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

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

Symbol algebras and cyclicity of algebras after a scalar extension

Пусть F —поле. Для семейства центральных простых F-алгебр мы доказываем, что существует регулярное расширение E/F, сохраняющее индексы F-алгебр, такое что все алгебры семейства циклические после расширения скаляров до E. Пусть A— центральная простая F-алгебра степени n и примитивный корень степени n из едини- цы принадлежит F. Построено квазиаффинное F-многообразие Symb(A), такое что для расширения L/F многообразие Symb(A) обладает L-рациональной точкой то- гда и только тогда, когда A⊗F L—символ-алгебра. Пусть A—центральная простая F-алгебра степени n и K/F —циклическое расширение степени n. Построено ква- зиаффинное F-многообразие C(A,K), такое что для расширения L/F со свойством [KL : L] = [K : F] многообразие C(A,K) обладает L-рациональной точкой тогда и только тогда, когда KL—подполе алгебры A⊗F L

The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

A second case of glutaminase hyperactivity: Expanding the phenotype with epilepsy

Glutaminase (GLS) hyperactivity was first described in 2019 in a patient with profound developmental delay and infantile cataract. Here, we describe a 4-year-old boy with GLS hyperactivity due to a de novo heterozygous missense variant in GLS, detected by trio whole exome sequencing. This boy also exhibits developmental delay without dysmorphic features, but does not have cataract. Additionally, he suffers from epilepsy with tonic clonic seizures. In line with the findings in the previously described patient with GLS hyperactivity, in vivo 3 T magnetic resonance spectroscopy (MRS) of the brain revealed an increased glutamate/glutamine ratio. This increased ratio was also found in urine with UPLC-MS/MS, however, inconsistently. This case indicates that the phenotypic spectrum evoked by GLS hyperactivity may include epilepsy. Clarifying this phenotypic spectrum is of importance for the prognosis and identification of these patients. The combination of phenotyping, genetic testing, and metabolic diagnostics with brain MRS and in urine is essential to identify new patients with GLS hyperactivity and to further extend the phenotypic spectrum of this disease