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931.
Jožica Dolenc John H. Missimer Michel O. Steinmetz Wilfred F. van Gunsteren 《Journal of biomolecular NMR》2010,47(3):221-235
The C-terminal trigger sequence is essential in the coiled-coil formation of GCN4-p1; its conformational properties are thus
of importance for understanding this process at the atomic level. A solution NMR model structure of a peptide, GCN4p16–31,
encompassing the GCN4-p1 trigger sequence was proposed a few years ago. Derived using a standard single-structure refinement
protocol based on 172 nuclear Overhauser effect (NOE) distance restraints, 14 hydrogen-bond and 11 ϕ torsional-angle restraints,
the resulting set of 20 NMR model structures exhibits regular α-helical structure. However, the set slightly violates some
measured NOE bounds and does not reproduce all 15 measured 3J(HN-HCα)-coupling constants, indicating that different conformers of GCN4p16–31 might be present in solution. With the aim to resolve
structures compatible with all NOE upper distance bounds and 3J-coupling constants, we executed several structure refinement protocols employing unrestrained and restrained molecular dynamics
(MD) simulations with two force fields. We find that only configurational ensembles obtained by applying simultaneously time-averaged
NOE distance and 3J-coupling constant restraining with either force field reproduce all the experimental data. Additionally, analyses of the
simulated ensembles show that the conformational variability of GCN4p16–31 in solution admitted by the available set of 187
measured NMR data is larger than represented by the set of the NMR model structures. The conformations of GCN4p16–31 in solution
differ in the orientation not only of the side-chains but also of the backbone. The inconsistencies between the NMR model
structures and the measured NMR data are due to the neglect of averaging effects and the inclusion of hydrogen-bond and torsional-angle
restraints that have little basis in the primary, i.e. measured NMR data. 相似文献
932.
Michel Besserve Bernhard Schölkopf Nikos K. Logothetis Stefano Panzeri 《Journal of computational neuroscience》2010,29(3):547-566
Characterizing how different cortical rhythms interact and how their interaction changes with sensory stimulation is important
to gather insights into how these rhythms are generated and what sensory function they may play. Concepts from information
theory, such as Transfer Entropy (TE), offer principled ways to quantify the amount of causation between different frequency
bands of the signal recorded from extracellular electrodes; yet these techniques are hard to apply to real data. To address
the above issues, in this study we develop a method to compute fast and reliably the amount of TE from experimental time series
of extracellular potentials. The method consisted in adapting efficiently the calculation of TE to analog signals and in providing
appropriate sampling bias corrections. We then used this method to quantify the strength and significance of causal interaction
between frequency bands of field potentials and spikes recorded from primary visual cortex of anaesthetized macaques, both
during spontaneous activity and during binocular presentation of naturalistic color movies. Causal interactions between different
frequency bands were prominent when considering the signals at a fine (ms) temporal resolution, and happened with a very short
(ms-scale) delay. The interactions were much less prominent and significant at coarser temporal resolutions. At high temporal
resolution, we found strong bidirectional causal interactions between gamma-band (40–100 Hz) and slower field potentials when
considering signals recorded within a distance of 2 mm. The interactions involving gamma bands signals were stronger during
movie presentation than in absence of stimuli, suggesting a strong role of the gamma cycle in processing naturalistic stimuli.
Moreover, the phase of gamma oscillations was playing a stronger role than their amplitude in increasing causations with slower
field potentials and spikes during stimulation. The dominant direction of causality was mainly found in the direction from
MUA or gamma frequency band signals to lower frequency signals, suggesting that hierarchical correlations between lower and
higher frequency cortical rhythms are originated by the faster rhythms. 相似文献
933.
David W. Pennington Kirana Chomkhamsri Rana Pant Marc-Andree Wolf Giovanni Bidoglio Klaus Kögler Pavel Misiga Michel Sponar Bettina Lorz Guido Sonnemann Paolo Masoni Hongtao Wang Lin Ling Carla Castanho Chen Sau Soon Maurizio Fieschi Assunta Filareto Michael Hauschild 《The International Journal of Life Cycle Assessment》2010,15(3):231-237
Introduction
The European Commission is supporting the development of the International Reference Life Cycle Data System (ILCD). This consists primarily of the ILCD Handbook and the ILCD Data Network. This paper gives an insight into the scientific positions of business, governments, consultants, academics, and others that were expressed at this public consultation workshop.Workshop focus
The workshop focused on four of the topics of the main guidance documents of the ILCD Handbook: (1) general guidance on life cycle assessment (LCA); (2) guidance for generic and average life cycle inventory (LCI) data sets; (3) requirements for environmental impact assessment methods, models and indicators for LCA; and (4) review schemes for LCA.Workshop participation
This consultation workshop was attended by more than 120 participants during the 4 days of the workshop. Representatives came from 23 countries, from both within and outside the European Union.Workshop structure
Approximately half of the participants were from business associations or individual companies. Another 20% were governmental representatives. Others came predominantly from consultancies and academia.Results
This public consultation workshop provided valuable inputs into the overall ILCD Handbook developments as well as for further development. This paper focuses on some of the main scientific issues that were raised. 相似文献934.
Mireia Martín-Satué Elise G. Lavoie Michel Fausther Joanna Lecka Elisabet Aliagas Filip Kukulski Jean Sévigny 《Histochemistry and cell biology》2010,133(6):659-668
Extracellular ATP and its hydrolysis product adenosine modulate various reproductive functions such as those requiring contraction,
steroidogenesis, and maintenance of fluid composition. Interestingly, adenosine might act as a key capacitative effector for
mammalian spermatozoa to acquire the capacity for fertilisation. Extracellular nucleotide levels are affected by cell surface
ectonucleotidases, amongst which the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family regroups the most abundant
and effective enzymes to hydrolyse ATP and ADP to AMP in physiological conditions. In the male reproductive tract three members
of this family have been indentified: NTPDase1, NTPDase2 and NTPDase3 (Martín-Satué et al. in Histochem Cell Biol 131:615–628,
2009). The purpose of the present study was to characterize in the male reproductive tract the expression profile of the main
enzyme responsible for the generation of adenosine from AMP, namely the ecto-5′-nucleotidase (CD73). The enzyme was identified
by immunological techniques and by in situ enzymatic assays, including inhibition experiments with α,β-methylene-ADP, a specific
CD73 inhibitor. High levels of ecto-5′-nucleotidase were detected in testes in association with both germinal and somatic
cells, in smooth muscle cells throughout the tract, in secretory epithelia from exocrine glands, and remarkably, in principal
cells of epididymis, where co-localization with NTPDase3 was found. The relevance of this co-expression on nucleotide hydrolysis
in these cells directly involved in the control of sperm fluid composition was addressed biochemically. This study suggests
close regulation of extracellular nucleoside and nucleotide levels in the genital tract by ecto-5′-nucleotidase that, in concurrence
with NTPDases, may impact male fertility. 相似文献
935.
936.
Robert J. Gleave Daryl S. Walter Paul J. Beswick Elena Fonfria Anton D. Michel Shilina A. Roman Sac-Pham Tang 《Bioorganic & medicinal chemistry letters》2010,20(16):4951-4954
A series of analogues of the pyrazole lead 1 were synthesized in which the heterocyclic core was replaced with an imidazole. A number of potent antagonists were identified and structure–activity relationships (SAR) were investigated both with respect to activity at the P2X7 receptor and in vitro metabolic stability. Compound 10 was identified as a potent P2X7 antagonist with reduced in vitro metabolism and high solubility. 相似文献
937.
938.
939.
Alexandre Hinzpeter Abdel Aissat Elvira Sondo Catherine Costa Nicole Arous Christine Gameiro Natacha Martin Agathe Tarze Laurence Weiss Alix de Becdelièvre Bruno Costes Michel Goossens Luis J. Galietta Emmanuelle Girodon Pascale Fanen 《PLoS genetics》2010,6(10)
Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies. 相似文献
940.
Gaudet MM Kirchhoff T Green T Vijai J Korn JM Guiducci C Segrè AV McGee K McGuffog L Kartsonaki C Morrison J Healey S Sinilnikova OM Stoppa-Lyonnet D Mazoyer S Gauthier-Villars M Sobol H Longy M Frenay M GEMO Study Collaborators Hogervorst FB Rookus MA Collée JM Hoogerbrugge N van Roozendaal KE;HEBON Study Collaborators Piedmonte M Rubinstein W Nerenstone S Van Le L Blank SV Caldés T de la Hoya M Nevanlinna H Aittomäki K Lazaro C Blanco I Arason A Johannsson OT Barkardottir RB Devilee P 《PLoS genetics》2010,6(10):e1001183
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer. 相似文献