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991.
Siobhan Malany Lisa M. Hernandez William F. Smith Paul D. Crowe Sam R. J. Hoare 《Journal of receptor and signal transduction research》2013,33(2):84-93
We introduce a novel experimental method to determine both the extent of ex vivo receptor occupancy of administered compound and its dissociation rate constant (k4). [Here, we reference k4 as the rate of offset of unlabeled ligand in convention with Motulsky and Mahan ()]. We derived a kinetic rate equation based on the dissociation rate constant for an unlabeled compound competing for the same site as a labeled compound and describe a model to simulate fractional occupancy. To validate our model, we performed in vitro kinetics and ex vivo occupancy experiments in rat cortex with varying concentrations of (R)-dimethindene, a sedating antihistamine. Brain tissue was removed at various times post oral administration, and histamine H1 receptor ligand [3H]-doxepin binding to homogenates from drug-treated or vehicle-treated rats was measured at multiple time points at room temperature. Fractional occupancy and k4 for (R)-dimethindene binding to H1 receptors were calculated by using our proposed model. Rats dosed with 30 and 60?mg/kg (R)-dimethindene showed 42% and 67% occupancy of central H1 receptors, respectively. These results were comparable to occupancy data determined by equilibrium radioligand binding. In addition, drug k4 rate determined by using our ex vivo method was equivalent to k4determined by in vitro competition kinetics (dissociation half-life t1/2 ~ 30?min). The outlined method can be used to assess, by simulation and experiment, occupancy for compounds based on dissociation rate constants and contributes to current efforts in drug optimization to profile antagonist efficacy in terms of its kinetic drug-target binding parameters. Data described by the method may be analyzed with commercially available software. Suggested fitting procedures are given in the appendix. 相似文献
992.
Haifeng Tang Reynald K. de Jesus Shawn P. Walsh Yuping Zhu Yan Yan Birgit T. Priest Andrew M. Swensen Magdalena Alonso-Galicia John P. Felix Richard M. Brochu Timothy Bailey Brande Thomas-Fowlkes Xiaoyan Zhou Lee-Yuh Pai Caryn Hampton Melba Hernandez Karen Owens Sophie Roy Alexander Pasternak 《Bioorganic & medicinal chemistry letters》2013,23(21):5829-5832
A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents. 相似文献
993.
Hui Shen Mitra Mazarei Hiroshi Hisano Luis Escamilla-Trevino Chunxiang Fu Yunqiao Pu Mary R. Rudis Yuhong Tang Xirong Xiao Lisa Jackson Guifen Li Tim Hernandez Fang Chen Arthur J. Ragauskas C. Neal Stewart Jr. Zeng-Yu Wang Richard A. Dixon 《The Plant cell》2013,25(11):4342-4361
It is necessary to overcome recalcitrance of the biomass to saccharification (sugar release) to make switchgrass (Panicum virgatum) economically viable as a feedstock for liquid biofuels. Lignin content correlates negatively with sugar release efficiency in switchgrass, but selecting the right gene candidates for engineering lignin biosynthesis in this tetraploid outcrossing species is not straightforward. To assist this endeavor, we have used an inducible switchgrass cell suspension system for studying lignin biosynthesis in response to exogenous brassinolide. By applying a combination of protein sequence phylogeny with whole-genome microarray analyses of induced cell cultures and developing stem internode sections, we have generated a list of candidate monolignol biosynthetic genes for switchgrass. Several genes that were strongly supported through our bioinformatics analysis as involved in lignin biosynthesis were confirmed by gene silencing studies, in which lignin levels were reduced as a result of targeting a single gene. However, candidate genes encoding enzymes involved in the early steps of the currently accepted monolignol biosynthesis pathway in dicots may have functionally redundant paralogues in switchgrass and therefore require further evaluation. This work provides a blueprint and resources for the systematic genome-wide study of the monolignol pathway in switchgrass, as well as other C4 monocot species. 相似文献
994.
Involvement of cytosolic ascorbate peroxidase and Cu/Zn-superoxide dismutase for improved tolerance against drought stress 总被引:2,自引:0,他引:2
Faize M Burgos L Faize L Piqueras A Nicolas E Barba-Espin G Clemente-Moreno MJ Alcobendas R Artlip T Hernandez JA 《Journal of experimental botany》2011,62(8):2599-2613
In order to understand the role of cytosolic antioxidant enzymes in drought stress protection, transgenic tobacco (Nicotiana tabacum cv. Xanthi) plants overexpressing cytosolic Cu/Zn-superoxide dismutase (cytsod) (EC 1.15.1.1) or ascorbate peroxidase (cytapx) (EC 1.11.1.1) alone, or in combination, were produced and tested for tolerance against mild water stress. The results showed that the simultaneous overexpression of Cu/Znsod and apx or at least apx in the cytosol of transgenic tobacco plants alleviates, to some extent, the damage produced by water stress conditions. This was correlated with higher water use efficiency and better photosynthetic rates. In general, oxidative stress parameters, such as lipid peroxidation, electrolyte leakage, and H(2)O(2) levels, were higher in non-transformed plants than in transgenic lines, suggesting that, at the least, overexpression of cytapx protects tobacco membranes from water stress. In these conditions, the activity of other antioxidant enzymes was induced in transgenic lines at the subcellular level. Moreover, an increase in the activity of some antioxidant enzymes was also observed in the chloroplast of transgenic plants overexpressing cytsod and/or cytapx. These results suggest the positive influence of cytosolic antioxidant metabolism on the chloroplast and underline the complexity of the regulation network of plant antioxidant defences during drought stress. 相似文献
995.
de Borsetti NH Dean BJ Bain EJ Clanton JA Taylor RW Gamse JT 《Developmental biology》2011,358(1):251-261
The formation of the embryonic brain requires the production, migration, and differentiation of neurons to be timely and coordinated. Coupling to the photoperiod could synchronize the development of neurons in the embryo. Here, we consider the effect of light and melatonin on the differentiation of embryonic neurons in zebrafish. We examine the formation of neurons in the habenular nuclei, a paired structure found near the dorsal surface of the brain adjacent to the pineal organ. Keeping embryos in constant darkness causes a temporary accumulation of habenular precursor cells, resulting in late differentiation and a long-lasting reduction in neuronal processes (neuropil). Because constant darkness delays the accumulation of the neurendocrine hormone melatonin in embryos, we looked for a link between melatonin signaling and habenular neurogenesis. A pharmacological block of melatonin receptors delays neurogenesis and reduces neuropil similarly to constant darkness, while addition of melatonin to embryos in constant darkness restores timely neurogenesis and neuropil. We conclude that light and melatonin schedule the differentiation of neurons and the formation of neural processes in the habenular nuclei. 相似文献
996.
Ricardo J. Soares Magalhães Maria Sonia Salamat Lydia Leonardo Darren J. Gray Hélène Carabin Kate Halton Donald P. McManus Gail M. Williams Pilarita Rivera Ofelia Saniel Leda Hernandez Laith Yakob Stephen McGarvey Archie Clements 《International journal for parasitology》2014
Schistosoma japonicum infection is believed to be endemic in 28 of the 80 provinces of The Philippines and the most recent data on schistosomiasis prevalence have shown considerable variability between provinces. In order to increase the efficient allocation of parasitic disease control resources in the country, we aimed to describe the small-scale spatial variation in S. japonicum prevalence across The Philippines, quantify the role of the physical environment in driving the spatial variation of S. japonicum, and develop a predictive risk map of S. japonicum infection. Data on S. japonicum infection from 35,754 individuals across the country were geo-located at the barangay level and included in the analysis. The analysis was then stratified geographically for the regions of Luzon, the Visayas and Mindanao. Zero-inflated binomial Bayesian geostatistical models of S. japonicum prevalence were developed and diagnostic uncertainty was incorporated. Results of the analysis show that in the three regions, males and individuals aged ?20 years had significantly higher prevalence of S. japonicum compared with females and children <5 years. The role of the environmental variables differed between regions of The Philippines. Schistosoma japonicum infection was widespread in the Visayas whereas it was much more focal in Luzon and Mindanao. This analysis revealed significant spatial variation in the prevalence of S. japonicum infection in The Philippines. This suggests that a spatially targeted approach to schistosomiasis interventions, including mass drug administration, is warranted. When financially possible, additional schistosomiasis surveys should be prioritised for areas identified to be at high risk but which were under-represented in our dataset. 相似文献
997.
Kimberly P. Keil Lisa L. Abler Vatsal Mehta Helene M. Altmann Jimena Laporta Erin H. Plisch M. Suresh Laura L. Hernandez Chad M. Vezina 《Developmental biology》2014
In prostate and other epithelial cancers, E-cadherin (CDH1) is downregulated inappropriately by DNA methylation to promote an invasive phenotype. Though cancer frequently involves a reawakening of developmental signaling pathways, whether DNA methylation of Cdh1 occurs during organogenesis has not been determined. Here we show that DNA methylation of Cdh1 mediates outgrowth of developing prostate ducts. During the three-day gestational window leading up to and including prostate ductal initiation, Cdh1 promoter methylation increases and its mRNA and protein abundance decreases in epithelium giving rise to prostatic buds. DNA methylation is required for prostate specification, ductal outgrowth, and branching morphogenesis. All three endpoints are impaired by a DNA methylation inhibitor, which also decreases Cdh1 promoter methylation and increases Cdh1 mRNA and protein abundance. A CDH1 function-blocking antibody restores prostatic identity, bud outgrowth, and potentiates epithelial differentiation in the presence of the DNA methylation inhibitor. This is the first study to mechanistically link acquired changes in DNA methylation to the normal process of prostate organogenesis. We propose a novel mechanism whereby Cdh1 promoter methylation restricts Cdh1 abundance in developing prostate epithelium to create a permissive environment for prostatic bud outgrowth. Thus, DNA methylation primes the prostate primordium to respond to developmental cues mediating outgrowth, differentiation and maturation of the ductal network. 相似文献
998.
999.
Charity M. Phillips-Lander David A. Fowle Anne Taunton Walter Hernandez Marielos Mora David Moore 《Geomicrobiology journal》2014,31(1):23-41
A longitudinal field microcosm study was conducted in the Las Pailas hot spring system, located on the SW flank of Rincon de la Vieja, Costa Rica, in order to investigate initial microbial attachment and colonization, as well as chemical (abiotic) and biological silicate weathering under hydrothermal conditions. Solution chemistry was pH = 2.42–3.96, T = 43–89.3°C, Si = 4.45–8.19 mmol L?1, Fe = 1.50–6.95 mmol L?1and PO3? 4 = below detection limits-4.9 μmol L?1. Microcosms consisted of washed, sonicated primary silicate samples in polycarbonate vessels. The vessels were enclosed either by mesh to observe water/rock/microbial interactions or by 0.2–0.45 μm filters to observe water/rock interactions. Microcosms were incubated for periods of 6 h, 24 h, or 2 mo, fixed in the field, then analyzed in the laboratory. Scanning electron microscopy (SEM) analysis revealed that microbial attachment to mineral samples occurred in as little as 6 h. Microbial colonization and the development of minor etch pits associated with microorganisms occurred within 24 h. The most significant differences in chemical vs. biological weathering were observed after 2 mo. SEM analysis of these incubated surfaces showed that volumetric losses to mineral samples were more than one order of magnitude greater for samples that had been colonized by microorganisms and thus weathered biologically. With time, preferential colonization of anorthoclase mineral samples with Fe-oxides and apatite inclusions occurred. Subsequent weathering, therefore, may be a metabolic strategy by microorganisms to access mineral-bound PO3? 4, which is otherwise scarce in solution. Results from this study suggest that microorganisms may play a significant role in weathering in some hydrothermal systems. 相似文献
1000.