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941.
Klabunde T Petrassi HM Oza VB Raman P Kelly JW Sacchettini JC 《Nature structural biology》2000,7(4):312-321
The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases. 相似文献
942.
Antibody-detected folding: kinetics of surface epitope formation are distinct from other folding phases 下载免费PDF全文
Raman CS Jemmerson R Nall BT 《Protein science : a publication of the Protein Society》2000,9(1):129-137
The rate of macromolecular surface formation in yeast iso-2 cytochrome c and its site-specific mutant, N52I iso-2, has been studied using a monoclonal antibody that recognizes a tertiary epitope including K58 and H39. The results indicate that epitope refolding occurs after fast folding but prior to slow folding, in contrast to horse cytochrome c where surface formation occurs early. The antibody-detected (ad) kinetic phase accompanying epitope formation has k(ad) = 0.2 s(-1) and is approximately 40-fold slower than the fastest detectable event in the folding of yeast iso-2 cytochrome c (k2f approximately 8 s(-1)), but occurs prior to the absorbance- and fluorescence-detected slow folding steps (k1a approximately 0.06 s(-1); k1b approximately 0.09 s(-1)). N5I iso-2 cytochrome c exhibits similar kinetic behavior with respect to epitope formation. A detailed dissection of the mechanistic differences between the folding pathways of horse and yeast cytochromes c identifies possible reasons for the slow surface formation in the latter. Our results suggest that non-native ligation involving H33 or H39 during refolding may slow down the formation of the tertiary epitope in iso-2 cytochrome c. This study illustrates that surface formation can be coupled to early events in protein folding. Thus, the rate of macromolecular surface formation is fine tuned by the residues that make up the surface and the interactions they entertain during refolding. 相似文献
943.
944.
A multiplex T-RFLP test was developed to detect and identify Salmonella enterica and all six species of Listeria inoculated into milk at minimal levels. Extensive in silico analysis was used to design a fifteen-primer, six-amplimer methodology and in vitro application showed target organism DNA, when amplified individually, yielded the predicted terminal restriction fragments (TRFs) following digestion. Non-target organisms were either not-amplified or yielded TRFs which did not interfere with target identification. Multiple target DNA analysis gave over 86% detection of total TRFs predicted, and this was improved to over 90% detection of total TRFs predicted when only two target DNA extracts were combined analysed. Co-inoculation of milk with five strains each of the target species of S. enterica and L. monocytogenes, along with five strains of the non-target species E. coli was followed by enrichment in SEL medium for M-TRFLP analysis. This allowed for detection of both target species in all samples, with detection of one S. enterica and two Listeria TRFs in all cases, and detection of a second S. enterica TRF in 91% of cases. This was from an initial inoculum of <5 cfu per 25 ml milk with a background of competing E. coli present, and gave a result from sampling of under 20 hours. The ability to increase target species number without loss of sensitivity means that extensive screening can be performed at reduced cost due to a reduction in the number of tests required. 相似文献
945.
Sivaji Patra A. V. Raman D. Ganguly R. S. Robin P. R. Muduli VishnuVardhan Kanuri K. R. Abhilash B. Charan Kumar B. R. Subramanian 《Limnology》2016,17(3):223-238
The behaviour of suspended particulate matter (SPM), salinity profile, dissolved nutrients, total (T.Chl-a) and size fractionated chlorophyll-a (F.Chl-a) were studied seasonally at Chilika Lagoon, east coast of India, during 2008–2009. The study showed large spatio-temporal variations among these parameters. The concentration of dissolved inorganic nitrogen and inorganic phosphate were found to be maximum during the monsoon, followed by post- and pre-monsoon, although the mean N:P ratios, which indicate the relative availability of N with respect to P, were 9.13 ± 3.09, 16.57 ± 11.53 and 5.47 ± 3.13, respectively. It was evident from the results that during pre-monsoon and postmonsoon, the lagoon exhibits nitrogen limitation. Mean T.Chl-a biomass in the lagoon showed distinct seasonality with maximum values during the pre-monsoon (23.12 ± 9.75 mg m?3) followed by monsoon and post-monsoon. Irrespective of seasons, maximum T.Chl-a was found in the northern part of the lagoon. SPM concentrations during the monsoon were relatively higher in the freshwater dominated zones compared to seawater dominated areas, indicating its riverine sources. The correlation between SPM and various dissolved nutrients (p < 0.05) suggests its influence on the physico-chemical conditions at varying levels. It is summarized that seasonal variation of SPM and nutrients contributed by rivers, wind induced re-suspension events and in situ regeneration processes play a crucial role in the lagoon biogeochemical cycle. 相似文献
946.
947.
A simple technique for staining synaptonemal complexes with Coomassie brilliant blue for light microscopy has been described. The testis cells were exposed to prolonged hypotonic treatment and dropped on Formvar-coated slides. Following fixation with paraformaldehyde the slides were stained with Coomassie brilliant blue for 15 min to 1 h at room temperature and rinsed in distilled water. For its simplicity and rapidity this technique may serve as an effective alternative to silver staining for light microscopic observation of synaptonemal complexes. 相似文献
948.
William P Bewg Scott A Harding Nancy L Engle Brajesh N Vaidya Ran Zhou Jacob Reeves Thomas W Horn Nirmal Joshee Jerry W Jenkins Shengqiang Shu Kerrie W Barry Yuko Yoshinaga Jane Grimwood Robert J Schmitz Jeremy Schmutz Timothy J Tschaplinski Chung-Jui Tsai 《Plant physiology》2022,189(2):516
As the focus for CRISPR/Cas-edited plants moves from proof-of-concept to real-world applications, precise gene manipulation will increasingly require concurrent multiplex editing for polygenic traits. A common approach for editing across multiple sites is to design one guide RNA (gRNA) per target; however, this complicates construct assembly and increases the possibility of off-target mutations. In this study, we utilized one gRNA to target MYB186, a known positive trichome regulator, as well as its paralogs MYB138 and MYB38 at a consensus site for mutagenesis in hybrid poplar (Populus tremula × P. alba INRA 717-1B4). Unexpected duplications of MYB186 and MYB138 resulted in eight alleles for the three targeted genes in the hybrid poplar. Deep sequencing and polymerase chain reaction analyses confirmed editing across all eight targets in nearly all of the resultant glabrous mutants, ranging from small indels to large genomic dropouts, with no off-target activity detected at four potential sites. This highlights the effectiveness of a single gRNA targeting conserved exonic regions for multiplex editing. Additionally, cuticular wax and whole-leaf analyses showed a complete absence of triterpenes in the trichomeless mutants, hinting at a previously undescribed role for the nonglandular trichomes of poplar. Targeting conserved sequences with a single gRNA allows efficient mutagenesis of a multigene family and the recovery of trichomeless and triterpene-free poplar mutants. 相似文献
949.
Qingmei Hong Raman K. Bakshi James Dellureficio Shuwen He Zhixiong Ye Peter H. Dobbelaar Iyassu K. Sebhat Liangqin Guo Jian Liu Tianying Jian Rui Tang Rubana N. Kalyani Tanya MacNeil Aurawan Vongs Charles I. Rosenblum David H. Weinberg Qingping Peng Constantin Tamvakopoulos Randy R. Miller Ralph A. Stearns Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(15):4483-4486
Design, syntheses and structure–activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties. 相似文献
950.
Shuwen He Zhixiong Ye Peter H. Dobbelaar Iyassu K. Sebhat Liangqin Guo Jian Liu Tianying Jian Yingjie Lai Christopher L. Franklin Raman K. Bakshi James P. Dellureficio Qingmei Hong Nancy N. Tsou Richard G. Ball Doreen E. Cashen William J. Martin David H. Weinberg Tanya MacNeil Rui Tang Constantin Tamvakopoulos Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(7):2106-2110
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models. 相似文献