A fluorescent polarization-based assay for the identification of disruptors of the RCAN1/calcineurin A protein complex

5 pages, 4 figures, a table. 19891949 [PubMed]Calcineurin is a Ca(2+)/calmodulin-dependent serine/threonine protein phosphatase involved in many biological processes and developmental programs, including immune response. One of the most studied substrates of calcineurin is the transcription factor NFAT (nuclear factor of activated T cells) responsible for T-cell activation. Different anticalcineurin drugs, such as cyclosporine A and FK506, are the most commonly used immunosuppressants in transplantation therapies. Unfortunately, their mechanism of action, completely blocking the calcineurin phosphatase activity while also requiring continuous administration, bears severe side effects. During recent years, the family of regulators of calcineurin (RCAN) has been described and studied extensively as modulators of calcineurin signaling pathways. The RCAN1 region, spanning amino acids 198 to 218 and responsible for inhibiting the calcineurin-NFAT signaling pathway in vivo, has been identified. An RCAN1-derived peptide spanning this sequence interferes with the calcineurin-NFAT interaction without affecting the general calcineurin phosphatase activity. Here we report the development of an optimized in vitro high-throughput fluorescence polarization assay based on the disruption of the RCAN1(198-218)-CnA interaction for identifying molecules with immunosuppressant potential. This approach led us to identify dipyridamole as a disruptor of such interaction. Moreover, three small molecules with a potential immunosuppressive effect were also identifiedThis work was supported by grants from Fundació La Marató de TV3 (Ref. 030830), the Spanish Ministry of Education and Science (SAF2006-04815, BIO2004-00998, BIO2007-60066, CTQ2005-00995/BQU), the Fundación Mutua Madrileña 2007 and from the Generalitat de Catalunya (Ref. 2006 BE 00051)Peer reviewe

Electronic structure and magnetic properties of RMnX (R= Mg, Ca, Sr, Ba, Y; X= Si, Ge) studied by KKR method

Electronic structure calculations, using the charge and spin self-consistent Korringa- Kohn-Rostoker (KKR) method, have been performed for several $R$Mn$X$ compounds ($R$ = Mg, Ca, Sr, Ba, Y; $X$ = Si, Ge) of the CeFeSi-type structure. The origin of their magnetic properties has been investigated emphasizing the role of the Mn sublattice. The significant influence of the Mn-Mn and Mn-$X$ interatomic distances on the Mn magnetic moment value is delineated from our computations, supporting many neutron diffraction data. We show that the marked change of $\mu_{Mn}$ with the Mn-Mn and Mn-$X$ distances resulted from a redistribution between spin-up and spin-down $d$-Mn DOS rather than from different fillings of the Mn 3$d$-shell. Bearing in mind that the neutron diffraction data reported for the $R$Mn$X$ compounds are rather scattered, the KKR computations of $\mu_{Mn}$ are in fair agreement with the experimental values. Comparing density of states near $E_{F}$ obtained in different magnetic orderings, one can notice that the entitled $R$Mn$X$ systems seem to 'adapt' their magnetic structures to minimize the DOS in the vicinity of the Fermi level. Noteworthy, the SrMnGe antiferromagnet exhibits a pseudo-gap behaviour at $E_{F}$, suggesting anomalous electron transport properties. In addition, the F-AF transition occurring in the disordered La$_{1-x}$Y$_{x}$MnSi alloy for the $0.8<x<1$ range is well supported by the DOS features of La$_{0.2}$Y$_{0.8}$MnSi. In contrast to the investigated $R$Mn$X$ compounds, YFeSi was found to be non-magnetic, which is in excellent agreement with the experimental data.Comment: 10 pages + 14 figures, to appear in Eur. Phys. Jour.

Nernst effect in Tl-Ba-Ca-Cu-O high-Tc superconducting thin films

The dynamical behavior of magnetic flux in superconducting Tl-Ba-Ca-Cu-O films has been studied using the Nernst effect. Large temperature gradients of ∼105 K/cm and, correspondingly, large thermal forces on flux lines were obtained by pulsed laser heating of films. Due to the large thermal driving forces it was possible to observe, at temperatures well below Tc, the transition from thermally assisted flux flow to flux creep and viscous flux flow

Tc enhancement by aliovalent anionic substitution in superconducting BaTi2(Sb1-xSnx)2O

BaTi2Sb2O is a Tc = 1.2K superconductor with a d1 square lattice, and isovalent Bi substitution for Sb can increase its Tc to 4.6K (BaTi2Bi2O), accompanied by the complete suppression of charge density wave (CDW) or spin density wave (SDW) transition. In the present study, we demonstrate that aliovalent Sn substitution (hole doping) also increases Tc up to 2.5K for BaTi2(Sb 0.7Sn0.3)2O, while suppressing CDW/SDW transition only slightly. The overall electronic phase diagram of BaTi2(Sb,Sn) 2O is qualitatively similar to that of cation-substituted (hole-doped) (Ba,Na)Ti2Sb2O, but quantitative differences such as in Tc are observed, which is discussed in terms of Ti-Pn hybridization and chemical disorder. © 2013 The Physical Society of Japan