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61.
Pinnen F Cacciatore I Cornacchia C Mollica A Sozio P Cerasa LS Iannitelli A Fontana A Nasuti C Di Stefano A 《Amino acids》2012,42(1):261-269
Parkinson’s disease (PD) is a neurodegenerative disorder associated primarily with loss of dopamine (DA) neurons in the nigrostriatal
system. With the aim of increasing the bioavailability of l-dopa (LD) after oral administration and of overcoming the pro-oxidant effect associated with LD therapy, we designed a peptidomimetic
LD prodrug (1) able to release the active agent by enzyme catalyzed hydrolysis. The physicochemical properties, as well as the chemical
and enzymatic stabilities of the new compound, were evaluated in order to check both its stability in aqueous medium and its
sensitivity towards enzymatic cleavage, providing the parent LD drug, in rat and human plasma. The radical scavenging activities
of prodrug 1 was tested by using both the DPPH–HPLC and the DMSO competition methods. The results indicate that the replacement of cysteine
GSH portion by methionine confers resistance to oxidative degradation in gastric fluid. Prodrug 1 demonstrated to induce sustained delivery of DA in rat striatal tissue with respect to equimolar LD dosages. These results
are of significance for prospective therapeutic application of prodrug 1 in pathological events associated with free radical damage and decreasing DA concentration in the brain. 相似文献
62.
63.
Heterogeneous PrPC metabolism in skeletal muscle cells 总被引:1,自引:0,他引:1
Recent reports have shown that prions, the causative agent of transmissible spongiform encephalopathies, accumulate in the skeletal muscle of diseased animals and man. In an attempt to characterise in this tissue the prion protein (PrP(C)), whose conformational rearrangement governs the generation of prions, we have analysed the protein in primary cultured murine myocytes and in different skeletal muscle types. Our results indicate that the expression and cellular processing of PrP(C) change during myogenesis, and in muscle fibres with different contractile properties. These findings imply a potential role for PrP(C) in the skeletal muscle physiology, but may also explain the different capability of muscles to sustain prion replication. 相似文献
64.
Roberto Giorda M. Clara Bonaglia Silvana Beri Francesca Novara Jill Urquhart Claudio Zucca Susan Marelli Daniela Di Benedetto Girolamo A. Vitello Santina Reitano Francesca Bisulli Massimo Mastrangelo Luigina Spaccini Elena Fontana Jill Clayton-Smith Philippe Jonveaux Marco Seri Bernardo dalla Bernardina 《American journal of human genetics》2009,85(3):394-400
Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8–9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome. 相似文献
65.
66.
Barbara D'haene Catia Attanasio Diane Beysen Jose Dostie Edmond Lemire Philippe Bouchard Michael Field Kristie Jones Birgit Lorenz Bjrn Menten Karen Buysse Filip Pattyn Marc Friedli Catherine Ucla Colette Rossier Carine Wyss Frank Speleman Anne De Paepe Job Dekker Stylianos E. Antonarakis Elfride De Baere 《PLoS genetics》2009,5(6)
To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs. Apart from three larger distant deletions, a de novo deletion as small as 7.4 kb was found at 283 kb 5′ to FOXL2. The deletion appeared to be triggered by an H-DNA-induced double-stranded break (DSB). In addition, it disrupts a novel long non-coding RNA (ncRNA) PISRT1 and 8 CNCs. The regulatory potential of the deleted CNCs was substantiated by in vitro luciferase assays. Interestingly, Chromosome Conformation Capture (3C) of a 625 kb region surrounding FOXL2 in expressing cellular systems revealed physical interactions of three upstream fragments and the FOXL2 core promoter. Importantly, one of these contains the 7.4 kb deleted fragment. Overall, this study revealed the smallest distant deletion causing monogenic disease and impacts upon the concept of mutation screening in human disease and developmental disorders in particular. 相似文献
67.
Laura Costarelli Elisa Muti Marco Malavolta Catia Cipriano Robertina Giacconi Silvia Tesei Francesco Piacenza Sara Pierpaoli Nazzarena Gasparini Emanuela Faloia Giacomo Tirabassi Marco Boscaro Angela Polito Beatrice Mauro Francesca Maiani Anna Raguzzini Fiorella Marcellini Cinzia Giuli Roberta Papa Monica Emanuelli Eugenio Mocchegiani 《The Journal of nutritional biochemistry》2010,21(5):432-437
Overweight and obesity are associated with low grade of inflammation and chronic inflammatory response characterized by abnormal production and activation of some pro-inflammatory signalling pathways. Taking into account that obesity is the direct result of an imbalance between energy intake and energy expenditure, the nutritional factors in the diet, with particular focus on zinc, may play a pivotal role in the development of obesity-associated comorbidities. Considering the potential interactions among zinc nutritional status, inflammation, overweight/obesity and insulin secretion, the aim of the present work was to clarify the influence of zinc dietary intake on some metabolic, inflammatory and zinc status parameters in adult overweight/obese subjects. We found a close interrelationship between nutritional zinc and obesity. In particular, subjects with a lower zinc dietary intake display a deeper inflammatory status, general impairment of the zinc status, an altered lipid profile and increased insulin production with respect to obese subjects with normal zinc dietary intake. Moreover, in the presence of low dietary zinc intake, the obese subjects are less capable to respond to oxidative stress and to inflammation leading to the development of obesity or to a worsening of already preexisting obesity status. In conclusion, a possible zinc supplementation in obese subjects with a deeper inflammatory status and more altered zinc profile may be suggested in order to limit or reduce the inflammation, taking also into account that zinc supplementation normalizes “inflammaging” as well as zinc profile leading to a correct intra- and extracellular zinc homeostasis. 相似文献
68.
Discovery and structure–activity relationship of a novel spirocarbamate series of NPY Y5 antagonists
Colin P. Leslie Jonathan Bentley Matteo Biagetti Stefania Contini Romano Di Fabio Daniele Donati Thorsten Genski Sebastien Guery Angelica Mazzali Giancarlo Merlo Domenica A. Pizzi Fabiola Sacco Catia Seri Michela Tessari Laura Zonzini Laura Caberlotto 《Bioorganic & medicinal chemistry letters》2010,20(20):6103-6107
A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3 mg/kg po. 相似文献
69.
Matteo Biagetti Colin Philip Leslie Angelica Mazzali Catia Seri Domenica Antonia Pizzi Jonathan Bentley Thorsten Genski Romano Di Fabio Laura Zonzini Laura Caberlotto 《Bioorganic & medicinal chemistry letters》2010,20(16):4741-4744
A novel class of small molecule NPY Y5 antagonists based around an azabicyclo[3.1.0]hexane scaffold was identified through modification of a screening hit. Structure–activity relationships and efforts undertaken to achieve a favourable pharmacokinetic profile in rat are described. 相似文献
70.
Gianandrea Pasquinelli Annalisa Pacilli Francesco Alviano Laura Foroni Francesca Ricci Sabrina Valente Catia Orrico Giacomo Lanzoni Marina Buzzi Pier Luigi Tazzari Pasqualepaolo Pagliaro Andrea Stella Gian Paolo Bagnara 《Cytotherapy》2010,12(3):275-287
Background aimsThe presence of ectopic tissues in the pathologic artery wall raises the issue of whether multipotent stem cells may reside in the vasculature itself. Recently mesenchymal stromal cells (MSC) have been isolated from different human vascular segments (VW MSC), belying the previous view that the vessel wall is a relatively quiescent tissue.MethodsResident multipotent cells were recovered from fresh arterial segments (aortic arches, thoracic and femoral arteries) collected in a tissue-banking facility and used to establish an in situ and in vitro study of the stemness features and multipotency of these multidistrict MSC populations.ResultsNotch-1+, Stro-1+, Sca-1+ and Oct-4+ cells were distributed along an arterial wall vasculogenic niche. Multidistrict VW MSC homogeneously expressed markers of stemness (Stro-1, Notch-1 and Oct-4) and MSC lineages (CD44, CD90, CD105, CD73, CD29 and CD166) whilst they were negative for hematopoietic and endothelial markers (CD34, CD45, CD31 and vWF). Each VW MSC population had characteristics of stem cells, i.e. a high efflux capability for Hoechst 33342 dye and the ability to form spheroids when grown in suspension and generate colonies when seeded at low density. Again, VW MSC cultured in induction media exhibited adipogenic, chondrogenic and leiomyogenic potential but less propensity to osteogenic differentiation, as documented by histochemical, immunohistochemical, molecular and electron microscopy analysis.ConclusionsOverall, these findings may enlighten the physiopathologic mechanisms of vascular wall diseases as well as having potential implications for cellular, genetic and tissue engineering approaches to treating vascular pathologies when these are unresponsive to medical and surgical therapies. 相似文献