New 7-piperazinylquinolones containing (benzo[<Emphasis Type="BoldItalic">d</Emphasis>]imidazol-2-yl)methyl moiety as potent antibacterial agents

A series of 7-piperazinylquinolones containing a (benzo[d]imidazol-2-yl)methyl moiety were designed and synthesized as new antibacterial agents. The antibacterial activity of title compounds was evaluated against Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumonia) microorganisms. Among the tested compounds, the N1-cyclopropyl derivative 4a showed the highest activity against S. aureus, S. epidermidis, B. subtilis and E. coli (\(\text {MIC} = 0.097\) \(\upmu \)g/mL), being 2–4 times more potent than reference drug norfloxacin. A structure-activity relationship study demonstrated that the effect of the nitro group on the benzimidazole ring depends on the pattern of substitutions on the piperazinylquinolone.     

The RgI<Subscript>2</Subscript> (ion-pair states) van der Waals complexes

This paper is an overview of our recent experimental investigations of the RgI₂ van der Waals complexes, Rg = He, Ar, Kr, performed by means of laser induced fluorescence spectroscopy, optical-optical double resonance and supersonic molecular beam techniques. Spectroscopic parameters of these complexes in the E0 _g ⁺ ion-pair state, such as binding energies and several spectroscopic constants, have been determined. Most likely, the potential energy surfaces of the all RgI₂(E) complexes under study present T-shaped minima. Vibrational and electronic predissociations of the RgI₂(E) complexes were analyzed. Relative contributions of the different electronic predissociation channels and vibrational distributions of the decay products were determined. Possible mechanisms of the complexes decay are suggested and discussed.     

Competitive FRET-Aptamer-Based Detection of Methylphosphonic Acid,a Common Nerve Agent Metabolite

Competitive fluorescence resonance energy transfer (FRET)-aptamer-based assay formats are described for one-step detection of methylphosphonic acid (MPA; a metabolite of several organophosphorus (OP) nerve agents). AminoMPA was attached to tosyl-magnetic beads and used for DNA aptamer selection from which one dominant aptamer sequence emerged. Two different FRET approaches were attempted. In one approach, the complementary DNA sequence was used as a template for labeling the aptamer with Alexa Fluor 546 (AF 546)-14-dUTP by asymmetric PCR. Following 3-dimensional (3-D), molecular modeling of the aptamer-MPA complex, a series of three fluoresceinated aptamers labeled at positions 50, 51, and 52 in the putative optimal binding pocket were synthesized. In both FRET formats, aminoMPA was linked to Black Hole Quencher (BHQ-1 or BHQ-2)-succinimides and allowed to bind the fluorescein or AF 546-labeled MPA aptamer. Following gel filtration to purify the labeled MPA aptamer-BHQ-aminoMPA FRET complexes, the complexes were competed against various concentrations of unlabeled MPA, MPA derivatives, and unrelated compounds in titration and cross-reactivity studies. Both approaches yielded low microgram per milliliter detection limits for MPA with generally low levels of cross-reactivity for unrelated compounds. However, the data suggest a pattern of traits that may effect the direction (lights on or off) and intensity of the FRET.     

Identification of a novel putative inhibitor of the <Emphasis Type="BoldItalic">Plasmodium falciparum</Emphasis> purine nucleoside phosphorylase: exploring the purine salvage pathway to design new antimalarial drugs

Malaria, a tropical parasitic disease caused by Plasmodium spp., continues to place a heavy social burden, with almost 200 million cases and more than 580,000 deaths per year. Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) can be targeted for antimalarial drug design since its inhibition kills malaria parasites both in vitro and in vivo. Although the currently known inhibitors of PfPNP, immucillins, are orally available and of low toxicity to animals and humans, to the best of our knowledge, none of these compounds has entered clinical trials for the treatment of malaria. Using a pharmacophore-based virtual screening coupled to a consensual molecular docking approach, we identified 59 potential PfPNP inhibitors that are predicted to be orally absorbed in a Caco-2 cell model. Although most of these compounds are predicted to have high plasma protein binding levels, poor water solubility (except for compound 25) and CYP3A4 metabolic stability (except for 4, 7 and 8), four structures (4, 7, 8 and 25) remain as potential leads because of their plausible interaction with a specific hydrophobic pocket of PfPNP, which would confer them higher selectivity for PfPNP over human PNP. Additionally, both predicted Gibbs free energies for binding and molecular dynamics suggest that compound 4 may form a more stable complex with PfPNP than 5\(^{\prime }\)-methylthio-immucillin-H, a potent and selective inhibitor of PfPNP.     

Förster Resonance Energy Transfer Study of Cytochrome <Emphasis Type="Italic">c</Emphasis>—Lipid Interactions

Specific interactions between a mitochondrial hemoprotein cytochrome c (cyt c) and cardiolipin, a lipid component of mitochondrial membrane, are crucial to electron shuttling and apoptotic activities of this protein. In the present study the Förster resonance energy transfer (FRET) between anthrylvinyl-labeled phosphatidylcholine as a donor and heme moiety of cyt c as an acceptor was employed to give a quantitative characterization of the protein binding to the model membranes from the mixtures of phosphatidylcholine (PC) with phosphatidylglycerol (PG), phosphatidylserine (PS) or cardiolipin (CL) in different molar ratios. The multiple arrays of the FRET data were globally analyzed in terms of the model of energy transfer in two-dimensional systems combined with the scaled particle adsorption model. The arguments in favor of the specificity of cyt c interactions with CL were obtained, including the higher adsorption potential and the deeper protein insertion in the lipid bilayer.     

Supramolecular Interaction of Two Tryptophans with <Emphasis Type="Italic">p</Emphasis>-sulfonated calix[<Emphasis Type="Italic">4,6,8</Emphasis>]arene

The complex characteristics of p-sulfonated calix[n]arene (SCnA) and two tryptophans N-[(tert-butoxy) carbonyl]-tryptophan (trp-A) and N-carbobenzoxy-tryptophane (trp-B) were examined through various techniques. Spectrofluorimetry was performed at different temperatures to determine the stability constants and evaluate the thermodynamic parameters of the two complexes. The effect of pH on complex formation was estimated. According to the fluorescence data, the assumption about the steric hindrance of the tert-butyl group of trp-A and the phenyl group of trp-B was put forward. ¹H NMR was also performed to determine the binding interaction mechanism. Results showed that the indole benzene rings of the two tryptophans partly penetrated into the cavity of p-sulfonated calix[n]arene. The shift in Ha, Hb and Hc, Hd positions became more significant as the number of phenolic units of the calixarene ring increased. Molecular modeling of the complexes elucidated the assumption about the steric hindrance of the tert-butyl group of trp-A and the phenyl group of trp-B. These observations of molecular modeling computation are consistent with previous fluorescence data and ¹H NMR results.     

Chiral and deconfinement phase transitions in QED<Subscript>3</Subscript> with finite gauge boson mass

Based on the experimental observation that there is a coexisting region between the antiferromagnetic (AF) and d-wave superconducting (dSC) phases, the influences of gauge boson mass m _a on chiral symmetry restoration and deconfinement phase transitions in QED₃ are investigated simultaneously within a unified framework, i.e., Dyson–Schwinger equations. The results show that the chiral symmetry restoration phase transition in the presence of the gauge boson mass m _a is a typical second-order phase transition; the chiral symmetry restoration and deconfinement phase transitions are coincident; the critical number of fermion flavors N ^c _f decreases as the gauge boson mass m _a increases, which implies that there exists a boundary that separates the N ^c _f –m _a plane into chiral symmetry breaking/confinement region for (N ^c _f , m _a ) below the boundary and chiral symmetry restoration/deconfinement region for (N ^c _f , m _a ) above it.     

Superconductivity of proximity coupled superconductor-antiferromagnetic multilayers

Nucleation of superconducting phase in proximity coupled superconductor(SC)-antiferromagnetic(AF) multilayers is studied theoretically. For SC layer we use the usual Usadel equations. As an AF layer we consider a normal metal which undergos the magnetic phase transition associated with the nesting electron and hole Fermi surfaces. The basic formalism, suitable for study of the SC phase of the SC/AF system is presented. The superconducting transition temperature,T _c , and upper critical fields,H _c2‖ (T) andH _c2⊥ (T) have been calculated.     

Low-energy Ce spin excitations in CeFeAsO and CeFeAsO<Subscript>0.84</Subscript>F<Subscript>0.16</Subscript>

We use inelastic neutron scattering to study the low-energy spin excitations of polycrystalline samples of nonsuperconducting CeFeAsO and superconducting CeFeAsO_0.84F_0.16. Two sharp dispersionless modes are found at 0.85 and 1.16 meV in CeFeAsO below the Ce antiferromagnetic (AF) ordering temperature of T _N ^Ce ? 4 K. On warming to above T _N ^Ce ? 4 K, these two modes become one broad dispersionless mode that disappears just above the Fe ordering temperature T _N ^Fe ? 140 K. For superconducting CeFeAsO_0.84F_0.16, where Fe static AF order is suppressed, we find a weakly dispersive mode center at 0.4 meV that may arise from short-range Ce-Ce exchange interactions. Using a Heisenberg model, we simulate powder-averaged Ce spin wave excitations. Our results show that we need both Ce spin wave and crystal electric field excitations to account for the whole spectra of low-energy spin excitations.     

A Fluorescence Study of New Angular Polycyclic Blue Light-Emitting pyrazolo[3,4-<Emphasis Type="Italic">h</Emphasis>][1,6]naphthyridine and their Interaction with Bovine Serum Albumin (BSA)

The blue light-emitting pyrazolo[3,4-h][1,6]naphthyridines has been synthesized by Friedländer condensation of 4-amino-3-(4-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (o-aminoaldehyde) 1 with different cyclic ketones and 1,3-diketones. The synthesized angular polycyclic naphthyridine derivatives were studied for Semi-empirical, thermal, UV–vis and fluorescence spectroscopic properties on binding with bovin serum albumin (BSA). These fluorescence properties together with the neutral, hydrophobic nature of these compounds make these fluorophores good fluorescence probe for studying the micropolarity of proteins like BSA and in general the ligand-protein interactions. All of them displays bright absorption at 394 nm &; emission in visible region (491 nm). Quantum yields of all synthesized compounds were calculated.     

Resonance Structure of the Charge-Exchange Strength Function and Neutrino-Capture Cross Sections for the Isotopes <Superscript>71</Superscript>Ga, <Superscript>98</Superscript>Mo,and <Superscript>127</Superscript>I

A resonance structure of the charge-exchange strength function S(E) and its effect on the neutrino-capture cross sections for the isotopes ⁷¹Ga, ⁹⁸Mo, and ¹²⁷I are studied within the self-consistent theory of finite Fermi systems. The calculation of the strength function S(E) takes into account Gamow–Teller, analog, and so-called lower lying pygmy resonances. The neutrino-capture cross sections σ(E) for the above three isotopes are calculated with allowance for the resonance structure of the strength function S(E), and the effect of each resonance on the energy dependence σ(E) is analyzed. It is found that all charge-exchange resonances in the strength function S(E) should be taken into account in calculating the neutrino-capture cross section σ(E) for the isotopes ⁷¹Ga, ⁹⁸Mo, and ¹²⁷I. The disregard of even highlying resonances leads to a substantial underestimation of the cross section σ(E), and this may affect the interpretation of respective experimental data.     

Determination of Copper(II) Ion Concentration by Lifetime Measurements of Green Fluorescent Protein

The understanding of cellular processes and functions and the elucidation of their physiological mechanisms is an important aim in the life sciences. One important aspect is the uptake and the release of essential substances as well as their interactions with the cellular environment. As green fluorescent protein (GFP) can be genetically encoded in cells it can be used as an internal sensor giving a deeper insight into biochemical pathways. Here we report that the presence of copper(II) ions leads to a decrease of the fluorescence lifetime (τ _fl) of GFP and provide evidence for Förster resonance energy transfer (FRET) as the responsible quenching mechanism. We identify the His₆-tag as the responsible binding site for Cu^2?+? with a dissociation constant K _d ?=?9 ±2 μM and a Förster radius R ₀?=?2.1 ±0.1 nm. The extent of the lifetime quenching depends on [Cu^2?+?] which is comprehended by a mathematical titration model. We envision that Cu^2?+? can be quantified noninvasively and in real-time by measuring τ _fl of GFP.     

Mixing of <Emphasis Type="Italic">K</Emphasis><Superscript>0</Superscript> and <Emphasis Type="Italic">B</Emphasis><Superscript>0</Superscript> neutral mesons within the minimum supersymmetry model

Mixing of K ⁰ and B ⁰ mesons is studied in the scope of the minimum supersymmetry model (MSSM) with a type II Yukawa sector and explicit violation of CP invariance in the Higgs potential. The mixing parameters Δm _LS and ? are calculated in the limit of the low-energy four-fermion approximation with a charged Higgs boson exchange. It is shown that supersymmetric effects are very small for K ⁰ mesons and may be quite significant for B _s ⁰ and B _d ⁰ mesons, which imposes constraints on the MSSM parameter space.     

<Emphasis Type="Italic">parkin</Emphasis> counteracts symptoms in a <Emphasis Type="Italic">Drosophila</Emphasis> model of Parkinson's disease

Background

Parkinson's disease, a prevalent neurodegenerative disease, is characterized by the reduction of dopaminergic neurons resulting in the loss of motor control, resting tremor, the formation of neuronal inclusions and ultimately premature death. Two inherited forms of PD have been linked to mutations in the α-synuclein and parkin genes. The parkin protein functions as an ubiquitin ligase targeting specific proteins for degradation. Expression of human α-synuclein in Drosophila neurons recapitulates the loss of motor control, the development of neuronal inclusions, degeneration of dopaminergic neurons and the ommatidial array to provide an excellent genetic model of PD.

Results

To investigate the role of parkin, we have generated transgenic Drosophila that conditionally express parkin under the control of the yeast UAS enhancer. While expression of parkin has little consequence, co-expression of parkin with α-synuclein in the dopaminergic neurons suppresses the α-synuclein-induced premature loss of climbing ability. In addition directed expression of parkin in the eye counteracts the α-synuclein-induced degeneration of the ommatidial array. These results show that parkin suppresses the PD-like symptoms observed in the α-synuclein-dependent Drosophila model of PD.

Conclusion

The highly conserved parkin E3 ubiquitin ligase can suppress the damaging effects of human α-synuclein. These results are consistent with a role for parkin in targeting α-synuclein to the proteasome. If this relationship is conserved in humans, this suggests that up-regulation of parkin should suppress α-synucleinopathic PD. The development of therapies that regulate parkin activity may be crucial in the treatment of PD.

     

Electron gas induced in SrTiO<Subscript>3</Subscript>

This mini-review is dedicated to the 85th birthday of Prof. L.V. Keldysh, from whom we have learned so much. In this paper, we study the potential and electron density depth profiles in surface accumulation layers in crystals with a large and nonlinear dielectric response such as SrTiO₃ (STO) in the cases of planar, spherical, and cylindrical geometries. The electron gas can be created by applying an induction D₀ to the STO surface. We describe the lattice dielectric response of STO using the Landau–Ginzburg free energy expansion and employ the Thomas–Fermi (TF) approximation for the electron gas. For the planar geometry, we arrive at the electron density profile n(x) ∝ (x + d)^–12/7, where d ∝ D₀^–12/7. We extend our results to overlapping electron gases in GTO/STO/GTO heterojunctions and electron gases created by spill-out from NSTO (heavily n-type doped STO) layers into STO. Generalization of our approach to a spherical donor cluster creating a big TF atom with electrons in STO brings us to the problem of supercharged nuclei. It is known that for an atom with a nuclear charge Ze where Z > 170, electrons collapse onto the nucleus, resulting in a net charge Zn < Z. Here, instead of relativistic physics, the collapse is caused by the nonlinear dielectric response. Electrons collapse into the charged spherical donor cluster with radius R when its total charge number Z exceeds the critical value Z_c ≈ R/a, where a is the lattice constant. The net charge eZ_n grows with Z until Z exceeds Z* ≈ (R/a)^9/7. After this point, the charge number of the compact core Z_n remains ≈ Z*, with the rest Z* electrons forming a sparse TF atom with it. We extend our studies of collapse to the case of long cylindrical clusters as well.     

Energy levels of ions of silver and rhodium isoelectronic sequences with <Emphasis Type="Italic">Z</Emphasis> < 86

The method of extrapolation of the parameter of a model potential for states of one electron (4f, 5s, 5p, 5d, 5f) above the core 1s ²2s ²2p ⁶3s ²3p ⁶3d ¹⁰4s ²4p ⁶4d ¹⁰ and one vacancy (4d ⁹) in the same core is applied to calculate the energy levels in the silver and rhodium isoelectronic sequences with the maximum nuclear charge Z = 86. The energy levels of Ag-and Rh-like ions were used for the calculation of the energies of resonance transitions to the ground state ¹ S ₀ in Pd-like ions. Good agreement between the theoretical and calculated energies of the resonance transitions in Pd-like ions indicates the reliability of the results obtained.     

Phonon and electronic properties of the LiCaAlF<Subscript>6</Subscript> crystal: Experiment and ab initio calculations

The results obtained in a cell with a distance between windows on the order of several hundreds of nanometers (the so-called “nanocell”) are presented. The nanocell thickness L in the vertical direction changes from 100 to 900 nm. It is shown that the use of a nanocell with thickness L = λ/2, where λ is a laser wavelength resonant to the atomic transition D2 in sodium atoms, provides sub-Doppler resolution of transmission and fluorescence spectra.     

Hall coefficient in heavy fermion metals

Experimental studies of the antiferromagnetic (AF) heavy fermion metal YbRh₂Si₂ in a magnetic field B indicate the presence of a jump in the Hall coefficient at a magnetic-field tuned quantum state in the zero temperature limit. This quantum state occurs at B ≥ B_c0 and induces the jump even though the change of the magnetic field at B = B_c0 is infinitesimal. We investigated this by using the model of heavy electron liquid with the fermion condensate. Within this model, the jump takes place when the magnetic field reaches the critical value B_c0 at which the ordering temperature T_N(B = B_c0) of the AF transition vanishes. We show that at B → B_c0, this second order AF phase transition becomes the first order one, making the corresponding quantum and thermal critical fluctuations vanish at the jump. At T → 0 and B = B_c0 the Grüneisen ratio as a function of the temperature T diverges. We demonstrate that both the divergence and the jump are determined by the specific low temperature behavior of the entropy \(S(T) \propto S_0 + a\sqrt T + bT\) with S₀; a and b are temperature independent constants.