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61.
SMC1 involvement in fragile site expression 总被引:2,自引:0,他引:2
Musio A Montagna C Mariani T Tilenni M Focarelli ML Brait L Indino E Benedetti PA Chessa L Albertini A Ried T Vezzoni P 《Human molecular genetics》2005,14(4):525-533
Common fragile sites have been involved in neoplastic transformation, although their molecular basis is still poorly understood. Here, we demonstrate that inhibition of the SMC1 by RNAi is sufficient to induce fragile site expression. By investigating normal, ATM- and ATR-deficient cell lines, we provide evidence that the contribution of SMC1 in preventing the collapse of stalled replication fork is an Atr-dependent pathway. Using a fluorescent antibody specific for gamma-H2AX, we show that very rare discrete nuclear foci appear 1 and 2 h after exposure to aphidicolin and/or RNAi-SMC1, but became more numerous and distinct after longer treatment times. In this context, fragile sites might be viewed as an in vitro phenomenon originating from double-strand breaks formed because of a stalled DNA replication that lasted too long to be managed by physiological rescue acting through the Atr/Smc1 axis. We propose that in vivo, following an extreme replication block, rare cells could escape checkpoint mechanisms and enter mitosis with a defect in genome assembly, eventually leading to neoplastic transformation. 相似文献
62.
63.
Pierangelo Geppetti Riccardo Patacchini Roberto Cecconi Manuela Tramontana Stefania Meini Andrea Romania Marco Nardi Carlo Alberto Maggi 《Naunyn-Schmiedeberg's archives of pharmacology》1990,341(4):301-307
Summary Capsaicin-sensitive sensory neurons of the rabbit iris, by releasing tachykinins, exert a major role in the control of pupil motility in response to various noxious stimuli. However, the contribution of sensory innervation to the regulation of iris smooth muscle tone in other mammals species is not known. We have studied the effects produced by electrical field stimulation, capsaicin, substance P, neurokinin A, calcitonin gene-related peptide (CGRP), and bradykinin in the isolated iris sphincter muscle of the pig.Capsaicin (10 M): a) contracted the isolated sphincter muscle and; b) released immunoreactivity for substance P (SP-LI) and CGRP (CGRP-LI) from this preparation. These two effects were no longer observed at the second exposure to the drug. Electrical field stimulation (10 Hz, 60 V, 0.5 ms for 5 s) produced a biphasic contractile response. The rapid component was inhibited by atropine (1 M), while the delayed response was blocked by previous exposure to capsaicin (10 M).Substance P and neurokinin A consistently produced contraction of the pig iris sphincter muscle, substance P being more potent than neurokinin A. CGRP induced a contractile response in more than 50% of the preparations. The tachykinin antagonist [D-Argl, D-Trp7,9, Leu11-substance P (3 M) blocked: a) the effect of substance P (1 nM); b) the delayed response to electrical field stimulation and; c) reduced by more than 50% response to capsaicin. Bradykinin (10 M) failed to release either SP-LI or CGRP-LI. The contractile response evoked by bradykinin was unaffected by in vitro pretreatment with capsaicin (10 M).The existence in the pig iris of capsaicin-sensitive sensory fibres releasing neuropeptides and thus regulating sphincter muscle tone is proposed.
Send offprint requests to Dr. P. Geppetti at the above address 相似文献
64.
Jenny Englert Lena Witzdam Dominik Söder Manuela Garay-Sarmiento Anton Joseph Anna M. Wagner Cesar Rodriguez-Emmenegger 《Macromolecular chemistry and physics.》2023,224(24):2300306
The immobilization of vesicles has been conceptualized as a method to functionalize biointerfaces. However, the preservation of their integrity post immobilization remains a considerable challenge. Interfacial interactions can cause vesicle rupture upon close surface contact and non-specific protein adsorption impairing surface functions. To date, immobilization of vesicles has relied solely on either entrapment or prior modification of vesicles, both of which require laborious preparation and limit their applications. This work develops a bioinspired strategy to pin vesicles without prior modification while preserving their intact shape. This work introduces antifouling diblock copolymers and ultrathin surface-attached hydrogels containing a brush-like interface consisting of a bottle brush copolymer of N-(2-hydroxypropyl) methacrylamide (HPMA) and N-(3-methacrylamidopropyl)-N,N-dimethyldodecan-1-aminiumiodide (C12+). The presence of positive charges generates an attractive force that pulls vesicles toward the surface. At the surface, the amphiphilic properties of the combs facilitate their insertion into the membrane, mimicking the harpooning mechanism observed in antimicrobial peptides. Importantly, the antifouling poly(HPMA) backdrop serves to safeguard the vesicles by preventing deformation and breakage. Using a combination of thermodynamic analysis, surface plasmon resonance, and confocal laser scanning microscopy, this work demonstrates the efficiency of this biomimetic system to capture vesicles while maintaining an antifouling interface necessary for bioapplications. 相似文献
65.
Modulation of electrically evoked [3H]-noradrenaline release from cultured chick sympathetic neurons
Clemens Allgaier Angelika Schobert Manuela Belledin Rolf Jackisch Georg Hertting 《Naunyn-Schmiedeberg's archives of pharmacology》1994,350(3):258-266
In the present study we attempted a comprehensive characterization of modulation of noradrenaline release from chick sympathetic neurons. To this purpose sympathetic neurons derived from chick lumbosacral paravertebral ganglia and kept in culture for 7 days were loaded with 0.05 mol/l [3H]-noradrenaline and subjected to electrical field stimulation (36 pulses/3 Hz). Since the released transmitter was partially recaptured, superfusion was usually performed in the presence of (+)-oxaprotiline, an inhibitor of noradrenaline re-uptake. [3H]-Noradrenaline was released in a manner which was dependent on extracellular Ca2+ and sensitive to tetrodotoxin (TTX). -Conotoxin (-CTX; 100 nmol/l) abolished [3H]-noradrenaline release indicating that influx through -CTX-sensitive Ca2+-channels was essential for transmitter release. 1,4-dihydro-2,6-dimethyl-5-nitro4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester ((±)Bay K 8644) and 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3-nitro-5-pyridinecarboxylic acid isopropyl ester ((±)-202-791), agonists at L-type voltage sensitive Ca2+-channels (VSCCs), increased noradrenaline release and induced, in addition, an overflow of tritium which was Ca2+-dependent and prevented by the presence of TTX. The L-type VSCC antagonists (–)-202-791 and (+)-4-(4-benzofurazanyl)-1,4-dihydro2,6-dimethyl-3,5-pyridinedicar boxylic acid methyl, isopropyl ester ((+)-PN 200–110) diminished [3H]-noradrenaline release. These data suggest that L-type VSCCs, probably located on the cell body of the neuron, play an additional role in modulation of release. The full 2-adrenoceptor agonists 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline ( UK-14,304) and noradrenaline significantly inhibited noradrenaline release, whereas clonidine, a partial a2-agonist, produced only a slight inhibition even at 10 mol/l. The facilitation of noradrenaline release observed in the presence of the 2-adrenoceptor antagonist rauwolscine was very low in comparison to that obtained with brain slices and isolated smooth muscle tissues. These results corroborate the observation that noradrenaline release from chick sympathetic neurons is regulated by an 2-adrenoceptor which needs further subtype characterization. The experiments were mostly performed at 25°C, since a rise in temperature to 37°C increased the resting outflow, but not the evoked overflow of tritium, approximately 4-fold. In the presence of pargyline to block monoamine oxidase, however, the temperature-dependent enhancement was diminshed and the release showed properties comparable to those observed at 25°C (with respect to TTX-sensitivity, Ca2+ dependence and modulation via 2-adrenoceptors). In addition to the 2-adrenoceptors, we detected inhibitory -adrenoceptors, opioid and receptors, and P2 purinoceptors as well as facilitatory prostaglandin (PG) E receptors. No indication was found for a functional relevance of 5-hydroxytryptamine (5-HT), opioid , PGD, adenosine A1 or glutamate receptors. In conclusion, electrically evoked noradrenaline release from cultured chick sympathetic neurons shows the properties of action-potential-induced transmitter release and is bidirectionally regulated by various substances. Therefore, sympathetic neurons in culture offer the possibility to investigate directly the mechanisms bringing about receptor-coupled modulation of transmitter release.Abbreviations ATP
adenosine 5-triphosphate
- Bay K 8644
1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester
- DAGO
(d-Ala2,N-methyl-Phe4,Gly-ol5)-enkephalin
- DPDPE
(d-Pen 2,5)-enkephalin
- 5-HT
5-hydroxytryptamine
- -CTX
-conotoxin
- KRBB
modified Krebs-Ringer bicarbonate buffer
- NMDA
N-methyl-d-aspartic acid
- PG
prostaglandin
- PN 200-110
4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxy lic acid methyl, isopropyl ester
- R-PIA
R(–)-N6-(2-phenyl-isopropyl)-adenosine
- TTX
tetrodotoxin
- U-50,488H
trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzene acetamide
- UK-14,304
5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline
- VSCC
voltage sensitive Ca2+-channel
- 202-791
4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3-nitro-5-pyridinecarboxylic acid isopropyl ester
Correspondence to: C. Allgaier at the above address 相似文献
66.
(-)Tabersonine and (-)-11-methoxytabersonine were isolated from fruits of Melodinus reticulatus. Stems and leaves contain uvaol and eight alkaloids, five of which were previously described: (-)tabersonine, venalstonidine, kopsinine, venalstonine and its 3-oxoderivative. Three are new: 19-hydroxyvenalstonine, 19-hydroxyvenalstonidine and 3-oxovenalstonidine. 相似文献
67.
Lori E Shapiro Sandra R Knowles Elizabeth Weber Manuela G Neuman Neil H Shear 《Drug safety》2003,26(3):187-195
OBJECTIVE: To evaluate cross reactivity between sulfonamide antimicrobials and celecoxib in patients with histories of allergies to sulfonamide antimicrobials. METHODS: Immunocompetent patients with a history of sulfonamide antimicrobial allergy who were being considered for therapy with celecoxib were prospectively enrolled. Sulfamethoxazole and trimethoprim skin prick and intradermal testing and/or an in vitro lymphocyte toxicity assay were performed. If skin testing was negative, an oral challenge with sulfamethoxazole and trimethoprim was performed. Oral challenges with celecoxib were administered to all patients. RESULTS: Twenty-eight immunocompetent patients (26 female; mean age 60 years) were evaluated. History of sulfonamide antimicrobial allergy included urticaria (n = 7), cutaneous eruptions (n = 9), and other (n = 12). Four of the 28 patients who were skin prick tested were positive to sulfamethoxazole and two of the ten patients who underwent in vitro testing were positive to sulfamethoxazole. All 28 patients were administered celecoxib and tolerated the medication. Phone call follow up in 25 patients disclosed that 15 patients continued to take celecoxib, while five patients did not take celecoxib following the oral challenge, and five discontinued celecoxib due to adverse effects, lack of drug efficacy or physician preference. CONCLUSIONS: Confusion exists regarding the potential for cross reactivity between sulfonamide antimicrobials and other sulfonamide-containing compounds. The six sulfonamide-allergic patients tolerated celecoxib uneventfully. This pilot study supports the hypothesis that the potential for cross-reactivity between celecoxib and sulfonamide antimicrobials appears to be low. However, further investigations are required to confirm this. 相似文献
68.
Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men 总被引:16,自引:0,他引:16
CONTEXT: In young adults, sleep affects the regulation of growth hormone (GH) and cortisol. The relationship between decreased sleep quality in older adults and age-related changes in the regulation of GH and cortisol is unknown. OBJECTIVE: To determine the chronology of age-related changes in sleep duration and quality (sleep stages) in healthy men and whether concomitant alterations occur in GH and cortisol levels. DESIGN AND SETTING: Data combined from a series of studies conducted between 1985 and 1999 at 4 laboratories. SUBJECTS: A total of 149 healthy men, aged 16 to 83 years, with a mean (SD) body mass index of 24.1 (2.3) kg/m( 2), without sleep complaints or histories of endocrine, psychiatric, or sleep disorders. MAIN OUTCOME MEASURES: Twenty-four-hour profiles of plasma GH and cortisol levels and polygraphic sleep recordings. RESULTS: The mean (SEM) percentage of deep slow wave sleep decreased from 18.9% (1.3%) during early adulthood (age 16-25 years) to 3.4% (1.0%) during midlife (age 36-50 years) and was replaced by lighter sleep (stages 1 and 2) without significant increases in sleep fragmentation or decreases in rapid eye movement (REM) sleep. The transition from midlife to late life (age 71-83 years) involved no further significant decrease in slow wave sleep but an increase in time awake of 28 minutes per decade at the expense of decreases in both light non-REM sleep (-24 minutes per decade; P<.001) and REM sleep (-10 minutes per decade; P<.001). The decline in slow wave sleep from early adulthood to midlife was paralleled by a major decline in GH secretion (-372 microg per decade; P<.001). From midlife to late life, GH secretion further declined at a slower rate (-43 microg per decade; P<.02). Independently of age, the amount of GH secretion was significantly associated with slow wave sleep (P<.001). Increasing age was associated with an elevation of evening cortisol levels (+19. 3 nmol/L per decade; P<.001) that became significant only after age 50 years, when sleep became more fragmented and REM sleep declined. A trend for an association between lower amounts of REM sleep and higher evening cortisol concentrations independent of age was detected (P<.10). CONCLUSIONS: In men, age-related changes in slow wave sleep and REM sleep occur with markedly different chronologies and are each associated with specific hormonal alterations. Future studies should evaluate whether strategies to enhance sleep quality may have beneficial hormonal effects. JAMA. 2000;284:861-868 相似文献
69.
Aldo Becciolini Manuela Balzi Paola Faraoni Elena Tisti Giorgia Zappoli Thyrion Valentino Giach Luca Bandettini Christopher S. Potten 《Acta oncologica (Stockholm, Sweden)》1998,37(1):65-71
Cell kinetics parameters have been analysed in colonic mucosa at different distances from a tumour in patients with colon carcinoma. Total cell number (TCN), H thymidine labelling index (TLI), mitotic index (MI), Goblet cell index (GCI) and the distribution of labelled cells along the crypt column (cell position frequency plot) were determined in well-aligned crypts. Total cell number, GCI and the labelled cell position frequency plots were similar in different samples from the same individual. A negative linear correlation between TCN and TLI was observed. The analysis of the cell position plots showed two patterns 1) with a high concentration in the bottom fifth of the crypt and 2) with frequent labelled cells at high positions. Whereas a negative correlation between overall TLI and the percent contribution to the TLI of the lowermost fifth was seen, the correlation was positive for the next 3 fifths and labelling was absent in the last part of the crypt. 相似文献
70.