全文获取类型
收费全文 | 7320篇 |
免费 | 571篇 |
国内免费 | 1篇 |
专业分类
7892篇 |
出版年
2023年 | 57篇 |
2022年 | 107篇 |
2021年 | 222篇 |
2020年 | 142篇 |
2019年 | 153篇 |
2018年 | 172篇 |
2017年 | 152篇 |
2016年 | 253篇 |
2015年 | 421篇 |
2014年 | 446篇 |
2013年 | 528篇 |
2012年 | 675篇 |
2011年 | 639篇 |
2010年 | 394篇 |
2009年 | 361篇 |
2008年 | 499篇 |
2007年 | 424篇 |
2006年 | 413篇 |
2005年 | 351篇 |
2004年 | 310篇 |
2003年 | 245篇 |
2002年 | 260篇 |
2001年 | 47篇 |
2000年 | 42篇 |
1999年 | 51篇 |
1998年 | 43篇 |
1997年 | 36篇 |
1996年 | 32篇 |
1995年 | 34篇 |
1994年 | 28篇 |
1993年 | 17篇 |
1992年 | 39篇 |
1991年 | 29篇 |
1990年 | 21篇 |
1989年 | 27篇 |
1988年 | 14篇 |
1987年 | 18篇 |
1986年 | 21篇 |
1985年 | 19篇 |
1984年 | 10篇 |
1983年 | 10篇 |
1982年 | 12篇 |
1981年 | 12篇 |
1980年 | 15篇 |
1979年 | 7篇 |
1978年 | 9篇 |
1977年 | 12篇 |
1976年 | 8篇 |
1975年 | 7篇 |
1973年 | 9篇 |
排序方式: 共有7892条查询结果,搜索用时 0 毫秒
171.
Marcus Weinguny Peter Eisenhut Gerald Klanert Nikolaus Virgolini Nicolas Marx Andreas Jonsson Daniel Ivansson Ann Lövgren Nicole Borth 《Biotechnology and bioengineering》2020,117(11):3435-3447
Chinese hamster ovary (CHO) cells produce a large share of today's biopharmaceuticals. Still, the generation of satisfactory producer cell lines is a tedious undertaking. Recently, it was found that CHO cells, when exposed to new environmental conditions, modify their epigenome, suggesting that cells adapt their gene expression pattern to handle new challenges. The major aim of the present study was to employ artificially induced, random changes in the DNA-methylation pattern of CHO cells to diversify cell populations and consequently increase the finding of cell lines with improved cellular characteristics. To achieve this, DNA methyltransferases and/or the ten-eleven translocation enzymes were downregulated by RNA interference over a time span of ∼16 days. Methylation analysis of the resulting cell pools revealed that the knockdown of DNA methyltransferases was highly effective in randomly demethylating the genome. The same approach, when applied to stable CHO producer cells resulted in (a) an increased productivity diversity in the cell population, and (b) a higher number of outliers within the population, which resulted in higher specific productivity and titer in the sorted cells. These findings suggest that epigenetics play a previously underestimated, but actually important role in defining the overall cellular behavior of production clones. 相似文献
172.
Hilde Schneemann Bianca De Sanctis Denis Roze Nicolas Bierne John J. Welch 《Evolution; international journal of organic evolution》2020,74(12):2575-2590
When divergent populations form hybrids, hybrid fitness can vary with genome composition, current environmental conditions, and the divergence history of the populations. We develop analytical predictions for hybrid fitness, which incorporate all three factors. The predictions are based on Fisher's geometric model, and apply to a wide range of population genetic parameter regimes and divergence conditions, including allopatry and parapatry, local adaptation, and drift. Results show that hybrid fitness can be decomposed into intrinsic effects of admixture and heterozygosity, and extrinsic effects of the (local) adaptedness of the parental lines. Effect sizes are determined by a handful of geometric distances, which have a simple biological interpretation. These distances also reflect the mode and amount of divergence, such that there is convergence toward a characteristic pattern of intrinsic isolation. We next connect our results to the quantitative genetics of line crosses in variable or patchy environments. This means that the geometrical distances can be estimated from cross data, and provides a simple interpretation of the “composite effects.” Finally, we develop extensions to the model, involving selectively induced disequilibria, and variable phenotypic dominance. The geometry of fitness landscapes provides a unifying framework for understanding speciation, and wider patterns of hybrid fitness. 相似文献
173.
Anne Gibaud Nicolas Vogt Olivier Brison Michelle Debatisse Bernard Malfoy 《Nucleic acids research》2013,41(17):8210-8219
The mechanisms of formation of intrachromosomal amplifications in tumours are still poorly understood. By using quantitative polymerase chain reaction, DNA sequencing, chromosome walking, in situ hybridization on metaphase chromosomes and whole-genome analysis, we studied two cancer cell lines containing an MYC oncogene amplification with acquired copies ectopically inserted in rearranged chromosomes 17. These intrachromosomal amplifications result from the integration of extrachromosomal DNA molecules. Replication stress could explain the formation of the double-strand breaks involved in their insertion and in the rearrangements of the targeted chromosomes. The sequences of the junctions indicate that homologous recombination was not involved in their formation and support a non-homologous end-joining process. The replication stress-inducible common fragile sites present in the amplicons may have driven the intrachromosomal amplifications. Mechanisms associating break-fusion-bridge cycles and/or chromosome fragmentation may have led to the formation of the uncovered complex structures. To our knowledge, this is the first characterization of an intrachromosomal amplification site at nucleotide resolution. 相似文献
174.
Oula Shahin Nicolas Martin-St Paul Serge Rambal Richard Joffre Franck Richard 《Symbiosis (Philadelphia, Pa.)》2013,61(1):1-12
Understanding the factors underlying the distribution of biodiversity is a challenging issue in ecology. Here, we examined the distribution patterns of ectomycorrhizal fungal diversity across the soil profile in three Quercus ilex forests. Contact exploration type strongly dominated at all sites, but was most prevalent in the upper, organic-rich soil layers. At each site, three quarters of the ectomycorrhizal tips and 59 % of taxa were restricted to the ten first centimeters of the soil profile. The relative abundance of the dominant family Russulaceae increased with increasing soil depth. Species composition varied significantly among sites, with most species being rare. Species that occurred in only one of the three sites accounted for 78.9 % of all species, and 57.3 % of species were represented by a single ECM root tip. Our results suggest that (i) rare species at both local and regional scales contribute to the highly diverse fungal assemblages in Mediterranean forests and (ii) multi-sites studies including the whole soil profile are needed to provide comprehensive overviews of the taxonomic and functional diversities of ectomycorrhizal communities. 相似文献
175.
Maud Martin Ilse Geudens Jonathan Bruyr Michael Potente Anouk Bleuart Marielle Lebrun Nicolas Simonis Christophe Deroanne Jean‐Claude Twizere Philippe Soubeyran Paul Peixoto Denis Mottet Veerle Janssens Wolf‐Karsten Hofmann Filip Claes Peter Carmeliet Richard Kettmann Holger Gerhardt Franck Dequiedt 《The EMBO journal》2013,32(18):2491-2503
176.
Feten Abbassi Zahid Raja Bruno Oury Elodie Gazanion Christophe Piesse Denis Sereno Pierre Nicolas Thierry Foulon Ali Ladram 《Biochimie》2013
Temporins are a family of short antimicrobial peptides (8–17 residues) that mostly show potent activity against Gram-positive bacteria. Herein, we demonstrate that temporin-SHd, a 17-residue peptide with a net charge of +2 (FLPAALAGIGGILGKLFamide), expressed a broad spectrum of antimicrobial activity. This peptide displayed potent antibacterial activities against Gram-negative and Gram-positive bacteria, including multi-drug resistant Staphylococcus aureus strains, as well as antiparasitic activity against promastigote and the intracellular stage (amastigote) of Leishmania infantum, at concentration not toxic for the macrophages. Temporin-SHd that is structured in a non-amphipathic α-helix in anionic membrane-mimetic environments, strongly and selectively perturbs anionic bilayer membranes by interacting with the polar head groups and acyl region of the phospholipids, with formation of regions of two coexisting phases: one phase rich in peptide and the other lipid-rich. The disruption of lipid packing within the bilayer may lead to the formation of transient pores and membrane permeation/disruption once a threshold peptide accumulation is reached. To our knowledge, Temporin-SHd represents the first known 17-residue long temporin expressing such broad spectrum of antimicrobial activity including members of the trypanosomatidae family. Additionally, since only a few shorter members (13 residues) of the temporin family are known to display antileishmanial activity (temporins-TA, -TB and -SHa), SHd is an interesting tool to analyze the antiparasitic mechanism of action of temporins. 相似文献
177.
Mucins belong to a heterogeneous family of large O-glycoproteins composed of a long peptidic chain called apomucin on which are linked hundreds of oligosaccharidic chains. Among mucins, membrane-bound mucins are modular proteins and have a structural organization usually containing Pro/Thr/Ser-rich O-glycosylated domains (PTS), EGF-like and SEA domains. Via these modular domains, the membrane-bound mucins participate in cell signalling and cell interaction with their environment in normal and pathological conditions. Moreover, the recent knowledge of these domains and their biological activities led to the development of new therapeutic approaches involving mucins. In this review, we show 3D structures of EGF and SEA domains. We also describe the functional features of the evolutionary conserved domains of membrane-bound mucins and discuss consequences of splice events. 相似文献
178.
179.
Ira Espuny-Camacho Kimmo A. Michelsen David Gall Daniele Linaro Anja Hasche Jérôme Bonnefont Camilia Bali David Orduz Angéline Bilheu Adèle Herpoel Nelle Lambert Nicolas Gaspard Sophie Péron Serge N. Schiffmann Michele Giugliano Afsaneh Gaillard Pierre Vanderhaeghen 《Neuron》2013,77(3):440-456
Download : Download video (68MB) 相似文献
180.
Audrey Boulamery Gais Kadra Nicolas Simon Thierry Besnard 《Chronobiology international》2013,30(5):961-968
There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10∶00, 16∶00, 22∶00, or 04∶00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were Cmax, Tmax, elimination half‐life (t1/2), area under the concentration‐versus‐time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of Cmax (49%), Tmax (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra‐individual variability. 相似文献