全文获取类型
收费全文 | 1399篇 |
免费 | 117篇 |
国内免费 | 1篇 |
出版年
2022年 | 8篇 |
2021年 | 28篇 |
2020年 | 21篇 |
2019年 | 22篇 |
2018年 | 23篇 |
2017年 | 22篇 |
2016年 | 35篇 |
2015年 | 63篇 |
2014年 | 75篇 |
2013年 | 89篇 |
2012年 | 102篇 |
2011年 | 89篇 |
2010年 | 77篇 |
2009年 | 70篇 |
2008年 | 93篇 |
2007年 | 88篇 |
2006年 | 71篇 |
2005年 | 71篇 |
2004年 | 66篇 |
2003年 | 71篇 |
2002年 | 47篇 |
2001年 | 6篇 |
2000年 | 5篇 |
1998年 | 13篇 |
1997年 | 13篇 |
1995年 | 5篇 |
1992年 | 5篇 |
1988年 | 6篇 |
1986年 | 5篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1983年 | 7篇 |
1982年 | 6篇 |
1980年 | 5篇 |
1979年 | 7篇 |
1978年 | 7篇 |
1976年 | 5篇 |
1973年 | 6篇 |
1969年 | 5篇 |
1967年 | 5篇 |
1965年 | 7篇 |
1962年 | 6篇 |
1956年 | 6篇 |
1938年 | 4篇 |
1936年 | 5篇 |
1927年 | 7篇 |
1926年 | 4篇 |
1920年 | 5篇 |
1917年 | 4篇 |
1908年 | 5篇 |
排序方式: 共有1517条查询结果,搜索用时 31 毫秒
921.
Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants 总被引:1,自引:0,他引:1
Pinto D Darvishi K Shi X Rajan D Rigler D Fitzgerald T Lionel AC Thiruvahindrapuram B Macdonald JR Mills R Prasad A Noonan K Gribble S Prigmore E Donahoe PK Smith RS Park JH Hurles ME Carter NP Lee C Scherer SW Feuk L 《Nature biotechnology》2011,29(6):512-520
We have systematically compared copy number variant (CNV) detection on eleven microarrays to evaluate data quality and CNV calling, reproducibility, concordance across array platforms and laboratory sites, breakpoint accuracy and analysis tool variability. Different analytic tools applied to the same raw data typically yield CNV calls with <50% concordance. Moreover, reproducibility in replicate experiments is <70% for most platforms. Nevertheless, these findings should not preclude detection of large CNVs for clinical diagnostic purposes because large CNVs with poor reproducibility are found primarily in complex genomic regions and would typically be removed by standard clinical data curation. The striking differences between CNV calls from different platforms and analytic tools highlight the importance of careful assessment of experimental design in discovery and association studies and of strict data curation and filtering in diagnostics. The CNV resource presented here allows independent data evaluation and provides a means to benchmark new algorithms. 相似文献
922.
Mayola E Gallerne C Esposti DD Martel C Pervaiz S Larue L Debuire B Lemoine A Brenner C Lemaire C 《Apoptosis : an international journal on programmed cell death》2011,16(10):1014-1027
A high resistance and heterogeneous response to conventional anti-cancer chemotherapies characterize malignant cutaneous melanoma,
the most aggressive and deadly form of skin cancer. Withaferin A (WFA), a withanolide derived from the medicinal plant Withania somnifera, has been reported for its anti-tumorigenic activity against various cancer cells. For the first time, we examined the death-inducing
potential of WFA against a panel of four different human melanoma cells and investigated the cellular mechanisms involved.
WFA induces apoptotic cell death with various IC50 ranging from 1.8 to 6.1 μM. The susceptibility of cells toward WFA-induced apoptosis correlated with low Bcl-2/Bax and Bcl-2/Bim
ratios. In all cell lines, the apoptotic process triggered by WFA involves the mitochondrial pathway and was associated with
Bcl-2 down regulation, Bax mitochondrial translocation, cytochrome c release into the cytosol, transmembrane potential (ΔΨm) dissipation, caspase 9 and caspase 3 activation and DNA fragmentation.
WFA cytotoxicity requires early reactive oxygen species (ROS) production and glutathione depletion, the inhibition of ROS
increase by the antioxidant N-acetylcysteine resulting in complete suppression of mitochondrial and nuclear events. Altogether, these results support the
therapeutic potential of WFA against human melanoma. 相似文献
923.
Markham JE Molino D Gissot L Bellec Y Hématy K Marion J Belcram K Palauqui JC Satiat-Jeunemaître B Faure JD 《The Plant cell》2011,23(6):2362-2378
Sphingolipids are a class of structural membrane lipids involved in membrane trafficking and cell polarity. Functional analysis of the ceramide synthase family in Arabidopsis thaliana demonstrates the existence of two activities selective for the length of the acyl chains. Very-long-acyl-chain (C > 18 carbons) but not long-chain sphingolipids are essential for plant development. Reduction of very-long-chain fatty acid sphingolipid levels leads in particular to auxin-dependent inhibition of lateral root emergence that is associated with selective aggregation of the plasma membrane auxin carriers AUX1 and PIN1 in the cytosol. Defective targeting of polar auxin carriers is characterized by specific aggregation of Rab-A2(a)- and Rab-A1(e)-labeled early endosomes along the secretory pathway. These aggregates correlate with the accumulation of membrane structures and vesicle fragmentation in the cytosol. In conclusion, sphingolipids with very long acyl chains define a trafficking pathway with specific endomembrane compartments and polar auxin transport protein cargoes. 相似文献
924.
Hegseth MN Camus L Helgason LB Bocchetti R Gabrielsen GW Regoli F 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2011,154(1):28-35
The efficiency of antioxidant defenses and relationship with body burden of metal and organic contaminants has not been previously investigated in arctic seabirds, neither in chicks nor in adults. The objective of this study was to compare such defenses in chicks from three species, Black-legged kittiwake (Rissa tridactyla), Northern fulmar (Fulmarus glacialis), and Herring gull (Larus argentatus), and the relationship with tissue concentrations of essential metals such as selenium and iron and halogenated organic compounds, represented by polychlorinated biphenyl (PCB). The results showed significant species-specific differences in the antioxidant responses which also corresponded with metal and PCB levels in different ways. The capability to neutralize hydroxyl radicals (TOSC-HO?) and the activities of catalase and Se-dependent glutathione peroxidases (GPX) clearly increased in species with the higher levels of metals and PCBs, while the opposite trend was observed for Se-independent GPX, TOSC against peroxyl radicals (ROO?) and peroxynitrite (ONOOH). Less clear relationships were obtained for glutathione levels, GSH/GSSG ratio, glutathione reductase and superoxide dismutase. The results showed differences in antioxidant efficiency between the species, and some of these defenses exhibited dose-response-like relationships with measured levels of selenium, iron and ΣPCBs. PCBs, selenium and iron levels were positively related to the responses of antioxidants with potential to reduce HO?/H?O? (Se-dependent GPX, CAT and TOSC against HO?). However, direct causal relationships between antioxidant responses and contaminant concentrations could not be shown on individual level. Varying levels of metals and contaminants due to different diet and age were probably the main explanations for the species differences in antioxidant defense. 相似文献
925.
Kahn JE Dutoit-Lefevre V Duban-Deweer S Chafey P Pottiez G Lefranc D Fain O Cordier JF Hatron PY Bletry O Prin L 《Journal of proteome research》2011,10(4):1468-1480
The FIP1L1-PDGFRA (F/P) fusion gene, which was identified as a recurrent molecular finding in hypereosinophilic syndrome (HES), lead to a constitutively increased tyrosine kinase activity of the fusion protein. Despite data obtained in animals or cell lines models, the mechanisms underlying the predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. To define more precisely intrinsic molecular events associated with F/P gene, we performed a proteomic analysis comparing F/P+ eosinophils (F/P-Eos) and eosinophils from healthy donors (C-Eos). Using 2D-DIGE and mass spectrometry techniques, we identified 41 proteins significantly overexpressed between F/P-Eos and C-Eos. Among them, 17.8% belonged to the oxidoreductase family. We further observed a down-expression of peroxiredoxin-2 (PRX-2) and an overexpression of src-homology-2 domain containing tyrosine phosphatase (SHP-1), enzymes regulating PDGFR downstream pathways, and especially intracellular reactive oxygen species (ROS) production. This profile, confirmed in immunoblot analysis, appears specific to F/P-Eos compared to controls and patients with idiopathic HES. In this clonal disorder possibly involving a pluripotent hematopoietic stem cell, we postulate that the well documented relationships between PDGFRA downstream signals and intracellular ROS levels might influence the phenotype of this leukemia. 相似文献
926.
Theory and research suggest that the transition to parenthood is a major life transition, and that adaptation to the parenting role is influenced by a complex set of factors, including the relationship with the child's mother, family of origin, and how the father is situated within sociocultural contexts. The father–]mother relationship is particularly important for men making the transition to fatherhood. This study examined patterns of fathering among young fathers (15–24 years) and investigated how fathers' relationships with the mothers of their young children (infants and toddlers) were related to fathering. In general, higher quality father–mother relationships were related to greater father involvement with children; when mothers were perceived as barriers to involved fathering fathers also had less accurate and adaptive parenting knowledge, attitudes, and behavior. Person-centered analyses revealed quite complex relations between father–mother relationships and father–child interaction. One pattern showed strong positive father–mother relationships associated with a disengaged pattern of father–child interaction, while another pattern showed sensitive and positive father–child engagement in the context of negative or distant father–mother relationships. Four patterns of association between fathering and mother–father relationships were demonstrated. Results highlight the complexity of understanding fathering and family relationships among young fathers. 相似文献
927.
928.
Charlotte Lombardi Maya Ayach Lionel Beaurepaire Mélanie Chenon Jessica Andreani Rapha?l Guerois Isabelle Jupin Stéphane Bressanelli 《PLoS pathogens》2013,9(8)
Turnip yellow mosaic virus (TYMV) - a member of the alphavirus-like supergroup of viruses - serves as a model system for positive-stranded RNA virus membrane-bound replication. TYMV encodes a precursor replication polyprotein that is processed by the endoproteolytic activity of its internal cysteine proteinase domain (PRO). We recently reported that PRO is actually a multifunctional enzyme with a specific ubiquitin hydrolase (DUB) activity that contributes to viral infectivity. Here, we report the crystal structure of the 150-residue PRO. Strikingly, PRO displays no homology to other processing proteinases from positive-stranded RNA viruses, including that of alphaviruses. Instead, the closest structural homologs of PRO are DUBs from the Ovarian tumor (OTU) family. In the crystal, one molecule''s C-terminus inserts into the catalytic cleft of the next, providing a view of the N-terminal product complex in replication polyprotein processing. This allows us to locate the specificity determinants of PRO for its proteinase substrates. In addition to the catalytic cleft, at the exit of which the active site is unusually pared down and solvent-exposed, a key element in molecular recognition by PRO is a lobe N-terminal to the catalytic domain. Docking models and the activities of PRO and PRO mutants in a deubiquitylating assay suggest that this N-terminal lobe is also likely involved in PRO''s DUB function. Our data thus establish that DUBs can evolve to specifically hydrolyze both iso- and endopeptide bonds with different sequences. This is achieved by the use of multiple specificity determinants, as recognition of substrate patches distant from the cleavage sites allows a relaxed specificity of PRO at the sites themselves. Our results thus shed light on how such a compact protein achieves a diversity of key functions in viral genome replication and host-pathogen interaction. 相似文献
929.
Binh Phuong Nhan Nguyen Nanjundan Ashok Kumar Joël Gaubicher Florence Duclairoir Thierry Brousse Olivier Crosnier Lionel Dubois Gérard Bidan Dominique Guyomard Bernard Lestriez 《Liver Transplantation》2013,3(10):1351-1357
Reduced graphene oxide (rGO) is used as a conductive additive for nanosilicon‐based lithium battery anodes with the high active‐mass loading typically required for industrial applications. In contrast to conventional Si electrodes that use acetylene black (AcB) as an additive, the rGO system shows pronounced improvement of electrochemical performance, irrespective of the cycling conditions. With capacity limitation, the rGO system results in improved coulombic efficiency (99.9%) and longer cycle life than conventional electrodes. Upon cycling without capacity limitation, much higher discharge capacity is maintained (2000 mAh g?1 after 100 cycles for 2.5 mg of Si cm?2). Used in conjunction with the bridging carboxymethyl cellulose binder, the crumpled and resilient rGO allows highly reversible functioning of the electrode in which the Si particles repeatedly inflate and deflate upon alloying and dealloying with lithium. 相似文献
930.
Azza Gramoun Lindsey A Crowe Lionel Maurizi Wolfgang Wirth Frank Tobalem Kerstin Grosdemange Geraldine Coullerez Felix Eckstein Marije I Koenders Wim B Van den Berg Heinrich Hofmann Jean-Paul Vallée 《Arthritis research & therapy》2014,16(3):R131