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91.
Iman Azimi Jack U. Flanagan Ralph J. Stevenson Marco Inserra Irina Vetter Gregory R. Monteith William A. Denny 《Bioorganic & medicinal chemistry》2017,25(1):440-449
The Orai1 Ca2+ permeable ion channel is an important component of store operated Ca2+ entry (SOCE) in cells. It’s over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays. The assay was also used in a screening project seeking novel inhibitors. Following a broad literature survey of classes of calcium channel inhibitors we used simplified ligand structures to query the ZINC on-line database, and following two iterations of refinement selected a novel Orai1-selective dichlorophenyltriazole hit compound. Analogues of this were synthesized and evaluated in the FLIPR assay to develop structure–activity relationships (SAR) for the three domains of the hit; triazole (head), dichlorophenyl (body) and substituted phenyl (tail). For this series, the results suggested the need for a lipophilic tail domain and an out-of-plane twist between the body and tail domains. 相似文献
92.
93.
Leuschner F Dutta P Gorbatov R Novobrantseva TI Donahoe JS Courties G Lee KM Kim JI Markmann JF Marinelli B Panizzi P Lee WW Iwamoto Y Milstein S Epstein-Barash H Cantley W Wong J Cortez-Retamozo V Newton A Love K Libby P Pittet MJ Swirski FK Koteliansky V Langer R Weissleder R Anderson DG Nahrendorf M 《Nature biotechnology》2011,29(11):1005-1010
Excessive and prolonged activity of inflammatory monocytes is a hallmark of many diseases with an inflammatory component. In such conditions, precise targeting of these cells could be therapeutically beneficial while sparing many essential functions of the innate immune system, thus limiting unwanted effects. Inflammatory monocytes-but not the noninflammatory subset-depend on the chemokine receptor CCR2 for localization to injured tissue. Here we present an optimized lipid nanoparticle and a CCR2-silencing short interfering RNA that, when administered systemically in mice, show rapid blood clearance, accumulate in spleen and bone marrow, and localize to monocytes. Efficient degradation of CCR2 mRNA in monocytes prevents their accumulation in sites of inflammation. Specifically, the treatment attenuates their number in atherosclerotic plaques, reduces infarct size after coronary artery occlusion, prolongs normoglycemia in diabetic mice after pancreatic islet transplantation, and results in reduced tumor volumes and lower numbers of tumor-associated macrophages. 相似文献
94.
95.
Annemarie MM Vlaar Angela EP Bouwmans Marinus JPG van Kroonenburgh Werner H Mess Selma C Tromp Piet GWM Wuisman Alfons GH Kessels Ania Winogrodzka Wim EJ Weber 《BMC neurology》2007,7(1):28
Background
Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD. 相似文献96.
Two experiments using human participants investigated whether a Pavlovian backward inhibitory treatment (nonreinforced trials in phase 1 followed by reinforced trials in phase 2; i.e., AX- followed by A+) produces a stimulus which can pass summation and retardation tests for inhibition. The rationale for conducting these experiments was that previous demonstrations of Pavlovian backward inhibition informed participants about the nature of the outcome before starting the experiment. According to some theoretical views, this is a potential confound. In the present experiments we used a predictive task in which participants had no knowledge about the outcome until phase 2, when reinforcement occurred. The results of Experiment 1 (summation test) and Experiment 2 (retardation test) provide a clear demonstration of backward conditioned inhibition. 相似文献
97.
Akihiro Kondo John Sidney Scott Southwood Marie-France del Guercio Ettore Appella Hiroshi Sakamoto Howard M. Grey Esteban Celis Robert W. Chesnut Ralph T. Kubo A. Sette 《Immunogenetics》1997,45(4):249-258
Previous studies have defined two different peptide binding motifs specific for HLA-A
*
0101. These motifs are characterized by the presence of tyrosine (Y) at the C-termini of 9-mer and 10-mer peptides, and either
a small polar or hydrophobic (S, T, M) residue in position 2, or a negatively charged (D or E) residue in position 3. In this
study, the structural requirements for peptide binding to A
*
0101 have been further analyzed by examining the binding capacity of large sets of peptides corresponding to naturally occurring
sequences which bore one or the other of these two A
*
0101-specific motifs. By correlating the presence of specific residue types at each position along the peptide sequence with increased
(or decreased) binding affinity, the prominent influence of secondary anchor residues was revealed. In most cases, the two
anchors in positions 2 and 3 appear to act synergistically. With the exception of the DE3 submotif in 9-mer peptides, a positive role for aromatic residues in position 1 and the center of the peptide (positions
4 or 5 of 9- or 10-mer peptides, respectively), and proline at C-3, were also consistently detected. However, secondary anchor
residues also appear to differ significantly between the two different submotifs, demonstrating that A
*
0101 can utilize alternative modes in binding its peptide ligands. According to these analyses, specific refined submotifs were
also established, and their merit verified by independent sets of potential A
*
0101 binding peptides. Besides providing useful insight into the nature of the interaction of the A
*
0101 allele with its peptide ligands, such refined motifs should also facilitate accurate prediction of potential A
*
0101-restricted peptide epitopes.
Received: 16 July 1996 / Revised: 18 September 1996 相似文献
98.
Accumulation of "lignin-like" material (L-LM) by plant tissues in response to injury or disease has been observed in a wide variety of plant taxa. The most intensively studied L-LM is that produced by members of the Cucurbitaceae; this material is thought to be an unusual lignin rich in p-coumaryl alcohol derived subunits. Employing acidolysis we found the primary degradation product of L-LM from squash fruit was p-coumaryl aldehyde. These findings conflict with the current concept of L-LM, but would be consistent with L-LM being a polymer derived directly from p-coumaryl aldehyde or a gum containing this compound. Results of hot water extraction support the latter possibility. Further, we report on a simple TLC method useful for rapid qualitative characterization of acidolysis degradation products. 相似文献
99.
A role for retinal gamma-aminobutyric acid Type A (GABA(A)) receptors in the regulation of circadian responses to light was examined. Intraocular injections of the GABA(A) antagonist, bicuculline, were performed during the early (Circadian Time [CT] 13.5) and late subjective night (CT 20), followed by a light pulse. Bicuculline significantly decreased the magnitude of phase delays induced by light to 65%, whereas it had no effect on phase advances. To explore the nature of the inhibition elicited by bicuculline, an intensity-response curve was performed. Intraocular injections of bicuculline inhibited phase delays only when induced by high-saturating light illuminances (20 and 100 lux). No effect was observed at light intensities < or = 5 lux. These results suggest that retinal GABA(A) receptors modulate the responsivity of the circadian system to light. 相似文献
100.
Mazhari-Tabrizi R Blank M Mumberg D Funk M Schwarz RT Eckert V 《Glycoconjugate journal》1999,16(11):673-679
Heterologous complementation in yeast has been a successful tool for cloning and characterisation of genes from various organisms. Therefore we constructed conditionally lethal Saccharomyces cerevisiae strains by replacing the endogenous promoter from the genes of interest (glycosyltransferases) by the stringently regulated GAL1-promoter, by a technique called chromosomal promoter replacement. Such yeast strains were constructed for the genes Alg 1, Alg7, Sec59, Wbp1 involved in N-Glycosylation, the genes Gpi2, Gpi3/Spt14, Gaal, Pis1, involved in GPI-anchor biosynthesis and Dpm involved in both pathways. All strains show the expected conditionally lethal phenotype on glucose-containing medium when expression of the respective gene is turned off. 相似文献