Search

There is a considerable interest in understanding the dependence of one-nucleon removal cross sections on the asymmetry of the neutron Sn and proton Sp separation energies, following a large amount of experimental data and theoretical analyses in a framework of sudden and eikonal approximations of the reaction dynamics. These theoretical calculations involve both the single-particle cross section and the shell-model description of the projectile initial state and final states of the reaction residues. The configuration mixing in shell-model description of nuclear states depends on the proximity of one-nucleon decay threshold but does it depend sensitively on Sn-Sp? To answer this question, we use the shell model embedded in the continuum to investigate the dependence of one-nucleon spectroscopic factors on the asymmetry of Sn and Sp for mirror nuclei 24Si, 24Ne and 28S, 28Mg and for a series of neon isotopes (20≤A≤28).

Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-1a and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not onlymitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protectedmouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration. © 2010 EMBO Molecular Medicine.

The article considers the actual problem of improving the physico-mechanical, thermophysical and electrical properties of polyorganosiloxane coatings. In this article, we propose a method for obtaining a multifunctional heat-resistant composition based on oligodimethylsiloxane with terminal hydroxyl groups filled with boron nitride. The curing process of oligodimethylsiloxane and the possible interaction of boron nitride with reactive resin groups are described. The structure of the manufactured composition is investigated, it is established that the filler in the form of dispersed particles touching throughout the volume is evenly distributed in the polymer matrix. The results of experimental studies of the dependence of the tensile strength on the percentage of boron nitride, indicating the hardening of the composite, are graphically presented. Studies of the strength at separation of the cured composition from the substrate (adhesion) of various materials have shown that this value increases with the introduction of boron nitride. The dependence of the thermal conductivity coefficient on the ratio of components is established. The percolation point is determined by the Monte Carlo method. The dependences of the electrical resistivity and temperature dependence on the content of boron nitride are determined. The Poisson equation is solved in MathCad and graphical results of solving the heat transfer problem for traditional and developed composites are presented. Based on the results obtained, the areas of application of the developed composites in construction are proposed.

The paper presents the results of experimental studies of the effect of cyclic exposure to elevated temperatures up to 90оС and 150оС and moistening to full water saturation on the strength of heavy concrete. Quantitative data on the change of concrete strength properties depending on the influence factors are obtained. Proposals are formulated to take into account in calculations the influence of heating and moistening modes on the strength of concrete in axial compression. Under cyclic exposure to elevated temperatures and subsequent moistening at normal temperature, there are significant changes in the compressive strength of concrete at different stages of each cycle. At the short-term heating stage, the reduction in the prismatic strength of the concrete amounted to 15 - 22% of the concrete strength before heating. Prolonged isothermal heating results in a 13 - 25% increase in concrete strength. At the stage of subsequent moistening of concrete after heating, there is a decrease in strength by 25 - 27%, while the relative magnitude of strength reduction does not significantly depend on the number of previous cycles. In the investigated interval of up to twenty-five cycles of exposure to elevated temperatures and moistening, the greatest reduction in concrete strength was observed in the first and last cycles. For cycles with heating temperature up to 90⁰C at short-term heating at the beginning of the second cycle the concrete strength drop was 45.5%, and the concrete strength drop at short-term heating for the 25th cycle was 9.7%. For cycles with heating temperature of 150⁰C the strength drop was 45.9% and 52.5%, respectively. The accepted experimental mode according to the formula of cycle (6+1) + (6+1) is the most unfavorable for the strength of concrete under cyclic effects of elevated temperatures and subsequent moistening.

Nowadays the level of development of finite element (FE) calculation systems allows us to count on the maximum level of design solutions quality, provided that is created an adequate and at the same time simple design model, which directly determines the level of accuracy of the results obtained when determining the parameters of the stress-strain state, as well as dynamic characteristics of buildings and structures. It is fundamentally necessary for the designer to know the degree of influence of various factors to the creation of a finite element design model on the dynamic response of the design object. There is no doubt the relevance of the problem of identifying the features of modeling tower-type structures, which will simplify the work of an engineer and at the same time reach a qualitatively new level in making design decisions. The purpose of this work is a comprehensive assessment of the influence of the features of creating a design model to the resulting parameter - the frequency behavior of a tubular tower for wind turbines which is the most popular at wind parks in Russia over the past two decades. For numerical research was used the domestic design complex SCAD Office. To create calculation models and perform a comparative analysis of the resulting parameters of tubular towers were used FE types 41, 42, 44, and 50. When determining the influence of the finite element type calculations were made for a cylindrical tower with fixed parameters, taking into account changes in the type and size of the FE. In the calculations the evaluating factors were: changing in the main and equivalent stresses, as well as the change in the frequency of the first form of own oscillations. When comparing the values of the main and equivalent stresses, the plate of the third row from the base was taken as the calculated one.

Of all the complex problems of museum storage of archaeological objects, iron objects represent one of the most difficult. In the process of corrosion, an iron object passes through several stages, from oxidation of the metal surface to full mineralization. The greatest problem consists of the items in the stages of oxidation, when the metal is almost completely corroded and converted into minerals. Mineral peels exfoliate under the influence of active corrosion, leading to a loss of historical significance of the object. In the world’s practice of archaeological iron conservation, there are several different ways of stabilization, but none of them can guarantee the integrity of the iron artifact during its museum storage. To date, the most effective conservation method of stabilizing archaeological iron is alkaline sulfite treatment. However, this method has a number of drawbacks, the main of which is the duration of the stabilizing treatment. The authors consider the possibility of increasing the efficiency of the method of processing archaeological iron objects in an alkaline sulfite solution by means of ultrasonic solution activation. In the course of the experimental study, it has been established that the use of ultrasonic in alkaline sulfite treatment hugely increases the efficiency of the method.

The article presents the results of research on the main characteristics of the structure and properties of modern stiffening fabrics. The indicators of surface density of fabrics, thread thickness of both systems and the number of threads per 10 cm on the base and weft are presented. A technique has been developed for determining bending hardness and elasticity using an automated measuring system. Reference information on hardness and elasticity in orthogonal directions has been compiled. An intelligent system based on artificial neural networks using the "Neuro-Prognosis" program has been developed. The system allows to predict the elasticity indicators of modern onboard fabrics and create a database to digitalize their selection. The advantage of the system is the ability to add refinement of the forecasting model when updating the range of stiffening fabrics. Using the system is convenient in the absence of expensive test equipment. В статье приведены результаты исследований основных характеристик строения и свойств современных бортовых тканей. Представлены показатели поверхностной плотности тканей, толщины нитей обеих систем и количество нитей на 10 см по основе и утку. Разработана методика определения жесткости и упругости при изгибе с использованием автоматизированной измерительной системы. Составлены справочные сведения по жесткости и упругости в ортогональных направлениях. Разработана интеллектуальная система, построенная на базе искусственных нейронных сетей с использованием программы Neuro-Prognosis. Система позволяет прогнозировать показатели упругости современных бортовых тканей и формировать базу данных для цифровизации их конфекционирования. Достоинством системы является возможность добавления уточнения модели прогнозирования при обновлении ассортимента бортовых тканей. Использование системы удобно при отсутствии дорогостоящего испытательного оборудования.

In Type-I X-ray bursts (XRBs), the rapid-proton capture (rp-) process passes through the NiCu and ZnGa cycles before reaching the region above Ge and Se isotopes that hydrogen burning actively powers the XRBs. The sensitivity study performed by Cyburt et al. [1] shows that the 57Cu(p,γ)58Zn reaction in the NiCu cycles is the fifth most important rp-reaction influencing the burst light curves. Langer et al. [2] precisely measured some low-lying energy levels of 58Zn to deduce the 57Cu(p,γ)58Zn reaction rate. Nevertheless, the order of the 1+1 $1_1^ + $11+ and 2+3 $2_3^ + $23+ resonance states that dominate at 0:2 ≲ T(GK) ≲ 0:8 is not confirmed. The 1+2 $1_2^ + $12+ resonance state, which dominates at the XRB sensitive temperature regime 0:8 ≲ T(GK) ≲ 2 was not detected. Using isobaric-multipletmass equation (IMME), we estimate the order of the 1+1 $1_1^ + $11+ and 2+3 $2_3^ + $23+ resonance states and estimate the lower limit of the 1+2 $1_2^ + $12+ resonance energy. We then determine the 57Cu(p,γ)58Zn reaction rate using the full pf -model space shell model calculations. The new rate is up to a factor of four lower than the Forstner et al. [3] rate recommended by JINA REACLIBv2.2. Using the present 57Cu(p,γ)58Zn, the latest 56Ni(p,γ)57Cu and 55Ni(p,γ)56Cu reaction rates, and 1D implicit hydrodynamic Kepler code, we model the thermonuclear XRBs of the clocked burster GS 1826–24. We find that the new rates regulate the reaction flow in the NiCu cycles and strongly influence the burst-ash composition. The 59Cu(p,γ)56Ni and 59Cu(p,α)60Zn reactions suppress the influence of the 57Cu(p,γ)58Zn reaction. They strongly diminish the impact of the nuclear reaction flow that bypasses the 56Ni waiting point induced by the 55Ni(p,γ)56Cu reaction on burst light curve.

A generalization of the discrete Fourier transform in the form of a parametric discrete Fourier transform is proposed. The analytical and stochastic properties of the introduced discrete transformation are investigated. An example of the application of the parametric discrete Fourier transform in telecommunications is given - a generalization of the well-known Herzel algorithm

A method of vertical sliding processing of two-dimensional discrete signals in the spatial frequency domain is proposed — a method of fast vertically sliding two-dimensional discrete Fourier transform. The mathematical representation of the two-dimensional discrete Fourier transform in algebraic and matrix form is considered. An effective method of vertically sliding two-dimensional discrete Fourier transform is proposed. The algorithm developed in the framework of the proposed method allows calculating the coefficients (bins) of this transformation in real time.

A new constructive design of a bridge column pier, which is a load-bearing component of bridges and overpasses as well as of complex multilevel interchanges underlying a transport infrastructure, is proposed. The design is based on a steel mesh casing that is made from a solid-web plate by means of cutting meshes and further expansion of the solid-web plate using non-waste technology. Experimental research data on the bearing capacity and deformability of the cylindrical steel-concrete load bearing components of bridge column piers are provided. They are compared with research data on load bearing components having a solid casing. To make the experimental picture complete, analogous research data on cylindrical concrete load bearing components are provided. This experiment includes static and low-cycle loadings of samples under axial compression mentioned above. On the basis of the information obtained, the effort and travel fields are formed, the critical forces of structure buckling are determined. The analysis of the rationality of the cylindrical steel-concrete load bearing component of bridge column piers is carried out, using the experimental research data. To verify the research data, which are obtained in the course of the study of the critical forces of cylindrical steel-concrete load bearing component buckling, the experimental results are compared with theoretical ones.

Subject: The purpose of this research work is to develop the most effective technological solution for underground waterproofing of operating structures with design features, as well as being in difficult and cramped conditions of nearby buildings. Objectives Outdoor underground waterproofing buildings, working «clamp» protects most of their supporting structures from aggressive ground waters, contributing to the acceleration of corrosion processes and leaks of water in technical room. Materials and methods: New types of waterproofing are considered and the technological scheme of performance of works is given. In addition, organizational methods of hydraulic protection of building structures have been developed. Results: This technology can be applied from the basements of the operated buildings and performed at any time of the year. Innovative technological solutions are based on mathematical calculations performed by the authors. Conclusions: Technological methods confirmed the choice of effective solutions for waterproofing, conducted by a mathematical apparatus using the methodological framework in the form of logical-probabilistic method and the method of pair comparison. The creation of “visual protection” from the mineral composition for the supporting structures of the operated buildings allows to increase the durability of their hydraulic protection, to work in cramped urban and difficult conditions, as well as to extend the life cycle of the building itself.

Up to now, empirical shell-model Hamiltonians for valence space calculations provide the most accurate description of the low-energy spectra and individual transitions of sd- and pf-shell nuclei. These features made them of particular importance for the description of the isospin-symmetry-breaking phenomena, such as energy splitting of the isobaric multiplets or isospin-forbidden transition rates. In this contribution, we demonstrate the applications of a recently constructed isospin non-conserving (INC) Hamiltonian in sd shell [Lam et al. Phys. Rev. C 87, 054304 (2013)]. First, we explore the partial decay scheme of 24Si and discuss the states affected by the Thomas-Ehrman shift. Second, we show the accuracy of the INC Hamiltonian for the description of the mirror energy differences.

We construct a new set of isospin-nonconserving (INC) shell-model Hamiltonians and apply it (i) to study the isobaric-mass multiplet equation (IMME) beyond a quadratic form in the A = 35, 3/2+ quartet, (ii) to compute the isospin mixing corrections to superallowed Fermi branch of 1+ → 1+ β decay of 32Cl, and (iii) to obtain the isospin-forbidden branching ratios of β-delayed proton emission from 25Si.

Classical novae are thermonuclear explosions in stellar binary systems, and important sources of 26 Al and 22 Na. While γ rays from the decay of the former radioisotope have been observed throughout the Galaxy, 22 Na remains untraceable. Its half-life (2.6 yr) would allow the observation of its 1.275 MeV γ-ray line from a cosmic source. However, the prediction of such an observation requires good knowledge of its nucleosynthesis. The 22 Na(p, γ) 23 Mg reaction remains the only source of large uncertainty about the amount of 22 Na ejected. Its rate is dominated by a single resonance on the short-lived state at 7785.0(7) keV in 23 Mg. Here, we propose a combined analysis of particle-particle correlations and velocity-difference profiles to measure femtosecond nuclear lifetimes. The application of this method to the study of the 23 Mg states, places strong limits on the amount of 22 Na produced in novae and constrains its detectability with future space-borne observatories., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase occur in Alzheimer's disease (AD). Thiamine deficiency exacerbates amyloid beta (Aβ) deposition, tau hyperphosphorylation and oxidative stress. Benfotiamine (BFT) rescued cognitive deficits and reduced Aβ burden in amyloid precursor protein (APP)/PS1 mice. In this study, we examined whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) in the P301S mouse model of tauopathy. Chronic dietary treatment with BFT increased lifespan, improved behavior, reduced glycated tau, decreased NFTs and prevented death of motor neurons. BFT administration significantly ameliorated mitochondrial dysfunction and attenuated oxidative damage and inflammation. We found that BFT and its metabolites (but not thiamine) trigger the expression of Nrf2/antioxidant response element (ARE)-dependent genes in mouse brain as well as in wild-type but not Nrf2-deficient fibroblasts. Active metabolites were more potent in activating the Nrf2 target genes than the parent molecule BFT. Docking studies showed that BFT and its metabolites (but not thiamine) bind to Keap1 with high affinity. These findings demonstrate that BFT activates the Nrf2/ARE pathway and is a promising therapeutic agent for the treatment of diseases with tau pathology, such as AD, frontotemporal dementia and progressive supranuclear palsy.

L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif. Challenging those HIF activators in the reporter system with D-Asc demonstrated that the D-isomer, despite exhibiting the same reducing potency with respect to ferric iron, had almost no effect compared to L-Asc. Similarly, no effect on reporter activation was observed with cell-permeable reducing agent NAC up to 1 mM. Docking of L-Asc and D-Asc acid into the HIF PHD2 crystal structure showed interference of Tyr310 with respect to D-Asc. This suggests that L-Asc is not merely a reducing agent preventing enzyme inactivation. Rather, the overall results identify L-Asc as a co-substrate of HIF PHD that may compete for the binding site of αKG in the enzyme active center. This conclusion is in agreement with the results obtained recently in cell-based systems for TET enzymes and jumonji histone demethylases, where L-Asc has been proposed to act as a co-substrate and not as a reducing agent preventing enzyme inactivation., (Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

An organism naturally responds to hypoxia via stabilization of hypoxia-inducible factor (HIF). There are three isoforms of HIFα subunits whose stability is regulated by three isozymes of HIF prolyl hydroxylase (PHD1-3). Despite intense studies on recombinant enzyme isoforms using homogeneous activity assay, there is no consensus on the PHD isoform preference for the HIF isoform as a substrate. This work provides a new approach to the problem of substrate specificity using cell-based reporters expressing the enzyme and luciferase-labeled substrate pair encoded in the same expression vector. The cell is used as a microbioreactor for running the reaction between the overexpressed enzyme and substrate. Using this novel approach, no PHD3 activity toward HIF3 was demonstrated, indirectly pointing to the hydroxylation of the second proline in 564PYIP567 (HIF1) catalyzed by this isozyme. The use of "paired" enzyme-substrate reporters to evaluate the potency of "branched tail" oxyquinoline inhibitors of HIF PHD allows higher precision in revealing the optimal structural motif for each enzyme isoform.

HIF prolyl hydroxylase is a major regulator of HIF stability. Branched tail oxyquinolines have been identified as specific inhibitors of HIF prolyl hydroxylase and recently demonstrated clear benefits in various scenarios of neuronal failure. The structural optimization for branched tail oxyquinolines containing an acetamide bond has been performed in the present study using HIF1 ODD-luc reporter assay. The special attention has been paid to the length of a linker between acetamide group and phenyl ring, as well as substitutions in the phenyl ring in the other branch of the tail. The optimized version of branched tail oxyquinolines is 3-fold more potent than the original one identified before and shows a submicromolar EC 50 in the reporter assay. The compounds have been studied in a "liver-on-a-chip" device to question their hepatotoxicity towards differentiated human HepaRG "hepatocytes": the absence of hepatotoxicity is observed up to 200 μM concentrations for all studied derivatives of branched tail oxyquinolines., (Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antihypoxic and antioxidant programs, we studied flavones, isoflavones and catechols including dihydroxybenzoate, didox, levodopa, and nordihydroguaiaretic acid (NDGA), using novel luciferase-based reporters specific for the first step in HIF1 or Nrf2 protein stabilization. Distinct structural requirements for either transcription factor stabilization have been found: as expected, these requirements for activation of HIF ODD-luc reporter correlate with in silico binding to HIF prolyl hydroxylase. By contrast, stabilization of Nrf2 requires the presence of 3,4-dihydroxy- (catechol) groups. Thus, only some but not all flavonoids are direct activators of the hypoxic and antioxidant genetic programs. NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal model of Parkinson's Disease and demonstrated neuroprotective effects.

A new model based on the quantum chemical approach is proposed to describe structural and thermodynamic parameters of clusterization for substituted alkanes at the air/liquid and liquid/liquid interfaces. The new model by the authors, unlike the previous one, proposes an explicit account of the liquid phase (phases) influence on the parameters of monomers, clusters and monolayers of substituted alkanes at the regarded interface. The calculations were carried out in the frameworks of the quantum chemical semiempirical PM3 method (Mopac 2012), using the COSMO procedure. The new model was tested in the calculations of the clusterization parameters of fatty alcohols under the standard conditions at the air/water interface. The enthalpy, Gibbs' energy and absolute entropy of formation for alcohol monomers alongside with clusterization parameters for the cluster series including the monolayer at air/water interface were calculated. In our calculations the sinkage of monomers, molecules in clusters and monolayers was varied from 1 up to 5 methylene groups. Thermodynamic parameters calculated using the proposed model for the alcohol monolayers are in a good agreement with the corresponding experimental data. However, the proposed model cannot define the most energetically preferable immersion of the monolayer molecules in the water phase.

Hypoxia-inducible factor (HIF) mediates a broad, conserved adaptive response to hypoxia, and the HIF pathway is a potential therapeutic target in cerebral ischemia. This study investigated the mechanism by which in vitro ischemia (oxygen-glucose deprivation; OGD) affects canonical hypoxic HIF-1α stabilization. We validated the use of a reporter containing the oxygen-dependent degradation domain of HIF-1α fused to firefly luciferase (ODD-luc) to monitor quantitatively distinct biochemical events leading to hypoxic HIF-1α expression or stabilization in a human neuroblastoma cell line (SH-SY5Y). When OGD was imposed following a 2-hr hypoxic stabilization of ODD-luc, the levels of the reporter were reduced, consistent with prior models proposing that OGD enhances HIF prolylhydroxylase (PHD) activity. Surprisingly, PHD inhibitors and proteasome inhibitors do not stabilize ODD-luc in OGD. Furthermore, OGD does not affect the half-life of ODD-luc protein following hypoxia, suggesting that OGD abrogates hypoxic HIF-1α induction by reducing HIF-1α synthesis rather than by enhancing its degradation. We observed ATP depletion under OGD vs. hypoxia and propose that ATP depletion enhances translational suppression, overcoming the selective synthesis of HIF concurrent with global decreases in protein synthesis in hypoxia. Taken together, these findings biochemically characterize a practical reporter for monitoring HIF-1α levels and support a novel model for HIF regulation in an in vitro model of human ischemia., (Copyright © 2013 Wiley Periodicals, Inc.)

Unlabelled: Although the etiology of Parkinson's disease (PD) remains unclear, ample empirical evidence suggests that oxidative stress is a major player in the development of PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that upregulates a battery of antioxidant response element (ARE)-driven antioxidative and cytoprotective genes that defend against oxidative stress., Aims: We evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with small molecule synthetic triterpenoids (TP) attenuate MPTP-induced PD in mice., Results: We show that synthetic TP are thus far the most potent and direct activators of the Nrf2 pathway using a novel Neh2-luciferase reporter. They upregulate several cytoprotective genes, including those involved in glutathione biosynthesis in vitro. Oral administration of TP that were structurally modified to penetrate the brain-induced messenger RNA and protein levels for a battery of Nrf2-dependent cytoprotective genes reduced MPTP-induced oxidative stress and inflammation, and ameliorated dopaminergic neurotoxicity in mice. The neuroprotective effect of these TP against MPTP neurotoxicity was dependent on Nrf2, since treatment with TP in Nrf2 knockout mice failed to block against MPTP neurotoxicity and induce Nrf2-dependent cytoprotective genes., Innovation: Extremely potent synthetic TP that are direct activators of the Nrf2 pathway block dopaminergic neurodegeneration in the MPTP mouse model of PD., Conclusion: Our results indicate that activation of Nrf2/antioxidant response element (ARE) signaling by synthetic TP is directly associated with their neuroprotective effects against MPTP neurotoxicity and suggest that targeting the Nrf2/ARE pathway is a promising approach for therapeutic intervention in PD.

The objective of the present study was to develop the algorithm for early clinical, laboratory, and instrumental diagnostics of sepsis in the patients presenting with pyo-inflammatory ENT diseases. The study included 50 patients with pyo-inflammatory ENT diseases complicated by generalization of infection. The scheme (algorithm) developed for their examination allowed to diagnose sepsis at the early stages of hospitalization in the patients presenting with pyo-inflammatory ENT pathology. The diagnostic algorithm included the criteria for syndrome of systemic inflammatory reaction (SSIR), the Kalf-Kalif leukocytic intoxication index (LII), the procalcitonin test (PKT), the integral severity of illness scale (APACHE-II) and the organ failure assessment score (SOFA). Timely preoperative diagnostics of septic complications and sanation of the primary infection site in the combination with early intensive therapy under conditions of a resuscitation department made it possible to avoid further progress of generalization of the infection and thereby to reduce the number of secondary interventions, to improve prognosis of the disease, and lower the mortality rate down to 12% in the study group (compared with 44% in the control one).

This review describes the catalytic mechanism, substrate specificity, and structural peculiarities of alpha-ketoglutarate dependent nonheme iron dioxygenases catalyzing prolyl hydroxylation of hypoxia-inducible factor (HIF). Distinct localization and regulation of three isoforms of HIF prolyl hydroxylases suggest their different roles in cells. The recent identification of novel substrates other than HIF, namely β2-adrenergic receptor and the large subunit of RNA polymerase II, places these enzymes in the focus of drug development efforts aimed at development of isoform-specific inhibitors. The challenges and prospects of designing isoform-specific inhibitors are discussed.

The NF-E2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant defense and detoxification. To directly monitor stabilization of Nrf2, we fused its Neh2 domain, responsible for the interaction with its nucleocytoplasmic regulator, Keap1, to firefly luciferase (Neh2-luciferase). We show that Neh2 domain is sufficient for recognition, ubiquitination, and proteasomal degradation of Neh2-luciferase fusion protein. The Neh2-luc reporter system allows direct monitoring of the adaptive response to redox stress and classification of drugs based on the time course of reporter activation. The reporter was used to screen the Spectrum library of 2000 biologically active compounds to identify activators of Nrf2. The most robust and yet nontoxic Nrf2 activators found--nordihydroguaiaretic acid, fisetin, and gedunin--induced astrocyte-dependent neuroprotection from oxidative stress via an Nrf2-dependent mechanism., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The results of treatment and examination were analyzed in 175 patients admitted to a clinic for sterile pancreonecrosis (PN). The significance of routinely available (clinical, biochemical, and microbiological) laboratory tests in the diagnosis of purulent complications was analyzed in patients with varying severity of pancreatic autolysis. Complex laboratory monitoring was found to be of importance in predicting and detecting infected PN with obligatory fine-needle punctures under ultrasound guidance and further microscopic studies of puncture specimens.

Neurons rely on their metabolic coupling with astrocytes to combat oxidative stress. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) appears important for astrocyte-dependent neuroprotection from oxidative insults. Indeed, Nrf2 activators are effective in stroke, Parkinson disease, and Huntington disease models. However, key endogenous signals that initiate adaptive neuroprotective cascades in astrocytes, including activation of Nrf2-mediated gene expression, remain unclear. Hydrogen peroxide (H(2)O(2)) plays an important role in cell signaling and is an attractive candidate mediator of adaptive responses in astrocytes. Here we determine (i) the significance of H(2)O(2) in promoting astrocyte-dependent neuroprotection from oxidative stress, and (ii) the relevance of H(2)O(2) in inducing astrocytic Nrf2 activation. To control the duration and level of cytoplasmic H(2)O(2) production in astrocytes cocultured with neurons, we heterologously expressed the H(2)O(2)-producing enzyme Rhodotorula gracilis D-amino acid oxidase (rgDAAO) selectively in astrocytes. Exposure of rgDAAO-astrocytes to D-alanine lead to the concentration-dependent generation of H(2)O(2). Seven hours of low-level H(2)O(2) production (∼3.7 nmol·min·mg protein) in astrocytes protected neurons from oxidative stress, but higher levels (∼130 nmol·min·mg protein) were neurotoxic. Neuroprotection occurred without direct neuronal exposure to astrocyte-derived H(2)O(2), suggesting a mechanism specific to astrocytic intracellular signaling. Nrf2 activation mimicked the effect of astrocytic H(2)O(2) yet H(2)O(2)-induced protection was independent of Nrf2. Astrocytic protein tyrosine phosphatase inhibition also protected neurons from oxidative death, representing a plausible mechanism for H(2)O(2)-induced neuroprotection. These findings demonstrate the utility of rgDAAO for spatially and temporally controlling intracellular H(2)O(2) concentrations to uncover unique astrocyte-dependent neuroprotective mechanisms.

Small molecules inhibiting hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are the focus of drug development efforts directed toward the treatment of ischemia and metabolic imbalance. A cell-based reporter produced by fusing HIF-1 alpha oxygen degradable domain (ODD) to luciferase was shown to work as a capture assay monitoring stability of the overexpressed luciferase-labeled HIF PHD substrate under conditions more physiological than in vitro test tubes. High throughput screening identified novel catechol and oxyquinoline pharmacophores with a "branching motif" immediately adjacent to a Fe-binding motif that fits selectively into the HIF PHD active site in in silico models. In accord with their structure-activity relationship in the primary screen, the best "hits" stabilize HIF1 alpha, upregulate known HIF target genes in a human neuronal line, and exert neuroprotective effects in established model of oxidative stress in cortical neurons., ((c) 2010 Elsevier Ltd. All rights reserved.)

Experimental data on micellization in aqueous solutions of 1-alkyl-3-methylimidazolium salts [C(n)mim]X and their mixtures with sodium dodecyl sulfate (NaDS) are reviewed. New results (the critical micelle concentration and enthalpy of micellization) are presented for mixtures of [C(4)mim]PF(6), [C(6)mim]BF(4), [C(6)mim]Br and [C(10)mim]Br with NaDS. Our data cover a wide range (from 0 to 0.9) of solvent-free based mole fractions of ionic liquid (IL). Even very small addition of ILs substantially decreases the cmc of NaDS due to the combined effect of electrostatic and hydrophobic interactions, and formation of mixed micelles. It is shown that the quasichemical aggregation model by Nagarajan and Ruckenstein may be successfully applied to aqueous solutions of long-chain ILs and their mixtures with NaDS. The local structure of micelles is obtained from all-atom MD simulations for [C(n)mim]Br and [C(n)mim]X+NaDS in aqueous medium.

The purpose of the investigation was to study the pattern of 99mTc (MIBI) technitrile uptake in the metastatically involved lymph nodes in breast cancer, by applying the plain scintigraphic technique. The scintigraphic study of the breast and regional metastatic areas by means of the radionuclide 99mTc (MIBI) technitrile was made on a Millennium GE tomographic gamma chamber. The radiotracer 550 (MBq) dissolved in 10-20 ml of saline solution was intravenously injected into the arm cubital vein contralaterally to the lesion. Following 20 minutes of injection of the agent, plain scintigraphy was carried out in three standard projections: frontal and two oblique ones. The scintigraphy was performed using a high-resolution collimator recording a 128 x 128 matrix image. The detector was maximally approximated to the organ being examined. A plain scintigraphic scan was recorded on each side for 10 minutes. By the degree of axillary lymph nodal involvement, the patients were divided into 3 groups in accordance with the international TNM classification: N0 (n = 55), N1 (n = 13), N2 (n = 4). Among 72 patients, axillary lymph nodes could be detected in 6, in 2 of them changes were not diagnosed by X-ray and ultrasound studies. The final pathomorphological study of intraoperative materials revealed axillary lymph nodal metastatic involvement in 17 patients. A micrometastasis in one lymph node was found in 1 patient. None of the radionuclide studies showed tumor spread in 5 cases. The sensitivity, specificity, and precision of the technique were 35.3, 100, and 84.7%, respectively. Thus, a combination of the high cost of the procedure, its radiation load on a patient, and its low sensitivity make the use of plain scintigraphy of axillary regions inexpedient in the complex of studies of the extent of breast cancer in the present development of technology.

Exposure of cells to ionizing radiation (IR) produces changes in the expression level of a large number of genes. However, less is known of gene-expression changes caused by local radiation exposure from radionuclides within cells. We studied changes in the genome-wide gene expression induced by decay of 125I incorporated into DNA as [125I]-iododeoxyuridine (125I-IUdR) in normal IMR-90 human lung fibroblasts and compared them with the changes produced by external gamma-radiation delivered at high (HDR) or low (LDR) dose rate. We found that more than 2000 genes were consistently up- or down-regulated following HDR and LDR gamma-radiation. The profiles of differentially expressed genes following HDR and LDR shared about 64% (up) and 74% (down) genes in common, with many genes identified as radiation-responsive for the first time. In contrast, in all only 206 genes changed their expression level in the 125I-IUdR-treated cells, even though the total number of DNA double-strand breaks (DSB) produced by 125I-IUdR exceeded that produced by the gamma-radiation. With few exceptions, the expression levels of 125I-IUdR-responsive genes were also altered following gamma-irradiation. Therefore, nuclear DNA-localized decays of 125I produce 10 times fewer differentially expressed genes than whole-cell exposure to gamma-radiation of comparable dose. These results suggest that the effect of IR on the changes in global gene expression depends on the distribution of energy depositions within the cell. In contrast to cell survival, DNA DSB may not be the major factor modulating changes in gene expression following irradiation.

Spo11, a meiosis-specific protein, introduces double-strand breaks on chromosomal DNA and initiates meiotic recombination in a wide variety of organisms. Mouse null Spo11 spermatocytes fail to synapse chromosomes and progress beyond the zygotene stage of meiosis. We analyzed gene expression profiles in Spo11(-/ -)adult and juvenile wild-type testis to describe genes expressed before and after the meiotic arrest resulting from the knocking out of Spo11. These genes were characterized using the Gene Ontology data base. To focus on genes involved in meiosis, we performed comparative gene expression analysis of Spo11(-/ -)and wild-type testes from 15-day mice, when spermatocytes have just entered pachytene. We found that the knockout of Spo11 causes dramatic changes in the level of expression of genes that participate in meiotic recombination (Hop2, Brca2, Mnd1, FancG) and in the meiotic checkpoint (cyclin B2, Cks2), but does not affect genes encoding protein components of the synaptonemal complex. Finally, we discovered unknown genes that are affected by the disruption of the Spo11 gene and therefore may be specifically involved in meiosis and spermatogenesis.

Sex chromosomes are subject to sex-specific selective evolutionary forces. One model predicts that genes with sex-biased expression should be enriched on the X chromosome. In agreement with Rice's hypothesis, spermatogonial genes are over-represented on the X chromosome of mice and sex- and reproduction-related genes are over-represented on the human X chromosome. Male-biased genes are under-represented on the X chromosome in worms and flies, however. Here we show that mouse spermatogenesis genes are relatively under-represented on the X chromosome and female-biased genes are enriched on it. We used Spo11(-/-) mice blocked in spermatogenesis early in meiosis to evaluate the temporal pattern of gene expression in sperm development. Genes expressed before the Spo11 block are enriched on the X chromosome, whereas those expressed later in spermatogenesis are depleted. Inactivation of the X chromosome in male meiosis may be a universal driving force for X-chromosome demasculinization.

Using resonant laser ionization, beta-decay studies, and for the first time mass measurements, three beta-decaying states have been unambiguously identified in 70Cu. A mass excess of -62 976.1(1.6) keV and a half-life of 44.5(2) s for the (6-) ground state have been determined. The level energies of the (3-) isomer at 101.1(3) keV with T(1/2)=33(2) s and the 1+ isomer at 242.4(3) keV with T(1/2)=6.6(2) s are confirmed by high-precision mass measurements. The low-lying levels of 70Cu populated in the decay of 70Ni and in transfer reactions compare well with large-scale shell-model calculations, and the wave functions appear to be dominated by one proton-one neutron configurations outside the closed Z=28 shell and N=40 subshell. This does not apply to the 1+ state at 1980 keV which exhibits a particular feeding and deexcitation pattern not reproduced by the shell-model calculations.

An experience with treatment of 14 women and 15 men aged from 41 to 83 years with Zenker's diverticulum was analyzed. Most liable to the disease were people at the age from 50 to 70 years. The average duration of the disease was 3-4 years. All the patients were subjected to improved surgical interventions: resection of the diverticulum (11 patients), operations under the control of the endoscopic technique (18 patients). Resections of the diverticulum were combined with cryopharyngeal myotomy. No complications were noted. There were no lethal outcomes. So, wider indications to operative treatment in patients with Zenker's diverticulum, endoscopic methods used at all stages of treatment as well as improved methods of performing the operation enabled the authors to obtain good immediate and long-term results.

Study included 115 women with suspicion of genital tuberculosis. Combined clinical, X-ray and laboratory examination made it possible to classify patients into 3 groups: group 1 included 44 patients with active genital tuberculosis, group 2 32 women with clinically cured tuberculosis of internal genitalia and group 3 39 women with nonspecific genital diseases. The haptoglobin-tuberculin test was given to all patients. High haptoglobin parameters before or 72 h after tuberculin administration were found only in the group of patients with active genital tuberculosis. In groups 2 and 3 the haptoglobin level did not exceed normal values both before and after tuberculin administration in a dose of 50 TU. The informative value of serum haptoglobin parameters in patients with active tuberculosis of internal genitalia constituted 88.6%.

Examination comprising the electrophysiologic method and study of the biochemical parameters of the antioxidant/lipid peroxidation system and metabolism of biologic amines in 163 patients with infiltrative pulmonary tuberculosis has revealed a clear interaction existing between the functional changes of the CNS state, the state of antioxidative defense (alpha-tocopherol) and serotonin. This allows an assumption that the antioxidant/lipid peroxidation system and serotoninergic system actively participate in the pathogenesis of development of neurotoxic reactions to antibacterial preparations in the clinical picture of tuberculosis.

Blood concentrations of LH, FSH, estradiol, prolactin, growth hormone, cortisol, testosterone and progesterone have been examined in 76 patients with active tuberculosis of the internal genitalia (group 1), 18 patients with longterm sequelae of clinically asymptomatic tuberculosis (group 2) and 41 patients with nontuberculous diseases of the internal genitalia. Abnormalities were identified in 56.5% of group 1 patients, 33% of group 2 and 46.4% of group 3 patients. The patients with active tuberculosis characteristically had a low gonadotropin and estradiol secretion. High prolactin levels were related to pituitary adenoma or tuberculous infection; polycystic ovaries were a cause of testosterone and stress of examination of cortisol elevation.

The role of cyclic nucleotides and prostaglandins E1 and F2 alpha in pulmonary hypertension formation was elucidated in experimental tuberculosis in dogs and the mechanism of a hypotensive action of sodium oxybutyrate specified with consideration of its influence on the non-gas exchange pulmonary function. The level of the above compounds was studied in the blood taken from the pulmonary artery and aorta in comparison with pulmonary artery pressure prior to and after intravenous injection of sodium oxybutyrate, an antihypoxant. Pulmonary vessel tone was found to depend on the cGMP content and synthesis in the lungs both in health and in tuberculosis and pulmonary hypertension in tuberculosis was associated with a deranged level and correlation of cAMP, cGMP and prostaglandins E1 and F2 alpha in pulmonary circulation. It has been demonstrated that the hypotensive effect of sodium oxybutyrate is associated with its influence on these biochemical parameters in plasma.

Sarcoidosis ran a favourable course in 166 out of 179 patients. The active phase of sarcoidosis was characterized by dysproteinemia, high content of histamine, STH and beta-lipoproteins together with a decrease of HPI and total protein. More remarkable shifts were observed in patients afflicted with sarcoidosis of the intrathoracic lymph nodes and of the lungs. In the phase of regression, there was a unidirectional change in the majority of the parameters, which correlated with the process liability to the reverse development. It may be recommended that the content of histamine, HPI and beta-lipoproteins should be measured along with other parameters to estimate the process activity in patients with respiratory sarcoidosis.

As a result of experimental research on rats with destructive pulmonary tuberculosis, oxidative action of isoniazid in a dose of 50 mg per kg body weight, corresponding to the mean therapeutic dose of 10 mg/kg in man, was clearly defined. Fibrotic action of the drug was also shown. It manifested itself by a sharp rise of insoluble collagen levels in the lung tissue tuberculous lesion focus of the treated animals and in the formation of mature connective tissue. Two mechanisms of isoniazid's pro-fibrotic action are presented.