全文获取类型
收费全文 | 2596篇 |
免费 | 183篇 |
出版年
2023年 | 9篇 |
2022年 | 20篇 |
2021年 | 33篇 |
2020年 | 28篇 |
2019年 | 27篇 |
2018年 | 51篇 |
2017年 | 49篇 |
2016年 | 75篇 |
2015年 | 106篇 |
2014年 | 123篇 |
2013年 | 195篇 |
2012年 | 197篇 |
2011年 | 179篇 |
2010年 | 138篇 |
2009年 | 130篇 |
2008年 | 175篇 |
2007年 | 162篇 |
2006年 | 160篇 |
2005年 | 125篇 |
2004年 | 153篇 |
2003年 | 113篇 |
2002年 | 115篇 |
2001年 | 16篇 |
2000年 | 12篇 |
1999年 | 32篇 |
1998年 | 29篇 |
1997年 | 21篇 |
1996年 | 19篇 |
1995年 | 30篇 |
1994年 | 18篇 |
1993年 | 23篇 |
1992年 | 21篇 |
1991年 | 16篇 |
1990年 | 24篇 |
1989年 | 16篇 |
1988年 | 10篇 |
1987年 | 5篇 |
1986年 | 7篇 |
1985年 | 7篇 |
1984年 | 7篇 |
1983年 | 8篇 |
1982年 | 12篇 |
1981年 | 16篇 |
1980年 | 8篇 |
1979年 | 5篇 |
1978年 | 10篇 |
1977年 | 7篇 |
1976年 | 9篇 |
1974年 | 12篇 |
1973年 | 4篇 |
排序方式: 共有2779条查询结果,搜索用时 15 毫秒
101.
Maria Maddalena Cavalluzzi Maurizio Viale Claudio Bruno Alessia Carocci Alessia Catalano Antonio Carrieri Carlo Franchini Giovanni Lentini 《Bioorganic & medicinal chemistry letters》2013,23(17):4820-4823
Lubeluzole, a neuroprotective anti-ischemic drug, and its enantiomer were prepared following a convenient procedure based on hydrolytic kinetic resolution. The ee values were >99% and 96%, respectively, as assessed by HPLC analysis. The chemosensitizing effects of both enantiomers were evaluated in combination with either doxorubicin (human ovarian adenocarcinoma A2780 cells) or paclitaxel (human lung carcinoma A549 cells) by the MTT assay. At the lowest concentrations used, lubeluzole showed an overall and remarkable tendency to synergize with both anticancer drugs. In ovarian cancer cells a clear prevalence of antagonistic effect was observed for the R-enantiomer. The synergistic effects of lubeluzole for both drugs were observed over a wide concentration window (0.005–5 μM), the lowest limit being at least 40 times lower than human plasma concentrations previously reported as causing serious side effects. 相似文献
102.
103.
Karen Sommerville Maurizio Rossetto Alex Pulkownik 《Wetlands Ecology and Management》2013,21(5):339-351
We investigated the implications of clonality for translocation of Wilsonia backhousei, a threatened, outbreeding, saltmarsh plant with tidally-dispersed fruit. Eight microsatellite loci were used to characterise samples from three estuaries in New South Wales, Australia, and to determine the size and distribution of genetically distinct individuals (genets). Within-population diversity was compared to the presence or absence of seed production using the t test. Ordinal logistic regression was used to investigate the relative influence on seed yield of soil characteristics (soil moisture, salinity, pH) and the number of clonal lineages within a 5 and 10 m radius. Principal coordinate analysis, analysis of molecular variance and Bayesian analysis were used to investigate the extent of gene flow within and among the three estuaries. We found individual genets could cover extensive areas (up to 225 m2) and apparently large populations could consist of only a few individuals. Populations that failed to produce seed had significantly less genetic diversity than populations that produced seed (P = 0.001). Seed yield showed a significant positive response to both increasing soil moisture content (P = 0.003) and increasing genetic diversity in a 5 m radius (P = 0.003). Gene flow was found to occur chiefly within estuaries though occasional longer-distance gene transfer was evident. To maximise adaptive potential in translocated populations of W. backhousei, we recommend sourcing propagules from multiple populations and planting representatives of the different populations in close proximity to facilitate sexual reproduction. These findings are likely to be applicable to other outbreeding clonal saltmarsh plants with tidally-dispersed fruit or seed. 相似文献
104.
Atiqul Islam Maurizio Labbate Steven P. Djordjevic Munirul Alam Aaron Darling Jacqueline Melvold Andrew J. Holmes Fatema T. Johura Alejandro Cravioto Ian G. Charles H. W. Stokes 《Open biology》2013,3(2)
Of the 200+ serogroups of Vibrio cholerae, only O1 or O139 strains are reported to cause cholera, and mostly in endemic regions. Cholera outbreaks elsewhere are considered to be via importation of pathogenic strains. Using established animal models, we show that diverse V. cholerae strains indigenous to a non-endemic environment (Sydney, Australia), including non-O1/O139 serogroup strains, are able to both colonize the intestine and result in fluid accumulation despite lacking virulence factors believed to be important. Most strains lacked the type three secretion system considered a mediator of diarrhoea in non-O1/O13 V. cholerae. Multi-locus sequence typing (MLST) showed that the Sydney isolates did not form a single clade and were distinct from O1/O139 toxigenic strains. There was no correlation between genetic relatedness and the profile of virulence-associated factors. Current analyses of diseases mediated by V. cholerae focus on endemic regions, with only those strains that possess particular virulence factors considered pathogenic. Our data suggest that factors other than those previously well described are of potential importance in influencing disease outbreaks. 相似文献
105.
Marzia Scortegagna Chelsea Ruller Surya K. De Elisa Barile Stan Krajewski Pedro Aza‐Blanc Roy Williams Anthony B. Pinkerton Michael Jackson Lynda Chin Maurizio Pellecchia Marcus Bosenberg Ze'ev A. Ronai 《Pigment cell & melanoma research》2013,26(1):136-142
To date, there are no effective therapies for tumors bearing NRAS mutations, which are present in 15–20% of human melanomas. Here we extend our earlier studies where we demonstrated that the small molecule BI‐69A11 inhibits the growth of melanoma cell lines. Gene expression analysis revealed the induction of interferon‐ and cell death‐related genes that were associated with responsiveness of melanoma cell lines to BI‐69A11. Strikingly, the administration of BI‐69A11 inhibited melanoma development in genetically modified mice bearing an inducible form of activated Nras and a deletion of the Ink4a gene (Nras(Q61K)::Ink4a?/?). Biweekly administration of BI‐69A11 starting at 10 weeks or as late as 24 weeks after the induction of mutant Nras expression inhibited melanoma development (100 and 36%, respectively). BI‐69A11 treatment did not inhibit the development of histiocytic sarcomas, which constitute about 50% of the tumors in this model. BI‐69A11‐resistant Nras(Q61K)::Ink4a?/? tumors exhibited increased CD45 expression, reflective of immune cell infiltration and upregulation of gene networks associated with the cytoskeleton, DNA damage response, and small molecule transport. The ability to attenuate the development of NRAS mutant melanomas supports further development of BI‐69A11 for clinical assessment. 相似文献
106.
Andre F. Marquand Maurizio Filippone John Ashburner Mark Girolami Janaina Mourao-Miranda Gareth J. Barker Steven C. R. Williams P. Nigel Leigh Camilla R. V. Blain 《PloS one》2013,8(7)
Progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and idiopathic Parkinson’s disease (IPD) can be clinically indistinguishable, especially in the early stages, despite distinct patterns of molecular pathology. Structural neuroimaging holds promise for providing objective biomarkers for discriminating these diseases at the single subject level but all studies to date have reported incomplete separation of disease groups. In this study, we employed multi-class pattern recognition to assess the value of anatomical patterns derived from a widely available structural neuroimaging sequence for automated classification of these disorders. To achieve this, 17 patients with PSP, 14 with IPD and 19 with MSA were scanned using structural MRI along with 19 healthy controls (HCs). An advanced probabilistic pattern recognition approach was employed to evaluate the diagnostic value of several pre-defined anatomical patterns for discriminating the disorders, including: (i) a subcortical motor network; (ii) each of its component regions and (iii) the whole brain. All disease groups could be discriminated simultaneously with high accuracy using the subcortical motor network. The region providing the most accurate predictions overall was the midbrain/brainstem, which discriminated all disease groups from one another and from HCs. The subcortical network also produced more accurate predictions than the whole brain and all of its constituent regions. PSP was accurately predicted from the midbrain/brainstem, cerebellum and all basal ganglia compartments; MSA from the midbrain/brainstem and cerebellum and IPD from the midbrain/brainstem only. This study demonstrates that automated analysis of structural MRI can accurately predict diagnosis in individual patients with Parkinsonian disorders, and identifies distinct patterns of regional atrophy particularly useful for this process. 相似文献
107.
Valeria Musella Paolo Verderio James Francis Reid Sara Pizzamiglio Manuela Gariboldi Maurizio Callari Milione Massimo Loris De Cecco Silvia Veneroni Marco Alessandro Pierotti Maria Grazia Daidone 《PloS one》2013,8(1)
Background
Genome-wide gene expression analyses of tumors are a powerful tool to identify gene signatures associated with biologically and clinically relevant characteristics and for several tumor types are under clinical validation by prospective trials. However, handling and processing of clinical specimens may significantly affect the molecular data obtained from their analysis. We studied the effects of tissue handling time on gene expression in human normal and tumor colon tissues undergoing routine surgical procedures.Methods
RNA extracted from specimens of 15 patients at four time points (for a total of 180 samples) after surgery was analyzed for gene expression on high-density oligonucleotide microarrays. A mixed-effects model was used to identify probes with different expression means across the four different time points. The p-values of the model were adjusted with the Bonferroni method.Results
Thirty-two probe sets associated with tissue handling time in the tumor specimens, and thirty-one in the normal tissues, were identified. Most genes exhibited moderate changes in expression over the time points analyzed; however four of them were oncogenes, and two confirmed the effect of tissue handling by independent validation.Conclusions
Our results suggest that a critical time point for tissue handling in colon seems to be 60 minutes at room temperature. Although the number of time-dependent genes we identified was low, the three genes that already showed changes at this time point in tumor samples were all oncogenes, hence recommending standardization of tissue-handling protocols and effort to reduce the time from specimen removal to snap freezing accounting for warm ischemia in this tumor type. 相似文献108.
Nicolò Musner Mariapaola Sidoli Desireè Zambroni Ubaldo Del Carro Daniela Ungaro Maurizio D’Antonio Maria L. Feltri Lawrence Wrabetz 《ASN neuro》2016,8(2)
In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot–Marie–Tooth disease type 1B (CMT1B)–S63del mice. Accumulation of P0S63del in the ER triggers a persistent unfolded protein response. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER stress sensor that phosphorylates eukaryotic initiation factor 2 alpha (eIF2alpha) in order to attenuate protein synthesis. We have shown that increasing phosphophorylated-eIF2alpha (P-eIF2alpha) is a potent therapeutic strategy, improving myelination and motor function in S63del mice. Here, we explore the converse experiment: Perk haploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy. Motor performance and myelin abnormalities improved in S63del//Perk+/− compared with S63del mice. These data suggest that mechanisms other than protein translation might be involved in CMT1B/S63del neuropathy. In addition, Perk deficiency in other cells may contribute to demyelination in a non–Schwann-cell autonomous manner. 相似文献
109.
Irene Cardinali Hovirag Lancioni Andrea Giontella Marco Rosario Capodiferro Stefano Capomaccio Luca Buttazzoni Giovanni Paolo Biggio Raffaele Cherchi Emidio Albertini Anna Olivieri Katia Cappelli Alessandro Achilli Maurizio Silvestrelli 《PloS one》2016,11(4)
BackgroundThe climatic and cultural diversity of the Italian Peninsula triggered, over time, the development of a great variety of horse breeds, whose origin and history are still unclear. To clarify this issue, analyses on phenotypic traits and genealogical data were recently coupled with molecular screening.MethodologyTo provide a comprehensive overview of the horse genetic variability in Italy, we produced and phylogenetically analyzed 407 mitochondrial DNA (mtDNA) control-region sequences from ten of the most important Italian riding horse and pony breeds: Bardigiano, Esperia, Giara, Lipizzan, Maremmano, Monterufolino, Murgese, Sarcidano, Sardinian Anglo-Arab, and Tolfetano. A collection of 36 Arabian horses was also evaluated to assess the genetic consequences of their common use for the improvement of some local breeds.ConclusionsIn Italian horses, all previously described domestic mtDNA haplogroups were detected as well as a high haplotype diversity. These findings indicate that the ancestral local mares harbored an extensive genetic diversity. Moreover, the limited haplotype sharing (11%) with the Arabian horse reveals that its impact on the autochthonous mitochondrial gene pools during the final establishment of pure breeds was marginal, if any. The only significant signs of genetic structure and differentiation were detected in the geographically most isolated contexts (i.e. Monterufolino and Sardinian breeds). Such a geographic effect was also confirmed in a wider breed setting, where the Italian pool stands in an intermediate position together with most of the other Mediterranean stocks. However, some notable exceptions and peculiar genetic proximities lend genetic support to historical theories about the origin of specific Italian breeds. 相似文献
110.
Hans Choi Daniel Conole Darcy J. Atkinson Olivia Laita Morgan Jay‐Smith Mario Angelo Pagano Giovanni Ribaudo Maurizio Cavalli Sergio Bova Brian Hopkins Margaret A. Brimble David Rennison 《化学与生物多样性》2016,13(6):762-775
Norbormide [5‐(α‐hydroxy‐α‐2‐pyridylbenzyl)‐7‐(α‐2‐pyridylbenzylidene)‐5‐norbornene‐2,3‐dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sublethal uptake and accompanying bait shyness. A series of NRB‐derived pro‐toxicants ( 3a – i , 4a – i , and 5a – i ) were prepared in an effort to ‘mask’ this acute response and improve both palatability and efficacy. Their synthesis, in vitro biological evaluation (vasocontractile response in rat vasculature, stability in selected rat media) and palatability/efficacy in Sprague–Dawley, wild Norway, and wild ship rats is described. Most notably, pro‐toxicant 3d was revealed to be free of all pre‐cleavage vasoconstrictory activity in rat caudal artery and was subsequently demonstrated to release NRB in the presence of rat blood, liver, and pancreatic enzymes. Moreover, it consistently displayed a high level of acceptance by rats in a two‐choice bait‐palatability and efficacy trial, with accompanying high mortality. On this evidence, fatty acid ester prodrugs would appear to offer a promising platform for the further development of NRB‐derived toxicants with enhanced palatability and efficacy profiles. 相似文献