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111.
Ong PC McGowan S Pearce MC Irving JA Kan WT Grigoryev SA Turk B Silverman GA Brix K Bottomley SP Whisstock JC Pike RN 《The Journal of biological chemistry》2007,282(51):36980-36986
A balance between proteolytic activity and protease inhibition is crucial to the appropriate function of many biological processes. There is mounting evidence for the presence of both papain-like cysteine proteases and serpins with a corresponding inhibitory activity in the nucleus. Well characterized examples of cofactors fine tuning serpin activity in the extracellular milieu are known, but such modulation has not been studied for protease-serpin interactions within the cell. Accordingly, we present an investigation into the effect of a DNA-rich environment on the interaction between model serpins (MENT and SCCA-1), cysteine proteases (human cathepsin V and human cathepsin L), and cystatin A. DNA was indeed found to accelerate the rate at which MENT inhibited cathepsin V, a human orthologue of mammalian cathepsin L, up to 50-fold, but unexpectedly this effect was primarily effected via the protease and secondarily by the recruitment of the DNA as a "template" onto which cathepsin V and MENT are bound. Notably, the protease-mediated effect was found to correspond both with an altered substrate turnover and a conformational change within the protease. Consistent with this, cystatin inhibition, which relies on occlusion of the active site rather than the substrate-like behavior of serpins, was unaltered by DNA. This represents the first example of modulation of serpin inhibition of cysteine proteases by a co-factor and reveals a mechanism for differential regulation of cathepsin proteolytic activity in a DNA-rich environment. 相似文献
112.
Lack of association between common polymorphisms in the 17beta-hydroxysteroid dehydrogenase type V gene (HSD17B5) and precocious pubarche 总被引:1,自引:0,他引:1
Petry CJ Ong KK Wingate DL de Zegher F Ibáñez L Dunger DB 《The Journal of steroid biochemistry and molecular biology》2007,105(1-5):176-180
BACKGROUND: 17beta-Hydroxysteroid dehydrogenase (type V; HSD17B5) is a key enzyme involved in testosterone production in females. A single nucleotide polymorphism (SNP) in the promoter region of its gene was recently found to be associated with polycystic ovary syndrome (PCOS) and its related hyperandrogenaemia. Precocious pubarche (PP) is a clinical entity pointing to adrenal androgen excess from mid-childhood onward and is associated with ovarian androgen excess from puberty onward. It is therefore a strong risk factor for PCOS. METHODS: To investigate associations between this promoter SNP along with three exonic SNPs (one non-synonymous and two synonymous) from the same gene, and PP, a case-control study was performed in 190 girls with PP (84 of which were also tested for functional ovarian hyperandrogenism) from Barcelona, Spain and 71 healthy controls. Clinical features and hormone concentrations relevant to hyperandrogenism were compared by HSD17B5 genotype and haplotype. RESULTS: Neither HSD17B5 genotypes nor haplotype were associated with PP, or subsequent androgen excess in girls from Barcelona (all P>0.05). CONCLUSIONS: HSD17B5 SNPs predicted to have functional effects do not appear to be a risk factor for PP in girls from Barcelona, despite these girls being at high risk of developing androgen excess in adulthood. 相似文献
113.
Multi‐isotype antibody responses against the multimeric Salmonella Typhi recombinant hemolysin E antigen 下载免费PDF全文
Eugene Boon Beng Ong Joshua Ignatius Amy Amilda Anthony Ismail Aziah Asma Ismail Theam Soon Lim 《Microbiology and immunology》2015,59(1):43-47
The detection and measurement of different antibody isotypes in the serum provide valuable indicators of the different stages of typhoid infection. Here, the ability of S. Typhi recombinant hemolysin E (HlyE) to detect multi‐isotype antibody responses in sera of patients with typhoid and paratyphoid A was investigated using an indirect antibody immunoassay. Nanogram amounts of HlyE were found to be sufficient for detection of IgG and IgA isotypes and, in a study of individuals' sera (n = 100), the immunoassay was able to distinguish between typhoid and non‐typhoid sera. The overall sensitivity, specificity and efficiency of the ELISA were 70% (39/56), 100% (44/44) and 83% respectively. 相似文献
114.
Homoserine and quorum‐sensing acyl homoserine lactones as alternative sources of threonine: a potential role for homoserine kinase in insect‐stage Trypanosoma brucei 下载免费PDF全文
Han B. Ong Wai S. Lee Stephen Patterson Susan Wyllie Alan H. Fairlamb 《Molecular microbiology》2015,95(1):143-156
De novo synthesis of threonine from aspartate occurs via the β‐aspartyl phosphate pathway in plants, bacteria and fungi. However, the Trypanosoma brucei genome encodes only the last two steps in this pathway: homoserine kinase (HSK) and threonine synthase. Here, we investigated the possible roles for this incomplete pathway through biochemical, genetic and nutritional studies. Purified recombinant TbHSK specifically phosphorylates L‐homoserine and displays kinetic properties similar to other HSKs. HSK null mutants generated in bloodstream forms displayed no growth phenotype in vitro or loss of virulence in vivo. However, following transformation into procyclic forms, homoserine, homoserine lactone and certain acyl homoserine lactones (AHLs) were found to substitute for threonine in growth media for wild‐type procyclics, but not HSK null mutants. The tsetse fly is considered to be an unlikely source of these nutrients as it feeds exclusively on mammalian blood. Bioinformatic studies predict that tsetse endosymbionts possess part (up to homoserine in Wigglesworthia glossinidia) or all of the β‐aspartyl phosphate pathway (Sodalis glossinidius). In addition S. glossinidius is known to produce 3‐oxohexanoylhomoserine lactone which also supports trypanosome growth. We propose that T. brucei has retained HSK and threonine synthase in order to salvage these nutrients when threonine availability is limiting. 相似文献
115.
Gianina Ravenscroft Flora Nolent Sulekha Rajagopalan Ana M. Meireles Kevin J. Paavola Dominique Gaillard Elisabeth Alanio Michael Buckland Susan Arbuckle Michael Krivanek Jérome Maluenda Stephen Pannell Rebecca Gooding Royston W. Ong Richard J. Allcock Ellaine D.F. Carvalho Maria D.F. Carvalho Fernando Kok William S. Talbot Judith Melki Nigel G. Laing 《American journal of human genetics》2015,96(6):955-961
116.
117.
Loader NJ Walsh RP Robertson I Bidin K Ong RC Reynolds G McCarroll D Gagen M Young GH 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2011,366(1582):3330-3339
Stable carbon isotope (δ(13)C) series were developed from analysis of sequential radial wood increments from AD 1850 to AD 2009 for four mature primary rainforest trees from the Danum and Imbak areas of Sabah, Malaysia. The aseasonal equatorial climate meant that conventional dendrochronology was not possible as the tree species investigated do not exhibit clear annual rings or dateable growth bands. Chronology was established using radiocarbon dating to model age-growth relationships and date the carbon isotopic series from which the intrinsic water-use efficiency (IWUE) was calculated. The two Eusideroxylon zwageri trees from Imbak yielded ages of their pith/central wood (±1 sigma) of 670 ± 40 and 759 ± 40 years old; the less dense Shorea johorensis and Shorea superba trees at Danum yielded ages of 240 ± 40 and 330 ± 40 years, respectively. All trees studied exhibit an increase in the IWUE since AD 1960. This reflects, in part, a response of the forest to increasing atmospheric carbon dioxide concentration. Unlike studies of some northern European trees, no clear plateau in this response was observed. A change in the IWUE implies an associated modification of the local carbon and/or hydrological cycles. To resolve these uncertainties, a shift in emphasis away from high-resolution studies towards long, well-replicated time series is proposed to develop the environmental data essential for model evaluation. Identification of old (greater than 700 years) ringless trees demonstrates their potential in assessing the impacts of climatic and atmospheric change. It also shows the scientific and applied value of a conservation policy that ensures the survival of primary forest containing particularly old trees (as in Imbak Canyon and Danum). 相似文献
118.
119.
This study aimed to express two major drug-metabolizing human hepatic cytochromes P450 (CYPs), CYP2D6 and CYP3A4, together
with NADPH-cytochrome P450 oxidoreductase (OxR) in Escherichia coli and to evaluate their catalytic activities. Full length cDNA clones of both isoforms in which the N-terminus was modified
to incorporate bovine CYP17α sequence were inserted into a pCWori+ vector. The modified CYP cDNAs were subsequently expressed individually, each together with OxR by means of separate, compatible
plasmids with different antibiotic selection markers. The expressed proteins were evaluated by immunoblotting and reduced
CO difference spectral scanning. Enzyme activities were examined using high performance liquid chromatography (HPLC) assays
with probe substrates dextromethorphan and testosterone for CYP2D6 and CYP3A4, respectively. Results from immunoblotting demonstrated
the presence of both CYP proteins in bacterial membranes and reduced CO difference spectra of the cell preparations exhibited
the characteristic absorbance peak at 450 nm. Co-expressed OxR also demonstrated an activity level comparable to literature
values. Kinetic parameters, Km and Vmax values determined from the HPLC assays also agreed well with literature values. As a conclusion, the procedures described
in this study provide a relatively convenient and reliable means of producing catalytically active CYP isoforms suitable for
drug metabolism and interaction studies. 相似文献
120.
Yu W Chan-On W Teo M Ong CK Cutcutache I Allen GE Wong B Myint SS Lim KH Voorhoeve PM Rozen S Soo KC Tan P Teh BT 《Genome biology》2011,12(9):R96-14