全文获取类型
收费全文 | 4524篇 |
免费 | 328篇 |
专业分类
4852篇 |
出版年
2023年 | 26篇 |
2022年 | 67篇 |
2021年 | 128篇 |
2020年 | 79篇 |
2019年 | 96篇 |
2018年 | 132篇 |
2017年 | 107篇 |
2016年 | 175篇 |
2015年 | 253篇 |
2014年 | 265篇 |
2013年 | 369篇 |
2012年 | 407篇 |
2011年 | 388篇 |
2010年 | 236篇 |
2009年 | 234篇 |
2008年 | 301篇 |
2007年 | 252篇 |
2006年 | 216篇 |
2005年 | 224篇 |
2004年 | 200篇 |
2003年 | 183篇 |
2002年 | 145篇 |
2001年 | 28篇 |
2000年 | 15篇 |
1999年 | 24篇 |
1998年 | 23篇 |
1997年 | 28篇 |
1996年 | 29篇 |
1995年 | 23篇 |
1994年 | 24篇 |
1993年 | 14篇 |
1992年 | 20篇 |
1991年 | 15篇 |
1990年 | 9篇 |
1989年 | 10篇 |
1988年 | 4篇 |
1987年 | 7篇 |
1986年 | 4篇 |
1985年 | 12篇 |
1984年 | 14篇 |
1983年 | 3篇 |
1982年 | 8篇 |
1981年 | 9篇 |
1980年 | 7篇 |
1979年 | 7篇 |
1978年 | 3篇 |
1977年 | 9篇 |
1976年 | 4篇 |
1975年 | 3篇 |
1974年 | 3篇 |
排序方式: 共有4852条查询结果,搜索用时 15 毫秒
91.
Alessandro Ghezzo Paola Visconti Provvidenza M. Abruzzo Alessandra Bolotta Carla Ferreri Giuseppe Gobbi Gemma Malisardi Stefano Manfredini Marina Marini Laura Nanetti Emanuela Pipitone Francesca Raffaelli Federica Resca Arianna Vignini Laura Mazzanti 《PloS one》2013,8(6)
It has been suggested that oxidative stress may play a role in the pathogenesis of Autism Spectrum Disorders (ASD), but the literature reports somewhat contradictory results. To further investigate the issue, we evaluated a high number of peripheral oxidative stress parameters, and some related issues such as erythrocyte membrane functional features and lipid composition. Twenty-one autistic children (Au) aged 5 to 12 years, were gender and age-matched with 20 typically developing children (TD). Erythrocyte thiobarbituric acid reactive substances, urinary isoprostane and hexanoyl-lysine adduct levels were elevated in Au, thus confirming the occurrence of an imbalance of the redox status of Au, whilst other oxidative stress markers or associated parameters (urinary 8-oxo-dG, plasma radical absorbance capacity and carbonyl groups, erythrocyte superoxide dismutase and catalase activities) were unchanged. A very significant reduction of Na+/K+-ATPase activity (−66%, p<0.0001), a reduction of erythrocyte membrane fluidity and alteration in erythrocyte fatty acid membrane profile (increase in monounsaturated fatty acids, decrease in EPA and DHA-ω3 with a consequent increase in ω6/ω3 ratio) were found in Au compared to TD, without change in membrane sialic acid content. Some Au clinical features appear to be correlated with these findings; in particular, hyperactivity score appears to be related with some parameters of the lipidomic profile and membrane fluidity. Oxidative stress and erythrocyte membrane alterations may play a role in the pathogenesis of ASD and prompt the development of palliative therapeutic protocols. Moreover, the marked decrease in NKA could be potentially utilized as a peripheral biomarker of ASD. 相似文献
92.
Elisa Bellucci Elena Bitocchi Domenico Rau Laura Nanni Nicoletta Ferradini Alessandro Giardini Monica Rodriguez Giovanna Attene Roberto Papa 《PloS one》2013,8(12)
Landraces are heterogeneous plant varieties that are reproduced by farmers as populations that are subject to both artificial and natural selection. Landraces are distinguished by farmers due to their specific traits, and different farmers often grow different populations of the same landrace. We used simple sequence repeats (SSRs) to analyse 12 barley landrace populations from Sardinia from two collections spanning 10 years. We analysed the population structure, and compared the population diversity of the landraces that were collected at field level (population). We used a representative pool of barley varieties for diversity comparisons and to analyse the effects of gene flow from modern varieties. We found that the Sardinian landraces are a distinct gene pool from those of both two-row and six-row barley varieties. There is also a low, but significant, mean level and population-dependent level of introgression from the modern varieties into the Sardinian landraces. Moreover, we show that the Sardinian landraces have the same level of gene diversity as the representative sample of modern commercial varieties grown in Italy in the last decades, even within population level. Thus, these populations represent crucial sources of germplasm that will be useful for crop improvement and for population genomics studies and association mapping, to identify genes, loci and genome regions responsible for adaptive variations. Our data also suggest that landraces are a source of valuable germplasm for sustainable agriculture in the context of future climate change, and that in-situ conservation strategies based on farmer use can preserve the genetic identity of landraces while allowing adaptation to local environments. 相似文献
93.
Laura Pasin Giovanni Landoni Maria Lourdes Castro Luca Cabrini Alessandro Belletti Paolo Feltracco Gabriele Finco Andrea Carozzo Roberto Chiesa Alberto Zangrillo 《PloS one》2013,8(12)
Objective
Statins are among the most prescribed drugs worldwide and their recently discovered anti-inflammatory effect seems to have an important role in inhibiting proinflammatory cytokine production, chemokines expression and counteracting the harmful effects of sepsis on the coagulation system. We decided to perform a meta-analysis of all randomized controlled trials ever published on statin therapy in septic patients to evaluate their effect on survival and length of hospital stay.Data sources and study selection
Articles were assessed by four trained investigators, with divergences resolved by consensus. BioMedCentral, PubMed, Embase and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocation to treatment and comparison of statins versus any comparator in septic patients.Data extraction and synthesis
Data from 650 patients in 5 randomized controlled studies were analyzed. No difference in mortality between patients receiving statins versus control (44/322 [14%] in the statins group vs 50/328 [15%] in the control arm, RR = 0.90 [95% CI 0.65 to 1.26], p = 0.6) was observed. No differences in hospital stay (p = 0.7) were found.Conclusions
Published data show that statin therapy has no effect on mortality in the overall population of adult septic patients. Scientific evidence on statins role in septic patients is still limited and larger randomized trials should be performed on this topic. 相似文献94.
Alessandro Tanca Antonio Palomba Massimo Deligios Tiziana Cubeddu Cristina Fraumene Grazia Biosa Daniela Pagnozzi Maria Filippa Addis Sergio Uzzau 《PloS one》2013,8(12)
Metaproteomics enables the investigation of the protein repertoire expressed by complex microbial communities. However, to unleash its full potential, refinements in bioinformatic approaches for data analysis are still needed. In this context, sequence databases selection represents a major challenge.This work assessed the impact of different databases in metaproteomic investigations by using a mock microbial mixture including nine diverse bacterial and eukaryotic species, which was subjected to shotgun metaproteomic analysis. Then, both the microbial mixture and the single microorganisms were subjected to next generation sequencing to obtain experimental metagenomic- and genomic-derived databases, which were used along with public databases (namely, NCBI, UniProtKB/SwissProt and UniProtKB/TrEMBL, parsed at different taxonomic levels) to analyze the metaproteomic dataset. First, a quantitative comparison in terms of number and overlap of peptide identifications was carried out among all databases. As a result, only 35% of peptides were common to all database classes; moreover, genus/species-specific databases provided up to 17% more identifications compared to databases with generic taxonomy, while the metagenomic database enabled a slight increment in respect to public databases. Then, database behavior in terms of false discovery rate and peptide degeneracy was critically evaluated. Public databases with generic taxonomy exhibited a markedly different trend compared to the counterparts. Finally, the reliability of taxonomic attribution according to the lowest common ancestor approach (using MEGAN and Unipept software) was assessed. The level of misassignments varied among the different databases, and specific thresholds based on the number of taxon-specific peptides were established to minimize false positives. This study confirms that database selection has a significant impact in metaproteomics, and provides critical indications for improving depth and reliability of metaproteomic results. Specifically, the use of iterative searches and of suitable filters for taxonomic assignments is proposed with the aim of increasing coverage and trustworthiness of metaproteomic data. 相似文献
95.
David Leaper Christian Münter Sylvie Meaume Alessandro Scalise Nacho Blanes Mompó Birte Petersen Jakobsen Finn Gottrup 《PloS one》2013,8(7)
Background
Venous leg ulcers are common, troublesome, and their failure to heal is often related to a heavy bio-burden. Ionized silver has both anti-inflammatory and antimicrobial properties. The ulcer healing properties of the silver releasing foam dressing Biatain Ag has been examined in 4 randomized controlled trials (RCTs).Aim
To evaluate ulcer healing through a meta-analytic approach after treatment with either Biatain Ag or a non-active dressing.Patients and Methods
685 subjects with pure or mixed hard-to-heal venous leg ulcers were included in the meta-analysis.Results
Biatain Ag showed a significant treatment effect (p<0.0001), responder rate (p<0.001), and healing rate (p = 0.002).Conclusion
The meta-analysis of the 4 RCTs provided statistical significant evidence to support the use of Biatain Ag dressing in treatment of hard-to-heal venous leg ulcers. 相似文献96.
MicroRNA-486-3p Regulates γ-Globin Expression in Human Erythroid Cells by Directly Modulating BCL11A
Valentina Lulli Paolo Romania Ornella Morsilli Paolo Cianciulli Marco Gabbianelli Ugo Testa Alessandro Giuliani Giovanna Marziali 《PloS one》2013,8(4)
MicroRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of mRNAs target. The functional relevance of microRNAs has been proven in normal and malignant hematopoiesis. While analyzing miRNAs expression profile in unilineage serum-free liquid suspension unilineage cultures of peripheral blood CD34+ hematopoietic progenitor cells (HPCs) through the erythroid, megakaryocytic, granulocytic and monocytic pathways, we identified miR-486-3p as mainly expressed within the erythroid lineage. We showed that miR-486-3p regulates BCL11A expression by binding to the extra-long isoform of BCL11A 3′UTR. Overexpression of miR-486-3p in erythroid cells resulted in reduced BCL11A protein levels, associated to increased expression of γ-globin gene, whereas inhibition of physiological miR-486-3p levels increased BCL11A and, consequently, reduced γ-globin expression. Thus, miR-486-3p regulating BCL11A expression might contributes to fetal hemoglobin (HbF) modulation and arise the question as to what extent this miRNA might contribute to different HbF levels observed among β-thalassemia patients. Erythroid cells, differentiated from PB CD34+ cells of a small cohort of patients affected by major or intermedia β-thalassemia, showed miR-486-3p levels significantly higher than those observed in normal counterpart. Importantly, in these patients, miR-486-3p expression correlates with increased HbF synthesis. Thus, our data indicate that miR-486-3p might contribute to different HbF levels observed among thalassemic patients and, possibly, to the clinical severity of the disease. 相似文献
97.
Thorsten Klampfl Jelena D. Milosevic Ana Puda Andreas Sch?negger Klaudia Bagienski Tiina Berg Ashot S. Harutyunyan Bettina Gisslinger Elisa Rumi Luca Malcovati Daniela Pietra Chiara Elena Matteo Giovanni Della Porta Lisa Pieri Paola Guglielmelli Christoph Bock Michael Doubek Dana Dvorakova Nada Suvajdzic Dragica Tomin Natasa Tosic Zdenek Racil Michael Steurer Sonja Pavlovic Alessandro M. Vannucchi Mario Cazzola Heinz Gisslinger Robert Kralovics 《PloS one》2013,8(10)
Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized. 相似文献
98.
Mattia Falconi Federico Iacovelli Alessandro Desideri 《Journal of molecular modeling》2013,19(9):3695-3704
Familial amyotrophic lateral sclerosis caused by mutations in copper-zinc superoxide dismutase (SOD1) is characterized by the presence of SOD1-rich inclusions in spinal cords. It has been shown that a reduced intra-subunit disulfide bridge apo-SOD1 can rapidly initiate fibrillation forming an inter-subunits disulfide under mild, physiologically accessible conditions. Once initiated, elongation can proceed via recruitment of either apo or partially metallated disulfide-intact SOD1 and the presence of copper, but not zinc, ions inhibit fibrillation. We propose a structural model, refined through molecular dynamics simulations, that, taking into account these experimental findings, provides a molecular explanation for the initiation and the elongation of SOD1 fibrils in physiological conditions. The model indicates the occurrence of a new dimeric unit, prone to interact one with the other due to the presence of a wide hydrophobic surface and specific electrostatic interactions. The model has dimensions consistent with the SOD1 fibril size observed through electron microscopy and provides a structural basis for the understanding of SOD1 fibrillation. Figure
ALS-linked superoxide dismutase fibrils 相似文献
99.
Massimo Collino Mara Rogazzo Alessandro Pini Elisa Benetti Arianna Carolina Rosa Fausto Chiazza Roberto Fantozzi Daniele Bani Emanuela Masini 《Journal of cellular and molecular medicine》2013,17(11):1494-1505
Although recent preclinical and clinical studies have demonstrated that recombinant human relaxin (rhRLX) may have important therapeutic potential in acute heart failure and chronic kidney diseases, the effects of acute rhRLX administration against renal ischaemia/reperfusion (I/R) injury have never been investigated. Using a rat model of 1‐hr bilateral renal artery occlusion followed by 6‐hr reperfusion, we investigated the effects of rhRLX (5 μg/Kg i.v.) given both at the beginning and after 3 hrs of reperfusion. Acute rhRLX administration attenuated the functional renal injury (increase in serum urea and creatinine), glomerular dysfunction (decrease in creatinine clearance) and tubular dysfunction (increase in urinary excretion of N‐acetyl‐β‐glucosaminidase) evoked by renal I/R. These beneficial effects were accompanied by a significant reduction in local lipid peroxidation, free radical‐induced DNA damage and increase in the expression/activity of the endogenous antioxidant enzymes Mn‐ and CuZn‐superoxide dismutases (SOD). Furthermore, rhRLX administration attenuated the increase in leucocyte activation, as suggested by inhibition of myeloperoxidase activity, intercellular‐adhesion‐molecule‐1 expression, interleukin (IL)‐1β, IL‐18 and tumour necrosis factor‐α production as well as increase in IL‐10 production. Interestingly, the reduced oxidative stress status and neutrophil activation here reported were associated with rhRLX‐induced activation of endothelial nitric oxide synthase and up‐regulation of inducible nitric oxide synthase, possibly secondary to activation of Akt and the extracellular signal‐regulated protein kinase (ERK) 1/2, respectively. Thus, we report herein that rhRLX protects the kidney against I/R injury by a mechanism that involves changes in nitric oxide signalling pathway. 相似文献
100.
Luigi Ornano Alessandro Venditti Mauro Ballero Cinzia Sanna Luana Quassinti Massimo Bramucci Giulio Lupidi Fabrizio Papa Sauro Vittori Filippo Maggi Armanodoriano Bianco 《化学与生物多样性》2013,10(8):1464-1474
The essential oils of Artemisia arborescens growing in Sardinia (Italy), collected during three plant growth stages, i.e., from the vegetative stage to post‐blooming time, were characterized. Moreover, the in vitro antiproliferative and antioxidant activities of the oil isolated from aerial parts collected in February were evaluated. The essential oils belonged to the β‐thujone/chamazulene chemotype, notably with the highest amount of chamazulene (ca. 52%) ever detected up to now in the genus Artemisia and, in general, in essential oils. Quantitative variations in the oil composition were observed as the plant passes from the vegetative to the blooming stage. The oil was tested for its potential tumor cell growth‐inhibitory effect on T98G, MDA‐MB 435S, A375, and HCT116 human cell lines, using the MTT (=3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide) assay. The highest activity was observed on A375 and HCT116 cell lines, with IC50 values of 14 μg/ml. Moreover, the in vitro antioxidant and free radical‐scavenging assays revealed the oil to be an effective scavenger of the ABTS radical cation, with an activity comparable to that of Trolox®. These results support the use of A. arborescens oil for the treatment of inflamed skin conditions. Finally, the composition of the polar fraction of the A. arborescens aerial parts was also examined, and the main component detected was 5‐O‐caffeoylquinic acid, which was identified for the first time in this plant. 相似文献