Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1

Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP. In contrast, there was very little agonist action of I942 towards EPAC2 or protein kinase A (PKA). To our knowledge, this is the first observation of non-cyclic-nucleotide small molecules with agonist properties towards EPAC1. Furthermore, the isoform selective agonist nature of these compounds highlights the potential for the development of small molecule tools that selectively up-regulate EPAC1 activity

Theory of Interplay of Nuclear Magnetism and Superconductivity in AuIn2

The recently reported coexistence of a magnetic order, with the critical temperature T_M=35 \mu*K, and superconductivity, with the critical temperature T_S=207 m*K, in AuIn_2 is studied theoretically. It is shown that superconducting (S) electrons and localized nuclear magnetic moments (LM's) interact dominantly via the contact hyperfine (EX) interaction, giving rise to a spiral (or domain-like) magnetic order in superconducting phase. The electromagnetic interaction between LM's and S electrons is small compared to the EX one giving minor contribution to the formation of the oscillatory magnetic order. In clean samples (l>\xi_0) of AuIn$_2$ the oscillatory magnetic order should produce a line of nodes in the quasiparticle spectrum of S electrons giving rise to the power law behavior. The critical field H_c(T=0) in the coexistence phase is reduced by factor two with respect to its bare value.Comment: 4 pages with 2 PS figures, RevTeX, submitted to Physical Review B - Rapid Communication

Energy- and flux-budget (EFB) turbulence closure model for the stably stratified flows. Part I: Steady-state, homogeneous regimes

We propose a new turbulence closure model based on the budget equations for the key second moments: turbulent kinetic and potential energies: TKE and TPE (comprising the turbulent total energy: TTE = TKE + TPE) and vertical turbulent fluxes of momentum and buoyancy (proportional to potential temperature). Besides the concept of TTE, we take into account the non-gradient correction to the traditional buoyancy flux formulation. The proposed model grants the existence of turbulence at any gradient Richardson number, Ri. Instead of its critical value separating - as usually assumed - the turbulent and the laminar regimes, it reveals a transition interval, 0.1< Ri <1, which separates two regimes of essentially different nature but both turbulent: strong turbulence at Ri<<1; and weak turbulence, capable of transporting momentum but much less efficient in transporting heat, at Ri>1. Predictions from this model are consistent with available data from atmospheric and lab experiments, direct numerical simulation (DNS) and large-eddy simulation (LES).Comment: 40 pages, 6 figures, Boundary-layer Meteorology, resubmitted, revised versio

Conventional Magnetic Superconductors: Coexistence of Singlet Superconductivity and Magnetic Order

The basic physics of bulk magnetic superconductors (MS) related to the problem of the coexistence of singlet superconductivity (SC) and magnetic order is reviewed. The interplay between exchange (EX) and electromagnetic (EM) interaction is discussed and argued that the singlet SC and uniform ferromagnetic (F) order practically never coexist. In case of their mutual coexistence the F order is modified into a domain-like or spiral structure depending on magnetic anisotropy. It turns out that this situation is realized in several superconductors such as $ErRh_{4}B_{4}$, $HoMo_{6}S_{8}$, $HoMo_{6}Se_{8}$ with electronic and in $AuIn_{2}$ with nuclear magnetic order. The later problem is also discussed here. The coexistence of SC and antiferromagnetism is more favorable than with the modified F order. Very interesting physics is realized in systems with SC and weak-ferromagnetism which results in an very reach phase diagram. The properties of magnetic superconductors in magnetic field are very peculiar, especially near the (ferro)magnetic transition temperature where the upper critical field becomes smaller than the thermodynamical critical field. The extremely interesting physics of Josephson junctions based on MS with spiral magnetic order is also discussed. The existence of the triplet pairing amplitude $F_{\uparrow \uparrow}$ ($F_{\downarrow \downarrow}$) in MS with rotating magnetization (the effect recently rediscovered in SFS junctions) gives rise to the so called $\pi$-contact. Furthermore, the interplay of the superconducting and magnetic phase in such a contact renders possibilities for a new type of coupled Josephson-qubits.Comment: 28 pages, 3 figures; submitted for the Special Issue Comptes de l'Academie des Sciences: Problems of the Coexistence of Magnetism and Superconductivity, edited by A. Buzdi

Decoupling of superconducting layers in magnetic superconductor RuSr_{2}GdCu_{2}O_{8}

We propose the model for magnetic properties of the magnetic superconductor RuSr$_{2}$GdCu$_{2}$O$_{8}$, which incorporates the theory of the superconducting/ferromagnetic multilayers. The transition line $T_{d}(h)$, on which the Josephson coupled superconducting planes are decoupled, i.e. $j_{c}(T_{d})=0$, is calculated as a function of the exchange energy $h$. As the result of this decoupling a nonmonotonic behavior of magnetic properties, like the lower critical field $H_{c1}$, Josephson plasma frequency, etc. is realized near (or by crossing) the $T_{d}(h)$ line. The obtained results are used in analyzing the newly discovered antiferromagnetic ruthenocuprate RuSr$_{2}$GdCu$_{2}$O$_{8}$ with possible weak ferromagnetic order in the RuO planes.Comment: 12 pages, 3 figs embede

Buoyancy generated turbulence in stably stratified flow with shear

The energy evolution in buoyancy-generated turbulence subjected to shear depends on the gradient Richardson number Ri and the stratification number St, which is a ratio of the time scale of the initial buoyancy fluctuations to the time scale of the mean stratification. During an initial period, the flow state evolves as in the unsheared case. After this period, shear generates fluctuating velocity components for St=0.25, but it depletes the fluctuating vertical velocity component and temperature variance faster than in the unsheared case for St=4. Weak shear causes the kinetic and total energy to decrease faster than in the unsheared case, whereas strong shear adds more energy in comparison with the unsheared case. Energy increased with time in only one case considered (St=0.1 and Ri=0.04). When St\u3e1, the nonlinearity of the flow does not become significant even when Ri is small. Thus, results from rapid distortion theory and direct numerical simulation compare well. In particular, the theory reproduces trends in the energy evolution for St\u3e1

The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity

Direct interaction between the catalytic domain of Epac1 and the nuclear pore component RanBP2 blocks Epac1 catalytic activity and downstream cAMP signaling

Structural and electrical transport properties of superconducting Au{0.7}In{0.3} films: A random array of superconductor-normal metal-superconductor (SNS) Josephson junctions

The structural and superconducting properties of Au{0.7}In{0.3} films, grown by interdiffusion of alternating Au and In layers, have been studied. The films were found to consist of a uniform solid solution of Au{0.9}In{0.1}, with excess In precipitated in the form of In-rich grains of various Au-In phases (with distinct atomic compositions), including intermetallic compounds. As the temperature was lowered, these individual grains became superconducting at a particular transition temperature (Tc), determined primarily by the atomic composition of the grain, before a fully superconducting state of zero resistance was established. From the observed onset Tc, it was inferred that up to three different superconducting phases could have formed in these Au{0.7}In{0.3} films, all of which were embedded in a uniform Au{0.9}In{0.1} matrix. Among these phases, the Tc of a particular one, 0.8 K, is higher than any previously reported for the Au-In system. The electrical transport properties were studied down to low temperatures. The transport results were found to be well correlated with those of the structural studies. The present work suggests that Au{0.7}In{0.3} can be modeled as a random array of superconductor-normal metal-superconductor (SNS) Josephson junctions. The effect of disorder and the nature of the superconducting transition in these Au{0.7}In{0.3} films are discussed.Comment: 8 text pages, 10 figures in one separate PDF file, submitted to PR

DNA cleavage and antitumour activity of platinum(II) and copper(II) compounds derived from 4-methyl-2-N-(2-pyridylmethyl)aminophenol: spectroscopic, electrochemical and biological investigation

The reaction of the redox-active ligand, Hpyramol (4-methyl-2-N-(2-pyridylmethyl)aminophenol) with K2PtCl4 yields monofunctional square-planar [Pt(pyrimol)Cl], PtL-Cl, which was structurally characterised by single-crystal X-ray diffraction and NMR spectroscopy. This compound unexpectedly cleaves supercoiled double-stranded DNA stoichiometrically and oxidatively, in a non-specific manner without any external reductant added, under physiological conditions. Spectro-electrochemical investigations of PtL-Cl were carried out in comparison with the analogue CuL-Cl as a reference compound. The results support a phenolate oxidation, generating a phenoxyl radical responsible for the ligand-based DNA cleavage property of the title compounds. Time-dependent in vitro cytotoxicity assays were performed with both PtL-Cl and CuL-Cl in various cancer cell lines. The compound CuL-Cl overcomes cisplatin-resistance in ovarian carcinoma and mouse leukaemia cell lines, with additional activity in some other cells. The platinum analogue, PtL-Cl also inhibits cell-proliferation selectively. Additionally, cellular-uptake studies performed for both compounds in ovarian carcinoma cell lines showed that significant amounts of Pt and Cu were accumulated in the A2780 and A2780R cancer cells. The conformational and structural changes induced by PtL-Cl and CuL-Cl on calf thymus DNA and phi X174 supercoiled phage DNA at ambient conditions were followed by electrophoretic mobility assay and circular dichroism spectroscopy. The compounds induce extensive DNA degradation and unwinding, along with formation of a monoadduct at the DNA minor groove. Thus, hybrid effects of metal-centre variation, multiple DNA-binding modes and ligand-based redox activity towards cancer cell-growth inhibition have been demonstrated. Finally, reactions of PtL-Cl with DNA model bases (9-Ethylguanine and 5'-GMP) followed by NMR and MS showed slow binding at Guanine-N7 and for the double stranded self complimentary oligonucleotide d(GTCGAC)(2) in the minor groove

Щодо утворення сімейств атомарних радіальних базисних функцій

Наведено схему побудови сімейств атомарних радіальних базисних функцій, які є нескінченно диференційовними фінітними розв'язками функціонально-диференціальних рівнянь, породжених операторами Лапласа та Гельмгольца.The scheme of building a family of atomic radial basis functions which are infinitely differentiable finite solutions of the functional-differential equations containing the Laplace and Helmholtz operators is introduced