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951.
Quantum-mechanical calculations of the stabilities of fluxional isomers of C4H(7)(+) in solution
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Casanova J Kent DR Goddard WA Roberts JD 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(1):15-19
Although numerous quantum calculations have been made over the years of the stabilities of the fluxional isomers of C(4)H(7)(+), none have been reported for other than the gas phase (which is unrealistic for these ionic species) that exhibit exceptional fluxional properties in solution. To be sure, quantum-mechanical calculations for solutions are subject to substantial uncertainties, but nonetheless it is important to see whether the trends seen for the gas-phase C(4)H(7)(+) species are also found in calculations for polar solutions. Of the C(4)H(7)(+) species, commonly designated bisected-cyclopropylcarbinyl 1, unsym-bicyclobutonium 2, sym-bicyclobutonium 3, allylcarbinyl 4, and pyramidal structure 6, the most advanced gas-phase calculations available thus far suggest that the order of stability is 1 > or = 2 > or = 3 4 6 with barriers of only approximately 1 kcalmol for interconversions among 1, 2, and 3. We report here that, when account is taken of solvation, 2 turns out to be slightly more stable than 1 or 3 in polar solvents. The pattern of the overall results is unexpected, in that despite substantial differences in structures and charge distributions between the primary players in the C(4)H(7)(+) equilibria and the large differences in solvation energies calculated for the solvents considered, the differential solvent effects from species to species are rather small. 相似文献
952.
Asnis GM Hameedi FA Goddard AW Potkin SG Black D Jameel M Desagani K Woods SW 《Psychiatry research》2001,106(1):1-14
Abnormalities in the integration of auditory and visual language inputs could underlie many core psychotic features. Perceptual confusion may arise because of the normal propensity of visual speech perception to evoke auditory percepts. Recent functional neuroimaging studies of normal subjects have demonstrated activation in auditory-linguistic brain areas in response to silent lip-reading. Three functional magnetic resonance imaging experiments were carried out on seven normal volunteers, and 14 schizophrenia patients, half of whom were actively psychotic. The tasks involved listening to auditory speech, silent lip-reading (visual speech), and perception of meaningless lip movements (visual non-speech). Subjects also undertook a behavioural study of audio-visual word identification designed to evoke perceptual fusions. Patients and controls both showed susceptibility to audio-visual fusions on the behavioural task. The patient group as a whole showed less activation relative to controls in superior and inferior posterior temporal areas while performing the silent lip-reading task. Attending to visual non-speech, the patients activated less posterior (occipito-temporal) and more anterior (frontal, insular and striatal) brain areas than controls. This difference was accounted for largely by the psychotic subgroup. Insular and striatal areas were also activated in both subject groups in the auditory speech perception condition, thus demonstrating the bimodal sensitivity of these regions. The results suggest that schizophrenia patients with psychotic symptoms respond to visually ambiguous stimuli (non-speech) by activation of polysensory structures. This could reflect particular processing strategies and may increase susceptibility to certain paranoid and hallucinatory symptoms. 相似文献
953.
Oumata N Bettayeb K Ferandin Y Demange L Lopez-Giral A Goddard ML Myrianthopoulos V Mikros E Flajolet M Greengard P Meijer L Galons H 《Journal of medicinal chemistry》2008,51(17):5229-5242
Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK1) are involved in the two key molecular features of Alzheimer's disease, production of amyloid-beta peptides (extracellular plaques) and hyper-phosphorylation of Tau (intracellular neurofibrillary tangles). A series of 2,6,9-trisubstituted purines, structurally related to the CDK inhibitor roscovitine, have been synthesized. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivatives displayed potent inhibition of both CDKs and CK1. In particular, derivative 13a was a potent inhibitor of CDK1/cyclin B (IC 50: 220 nM), CDK5/p25 (IC 50: 80 nM), and CK1 (IC 50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1delta provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of amyloid-beta in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers. 相似文献
954.
Sumner JW Durden LA Goddard J Stromdahl EY Clark KL Reeves WK Paddock CD 《Emerging infectious diseases》2007,13(5):751-753
Geographic distribution of Rickettsia parkeri in its US tick vector, Amblyomma maculatum, was evaluated by PCR. R. parkeri was detected in ticks from Florida, Georgia, Kentucky, Mississippi, Oklahoma, and South Carolina, which suggests that A. maculatum may be responsible for additional cases of R. parkeri rickettsiosis throughout much of its US range. 相似文献
955.
Raynaud FI Fischer PM Nutley BP Goddard PM Lane DP Workman P 《Molecular cancer therapeutics》2004,3(3):353-362
Determination of pharmacokinetic properties in the intact animal remains a major bottleneck in drug discovery. Cassette dosing involves administration of a cocktail of drugs to individual animals. Here we describe the cassette dosing properties of a 107-membered library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 (CDK2) inhibitors. A three-step parallel synthesis approach produced compounds with purity ranging from 63% to 100%. Cassette dosing was validated by comparing the pharmacokinetic parameters obtained following i.v. administration of a mixture of olomoucine, R-roscovitine (CYC202), and bohemine, each at 16.6 mg/kg, with results for administration of single agents at 50 mg/kg. No significant difference was observed between the pharmacokinetic parameters of agents when dosed in combination compared with those of individual compounds. CYC202 showed the highest area under the curve (AUC) and the longest elimination half-life (t(1/2)). Further cassettes evaluated the library of trisubstituted purines with CYC202 and purvalanol A included as pharmacokinetic standards in a validated limited sampling strategy. The ratios of pharmacokinetic parameters to that of CYC202 [AUC, maximum concentration (C(max)), and t(1/2)] remained similar when compounds were tested in two different cassettes or as individual compounds. Following dosing of the same cassette on three different days, there was less than 20% variation in pharmacokinetic parameters between days. The structure-pharmacokinetics relationship showed that the favored purine substituents are benzylamine and veratrylamine at position 6, amino-2 propanol at position 2, and methylpropyl or hydroxyethyl at position 9. Without cassette dosing, this study would have used 3 times as many animals and would have taken 4 times longer, illustrating the power of this method in lead optimization. 相似文献
956.
957.
Elizabeth G. Liles Michael C. Leo Amanda S. Freed Kathryn M. Porter Jamilyn M. Zepp Tia L. Kauffman Erin Keast Carmit K. McMullen Inga Gruß Barbara B. Biesecker Kristin R. Muessig Donna J. Eubanks Laura M. Amendola Michael O. Dorschner Bradley A. Rolf Gail P. Jarvik Katrina A.B. Goddard Benjamin S. Wilfond 《Genetics in medicine》2022,24(8):1664-1674
PurposeIndividuals having genomic sequencing can choose to be notified about pathogenic variants in genes unrelated to the testing indication. A decision aid can facilitate weighing one’s values before making a choice about these additional results.MethodsWe conducted a randomized trial (N = 231) comparing informed values-choice congruence among adults at risk for a hereditary cancer syndrome who viewed either the Optional Results Choice Aid (ORCA) or web-based additional findings information alone. ORCA is values-focused with a low-literacy design.ResultsIndividuals in both arms had informed values-choice congruence (75% and 73% in the decision aid and web-based groups, respectively; odds ratio [OR] = 1.10, 95% CI = 0.58-2.08). Most participants had adequate knowledge (79% and 76% in the decision aid and web-based groups, respectively; OR = 1.20, 95% CI = 0.61-2.34), with no significant difference between groups. Most had information-seeking values (97% and 98% in the decision aid and web-based groups, respectively; OR = 0.59, 95% CI = 0.10-3.61) and chose to receive additional findings.ConclusionThe ORCA decision aid did not significantly improve informed values-choice congruence over web-based information in this cohort of adults deciding about genomic results. Both web-based approaches may be effective for adults to decide about receiving medically actionable additional results. 相似文献
958.
959.
960.
Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain‐death induced immunological injury post–lung transplant
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Qi Cheng Kunal Patel Biao Lei Lindsay Rucker D. Patterson Allen Peng Zhu Chentha Vasu Paulo N. Martins Martin Goddard Satish N. Nadig Carl Atkinson 《American journal of transplantation》2018,18(10):2417-2428
Donor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia‐reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post‐LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post‐LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle‐treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post‐LTx in the context of donor BD. 相似文献