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971.
Chen ZW Vignaud C Jaafar A Lévy B Guéritte F Guénard D Lederer F Mathews FS 《Biochimie》2012,94(5):1172-1179
Long chain hydroxy acid oxidase (LCHAO) is responsible for the formation of methylguanidine, a toxic compound with elevated serum levels in patients with chronic renal failure. Its isozyme glycolate oxidase (GOX), has a role in the formation of oxalate, which can lead to pathological deposits of calcium oxalate, in particular in the disease primary hyperoxaluria. Inhibitors of these two enzymes may have therapeutic value. These enzymes are the only human members of the family of FMN-dependent l-2-hydroxy acid-oxidizing enzymes, with yeast flavocytochrome b2 (Fcb2) among its well studied members. We screened a chemical library for inhibitors, using in parallel rat LCHAO, human GOX and the Fcb2 flavodehydrogenase domain (FDH). Among the hits was an inhibitor, CCPST, with an IC50 in the micromolar range for all three enzymes. We report here the crystal structure of a complex between this compound and LCHAO at 1.3 Å resolution. In comparison with a lower resolution structure of this enzyme, binding of the inhibitor induces a conformational change in part of the TIM barrel loop 4, as well as protonation of the active site histidine. The CCPST interactions are compared with those it forms with human GOX and those formed by two other inhibitors with human GOX and spinach GOX. These compounds differ from CCPST in having the sulfur replaced with a nitrogen in the five-membered ring as well as different hydrophobic substituents. The possible reason for the ∼100-fold difference in affinity between these two series of inhibitors is discussed. The present results indicate that specificity is an issue in the quest for therapeutic inhibitors of either LCHAO or GOX, but they may give leads for this quest. 相似文献
972.
Lino Cardenas CL Devos A Toure A Cardenas Garcia J Kenani A Migot-Nabias F Broly F Chevalier D 《Molecular biology reports》2012,39(2):1503-1508
The human Cytochrome P450 4A11 (CYP4A11) is a major ω-hydroxylase involved in the regulation of blood pressure in the kidney
through the conversion of arachidonic acid into 20-hydroxyeicosatetraenoic acid (20-HETE). Previous studies have reported
a significant association between the 8590T>C genetic variant of CYP4A11 and hypertension. Interestingly, several population-based studies have reported ethnic differences in the prevalence of hypertension,
with the highest prevalence in African populations. The aim of this work was to determine the frequency and inter-ethnic comparison
of the CYP4A11 (8590T>C) functional polymorphism, in five new ethnic groups: European (99 French Caucasians), African (36 Gabonese and 50
Senegalese), South American (60 Peruvians) and North African (53 Tunisians) populations, using polymerase chain reaction-single
strand conformational polymorphism and sequencing strategies. We confirmed that the CYP4A11 (8590T>C) functional polymorphism exhibits inter-ethnic frequency differences. Noteworthy, the highest 8590C allele frequency
was observed in the Tunisian (30.2%), followed by Senegalese (20%) populations. In addition, the CC genotype was only found
in the Gabonese and Tunisian populations (5.6% and 8.4%, respectively). These populations may be of major interest to help
to clarify the linkage between hypertension and CYP4A11 (8590T>C) genotype in African populations. These findings provide data for further studies that investigate the potential
association of CYP4A11 (8590T>C) variant with an incidence of hypertension genesis in respect of ethnicity. 相似文献
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974.
975.
Ahmad Z Ahmad M Okafor F Jones J Abunameh A Cheniya RP Kady IO 《International journal of biological macromolecules》2012,50(3):476-486
In this paper we present the inhibitory effect of a variety of structurally modulated/modified polyphenolic compounds on purified F(1) or membrane bound F(1)F(o)Escherichia coli ATP synthase. Structural modulation of polyphenols with two phenolic rings inhibited ATP synthase essentially completely; one or three ringed polyphenols individually or fused together inhibited partially. We found that the position of hydroxyl and nitro groups plays critical role in the degree of binding and inhibition of ATPase activity. The extended positioning of hydroxyl groups on imino diphenolic compounds diminished the inhibition and abridged position enhanced the inhibition potency. This was contrary to the effect by simple single ringed phenolic compounds where extended positioning of hydroxyl group was found to be effective for inhibition. Also, introduction of nitro group augmented the inhibition on molar scale in comparison to the inhibition by resveratrol but addition of phosphate group did not. Similarly, aromatic diol or triol with rigid or planar ring structure and no free rotation poorly inhibited the ATPase activity. The inhibition was identical in both F(1)F(o) membrane preparations as well as in isolated purified F(1) and was reversible in all cases. Growth assays suggested that modulated compounds used in this study inhibited F(1)-ATPase as well as ATP synthesis nearly equally. 相似文献
976.
Fruzzetti F Trémollieres F Bitzer J 《Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology》2012,28(5):400-408
Natural estrogens such as estradiol (E(2)) or its valerate ester (E(2)V) offer an alternative to ethinyl estradiol (EE). E(2)-containing combined oral contraceptives (COCs) have demonstrated sufficient ovulation inhibition and acceptable contraceptive efficacy. However, earlier formulations were generally associated with unacceptable bleeding profiles. Two E(2)V-containing preparations have been approved to date for contraceptive use: E(2)V/cyproterone acetate (CPA) (Femilar(?); only approved in Finland and only in women >40 years or women aged 35-40 years in whom a COC containing EE is not appropriate) and E(2)V/dienogest (DNG; Qlaira(?)/Natazia(?)). The objective of the current review is to provide an overview of the development of COCs containing natural estrogen, highlighting past issues and challenges faced by earlier formulations, as well as the current status and future directions. The majority of information to date pertains to the development of E(2)V/DNG. 相似文献
977.
Kosior E Bohic S Suhonen H Ortega R Devès G Carmona A Marchi F Guillet JF Cloetens P 《Journal of structural biology》2012,177(2):239-247
Hard X-ray fluorescence microscopy and magnified phase contrast imaging are combined to obtain quantitative maps of the projected metal concentration in whole cells. The experiments were performed on freeze dried cells at the nano-imaging station ID22NI of the European Synchrotron Radiation Facility (ESRF). X-ray fluorescence analysis gives the areal mass of most major, minor and trace elements; it is validated using a biological standard of known composition. Quantitative phase contrast imaging provides maps of the projected mass and is validated using calibration samples and through comparison with Atomic Force Microscopy and Scanning Transmission Ion Microscopy. Up to now, absolute quantification at the sub-cellular level was impossible using X-ray fluorescence microscopy but can be reached with the use of the proposed approach. 相似文献
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979.
David Halter Florence Goulhen-Chollet Sébastien Gallien Corinne Casiot Jér?me Hamelin Fran?oise Gilard Dimitri Heintz Christine Schaeffer Christine Carapito Alain Van Dorsselaer Guillaume Tcherkez Florence Arsène-Ploetze Philippe N Bertin 《The ISME journal》2012,6(7):1391-1402
Euglena mutabilis is a photosynthetic protist found in acidic aquatic environments such as peat bogs, volcanic lakes and acid mine drainages (AMDs). Through its photosynthetic metabolism, this protist is supposed to have an important role in primary production in such oligotrophic ecosystems. Nevertheless, the exact contribution of E. mutabilis in organic matter synthesis remains unclear and no evidence of metabolite secretion by this protist has been established so far. Here we combined in situ proteo-metabolomic approaches to determine the nature of the metabolites accumulated by this protist or potentially secreted into an AMD. Our results revealed that the secreted metabolites are represented by a large number of amino acids, polyamine compounds, urea and some sugars but no fatty acids, suggesting a selective organic matter contribution in this ecosystem. Such a production may have a crucial impact on the bacterial community present on the study site, as it has been suggested previously that prokaryotes transport and recycle in situ most of the metabolites secreted by E. mutabilis. Consequently, this protist may have an indirect but important role in AMD ecosystems but also in other ecological niches often described as nitrogen-limited. 相似文献
980.