全文获取类型
收费全文 | 2537篇 |
免费 | 320篇 |
国内免费 | 1篇 |
出版年
2023年 | 17篇 |
2022年 | 37篇 |
2021年 | 72篇 |
2020年 | 50篇 |
2019年 | 44篇 |
2018年 | 72篇 |
2017年 | 46篇 |
2016年 | 98篇 |
2015年 | 146篇 |
2014年 | 142篇 |
2013年 | 155篇 |
2012年 | 153篇 |
2011年 | 138篇 |
2010年 | 92篇 |
2009年 | 93篇 |
2008年 | 98篇 |
2007年 | 136篇 |
2006年 | 98篇 |
2005年 | 93篇 |
2004年 | 76篇 |
2003年 | 76篇 |
2002年 | 92篇 |
2001年 | 77篇 |
2000年 | 65篇 |
1999年 | 61篇 |
1998年 | 27篇 |
1997年 | 31篇 |
1996年 | 20篇 |
1995年 | 19篇 |
1994年 | 27篇 |
1993年 | 12篇 |
1992年 | 53篇 |
1991年 | 36篇 |
1990年 | 35篇 |
1989年 | 43篇 |
1988年 | 20篇 |
1987年 | 29篇 |
1986年 | 27篇 |
1985年 | 25篇 |
1984年 | 37篇 |
1983年 | 22篇 |
1982年 | 24篇 |
1981年 | 17篇 |
1979年 | 12篇 |
1978年 | 18篇 |
1977年 | 15篇 |
1976年 | 8篇 |
1975年 | 11篇 |
1973年 | 14篇 |
1970年 | 8篇 |
排序方式: 共有2858条查询结果,搜索用时 31 毫秒
921.
The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs 总被引:2,自引:0,他引:2
Tenev T Bianchi K Darding M Broemer M Langlais C Wallberg F Zachariou A Lopez J MacFarlane M Cain K Meier P 《Molecular cell》2011,43(3):432-448
A better understanding of the mechanisms through which anticancer drugs exert their effects is essential to improve combination therapies. While studying how genotoxic stress kills cancer cells, we discovered a large ~2MDa cell death-inducing platform, referred to as "Ripoptosome." It contains the core components RIP1, FADD, and caspase-8, and assembles in response to genotoxic stress-induced depletion of XIAP, cIAP1 and cIAP2. Importantly, it forms independently of TNF, CD95L/FASL, TRAIL, death-receptors, and mitochondrial pathways. It also forms upon Smac-mimetic (SM) treatment without involvement of autocrine TNF. Ripoptosome assembly requires RIP1's kinase activity and can stimulate caspase-8-mediated apoptosis as well as caspase-independent necrosis. It is negatively regulated by FLIP, cIAP1, cIAP2, and XIAP. Mechanistically, IAPs target components of this complex for ubiquitylation and inactivation. Moreover, we find that etoposide-stimulated Ripoptosome formation converts proinflammatory cytokines into prodeath signals. Together, our observations shed new light on fundamental mechanisms by which chemotherapeutics may kill cancer cells. 相似文献
922.
Lopez RM Casa DJ Jensen KA DeMartini JK Pagnotta KD Ruiz RC Roti MW Stearns RL Armstrong LE Maresh CM 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(11):2944-2954
The purpose of this study was to determine the effects of dehydration at a controlled relative intensity on physiological responses and trail running speed. Using a randomized, controlled crossover design in a field setting, 14 male and female competitive, endurance runners aged 30 ± 10.4 years completed 2 (hydrated [HY] and dehydrated [DHY]) submaximal trail runs in a warm environment. For each trial, the subjects ran 3 laps (4 km per lap) on trails with 4-minute rests between laps. The DHY were fluid restricted 22 hours before the trial and during the run. The HY arrived euhydrated and were given water during rest breaks. The subjects ran at a moderate pace matched between trials by providing pacing feedback via heart rate (HR) throughout the second trial. Gastrointestinal temperature (T(GI)), HR, running time, and ratings of perceived exertion (RPE) were monitored. Percent body mass (BM) losses were significantly greater for DHY pretrial (-1.65 ± 1.34%) than for HY (-0.03 ± 1.28%; p < 0.001). Posttrial, DHY BM losses (-3.64 ± 1.33%) were higher than those for HY (-1.38 ± 1.43%; p < 0.001). A significant main effect of T(GI) (p = 0.009) was found with DHY having higher T(GI) postrun (DHY: 39.09 ± 0.45°C, HY: 38.71 ± 0.45°C; p = 0.030), 10 minutes post (DHY: 38.85 ± 0.48°C, HY: 38.46 ± 0.46°C; p = 0.009) and 30 minutes post (DHY: 38.18 ± 0.41°C, HY: 37.60 ± 0.25°C; p = 0.000). The DHY had slower run times after lap 2 (p = 0.019) and lap 3 (p = 0.025). The DHY subjects completed the 12-km run 99 seconds slower than the HY (p = 0.027) subjects did. The RPE in DHY was slightly higher than that in HY immediately postrun (p = 0.055). Controlling relative intensity in hypohydrated runners resulted in slower run times, greater perceived effort, and elevated T(GI), which is clinically meaningful for athletes using HR as a gauge for exercise effort and performance. 相似文献
923.
Fugier C Klein AF Hammer C Vassilopoulos S Ivarsson Y Toussaint A Tosch V Vignaud A Ferry A Messaddeq N Kokunai Y Tsuburaya R de la Grange P Dembele D Francois V Precigout G Boulade-Ladame C Hummel MC Lopez de Munain A Sergeant N Laquerrière A Thibault C Deryckere F Auboeuf D Garcia L Zimmermann P Udd B Schoser B Takahashi MP Nishino I Bassez G Laporte J Furling D Charlet-Berguerand N 《Nature medicine》2011,17(6):720-725
Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy. 相似文献
924.
925.
Hesling C Fattet L Teyre G Jury D Gonzalo P Lopez J Vanbelle C Morel AP Gillet G Mikaelian I Rimokh R 《EMBO reports》2011,12(7):665-672
TGF-β is a potent inducer of epithelial-to-mesenchymal transition (EMT), a process involved in tumour invasion. TIF1γ participates in TGF-β signalling. To understand the role of TIF1γ in TGF-β signalling and its requirement for EMT, we analysed the TGF-β1 response of human mammary epithelial cell lines. A strong EMT increase was observed in TIF1γ-silenced cells after TGF-β1 treatment, whereas Smad4 inactivation completely blocked this process. Accordingly, the functions of several TIF1γ target genes can be linked to EMT, as shown by microarray analysis. As a negative regulator of Smad4, TIF1γ could be crucial for the regulation of TGF-β signalling. Furthermore, TIF1γ binds to and represses the plasminogen activator inhibitor 1 promoter, demonstrating a direct role of TIF1γ in TGF-β-dependent gene expression. This study shows the molecular relationship between TIF1γ and Smad4 in TGF-β signalling and EMT. 相似文献
926.
927.
Jose Luis Lopez Concepcion Pérez Catalina Marquez Patricia Cabrera Jose Maria Perez Gema Lucia Ramirez Rafael Ordo?ez Juan Manuel Praena-Fernandez Maria Jose Ortiz 《Reports of Practical Oncology and Radiotherapy》2011,16(5):163-169
Background
Attempts to improve survival outcomes of patients with high risk Ewing''s sarcoma (ES) have focused on chemotherapy dose intensification strategies.Aim
The objective of this study is to retrospectively evaluate clinical characteristics and outcome of pediatric patients with high risk ES treated at a single institution.Materials and methods
From 1995 to 2008, seventeen patients (male:female, 14:3) were treated with dose-intensive therapy in our institution. Median age at diagnosis was 10 years (range: 2–15). Seven patients had metastases at diagnosis (lung in 6 cases and bone in one case). Eleven patients presented with unresectable disease. Fifteen (88.2%) received the Spanish Society of Pediatric Oncology protocol which includes six cycles of vincristine, doxorubicin, ifosfamide and etoposide. Two out of the six cases that were resectable received postoperative radiation. In addition, eleven patients received definitive radiation therapy. Finally, twelve (70.5%) out of 17 patients received myeloablative therapy with melphalan/etoposide. The rest of patients (N = 5) received busulfan/melphalan.Results
Median follow-up was 78 months (range: 15–155 months). Initial responses were complete in all patients, but 9 of them developed progression disease. Seven patients became long-term event-free survivors. No patient died of toxicity after transplantation. The 2- and 5-year overall survival rates for all patients were 93% and 73%, respectively. Event-free survival rates were 74% and 54% at 2 and 5 years, respectively.Conclusion
This single-institution experience suggests that myeloablative therapy against high risk ES is effective and safe. 相似文献928.
Vitulo N Albiero A Forcato C Campagna D Dal Pero F Bagnaresi P Colaiacovo M Faccioli P Lamontanara A Šimková H Kubaláková M Perrotta G Facella P Lopez L Pietrella M Gianese G Doležel J Giuliano G Cattivelli L Valle G Stanca AM 《PloS one》2011,6(10):e26421
Wheat is one of the world's most important crops and is characterized by a large polyploid genome. One way to reduce genome complexity is to isolate single chromosomes using flow cytometry. Low coverage DNA sequencing can provide a snapshot of individual chromosomes, allowing a fast characterization of their main features and comparison with other genomes. We used massively parallel 454 pyrosequencing to obtain a 2x coverage of wheat chromosome 5A. The resulting sequence assembly was used to identify TEs, genes and miRNAs, as well as to infer a virtual gene order based on the synteny with other grass genomes. Repetitive elements account for more than 75% of the genome. Gene content was estimated considering non-redundant reads showing at least one match to ESTs or proteins. The results indicate that the coding fraction represents 1.08% and 1.3% of the short and long arm respectively, projecting the number of genes of the whole chromosome to approximately 5,000. 195 candidate miRNA precursors belonging to 16 miRNA families were identified. The 5A genes were used to search for syntenic relationships between grass genomes. The short arm is closely related to Brachypodium chromosome 4, sorghum chromosome 8 and rice chromosome 12; the long arm to regions of Brachypodium chromosomes 4 and 1, sorghum chromosomes 1 and 2 and rice chromosomes 9 and 3. From these similarities it was possible to infer the virtual gene order of 392 (5AS) and 1,480 (5AL) genes of chromosome 5A, which was compared to, and found to be largely congruent with the available physical map of this chromosome. 相似文献
929.
Ghosn J Delaugerre C Flandre P Galimand J Cohen-Codar I Raffi F Delfraissy JF Rouzioux C Chaix ML 《PloS one》2011,6(9):e24798
Virological failure on a boosted-protease inhibitor (PI/r) first-line triple combination is usually not associated with the detection of resistance mutations in the protease gene. Thus, other resistance pathways are being investigated. First-line PI/r monotherapy is the best model to investigate in vivo if the presence of mutations in the cleavage sites (CS) of gag gene prior to any antiretroviral treatment might influence PI/r efficacy. 83 patients were assigned to initiate antiretroviral treatment with first-line lopinavir/r monotherapy in the randomised Monark trial. We compared baseline sequence of gag CS between patients harbouring B or non-B HIV-1 subtype, and between those who achieved viral suppression and those who experienced virological failure while on LPV/r monotherapy up to Week 96. Baseline sequence of gag CS was available for 82/83 isolates; 81/82 carried at least one substitution in gag CS compared to HXB2 sequence. At baseline, non-B subtype isolates were significantly more likely to harbour mutations in gag CS than B subtype isolates (p<0.0001). Twenty-three patients experienced virological failure while on lopinavir/r monotherapy. The presence of more than two substitutions in p2/NC site at baseline significantly predicted virological failure (p = 0.0479), non-B subtype isolates being more likely to harbour more than two substitutions in this specific site. In conclusion, gag cleavage site was highly polymorphic in antiretroviral-naive patients harbouring a non-B HIV-1 strain. We show that pre-therapy mutations in gag cleavage site sequence were significantly associated with the virological outcome of a first-line LPV/r single drug regimen in the Monark trial. 相似文献
930.
Rieder F Lopez R Franke A Wolf A Schleder S Dirmeier A Schirbel A Rosenstiel P Dotan N Schreiber S Rogler G Klebl F 《PloS one》2011,6(5):e18172