全文获取类型
收费全文 | 6705篇 |
免费 | 566篇 |
国内免费 | 1篇 |
出版年
2023年 | 21篇 |
2022年 | 51篇 |
2021年 | 134篇 |
2020年 | 74篇 |
2019年 | 95篇 |
2018年 | 108篇 |
2017年 | 99篇 |
2016年 | 180篇 |
2015年 | 327篇 |
2014年 | 335篇 |
2013年 | 422篇 |
2012年 | 559篇 |
2011年 | 509篇 |
2010年 | 350篇 |
2009年 | 243篇 |
2008年 | 424篇 |
2007年 | 376篇 |
2006年 | 350篇 |
2005年 | 327篇 |
2004年 | 330篇 |
2003年 | 318篇 |
2002年 | 270篇 |
2001年 | 106篇 |
2000年 | 93篇 |
1999年 | 82篇 |
1998年 | 65篇 |
1997年 | 55篇 |
1996年 | 57篇 |
1995年 | 50篇 |
1994年 | 33篇 |
1993年 | 42篇 |
1992年 | 60篇 |
1991年 | 44篇 |
1990年 | 38篇 |
1989年 | 39篇 |
1988年 | 30篇 |
1987年 | 33篇 |
1986年 | 34篇 |
1985年 | 32篇 |
1984年 | 31篇 |
1983年 | 31篇 |
1982年 | 24篇 |
1981年 | 25篇 |
1979年 | 26篇 |
1978年 | 27篇 |
1977年 | 22篇 |
1976年 | 27篇 |
1974年 | 25篇 |
1973年 | 24篇 |
1972年 | 21篇 |
排序方式: 共有7272条查询结果,搜索用时 15 毫秒
941.
Nielen S Vidigal BS Leal-Bertioli SC Ratnaparkhe M Paterson AH Garsmeur O D'Hont A Guimarães PM Bertioli DJ 《Molecular genetics and genomics : MGG》2012,287(1):21-38
Cultivated peanut is an allotetraploid with an AB-genome. In order to learn more of the genomic structure of peanut, we characterized
and studied the evolution of a retrotransposon originally isolated from a resistance gene analog (RGA)-containing bacterial
artificial chromosome (BAC) clone. It is a moderate copy number Ty1-copia retrotransposon from the Bianca lineage and we named it Matita. Fluorescent in situ hybridization (FISH) experiments showed that Matita is mainly located on the distal regions of chromosome arms and is of approximately equal frequency on both A- and B-chromosomes.
Its chromosome-specific hybridization pattern facilitates the identification of individual chromosomes, a useful cytogenetic
tool considering that chromosomes in peanut are mostly metacentric and of similar size. Phylogenetic analysis of Matita elements, molecular dating of transposition events, and an estimation of the evolutionary divergence of the most probable
A- and B-donor species suggest that Matita underwent its last major burst of transposition activity at around the same time of the A- and B-genome divergence about
3.5 million years ago. By probing BAC libraries with overgos probes for Matita, resistance gene analogues, and single- or low-copy genes, it was demonstrated that Matita is not randomly distributed in the genome but exhibits a significant tendency of being more abundant near resistance gene
homologues than near single-copy genes. The described work is a further step towards broadening the knowledge on genomic and
chromosomal structure of peanut and on its evolution. 相似文献
942.
Vijay Alla Bhavani S. Kowtharapu David Engelmann Stephan Emmrich Ulf Schmitz Marc Steder Brigitte M. Pützer 《Cell cycle (Georgetown, Tex.)》2012,11(16):3067-3078
Resistance to anti-neoplastic agents is the major cause of therapy failure, leading to disease recurrence and metastasis. E2F1 is a strong inducer of apoptosis in response to DNA damage through its capacity to activate p53/p73 death pathways. Recent evidence, however, showed that E2F1, which is aberrantly expressed in advanced malignant melanomas together with antagonistic p73 family members, drives cancer progression. Investigating mechanisms responsible for dysregulated E2F1 losing its apoptotic function, we searched for genomic signatures in primary and late clinical tumor stages to allow the prediction of downstream effectors associated with apoptosis resistance and survival of aggressive melanoma cells. We identified miR-205 as specific target of p73 and found that upon genotoxic stress, its expression is sufficiently abrogated by endogenous DNp73. Significantly, metastatic cells can be rescued from drug resistance by selective knockdown of DNp73 or overexpression of miR-205 in p73-depleted cells, leading to increased apoptosis and the reduction of tumor growth in vivo. Our data delineate an autoregulatory circuit, involving high levels of E2F1 and DNp73 to downregulate miR-205, which, in turn, controls E2F1 accumulation. Finally, drug resistance associated to this genetic signature is mediated by removing the inhibitory effect of miR-205 on the expression of Bcl-2 and the ATP-binding cassette transporters A2 (ABCA2) and A5 (ABCA5) related to multi-drug resistance and malignant progression. These results define the E2F1-p73/DNp73-miR-205 axis as a crucial mechanism for chemoresistance and, thus, as a target for metastasis prevention. 相似文献
943.
Ferenc G. Rick Stefan Buchholz Andrew V. Schally Luca Szalontay Awtar Krishan Christian Datz Andreas Stadlmayr Elmar Aigner Roberto Perez Stephan Seitz Norman L. Block Florian Hohla 《Cell cycle (Georgetown, Tex.)》2012,11(13):2518-2525
We investigated the efficacy of a powerful antagonist of bombesin/gastrin-releasing peptide (BN/GRP) RC-3940-II administered as a single agent or in combination with cytotoxic agents on the growth of HT-29, HCT-116 and HCT-15 human colon cancer in vitro and in vivo. GRP-receptor mRNA and protein were found in all three cell lines tested. Exposure of HT-29 cells to 10 μM RC-3940-II led to an increase in the number of cells blocked in S phase and G2/M and cells with lower G0/G1 DNA content. Similar changes on the cell cycle traverse of HT-29 cells could also be seen at lower concentrations of RC-3940-II (1 μM) after pretreatment with 100 nM GRP (14–27), indicating a dose-dependent mechanism of action based on the blockage of BN/GRP induced proliferation of tumor cells at lower concentrations.
Daily in vivo treatment with BN/GRP antagonist RC-3940-II decreased the volume of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice by 25 to 67% (p < 0.005). Combined treatment with RC-3940-II and chemotherapeutic agents 5-FU and irinotecan resulted in a synergistic tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts by 43% to 78%. In HT-29 and HCT-116 xenografts the inhibition for the combinations of RC-3940-II and irinotecan vs. single substances (p < 0.05) was significantly greater.
These findings support the use of RC-3940-II as an anticancer agent and may help to design clinical trials using RC-3940-II in combinations with cytotoxic agents. 相似文献
944.
Anatomy of large biological specimens is often reconstructed from serially sectioned volumes imaged by high-resolution microscopy. We developed a method to reassemble a continuous volume from such large section series that explicitly minimizes artificial deformation by applying a global elastic constraint. We demonstrate our method on a series of transmission electron microscopy sections covering the entire 558-cell Caenorhabditis elegans embryo and a segment of the Drosophila melanogaster larval ventral nerve cord. 相似文献
945.
Srinivasan J von Reuss SH Bose N Zaslaver A Mahanti P Ho MC O'Doherty OG Edison AS Sternberg PW Schroeder FC 《PLoS biology》2012,10(1):e1001237
The nematode C. elegans is an important model for the study of social behaviors. Recent investigations have shown that a family of small molecule signals, the ascarosides, controls population density sensing and mating behavior. However, despite extensive studies of C. elegans aggregation behaviors, no intraspecific signals promoting attraction or aggregation of wild-type hermaphrodites have been identified. Using comparative metabolomics, we show that the known ascarosides are accompanied by a series of derivatives featuring a tryptophan-derived indole moiety. Behavioral assays demonstrate that these indole ascarosides serve as potent intraspecific attraction and aggregation signals for hermaphrodites, in contrast to ascarosides lacking the indole group, which are repulsive. Hermaphrodite attraction to indole ascarosides depends on the ASK amphid sensory neurons. Downstream of the ASK sensory neuron, the interneuron AIA is required for mediating attraction to indole ascarosides instead of the RMG interneurons, which previous studies have shown to integrate attraction and aggregation signals from ASK and other sensory neurons. The role of the RMG interneuron in mediating aggregation and attraction is thought to depend on the neuropeptide Y-like receptor NPR-1, because solitary and social C. elegans strains are distinguished by different npr-1 variants. We show that indole ascarosides promote attraction and aggregation in both solitary and social C. elegans strains. The identification of indole ascarosides as aggregation signals reveals unexpected complexity of social signaling in C. elegans, which appears to be based on a modular library of ascarosides integrating building blocks derived from lipid β-oxidation and amino-acid metabolism. Variation of modules results in strongly altered signaling content, as addition of a tryptophan-derived indole unit to repellent ascarosides produces strongly attractive indole ascarosides. Our findings show that the library of ascarosides represents a highly developed chemical language integrating different neurophysiological pathways to mediate social communication in C. elegans. 相似文献
946.
Johansson LC Arnlund D White TA Katona G Deponte DP Weierstall U Doak RB Shoeman RL Lomb L Malmerberg E Davidsson J Nass K Liang M Andreasson J Aquila A Bajt S Barthelmess M Barty A Bogan MJ Bostedt C Bozek JD Caleman C Coffee R Coppola N Ekeberg T Epp SW Erk B Fleckenstein H Foucar L Graafsma H Gumprecht L Hajdu J Hampton CY Hartmann R Hartmann A Hauser G Hirsemann H Holl P Hunter MS Kassemeyer S Kimmel N Kirian RA Maia FR Marchesini S Martin AV Reich C Rolles D Rudek B Rudenko A Schlichting I 《Nature methods》2012,9(3):263-265
X-ray free electron laser (X-FEL)-based serial femtosecond crystallography is an emerging method with potential to rapidly advance the challenging field of membrane protein structural biology. Here we recorded interpretable diffraction data from micrometer-sized lipidic sponge phase crystals of the Blastochloris viridis photosynthetic reaction center delivered into an X-FEL beam using a sponge phase micro-jet. 相似文献
947.
Friston KJ Shiner T FitzGerald T Galea JM Adams R Brown H Dolan RJ Moran R Stephan KE Bestmann S 《PLoS computational biology》2012,8(1):e1002327
The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level. 相似文献
948.
Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the "Guard-Hypothesis," R proteins (the "guards") can sense modification of target molecules in the host (the "guardees") by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the "guardee-effector" interface for pathogen recognition, natural selection acts on the "guard-guardee" interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen. 相似文献
949.
Till Lei?ner Kasper Thilsing-Hansen Christoph Lemke Stephan Jauernik Jakob Kjelstrup-Hansen Michael Bauer Horst-Günter Rubahn 《Plasmonics (Norwell, Mass.)》2012,7(2):253-260
The excitation of surface plasmon polaritons (SPP) at a gold?Cvacuum interface by femtosecond light pulses mediated by organic nanofiber-induced dielectric perturbations is observed using interferometric time-resolved photoemission electron microscopy. The experimental data are quantitatively reproduced by analytic simulations, where the nanofibers are considered as superior source of the SPP emission. The flexibility and tuneability of phenylene-based nanofibers in their morphology and intrinsic optical properties open up future applications to fabricate custom-designed nanoscale sources of SPP. 相似文献
950.
Stephan T. Koev Amit Agrawal Henri J. Lezec Vladimir A. Aksyuk 《Plasmonics (Norwell, Mass.)》2012,7(2):269-277
We report the design, fabrication, and characterization of a periodic grating of shallow rectangular grooves in a metallic film with the goal of maximizing the coupling efficiency of an extended plane wave (PW) of visible or near-infrared light into a single surface plasmon polariton (SPP) mode on a flat metal surface. A PW-to-SPP power conversion factor >45% is demonstrated at a wavelength of 780?nm, which exceeds by an order of magnitude the experimental performance of SPP grating couplers reported to date at any wavelength. Conversion efficiency is maximized by matching the dissipative SPP losses along the grating surface to the local coupling strength. This critical coupling condition is experimentally achieved by tailoring the groove depth and width using a focused ion beam. 相似文献