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Using an original method, we have received Drosophila melanogaster with a deficiency including a complete sequence of quick-to-court gene. In this report, we describe the behavioural features of this new deletion mutant. There were no serious deviations from the normal mating behaviour in flies with the deletion, but the behaviour of deletion mutants still had some features. Of all the elements, only the frequency of licking significantly increased in mutants. The duration of mating elements did not change in flies with deletion, and the latent period decreased only for following the female and licking. We have found that mutant males produce more courtship song than control males when courting Oregon R females as estimated by the pulse song index. In our experiment, mutant females provoked much less pulse song production by Oregon R males than control females do. Moreover, Oregon R males initiate courtship song towards mutant females later than towards control females. In other words, the study of pulse song production showed that the deficiency in females leads to a decrease in the intensity of courtship of wild-type males, whereas the deficiency in males leads to more intensive care for wild-type females. [ABSTRACT FROM AUTHOR]

Neuronal excitotoxicity which is induced by exposure to excessive extracellular glutamate is shown to be involved in neuronal cell death in acute brain injury and a number of neurological diseases. High concentration of glutamate induces calcium deregulation which results in mitochondrial calcium overload and mitochondrial depolarization that triggers the mechanism of cell death. Inhibition of mitochondrial calcium uptake could be potentially neuroprotective but complete inhibition of mitochondrial calcium uniporter could result in the loss of some physiological processes linked to Ca2+ in mitochondria. Here, we found that a novel compound, TG-2112x, can inhibit only the lower concentrations mitochondrial calcium uptake (induced by 100 nM-5 μM) but not the uptake induced by higher concentrations of calcium (10 μM and higher). This effect was not associated with changes in mitochondrial membrane potential and cellular respiration. However, a pre-treatment of neurons with TG-2112x protected the neurons against calcium overload upon application of toxic concentrations of glutamate. Thus, sequestration of mitochondrial calcium uptake protected the neurons against glutamate-induced mitochondrial depolarization and cell death. In our hands, TG-2112x was also protective against ionomycin-induced cell death. Hence, low rate mitochondrial calcium uptake plays an underestimated role in mitochondrial function, and its inhibition could protect neurons against calcium overload and cell death in glutamate excitotoxicity. [ABSTRACT FROM AUTHOR]

A comparative study performed in mice investigating the action of DF302, a novel fluoride-containing gamma-carboline derivative, in comparison to the structurally similar neuroprotective drug dimebon. Drug effects on learning and memory, emotionality, hippocampal neurogenesis and mitochondrial functions, as well as AMPA-mediated currents and the 5-HT6 receptor are reported. In the step-down avoidance and fear-conditioning paradigms, bolus administration of drugs at doses of 10 or 40 mg/kg showed that only the higher dose of DF302 improved long-term memory while dimebon was ineffective at either dosage. Short-term memory and fear extinction remained unaltered across treatment groups. During the 5-day predation stress paradigm, oral drug treatment over a period of 2 weeks at the higher dosage regimen decreased anxiety-like behaviour. Both compounds supressed inter-male aggression in CD1 mice, the most eminent being the effects of DF302 in its highest dose. DF302 at the higher dose decreased floating behaviour in a 2-day swim test and after 21-day ultrasound stress. The density of Ki67-positive cells, a marker of adult neurogenesis, was reduced in the dentate gyrus of stressed dimebon-treated and non-treated mice, but not in DF302-treated mice. Non-stressed mice that received DF302 had a higher density of Ki67-positive cells than controls unlike dimebon-treated mice. Similar to dimebon, DF302 effectively potentiated AMPA receptor-mediated currents, bound to the 5-HT6 receptor, inhibited mitochondrial permeability transition and displayed cytoprotective properties in cellular models of neurodegeneration. Thus, DF302 exerts multi-target effects on the key mechanisms of neurodegenerative pathologies and can be considered as an optimized novel analogue of the neuroprotective agent dimebon. [ABSTRACT FROM AUTHOR]

We analyze the results of a Probabilistic Seismic Hazard Assessment obtained for Saudi Arabia using a spatially smoothed seismicity model. The composite up-to-date earthquake catalog is used to model seismicity and to determine earthquake recurrence characteristics. Different techniques that are frequently used for the analysis of input data are applied in the study. The alternative techniques include the declustering procedures for catalog processing, statistical techniques for estimation the magnitude-frequency relationship (MFR), and the seismicity smoothing parameter. The scheme represents epistemic uncertainty that results from an incomplete knowledge of earthquake process and application of alternative mathematical models for a description of the process. Our calculations that are based on the Monte Carlo technique include also a consideration of the aleatory uncertainty related to the dimensions and depths of earthquake sources, parameters of MFR, and scatter of ground-motion parameter. The hazard maps show that the rock-site peak ground acceleration (PGA) is the highest for the seismically active areas in the north-western (Gulf of Aqaba, PGA > 300 cm/s for return period 2475 years) and south-western (PGA > 100 cm/s for return period 2475 years) parts of the country. We show that the procedures for catalog declustering have the highest influence on the results of hazard estimations, especially for high levels of hazard. The choice of smoothing parameter is a very important decision that requires proper caution. The relative uncertainty that is ratio between the 85th and 15th percentiles may reach 50-60% for the areas located near the zones of high-level seismic activity. [ABSTRACT FROM AUTHOR]

An approach to seismic hazard assessment that is based on consideration of spatial distribution of possible earthquakes with maximum credible magnitudes is proposed. A set of catalogs consisting in a large number of the earthquakes randomly distributed inside seismic source areas is generated using Monte Carlo technique. Magnitudes and parameters of the earthquake sources are considered as random variables with corresponding probability distribution functions. The modeling takes into account inherent uncertainty in location, magnitude, size of faulting and other characteristics of future large earthquakes. The ground-motion parameters at the point of interest are calculated from all events in the catalogs using ground motion prediction equations taking into account ground-motion variability. Seismic hazard for every site is described by a set of possible values of the ground-motion parameters, from which probability density function and cumulative distribution function are determined. The approach is discussed in application to region of western Saudi Arabia which is characterized by various levels of seismicity. Such type of seismic hazard analysis may be useful to constrain the expected level of maximum ground motion to be considered in design, seismic risk mitigation and reinsurance, bearing in mind necessity for estimations of ground motions from large rare earthquakes. [ABSTRACT FROM AUTHOR]

A new seismic source model has been developed for the western part of the Arabian Peninsula, which has experienced considerable earthquake activity in the historical past and in recent times. The data used for the model include an up-to-date seismic catalog, results of recent studies of Cenozoic faulting in the area, aeromagnetic anomaly and gravity maps, geological maps, and miscellaneous information on volcanic activity. The model includes 18 zones ranging along the Red Sea and the Arabian Peninsula from the Gulf of Aqaba and the Dead Sea in the north to the Gulf of Aden in the south. The seismic source model developed in this study may be considered as one of the basic branches in a logic tree approach for seismic hazard assessment in Saudi Arabia and adjacent territories. [ABSTRACT FROM AUTHOR]

The results of classical probabilistic seismic hazard analysis (PSHA) contain no information about simultaneous ground motions at different sites during a particular earthquake. Seismic risk analysis for distributed critical structures requires estimates of the level of earthquake shaking that are likely to occur concurrently at multiple locations: whether the vulnerable elements of a lifeline system are likely to be simultaneously affected by shaking of sufficient strength to disable them and whether the shaking at any one of critical points may be sufficient to cause failure of the whole system. While the analysis of lifeline performance requires multiple-location estimations, the sparsely located elements of a network or critical facilities are designed on the basis of point-wise PSHA. In this paper we study specific features of multiple-location PSHA, as compared with the classical point-wise PSHA, using Monte Carlo simulations. We analyze the level of ground motion (PGA) that will be exceeded at any site inside a particular area or at several sites simultaneously with reference annual probability. The analysis has been performed for regions of Western and South-Western Germany, Northern and Eastern Taiwan, which represent different levels of seismicity (low, moderate and high, respectively). The relationship between the multiple-location and point-wise estimations are analyzed and quantified. Results of the study may be used to decide whether it may be possible to utilize the procedure of point-wise PSHA in particular cases of multiple-location PSHA, i.e. for assessment of maximum level of ground motion among several sites, or for estimation a reasonable lower safety level when considering simultaneous exceedances. [ABSTRACT FROM AUTHOR]

Consideration of within-earthquake ground-motion correlation is essential for the estimation of seismic hazards, damage, and loss for spatially distributed systems. In many seismically active regions, the strong motion data of real engineering significance are completely unavailable or very scarce. The absence of necessary data does not allow developing regional empirical correlation models, and the models obtained for other regions should be used with correspondent sensitivity analysis. The level of within-earthquake correlation may vary in broad range; therefore, development of correspondent criteria for selection from available models is important. In this paper, we analyzed the performance of a system of critical elements of electric power network (substations) depending on variations in within-earthquake correlation. The performance is described as probability of different levels of non-functionality, i.e., percentage of area suffering power outage, and probability of expected number of customers without power. We have shown that the proper choice of the within-earthquake correlation model is critical in comprehensive estimations of functionality of substations in electrical power system. Skipping the ground-motion variability and within-earthquake correlation may lead to unreliable results. Relevance of geology-based within-earthquake correlation models has been demonstrated, and a scheme, which allows reducing uncertainty in the choice of realistic correlation, has been proposed. [ABSTRACT FROM AUTHOR]

The complete lists of vector hyperbolic equations on the sphere that have integrable third-order vector isotropic and anisotropic symmetries are presented. Several new integrable hyperbolic vector models are found. By their integrability, we mean the existence of vector Bäcklund transformations depending on a parameter. For all new equations, such transformations are constructed. [ABSTRACT FROM AUTHOR]

We analyzed the within-earthquake correlation (peak ground acceleration PGA and velocity PGV) in Japan by taking into account local geological conditions. The database includes more than 23,700 records (K-NET and the KiK-net networks) from 84 events (M 4.2–7.4) occurring in 1999–2011. The correlation structure was investigated for residuals obtained using two recently developed ground-motion models for Japan. We have shown that the level of within-earthquake correlation may vary significantly depending on site classes, general geological conditions and earthquake magnitude. The results of the analysis are in general agreement with the findings obtained recently for Taiwan (Sokolov et al. in Bull Earthq Eng 10(5):1401–1429, 2012 . doi: 10.1007/s10518-012-9368-5 ). The high level of ground-motion correlation reflects the presence of a non-random component in the residuals that may be caused by the joint influence of surface soil and thick sediments, and this influence depends on the earthquake magnitude. Therefore, a single generalized model of within-earthquake correlation across geologically heterogeneous regions may not be adequate. The application of empirical correction factors, which may be a function of earthquake magnitude, source-to-site distance, site class, and average shear-wave velocity for a given station, allows for effective reduction in the level of within-earthquake correlation. [ABSTRACT FROM AUTHOR]

We analysed the within-earthquake correlation of ground motion using the strong-motion records accumulated by the TSMIP (Taiwan Strong Motion Instrumentation Program) network in Taiwan during 1993-2009. Two ground-motion prediction equations, which were recently developed for peak ground acceleration (PGA) in the region and based on moment and local magnitude and hypocentral distance, were used for the calculation and analysis of ground-motion residuals. We also used the database containing shear-wave velocity data averaged for the top 30 m of the soil column (Vs30) for the TSMIP stations. We showed that the within-earthquake correlation may vary significantly depending on site classes, gross geological features of the area, and magnitude of earthquakes, records of which dominate the analysed dataset. On the one hand, there is a prominent correspondence between the within-earthquake correlation of PGA residuals and spatial correlation of Vs30 values, which was estimated for particular geological structures (e.g., sedimentary filled basins and large plain areas). On the other hand, the high level of ground-motion correlation (or significant non-random component of residuals) may be caused by the joint influence of soft surface soil and thick sediments and by the path or azimuthal effects. The point-source approximation of extended fault and neglected hanging- and foot-wall effects may also result in non-random residuals. The application of empirical correction factors, which consider the magnitude of earthquakes, source-to-site distance and Vs30 value for given stations, allows for the effective reduction in the level of within-earthquake correlation, as well as the within-earthquake standard deviation. The results of the analysis may be used in practical estimates of seismic hazard, damage and loss for spatially distributed structures (portfolios, lifelines) in Taiwan, as well in other regions with similar geological characteristics. [ABSTRACT FROM AUTHOR]

Recent studies have shown that the proper treatment of ground-motion variability and, particularly, the correlation of ground motion are essential for the estimation of the seismic hazard, damage and loss for distributed portfolios. In this work we compared the effects of variations in the between-earthquake correlation and in the site-to-site correlation on probabilistic estimations of seismic damage and loss for the extended objects (hypothetical portfolio) and critical elements (e.g. bridges) of a network. Taiwan Island has been chosen as a test case for this study because of relatively high seismicity and previous experience in earthquake hazard modelling. The hazard and loss estimations were performed using Monte Carlo approach on the basis of stochastic catalogues and random ground-motion fields. We showed that the influence of correlation on parameters of seismic hazard, characteristics of loss distribution and the probability of damage depend, on one hand, on level of hazard and probability level of interest (return period) and, on the other hand, the relative influence of each type of correlation is not equal. [ABSTRACT FROM AUTHOR]

Taipei, the capital of Taiwan, suffered from destructive earthquakes four times during the 20th century ( ML = 7.3 on April 15, 1909; ML = 6.8 on November 15, 1986; the Chi–Chi ML = 7.3 earthquake on September 21, 1999; and ML = 6.8 on March 31, 2002). Analysis of recorded data shows a strong dependence of spectral amplification in the Taipei Basin on earthquake depth and azimuth. At low frequencies ( f < 3 Hz) significant larger amplifications are observed for shallow earthquakes as compared to intermediate depth events. The former ones also display strong azimuthal dependence. As structures with large response periods such as bridges and tall buildings are sensitive to these low frequencies the understanding of the associated wave effects within the basin and their role for site effect amplification is critical. The tool we employ is 3D finite-difference modeling of wave propagation of incident wave fronts. The available detailed model of the basin allows studying the wave effects. Modeling clearly reveals that basin edge effects as observed in data are related to surface wave generation at the basin edges with a high degree of azimuthal dependency. The reproduced site amplification effects are in qualitative agreement with the observations from strong motion data. [ABSTRACT FROM AUTHOR]

The estimation of strength of shaking at a site from the initial P-wave portion of ground motion is the key problems for shortening the alert time of the earthquake Early Warning (EEW). The most of the techniques proposed for the purpose utilize (a) ground motion models based on the estimated magnitude and hypocentral distance, or (b) the interim proxies, such as initial vertical displacement P d. We suggest the instrumental Japan Meteorological Agency (JMA) intensity (JMAI) as a characteristic for fast estimation of damage potential in the EEW systems. We investigated the scaling relations between JMAI measured using the whole earthquake recordings (overall intensity) and using particular time intervals of various duration (2.0–8.0 s) starting from the P-wave arrival (preliminary intensity). The dataset included 3,660 records (K-NET and the KiK-net networks) from 55 events ( MW 4.1–7.4) occurred in 1999–2008 in Japan. We showed that the time interval of 4–5 s from the P-wave arrival can be used for reliable estimations of the overall intensity with the average standard error of about 0.5 JMA units. The uncertainty in the prediction may be reduced by consideration of local site conditions or by development of the station-specific models. [ABSTRACT FROM AUTHOR]

We present the regional ground-motion prediction equations for peak ground acceleration (PGA), peak ground velocity (PGV), pseudo-spectral acceleration (PSA), and seismic intensity (MSK scale) for the Vrancea intermediate depth earthquakes (SE-Carpathians) and territory of Romania. The prediction equations were constructed using the stochastic technique on the basis of the regional Fourier amplitude spectrum (FAS) source scaling and attenuation models and the generalised site amplification functions. Values of considered ground motion parameters are given as the functions of earthquake magnitude, depth and epicentral distance. The developed ground-motion models were tested and calibrated using the available data from the large Vrancea earthquakes. We suggest to use the presented equations for the rapid estimation of seismic effect after strong earthquakes (Shakemap generation) and seismic hazard assessment, both deterministic and probabilistic approaches. [ABSTRACT FROM AUTHOR]

Given an associative multiplication in matrix algebra compatible with the usual one or, in other words, a linear deformation of the matrix algebra, we construct a solution to the classical Yang-Baxter equation. We also develop a theory of such deformations and construct numerous examples. It turns out that these deformations are in one-to-one correspondence with representations of certain algebraic structures, which we call M-structures. We also describe an important class of M-structures related to the affine Dynkin diagrams of A, D, E-type. These M-structures and their representations are described in terms of quiver representations. [ABSTRACT FROM AUTHOR]

Intermediate-depth earthquakes in the Vrancea region occur in response to stress generation due to descending lithosphere beneath the southeastern Carpathians. In this article, tectonic stress and seismicity are analyzed in the region on the basis of a vast body of observations. We show a correlation between the location of intermediate-depth earthquakes and the predicted localization of maximum shear stress in the lithosphere. A probabilistic seismic hazard assessment (PSHA) for the region is presented in terms of various ground motion parameters on the utilization of Fourier amplitude spectra used in engineering practice and risk assessment (peak ground acceleration, response spectra amplitude, and seismic intensity). We review the PSHA carried out in the region, and present new PSHA results for the eastern and southern parts of Romania. Our seismic hazard assessment is based on the information about the features of earthquake ground motion excitation, seismic wave propagation (attenuation), and site effect in the region. Spectral models and characteristics of site-response on earthquake ground motions are obtained from the regional ground motion data including several hundred records of small and large earthquakes. Results of the probabilistic seismic hazard assessment are consistent with the features of observed earthquake effects in the southeastern Carpathians and show that geological factors play an important part in the distribution of the earthquake ground motion parameters. [ABSTRACT FROM AUTHOR]

The paper describes an integrated approach to seismic hazard assessment, which was applied for the Taiwan region. First, empirical modelsfor ground motion estimation in the region were obtained on the basisof records from recent (1993-1999) earthquakes. The databaseincludes strong-motion data collected during the recent Chi-Chiearthquake (M=7.6, 21 September 1999) and large (M=6.8)aftershocks. The ground-motion database was also used for evaluationof generalised site amplification functions for typical soil classes(B, C and D). Second, the theoretical seismic catalogue (2001–2050)for the Taiwan region had been calculated using the 4D-model(location, depth, time) for dynamic deformation of the Earth' crustand 5D-model (location, depth, time, magnitude) for seismic process.The models were developed on the basis of available geophysical andgeodynamic data that include regional seismic catalogue. Third, theregion & site & time-dependent seismic analysis, which is basedon schemes of probable earthquake zones evaluated from the theoreticalcatalogue, regional ground motion models, and local site responsecharacteristics, has been performed. The seismic hazard maps arecompiled in terms of Peak Ground Acceleration (PGA) and ResponseSpectra (RS) amplitudes. The maps show distribution of amplitudesthat will not be exceeded with certain probability in condition oftypical soil classes during all possible earthquakes that may occur inthe region during time period of 2003–2025. The approach allowsintroducing new parameter that describes dependency of seismichazard on time, so-called ''period of maximum hazard''. Theparameter shows the period, during which every considered sitewill be subjected by the maximum value of ground motioncharacteristic (PGA or RS). [ABSTRACT FROM AUTHOR]

This paper surveys the classification of integrable evolution equations whose field variables take values in an associative algebra, which includes matrix, Clifford, and group algebra valued systems. A variety of new examples of integrable systems possessing higher order symmetries are presented. Symmetry reductions lead to an associative algebra-valued version of the Painlevé transcendent equations. The basic theory of Hamiltonian structures for associative algebra-valued systems is developed and the biHamiltonian structures for several examples are found. [ABSTRACT FROM AUTHOR]

Two regional ground-motion models are available at present for western Saudi Arabia, a region that is characterized by considerable seismic activity due to the spreading in the Red Sea and continental volcanism. The first model was created by Sokolov and Zahran (Arab J Geosci 11:38, 2018) using the stochastic simulation technique (Boore in Pure Appl Geoph 160(3):635–676, 2003) and it was reported in tabular form for moment magnitudes (M) from 5 to 7. The second model was developed by Kiuchi et al. (Bull Seismol Soc Am 109:2722–2737, 2019) as mathematical expression (empirical ground motion prediction equation, GMPE) on the basis of records from regional earthquakes with local magnitudes from ML 3 to 5.4. In this work, we first construct a GMPE using stochastic simulation data. This stochastic GMPE considers magnitude, distance and stress drop as input parameters. Second, we compare these two independently developed regional ground-motion models and employ a scheme for the modification of the empirical GMPE up to M 7.5 using the stochastic GMPE as the reference model. The revised GMPEs presented here provide regional ground motion models (PGA and spectral amplitudes at natural periods 0.2 s and 1.0 s) that may be used in logic tree scheme for assessment of seismic hazard in western Saudi Arabia. [ABSTRACT FROM AUTHOR]

Rapid social and industrial development of the Makkah and Jeddah regions emphasizes necessity of reassessment of seismic hazard, results of which are essential for aseismic design, emergency management, and insurance regulations. In this work, the deterministic seismic hazard studies are applied to evaluate level of seismic hazard for the Makkah region using the up-to-date geophysical, geological, and seismological database, and using different techniques. The assessment has been performed in terms of peak ground acceleration (PGA) and presumably active faults are considered as sources of earthquakes. Results of the study show that, in the context of the used models of seismic sources, the level of seismic hazard in the region is controlled by magnitude of earthquakes that may occur at the intersection of NE-SW faults (the Ad Damm fault zone and the Wadi Fatima Shear Zone) and the NNW-oriented faults that run parallel to the Red Sea coast (Red Sea Margin Faults group). It is important to make accurate mapping of faults using up-to-date data and to estimate if the faults are active at present. Particular attention should be given to careful estimation of maximum magnitude of possible earthquakes that can occur along the active fault. [ABSTRACT FROM AUTHOR]

We studied the inhibitory activity of methylene blue (MB) γ-carbolines (gC) conjugates (MB-gCs) against human erythrocyte acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and a structurally related enzyme, porcine liver carboxylesterase (CaE). In addition, we determined the ability of MB-gCs to bind to the peripheral anionic site (PAS) of Electrophorus electricus AChE (EeAChE) and competitively displace propidium iodide from this site. Moreover, we examined the ability of MB-gCs to scavenge free radicals as well as their influence on mitochondrial potential and iron-induced lipid peroxidation. We found that MB-gCs effectively inhibited AChE and BChE with IC50 values in the range 1.73-10.5 μM and exhibited low potencies against CaE (9.8-26% inhibition at 20 μM). Kinetic studies showed that MB-gCs were mixed-type reversible inhibitors of both cholinesterases. Molecular docking results showed that the MB-gCs could bind both to the catalytic active site and to the PAS of human AChE and BChE. Accordingly, MB-gCs effectively displaced propidium from the peripheral anionic site of EeAChE. In addition, MB-gCs were extremely active in both radical scavenging tests. Quantum mechanical DFT calculations suggested that free radical scavenging was likely mediated by the sulfur atom in the MB fragment. Furthermore, the MB-gCs, in like manner to MB, can restore mitochondrial membrane potential after depolarization with rotenone. Moreover, MB-gCs possess strong antioxidant properties, preventing iron-induced lipid peroxidation in mitochondria. Overall, the results indicate that MB-gCs are promising candidates for further optimization as multitarget therapeutic agents for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Earthquake ground motion model is an essential part of seismic hazard assessment. The model consists in several empirical ground motion prediction equations (GMPEs) that are considered to be applicable to the given region. When the recorded ground motion data are scarce, numerical modeling of ground motion based on available seismological information is widely used. We describe results of stochastic simulation of ground motion acceleration records for western Saudi Arabia. The simulation was performed using the finite fault model and considering peak ground acceleration and amplitudes of spectral acceleration at natural frequencies 0.2 and 1.0 s. Based on the parameters of the input seismological model that were accepted in similar previous studies, we analyze influence of variations in the source factor (stress drop) and in the local attenuation and amplification factors (kappa value, crustal amplification). These characteristics of the model are considered as the major contributors to the ground motion variability. The results of our work show that distribution of simulated ground motion parameters versus magnitude and distance reveals an agreement with the GMPEs recently used in seismic hazard assessment for the region. Collection of credible information about seismic source, propagation path, and site attenuation parameters using the regional ground motion database would allow constraining the seismological model and developing regional GMPEs. The stochastic simulation based on regional seismological model may be applied for generation of ground motion time histories used for development of analytical fragility curves for typical constructions in the region. [ABSTRACT FROM AUTHOR]

A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies. [ABSTRACT FROM AUTHOR]

Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions. [ABSTRACT FROM AUTHOR]

The August 17, 1999 Kocaeli earthquake ruptured the earth’s surface along 145 km and produced a magnitude ofM w=7.4. As expected for such an event Modified Mercalli intensities of typically IX and X in the vicinity of the fault were determined. Yet the observed accelerations at the five near-fault sites remained amazingly small with horizontal PGA values of 0.14 g to 0.4 g. We attempt to resolve the enigma by modeling surface ground motion with a finite-difference algorithm, utilizing two different rupture and slip histories derived from the strong-motion observations and ‘translate’ the computed horizontal motion in intensity values. We can show that (a) in a given simple crustal velocity model different slip distributions result in significantly different ground motion distributions in the vicinity of the fault even though both slip distributions fit the observed accelerometer data quite well. (b) Both slip distributions ‘project’ high ground motion into areas adjacent to the fault where no accelerometer was located. (c) Both slip distributions are not fully compatible with observed intensity observations around the fault, although this could be partly attributed to the lack of knowledge regarding to the crustal structure. In the light of our results it would thus be misleading if the few strong-motion observations around the Kocaeli earthquake fault were taken as typical or representative for the entire area and for potential future events. [ABSTRACT FROM AUTHOR]