Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates

Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer"s disease (AD), where the overproduction and aggregation of the β-amyloid peptide (Aβ) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (Aβ aggregation) phases of the disease. Dual inhibitors of Aβ aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of Aβ aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic Aβ peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multi-target anti-Alzheimer compounds that exhibit both Aβ aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of Aβ aggregation inhibitors that rely on the overexpression of Aβ42 alone or fused with reporter proteins in Escherichia coli.

High capacity audio watermarking using the high frequency band of the wavelet domain

This paper proposes a novel high capacity robust audio watermarking algorithm by using the high frequency band of the wavelet decomposition at which the human auditory system (HAS) is not very sensitive to alteration. The main idea is to divide the high frequency band into frames and, for embedding, to change the wavelet samples depending on the average of relevant frame¿s samples. The experimental results show that the method has a very high capacity (about 11,000 bps), without significant perceptual distortion (ODG in [¿1 ,0] and SNR about 30dB), and provides robustness against common audio signal processing such as additive noise, filtering, echo and MPEG compression (MP3).

Free Open Source Software and Dual-Use: Loophole or Dissent?

The Free Open Source Software (FOSS) seem far from the military field but in some cases, some technologies normally used for civilian purposes may have military applications. These products and technologies are called dual-use. Can we manage to combine FOSS and dual-use products? On one hand, we have to admit that this kind of association exists - dual-use software can be FOSS and many examples demonstrate this duality - but on the other hand, dual-use software available under free licenses lead us to ask many questions. For example, the dual-use export control laws aimed at stemming the proliferation of weapons of mass destruction. Dual-use export in United States (ITAR) and Europe (regulation 428/2009) implies as a consequence the prohibition or regulation of software exportation, involving the closing of source code. Therefore, the issues of exported softwares released under free licenses arises. If software are dual-use goods and serve for military purposes, they may represent a danger. By the rights granted to licenses to run, study, redistribute and distribute modified versions of the software, anyone can access the free dual-use software. So, the licenses themselves are not at the origin of the risk, it is actually linked to the facilitated access to source codes. Seen from this point of view, it goes against the dual-use regulation which allows states to control these technologies exportation. For this analysis, we will discuss about various legal questions and draft answers from either licenses or public policies in this respect.

Sea state effect on the sea surface emissivity at L-band

In May 1999, the European Space Agency (ESA) selected the Earth Explorer Opportunity Soil Moisture and Ocean Salinity (SMOS) mission to obtain global and frequent soil moisture and ocean salinity maps. SMOS' single payload is the Microwave Imaging Radiometer by Aperture Synthesis (MIRAS), an L-band two-dimensional aperture synthesis radiometer with multiangular observation capabilities. At L-band, the brightness temperature sensitivity to the sea surface salinity (SSS) is low, approximately 0.5 K/psu at 20/spl deg/C, decreasing to 0.25 K/psu at 0/spl deg/C, comparable to that to the wind speed /spl sim/0.2 K/(m/s) at nadir. However, at a given time, the sea state does not depend only on local winds, but on the local wind history and the presence of waves traveling from far distances. The Wind and Salinity Experiment (WISE) 2000 and 2001 campaigns were sponsored by ESA to determine the impact of oceanographic and atmospheric variables on the L-band brightness temperature at vertical and horizontal polarizations. This paper presents the results of the analysis of three nonstationary sea state conditions: growing and decreasing sea, and the presence of swell. Measured sea surface spectra are compared with the theoretical ones, computed using the instantaneous wind speed. Differences can be minimized using an "effective wind speed" that makes the theoretical spectrum best match the measured one. The impact on the predicted brightness temperatures is then assessed using the small slope approximation/small perturbation method (SSA/SPM).

A two-dimensional doppler-radiometer for earth observation

Compared to synthetic aperture radars (SARs), the angular resolution of microwave radiometers is quite poor. Traditionally, it has been limited by the physical size of the antenna. However, the angular resolution can be improved by means of aperture synthesis interferometric techniques. A narrow beam is synthesized during the image formation processing of the cross-correlations measured at zero-lag between pairs of signals collected by an array of antennas. The angular resolution is then determined by the maximum antenna spacing normalized to the wavelength (baseline). The next step in improving the angular resolution is the Doppler-Radiometer, somehow related to the super-synthesis radiometers and the Radiometer-SAR. This paper presents the concept of a three-antenna Doppler-Radiometer for 2D imaging. The performance of this instrument is evaluated in terms of angular/spatial resolution and radiometric sensitivity, and an L-band illustrative example is presented.

General electromagnetic simulation tool to predict the microwave nonlinear response of planar, arbitrarily-shaped HTS structures

This work describes a simulation tool being developed at UPC to predict the microwave nonlinear behavior of planar superconducting structures with very few restrictions on the geometry of the planar layout. The software is intended to be applicable to most structures used in planar HTS circuits, including line, patch, and quasi-lumped microstrip resonators. The tool combines Method of Moments (MoM) algorithms for general electromagnetic simulation with Harmonic Balance algorithms to take into account the nonlinearities in the HTS material. The Method of Moments code is based on discretization of the Electric Field Integral Equation in Rao, Wilton and Glisson Basis Functions. The multilayer dyadic Green's function is used with Sommerfeld integral formulation. The Harmonic Balance algorithm has been adapted to this application where the nonlinearity is distributed and where compatibility with the MoM algorithm is required. Tests of the algorithm in TM010 disk resonators agree with closed-form equations for both the fundamental and third-order intermodulation currents. Simulations of hairpin resonators show good qualitative agreement with previously published results, but it is found that a finer meshing would be necessary to get correct quantitative results. Possible improvements are suggested.

Contact force transitions in regrasp tasks of planar objects

This paper presents a simple and fast solution to the problem of finding the time variations of the forces that keep the object equilibrium when a finger is removed from a three contact point grasp or a finger is added to a two contact point grasp, assuming the existence of an external perturbation force (that can be the object weight itself). The procedure returns force set points for the control system of a manipulator device in a regrasping action. The approach was implemented and a numerical example is included in the paper to illustrate how it works.

Reconstruction of the join time-delay Doppler-scale reflectivity density in the wide-band regime. A frame theory based approach

The inverse scattering problem concerning the determination of the joint time-delayDoppler-scale reflectivity density characterizing continuous target environments is addressed by recourse to the generalized frame theory. A reconstruction formula,involving the echoes of a frame of outgoing signals and its corresponding reciprocalframe, is developed. A ‘‘realistic’’ situation with respect to the transmission ofa finite number of signals is further considered. In such a case, our reconstruction formula is shown to yield the orthogonal projection of the reflectivity density onto a subspace generated by the transmitted signals.

Compact thermal storage: a-state-of-the-art review of experimental results

Thermal energy storage (TES) can increase the thermal energy effieresa, of a process by reusing the waste heat from industrial process, solar energy or other sources. There are different ways to store thermal energy: by sensible heat, by latest heat, by sorption process or by chemical reaction. This thesrs provides a-state-of-the-art review of the experimental performance of TES systems based on solid gas sorption process and chemical reactions. The importance of theses processes is that provides a heat loss free storage system with a high energy density.

An activator/repressor dual system allows tight tetracycline-regulated gene expression in budding yeast

We have developed an activator/repressor expression system for budding yeast in which tetracyclines control in opposite ways the ability of tetR-based activator and repressor molecules to bind tetO promoters. This combination allows tight expression of tetO-driven genes, both in a direct (tetracycline-repressible) and reverse (tetracycline-inducible) dual system. Ssn6 and Tup1, that are components of a general repressor complex in yeast, have been tested for their repressing properties in the dual system, using lacZ and CLN2 as reporter genes. Ssn6 gives better results and allows complete switching-off of the regulated genes, although increasing the levels of the Tup1-based repressor by expressing it from a stronger promoter improves repressing efficiency of the latter. Effector-mediated shifts between expression and non-expression conditions are rapid. The dual system here described may be useful for the functional analysis of essential genes whose conditional expression can be tightly controlled by tetracyclines.

Supergravity models of (3+1)-dimensional QCD

The most general black M5-brane solution of eleven-dimensional supergravity (with a flat R4 spacetime in the brane and a regular horizon) is characterized by charge, mass and two angular momenta. We use this metric to construct general dual models of large-N QCD (at strong coupling) that depend on two free parameters. The mass spectrum of scalar particles is determined analytically (in the WKB approximation) and numerically in the whole two-dimensional parameter space. We compare the mass spectrum with analogous results from lattice calculations, and find that the supergravity predictions are close to the lattice results everywhere on the two dimensional parameter space except along a special line. We also examine the mass spectrum of the supergravity Kaluza-Klein (KK) modes and find that the KK modes along the compact D-brane coordinate decouple from the spectrum for large angular momenta. There are however KK modes charged under a U(1)×U(1) global symmetry which do not decouple anywhere on the parameter space. General formulas for the string tension and action are also given.

The membrane-permeable calmodulin inhibitors (W-7/W-13) bind to membranes changing the electrostatic surface potential. Dual effect of W-13 on EGFR activation

Membrane-permeable calmodulin inhibitors, such as the napthalenesulfonamide derivatives W-7/W-13, trifluoperazine, and calmidazolium, are used widely to investigate the role of calcium/calmodulin (Ca2+/CaM) in living cells. If two chemically different inhibitors (e.g. W-7 and trifluoperazine) produce similar effects, investigators often assume the effects are due to CaM inhibition. Zeta potential measurements, however, show that these amphipathic weak bases bind to phospholipid vesicles at the same concentrations as they inhibit Ca 2 /CaM; this suggests that they also bind to the inner leaflet of the plasma membrane, reducing its negative electrostatic surface potential. This change will cause electrostatically bound clusters of basic residues on peripheral (e.g. Src and K-Ras4B) and integral (e.g. epidermal growth factor receptor (EGFR)) proteins to translocate from the membrane to the cytoplasm. We measured inhibitor-mediated translocation of a simple basic peptide corresponding to the calmodulin-binding juxtamembrane region of the EGFR on model membranes; W-7/W-13 causes translocation of this peptide from membrane to solution, suggesting that caution must be exercised when interpreting the results obtained with these inhibitors in living cells. We present evidence that they exert dual effects on autophosphorylation of EGFR;W-13 inhibits epidermal growth factordependent EGFR autophosphorylation under different experimental conditions, but in the absence of epidermal growth factor, W-13 stimulates autophosphorylation of the receptor in four different cell types. Our interpretation is that the former effect is due toW-13inhibition of Ca 2 /CaM, but thelatter results could be due to binding of W-13 to the plasma membrane.

Health-related quality of life in patients with dual diagnosis: clinical correlates

Background: Although the studies published so far have found an affectation in the Health Related Quality of Life (HRQOL) in both psychiatric and substance use dependence disorders, very few studies have applied HRQOL as an assessment measure in patients suffering both comorbid conditions, or Dual Diagnosis. The aim of the current study was to assess HRQOL in a group of patients with Dual Diagnosis compared to two other non-comorbid groups and to determine what clinical factors are related to HRQOL. Methods: Cross-sectional assessment of three experimental groups was made through the Short Form 36 Item Health Survey (SF-36). The sample consisted of a group with Dual Diagnosis (DD; N=35), one with Severe Mental Illness alone (SMI; N=35) and another one with Substance Use Dependence alone (SUD; N=35). The sample was composed only by males. To assess the clinical correlates of SF-36 HRQOL, lineal regression analyses were carried out. Results: The DD group showed lower scores in most of the subscales, and in the mental health domain. The group with SUD showed in general a better state in the HRQOL while the group with SMI held an intermediate position with respect to the other two groups. Daily medication, suicidal attempts and daily number of coffees were significantly associated to HRQOL, especially in the DD group. Conclusions: The DD group showed lower self-reported mental health quality of life. Assessment of HRQOL in dual patients allows to identify specific needs in this population, and may help to establish therapeutic goals to improve interventions.

The valence band alignment at ultrathin SiO2/Si interfaces

High resolution x-ray photoelectron spectroscopy has been used to determine the valence band alignment at ultrathin SiO2/Si interfaces. In the oxide thickness range 1.6-4.4 nm the constant band-offset values of 4.49 and 4.43 eV have been obtained for the dry SiO2/Si(100) and the wet SiO2/Si(100) interfaces, respectively. The valence band alignment of dry SiO2/Si(111) (4.36 eV) is slightly smaller than the case of the dry SiO2/Si(100) interface.

All-sky search algorithms for monochromatic signals in bar gravitational wave detector data

In this paper we design and develop several filtering strategies for the analysis of data generated by a resonant bar gravitational wave (GW) antenna, with the goal of assessing the presence (or absence) therein of long-duration monochromatic GW signals, as well as the eventual amplitude and frequency of the signals, within the sensitivity band of the detector. Such signals are most likely generated in the fast rotation of slightly asymmetric spinning stars. We develop practical procedures, together with a study of their statistical properties, which will provide us with useful information on the performance of each technique. The selection of candidate events will then be established according to threshold-crossing probabilities, based on the Neyman-Pearson criterion. In particular, it will be shown that our approach, based on phase estimation, presents a better signal-to-noise ratio than does pure spectral analysis, the most common approach.