全文获取类型
收费全文 | 5946篇 |
免费 | 553篇 |
国内免费 | 4篇 |
专业分类
6503篇 |
出版年
2023年 | 56篇 |
2022年 | 93篇 |
2021年 | 192篇 |
2020年 | 93篇 |
2019年 | 145篇 |
2018年 | 128篇 |
2017年 | 125篇 |
2016年 | 172篇 |
2015年 | 308篇 |
2014年 | 297篇 |
2013年 | 383篇 |
2012年 | 423篇 |
2011年 | 384篇 |
2010年 | 253篇 |
2009年 | 239篇 |
2008年 | 290篇 |
2007年 | 283篇 |
2006年 | 264篇 |
2005年 | 236篇 |
2004年 | 196篇 |
2003年 | 212篇 |
2002年 | 204篇 |
2001年 | 71篇 |
2000年 | 70篇 |
1999年 | 84篇 |
1998年 | 49篇 |
1997年 | 44篇 |
1996年 | 42篇 |
1995年 | 31篇 |
1994年 | 42篇 |
1993年 | 44篇 |
1992年 | 53篇 |
1991年 | 61篇 |
1990年 | 49篇 |
1989年 | 41篇 |
1988年 | 47篇 |
1987年 | 48篇 |
1986年 | 42篇 |
1985年 | 35篇 |
1984年 | 48篇 |
1983年 | 29篇 |
1982年 | 35篇 |
1980年 | 29篇 |
1979年 | 43篇 |
1978年 | 34篇 |
1977年 | 42篇 |
1976年 | 42篇 |
1975年 | 55篇 |
1974年 | 30篇 |
1972年 | 31篇 |
排序方式: 共有6503条查询结果,搜索用时 103 毫秒
141.
Aiguadé J Balagué C Carranco I Caturla F Domínguez M Eastwood P Esteve C González J Lumeras W Orellana A Preciado S Roca R Vidal L Vidal B 《Bioorganic & medicinal chemistry letters》2012,22(10):3431-3436
A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy. 相似文献
142.
Aims A plant has a limited amount of resources at any time and it allocates them to different structures. In spite of the large number of previous studies on allocation patterns within single species, knowledge of general patterns in species allocation is still very limited. This is because each study was done in different conditions using different methodology, making generalization difficult. We investigate intraspecific above- versus below-ground biomass allocation among individuals across a spectrum of dry-grassland plant species at two different developmental stages and ask whether allocation is age- and species specific, and whether differences among species can be explained by their life-history traits and phylogeny.Methods We collected data on above- and below-ground biomass of seedlings and adult plants of 20 species from a common garden experiment. We analysed data on shoot–root biomass allocation allometrically and studied the relationship between the allometric exponents (slopes on log–log scale), species life-history traits and phylogenetic distances.Important findings We found isometric as well as allometric patterns of biomass allocation in the studied species. Seedlings and adult individuals of more than half of the species differed in their above- versus below-ground biomass allometric exponents. Seedlings and adult individuals of the remaining species differed in their allometric coefficients (intercepts). Annual species generally allocated proportionally more to above- than below-ground biomass as seedlings than as adults, whereas perennial species showed the opposite pattern. Plant life-history traits, such as plant life span, age of first flowering, month in which the species begin flowering and specific leaf area were much more important in explaining differences in shoot–root allometry among species than were phylogenetic relationships. This suggests that allocation patterns vary greatly among closely related species but can be predicted based on species life-history traits. 相似文献
143.
Asaf Zviran Nofar Mor Yoach Rais Hila Gingold Shani Peles Elad Chomsky Sergey Viukov Jason D. Buenrostro Roberta Scognamiglio Leehee Weinberger Yair S. Manor Vladislav Krupalnik Mirie Zerbib Hadas Hezroni Diego Adhemar Jaitin David Larastiaso Shlomit Gilad Sima Benjamin Jacob H. Hanna 《Cell Stem Cell》2019,24(2):328-341.e9
144.
Mette Munk Jensen Kamille Dumong Erichsen Camilla Bardram Johnbeck Fredrik Bj?rkling Jacob Madsen Michael Bzorek Peter Buhl Jensen Liselotte H?jgaard Maxwell Sehested Andreas Kj?r 《PloS one》2013,8(1)
Introduction
APO866 is a new anti-tumor compound inhibiting nicotinamide phosphoribosyltransferase (NAMPT). APO866 has an anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of this study was non-invasively to study effect of APO866 treatment on [18F]FLT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake.Methods
In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment. Baseline [18F]FLT or [18F]FDG scans were made before treatment and repeated after 24 hours, 48 hours and 7 days. Tumor volume was followed with computed tomography (CT). Tracer uptake was quantified using small animal PET/CT. One hour after iv injection of tracer, static PET scans were performed. Imaging results were compared with Ki67 immunohistochemistry.Results
Tumors treated with APO866 had volumes that were 114% (24 h), 128% (48 h) and 130% (Day 7) relative to baseline volumes at Day 0. In the control group tumor volumes were 118% (24 h), 145% (48 h) and 339% (Day 7) relative to baseline volumes Day 0. Tumor volume between the treatment and control group was significantly different at Day 7 (P = 0.001). Compared to baseline, [18F]FLT SUVmax was significantly different at 24 h (P<0.001), 48 h (P<0.001) and Day 7 (P<0.001) in the APO866 group. Compared to baseline, [18F]FDG SUVmax was significantly different at Day 7 (P = 0.005) in the APO866 group.Conclusions
APO866 treatment caused a significant decrease in [18F]FLT uptake 24 and 48 hours after treatment initiation. The early reductions in tumor cell proliferation preceded decrease in tumor volume. The results show the possibility to use [18F]FLT and [18F]FDG to image treatment effect early following treatment with APO866 in future clinical studies. 相似文献145.
Talia Herman Keren Rosenberg-Katz Yael Jacob Eitan Auriel Tanya Gurevich Nir Giladi Jeffrey M. Hausdorff 《PloS one》2013,8(1)
Background
Brain white matter hyperintensities (WMHs) commonly observed on brain imaging of older adults are associated with balance and gait impairment and have also been linked to cognitive deficits. Parkinson’s disease (PD) is traditionally sub-classified into the postural instability gait difficulty (PIGD) sub-type, and the tremor dominant (TD) sub-type. Considering the known association between WMHs and axial symptoms like gait disturbances and postural instability, one can hypothesize that WMHs might contribute to the disparate clinical sub-types of patients with PD.Methods
110 patients with PD underwent a clinical evaluation and a 3T MRI exam. Based on the Unified Parkinson Disease Rating Scale, the patients were classified into motor sub-types, i.e., TD or PIGD, and scores reflecting PIGD and TD symptoms were computed. We compared white matter burden using three previously validated methods: one using a semi-quantitative visual rating scale in specific brain regions and two automated methods.Results
Overall, MRI data were obtained in 104 patients. The mean WMHs scores and the percent of subjects with lesions in specific brain regions were similar in the two subtypes, p = 0.678. The PIGD and the TD scores did not differ even when comparing patients with a relatively high burden of WMHs to patients with a relatively low burden. Across most of the brain regions, mild to moderate correlations between WMHs and age were found (r = 0.23 to 0.41; p<0.021). Conversely, no significant correlations were found between WMHs and the PIGD score or disease duration. In addition, depressive symptoms and cerebro-vascular risk factors were similar among the two subtypes.Conclusions
In contrast to what has been reported previously among older adults, the present study could not demonstrate any association between WMHs and the PIGD or TD motor sub-types in patients with PD. 相似文献146.
Reactive oxygen species are important mediators of taurine release from skeletal muscle cells 总被引:3,自引:0,他引:3
Ørtenblad N Young JF Oksbjerg N Nielsen JH Lambert IH 《American journal of physiology. Cell physiology》2003,284(6):C1362-C1373
The present study illustrates elements ofthe signal cascades involved in the activation of taurine effluxpathways in myotubes derived from skeletal muscle cells. Exposingprimary skeletal muscle cells, loaded with 14C-taurine, to1) hypotonic media, 2) the phospholipaseA2 (PLA2) activator melittin, 3)anoxia, or 4) lysophosphatidyl choline (LPC) causes anincrease in 14C-taurine release and a concomitantproduction of reactive oxygen species (ROS). The antioxidants butulatedhydroxy toluene and vitamin E inhibit the taurine efflux after cellswelling, anoxia, and addition of LPC. The muscle cells possess twoseparate taurine efflux pathways, i.e., a swelling- andmelittin-induced pathway that requires 5-lipoxygenase activity foractivation and a LPC-induced pathway. The two pathways aredistinguished by their opposing sensitivity toward the anion channelblocker DIDS and cholesterol. These data provide evidence forPLA2 products and ROS as key mediators of the signalcascade leading to taurine efflux in muscle. 相似文献
147.
Tsutomu Akama Yong-Kang Zhang Yvonne R. Freund Pamela Berry Joanne Lee Eric E. Easom Robert T. Jacobs Jacob J. Plattner Michael J. Witty Rosemary Peter Tim G. Rowan Kirsten Gillingwater Reto Brun Bakela Nare Luke Mercer Musheng Xu Jiangong Wang Hao Liang 《Bioorganic & medicinal chemistry letters》2018,28(1):6-10
Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15?nM against T. congolense and 1.3?nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10?mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies. 相似文献
148.
Jacob Holechek Robert Lease Ann-Gerd Thorsell Tobias Karlberg Caitlin McCadden Ryan Grant Abby Keen Evan Callahan Herwig Schüler Dana Ferraris 《Bioorganic & medicinal chemistry letters》2018,28(11):2050-2054
A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with?~15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets. 相似文献
149.
Circulating plasma microRNAs in colorectal neoplasia: A pilot study in assessing response to therapy
Stephen J O'Brien Uri Netz Jacob Hallion Campbell Bishop Vincent Stephen James Burton Mason Paas Kayla Feagins Jianmin Pan Shesh N. Rai Susan Galandiuk 《Translational oncology》2021,14(1)
IntroductionCurrent serological surveillance markers to monitor colorectal cancer (CRC) or colorectal advanced adenomas (CAA) are hampered by poor sensitivity and specificity. The aim of this study is to identify and validate a panel of plasma microRNAs which change in expression after resection of such lesions.MethodsA prospectively maintained colorectal surgery database was queried for patients in whom both pre- and post-procedural serum samples had been obtained. An initial screening analysis of CRC and CAA patients (5 each) was conducted using screening cards for 380 miRNAs. Four identified miRNAs were combined with a previously described panel of 7 miRNAs that were diagnostically predictive of CRC and CAA. Differential miRNA expression was assessed using quantitative real-time polymerase chain reaction(qRT-PCR).ResultsFifty patients were included (n = 27 CRC, n = 23 CAA). There was no difference in age, gender, or race profile of CRC patients compared to CAA patients. Six miRNA were significantly increased after CRC resection (miR-324, let7b, miR-454, miR-374a, miR-122, miR-19b, all p<0.05), while three miRNAs were significantly increased following CAA resection (miR-454, miR-374a, miR-122, all p<0.05). Three miRNA were increased in common for both (miR-454, miR-374a, miR-122).DiscussionThe expression of miRNAs associated with neoplasia (either CRC or CAA) was significantly increased following surgical resection or endoscopic removal of CRC or CAA. Future studies should focus on the evaluation of these miRNAs in CRC and CAA prognosis. 相似文献
150.
Use of short sequence repeat DNA polymorphisms after PCR amplification to detect the parental origin of the additional chromosome 21 in Down syndrome. 总被引:10,自引:10,他引:10 下载免费PDF全文
M B Petersen A A Schinzel F Binkert L Tranebjaerg M Mikkelsen F A Collins E P Economou S E Antonarakis 《American journal of human genetics》1991,48(1):65-71
The origin of nondisjunction in trisomy 21 has so far been studied using cytogenetic heteromorphisms and DNA polymorphisms using Southern blot analysis. Short sequence repeats have recently been described as an abundant class of DNA polymorphisms in the human genome, which can be typed using the polymerase chain reaction (PCR) amplification. We describe the usage of such markers on chromosome 21 in the study of parental origin of the additional chromosome 21 in 87 cases of Down syndrome. The polymorphisms studied were (a) two (GT)n repeats and a poly(A) tract of an Alu sequence within the HMG14 gene and (b) a (GT)n repeat of locus D21S156. The parental origin was determined in 68 cases by studying the segregation of polymorphic alleles in the nuclear families (either by scoring three different alleles in the proband or by dosage comparison of two different alleles in the proband). Our results demonstrate the usefulness of highly informative PCR markers for the study of nondisjunction in Down syndrome. 相似文献