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991.
- Studies were directed at determining whether hepatocytes, isolated from female Sprague-Dawley rats, facilitate the uptake of protein-bound long-chain fatty acids. We postulated one form of facilitated uptake may occur through an ionic interaction between the protein-ligand complex and the cell surface. These interactions are expected to supply additional ligand to the cell for uptake.
- The clearance rate of [3H]-palmitate in the presence of α1-acid-glycoprotein (pI=2.7), albumin (pI=4.9) and lysozyme (pI=11.0) was investigated. Palmitate uptake was determined in the presence of protein concentrations that resulted in similar unbound ligand fractions (=0.03). The experimental clearance rates were compared to the theoretical predictions based upon the diffusion-reaction model.
- By use of our experimentally determined equilibrium binding and dissociation rate constants for the various protein-palmitate complexes, the diffusion-reaction model predicted clearance rates were 4.9 μl s−1/106 cells, 4.8 μl s−1/106 cells and 5.5 μl s−1/106 cells for α1-acid-glycoprotein, albumin and lysozyme, respectively; whereas the measured hepatocyte palmitate clearance rates were 1.2±0.1 μl s−1/106 cells, 2.3±0.3 μl s−1/106 cells and 7.1±0.7 μl s−1/106, respectively.
- Hepatocyte palmitate clearance was significantly faster (P<0.01) in the presence of lysozyme than albumin which was significantly faster than α1-acid-glycoprotein (P<0.01). The marked difference in clearance rates could not be explained by considering differences in solution viscosity.
- Our results are consistent with the notion that ionic interactions between protein-ligand complexes and the cell surface facilitate the ligand uptake by decreasing the diffusional distance of the unbound ligand and/or by facilitating the protein-ligand dissociation rate.
992.
Karen B Jourdan Timothy W Evans Nicholas P Curzen Jane A Mitchell 《British journal of pharmacology》1997,120(7):1280-1285
- 8-Iso prostaglandin F2α (8-iso PGF2α) is one of a series of prostanoids formed independently of the cyclo-oxygenase pathway. It has been shown to be upregulated in many conditions of oxidant stress where its formation is induced by free radical-catalysed actions on arachidonic acid. As 8-iso PGF2α is formed in vivo in diseases in which oxidant stress is high such as septic shock, we have assessed the relative potency and efficacy of this compound in pulmonary arteries from control and lipopolysaccharide (LPS)-treated rats.
- Several studies have characterized the contractile actions of 8-iso PGF2α on various smooth muscle preparations, but its potential dilator actions have not been addressed. Thus these studies examined both the contractile and dilator actions of 8-iso PGF2α in rat pulmonary artery rings. The thromboxane mimetic U46619, PGE2 sodium nitroprusside (SNP) and acetyl choline (ACh) were used for comparison. Each prostanoid had to be dissolved in ethanol to a maximum concentration of 1×10−2 M. At high concentrations, ethanol directly contracted pulmonary vessels. We were therefore limited by the actions of the vehicle such that we were unable to add prostanoids at concentrations higher than 1×10−4 M. In some cases this meant that maximum responses were not achieved and in these cases the Emax and pD2 values are apparent estimates.
- The following rank order of potency was obtained from contractile studies; U46619>8-iso PGF2α>PGE2, each prostanoid producing concentration-dependent contractions (10−103×10−4 M, 10−910−4 M, 10−810−4 M, respectively). As has been shown previously for other smooth muscle preparations, the thromboxane receptor (TP) antagonist ICI 192605, (1×10−6, 1×10−5 and 1×10−4 M), inhibited the contractions of 8-iso PGF2α in a concentration-dependent fashion.
- The nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1×10−4 M), enhanced the contractile function of both 8-iso PGF2α and PGE2, but had no effect on that caused by U46619. Similarly, L-NAME inhibited the dilator function of all agents tested except the exogenous nitric oxide (NO) donor SNP, indicating that PGE2 and 8-iso PGF2α like ACh, act through the release of NO. The specificity of the effects of L-NAME were confirmed in studies with the inactive enantiomer D-NAME (1×10−4 M), which did not affect the contractile or the dilator actions of 8-iso PGF2α. Furthermore, ICI 192605 enhanced the dilator actions of 8-iso PGF2α, suggesting that the dilator component of 8-iso PGF2α was achieved via activation of a non-TP receptor.
- Isoprostanes may modulate vascular tone by a direct action on TP receptors to cause contraction and via a distinct receptor leading to the release of NO to cause dilatation.
993.
Ohta T Fukuda M Arima K Kawamoto H Hashizume R Arimura T Yamaguchi S 《Breast cancer (Tokyo, Japan)》1997,4(1):17-24
Cyclins and cyclin-dependent kinases may reflect the status of cell proliferation in cancer tissues. The authors sought to
determine whether cdc2 and cyclin D1 are expressed in breast cancer and are useful as prognostic factors. Accumulation of
cdc2 and cyclin D1 proteins was examined in 88 cases of breast cancer using immunoblotting techniques and correlations with
clinicopathological factors and prognoses were investigated. Cdc2 and cyclin D1 proteins were observed in 27.3% and 75.0%
of breast cancers studied, respectively. The incidence of lymph node metastasis was significantly high in cdc2/cyclin D1-double
positive group and low in double negative group. On the other hand, the incidence of estrogen receptor (ER) negative cases
was significantly higher in the cdc2-positive/cyclin D1-negative group. Relapse-free survival times of cdc2-positive cases
were significantly shorter than those of cdc2-negative cases. The relapse-free survival times of cyclin D1-positive cases
also tended to be poorer than those of cyclin D1-negative cases. Multivariate analyses revealed cdc2 as the second most significant
of the prognostic variables, following lymph node status. The three-year relapse-free survival rate of cdc2/cyclin D1-double
positive cases was 58.9%, whereas that of cdc2/cyclin D1-double negative cases was 100%. Cdc2 and cyclin D1 represent the
status of cell proliferation in breast cancer, and may be useful in breast cancer assessment. 相似文献
994.
Masatsugu Nakamura Keiko Ofuji Tai-ichiro Chikama Teruo Nishida 《British journal of pharmacology》1997,120(4):547-552
- We have previously shown that substance P (SP) and insulin-like growth factor-1 (IGF-1) act synergistically to enhance the migration of rabbit corneal epithelial cells in an organ culture model. The present study was designed to identify the epithelial cell SP receptor that participates in this synergistic effect.
- Rabbit corneal blocks were incubated for 24 h, then the length of the path of epithelial migration was measured. Reagents tried in the TC-199 culture medium, in the presence or absence of IGF-1, were: SP, agonists of tachykinin receptors NK1, NK2 or NK3 and antagonists of tachykinin receptors NK1 or NK2.
- The binding characteristics of SP receptors were examined in rabbit cultured corneal epithelial cells by binding assays with [125I]-SP in the presence or absence of excess unlabelled SP or ligands of NK1, NK2 or NK3 receptors.
- As was demonstrated previously, SP and IGF-1 stimulated epithelial migration when they were added to the culture medium together, but individually they had no effect. NK1 agonists had the same synergistic effect with IGF-1 as did SP, but the NK2 and NK3 agonists did not. Furthermore, the NK1 antagonist abolished the synergistic effect of SP and IGF-1, but the NK2 antagonist had no effect.
- SP bound specifically to rabbit cultured corneal epithelial cells. The binding affinity was 0.44 nM and there were 2.43×104 binding sites per cell. The NK1 ligand competed, in a dose-dependent fashion, with the binding of SP to corneal epithelial cells, but neither the NK2 nor NK3 ligand affected binding.
- We conclude that the SP receptor in rabbit corneal epithelial cells is NK1 and that this receptor participates in the synergistic enhancement of corneal epithelial migration by SP and IGF-1. The precise mechanism(s) of this interaction requires more study. These findings imply that both neural and humoral factors are essential for the maintenance and healing of corneal epithelium.
995.
M Grandati C Verrecchia M L Revaud M Allix R G Boulu M Plotkine 《British journal of pharmacology》1997,120(4):625-630
- An obligatory step in the biosynthesis of endothelin-1 (ET-1) is the conversion of its inactive precursor, big ET-1, into the mature form by the action of specific, phosphoramidon-sensitive, endothelin converting enzyme(s) (ECE). Disparate effects of big ET-1 and ET-1 on renal tubule function suggest that big ET-1 might directly influence renal tubule function. Therefore, the role of the enzymatic conversion of big ET-1 into ET-1 in eliciting the functional response (generation of 1,2-diacylglycerol) to big ET-1 was studied in the rat proximal tubules.
- In renal cortical slices incubated with big ET-1, pretreatment with phosphoramidon (an ECE inhibitor) reduced tissue immunoreactive ET-1 to a level similar to that of cortical tissue not exposed to big ET-1. This confirms the presence and effectiveness of ECE inhibition by phosphoramidon.
- In freshly isolated proximal tubule cells, big ET-1 stimulated the generation of 1,2-diacylglycerol (DAG) in a time- and dose-dependent manner. Neither phosphoramidon nor chymostatin, a chymase inhibitor, influenced the generation of DAG evoked by big ET-1.
- Big ET-1-dependent synthesis of DAG was found in the brush-border membrane. It was unaffected by BQ123, an ETA receptor antagonist, but was blocked by bosentan, an ETA,B-nonselective endothelin receptor antagonist.
- These results suggest that the proximal tubule is a site for the direct effect of big ET-1 in the rat kidney. The effect of big ET-1 is confined to the brush-border membrane of the proximal tubule, which may be the site of big ET-1-sensitive receptors.
996.
Wilhelm G Lachnit Antares M Tran David E Clarke Anthony P D W Ford 《British journal of pharmacology》1997,120(5):819-826
- The α1-adrenoceptor population mediating contraction of caudal artery of rat has been characterized by using quantitative receptor pharmacology.
- Cumulative concentration-effect (E/[A]) curves to noradrenaline (NA) yielded a p[A]50 of 5.56±0.05 (n=16). Prazosin caused concentration-dependent, parallel, dextral shifts of E/[A] curves to NA yielding a pKb of 8.9 (Schild regression slope=1.0). RS-17053 (N-[2-(2-cyclopropyl methoxy phenoxy) ethyl]-5-chloro-α ,α-dimethyl -1H-indole- 3-ethanamine hydrochloride; 10–100 nM), a selective α1A-adrenoceptor antagonist, produced non-parallel, biphasic, dextral shifts of E/[A] curves to NA, suggesting the involvement of more than one α1-adrenoceptor subtype. Analysis of the high affinity component yielded an apparent pA2 value of 9.2±0.3.
- A-61603, a selective agonist at α1A adrenoceptors behaved as a full agonist relative to NA and yielded monophasic E/[A] curves with a p[A50] of 7.59±0.04 (n=15). Pretreatment of tissues with chloroethylclonidine (CEC; 100 μM for 20 min, followed by 40 min washout), which preferentially alkylates α1B- and α1D-adrenoceptors, did not alter E/[A] curves to A-61603. Prazosin (3–300 nM) caused concentration-dependent, parallel, dextral shifts of E/[A] curves to A-61603 yielding a pA2 estimate of 9.2±0.2.
- Experiments with α1-adrenoceptor antagonists of varying subtype selectivities (RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739) revealed parallel dextral shifts of E/[A] curves to A-61603. Schild regression analyses yielded pA2 estimates of 9.2, 9.3, 11.2, 9.0, 6.3, 8.7 and 10.0 for RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739, respectively, although deviations from unit slope (possibly reflecting a secondary involvement of another α1-adrenoceptor) hindered estimations of pKb for some antagonists. The antagonist affinity profile obtained reflects best that described for the α1A-adrenoceptor.
- In conclusion, caudal artery of rat contracts in response to NA via activation of at least two α1-adrenoceptor subtypes. One of these subtypes displays the pharmacology of the α1A-adrenoceptor, while the other remains to be defined. Use of the novel selective agonist, A-61603, allows for limited pharmacological isolation of the α1A-adrenoceptor permitting characterization of the properties of selective antagonists.
997.
Ping Gao Yinglin Lu Xueming Ge Wenhong Fan Shengfa Fu Shuang Liu Heping Yang 《中国癌症研究》1997,9(3):192-194
In order to investigate TGFβ1 gene expression and its effect on murine tumor growth following direct intratumoral injection
of naked plasmid DNA encoding human TGFβ1, LM3 murine lung adenocarcinoma cells were inoculated subcutaneously to T739 mice and grew to tumor nodules in 2 weeks. Multiple direct intratumoral injection of plasmid DNA, PMAMneo- TGFβ1, were given
and compared with saline or vector plasmid administration groups. The growth of tumor was observed till the 8th week when
the mice were killed for Northern blot analysis and histopathological study of tumoral tissue. The results showed that the
growth of tumor was boosted in the TGFβ1 gene treated mice as compared with the control groups, whereas there was no significant
difference in the metastatic behavior. Northern blot showed efficient expression of TGFβ1 mRNA in the treated group. The present
study indicated that TGFβ1 may stimulate tumor growthin vivo through certain mechanisms. And direct intra-tumoral injection of nude plasmid DNA may be a promising gene transfer strategyin vivo.
This work was supported by the National Natural Science Foundation of China (No. 39370761). 相似文献
998.
The antioxidant activity ofArtemisia iwayomogi was determined by measuring the radical scavenging effect on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical The methanol extract
ofA. iwayomogi showed strong antioxidant activity, and thus fractionated with several solvents. The antioxidant activity potential of the
individual fraction was in the order of ethyl acetate>n-butanol>water>chloroform>n-hexane fraction. The ethyl acetate andn-butanol soluble fractions exhibiting strong antioxidant activity were further purified by repeated silica gel and Sephadex
LH-20 column chromatography. Antioxidant chlorogenic acid was isolated as one of the active principles from then-butanol fraction, together with the inactive components, 1-octacosanol, scopoletin, scopolin, apigenin 7,4′-di-O-methylether luteolin 6,3′-di-O-methylether (jaceosidin), apigenin 7-methylether (genkwanin), 2,4-dihydroxy-6-methoxyacetophenone 4-O-β-D-glucopyranoside and quebrachitol. The antioxidant activity of chlorogenic acid was comparable to that of L-ascorbic acid,
which is a well known antioxidant. 相似文献
999.
The1H-NMR signals of 2-cephems and 3-cephems have been assigned and the Nuclear Overhauser Effect (NOE) study of these compounds
was undertaken. 相似文献
1000.
M J Field R J Oles A S Lewis S McCleary J Hughes L Singh 《British journal of pharmacology》1997,121(8):1513-1522
- Gabapentin (neurontin) is a novel antiepileptic agent that binds to the α2δ subunit of voltage-dependent calcium channels. The only other compound known to possess affinity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the corresponding (R)-(−)-enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba in formalin and carrageenan-induced inflammatory pain models.
- In the rat formalin test, S-(+)-3-isobutylgaba (1–100 mg kg−1) and gabapentin (10–300 mg kg−1) dose-dependently inhibited the late phase of the nociceptive response with respective minimum effective doses (MED) of 10 and 30 mg kg−1, s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1–10.0 mg kg−1, s.c.). In contrast, the R-(−)-enantiomer of 3-isobutylgaba (1–100 mg kg−1) produced a modest inhibition of the late phase at the highest dose of 100 mg kg−1. However, none of the compounds showed any effect during the early phase of the response.
- The s.c. administration of either S-(+)-3-isobutylgaba (1–30 mg kg−1) or gabapentin (10–100 mg kg−1), after the development of peak carrageenan-induced thermal hyperalgesia, dose-dependently antagonized the maintenance of this response with MED of 3 and 30 mg kg−1, respectively. Similar administration of the two compounds also blocked maintenance of carrageenan-induced mechanical hyperalgesia with MED of 3 and 10 mg kg−1, respectively. In contrast, R-(−)-3-isobutylgaba failed to show any effect in the two hyperalgesia models.
- The intrathecal administration of gabapentin dose-dependently (1–100 μg/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the inflamed paw was ineffective at blocking this response.
- Unlike morphine, the repeated administration of gabapentin (100 mg kg−1 at start and culminating to 400 mg kg−1) over 6 days did not lead to the induction of tolerance to its antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not cross generalize to gabapentin. The s.c. administration of gabapentin (10–300 mg kg−1), R-(−) (3–100 mg kg−1) or S-(+)-3-isobutylgaba (3–100 mg kg−1) failed to inhibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1–100 mg kg−1, s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (30–300 mg kg−1) and S-(+)-isobutylgaba (1–100 mg kg−1) showed sedative/ataxic properties only at the highest dose tested in the rota-rod apparatus.
- Gabapentin (30–300 mg kg−1, s.c.) failed to show an antinociceptive action in transient pain models. It is concluded that gabapentin represents a novel class of antihyperalgesic agents.