全文获取类型
收费全文 | 247篇 |
免费 | 7篇 |
出版年
2024年 | 1篇 |
2023年 | 4篇 |
2022年 | 11篇 |
2021年 | 19篇 |
2020年 | 8篇 |
2019年 | 8篇 |
2018年 | 11篇 |
2017年 | 12篇 |
2016年 | 11篇 |
2015年 | 18篇 |
2014年 | 9篇 |
2013年 | 18篇 |
2012年 | 12篇 |
2011年 | 17篇 |
2010年 | 5篇 |
2009年 | 11篇 |
2008年 | 9篇 |
2007年 | 9篇 |
2006年 | 7篇 |
2005年 | 9篇 |
2004年 | 4篇 |
2003年 | 7篇 |
2002年 | 4篇 |
2001年 | 1篇 |
2000年 | 4篇 |
1999年 | 1篇 |
1998年 | 3篇 |
1997年 | 2篇 |
1993年 | 1篇 |
1990年 | 1篇 |
1989年 | 2篇 |
1987年 | 1篇 |
1985年 | 5篇 |
1984年 | 7篇 |
1983年 | 1篇 |
1975年 | 1篇 |
排序方式: 共有254条查询结果,搜索用时 296 毫秒
11.
A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents. 相似文献
12.
13.
Umar S Wang Y Morris AP Sellin JH 《American journal of physiology. Gastrointestinal and liver physiology》2007,292(2):G599-G607
Casein kinase I (CKI)-epsilon and GSK-3beta phosphorylate beta-catenin at Ser(45) (beta-cat(45)) and Thr(41)/Ser(37,33) (beta-cat(33,37,41)) residues, thereby facilitating its ubiquitination and proteasomal degradation. We used a Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model to determine Ser/Thr phosphorylation and biological function of beta-catenin during crypt hyperproliferation. TMCH was associated with 3-fold and 3.3-fold increases in CKI-epsilon cellular abundance and 2-fold and 1.8-fold increase in its activity at 6 and 12 days after infection, respectively. beta-Catenin coimmunoprecipitated with both cellular and nuclear CKI-epsilon and cellular axin at these time points. Cellular beta-catenin was constitutively phosphorylated at Ser(45) and underwent subcellular redistribution to cytoskeletal and nuclear fractions at days 6 and 12 of TMCH, respectively. beta-cat(33,37,41), however, exhibited only subtle changes in either phosphorylation status or subcellular distribution even after blocking proteasomal degradation in vivo. Interestingly, GSK-3beta underwent increased phosphorylation at Ser(9), leading to 40% and 70% decreases in its activity at these time points, respectively. Coimmunoprecipitation studies exhibited strong association of GSK-3beta with PKC-zeta at either time point. Cellular beta-cat(45) stabilized and, along with unphosphorylated beta-catenin, underwent nuclear translocation, associated with nuclear accumulated Tcf-4 and cAMP response element binding protein binding protein, and was significantly acetylated, leading to increases in DNA binding. Priming of beta-catenin at Ser(45) exists in vivo. However, beta-cat(45) does not necessarily enter the degradation pathway. Impairment in linking beta-cat(45) to subsequent GSK-3beta-mediated phosphorylation and degradation may account for increased steady-state levels of both unphosphorylated as well as Ser(45)-phosphorylated beta-catenin, which may be causally linked to increases in cell census during TMCH. 相似文献
14.
Dawar Khadim Rahman Umar Alam Syed Sartaj Tariq Mohammad Khan Aamir Fahad Shah Datta Rahul Danish Subhan Saud Shah Noor Muhammad 《Journal of Plant Growth Regulation》2022,41(1):216-226
Journal of Plant Growth Regulation - The field experiment was conducted to investigate the effects of applying urea with nitrification inhibitor (NI) (Nitrapyrine) alone or in combination with... 相似文献
15.
Quraishi UM Abrouk M Murat F Pont C Foucrier S Desmaizieres G Confolent C Rivière N Charmet G Paux E Murigneux A Guerreiro L Lafarge S Le Gouis J Feuillet C Salse J 《The Plant journal : for cell and molecular biology》2011,65(5):745-756
Monitoring nitrogen use efficiency (NUE) in plants is becoming essential to maintain yield while reducing fertilizer usage. Optimized NUE application in major crops is essential for long-term sustainability of agriculture production. Here, we report the precise identification of 11 major chromosomal regions controlling NUE in wheat that co-localise with key developmental genes such as Ppd (photoperiod sensitivity), Vrn (vernalization requirement), Rht (reduced height) and can be considered as robust markers from a molecular breeding perspective. Physical mapping, sequencing, annotation and candidate gene validation of an NUE metaQTL on wheat chromosome 3B allowed us to propose that a glutamate synthase (GoGAT) gene that is conserved structurally and functionally at orthologous positions in rice, sorghum and maize genomes may contribute to NUE in wheat and other cereals. We propose an evolutionary model for the NUE locus in cereals from a common ancestral region, involving species specific shuffling events such as gene deletion, inversion, transposition and the invasion of repetitive elements. 相似文献
16.
Shahid Umar Iram Diva Naser A. Anjum Muhammad Iqbal Iqbal Ahmad Eduarda Pereira 《Central European Journal of Biology》2011,6(6):1054-1063
Salinity is an important abiotic factor that adversely affects major agricultural soils of the world and hence limits crop
productivity. An optimum mineral-nutrient status of plants plays critical role in determining plant tolerance to various stresses.
A pot experiment was conducted on mustard (Brassica campestris L.) to study the protective role of added potassium (K, 40 mg kg−1 soil) against salinity-stress (0, 40 and 80 mM NaCl)-induced changes in plant growth, photosynthetic traits, ion accumulation,
oxidative stress, enzymatic antioxidants and non-enzymatic antioxidants at 30 days after sowing. Increasing NaCl levels decreased
the growth, photosynthetic traits and the leaf ascorbate and glutathione content but increased the leaf ion accumulation and
oxidative stress, and the activity of antioxidant enzymes. In contrast, K-nutrition improved plant growth, photosynthetic
traits, activity of antioxidant enzymes and the ascorbate and glutathione content, and reduced ion accumulation and oxidative
stress traits in the leaves, more appreciably at 40 mM than at 80 mM NaCl. The study illustrates the physiological and biochemical
basis of K-nutrition-induced NaCl tolerance in mustard as a means to achieving increased crop productivity in a sustainable
way. 相似文献
17.
Characterization of gp120 and its single-chain derivatives, gp120-CD4D12 and gp120-M9: implications for targeting the CD4i epitope in human immunodeficiency virus vaccine design
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Varadarajan R Sharma D Chakraborty K Patel M Citron M Sinha P Yadav R Rashid U Kennedy S Eckert D Geleziunas R Bramhill D Schleif W Liang X Shiver J 《Journal of virology》2005,79(3):1713-1723
Single-chain derivatives of JRFL gp120 linked to the first two domains of human CD4 (gp120-CD4D12) or to the CD4 miniprotein analog CD4M9 (gp120-M9), have been constructed. Biacore studies revealed that gp120-CD4D12 and gp120-M9 bound to antibody 17b with dissociation constants of 0.8 and 25 nM, respectively, at pH 7.0, while gp120 alone did not bind. The binding of gp120-CD4D12 to 17b is not affected by the addition of excess soluble CD4D12, while the binding of gp120-M9 is enhanced. This finding indicates that the M9 component of the single chain interacts relatively weakly with gp120 and can be displaced by soluble CD4D12. Immunogenicity studies of gp120, gp120-CD4D12, and gp120-M9 were carried out with guinea pigs. All three molecules were highly immunogenic. The resulting antisera were examined for neutralizing activities against various human immunodeficiency virus type 1 isolates. Broadly neutralizing activity was observed only with sera generated against gp120-CD4D12. These antisera were depleted of anti-CD4D12 antibodies by being passed over a column containing immobilized CD4D12. The depleted sera showed a loss of broadly neutralizing activity. Sera that were affinity purified over a column containing immobilized gp120-M9 also lacked such neutralizing activity. This finding suggests that the broadly neutralizing response observed is exclusively due to anti-CD4 antibodies. Competition experiments showed that only antisera generated against gp120-CD4D12 competed with the CD4i antibody 17b and that this activity was not affected by depletion of anti-CD4 antibodies. The data indicate that although antibodies targeting the CD4i epitope were generated by the gp120-CD4D12 immunogen, these antibodies were nonneutralizing. 相似文献
18.
19.
Schallreuter KU Wazir U Kothari S Gibbons NC Moore J Wood JM 《Biochemical and biophysical research communications》2004,322(1):88-92
Epidermal phenylalanine hydroxylase (PAH) produces L-tyrosine from the essential amino acid L-phenylalanine supporting melanogenesis in human melanocytes. Those PAH activities increase linearly in the different skin phototypes I-VI (Fitzpatrick classification) and also increase up to 24h after UVB light with only one minimal erythemal dose. Since UVB generates also H(2)O(2), we here asked the question whether this reactive oxygen species could influence the activity of pure recombinant human PAH. Under saturating conditions with the substrate L-phenylalanine (1x10(-3)M), the V(max) for enzyme activity increased 4-fold by H(2)O(2) (>2.0x10(-3)M). Lineweaver-Burk analysis identified a mixed activation mechanism involving both the regulatory and catalytic domains of PAH. Hyperchem molecular modelling and Deep View analysis support oxidation of the single Trp(120) residue to 5-OH-Trp(120) by H(2)O(2) causing a conformational change in the regulatory domain. PAH was still activated by H(2)O(2) in the presence of the electron donor/cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin despite slow oxidation of this cofactor. In vivo FT-Raman spectroscopy confirmed decreased epidermal phenylalanine in association with increased tyrosine after UVB exposure. Hence, generation of H(2)O(2) by UVB can activate epidermal PAH leading to an increased L-tyrosine pool for melanogenesis. 相似文献
20.
Parthasarathy Chandrakesan Ishfaq Ahmed Tariq Anwar Yu Wang Shubhashish Sarkar Pomila Singh Sara Peleg Shahid Umar 《The Journal of biological chemistry》2010,285(43):33485-33498
Utilizing the Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model, we measured hyperplasia and NF-κB activation during progression (days 6 and 12 post-infection) and regression (days 20–34 post-infection) phases of TMCH. NF-κB activity increased at progression in conjunction with bacterial attachment and translocation to the colonic crypts and decreased 40% by day 20. NF-κB activity at days 27 and 34, however, remained 2–3-fold higher than uninfected control. Expression of the downstream target gene CXCL-1/KC in the crypts correlated with NF-κB activation kinetics. Phosphorylation of cellular IκBα kinase (IKK)α/β (Ser176/180) was elevated during progression and regression of TMCH. Phosphorylation (Ser32/36) and degradation of IκBα, however, contributed to NF-κB activation only from days 6 to 20 but not at later time points. Phosphorylation of MEK1/2 (Ser217/221), ERK1/2 (Thr202/Tyr204), and p38 (Thr180/Tyr182) paralleled IKKα/β kinetics at days 6 and 12 without declining with regressing hyperplasia. siRNAs to MEK, ERK, and p38 significantly blocked NF-κB activity in vitro, whereas MEK1/2-inhibitor (PD98059) also blocked increases in MEK1/2, ERK1/2, and IKKα/β thereby inhibiting NF-κB activity in vivo. Cellular and nuclear levels of Ser536-phosphorylated (p65536) and Lys310-acetylated p65 subunit accompanied functional NF-κB activation during TMCH. RSK-1 phosphorylation at Thr359/Ser363 in cellular/nuclear extracts and co-immunoprecipitation with cellular p65-NF-κB overlapped with p65536 kinetics. Dietary pectin (6%) blocked NF-κB activity by blocking increases in p65 abundance and nuclear translocation thereby down-regulating CXCL-1/KC expression in the crypts. Thus, NF-κB activation persisted despite the lack of bacterial attachment to colonic mucosa beyond peak hyperplasia. The MEK/ERK/p38 pathway therefore seems to modulate sustained activation of NF-κB in colonic crypts in response to C. rodentium infection. 相似文献