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911.
Emily M. Stocking Leah Aluisio John R. Atack Pascal Bonaventure Nicholas I. Carruthers Christine Dugovic Anita Everson Ian Fraser Xiaohui Jiang Perry Leung Brian Lord Kiev S. Ly Kirsten L. Morton Diane Nepomuceno Chandravadan R. Shah Jonathan Shelton Akinola Soyode-Johnson Michael A. Letavic 《Bioorganic & medicinal chemistry letters》2010,20(9):2755-2760
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H3 receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H3 receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate. 相似文献
912.
Robert R. Singhaus Ronald C. Bernotas Robert Steffan Edward Matelan Elaine Quinet Ponnal Nambi Irene Feingold Christine Huselton Anna Wilhelmsson Annika Goos-Nilsson Jay Wrobel 《Bioorganic & medicinal chemistry letters》2010,20(2):521-525
Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs. 相似文献
913.
Kristen L.G. Jones M. Katharine Holloway Hua-Poo Su Steven S. Carroll Christine Burlein Sinoeun Touch Daniel J. DiStefano Rosa I. Sanchez Theresa M. Williams Joseph P. Vacca Craig A. Coburn 《Bioorganic & medicinal chemistry letters》2010,20(14):4065-4068
A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-l-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket. 相似文献
914.
Jeffrey Y. Melamed Amy E. Zartman Nathan R. Kett Anthony L. Gotter Victor N. Uebele Duane R. Reiss Cindra L. Condra Christine Fandozzi Laura S. Lubbers Blake A. Rowe Georgia B. McGaughey Martin Henault Rino Stocco John J. Renger George D. Hartman Mark T. Bilodeau B. Wesley Trotter 《Bioorganic & medicinal chemistry letters》2010,20(15):4700-4703
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood–brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited 125I-NPS binding in the CNS when administered to rats. 相似文献
915.
916.
Duane L. Guernsey Haiyan Jiang Karen Bedard Susan C. Evans Meghan Ferguson Makoto Matsuoka Christine Macgillivray Mathew Nightingale Scott Perry Andrea L. Rideout Andrew Orr Mark Ludman David L. Skidmore Timothy Benstead Mark E. Samuels 《PLoS genetics》2010,6(8)
Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred. 相似文献
917.
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
918.
Gary K. Chen Robert C. Millikan Esther M. John Christine B. Ambrosone Leslie Bernstein Wei Zheng Jennifer J. Hu Stephen J. Chanock Regina G. Ziegler Elisa V. Bandera Brian E. Henderson Christopher A. Haiman Daniel O. Stram 《PLoS genetics》2010,6(9)
We consider the feasibility of reusing existing control data obtained in genetic association studies in order to reduce costs for new studies. We discuss controlling for the population differences between cases and controls that are implicit in studies utilizing external control data. We give theoretical calculations of the statistical power of a test due to Bourgain et al (Am J Human Genet 2003), applied to the problem of dealing with case-control differences in genetic ancestry related to population isolation or population admixture. Theoretical results show that there may exist bounds for the non-centrality parameter for a test of association that places limits on study power even if sample sizes can grow arbitrarily large. We apply this method to data from a multi-center, geographically-diverse, genome-wide association study of breast cancer in African-American women. Our analysis of these data shows that admixture proportions differ by center with the average fraction of European admixture ranging from approximately 20% for participants from study sites in the Eastern United States to 25% for participants from West Coast sites. However, these differences in average admixture fraction between sites are largely counterbalanced by considerable diversity in individual admixture proportion within each study site. Our results suggest that statistical correction for admixture differences is feasible for future studies of African-Americans, utilizing the existing controls from the African-American Breast Cancer study, even if case ascertainment for the future studies is not balanced over the same centers or regions that supplied the controls for the current study. 相似文献
919.
Yacine Hemar Li Jiang Cheng Christine M. Oliver Luz Sanguansri Maryann Augustin 《Food biophysics》2010,5(2):120-127
The suitability of water-in-oil-in-water multiple emulsions to encapsulate resveratrol was assessed. Multiple emulsions were
prepared by emulsifying a primary emulsion (40 wt.%) in water containing 0.5 wt.% sodium caseinate and 0.1 M NaCl. Four primary
emulsions of canola oil (20 wt.%) stabilized by 8 wt.% polyglycerol polyricinoleate were chosen. The dispersed phase of the
primary emulsions contained 0.1 M NaCl and either water, 20 wt.% ethanol in water, 2.5 wt.% whey protein isolate (WPI) in
water, or 2.5 wt.% WPI and 5 wt.% gelatine in water. Resveratrol was incorporated into these primary emulsions at 0.25 wt.%
to give a final 0.02 wt.% resveratrol in the multiple emulsions. Slight increase in particle size with storage at 23 °C for
up to 2 weeks was observed. Further, less than 10% of the total encapsulated resveratrol is released to the external, continuous,
aqueous phase. This work demonstrates the potential of multiple emulsions to encapsulate resveratrol for food applications. 相似文献
920.
Christine A. Farthing Don E. Farthing Saisudha Koka Terri Larus Itaf Fakhry Lei Xi Rakesh C. Kukreja Domenic Sica Todd W.B. Gehr 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(28):2891-2895
A simple and sensitive high-performance liquid chromatographic (HPLC) method utilizing fluorescence detection was developed for the determination of the phosphodiesterase type 5 inhibitor tadalafil in mouse plasma. This method utilizes a simple sample preparation (protein precipitation) with high recovery of tadalafil (∼98%), which eliminates the need for an internal standard. For constituent separation, the method utilized a monolithic C18 column and a flow rate of 1.0 mL/min with a mobile phase gradient consisting of aqueous trifluoroacetic acid (0.1% TFA in deionized water pH 2.2, v/v) and acetonitrile. The method calibration was linear for tadalafil in mouse plasma from 100 to 2000 ng/mL (r > 0.999) with a detection limit of approximately 40 ng/mL. Component fluorescence detection was achieved using an excitation wavelength of 275 nm with monitoring of the emission wavelength at 335 nm. The intra-day and inter-day precision (relative standard deviation, RSD) values for tadalafil in mouse plasma were less than 14%, and the accuracy (percent error) was within −14% of the nominal concentration. The method was utilized on mouse plasma samples from research evaluating the potential cardioprotective effects of tadalafil on mouse heart tissue exposed to doxorubicin, a chemotherapeutic drug with reported cardiotoxic effects. 相似文献