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91.
MS Malamas H Stange R Schindler HJ Lankau C Grunwald B Langen U Egerland T Hage Y Ni J Erdei KY Fan K Parris KL Marquis S Grauer J Brennan R Navarra R Graf BL Harrison A Robichaud T Kronbach MN Pangalos NJ Brandon N Hoefgen 《Bioorganic & medicinal chemistry letters》2012,22(18):5876-5884
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2mg/kg). 相似文献
92.
We tested the hypothesis that leaves of broad-leaved tree species are more highly defended at low latitudes than at high latitudes. We used canonical discriminant analysis to compare tree species from Panama (9°N, 39 species), Missouri, USA (38°N, 37 species), and southern Ontario, Canada (44°N, 34 species) with respect to two structural and five nutritional traits, taking into account each species' tolerance to shade. Trees from the three locations differed significantly, with Panamanian species the most distinct. Defenses of shade-tolerant species were significantly greater than those of shade-intolerant species, but only for the Panamanian sample, which is consistent with the low latitude/high defense hypothesis. Because we sampled many of the same tree species from Missouri and southern Ontario, and many tree species in the same taxonomic families in Missouri and Panama, we were able to control for the potential confounding effects of phylogeny. Overall defense levels, calculated by summing the z-scores for individual traits in each location, were significantly higher for Panama compared to Missouri, and marginally so for Missouri compared to southern Ontario, again consistent with the low latitude/high defense hypothesis. Traits contributing to these differences were mostly structural factors (e.g., fiber) and to a lesser degree nutritional traits, while secondary compounds made no independent contribution to differences in overall defense levels (four traits compared between Panama and Missouri). Contrary to our expectation, the number and types of secondary compounds per species reported in the literature for our species did not differ between temperate and tropical locations, while the diversity of these compounds was greater for the temperate species. Overall, our results provide some support for the hypothesis that leaf defenses against herbivory are better developed in tropical than in temperate trees, but the differences were due to structural and nutritional factors rather than secondary compounds. 相似文献
93.
Multiple linkage regions have been reported in schizophrenia, and some appear to harbor susceptibility genes that are differentially expressed in postmortem brain tissue derived from unrelated individuals. We combined traditional genome-wide linkage analysis in a multiplex family with lymphocytic genome-wide expression analysis. A genome scan suggested linkage to a chromosome 4q marker (D4S1530, LOD 2.17, θ=0) using a dominant model. Haplotype analysis using flanking microsatellite markers delineated a 14 Mb region that cosegregated with all those affected. Subsequent genome-wide scan with SNP genotypes supported the evidence of linkage to 4q33–35.1 (LOD=2.39) using a dominant model. Genome-wide microarray analysis of five affected and five unaffected family members identified two differentially expressed genes within the haplotype AGA and GALNT7 (aspartylglucosaminidase and UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 7) with nominal significance; however, these genes did not remain significant following analysis of covariance. We carried out genome-wide linkage analyses between the quantitative expression phenotype and genetic markers. AGA expression levels showed suggestive linkage to multiple markers in the haplotype (maximum LOD=2.37) but to no other genomic region. GALNT7 expression levels showed linkage to regulatory loci at 4q28.1 (maximum LOD=3.15) and in the haplotype region at 4q33–35.1 (maximum LOD=2.37). ADH1B (alcohol dehydrogenase IB) was linked to loci at 4q21–q23 (maximum LOD=3.08) and haplotype region at 4q33–35.1 (maximum LOD=2.27). Seven differentially expressed genes were validated with RT-PCR. Three genes in the 4q33–35.1 haplotype region were also differentially expressed in schizophrenia in postmortem dorsolateral prefrontal cortex: AGA, HMGB2, and SCRG1. These results indicate that combining differential gene expression with linkage analysis may help in identifying candidate genes and potential regulatory sites. Moreover, they also replicate recent findings of complex trans- and cis- regulation of genes. 相似文献
94.
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96.
Adolfo Sequeira Firoza Mamdani Carl Ernst Marquis P. Vawter William E. Bunney Veronique Lebel Sonia Rehal Tim Klempan Alain Gratton Chawki Benkelfat Guy A. Rouleau Naguib Mechawar Gustavo Turecki 《PloS one》2009,4(8)
Background
Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations.Methodology/Principal Findings
We performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data.Conclusions/Significance
The observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions. 相似文献97.
Keith J. Murphy Judith P. F. Ter Horst Andrew W. Cassidy Ian E. J. DeSouza Marina Morgunova Christine Li Laura M. Connole Niamh C. O’Sullivan Jennifer S. Loscher Angela T. Brady Nanette Rombach Joanna Connellan Paul A. McGettigan Darren Scully Rocio Fedriani Bartlomiej Lukasz Mary P. Moran Olive M. McCabe Caitlin M. Wantuch Zoe A. Hughes Sean K. Mulvany Desmond G. Higgins Menelas N. Pangalos Karen L. Marquis William T. O’Connor Robert H. Ring David Von Schack Ciaran M. Regan 《Journal of neurochemistry》2010,113(3):601-614
98.
Yinfa Yan Ping Zhou David P. Rotella Rolf Feenstra Chris G. Kruse Jan-Hendrik Reinders Martina van der Neut Margaret Lai Jean Zhang Dianne M. Kowal Tikva Carrick Karen L. Marquis Mark H. Pausch Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2010,20(9):2983-2986
A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D2 ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D2 partial agonists and serotonin reuptake inhibitors. Structure–activity studies revealed that the linker plays a key role in contributing to D2 affinity, function, and SRI activity. 相似文献
99.
100.
KK Chan B Dassanayake R Deen RE Wickramarachchi SK Kumarage S Samita KI Deen 《World journal of surgical oncology》2010,8(1):1-11