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81.
Discovery and structure–activity relationship of a novel spirocarbamate series of NPY Y5 antagonists
Colin P. Leslie Jonathan Bentley Matteo Biagetti Stefania Contini Romano Di Fabio Daniele Donati Thorsten Genski Sebastien Guery Angelica Mazzali Giancarlo Merlo Domenica A. Pizzi Fabiola Sacco Catia Seri Michela Tessari Laura Zonzini Laura Caberlotto 《Bioorganic & medicinal chemistry letters》2010,20(20):6103-6107
A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3 mg/kg po. 相似文献
82.
KASSO DAÏNOU JEAN‐PHILIPPE BIZOUX JEAN‐LOUIS DOUCET GRÉGORY MAHY OLIVIER J. HARDY MYRIAM HEUERTZ 《Molecular ecology》2010,19(20):4462-4477
The impact of the Pleistocene climate oscillations on the structure of biodiversity in tropical regions remains poorly understood. In this study, the forest refuge theory is examined at the molecular level in Milicia excelsa, a dioecious tree with a continuous range throughout tropical Africa. Eight nuclear microsatellites (nSSRs) and two sequences and one microsatellite from chloroplast DNA (cpDNA) showed a deep divide between samples from Benin and those from Lower Guinea. This suggests that these populations were isolated in separate geographical regions, probably for several glacial cycles of the Pleistocene, and that the nuclear gene pools were not homogenized despite M. excelsa’s wind‐pollination syndrome. The divide could also be related to seed dispersal patterns, which should be largely determined by the migration behaviour of M. excelsa’s main seed disperser, the frugivorous bat Eidolon helvum. Within Lower Guinea, a north–south divide, observed with both marker types despite weak genetic structure (nSSRs: FST = 0.035, cpDNA: GST = 0.506), suggested the existence of separate Pleistocene refugia in Cameroon and the Gabon/Congo region. We inferred a pollen‐to‐seed dispersal distance ratio of c. 1.8, consistent with wide‐ranging gene dispersal by both wind and bats. Simulations in an Approximate Bayesian Computation framework suggested low nSSR and cpDNA mutation rates, but imprecise estimates of other demographic parameters, probably due to a substantial gene flow between the Lower Guinean gene pools. The decline of genetic diversity detected in some Gabonese populations could be a consequence of the relatively recent establishment of a closed canopy forest, which could negatively affect M. excelsa’s reproductive system. 相似文献
83.
L. Mesin E. Merlo R. Merletti C. Orizio 《Journal of electromyography and kinesiology》2010,20(4):580-589
This work investigated motor unit (MU) recruitment during transcutaneous electrical stimulation (TES) of the tibialis anterior (TA) muscle, using experimental and simulated data. Surface electromyogram (EMG) and torque were measured during electrically-elicited contractions at different current intensities, on eight healthy subjects.EMG detected during stimulation (M-wave) was simulated selecting the elicited MUs on the basis of: (a) the simulated current density distribution in the territory of each MU and (b) the excitation threshold characteristic of the MU. Exerted force was simulated by adding the contribution of each of the elicited MUs. The effects of different fat layer thickness (between 2 and 8 mm), different distributions of excitation thresholds (random excitation threshold, higher threshold for larger MUs or smaller MUs), and different MU distributions within the muscle (random distribution, larger MU deeper in the muscle, smaller MU deeper) on EMG variables and torque were tested.Increase of the current intensity led to a first rapid increase of experimental M-wave amplitude, followed by a plateau. Further increases of the stimulation current determined an increase of the exerted force, without relevant changes of the M-wave. Similar results were obtained in simulations.Rate of change of conduction velocity (CV) and leading coefficient of the second order polynomial interpolating the force vs. stimulation level curve were estimated as a function of increasing current amplitudes. Experimental data showed an increase of estimated CV with increasing levels of the stimulation current (for all subjects) and a positive leading coefficient of force vs. stimulation current curve (for five of eight subjects). Simulations matched the experimental results only when larger MUs were preferably located deeper in the TA muscle (in line with a histochemical study). Marginal effect of MU excitation thresholds was observed, suggesting that MUs closer to the stimulation electrode are recruited first during TES regardless of their excitability. 相似文献
84.
85.
Isabella Campanini Andrea Merlo Dario Farina 《Journal of electromyography and kinesiology》2009,19(1):22-29
Motor unit properties were analyzed in patients with upper motor neuron syndrome (UMNS). Multi-channel surface electromyographic (EMG) signals were recorded for 300 s from the biceps brachii muscle of seven male subacute patients (time from lesion, mean ± SE, 4.9 ± 1.0 months). In three patients, both arms were investigated, leading to 10 recorded muscles. Patients were analyzed in rest-like condition with motor units activated due to pathological muscle overactivity. For a total of 12 motor units, the complete discharge pattern was extracted from EMG decomposition. Interpulse interval variability was 7.8 ± 0.9%. At minimum discharge rate (6.4 ± 0.4 pulses per second, pps), conduction velocity was smaller than at maximum discharge rate (12.0 ± 0.9 pps) in all motor units (3.60 ± 0.21 m/s vs. 3.84 ± 0.20 m/s). Conduction velocity changed by 1.35 ± 0.48% (different from zero, P < 0.01) for each increase of 1 pps in discharge rate. It was concluded that conduction velocity of low-threshold motor units in subacute patients with UMNS had similar values as reported in healthy subjects and was positively correlated to instantaneous discharge rate (velocity recovery function of muscle fibers). 相似文献
86.
p73 is regulated by phosphorylation at the G2/M transition 总被引:6,自引:0,他引:6
Fulco M Costanzo A Merlo P Mangiacasale R Strano S Blandino G Balsano C Lavia P Levrero M 《The Journal of biological chemistry》2003,278(49):49196-49202
87.
Genova ML Pich MM Biondi A Bernacchia A Falasca A Bovina C Formiggini G Parenti Castelli G Lenaz G 《Experimental biology and medicine (Maywood, N.J.)》2003,228(5):506-513
The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), which is considered as the pathogenic agent of many diseases and of aging. We have investigated the role of complex I in superoxide radical production and found by the combined use of specific inhibitors of complex I that the one-electron donor to oxygen in the complex is a redox center located prior to the sites where three different types of Coenzyme Q (CoQ) competitors bind, to be identified with an Fe-S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain Coenzyme Q analogs enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analog, idebenone, is particularly effective, raising doubts on its safety as a drug. Cells counteract oxidative stress by antioxidants. CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT-diaphorase are two such systems, likewise, they are overexpressed under oxidative stress conditions. 相似文献
88.
89.
Labelling experiments in which high-specific-activity [U-14C]sucrose or [U-14C]hexoses were injected into potato (Solanum tuberosum L. cv. Desiree) tubers showed that within 1 d of detaching growing tubers from their mother plant, there is an inhibition
of starch synthesis, a stimulation of the synthesis of other major cell components, and rapid resynthesis of sucrose. This
is accompanied by a general increase in phosphorylated intermediates, an increase in UDP-glucose, and a dramatic decrease
of ADP-glucose. No significant decline in the extracted activity of enzymes for sucrose degradation or synthesis, or starch
synthesis is seen within 1 d, nor is there a significant decrease in sucrose, amino acids, or fresh weight. Over the next
7 d, soluble carbohydrates decline. This is accompanied by a decline in sucrose-synthase activity, hexose-phosphate levels,
and the synthesis of structural cell components. It is argued that a previously unknown mechanism acting at ADP-glucose pyrophosphorylase
allows sucrose-starch interconversions to be regulated independently of the use of sucrose for cell growth. 相似文献
90.
K. Sukhapinda M. E. Kozuch B. Rubin-Wilson W. M. Ainley D. J. Merlo 《Plant cell reports》1993,13(2):63-68
Transgenic haploid maize (Zea mays L.) plants were obtained from protoplasts isolated from microspore-derived cell suspension cultures. Protoplasts were electroporated in the presence of plasmid DNA containing the gus A and npt II genes encoding ß-glucuronidase (GUS) and neomycin phosphotransferase II (NPT II), respectively. Transformed calli were selected and continuously maintained on kanamycin containing medium. Stable transformation was confirmed by enzyme assays and DNA. analysis. Stably transformed tissue was transferred to regeneration medium and several plants were obtained. Most plants showed NPT II activity, and some also showed GUS activity. Chromosome examinations performed on representative plants showed that they were haploid. As expected, these plants were infertile. 相似文献