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921.
Rossi C Porcelloni M D'Andrea P Fincham CI Ettorre A Mauro S Squarcia A Bigioni M Parlani M Nardelli F Binaschi M Maggi CA Fattori D 《Bioorganic & medicinal chemistry letters》2011,21(8):2305-2308
We report here the strategy used in our research group to find a new class of histone deacetylase (HDAC) inhibitors.A series of N-substituted 4-alkylpiperazine and 4-alkylpiperidine hydroxamic acids, corresponding to the basic structure of HDAC inhibitors (zinc binding moiety-linker-capping group) has been designed, prepared, and tested for HDAC inhibition.Linker length and aromatic capping group connection were systematically varied to find the optimal geometric parameters. A new series of submicromolar inhibitors was thus identified, which showed antiproliferative activity on HCT-116 colon carcinoma cells. 相似文献
922.
Donnini S Finetti F Francese S Boscaro F Dani FR Maset F Frasson R Palmieri M Pazzagli M De Filippis V Garaci E Ziche M 《The Biochemical journal》2011,440(2):251-262
Cytotoxic and antitumour factors have been documented in the venom of snakes, although little information is available on the identification of cytotoxic products in snake serum. In the present study, we purified and characterized a new cytotoxic factor from serum of the non-venomous African rock python (Python sebae), endowed with antitumour activity. PSS (P. sebae serum) exerted a cytotoxic activity and reduced dose-dependently the viability of several different tumour cell lines. In a model of human squamous cell carcinoma xenograft (A431), subcutaneous injection of PSS in proximity of the tumour mass reduced the tumour volume by 20%. Fractionation of PSS by ion-exchange chromatography yielded an active protein fraction, F5, which significantly reduced tumour cell viability in vitro and, strikingly, tumour growth in vivo. F5 is composed of P1 (peak 1) and P2 subunits interacting in a 1:1 stoichiometric ratio to form a heterotetramer in equilibrium with a hexameric form, which retained biological activity only when assembled. The two peptides share sequence similarity with PIP {PLI-γ [type-γ PLA(2) (phospholipase A(2)) inhibitor] from Python reticulatus}, existing as a homohexamer. More importantly, although PIP inhibits the hydrolytic activity of PLA(2), the anti-PLA(2) function of F5 is negligible. Using high-resolution MS, we covered 87 and 97% of the sequences of P1 and P2 respectively. In conclusion, in the present study we have identified and thoroughly characterized a novel protein displaying high sequence similarity to PLI-γ and possessing remarkable cytotoxic and antitumour effects that can be exploited for potential pharmacological applications. 相似文献
923.
(1)H NMR (nuclear magnetic resonance spectroscopy) has been used for metabolomic analysis of 'Riesling' and 'Mueller-Thurgau' white wines from the German Palatinate region. Diverse two-dimensional NMR techniques have been applied for the identification of metabolites, including phenolics. It is shown that sensory analysis correlates with NMR-based metabolic profiles of wine. (1)H NMR data in combination with multivariate data analysis methods, like principal component analysis (PCA), partial least squares projections to latent structures (PLS), and bidirectional orthogonal projections to latent structures (O2PLS) analysis, were employed in an attempt to identify the metabolites responsible for the taste of wine, using a non-targeted approach. The high quality wines were characterized by elevated levels of compounds like proline, 2,3-butanediol, malate, quercetin, and catechin. Characterization of wine based on type and vintage was also done using orthogonal projections to latent structures (OPLS) analysis. 'Riesling' wines were characterized by higher levels of catechin, caftarate, valine, proline, malate, and citrate whereas compounds like quercetin, resveratrol, gallate, leucine, threonine, succinate, and lactate, were found discriminating for 'Mueller-Thurgau'. The wines from 2006 vintage were dominated by leucine, phenylalanine, citrate, malate, and phenolics, while valine, proline, alanine, and succinate were predominantly present in the 2007 vintage. Based on these results, it can be postulated the NMR-based metabolomics offers an easy and comprehensive analysis of wine and in combination with multivariate data analyses can be used to investigate the source of the wines and to predict certain sensory aspects of wine. 相似文献
924.
GM1 gangliosidosis and Morquio B disease: An update on genetic alterations and clinical findings 总被引:1,自引:0,他引:1
Anna CaciottiScott C. Garman Yadilette Rivera-ColónElena Procopio Serena CatarziLorenzo Ferri Carmen GuidoPaola Martelli Rossella PariniDaniela Antuzzi Roberta BattiniMichela Sibilio Alessandro SimonatiElena Fontana Alessandro SalviatiGulcin Akinci Cristina CeredaCarlo Dionisi-Vici Francesca DeodatoAdele d'Amico Alessandra d'AzzoEnrico Bertini Mirella FilocamoMaurizio Scarpa Maja di RoccoCynthia J. Tifft Federica CianiSerena Gasperini Elisabetta PasquiniRenzo Guerrini Maria Alice DonatiAmelia Morrone 《生物化学与生物物理学报:疾病的分子基础》2011,1812(7):782-790
GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes showed that all the amino acid replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease. 相似文献
925.
Mollica A Pinnen F Feliciani F Stefanucci A Lucente G Davis P Porreca F Ma SW Lai J Hruby VJ 《Amino acids》2011,40(5):1503-1511
We report the synthesis and the biological evaluation of two new analogues of the potent dimeric opioid peptide biphalin.
The performed modification is based on the replacement of two key structural elements of the native biphalin, namely: the
hydrazine bridge which joins the two palindromic moieties and the phenylalanine residues at the 4,4′ positions of the backbone.
The new analogues 9 and 10 contain 1,2-phenylenediamine and piperazine, respectively, in place of the hydrazidic linker and p-fluoro-l-phenylalanine residues at 4 and 4′ positions. Binding values are:
K\textim = 0.51 \textnM K_{\text{i}}^{\mu } = 0.51\,{\text{nM}} and
K\textid = 12.8 \textnM K_{\text{i}}^{\delta } = 12.8\,{\text{nM}} for compound 9,
K\textim = 0.09 \textnM K_{\text{i}}^{\mu } = 0.09\,{\text{nM}} and
K\textid = 0.11 \textnM K_{\text{i}}^{\delta } = 0.11\,{\text{nM}} for analogue 10. 相似文献
926.
Di Bucchianico S Giardi MF De Marco P Ottaviano L Botti D 《Journal of molecular recognition : JMR》2011,24(4):608-618
The Marek's disease virus (MDV) integration may induce a novel organization of chromatin architecture with a modified genetic expression. In our opinion it is worthwhile trying to relate cytogenetic stability to functional modifications. Recently, atomic force microscopy technique was applied to study the structure of chromosomes at a nanoscale level. This high resolution allows to investigate the different structure of chromatin in order to study cytogenetic stability and chromosome aberrations due to MDV insertion. In this paper data are presented indicating a duplication [78,WZ,dup(1p)(p22-p23)] and a deletion [78,WZ cht del(3)(q2.10)] of Chromosomes 1 and 3 relatively. Relationships between GTG (G-bands by Trypsin using Giemsa) bands and the topography of chromosomes are also discussed, naming them Topographic Banding. The architecture of chromosomes observed by AFM can be related to the data obtained with classic banding techniques thus overcoming the optical resolution limits. The presence of chromatin bridges between sister chromatids at most of the heterochromatic regions is also evidenced. Besides, we present different studies of the longitudinal and transversal symmetry of the hetero and euchromatic regions to clearly demonstrate a different underlying architecture of these regions. It is indeed evident that the heterochromatic bands are more symmetrical than euchromatic bands. 相似文献
927.
Massarelli I Imbriani M Chiellini F Chiellini E Bianucci AM 《Journal of molecular recognition : JMR》2011,24(5):824-832
The ultimate aim of this study is to identify new molecules that are able to recognize polymerized fibrin, which is the main component of a thrombus. These selective ligands can be exposed on the surface of particular nanoparticles used for the targeted delivery of fibrinolytic drugs. The targeted delivery of these drugs is expected to help to keep under control the severe side effects which can occur if the drugs are administered systemically. The study focuses on the application of high-throughput docking methods used to screen a library of thousands of commercial compounds. The aim was to identify molecules that are potentially capable of interacting with the human fibrin γ(312-324) epitope. The best scoring compounds were purchased and tested through fluorimetric assays in order to estimate their affinity toward fibrin. The results show that the protocol proposed here for identifying new compounds of interest may provide a valuable contribution to the discovery of lead molecules for human fibrin recognition. 相似文献
928.
Cristina Menta Alan Leoni Ciro Gardi Federica Delia Conti 《Biodiversity and Conservation》2011,20(5):1073-1087
Biodiversity has been a focal aim of environmental protection since the Rio conference, but only with the beginning of the
new millennium did soil biodiversity become an important aspect of international policy. Edaphic fauna play a key role in
many soil functions, such as organic matter decomposition, humus formation and nutrient element cycling; moreover, affect
the porosity, aeration, infiltration and distribution of organic matter in soil horizons, modifying soil structure and improving
its fertility. The ecosystem services provided by soil animals are becoming progressively lost due to agricultural practice
intensification, which causes a reduction in both abundance and taxonomic diversity of soil communities. In the present study,
a permanent grassland habitat was studied in order to evaluate its potential as a soil biodiversity reservoir in agroecosystems.
Grassland samples were compared with samples from a semi-natural woodland area and an arable land site. Microarthropod abundances,
Acari/Collembola ratio (A/C), Shannon diversity index (H′) and evenness index (E) were calculated. QBS-ar index was used in
order to evaluate soil biological quality. Microarthropod communities of the three land use typologies differed in both the
observed groups and their abundance. Steady soil taxa characterized both woodland and grassland soils, whereas their abundances
were significantly higher in woodland soil. Taxon diversity and soil biological quality in the grasslands did not differ from
the woodland samples. The microarthropod community in the arable land showed a reduction both in taxa numbers and soil biological
quality compared with the other sites. Soil biological quality and edaphic community composition highlighted the importance
of grassland habitats in the protection of soil biodiversity. 相似文献
929.
Giovanna Pescatore Danila Branca Fabrizio Fiore Olaf Kinzel Laura Llauger Bufi Ester Muraglia Federica Orvieto Michael Rowley Carlo Toniatti Caterina Torrisi Philip Jones 《Bioorganic & medicinal chemistry letters》2010,20(3):1094-1099
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells. 相似文献
930.
Maria De Salvo Lavinia Raimondi Serena Vella Laura Adesso Roberta Ciarapica Federica Verginelli Antonio Pannuti Arianna Citti Renata Boldrini Giuseppe M. Milano Antonella Cacchione Andrea Ferrari Paola Collini Angelo Rosolen Gianni Bisogno Rita Alaggio Alessandro Inserra Mattia Locatelli Stefano Stifani Isabella Screpanti Lucio Miele Franco Locatelli Rossella Rota 《PloS one》2014,9(5)
Rhabdomyosarcoma (RMS) is a pediatric myogenic-derived soft tissue sarcoma that includes two major histopathological subtypes: embryonal and alveolar. The majority of alveolar RMS expresses PAX3-FOXO1 fusion oncoprotein, associated with the worst prognosis. RMS cells show myogenic markers expression but are unable to terminally differentiate. The Notch signaling pathway is a master player during myogenesis, with Notch1 activation sustaining myoblast expansion and Notch3 activation inhibiting myoblast fusion and differentiation. Accordingly, Notch1 signaling is up-regulated and activated in embryonal RMS samples and supports the proliferation of tumor cells. However, it is unable to control their differentiation properties. We previously reported that Notch3 is activated in RMS cell lines, of both alveolar and embryonal subtype, and acts by inhibiting differentiation. Moreover, Notch3 depletion reduces PAX3-FOXO1 alveolar RMS tumor growth in vivo. However, whether Notch3 activation also sustains the proliferation of RMS cells remained unclear. To address this question, we forced the expression of the activated form of Notch3, Notch3IC, in the RH30 and RH41 PAX3-FOXO1-positive alveolar and in the RD embryonal RMS cell lines and studied the proliferation of these cells. We show that, in all three cell lines tested, Notch3IC over-expression stimulates in vitro cell proliferation and prevents the effects of pharmacological Notch inhibition. Furthermore, Notch3IC further increases RH30 cell growth in vivo. Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation. Finally, the expression of Notch3IC and its target gene HES1 correlates with that of the proliferative marker Ki67 in a small cohort of primary PAX-FOXO1 alveolar RMS samples. These results strongly suggest that high levels of Notch3 activation increase the proliferative potential of RMS cells. 相似文献