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101.
102.
Haffner CD McDougald DL Reister SM Thompson BD Conlee C Fang J Bass J Lenhard JM Croom D Secosky-Chang MB Tomaszek T McConn D Wells-Knecht K Johnson PR 《Bioorganic & medicinal chemistry letters》2005,15(23):5257-5261
We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog. 相似文献
103.
Dellinger TA Youngman RR Laub CA Brewster CC Kuhar TP 《Journal of economic entomology》2005,98(1):72-81
Cultivars of glandular-haired alfalfa, Medicago sativa L., such as '54H69', are currently available and marketed as being resistant to potato leafhopper, Empoasca fabae (Harris). Between 2000 and 2002, studies were conducted to compare the effects of '54H69' and a standard, nonglandular-haired alfalfa cultivar, 'Choice', on alfalfa weevil, Hypera postica (Gyllenhal), and potato leafhopper populations at Campbell and Montgomery counties, Virginia. '54H69' had no effect on alfalfa weevil populations. At each location, densities of alfalfa weevil in '54H69' and 'Choice' were similar, but pest pressure was higher at Campbell Co. than at Montgomery Co. and always exceeded the economic threshold before insecticide was applied. Densities of potato leafhopper also did not differ between '54H69' and 'Choice' in any year at the two locations. Insecticide treatment effectively reduced potato leafhopper densities in the two cultivars, although populations were below the economic threshold at both locations when the insecticides were applied. Overall, postinsecticide treatment comparisons showed that the densities of alfalfa weevil and potato leafhoppers were similar or higher in untreated '54H69' compared with insecticide-treated 'Choice'. In addition, there were no differences in seasonal dry yields between '54H69' and 'Choice' in any year at either location. Our results indicate that the glandular-haired alfalfa '54H69' does not provide acceptable resistance to potato leafhopper and also does not offer a yield advantage to growers in Virginia. 相似文献
104.
105.
Sherrod M Davis DR Zhou X Cassell MD Sigmund CD 《American journal of physiology. Regulatory, integrative and comparative physiology》2005,289(6):R1763-R1769
Angiotensinogen (AGT) is mainly expressed in glial cells in close proximity to renin-expressing neurons in the brain. We previously reported that glial-specific overexpression of ANG II results in mild hypertension. Here, we tested the hypothesis that glial-derived AGT plays an important role in blood pressure regulation in hypertensive mice carrying human renin (hREN) and human AGT transgenes under the control of their own endogenous promoters. To perform a glial-specific deletion of AGT, we used an AGT transgene containing loxP sites (hAGT(flox)), so the gene can be permanently ablated in the presence of cre-recombinase expression, driven by the glial fibrillary acidic protein (GFAP) promoter. Triple transgenic mice (RAC) containing a: 1) systemically expressed hREN transgene, 2) systemically expressed hAGT(flox) transgene, and 3) GFAP-cre-recombinase were generated and compared with double transgenic mice (RA) lacking cre-recombinase. Liver and kidney hAGT mRNA levels were unaltered in RAC and RA mice, as was the level of hAGT in the systemic circulation, consistent with the absence of cre-recombinase expression in those tissues. Whereas hAGT mRNA was present in the brain of RA mice (lacking cre-recombinase), it was absent from the brain of RAC mice expressing cre-recombinase, confirming brain-specific elimination of AGT. Immunohistochemistry revealed a loss of AGT immunostaining glial cells throughout the brain in RAC mice. Arterial pressure measured by radiotelemetry was significantly lower in RAC than RA mice and unchanged from nontransgenic control mice. These data suggest that there is a major contribution of glial-AGT to the hypertensive state in mice carrying systemically expressed hREN and hAGT genes and confirm the importance of a glial source of ANG II substrate in the brain. 相似文献
106.
To better understand the development of ventral mesencephalic dopamine neurons, we performed subtractive hybridization screens to find ventral mesencephalic genes expressed at rat embryonic day 10 when these neurons begin to differentiate. The most commonly identified genes in these screens were members of the Bex (Brain expressed X-linked) gene family, rat Bex1 (Rex3), and a novel gene, rat Bex4. After identifying these genes, we then sought to characterize the Bex gene family. Two additional novel Bex genes (human Bex5 and mouse Bex6) were discovered through genomic databases. Bex5 is present in humans and monkeys, but not rodents, while Bex6 exists in mice, but not humans. Bex4 and Bex5 are localized to the X chromosome, are expressed in brain, and are similar in sequence. Bex4 and Bex5 are 54% and 56% identical to human Bex3 (pHGR74, NADE). Mouse Bex6 is on chromosome 16 and is 67% identical to mouse Bex4. Human Bex gene expression was studied with tissue expression arrays probed with specific oligonucleotides. Human Bex1 and Bex2 have similar expression patterns in the central nervous system with high levels in pituitary, cerebellum, and temporal lobe, and Bex1 is widely expressed outside of the central nervous system with high expression in the liver. Human Bex4 is highly expressed in heart, skeletal muscle, and liver, while Bex3 and Bex5 are more widely expressed. The subcellular localization of the Bex proteins varies from nuclear (rat Bex1) to cytoplasmic (rat Bex3, human Bex5, and mouse Bex6) and to both nuclear and cytoplasmic (rat Bex2 and rat Bex4). Rat Bex3, rat Bex4, human Bex5, and mouse Bex6 are degraded by the proteasome, while rat Bex1 or Bex2 are not. Rat Bex3 protein can likely bind transition metals through a histidine-rich domain. Because this gene family was originally named Bex and because these genes are unified by sequence similarity and gene structure, we believe the Bex nomenclature should prevail over nomenclature based on function (NADE) that has not been extended to the other Bex genes. We conclude that the Bex gene family members are highly homologous but differ in their expression patterns, subcellular localization, and degradation by the proteasome. 相似文献
107.
Haffner CD Thomson SA Guo Y Petrov K Larkin A Banker P Schaaf G Dickerson S Gobel J Gillie D Condreay JP Poole C Carpenter T Ulrich J 《Bioorganic & medicinal chemistry letters》2010,20(23):6989-6992
We report the synthesis and in vitro activity of a series of novel substituted N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs. These analogs showed potent inhibitory activity against Kv1.3. Several demonstrated similar potency to the known Kv1.3 inhibitor PAP-1 when tested under the IonWorks patch clamp assay conditions. Two compounds 13i and 13rr were advanced further as potential tool compounds for in vivo validation studies. 相似文献
108.
Paul E. Gold Robert P. Rose Curt W. Spanis Linda L. Hankins 《Hormones and behavior》1977,8(3):363-371
These experiments examined the effects of hypophysectomy on retention of avoidance training. In addition, the experiments examined the effects, on retention, of post-training ACTH injections administered to hypophysectomized rats. Rats were trained in a visual discriminated avoidance Y maze. Each rat received six training trials followed by six retraining trials the next day. Retention was measured by the number of correct choices during the retraining trials. When trained with a low-footshock intensity (0.8 mA), hypophysectomized rats showed retention performance which was significantly poorer than that of intact animals. There was no significant difference in performance when the animals were trained with a higher footshock intensity (1.4 mA), in part because of poorer retention performance of intact animals under these training conditions. Under both footshock conditions, a single post-training injection of ACTH enhanced later retention performance of hypophysectomized rats. This effect on memory was timedependent; injections delayed 2 or 6 hr after training did not significantly enhance retention. These findings are consistent with the view that hormonal responses to training may modulate later retention of the training experience. 相似文献
109.
Paymaan Jafar-nejad Berit Powers Armand Soriano Hien Zhao Daniel A Norris John Matson Beatrice DeBrosse-Serra Jamie Watson Padmakumar Narayanan Seung
J Chun Curt Mazur Holly Kordasiewicz Eric E Swayze Frank Rigo 《Nucleic acids research》2021,49(2):657
Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available. 相似文献
110.
Claude Miaud Tony Dejean Karine Savard Annie Millery-Vigues Alice Valentini Nadine Curt Grand Gaudin Trenton W. J. Garner 《Biological invasions》2016,18(8):2299-2308
Invasive species can be a threat to native species in several ways, including transmitting lethal infections caused by the parasites they carry. However, invasive species may also be plagued by novel and lethal infections they acquire when invading, making inferences regarding the ability of an invasive host to vector disease difficult from field observations of infection and disease. This is the case for the pathogenic fungus Batrachochytrium dendrobatidis (Bd) in Europe and one invasive host species, the North American bullfrog Lithobates catesbeianus, hypothesized to be responsible for vectoring lethal infection to European native amphibians. We tested this hypothesis experimentally using the alpine newt Ichthyosaura alpestris as our model native host. Our results show that infected bullfrog tadpoles are effective vectors of Bd. Native adult newts co-housed with experimentally infected bullfrog tadpoles became Bd infected (molecular and histological tests). Moreover, the exposed adult newts suffered mortality while the majority of infected bullfrog tadpoles survived until metamorphosis. These results cannot resolve the historical role of alien species in establishing the distribution of Bd across Europe or other regions in the world where this species was introduced, but they show its potential role as a Bd reservoir capable of transmitting lethal infections to native amphibians. Finally, our results also suggest that the removal of infected bullfrogs from aquatic environments may serve to reduce the availability of Bd in European amphibian communities, offering another justification for bullfrog eradication programmes that are currently underway or may be considered. 相似文献