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It has become common practice to rely on fitted estimates ofapparent in vivo metabolic constants (e.g., Vmax and KM) inparameterization of PBPK models. Yet, quantitative estimatesof precision in these fitted parameters are not routinely reported.Such information is needed to assess the reliability of modelpredictions. The purpose of this study was to assess the precisionin estimates of Vmax and KM for chloroform, accounting for boththe statistical uncertainties in parameter estimates from individualdata sets and any additional uncertainty due to differencesin the parameter estimates derived from various experiments.Joint confidence regions for Vmax and KM from each experiment,generated using maximum likelihood techniques, were used toevaluate these questions. Three previously published data setswere considered. Estimates of Vmax and KM obtained from thesedata sets differed more than could be explained as a consequenceof a limited number of observations, measurement error, or stochasticerror. Issues associated with the use of maximum likelihoodtechniques to estimate joint confidence regions, the estimationof metabolic constants from individual experiments within agas uptake study versus the full data set, the degree of overlapin the joint confidence regions for metabolic constants obtainedfrom separate data sets, and the implications for risk assessmentare discussed. 相似文献
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JANE P. F. BAI HAE-JIN HONG DAVID A. ROTH ENBERGER W. DOUGLAS WONG JOHN G. BULS 《The Journal of pharmacy and pharmacology》1996,48(11):1180-1184
The aim of this research is to characterize the presence of insulin-degrading enzyme in human colon and ileal mucosal cells. Biochemical studies, including the activity-pH profiles, the effects of enzyme inhibitors, immunoprecipitation and western blots, were conducted. The majority of insulin-degrading activity in colon mucosal cells was localized in the cytosol. In both colon and ileum, cytosolic insulin-degrading activities had a pH optimum at pH 7.5, and were extensively inhibited by each of N-ethylmaleimide, p-chloromercuribenzoate, and 1,10-phenanthroline, but were very weakly affected by each of leupeptin, chymostatin, diisopropyl phosphofluoridate and soybean trypsin inhibitor. In the colon and ileum, more than 93% and 96%, respectively, of cytosolic insulin-degrading activities were removed by the mouse monoclonal antibody to human RBC insulin-degrading enzyme, as compared with less than 20% by the normal mouse IgG for both tissues. Further, a western blot analysis revealed that a cytosolic protein of 110 kD, in both human colon and ileum, reacted with the monoclonal antibody to insulin-degrading enzyme. It is concluded that insulin-degrading enzyme is present in the cytosol of human colon and ileal mucosal cells. 相似文献
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JOHN A. CARVER KERRIE A. NICHOLLS ANDREW J. AQUILINA ROGER J.W. TRUSCOTT 《Experimental eye research》1996,63(6):639-647
The high-molecular-weight (HMW) protein from the lens is composed mostly of α-crystallin in a highly aggregated state. Bovine HMW protein was carefully separated from α-crystallin by size-exclusion chromatography. α-Crystallin has chaperone-like ability whereby it stabilizes other proteins under conditions of stress (e.g. heat). Comparison of bovine HMW protein and α-crystallin shows that the HMW protein has a markedly reduced chaperone ability compared to α-crystallin. However, in contrast to the results of other workers, we observe no alteration with age in the ability of α-crystallin to act as a chaperone. Using electrospray ionisation mass spectrometry, changes in the phosphorylation of the α-crystallin subunits with age have been quantified. Phosphorylation of α-crystallin occurs early in life but does not alter in proportion after about three years of age. In addition, phosphorylation of the A subunit of α-crystallin has little effect on its chaperone ability. As is found in the artificially prepared HMW complex of α- and γ-crystallin, NMR spectroscopy shows that in the naturally occurring HMW protein, the short C-terminal extension of the αBsubunit has lost its flexibility whereas the αAsubunit extension is still flexible. Post-translational modifications therefore seem to have little effect on the chaperone action of α-crystallin, but alterations in the quaternary structure of α-crystallin via incorporation into the HMW aggregate, lead to major changes in the chaperone ability of the protein. The results are consistent with the notion that one of the contributing factors to cataract formation in the lens is the depletion of α-crystallin with age as it is converted into the HMW protein. 相似文献
5.
A wide range of databases and databanks are presently availableto medical researchers. This paper outlines the scope of thedatabases available through a commercial host system and describesthe procedures required for their access and use. A discussionof some of the limitations and likely future developments ispresented in the context of our experience of their use.
Requests for reprints should be addressed to: Dr N. Wood, Department of Epidemiology and Community Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK 相似文献
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WARHEIT DAVID B.; KELLY DAVID P.; CARAKOSTAS MICHAEL C.; SINGER ALLEN W. 《Toxicological sciences》1989,12(2):333-345
A 90-Day Inhalation Toxiaty Study with Benomyl in Rats. WARHEIT,D. B., KELLY, D. P., CARAKOSTAS, M. C., AND SINGER, A. W. (1989).Fundam Appl Toxicol./ 12, 333-345. Benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate,CAS Registry No. 17804-35-2] is a fungicide and the possibilityfor inhalation exposure exists for field workers. To assessthe toxicity of benomyl, groups of 20 male and 20 female CDrats were exposed nose-only 6 hr a day, 5 days a week, to concentrationsof 0, 10, 50 or 200 mg/m3 of a benomyl atmosphere. At the midpoint(approximately 45 days on test) and at the end of the exposureperiod, blood and urine samples for clinical evaluation werecollected from 10 rats/group/sex, and these animals were sacrificedfor pathological examination. Similar evaluations were performadon all remaining rats at the end of the 90-day test period.After approximately 45 days on test, compoundrelated degenerationof the olfactory epithelium was observed in all males and in8 of 10 female rats exposed to 200 mg/m3 benomyl. Two male ratsexposed to 50 mg/m3 had similar, although less severe, areasof olfactory epithelial degeneration. After approximately 90days of exposure, the remaining 10 rats/group/sex were sacrificedand examined. Of these rats, all of the males and females exposedto 200 mg/m3 had olfactory degeneration, along with 3 malesexposed to 50 mg/m3 of benomyl. No other observed lesions wereinterpreted to have been caused by the benomyl exposure. Inaddition, male rats exposed to 200 mg/m3 benomyl had depressedmean body weights compared to controls and this finding correlatedwith a reduction in food consumption. Based on pathologicalobservations, 10 mg/m3 represents the no-observable-effect level(NOEL) for the male rats, and 50 mg/m3 is the NOEL for the femalerats. 相似文献
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CHARLES STEADMAN CLINTON TEAGUE PAUL KERLIN OWEN HARRIS KEVIN HOURIGAN JOHN SAMPSON 《Journal of gastroenterology and hepatology》1987,2(5):459-466
Collagenous colitis is characterized by the presence of a thick subepithelial collagen band in the colonic mucosa. The condition was diagnosed on rectal biopsy in 10 patients (one male, nine females) who presented with watery diarrhoea. Although rectal mucosal erythema was present in three and ulceration in two, the mucosa was of normal endoscopic appearance in five of the patients. There was marked variability in the thickness of the submucosal collagen band, both between and within individuals. Empirical drug therapy included sulphasalazine, glucocorticoids and antidiarrhoeals. All patients reported symptomatic improvement. 相似文献
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