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排序方式: 共有448条查询结果,搜索用时 15 毫秒
1.
Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
2.
AD Santin PL Hermonat JC Hiserodt J Fruehauf V Schranz D Barclay S Pecorelli GP Parham 《Canadian Metallurgical Quarterly》1997,64(3):477-480
Tumor cells from eight freshly isolated cervical cancers (i.e., four adenocarcinomas and four squamous carcinomas) were analyzed for their production of the immune-inhibitory cytokine transforming growth factor-beta (TGF-beta) in vitro. All fresh adenocarcinomas secreted significant levels of TGF-beta (mean 397, range between 207 and 782 pg/ml/10(5) cells/48 hr). In contrast, no detectable TGF-beta was present in the supernatants from the four fresh squamous carcinoma cultures (P < 0.001). These data suggest that major differences in the secretion of the immunoinhibitory cytokine TGF-beta exist between squamous cell carcinomas and adenocarcinomas of the uterine cervix. Furthermore, these findings suggest that at least some of the differences in the natural biologic behavior, as well as in the response to radiation treatment, between these two histologic types of cervical cancer could be related to differences in secretion of this immune-inhibitory cytokine. 相似文献
3.
A broadly cross-protective monoclonal antibody binding to Escherichia coli and Salmonella lipopolysaccharides 总被引:1,自引:0,他引:1
FE Di Padova H Brade GR Barclay IR Poxton E Liehl E Schuetze HP Kocher G Ramsay MH Schreier DB McClelland 《Canadian Metallurgical Quarterly》1993,61(9):3863-3872
During the last decade, episodes of sepsis have increased and Escherichia coli has remained the most frequent clinical isolate. Lipopolysaccharides (LPS; endotoxin) are the major toxic and antigenic components of gram-negative bacteria and qualify as targets for therapeutic interventions. Molecules that neutralize the toxic effects of LPS are actively investigated. In this paper, we describe a murine monoclonal antibody (MAb; WN1 222-5), broadly cross-reactive and cross-protective for smooth (S)-form and rough (R)-form LPS. As shown in enzyme-linked immunosorbent assay and the passive hemolysis assay, WN1 222-5 binds to the five known E. coli core chemotypes, to Salmonella core, and to S-form LPS having these core structures. In immunoblots, it is shown to react with both the nonsubstituted core LPS and with LPS carrying O-side chains, indicating the exposure of the epitope in both S-form and R-form LPS. This MAb of the immunoglobulin G2a class is not lipid A reactive but binds to E. coli J5, an RcP+ mutant which carries an inner core structure common to many members of the family Enterobacteriaceae. Phosphate groups present in the inner core contribute to the epitope but are not essential for the binding of WN1 222-5 to complete core LPS. Cross-reactivity for clinical bacterial isolates is broad. WN1 222-5 binds to all E. coli clinical isolates tested so far (79 blood isolates, 80 urinary isolates, and 21 fecal isolates) and to some Citrobacter, Enterobacter, and Klebsiella isolates. This pattern of reactivity indicates that its binding epitope is widespread among members of the Enterobacteriaceae. WN1 222-5 exhibits biologically relevant activities. In vitro, it inhibits the Limulus amoebocyte lysate assay activity of S-form and R-form LPS in a dose-dependent manner and it neutralizes the LPS-induced release of clinically relevant monokines (interleukin 6 and tumor necrosis factor). In vivo, WN1 222-5 blocks endotoxin-induced pyrogenicity in rabbits and lethality in galactosamine-sensitized mice. The discovery of WN1 222-5 settles the long-lasting controversy over the existence of anti-core LPS MAbs with both cross-reactive and cross-protective activity, opening new possibilities for the immunotherapy of sepsis caused by gram-negative bacteria. 相似文献
4.
I. Egli L. Davidsson M.-A. Juillerat D. Barclay R. Hurrell 《Journal of food science》2003,68(5):1855-1859
Complementary foods based on cereals and legumes often contain high amounts of phytic acid, a potent inhibitor of mineral and trace element absorption. The possibility to degrade phytic acid during the production of complementary foods by using whole grain cereals as the phytase source was investigated. Whole grain rye, wheat, or buckwheat (10%) were added to cereal‐legume‐based complementary food mixtures, and phytic acid was shown to be completely degraded in a relatively short time (1.5 to 3 h) when incubated at optimal conditions for cereal phytase. The potential usefulness of the method for industrial production was demonstrated with a complementary food based on wheat and soybean. 相似文献
5.
Faking behavior was studied by comparing the personality profiles of 161 job applicants (motivated to be hired) with those of a control group of 73 graduate and undergraduate business students (motivated to obtain personal information for their own enlightenment). 44% of the Ss were female. Both groups were instructed to describe themselves honestly while completing the Self-Perception Test. Applicants did "fake good," scoring significantly higher on 10 of 11 scales; variance was significantly lower among applicants on 7 scales. Gender differences, consistent with cultural stereotypes, occurred on 5 scales. Overall profile shapes were virtually identical for student and applicant groups, suggesting that faking may not have dramatically altered the essence of the personality constructs. The scales of the test were found to have high reliability. Scale independence is discussed in relation to the 5-factor model of personality. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
6.
The moment-method technique utilizing entire domain basis functions is applied to the analysis of large, axially symmetric reflector antennas. The electric surface current is modeled as a finite series of sinusoids whose domain consists of the entire generating curve. This expansion results in a matrix size of less than 5% of that produced with subdomain basis functions. Only a slight increase in the CPU requirements occurs from this analysis. The results from this technique show good agreement when compared to both physical optics and a subdomain-based moment-method formulation on small, axially fed paraboloidal and hyperboloidal reflector antennas. Extension to a large 100-λ paraboloidal reflector with f/D=0.4 produces results comparable to that obtained using physical optics. Convergence is obtained with as few as two expansion terms per wavelength. Discretization of the generating curve with four points per wavelength leads to results which agree within 0.5 dB over data from a more densely defined curve 相似文献
7.
The catecholamines norepinephrine (NE) and dopamine (DA) have been implicated in the sexual differentiation of brain and behavior and in species-specific learning in several species. To determine if these neurotransmitters might be involved in sexual differentiation of the vocal control system and song learning in male zebra finches, NE and DA levels and turnover rates were quantified in 10 behaviorally relevant brain nuclei [6 vocal control (VCN), 2 auditory (AN), and 2 hypothalamic (HN)] at four critical points during sexual differentiation of the VCN and the period of song learning, 25, 35, 55, and 90 days of age. Some birds were pretreated with alpha-methyl-para-tyrosine (alphaMPT) to allow estimation of NE and DA turnover rates. NE and DA levels in microdissected nuclei were quantified using high-performance liquid chromatography with electrochemical detection. AlphaMPT treatment suppressed catecholamine synthesis just as effectively in juveniles as it does in adults and proved an effective method for estimating NE and DA turnover rates. Patterns of NE and DA function in most VCN and AN over development were quite different from those in HN in which NE and DA function changed gradually and showed no striking peaks. NE turnover rates changed significantly over development in all six VCN [nucleus interfacialis (Nlf), high vocal center (HVC), nucleus robustus of the archistriatum (RA), dorsomedial portion of the intercollicular nucleus (DM), Area X of the parolfactory lobe, and lateral portion of the magnocellular nucleus of the anterior neostriatum (IMAN)]; one AN [nucleus mesencephalicus lateralis pars dorsalis (MLd)], and one HN [preopticus anterior (POA)]. NE levels changed significantly in two VCN (Nlf and Area X). In Nlf, RA, Area X, IMAN, and MLd, NE levels and/or turnover rates showed a striking peak at day 25, which was not seen in HN. Both DA levels and turnover rates changed profoundly over development in 5 of 6 VCN (Nlf, RA, DM, Area X, and IMAN) and both AN (MLd and Field L). These nuclei showed striking peaks in DA levels and turnover rates, primarily on day 35 and/or 55, which then declined profoundly by day 90. This contrasted with the minimal change in DA turnover rates seen in one HN (POA) and the sixth VCN, HVC. In several VCN and AN, NE and DA levels and turnover rates during development reached levels never seen in adult males. Previous research has shown that catecholamine function is heightened in VCN during development compared to surrounding tissues. Our data demonstrate that NE and DA function during development shows pronounced peaks in most VCN not seen in HN. This is interesting because both VCN and HN are hormone sensitive, and both show hormone-modulated NE and DA function in adult males. The timing of these peaks suggests that increased catecholaminergic function may be involved in sexual differentiation of the VCN and song learning in finches. 相似文献
8.
The optical properties of gold nanoparticles have been known for a number of years and recent advances in laser power have now allowed the non-linear optical properties to be studied. In this short review paper, the various theories that have been used to describe the optical properties of gold nanoparticles are presented. Methods of preparing gold nanoparticles in glasses are explained briefly, as well as characterization techniques. The optical properties of gold nanoparticles are reviewed, as well as the effects of particle size, shape, concentration and c. 相似文献
9.
A. H. Moinuddin Ahmed Lesley S. Dent Glasser 《Journal of chemical technology and biotechnology (Oxford, Oxfordshire : 1986)》1973,23(6):457-463
α-BaO.Al2O3.4H2O has been synthesised and studied by infrared, X-ray and thermal analytical techniques. The compound of approximate formula BaO.Al2O3.0.5H2O, described in Part III, forms as a dehydration product, and appears to be identical with the compound β-BAH2 described by other workers. A possible explanation for the discrepancy in water content is discussed. 相似文献
10.
M. Hossein Nouri-Sorkhabi Lesley C. Wright David R. Sullivan Philip W. Kuchel 《Lipids》1996,31(7):765-770
31P Nuclear magnetic resonance (NMR) spectra of human erythrocyte lysates dissolved in sodium cholate were acquired. The narrow
resonances of phospholipids were mostly well resolved, allowing identification and accurate quantitative analysis of phospholipid
classes of the erythrocyte membranes. The ether-linked phosphatidylethanolamine components of the erythrocyte membranes were
identified, based on the removal of plasmalogens by acidolysis and of diacyl phospholipid species by degradation using phospholipase
A1. It was also shown that the introduction of double bonds on the acyl chains of phosphatidylcholine shifted the31P NMR resonances to lower frequencies. Quantitative analyses of phospholipids from the spectra were based on their apparent
molar concentrations. The recoveries of phospholipids from erythrocytes were significantly higher than those using conventional
extraction procedures. 相似文献