Sphingosine 1-phosphate (S1P) receptors are G-protein-coupled receptors. Among the five identified subtypes S1P1-5, the S1P3 receptor expressed on vascular endothelial cells has been shown to play an important role in cell proliferation, migration, and inflammation. A pharmacophore-based database search was used to identify a potent scaffold for an S1P3 receptor antagonist by common feature-based alignment and further validated using the Güner-Henry (GH) scoring method. Assumed excluded volumes were merged into this model to evaluate the steric effect with the S1P3 receptor. Three commercially available compounds were identified as S1P3 receptor antagonists, with IC50 values <5 microM. The synthesis of further derivatives revealed that the 3,4-dialkoxybenzophenone scaffold is a potent component of an S1P3 receptor antagonist. Our results indicate that pharmacophore-based design of S1P3 receptor antagonists can be used to expand the possibility of structural modification through scaffold-hopping based on a database search.
We evaluated the diagnostic value of atrial fibrillation (AF) measured by a wrist-type pulse wave monitor in this case-control study. Six serial pulse wave values (three in the left and three in the right wrist) were measured using a wrist-type monitor in 29 AF patients and 30 subjects with sinus rhythm. We defined "monitor AF in irregular pulse peak (IPP) 15/20/25" as follows: (a) IPP: |interval of pulse peak − the average of the interval of the pulse peak| ≥ the average of the interval of the pulse peak × 15/20/25%; (b) irregular heartbeat (IHB): beats of IPP ≥ total pulse × 20%; and (c) monitor AF: ≥4 IHBs of the six pulse wave measurements. In IPP 15, the sensitivity and specificity were 0.97 and 1.00, respectively. Pulse wave analysis by a wrist-type monitor was shown to have high sensitivity and specificity for the diagnosis of AF.
A fundamental problem posed from the study of correlated electron compounds, of which heavy-fermion systems are prototypes, is the need to understand the physics of states near a quantum critical point (QCP). At a QCP, magnetic order is suppressed continuously to zero temperature and unconventional superconductivity often appears. Here, we report pressure (P)-dependent 115 In nuclear quadrupole resonance (NQR) measurements on heavy-fermion antiferromagnet CeRh 0.5 Ir 0.5 In 5. These experiments reveal an antiferromagnetic (AF) QCP at P AF c ¼ 1:2 GPa where a dome of superconductivity reaches a maximum transition temperature T c. Preceding P AF c , however, the NQR frequency ν Q undergoes an abrupt increase at P Ã c = 0.8 GPa in the zero-temperature limit, indicating a change from localized to itinerant character of cerium's f-electron and associated small-to-large change in the Fermi surface. At P AF c where T c is optimized, there is an unusually large fraction of gapless excitations well below T c that implicates spin-singlet, odd-frequency pairing symmetry.
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