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71.
Sexton T Yaffe E Kenigsberg E Bantignies F Leblanc B Hoichman M Parrinello H Tanay A Cavalli G 《Cell》2012,148(3):458-472
Chromosomes are the physical realization of genetic information and thus form the basis for its readout and propagation. Here we present a high-resolution chromosomal contact map derived from a modified genome-wide chromosome conformation capture approach applied to Drosophila embryonic nuclei. The data show that the entire genome is linearly partitioned into well-demarcated physical domains that overlap extensively with active and repressive epigenetic marks. Chromosomal contacts are hierarchically organized between domains. Global modeling of contact density and clustering of domains show that inactive domains are condensed and confined to their chromosomal territories, whereas active domains reach out of the territory to form remote intra- and interchromosomal contacts. Moreover, we systematically identify specific long-range intrachromosomal contacts between Polycomb-repressed domains. Together, these observations allow for quantitative prediction of the Drosophila chromosomal contact map, laying the foundation for detailed studies of chromosome structure and function in a genetically tractable system. 相似文献
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73.
One of the main motivations to study amphioxus is its potential for understanding the last common ancestor of chordates, which notably gave rise to the vertebrates. An important feature in this respect is the slow evolutionary rate that seems to have characterized the cephalochordate lineage, making amphioxus an interesting proxy for the chordate ancestor, as well as a key lineage to include in comparative studies. Whereas slow evolution was first noticed at the phenotypic level, it has also been described at the genomic level. Here, we examine whether the amphioxus genome is indeed a good proxy for the genome of the chordate ancestor, with a focus on protein-coding genes. We investigate genome features, such as synteny, gene duplication and gene loss, and contrast the amphioxus genome with those of other deuterostomes that are used in comparative studies, such as Ciona, Oikopleura and urchin. 相似文献
74.
M Hersch B Peter HM Kang F Schüpfer H Abriel T Pedrazzini E Eskin JS Beckmann S Bergmann F Maurer 《PloS one》2012,7(7):e41032
β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β(1)-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8)). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6)). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied. 相似文献
75.
Yann Neuzillet Xavier Paoletti Slah Ouerhani Pierre Mongiat-Artus Hany Soliman Hugues de The Mathilde Sibony Yves Denoux Vincent Molinie Aurélie Herault May-Linda Lepage Pascale Maille Audrey Renou Dimitri Vordos Claude-Clément Abbou Ashraf Bakkar Bernard Asselain Nadia Kourda Amel El Gaaied Karen Leroy Agnès Laplanche Simone Benhamou Thierry Lebret Yves Allory Fran?ois Radvanyi 《PloS one》2012,7(12)
TP53 and FGFR3 mutations are the most common mutations in bladder cancers. FGFR3 mutations are most frequent in low-grade low-stage tumours, whereas TP53 mutations are most frequent in high-grade high-stage tumours. Several studies have reported FGFR3 and TP53 mutations to be mutually exclusive events, whereas others have reported them to be independent. We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications) and additional unpublished data for 382 tumours. TP53 and FGFR3 mutations were not independent events for all tumours considered together (OR = 0.25 [0.18–0.37], p = 0.0001) or for pT1 tumours alone (OR = 0.47 [0.28–0.79], p = 0.0009). However, if the analysis was restricted to pTa tumours or to muscle-invasive tumours alone, FGFR3 and TP53 mutations were independent events (OR = 0.56 [0.23–1.36] (p = 0.12) and OR = 0.99 [0.37–2.7] (p = 0.35), respectively). After stratification of the tumours by stage and grade, no dependence was detected in the five tumour groups considered (pTaG1 and pTaG2 together, pTaG3, pT1G2, pT1G3, pT2-4). These differences in findings can be attributed to the putative existence of two different pathways of tumour progression in bladder cancer: the CIS pathway, in which FGFR3 mutations are rare, and the Ta pathway, in which FGFR3 mutations are frequent. TP53 mutations occur at the earliest stage of the CIS pathway, whereas they occur would much later in the Ta pathway, at the T1G3 or muscle-invasive stage. 相似文献
76.
Lorenzo Galluzzi Ilio Vitale Laura Senovilla Tobias Eisenberg Didac Carmona-Gutierrez Erika Vacchelli Thomas Robert Hugues Ripoche Nora J?gemann Caroline Paccard Nicolas Servant Philippe Hupé Vladimir Lazar Philippe Dessen Emmanuel Barillot Hans Zischka Frank Madeo Guido Kroemer 《Cell cycle (Georgetown, Tex.)》2012,11(18):3472-3480
77.
Schann S Greney H Gasparik V Dontenwill M Rascente C Lacroix G Monassier L Bruban V Feldman J Ehrhardt JD Bousquet P 《Bioorganic & medicinal chemistry》2012,20(15):4710-4715
Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I(1) imidazoline receptors (I(1)Rs), I(2) imidazoline binding sites (I(2)BS) and α(2)-adrenoceptor subtypes (α(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of α(2)AR affinity. Amongst the selective ligands obtained, LNP 630 (4) constitutes the first highly selective I(1)R agent showing hypotensive activity after intravenous administration. 相似文献
78.
Muffato M Roest Crollius H 《BioEssays : news and reviews in molecular, cellular and developmental biology》2008,30(2):122-134
Knowledge of the structure of ancestral genomes provides the basis of a new framework to better represent and interpret results from genomic and evolutionary studies. Because these ancestors lived tens of hundreds of million years ago, this knowledge will inevitably take the form of abstract representations, reconstructed on the basis both of experimental evidence collected on extant genomes and of our understanding of evolutionary processes. This is the field of Paleogenomics, a young discipline that is providing an increasingly precise picture of our ancestral vertebrate genomes based on cytogenetic data, genome sequences and new algorithmic developments. Many recent studies have focused on the ancestral placental mammal and teleost fish genomes, although the outlines of even more distant pre-vertebrate ancestors are being reported. 相似文献
79.
Dexamethasone treatment of post-MI rats attenuates sympathetic innervation of the infarct region. 总被引:1,自引:0,他引:1
Viviane El-Helou Cindy Proulx Hugues Gosselin Robert Clement Andrea Mimee Louis Villeneuve Angelino Calderone 《Journal of applied physiology》2008,104(1):150-156
Sympathetic fiber innervation of the damaged region following injury represents a conserved event of wound healing. The present study tested the hypothesis that impaired scar healing in post-myocardial infarction (post-MI) rats was associated with a reduction of sympathetic fibers innervating the infarct region. In 1-wk post-MI rats, neurofilament-M-immunoreactive fibers (1,116 +/- 250 microm(2)/mm(2)) were detected innervating the infarct region and observed in close proximity to a modest number of endothelial nitric oxide synthase-immunoreactive scar-residing vessels. Dexamethasone (Dex) treatment (6 days) of post-MI rats led to a significant reduction of scar weight (Dex + MI 38 +/- 4 mg vs. MI 63 +/- 2 mg) and a disproportionate nonsignificant decrease of scar surface area (Dex + MI 0.54 +/- 0.06 cm(2) vs. MI 0.68 +/- 0.06 cm(2)). In Dex-treated post-MI rats, the density of neurofilament-M-immunoreactive fibers (125 +/- 47 microm(2)/mm(2)) innervating the infarct region was significantly reduced and associated with a decreased expression of nerve growth factor (NGF) mRNA (Dex + MI 0.80 +/- 0.07 vs. MI 1.11 +/- 0.08; P < 0.05 vs. MI). Previous studies have demonstrated that scar myofibroblasts synthesize NGF and may represent a cellular target of Dex. The exposure of 1st passage scar myofibroblasts to Dex led to a dose-dependent suppression of [(3)H]thymidine uptake and a concomitant attenuation of NGF mRNA expression (untreated 3.47 +/- 0.35 vs. Dex treated 2.28 +/- 0.40; P < 0.05 vs. untreated). Thus the present study has demonstrated that impaired scar healing in Dex-treated post-MI rats was associated with a reduction of neurofilament-M-immunoreactive fibers innervating the infarct region. The attenuation of scar myofibroblast proliferation and NGF mRNA expression may represent underlying mechanisms contributing to the diminished neural response in the infarct region of Dex-treated post-MI rats. 相似文献
80.
The HIV-1 envelope glycoprotein gp120 features four heparan sulfate binding domains, including the co-receptor binding site 总被引:1,自引:0,他引:1
Crublet E Andrieu JP Vivès RR Lortat-Jacob H 《The Journal of biological chemistry》2008,283(22):15193-15200
It is well established that the human immunodeficiency virus-1 envelope glycoprotein surface unit, gp120, binds to cell-associated heparan sulfate (HS). Virus infectivity is increased by such interaction, and a variety of soluble polyanions efficiently neutralize immunodeficiency virus-1 in vitro. This interaction has been mainly attributed to the gp120 V3 loop. However, although evidence suggested that this particular domain does not fully recapitulate the binding activity of the protein, the ability of HS to bind to other regions of gp120 has not been completely addressed, and the exact localizations of the polysaccharide binding sites are not known. To investigate in more detail the structural basis of the HS-gp120 interaction, we used a mapping strategy and compared the heparin binding activity of wild type and mutant gp120 using surface plasmon resonance-based binding assays. Four heparin binding domains (1-4) were identified in the V2 and V3 loops, in the C-terminal domain, and within the CD4-induced bridging sheet. Interestingly, three of them were found in domains of the protein that undergo structural changes upon binding to CD4 and are involved in co-receptor recognition. In particular, Arg(419), Lys(421), and Lys(432), which directly interact with the co-receptor, are targeted by heparin. This study provides a complete account of the gp120 residues involved in heparin binding and identified several binding surfaces that constitute potential target for viral entry inhibition. 相似文献