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961.
Chaya Pooput Erica Rosemond Joel Karpiak Francesca Deflorian Santiago Vilar Stefano Costanzi Jürgen Wess Kenneth L. Kirk 《Bioorganic & medicinal chemistry》2009,17(23):7987-7992
The important and diverse biological functions of adrenergic receptors, a subclass of G protein-coupled receptors (GPCRs), have made the search for compounds that selectively stimulate or inhibit the activity of different adrenergic receptor subtypes an important area of medicinal chemistry. We previously synthesized 2-, 5-, and 6-fluoronorepinehprine (FNE) and 2-, 5-, and 6-fluoroepinephrine (FEPI) and found that 2FNE and 2FEPI were selective β-adrenergic agonists and that 6FNE and 6FEPI were selective α-adrenergic agonists, while 5FNE and 5FEPI were unselective. Agonist potencies correlated well with receptor binding affinities. Here, through a combination of molecular modeling and site-directed mutagenesis, we have identified N293 in the β2-adrenergic receptor as a crucial residue for the selectivity of the receptor for catecholamines fluorinated at different positions. 相似文献
962.
Numerous studies of birds have demonstrated the value of producinginsurance eggs. We have previously found that second eggs provideinsurance against failure of first eggs for Nazca boobies (Sulagranti), which raise only one chick to fledging, yet some femaleslay only one egg. We used an 8-year data set to compare 2 hypothesesfor clutch size variation: one based on trade-offs, predictingdeclining future performance by females that lay a costly secondegg and one based on parental quality, predicting that intrinsicallysuperior females lay 2 eggs both currently and in the future.Clutch size variation did not contribute to the best multistatemark–recapture model of survival, suggesting that clutchsize and survival are unrelated and that any survival cost ofreproduction related to laying second eggs is small. Transitionprobabilities between reproductive states were generally, butnot entirely, inconsistent with fecundity costs of producinga marginal egg. Parental quality effects were apparent, withfemales tending to remain in a given reproductive state acrossseasons. Parents producing a marginal egg had consistently higherbreeding success than did parents of 1-egg clutches, due principallyto the insurance effect and secondarily to differences in parentalquality after hatching. Different model selection approachesgave differing results for logistic regression analyses of breedingsuccess of females that hatched eggs. A conventional significance-testing,iterative-fitting approach excluded insurance state from thetop model, whereas the information-theoretic (I-T) approachdetected an association between current insurance state andsubsequent survival and fecundity. Using the I-T approach, potentiallybiological significant (but not statistically significant underconventional analysis) effects were detected that may otherwisehave been ignored. 相似文献
963.
Bcl-2-related proteins and cancer 总被引:2,自引:0,他引:2
964.
Porcari AR Borysko KZ Ptak RG Breitenbach JM Wotring LL Drach JC Townsend LB 《Nucleosides & nucleotides》1999,18(11-12):2475-2497
Triciribine and triciribine monophosphate have antiviral and antiproliferative activity at low or submicromolar concentrations. In an effort to improve and better understand this activity, we have synthesized a series of acyclic analogs and evaluated them for activity against select viruses and cancer cell lines. We conclude that the rigid ribosyl ring system of triciribine must be intact in order to be phosphorylated and to obtain significant antiviral and antiproliferative activity. 相似文献
965.
966.
Anton Montsant Andrew E. Allen Sacha Coesel Alessandra De Martino Angela Falciatore Manuela Mangogna Magali Siaut Marc Heijde Kamel Jabbari Uma Maheswari Edda Rayko Assaf Vardi Kirk E. Apt John A. Berges Anthony Chiovitti Aubrey K. Davis Kimberlee Thamatrakoln Masood Z. Hadi Todd W. Lane J. Casey Lippmeier Diego Martinez Micaela S. Parker Gregory J. Pazour Mak A. Saito Dan S. Rokhsar E. Virginia Armbrust Chris Bowler 《Journal of phycology》2007,43(3):585-604
967.
Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux
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Bartels CF Bükülmez H Padayatti P Rhee DK van Ravenswaaij-Arts C Pauli RM Mundlos S Chitayat D Shih LY Al-Gazali LI Kant S Cole T Morton J Cormier-Daire V Faivre L Lees M Kirk J Mortier GR Leroy J Zabel B Kim CA Crow Y Braverman NE van den Akker F Warman ML 《American journal of human genetics》2004,75(1):27-34
The homodimeric transmembrane receptor natriuretic peptide receptor B (NPR-B [also known as guanylate cyclase B, GC-B, and GUC2B]; gene name NPR2) produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligand, C-type natriuretic peptide (CNP). CNP has previously been implicated in the regulation of skeletal growth in transgenic and knockout mice. The autosomal recessive skeletal dysplasia known as "acromesomelic dysplasia, type Maroteaux" (AMDM) maps to an interval that contains NPR2. We sequenced DNA from 21 families affected by AMDM and found 4 nonsense mutations, 4 frameshift mutations, 2 splice-site mutations, and 11 missense mutations. Molecular modeling was used to examine the putative protein change brought about by each missense mutation. Three missense mutations were tested in a functional assay and were found to have markedly deficient guanylyl cyclase activity. We also found that obligate carriers of NPR2 mutations have heights that are below the mean for matched controls. We conclude that, although NPR-B is expressed in a number of tissues, its major role is in the regulation of skeletal growth. 相似文献
968.
Y.Kirk Lin 《Animal behaviour》2004,68(2):367-372
We tested the hypothesis that dispersal and philopatry are components of a mixed evolutionarily stable strategy (ESS). The hypothesis predicts that fitness of dispersers should be equal to that of philopatric individuals. Alternatively, fitness of dispersers could be lower (the resident fitness hypothesis) or greater (the cost of dispersal hypothesis) than that of philopatric individuals. We compared fitness of individuals that moved to new habitats (emigrants) and those that remained within habitat boundaries (residents) in populations of the prairie vole, Microtus ochrogaster, and the meadow vole, M. pennsylvanicus. We established vole populations in four enclosures (). Within each enclosure, voles were free to move between four types of habitats that varied in the availability of supplemental food and the amount of vegetative cover. We analysed two fitness components: the survival rates of all individuals, and pregnancy rates of females. Our study showed that emigrants generally had greater fitness than residents and that the difference in fitness was habitat dependent (i.e. was greater when individuals were emigrating from low-quality habitats than from high-quality habitats). High-food, high-cover habitats were the only habitat types for which fitness of emigrants was lower than that of residents. Similar patterns occurred in both prairie voles and meadow voles. Our results support the cost of dispersal hypothesis. 相似文献
969.
Inhibition of hexose transport and abrogation of pH homeostasis in the intraerythrocytic malaria parasite by an O-3-hexose derivative 总被引:1,自引:0,他引:1
An O-3-hexose derivative, shown previously to inhibit a malaria parasite hexose transporter expressed in Xenopus oocytes as well as to suppress the multiplication of parasites, both in vitro and in vivo, was shown here to block the uptake of hexose sugars into isolated blood-stage parasites. This led to a decline in ATP levels and the loss of intracellular pH control. The results are consistent with those obtained with the cloned transporter. They support the notion that the transporter mediates uptake of glucose into the intraerythrocytic parasite and provide further support for the view that it is a suitable antimalarial drug target. 相似文献
970.
Li J O'Connor KL Hellmich MR Greeley GH Townsend CM Evers BM 《The Journal of biological chemistry》2004,279(27):28466-28474
Neurotensin (NT) is a gut peptide that plays an important role in gastrointestinal (GI) secretion, motility, and growth as well as the proliferation of NT receptor positive cancers. Secretion of NT is regulated by phorbol ester-sensitive protein kinase C (PKC) isoforms-alpha and -delta and may involve protein kinase D (PKD). The purpose of our present study was: (i) to define the role of PKD in NT release from BON endocrine cells and (ii) to delineate the upstream signaling mechanisms mediating this effect. Here, we demonstrate that small interfering RNA (siRNA) targeted against PKD dramatically inhibited both basal and PMA-stimulated NT secretion; NT release is significantly increased by overexpression of PKD. PKC-alpha and -delta siRNA attenuated PKD activity, whereas overexpression of PKC-alpha and -delta enhanced PKD activity. Rho kinase (ROK) siRNA significantly inhibited NT secretion, whereas overexpression of ROKalpha effectively increased NT release. Rho protein inhibitor C3 dramatically inhibited both NT secretion and PKD activity. In conclusion, our results demonstrate that PKD activation plays a central role in NT peptide secretion; upstream regulators of PKD include PKC-alpha and -delta and Rho/ROK. Importantly, our results identify novel signaling pathways, which culminate in gut peptide release. 相似文献