全文获取类型
收费全文 | 5402篇 |
免费 | 471篇 |
国内免费 | 1篇 |
出版年
2022年 | 28篇 |
2021年 | 64篇 |
2020年 | 69篇 |
2019年 | 66篇 |
2018年 | 99篇 |
2017年 | 73篇 |
2016年 | 111篇 |
2015年 | 189篇 |
2014年 | 189篇 |
2013年 | 311篇 |
2012年 | 317篇 |
2011年 | 322篇 |
2010年 | 232篇 |
2009年 | 182篇 |
2008年 | 250篇 |
2007年 | 265篇 |
2006年 | 271篇 |
2005年 | 229篇 |
2004年 | 229篇 |
2003年 | 244篇 |
2002年 | 242篇 |
2001年 | 70篇 |
2000年 | 59篇 |
1999年 | 91篇 |
1998年 | 76篇 |
1997年 | 49篇 |
1996年 | 59篇 |
1995年 | 60篇 |
1994年 | 56篇 |
1993年 | 54篇 |
1992年 | 57篇 |
1991年 | 39篇 |
1990年 | 46篇 |
1989年 | 47篇 |
1988年 | 41篇 |
1987年 | 46篇 |
1986年 | 39篇 |
1985年 | 50篇 |
1984年 | 62篇 |
1983年 | 39篇 |
1982年 | 60篇 |
1981年 | 43篇 |
1980年 | 59篇 |
1979年 | 40篇 |
1978年 | 40篇 |
1977年 | 35篇 |
1976年 | 34篇 |
1975年 | 30篇 |
1974年 | 30篇 |
1973年 | 30篇 |
排序方式: 共有5874条查询结果,搜索用时 15 毫秒
911.
Phosphorylation of glucose in isolated rat hepatocytes. Sigmoidal kinetics explained by the activity of glucokinase alone 下载免费PDF全文
The conversion of glucose into glucose 6-phosphate in an extract of isolated rat hepatocytes incubated in the presence of MgATP was studied spectrophotometrically at 340nm and also by a radiochemical procedure based on the release of (3)H from [2-(3)H]glucose. Both methods gave similar results. The glucose-saturation curve was sigmoidal and the shape of this curve was not influenced by the ionic composition of the incubation medium. The activity at 0.5mm-glucose was only 1-2% of V(max.), indicating a virtual absence of low-K(m) hexokinase in the preparation. The radiochemical method was also used for the determination of glucose phosphorylation by intact hepatocytes. The glucose-saturation curve was also markedly sigmoidal, but the s(0.5) (substrate concentration at half-maximal velocity) and the Hill coefficient were larger than in extracts of hepatocytes. These two parameters became smaller when cells were incubated in a medium in which Na(+) ions were replaced by K(+) ions. The increased rate of phosphorylation at low glucose concentration in a K(+) medium was accompanied by an increased rate of metabolite recycling between glucose and glucose 6-phosphate and also by an increased uptake of glucose. In both media phosphorylation of glucose was inhibited co-operatively by N-acetylglucosamine. Calculations indicate that this inhibition would reach 100% at saturation of the inhibitor, although at lower concentrations of N-acetylglucosamine it was smaller than expected from the known K(i) of N-acetylglucosamine for glucokinase. The rate of phosphorylation of glucose was proportional to the amount of glucokinase in hepatocytes from newborn rats and in conditions such as starvation and diabetes in which the total amount of glucokinase in the liver is decreased. In the same conditions, glucose 6-phosphatase activity was either normal or increased. It is concluded that the phosphorylation of glucose in isolated hepatocytes follows sigmoidal kinetics, which can be explained by the activity of glucokinase alone with no participation of low-K(m) hexokinase or of glucose 6-phosphatase. 相似文献
912.
Su-Li Cheng Shu-Fang Zhang Subburaman Mohan Fernando Lecanda Aurora Fausto Ann H. Hunt Ernesto Canalis Louis V. Avioli 《Journal of cellular biochemistry》1998,71(3):449-458
Glucocorticoids inhibit the proliferation, but induce the differentiation, of bone marrow stromal cells into osteoblast-like cells. The mechanisms, however, are still conjectural. Since insulin-like growth factors (IGFs) have profound effects on osteoblast growth and differentiation, it is possible that glucocorticoids exert their effects on bone marrow stromal cells in part via regulation of IGFs. Therefore, we analyzed the effects of dexamethasone (Dex) on the expression of IGF I and IGF II in cultured preosteoblastic normal human bone marrow stromal cells (HBMSC). Whereas Dex decreased the concentration of IGF I in the conditioned medium since early in the treatment, the concentration of IGF II was increased progressively as culture period lengthened. As the activities of IGF I and IGF II are regulated by the IGF binding proteins (IGFBPs), we analyzed the effects of Dex on the expression of IGFBPs. Dex increased IGFBP-2 in a time-dependent manner. The increase in IGFBP-2, however, was only to the same extent as that of IGF II at most, depending on the length of treatment. Therefore, the increase in IGFBP-2 would dampen, but not eliminate, the increased IGF II activities. By contrast, Dex decreased IGFBP-3 levels, the latter increasing the bioavailability of IGF II. Although IGFBP-4 mRNA levels were stimulated by Dex, IGFBP-4 concentration in the conditioned medium was unchanged as measured by RIA. IGFBP-5 and IGFBP-6 mRNA levels were decreased by Dex in a time-dependent fashion. IGFBP-5 protein level was also decreased 1–4 days after Dex treatment. IGFBP-1 mRNA was not detectable in HBMSC. These accumulated data indicate that Dex regulates IGF I and IGF II and their binding proteins differentially in normal human bone marrow stromal cells. The progressive increase in IGF II may contribute to Dex-induced cell differentiation. J. Cell. Biochem. 71:449–458, 1998. © 1998 Wiley-Liss, Inc. 相似文献
913.
Manisha Dixit Silvana DuranOrtiz Godze Yildirim Sher Bahadur Poudel Leeann D. Louis Andrzej Bartke Mitchell B. Schaffler John J. Kopchick Shoshana Yakar 《Aging cell》2021,20(12)
Somatopause refers to the gradual declines in growth hormone (GH) and insulin‐like growth factor‐1 throughout aging. To define how induced somatopause affects skeletal integrity, we used an inducible GH receptor knockout (iGHRKO) mouse model. Somatopause, induced globally at 6 months of age, resulted in significantly more slender bones in both male and female iGHRKO mice. In males, induced somatopause was associated with progressive expansion of the marrow cavity leading to significant thinning of the cortices, which compromised bone strength. We report progressive declines in osteocyte lacunar number, and increases in lacunar volume, in iGHRKO males, and reductions in lacunar number accompanied by ~20% loss of overall canalicular connectivity in iGHRKO females by 30 months of age. Induced somatopause did not affect mineral/matrix ratio assessed by Raman microspectroscopy. We found significant increases in bone marrow adiposity and high levels of sclerostin, a negative regulator of bone formation in iGHRKO mice. Surprisingly, however, despite compromised bone morphology, osteocyte senescence was reduced in the iGHRKO mice. In this study, we avoided the confounded effects of constitutive deficiency in the GH/IGF‐1 axis on the skeleton during growth, and specifically dissected its effects on the aging skeleton. We show here, for the first time, that induced somatopause compromises bone morphology and the bone marrow environment. 相似文献
914.
Louis Safranek 《Archives of insect biochemistry and physiology》1997,34(1):43-56
Administration of the anti-ecdysteroid azasteroid 25-azacoprostane (AZCP) to larvae of the tobacco hornworm, Manduca sexta, often inhibits molting without curtailing growth. As a result, AZCP-treated larvae may attain weights 2–3 times greater than normal during the first four instars. This may explain the paradoxical anti-juvenoid activity of AZCP evident in the precocious metamorphosis of AZCP-treated fourth-instar larvae, which was noted only after those larvae attained unusually large weights over 2 g. The weight interval of 2–3 g has been previously identified as a critical threshold for initiation of metamorphosis by normal final (fifth) instar larvae. The premature attainment of this weight threshold by AZCP-treated fourth-instar larvae probably activates the same premetamorphic sequence of events that normally occurs in the fifth instar at this threshold, including activation of potent endogenous anti-juvenoids. Anti-juvenoid activity limited to the penultimate instar is likely to be a general feature of compounds that block molting without inhibiting growth. © 1997 Wiley-Liss, Inc. 相似文献
915.
916.
Tyler D. Rudolph Pierre Drapeau Louis Imbeau Vincent Brodeur Sonia Légaré Martin-Hugues St-Laurent 《Biodiversity and Conservation》2017,26(5):1179-1198
Conserving species-at-risk requires quantifiable knowledge of the key drivers of population change. Non-linear demographic responses to habitat loss have been documented for many species and may serve to establish quantitative habitat thresholds for management purposes. In Canada, boreal populations of woodland caribou are considered threatened; Environment Canada’s empirical model of calf recruitment–range disturbance suggests that at least 65% undisturbed habitat is required to ensure viability. We tested the relationship upon which this conservation guideline is based by pairing demographic estimates with range conditions over a 10-year period for three boreal caribou populations. Our objectives were (1) to evaluate evidence of intra-population demographic responses to fluctuations in range quality over time; (2) to evaluate inter-population differences in demographic responses to cumulative range disturbances; and (3) to evaluate the sensitivity of disturbance tolerance thresholds to variation in local population demography. We found strong evidence in support of the disturbance–recruitment relationship for within-population responses over time (R2 = 0.77). Mixed effects logistic regression modeling revealed variations in local population responses to cumulative habitat depletion. Range-specific disturbance thresholds derived from Monte Carlo simulations were highly elastic in response to observed variation in local population demography, suggesting that 65% undisturbed habitat is insufficient when adult female survival and/or sex ratio is suboptimal. Study populations were determined to be not self-sustaining (Pr(λ ≥ 0.99) = 37–47%). Adult survival was comparable to estimates reported elsewhere despite Aboriginal harvesting for subsistence purposes. Results underscored potential trade-offs between forest harvesting and wildlife habitat conservation. Protection and restoration of sufficient quantities of undisturbed habitat, particularly via road reclamation, is essential for caribou population recovery. 相似文献
917.
Andrew M. Thompson Adrian Blaser Brian D. Palmer Robert F. Anderson Sujata S. Shinde Delphine Launay Eric Chatelain Louis Maes Scott G. Franzblau Baojie Wan Yuehong Wang Zhenkun Ma William A. Denny 《Bioorganic & medicinal chemistry letters》2017,27(11):2583-2589
As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis. Favourable microsomal stability data for a biaryl thiazole (45) led to its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, “thio-delamanid” (49) is regarded as the best lead. 相似文献
918.
Lara Massai Luigi Messori Nicola Micale Tanja Schirmeister Louis Maes Dolores Fregona Maria Agostina Cinellu Chiara Gabbiani 《Biometals》2017,30(2):313-320
Gold compounds form a new class of promising metal-based drugs with a number of potential therapeutic applications, particularly in the fields of anticancer and antimicrobial treatments. Previous research revealed that a group of structurally diverse gold compounds cause conspicuous inhibition of the protease activities of the human proteasome. Given the pharmacological importance of protease inhibition, the present study further explored whether these gold compounds might inhibit a few other proteases that are accepted druggable targets for disease treatment. In particular, four distinct cysteine proteases were considered here: cathepsin B and L that play a primary role in tumor-cell invasion and metastasis; rhodesain, the major cathepsin L-like cysteine protease of Trypanosoma brucei rhodesiense and CPB2.8ΔCTE, a Leishmania mexicana mature cysteine protease. Based on the encouraging results obtained for some of the tested gold compounds on the two parasitic cysteine proteases, especially against CPB2.8ΔCTE, with IC50s in the micromolar range, we next evaluated whether those gold compounds might contrast effectively the growth of the respective protozoa and indeed important antiprotozoal properties were disclosed; on the other hand a certain lack of selectivity was highlighted. Also, no direct or clear correlation could be established between the in vitro antiprotozoal properties and the level of protease inhibition. The implications of these results are discussed in relation to possible pharmaceutical applications. 相似文献
919.
Mycobacterium tuberculosis, the etiological agent of human tuberculosis, harbours five ESAT‐6/type VII secretion (ESX/T7S) systems. The first esx gene clusters were identified during the genome‐sequencing project of M. tuberculosis H37Rv. Follow‐up studies revealed additional genes playing important roles in ESX/T7S systems. Among the latter genes, one can find those that encode Pro‐Glu (PE) and Pro‐Pro‐Glu (PPE) proteins as well as a gene cluster that is encoded >260 kb upstream of the esx‐1 locus and encodes ESX‐1 secretion‐associated proteins EspA (Rv3616c), EspC (Rv3615c) and EspD (Rv3614c). The espACD cluster has been suggested to have an important function in ESX‐1 secretion since EspA‐EspC and EsxA–EsxB are mutually co‐dependent on each other for secretion. However, the molecular mechanism of this co‐dependence and interaction between the substrates remained unknown. In this issue of Molecular Microbiology, Lou and colleagues show that EspC forms high‐molecular weight polymerization complexes that resemble selected components of type II, III and/or IV secretion systems of Gram‐negative bacteria. Indeed, EspC‐multimeric complexes form filamentous structures that could well represent a secretion needle of ESX‐1 type VII secretion systems. This exciting observation opens new avenues for research to discover and characterize ESX/T7S components and elucidates the co‐dependence of EsxA/B secretion with EspA/C. 相似文献
920.
Louis Bernatchez Maren Wellenreuther Cristián Araneda David T. Ashton Julia M.I. Barth Terry D. Beacham Gregory E. Maes Jann T. Martinsohn Kristina M. Miller Kerry A. Naish Jennifer R. Ovenden Craig R. Primmer Ho Young Suk Nina O. Therkildsen Ruth E. Withler 《Trends in ecology & evolution》2017,32(9):665-680