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991.
Peterson LW Kim JS Kijek P Mitchell S Hilfinger J Breitenbach J Borysko K Drach JC Kashemirov BA McKenna CE 《Bioorganic & medicinal chemistry letters》2011,21(13):4045-4049
We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO2R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)2 group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC50 value against human cytomegalovirus comparable to 1. Neither 6 nor 7 exhibited toxicity up to 100 μM in KB or HFF cells. 相似文献
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Flannigan KL McCoy KD Wallace JL 《American journal of physiology. Gastrointestinal and liver physiology》2011,301(1):G188-G193
Hydrogen sulfide (H(2)S) is an important modulator of many aspects of digestive function, both in health and disease. Colonic tissue H(2)S synthesis increases markedly during injury and inflammation and appears to contribute to resolution. Some of the bacteria residing in the colon can also produce H(2)S. The extent to which bacterial H(2)S synthesis contributes to what is measured as colonic H(2)S synthesis is not clear. Using conventional and germ-free mice, we have delineated the eukaryotic vs. prokaryotic contributions to colonic H(2)S synthesis, both in healthy and colitic mice. Colonic tissue H(2)S production is entirely dependent on the presence of the cofactor pyridoxal 5'-phosphate (vitamin B(6)), while bacterial H(2)S synthesis appears to occur independent of this cofactor. As expected, approximately one-half of the H(2)S produced by feces is derived from eukaryotic cells. While colonic H(2)S synthesis is markedly increased when the tissue is inflamed, and, in proportion to the extent of inflammation, fecal H(2)S synthesis does not change and tissue granulocytes do not appear to be the source of the elevated H(2)S production. Rats fed a B vitamin-deficient diet for 6 wk exhibited significantly diminished colonic H(2)S synthesis, but fecal H(2)S synthesis was not different from that of rats on the control diet. Our results demonstrate that H(2)S production by colonic bacteria does not contribute significantly to what is measured as colonic tissue H(2)S production, using the acetate trapping assay system employed in this study. 相似文献
994.
Background and Aims
Girdling, or the removal of a strip of bark around a tree''s outer circumference, is often used to study carbon relationships, as it triggers several carbon responses which seem to be interrelated.Methods
An existing plant model describing water and carbon transport in a tree was used to evaluate the mechanisms behind the girdling responses. Therefore, the (un)loading functions of the original model were adapted and became a function of the phloem turgor pressure.Key Results
The adapted model successfully simulated the measured changes in stem growth induced by girdling. The model indicated that the key driving variables for the girdling responses were changes in turgor pressure due to local changes in sugar concentrations. Information about the local damage to the phloem system was transferred to the other plant parts (crown and roots) by a change in phloem pressure. After girdling, the loading rate was affected and corresponded to the experimentally observed feedback inhibition. In addition, the unloading rate decreased after girdling and even reversed in some instances. The model enabled continuous simulation of changes in starch content, although a slight underestimation was observed compared with measured values.Conclusions
For the first time a mechanistic plant model enabled simulation of tree girdling responses, which have thus far only been experimentally observed and fragmentally reported in literature. The close agreement between measured and simulated data confirms the underlying mechanisms introduced in the model. 相似文献995.
Lembrechts R Pintelon I Schnorbusch K Timmermans JP Adriaensen D Brouns I 《Histochemistry and cell biology》2011,136(4):371-385
Afferent activities arising from sensory nerve terminals located in lungs and airways are carried almost exclusively by fibres
travelling through the vagus nerve. Based on electrophysiological investigations, intrapulmonary airway-related vagal afferent
receptors have been classified into three main subtypes, two of which are myelinated and mechanosensitive, i.e., rapidly and
slowly adapting receptors. To allow for a full functional identification of the distinct populations of airway receptors,
morphological and neurochemical characteristics still need to be determined. Nerve terminals visualised using markers for
myelinated vagal afferents seem to be almost uniquely associated with two morphologically well-formed airway receptor end
organs, smooth muscle-associated airway receptors (SMARs) and neuroepithelial bodies (NEBs), localised in airway smooth muscle
and epithelium, respectively. Due to the lack of a selective marker for SMARs in mice, no further neurochemical coding is
available today. NEBs are extensively innervated diffusely spread groups of neuroendocrine cells in the airway epithelium,
and are known to receive at least two separate populations of myelinated vagal afferent nerve terminals. So far, however,
no evidence has been reported for the expression of channels that may underlie direct sensing and transduction of mechanical
stimuli by the receptor terminals in NEBs and SMARs. This study focused on the expression of mechanogated two-pore domain
K+ (K2P) channels, TREK-1 and TRAAK, in mouse airways and more particular in the NEB micro-environment and in SMARs by multiple immunostaining.
TREK-1 could be detected on smooth muscle cells surrounding intrapulmonary airways and blood vessels, while TRAAK was expressed
on myelinated vagal afferents terminating both in SMARs and in the NEB micro-environment. Co-stainings with known markers
for subpopulations of myelinated vagal afferents and general neuronal markers revealed that all identified SMARs exhibit TRAAK
immunoreactivity, and that at least three subpopulations exist in mouse airways. Also, the intraepithelial terminals of both
subpopulations of NEB-associated myelinated vagal sensory nerve fibres were shown to express TRAAK. In conclusion, the present
study finally characterised an intrinsically mechanosensitive ion channel, the K2P channel TRAAK, on the terminals of identified myelinated vagal nodose airway afferents, organised as SMARs and as components
of the innervation of NEBs. These data support the hypothesis that both SMARs and NEBs harbour the morphological counterparts
of electrophysiologically identified myelinated vagal airway mechanoreceptors. TRAAK appears to be strongly involved in regulating
airway mechanosensing since it was found to be expressed on the terminals of all subpopulations of potential vagal mechanosensors. 相似文献
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Ruth Lynfield Richard Davey Dominic E. Dwyer Marcelo H. Losso Deborah Wentworth Alessandro Cozzi-Lepri Kathy Herman-Lamin Grazyna Cholewinska Daniel David Stefan Kuetter Zelalem Ternesgen Timothy M. Uyeki H. Clifford Lane Jens Lundgren James D. Neaton for the INSIGHT Influenza Study Group 《PloS one》2014,9(7)