全文获取类型
收费全文 | 278篇 |
免费 | 13篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 19篇 |
2020年 | 12篇 |
2019年 | 8篇 |
2018年 | 10篇 |
2017年 | 10篇 |
2016年 | 14篇 |
2015年 | 25篇 |
2014年 | 29篇 |
2013年 | 25篇 |
2012年 | 29篇 |
2011年 | 20篇 |
2010年 | 13篇 |
2009年 | 5篇 |
2008年 | 13篇 |
2007年 | 11篇 |
2006年 | 5篇 |
2005年 | 10篇 |
2004年 | 6篇 |
2003年 | 2篇 |
2002年 | 5篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1992年 | 3篇 |
1990年 | 2篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1974年 | 1篇 |
排序方式: 共有291条查询结果,搜索用时 15 毫秒
41.
Cellulolytic microbes in the soil of the Yanbaru, a subtropical forest with an endemic biota, on Okinawa Island, were isolated and characterized in a search for novel microbial strains with biotechnological potential. Soil samples of the Yanbaru were suspended in sterilized water, inoculated on mineral salt agar overlaid with a filter paper as carbon source, and cultivated aerobically at 30 °C. After 2 weeks of cultivation, emerging colonies were isolated and subjected to phylogenetic and enzyme analyses. The phylogenetic analyses revealed bacterial and fungal isolates belonging to nine and three genera respectively. All isolates possessed cellulase activity, and several strains showed strong activity comparable to Trichoderma cellulase. Many isolates also exhibited xylanase activity. 相似文献
42.
Vacuolar protein sorting 9 (VPS9)-ankyrin-repeat protein (Varp) has recently been identified as an effector molecule for two small GTPases-Rab32 and Rab38-in the transport of a melanogenic enzyme tyrosinase-related protein 1 (Tyrp1) to melanosomes in melanocytes. Although Varp contains a Rab21-guanine nucleotide exchange factor (GEF) domain (i.e., VPS9 domain), since Rab21-GEF activity is not required for Tyrp1 transport, nothing is known about the physiological significance of the Rab21-GEF activity in melanocytes. Here we show by knockdown-rescue experiments that the Rab21-GEF activity of Varp, but not its Rab32/38 effector function, is required for forskolin-induced dendrite formation of cultured melanocytes. We found that Varp-deficient cells are unable to extend dendrites in response to forskolin stimulation and that reexpression of wild-type Varp or a Rab32/38-binding-deficient mutant Varp(Q509A/Y550A) in Varp-deficient cells completely restores their ability to form dendrites. By contrast, VPS9 mutants (D310A and Y350A) and a vesicle-associated membrane protein 7 (VAMP7)-binding-deficient mutant were unable to support forskolin-induced dendrite formation in Varp-deficient cells. These findings indicate that the Rab21-GEF activity and Rab32/38 binding activity of Varp are required for different melanocyte functions, that is, Rab21 activation by the VPS9 domain is required for dendrite formation, and the Rab32/38 effector function of the ankyrin repeat 1 domain is required for Tyrp1 transport to melanosomes, although VAMP7-binding ability is required for both functions. 相似文献
43.
Yoshihiro Ida Ayaka Matsubara Toru Nemoto Manabu Saito Shigeto Hirayama Hideaki Fujii Hiroshi Nagase 《Bioorganic & medicinal chemistry》2012,20(19):5810-5831
We have reported previously the novel δ opioid agonist KNT-127 which showed high affinity and selectivity for the δ receptor. Moreover, the analgesic effect of subcutaneously administered KNT-127 was more potent than that of a prototypical δ agonist (?)-TAN-67 in the acetic acid writhing test. This study of the structure–activity relationship of KNT-127 derivatives focused on the introduction of substituents onto the 5′-, 6′-, 7′- or 8′-position of the quinoline ring and revealed that many derivatives with 5′- or 8′-substituents showed high affinities and selectivities for the δ receptor. Especially, SYK-153 with an 8′-OH group showed the highest affinity and the most balanced and highest selectivity for the δ receptor among the synthesized compounds. 相似文献
44.
Suzuki H Kanai A Uehara T Guerra Gomez FL Hanaoka H Arano Y 《Bioorganic & medicinal chemistry》2012,20(2):978-984
A 12-membered polyazamacrocycle, 1-oxa-4,7,10-triazacyclododecane-N,N′,N″-triacetic acid (ODTA), has been reported to provide an indium chelate of net neutral charge with thermodynamic stability higher than 1,4,7,10-tetraazacyclododecane-N,N′,N″,N?-tetraacetic acid (DOTA). However, neither synthetic procedure for a C-functionalized ODTA (C-ODTA) nor its chelating ability with a trace amount of radioactive indium-111 (111In) has been elucidated. We herein present a facile synthetic procedure for C-ODTA, and estimated its ability as a chelating agent for radiolabeling peptides and proteins with 111In. The synthetic procedure involves the synthesis of a linear precursor using a para-substituted phenylalanine derivative as a starting material. The following intramolecular cyclization reaction was best performed (>73% yield) when Boc-protected linear compound and the condensation reagent, HATU, were simultaneously added to the reaction vessel at the same flow rate. The cyclic compound was then reduced with BH3 and alkylated with tert-butyl bromoacetate. The synthetic procedure was straightforward and some optimization would be required. However, most of the intermediate compounds were obtained easily in good yields, suggesting that the present synthetic procedure would be useful to synthesize C-ODTA derivatives. The intramolecular cyclization reaction might also be applicable to synthesize polyazamacrocycles of different ring sizes and cyclic peptides. In 111In radiolabeling reactions, C-ODTA provided 111In chelates in higher radiochemical yields at low ligand concentrations when compared with C-DOTA. The 111In-labeled C-ODTA remained unchanged in the presence of apo-transferrin. The biodistribution studies also showed that the 111In-labeled compound was mainly excreted into urine as intact. These findings indicate that C-ODTA would be useful to prepare 111In-labeled peptides of high specific activities in high radiochemical yields. 相似文献
45.
46.
Shin Numao Robert Maurus Gary Sidhu Yili Wang Christopher M Overall Gary D Brayer Stephen G Withers 《Biochemistry》2002,41(1):215-225
Human pancreatic alpha-amylase (HPA) is a member of the alpha-amylase family involved in the degradation of starch. Some members of this family, including HPA, require chloride for maximal activity. To determine the mechanism of chloride activation, a series of mutants (R195A, R195Q, N298S, R337A, and R337Q) were made in which residues in the chloride ion binding site were replaced. Mutations in this binding site were found to severely affect the ability of HPA to bind chloride ions with no binding detected for the R195 and R337 mutant enzymes. X-ray crystallographic analysis revealed that these mutations did not result in significant structural changes. However, the introduction of these mutations did alter the kinetic properties of the enzyme. Mutations to residue R195 resulted in a 20-450-fold decrease in the activity of the enzyme toward starch and shifted the pH optimum to a more basic pH. Interestingly, replacement of R337 with a nonbasic amino acid resulted in an alpha-amylase that no longer required chloride for catalysis and has a pH profile similar to that of wild-type HPA. In contrast, a mutation at residue N298 resulted in an enzyme that had much lower binding affinity for chloride but still required chloride for maximal activity. We propose that the chloride is required to increase the pK(a) of the acid/base catalyst, E233, which would otherwise be lower due to the presence of R337, a positively charged residue. 相似文献
47.
Camille V. Chagneau Clmence Massip Nadge Bossuet-Greif Christophe Fremez Jean-Paul Motta Ayaka Shima Cline Besson Pauline Le Faouder Nicolas Cnac Marie-Paule Roth Hlne Coppin Maxime Fontani Patricia Martin Jean-Philippe Nougayrde Eric Oswald 《PLoS pathogens》2021,17(2)
Urinary tract infections (UTIs) are among the most common outpatient infections, with a lifetime incidence of around 60% in women. We analysed urine samples from 223 patients with community-acquired UTIs and report the presence of the cleavage product released during the synthesis of colibactin, a bacterial genotoxin, in 55 of the samples examined. Uropathogenic Escherichia coli strains isolated from these patients, as well as the archetypal E. coli strain UTI89, were found to produce colibactin. In a murine model of UTI, the machinery producing colibactin was expressed during the early hours of the infection, when intracellular bacterial communities form. We observed extensive DNA damage both in umbrella and bladder progenitor cells. To the best of our knowledge this is the first report of colibactin production in UTIs in humans and its genotoxicity in bladder cells. 相似文献
48.
Akira Makino Anna Miyazaki Ayaka Tomoike Hiroyuki Kimura Kenji Arimitsu Masahiko Hirata Yoshiro Ohmomo Ryuichi Nishii Hidehiko Okazawa Yasushi Kiyono Masahiro Ono Hideo Saji 《Bioorganic & medicinal chemistry》2018,26(8):1609-1613
Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR-TKIs) are used as molecular targeted therapy for non-small cell lung cancer (NSCLC) patients. The therapy is applied to the patients having EGFR-primary L858R mutation, but drug tolerance caused by EGFR-secondary mutation is occurred within one and half years. For the non-invasive detection of the EGFR-TKIs treatment positive patients by positron emission tomograpy (PET) imagaing, fluorine-18 labeled thienopyrimidine derivative, [18F]FTP2 was newly synthesized. EGFR inhibition assay, cell uptake study, and blocking study indicated [18F]FTP2 binds with high and selective affinity for EGFR with L858R mutation, and not with L858R/T790M dual mutations. On animal PET study using tumor bearing mice, H3255 cells expressing L858R mutated EGFR was more clearly visualized than H1975 cells expressing L858R/T790M dual mutated EGFR. [18F]FTP2 has potential for detecting NSCLC which is susceptible to EGFR-TKI treatment. 相似文献
49.
50.
An evolutionarily conserved P‐subfamily pentatricopeptide repeat protein is required to splice the plastid ndhA transcript in the moss Physcomitrella patens and Arabidopsis thaliana 下载免费PDF全文