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Nancy J Ganson Susan J Kelly Edna Scarlett John S Sundy Michael S Hershfield 《Arthritis research & therapy》2005,8(1):R12
PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic
gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial,
single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout),
whose plasma uric acid concentration (pUAc) was 11.3 ± 2.1 mg/dl (mean ± SD). By day seven after injection of PEG-uricase,
pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 ± 2.2 mg/dl.
At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma
uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects,
plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of
relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG
itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after
injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well
tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest
that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous
gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption
that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for
other PEGylated therapeutic agents in clinical use. 相似文献
74.
Two Southern Ocean diatoms are more sensitive to ocean acidification and changes in irradiance than the prymnesiophyte Phaeocystis antarctica
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Scarlett Trimborn Silke Thoms Tina Brenneis Jasmin P. Heiden Sara Beszteri Kai Bischof 《Physiologia plantarum》2017,160(2):155-170
To better understand the impact of ocean acidification (OA) and changes in light availability on Southern Ocean phytoplankton physiology, we investigated the effects of pCO2 (380 and 800 µatm) in combination with low and high irradiance (20 or 50 and 200 µmol photons m?2 s?1) on growth, particulate organic carbon (POC) fixation and photophysiology in the three ecologically relevant species Chaetoceros debilis, Fragilariopsis kerguelensis and Phaeocystis antarctica. Irrespective of the light scenario, neither growth nor POC per cell was stimulated by OA in any of the tested species and the two diatoms even displayed negative responses in growth (e.g. C. debilis) or POC content (e.g. F. kerguelensis) under OA in conjunction with high light. For both diatoms, also maximum quantum yields of photosystem II (Fv/Fm) were decreased under these conditions, indicating lowered photochemical efficiencies. To counteract the negative effects by OA and high light, the two diatoms showed diverging photoacclimation strategies. While cellular chlorophyll a (Chl a) and fucoxanthin contents were enhanced in C. debilis to potentially maximize light absorption, F. kerguelensis exhibited reduced Chl a per cell, increased disconnection of antennae from photosystem II reaction centers and strongly lowered absolute electron transport rates (ETR). The decline in ETRs in F. kerguelensis might be explained in terms of different species‐specific strategies for tuning the available flux of adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. Overall, our results revealed that P. antarctica was more tolerant to OA and changes in irradiance than the two diatoms, which may have important implications for biogeochemical cycling. 相似文献
75.
Jun Han Ryan M. Danell Jayanti R. Patel Dmitry R. Gumerov Cameron O. Scarlett J. Paul Speir Carol E. Parker Ivan Rusyn Steven Zeisel Christoph H. Borchers 《Metabolomics : Official journal of the Metabolomic Society》2008,4(2):128-140
With unmatched mass resolution, mass accuracy, and exceptional detection sensitivity, Fourier Transform Ion Cyclotron Resonance
Mass Spectrometry (FTICR-MS) has the potential to be a powerful new technique for high-throughput metabolomic analysis. In
this study, we examine the properties of an ultrahigh-field 12-Tesla (12T) FTICR-MS for the identification and absolute quantitation
of human plasma metabolites, and for the untargeted metabolic fingerprinting of inbred-strain mouse serum by direct infusion
(DI). Using internal mass calibration (mass error ≤1 ppm), we determined the rational elemental compositions (incorporating
unlimited C, H, N and O, and a maximum of two S, three P, two Na, and one K per formula) of approximately 250 out of 570 metabolite
features detected in a 3-min infusion analysis of aqueous extract of human plasma, and were able to identify more than 100
metabolites. Using isotopically-labeled internal standards, we were able to obtain excellent calibration curves for the absolute
quantitation of choline with sub-pmol sensitivity, using 500 times less sample than previous LC/MS analyses. Under optimized
serum dilution conditions, chemical compounds spiked into mouse serum as metabolite mimics showed a linear response over a
600-fold concentration range. DI/FTICR-MS analysis of serum from 26 mice from 2 inbred strains, with and without acute trichloroethylene
(TCE) treatment, gave a relative standard deviation (RSD) of 4.5%. Finally, we extended this method to the metabolomic fingerprinting
of serum samples from 49 mice from 5 inbred strains involved in an acute alcohol toxicity study, using both positive and negative
electrospray ionization (ESI). Using these samples, we demonstrated the utility of this method for high-throughput metabolomics,
with more than 400 metabolites profiled in only 24 h. Our experiments demonstrate that DI/FTICR-MS is well-suited for high-throughput
metabolomic analysis.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
76.
77.
A J Barker K H Gibson W Grundy A A Godfrey J J Barlow M P Healy J R Woodburn S E Ashton B J Curry L Scarlett L Henthorn L Richards 《Bioorganic & medicinal chemistry letters》2001,11(14):1911-1914
This paper describes the development of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 from a lead series of 4-anilinoquinazoline compounds. ZD1839 has suitable properties for use as a clinically effective drug and shows activity against human tumours. In particular, the use of pharmacokinetic data in the development of ZD1839 is discussed. 相似文献
78.
We purified and characterized both the methyltransferase and the endonuclease containing the HsdS delta 50 subunit (type I restriction endonucleases are composed of three subunits--HsdR required for restriction, HsdM required for methylation and HsdS responsible for DNA recognition) produced from the deletion mutation hsdS delta 50 of the type IC R-M system EcoR 124I; this mutant subunit lacks the C-terminal 163 residues of HsdS and produces a novel DNA specificity. Analysis of the purified HsDs delta 50 subunit indicated that during purification it is subject to partial proteolysis resulting in removal of approximately 1 kDa of the polypeptide at the C-terminus. This proteolysis prevented the purification of further deletion mutants, which were determined as having a novel DNA specificity in vivo. After biochemical characterization of the mutant DNA methyltransferase (MTase) and restriction endonuclease we found only one difference comparing with the wild-type enzyme--a significantly higher binding affinity of the MTase for the two substrates of hemimethylated and fully methylated DNA. This indicates that MTase delta 50 is less able to discriminate the methylation status of the DNA during its binding. However, the mutant MTase still preferred hemimethylated DNA as the substrate for methylation. We fused the hsdM and hsdS delta 50 genes and showed that the HsdM-HsdS delta 50 fusion protein is capable of dimerization confirming the model for assembly of this deletion mutant. 相似文献
79.
Synthesis and biological evaluation of new derivatives of emodin 总被引:7,自引:0,他引:7
Teich L Daub KS Krügel V Nissler L Gebhardt R Eger K 《Bioorganic & medicinal chemistry》2004,12(22):5961-5971
Drugs containing an anthraquinone moiety such as daunorubicin (Daunoblastin) and mitoxantrone (Onkotrone) constitute some of the most powerful cytostatics. They suppress tumor growth mainly by intercalation into DNA and inhibition of topoisomerase II, and are suspected to generate free radicals leading to DNA strand scission. We established a novel strategy for obtaining new highly functionalized derivatives of emodin (1,3,8-trihydroxy-6-methyl-anthraquinone). Using emodin, DIB, and an appropriate amine as starting materials, we obtained a wide range of emodin-related structures by one-pot synthesis. Several of these derivatives showed stronger cytotoxic and cytostatic activity than emodin. In particular, compound 6 was highly effective on the HepG2 tumor cell line, but did not show any cytotoxicity on normal hepatocytes. In addition to this favorable feature, compound 6 revealed interesting binding properties to a recombinant fragment of the multi-drug-resistance transporter, pgp, and reversed the multi-drug-resistance phenotype of H4-II-E cells, thus making this compound a promising potential anti-tumor drug. 相似文献
80.