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排序方式: 共有188条查询结果,搜索用时 15 毫秒
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22.
Lamberto I Qin H Noberini R Premkumar L Bourgin C Riedl SJ Song J Pasquale EB 《The Biochemical journal》2012,445(1):47-56
The EphA4 receptor tyrosine kinase interacts with ephrin ligands to regulate many processes, ranging from axon guidance and nerve regeneration to cancer malignancy. Thus antagonists that inhibit ephrin binding to EphA4 could be useful for a variety of research and therapeutic applications. In the present study we characterize the binding features of three antagonistic peptides (KYL, APY and VTM) that selectively target EphA4 among the Eph receptors. Isothermal titration calorimetry analysis demonstrated that all three peptides bind to the ephrin-binding domain of EphA4 with low micromolar affinity. Furthermore, the effects of a series of EphA4 mutations suggest that the peptides interact in different ways with the ephrin-binding pocket of EphA4. Chemical-shift changes observed by NMR spectroscopy upon binding of the KYL peptide involve many EphA4 residues, consistent with extensive interactions and possibly receptor conformational changes. Additionally, systematic replacement of each of the 12 amino acids of KYL and VTM identify the residues critical for EphA4, binding. The peptides exhibit a long half-life in cell culture medium which, with their substantial binding affinity and selectivity for EphA4, makes them excellent research tools to modulate EphA4 function. 相似文献
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24.
Considine RV Premkumar A Reynolds JC Sebring NG Ricks M Sumner AE 《Obesity (Silver Spring, Md.)》2008,16(2):428-434
Objective: African Americans (AAs) have less visceral and more subcutaneous fat than whites, thus the relationship of adiponectin and leptin to body fat and insulin sensitivity in AA may be different from that in whites. Methods and Procedures: Sixty‐nine non‐diabetic AA (37 men and 32 women), aged 33 ± 1 year participated. The percent fat was determined by dual‐energy X‐ray absorptiometry, abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume by computerized tomography (CT), and insulin sensitivity by homeostasis model assessment (HOMA). Results: VAT was greater in men (1,619 ± 177 cm3 vs. 1,022 ± 149 cm3; P = 0.01); women had a higher percentage of body fat (34.1 ± 1.4 vs. 24.0 ± 1.2; P < 0.0001), adiponectin (15.8 ± 1.2 μg/ml vs. 10.4 ± 0.8 μg/ml; P = 0.0004) and leptin (23.2 ± 15.8 ng/ml vs. 9.2 ± 7.2 ng/ml; P < 0.0001). SAT and HOMA did not differ because of the sex. Adiponectin negatively correlated with VAT (r = ?0.41, P < 0.05) in men, and with VAT (r = ?0.55, P < 0.01), and SAT (r = ?0.35, P < 0.05) in women. Adiponectin negatively correlated with HOMA in men (r = ?0.38, P < 0.05) and women (r = ?0.44, P < 0.05). In multiple regression, sex (P = 0.02), HOMA (P = 0.03) and VAT (P = 0.003) were significant predictors of adiponectin (adj R 2 = 0.38, P < 0.0001). Leptin positively correlated with VAT, SAT, percent fat and HOMA in men (r = 0.79, r = 0.86, r = 0.89, and r = 0.53; P < 0.001) and women (r = 0.62, r = 0.75, r = 0.83, and r = 0.55; P < 0.01). In multiple regression VAT (P = 0.04), percent body fat (P < 0.0001) and sex (P = 0.01), but not HOMA were significant predictors of serum leptin (adj R 2= 0.82, P < 0.0001). Discussion: The relationship of adiponectin and leptin to body fat content and distribution in AA is dependent on sex. Although VAT and insulin sensitivity are significant determinants of adiponectin, VAT and percent body fat determine leptin. 相似文献
25.
Sambou T Dinadayala P Stadthagen G Barilone N Bordat Y Constant P Levillain F Neyrolles O Gicquel B Lemassu A Daffé M Jackson M 《Molecular microbiology》2008,70(3):762-774
Mycobacterium tuberculosis and other pathogenic mycobacterial species produce large amounts of a glycogen-like alpha-glucan that represents the major polysaccharide of their outermost capsular layer. To determine the role of the surface-exposed glucan in the physiology and virulence of these bacteria, orthologues of the glg genes involved in the biosynthesis of glycogen in Escherichia coli were identified in M. tuberculosis H37Rv and inactivated by allelic replacement. Biochemical analyses of the mutants and complemented strains indicated that the synthesis of glucan and glycogen involves the alpha-1,4-glucosyltransferases Rv3032 and GlgA (Rv1212c), the ADP-glucose pyrophosphorylase GlgC (Rv1213) and the branching enzyme GlgB (Rv1326c). Disruption of glgC reduced by half the glucan and glycogen contents of M. tuberculosis, whereas the inactivation of glgA and Rv3032 affected the production of capsular glucan and glycogen, respectively. Attempts to disrupt Rv3032 in the glgA mutant were unsuccessful, suggesting that a functional copy of at least one of the two alpha-1,4-glucosyltransferases is required for growth. Importantly, the glgA mutant was impaired in its ability to persist in mice, suggesting a role for the capsular glucan in the persistence phase of infection. Unexpectedly, GlgB was found to be an essential enzyme. 相似文献
26.
Marshall K. Tulloch‐Reid Robert L. Hanson Nancy G. Sebring James C. Reynolds Ahalya Premkumar David J. Genovese Anne E. Sumner 《Obesity (Silver Spring, Md.)》2004,12(8):1352-1359
Objective: The contribution of visceral adipose tissue (VAT) to insulin resistance is well‐established; however, the role of subcutaneous abdominal adipose tissue (SAT) in insulin resistance remains controversial. Sex may determine which of these two components of abdominal obesity is more strongly related to insulin resistance and its consequences. The aim of this study was to determine whether both VAT and SAT contribute to insulin resistance in African Americans and to examine the effects of sex on this relationship. Research Methods and Procedures: This was a cross‐sectional study of 78 nondiabetic African‐American volunteers (44 men, 35 women; age 33.8 ± 7.3 years; BMI 30.9 ± 7.4 kg/m2). VAT and SAT volumes were measured using serial computerized tomography slices from the dome of the diaphragm to the iliac crest. The insulin sensitivity index (SI) was determined from the minimal model using data obtained from the frequently sampled intravenous glucose tolerance test. Results: In men, both VAT and SAT were negatively correlated with SI (r for both correlations = ?0.57; p < 0.01). In women, the correlation coefficient between VAT and SI was ?0.50 (p < 0.01) and between SAT and SI was ?0.67 (p < 0.01). In women, the correlation coefficient for SI with SAT was significantly greater than the correlation coefficient with VAT (p = 0.02). Discussion: Both SAT and VAT are strongly correlated with insulin resistance in African Americans. For African‐American women, SAT may have a greater effect than VAT on insulin resistance. 相似文献
27.
Benjamin E. Blass Pravin Iyer Magid Abou-Gharbia Wayne E. Childers John C. Gordon Mercy Ramanjulu George Morton Premkumar Arumugam Joshodeep Boruwa John Ellingboe Sayan Mitra Rajashekar Reddy Nimmareddy Shalini Paliwal Jamallamudi Rajasekhar Savithiri Shivakumar Pratima Srivastava Raghuram S. Tangirala Konda Venkataramanaiah L. Krishnakanth Reddy 《Bioorganic & medicinal chemistry letters》2018,28(13):2270-2274
The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation. 相似文献
28.
Aaren S. Freeman Alejandro Frischeisen April MH. Blakeslee 《Biological invasions》2016,18(6):1653-1665
Interactions between anthropogenic disturbances and introduced and native species can shift ecological communities, potentially leading to the successful establishment of additional invaders. Since its discovery in New Jersey in 1988, the Asian shore crab (Hemigrapsus sanguineus) has continued to expand its range, invading estuarine and coastal habitats in eastern North America. In estuarine environments, H. sanguineus occupies similar habitats to native, panopeid mud crabs. These crabs, and a variety of fouling organisms (both NIS and native), often inhabit man-made substrates (like piers and riprap) and anthropogenic debris. In a series of in situ experiments at a closed dock in southwestern Long Island (New York, USA), we documented the impacts of these native and introduced crabs on hard-substrate fouling communities. We found that while the presence of native mud crabs did not significantly influence the succession of fouling communities compared to caged and uncaged controls, the presence of introduced H. sanguineus reduced the biomass of native tunicates (particularly Molgula manhattensis), relative to caged controls. Moreover, the presence of H. sanguineus favored fouling communities dominated by introduced tunicates (especially Botrylloides violaceous and Diplosoma listerianum). Altogether, our results suggest that H. sanguineus could help facilitate introduced fouling tunicates in the region, particularly in locations where additional solid substrates have created novel habitats. 相似文献
29.
Mandel U; Hassan H; Therkildsen MH; Rygaard J; Jakobsen MH; Juhl BR; Dabelsteen E; Clausen H 《Glycobiology》1999,9(1):43-52
Mucin-type O-glycosylation is initiated by a large family of UDP- GalNAc:
polypeptide N -acetyl-galactosaminyltransferases (GalNAc- transferases).
Individual GalNAc-transferases appear to have different functions and
Northern analysis indicates that they are differently expressed in
different organs. This suggests that O-glycosylation may vary with the
repertoire of GalNAc-transferases expressed in a given cell. In order to
study the repertoire of GalNAc-transferases in situ in tissues and changes
in tumors, we have generated a panel of monoclonal antibodies (MAbs) with
well defined specificity for human GalNAc-T1, -T2, and -T3. Application of
this panel of novel antibodies revealed that GalNAc- transferases are
differentially expressed in different cell lines, in spermatozoa, and in
oral mucosa and carcinomas. For example, GalNAc-T1 and -T2 but not -T3 were
highly expressed in WI38 cells, and GalNAc-T3 but not GalNAc-T1 or -T2 was
expressed in spermatozoa. The expression patterns in normal oral mucosa
were found to vary with cell differentiation, and for GalNAc-T2 and -T3
this was reflected in oral squamous cell carcinomas. The expression pattern
of GalNAc-T1 was on the other hand changed in tumors to either total loss
or expression in cytological poorly differentiated tumor cells, where the
normal undifferentiated cells lacked expression. These results demonstrate
that the repertoire of GalNAc-transferases is different in different cell
types and vary with cellular differentiation, and malignant transformation.
The implication of this is not yet fully understood, but it suggests that
specific changes in sites of O-glycosylation of proteins may occur as a
result of changes in the repertoire of GalNAc-transferases.
相似文献
30.
Reddy MV Billa VK Pallela VR Mallireddigari MR Boominathan R Gabriel JL Reddy EP 《Bioorganic & medicinal chemistry》2008,16(7):3907-3916
A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity (5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib. 相似文献