability (DeltaG degrees ) of these macromolecules in frozen aqueous solutions. The results obtained by guanidinium chloride denaturation of the azurin mutant C112S from Pseudomonas aeruginosa, in the temperature range from -8 to -16 degrees C, demonstrate that the stability of the native fold may be significantly perturbed in ice depending mainly on the size of the liquid water pool (V(L)) in equilibrium with the solid phase. The data establish a threshold, around V(L)=1.5%, below which in ice DeltaG degrees decreases progressively relative to liquid state, up to 3 kcal/mole for V(L)=0.285%. The sharp dependence of DeltaG degrees on V(L) is consistent with a mechanism based on adsorption of the protein to the ice surface. The reduction in DeltaG degrees is accompanied by a corresponding decrease in m-value indicating that protein-ice interactions increase the solvent accessible surface area of the native fold or reduce that of the denatured state, or both. The method opens the possibility for examining in a more quantitative fashion the influence of various experimental conditions on the ice perturbation and in particular to test the effectiveness of numerous additives used in formulations to preserve labile pharmaco proteins. 相似文献
107.
Gianfranco Fornasini Nunzia Monti Giandomenico Brogin Maddalena Gallina Mario Eandi Stefano Persiani Massimo Bani Carlo Della Pepa Gianpaolo Zara Margherita Strolin Benedetti 《Chirality》1997,9(3):297-302
The pharmacokinetics of ibuprofen enantiomers were investigated in a crossover study in which seven healthy male volunteers received single oral doses of 800 mg racemic ibuprofen as a soluble granular formulation (sachet) containing L-arginine (designated trade name: Spedifen®), 400 mg (-)R-ibuprofen arginine or 400 mg (+)S-ibuprofen arginine. Plasma levels of both enantiomers were monitored up to 480 minutes after drug intake using an enantioselective analytical method (HPLC with ultraviolet detection) with a quantitation limit of 0.25 mg/l. Substantial inter-subject variability in the evaluated pharmacokinetic parameters was observed in the present study. After (+)S-ibuprofen arginine, the following mean pharmacokinetic parameters ±SD were calculated for (+)S-ibuprofen: tmax 28.6 ± 28.4 min; Cmax 36.2 ± 7.7 mg/l; AUC 86.4 ± 14.9 mg · h/l; t½ 105.2 ± 20.4 min. After (-)R-ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S-ibuprofen and (-)R-ibuprofen, respectively: tmax 90.0 ± 17.3 and 50.5 ± 20.5 min; Cmax 9.7 ± 3.0 and 35.3 ± 5.0 mg/l; AUC 47.0 ± 17.2 and 104.7 ± 27.7 mg · h/l; t½ 148.1 ± 63.6 and 97.7 ± 23.3 min. After racemic ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S- and (-)R-ibuprofen, respectively: tmax 30.7 ± 29.1 and 22.9 ± 29.8 min.; Cmax 29.9 ± 5.6 and 25.6 ± 4.4 mg/l; AUC 105.1 ± 23.0 and 65.3 ± 15.0 mg · h/l; t½ 136.6 ± 20.7 and 128.6 ± 45.0 min. Tmax values of S(+)- and (-)R-ibuprofen after a single dose of 400 mg of each enantiomer did not differ significantly from the corresponding parameters obtained after a single dose of 800 mg of racemic ibuprofen arginine, indicating that the absorption rate of (-)R- and (+)S-ibuprofen is not different when the two enantiomers are administered alone or as a racemic compound. An average of 49.3 ± 9.0% of a dose of the (-)R-ibuprofen arginine was bioinverted into its antipode during the study period (480 minutes post-dosing). The percent bioinversion during the first 30 minutes after (-)R-ibuprofen arginine intake averaged 8.1 ± 3.9%. The mean AUC of (+)S-ibuprofen calculated after 800 mg racemic ibuprofen arginine (105.1 ± 23.0 mg · h/l) was lower than the mean AUC value obtained by summing the AUCs of (+)S-ibuprofen after administration of 400 mg (+)S-ibuprofen arginine and 400 mg (-)R-ibuprofen arginine (133.4 ± 26.6 mg · h/l). In conclusion, the administration of Spedifen® resulted in very rapid absorption of the (+)S-isomer (eutomer) with tmax values much lower than those observed for this isomer when conventional oral solid formulations such as capsules or tablets of racemic ibuprofen are administered. This characteristic is particularly favourable in those conditions in which a very rapid analgesic effect is required. Chirality 9:297–302, 1997. © 1997 Wiley-Liss, Inc. 相似文献
108.
Arun K. Ghosh Margherita Brindisi Yu-Chen Yen Emilio L. Cárdenas Jean-Rene Ella-Menye Nagaswamy Kumaragurubaran Xiangping Huang Jordan Tang Andrew D. Mesecar 《Bioorganic & medicinal chemistry letters》2017,27(11):2432-2438
We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1′ and P2′ ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki = 2 nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated. Inhibitor 6j with an oxazolidinone derivative showed a BACE1 inhibitory activity of 23 nM and cellular EC50 of 80 nM. 相似文献
109.
FOXM1 Transcription Factor: A New Component of Chronic Myeloid Leukemia Stem Cell Proliferation Advantage
下载免费PDF全文
![点击此处可从《Journal of cellular biochemistry》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Manuela Mancini Fausto Castagnetti Simona Soverini Elisa Leo Caterina De Benedittis Gabriele Gugliotta Gianantonio Rosti Luana Bavaro Sara De Santis Cecilia Monaldi Margherita Martelli Maria Alessandra Santucci Michele Cavo Giovanni Martinelli 《Journal of cellular biochemistry》2017,118(11):3968-3975
110.
Mariachiara Zuccarini Patricia Giuliani Silvana Buccella Valentina Di Liberto Giuseppa Mudò Natale Belluardo Marzia Carluccio Margherita Rossini Daniele Filippo Condorelli Michel Piers Rathbone Francesco Caciagli Renata Ciccarelli Patrizia Di Iorio 《Purinergic signalling》2017,13(4):429-442
Epithelial to mesenchymal transition (EMT) occurs during embryogenesis or under pathological conditions such as hypoxia, injury, chronic inflammation, or tissue fibrosis. In renal tubular epithelial cells (MDCK), TGF-β1 induces EMT by reducing or increasing epithelial or mesenchymal marker expression, respectively. In this study, we confirmed that the cAMP analogues, 8-CPT-cAMP or N6-Ph-cAMP, inhibited the TGF-β1-driven overexpression of the mesenchymal markers ZEB-1, Slug, Fibronectin, and α-SMA. Furthermore, we showed that A1, A2A, P2Y1, P2Y11, and P2X7 purine receptor agonists modulated the TGF-β1-induced EMT through the involvement of PKA and/or MAPK/ERK signaling. The stimulation of A2A receptor reduced the overexpression of the EMT-related markers, mainly through the cAMP-dependent PKA pathway, as confirmed by cell pre-treatment with Myr-PKI. Both A1 and P2Y1 receptor stimulation exacerbated the TGF-β1-driven effects, which were reduced by cell pre-treatment with the MAPK inhibitor PD98059, according to the increased ERK1/2 phosphorylation upon receptor activation. The effects induced by P2Y11 receptor activation were oppositely modulated by PKA or MAPK inhibition, in line with the dual nature of the Gs- and Gq-coupled receptor. Differently, P2X7 receptor induced, per se, similar and not additive effects compared to TGF-β1, after prolonged cell exposure to BzATP. These results suggest a putative role of purine receptors as target for anti-fibrotic agents. 相似文献