全文获取类型
收费全文 | 2298篇 |
免费 | 173篇 |
出版年
2024年 | 3篇 |
2023年 | 11篇 |
2022年 | 33篇 |
2021年 | 59篇 |
2020年 | 32篇 |
2019年 | 53篇 |
2018年 | 79篇 |
2017年 | 52篇 |
2016年 | 92篇 |
2015年 | 117篇 |
2014年 | 156篇 |
2013年 | 169篇 |
2012年 | 222篇 |
2011年 | 215篇 |
2010年 | 141篇 |
2009年 | 99篇 |
2008年 | 152篇 |
2007年 | 151篇 |
2006年 | 114篇 |
2005年 | 111篇 |
2004年 | 107篇 |
2003年 | 77篇 |
2002年 | 67篇 |
2001年 | 7篇 |
2000年 | 9篇 |
1999年 | 18篇 |
1998年 | 18篇 |
1997年 | 17篇 |
1996年 | 11篇 |
1995年 | 9篇 |
1994年 | 6篇 |
1993年 | 10篇 |
1992年 | 8篇 |
1991年 | 6篇 |
1990年 | 6篇 |
1989年 | 4篇 |
1988年 | 6篇 |
1987年 | 2篇 |
1985年 | 4篇 |
1983年 | 2篇 |
1981年 | 6篇 |
1980年 | 2篇 |
1977年 | 2篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1969年 | 1篇 |
1959年 | 1篇 |
1909年 | 1篇 |
排序方式: 共有2471条查询结果,搜索用时 15 毫秒
71.
Limatola C Massa V Lauro C Catalano M Giovanetti A Nuccitelli S Spinedi A 《FEBS letters》2007,581(14):2641-2646
Chemotaxis induction is a major effect evoked by stimulation of the chemokine receptor CXCR4 with its sole ligand CXCL12. We now report that treatment of CHP-100 human neuroepithelioma cells with the glucosylceramide synthase (GCS) inhibitor DL-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol inhibits CXCR4-dependent chemotaxis. We provide evidence that the phenomenon is not due to unspecific effects of the inhibitor employed and that inhibition of GCS neither affects total or plasmamembrane CXCR4 expression, nor CXCL12-induced Ca(2+) mobilization. The effects of the GCS inhibitor on impairment of CXCL12-induced cell migration temporally correlated with a pronounced downregulation of neutral glycosphingolipids, particularly glucosylceramide, and with a delayed and more moderate downregulation of gangliosides; moreover, exogenously administered glycosphingolipids allowed resumption of CXCR4-dependent chemotaxis. Altogether our results provide evidence, for the first time, for a role glycosphingolipids in sustaining CXCL12-induced cell migration. 相似文献
72.
Huang Y Qiu J Dong S Redell MS Poli V Mancini MA Tweardy DJ 《The Journal of biological chemistry》2007,282(48):34958-34967
73.
Bernardinelli L Murgia SB Bitti PP Foco L Ferrai R Musu L Prokopenko I Pastorino R Saddi V Ticca A Piras ML Cox DR Berzuini C 《PloS one》2007,2(5):e480
Multiple genome screens have been performed to identify regions in linkage or association with Multiple Sclerosis (MS, OMIM 126200), but little overlap has been found among them. This may be, in part, due to a low statistical power to detect small genetic effects and to genetic heterogeneity within and among the studied populations. Motivated by these considerations, we studied a very special population, namely that of Nuoro, Sardinia, Italy. This is an isolated, old, and genetically homogeneous population with high prevalence of MS. Our study sample includes both nuclear families and unrelated cases and controls. A multi-stage study design was adopted. In the first stage, microsatellites were typed in the 17q11.2 region, previously independently found to be in linkage with MS. One significant association was found at microsatellite D17S798. Next, a bioinformatic screening of the region surrounding this marker highlighted an interesting candidate MS susceptibility gene: the Amiloride-sensitive Cation Channel Neuronal 1 (ACCN1) gene. In the second stage of the study, we resequenced the exons and the 3' untranslated (UTR) region of ACCN1, and investigated the MS association of Single Nucleotide Polymorphisms (SNPs) identified in that region. For this purpose, we developed a method of analysis where complete, phase-solved, posterior-weighted haplotype assignments are imputed for each study individual from incomplete, multi-locus, genotyping data. The imputed assignments provide an input to a number of proposed procedures for testing association at a microsatellite level or of a sequence of SNPs. These include a Mantel-Haenszel type test based on expected frequencies of pseudocase/pseudocontrol haplotypes, as well as permutation based tests, including a combination of permutation and weighted logistic regression analysis. Application of these methods allowed us to find a significant association between MS and the SNP rs28936 located in the 3' UTR segment of ACCN1 with p = 0.0004 (p = 0.002, after adjusting for multiple testing). This result is in tune with several recent experimental findings which suggest that ACCN1 may play an important role in the pathogenesis of MS. 相似文献
74.
Bozzao C Rimoldi V Asselta R Landau M Ghiotto R Tenchini ML De Cristofaro R Castaman G Duga S 《The FEBS journal》2007,274(23):6128-6138
Coagulation factor XI (FXI) is the zymogen of a serine protease that, when converted to its active form, contributes to blood coagulation through proteolytic activation of factor IX. FXI deficiency is typically an autosomal recessive disorder, characterized by bleeding symptoms mainly associated with injury or surgery. Of the more than 100 FXI gene mutations reported in FXI-deficient patients, most are associated with a proportional decrease in FXI functional and immunologic levels (type I defects), whereas only a few mutations leading to the presence of dysfunctional molecules in plasma have been molecularly analyzed to date (type II deficiencies). We report the functional and molecular characterization of a missense mutation (Val371Ile) identified, in the heterozygous state, in a 25-year-old Italian male with mild FXI deficiency. Laboratory analysis revealed reduced functional FXI levels (34%), but normal antigen levels (102%), distinctive of a type II defect. Given the proximity of Val371 to the FXI activation site, a possible interference with zymogen activation was postulated. Expression experiments of the FXI-Val371Ile recombinant protein, followed by activation assays, showed both a different time course in FXI activation and a slight delay in factor IX activation by thrombin-activated FXI. 相似文献
75.
Orefice Ida Di Dato Valeria Sardo Angela Lauritano Chiara Romano Giovanna 《Aquatic Ecology》2022,56(2):377-397
Aquatic Ecology - Diatoms are eukaryotic microalgae representing one of the major groups in the marine phytoplankton, accounting for up to 40% of annual productivity at sea. They are widely... 相似文献
76.
Valeria Agamennone Joeri van Straalen Abraham Brouwer Tjalf E. de Boer Paul J. Hensbergen Niels Zaagman Martin Braster Nico M. van Straalen Dick Roelofs Thierry K.S. Janssens 《Entomologia Experimentalis et Applicata》2019,167(3):269-285
Antibiotic resistance necessitates the search for new bioactive compounds with novel mechanisms of action. Natural products derived from bacteria and fungi are widely used in the field of medicine and new environments can be explored as sources of antimicrobials. Bacteria associated with springtails have shown high inhibitory activity against pathogens. Here, we characterized a bacterial strain with high potential for antimicrobial activity, isolated from the gut of the springtail Folsomia candida Willem (Collembola: Isotomidae). The strain was characterized using the ‘analytical profile index’ and the ‘minimal inhibitory concentration’ assay to test for antibiotic resistance. Agar overlay and agar disk diffusion assays were used to test the inhibitory activity of the strain and its extract against a variety of pathogens, and reporter assays were used to investigate the mode of action. High‐performance liquid chromatography was used to analyze and fractionate the extract of bacterial culture, followed by additional assays on the fractions. The genome of the strain was screened for presence of antibiotic resistance genes and secondary metabolite gene clusters. The isolate was identified as Bacillus toyonensis Jiménez et al., but it displayed differences in metabolic profile when compared to the type species. The isolate was highly resistant to penicillin and inhibited the growth of a variety of pathogenic microorganisms. Genome analysis revealed an enrichment of resistance genes for β‐lactam antibiotics compared to the type isolate. Also, secondary metabolite clusters involved in the production of siderophores, bacteriocins, and nonribosomal peptide synthetases were identified. In conclusion, a unique Bacillus strain was isolated from the gut of F. candida, for which we provide evidence of inhibitory activity against an array of pathogens. This, coupled with high resistance to penicillin as substantiated by the presence of resistance genes, points to the potential of B. toyonensis VU‐DES13 to provide a new source of antimicrobial compounds. 相似文献
77.
Esposito Francesco Memoli Valeria Panico Speranza Claudia Trifuoggi Marco Di Natale Gabriella Maisto Giulia 《Plant and Soil》2019,436(1-2):517-526
Plant and Soil - The aims of this research were: i) to compare Cr, Cu, Ni and Pb concentrations in Quercus ilex L. leaves collected at urban/industrial and urban areas; ii) to investigate the main... 相似文献
78.
79.
Teresa Fazia Daria Marzanati Anna Laura Carotenuto Ashley Beecham Athena Hadjixenofontos Jacob L. McCauley Valeria Saddi Marialuisa Piras Luisa Bernardinelli Davide Gentilini 《Current issues in molecular biology》2021,43(3):1778
Multiple Sclerosis (MS) is a complex multifactorial autoimmune disease, whose sex- and age-adjusted prevalence in Sardinia (Italy) is among the highest worldwide. To date, 233 loci were associated with MS and almost 20% of risk heritability is attributable to common genetic variants, but many low-frequency and rare variants remain to be discovered. Here, we aimed to contribute to the understanding of the genetic basis of MS by investigating potentially functional rare variants. To this end, we analyzed thirteen multiplex Sardinian families with Immunochip genotyping data. For five families, Whole Exome Sequencing (WES) data were also available. Firstly, we performed a non-parametric Homozygosity Haplotype analysis for identifying the Region from Common Ancestor (RCA). Then, on these potential disease-linked RCA, we searched for the presence of rare variants shared by the affected individuals by analyzing WES data. We found: (i) a variant (43181034 T > G) in the splicing region on exon 27 of CUL9; (ii) a variant (50245517 A > C) in the splicing region on exon 16 of ATP9A; (iii) a non-synonymous variant (43223539 A > C), on exon 9 of TTBK1; (iv) a non-synonymous variant (42976917 A > C) on exon 9 of PPP2R5D; and v) a variant (109859349-109859354) in 3′UTR of MYO16. 相似文献
80.
Jonathan R.M. Millet Luis O. Romero Jungsoo Lee Briar Bell Valeria Vsquez 《The Journal of general physiology》2022,154(1)
PIEZO channels are force sensors essential for physiological processes, including baroreception and proprioception. The Caenorhabditis elegans genome encodes an orthologue gene of the Piezo family, pezo-1, which is expressed in several tissues, including the pharynx. This myogenic pump is an essential component of the C. elegans alimentary canal, whose contraction and relaxation are modulated by mechanical stimulation elicited by food content. Whether pezo-1 encodes a mechanosensitive ion channel and contributes to pharyngeal function remains unknown. Here, we leverage genome editing, genetics, microfluidics, and electropharyngeogram recording to establish that pezo-1 is expressed in the pharynx, including in a proprioceptive-like neuron, and regulates pharyngeal function. Knockout (KO) and gain-of-function (GOF) mutants reveal that pezo-1 is involved in fine-tuning pharyngeal pumping frequency, as well as sensing osmolarity and food mechanical properties. Using pressure-clamp experiments in primary C. elegans embryo cultures, we determine that pezo-1 KO cells do not display mechanosensitive currents, whereas cells expressing wild-type or GOF PEZO-1 exhibit mechanosensitivity. Moreover, infecting the Spodoptera frugiperda cell line with a baculovirus containing the G-isoform of pezo-1 (among the longest isoforms) demonstrates that pezo-1 encodes a mechanosensitive channel. Our findings reveal that pezo-1 is a mechanosensitive ion channel that regulates food sensation in worms. 相似文献