Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies

β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer’s disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is −1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors.     

Analysis of hybrid systems’ dynamics using the common Lyapunov functions and multiple homomorphisms

Consideration was given to the hybrid systems obeying the nonlinear common differential equations with switched right-hand sides and state jumps (pulses). Conditions for availability of dynamic characteristics like stability, attraction, invariance, and boundedness were formulated in terms of the common Lyapunov functions or multiple homomorphisms.     

Elements of the theory and methods of parametric regulation of national economy’s evolution using discrete dynamic stochastic models

For the class of discreet stochastic dynamic systems with additive noise, advances of the theory of parametric regulation were presented. Efficiency of their use was demonstrated by way of the example of a stochastic computable model of general equilibrium of the major industries.     

CSF amyloid-β 1-38 and 1-42 in FTD and AD: Biomarker performance critically depends on the detergent accessible fraction

Cerebrospinal fluid (CSF) Aβ1-38, Aβ1-40, and Aβ1-42 were comparatively analyzed by amyloid-beta SDS-PAGE with Western immunoblot (Aβ-SDS-PAGE/immunoblot), electrochemiluminescence detection and ELISA (MSD/ELISA) in patients with Alzheimer's disease (AD, n?=?40), frontotemporal dementia (FTD, n?=?30), and other dementias (n?=?50) and nondemented disease controls (n?=?30). CSF Aβ-peptide concentrations were higher and selective decreases of CSF Aβ1-38 in FTD and Aβ1-42 in AD were more evident as measured after SDS-denaturizing of samples by Aβ-SDS-PAGE/immunoblot. The SDS-accessible pool of CSF Aβ1-38 and Aβ1-42, represented by the individual gain of Aβ-peptide yield using Aβ-SDS-PAGE/immunoblot, was reduced in both FTD and AD. Accordingly, biomarker accuracies of Aβ1-38 and Aβ1-42 for detection of FTD and AD, respectively declined as determined by MSD/ELISA. We conclude that a pool of CSF Aβ1-38 and Aβ1-42, which shows disease-specific reductions in FTD and AD, may be bound to carriers and can be released by SDS. Assessing this SDS-accessible Aβ-peptide pool may crucially enhance the accuracy of CSF biomarker tests. Identifying disease-specific binding properties of affected Aβ carriers may elucidate pathogenic aspects and open up a novel field for therapeutic approaches.     

Evaluation of reduced point charge models of proteins through Molecular Dynamics simulations: Application to the Vps27 UIM-1–Ubiquitin complex

Reduced point charge models of amino acids are designed, (i) from local extrema positions in charge density distribution functions built from the Poisson equation applied to smoothed molecular electrostatic potential (MEP) functions, and (ii) from local maxima positions in promolecular electron density distribution functions. Corresponding charge values are fitted versus all-atom Amber99 MEPs. To easily generate reduced point charge models for protein structures, libraries of amino acid templates are built. The program GROMACS is used to generate stable Molecular Dynamics trajectories of an Ubiquitin-ligand complex (PDB: 1Q0W), under various implementation schemes, solvation, and temperature conditions. Point charges that are not located on atoms are considered as virtual sites with a nul mass and radius. The results illustrate how the intra- and inter-molecular H-bond interactions are affected by the degree of reduction of the point charge models and give directions for their implementation; a special attention to the atoms selected to locate the virtual sites and to the Coulomb-14 interactions is needed. Results obtained at various temperatures suggest that the use of reduced point charge models allows to probe local potential hyper-surface minima that are similar to the all-atom ones, but are characterized by lower energy barriers. It enables to generate various conformations of the protein complex more rapidly than the all-atom point charge representation.     

Assessment of rainfall and NDVI anomalies in Spain (1989–1999) using distributed lag models

In this study a link was established between anomalies in climatic and Advanced Very High Resolution Radiometer (AVHRR)/Normalized Difference Vegetation Index (NDVI) data in Spain for the period from 1989 to 1999 on a monthly and annual basis using multivariate distributed lag (DL) models and generalized least‐square (GLS) parameter estimation. In most areas significant time‐delayed correlation between anomalies of monthly rainfall and NDVI data was confined to an interval of 1 month. Locally higher lag orders of up to 3 months were found. By contrast, relationships between surface temperature and the NDVI were insignificant in the multivariate context at most locations. The multiple correlation coefficients of the DL models achieved 0.6 in the maximum. Regions characterized by the most significant NDVI–rainfall correlations include the southern forelands of the Pyrenees in Catal?na, rainfed agricultural areas in Extremadura, Andalusia, and the western parts of Castilla y Leon. Average ratios of rainfall to potential evapotranspiration (PET) in the sensitive areas ranged between 0.5 and 2, with annual rainfall amounts less than 700 mm. For each land‐cover class a linear discriminant analysis (LDA) was carried out to assess the environmental factors that might explain the differences in the NDVI–rainfall relationships. The highest discriminant coefficients and factor loadings were recorded for those factors that recurrently trigger water deficit in the sensitive regions, such as low total annual rainfall, large seasonal rainfall variability, high average PET and surface temperature. On the annual basis the lagged correlation of the NDVI and rainfall data was confined to natural vegetation (grassland and scrubland) areas in western Spain. This region suffered from a severe drought in the early 1990s, after which biomass production lagged several years behind improved rainfall conditions. The approach presented is useful for assessing the influence of climatic variables on the pattern of temporal anomalies in the NDVI or related vegetation parameters.     

Elucidating the catalytic mechanism of β-secretase (BACE1): A quantum mechanics/molecular mechanics (QM/MM) approach

In this quantum mechanics/molecular mechanics (QM/MM) study, the mechanisms of the hydrolytic cleavage of the Met2-Asp3 and Leu2-Asp3 peptide bonds of the amyloid precursor protein (WT-substrate) and its Swedish mutant (SW) respectively catalyzed by β-secretase (BACE1) have been investigated by explicitly including the electrostatic and steric effects of the protein environment in the calculations. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely acknowledged as a promising therapeutic target. The general acid-base mechanism followed by the enzyme proceeds through the following two steps: (1) formation of the gem-diol intermediate and (2) cleavage of the peptide bond. The formation of the gem-diol intermediate occurs with the barriers of 19.6 and 16.1 kcal/mol for the WT- and SW-substrate respectively. The QM/MM energetics predict that with the barriers of 21.9 and 17.2 kcal/mol for the WT- and SW-substrate respectively the cleavage of the peptide bond occurs in the rate-determining step. The computed barriers are in excellent agreement with the measured barrier of ∼18.0 kcal/mol for the SW-substrate and in line with the experimental observation that the cleavage of this substrate is sixty times more efficient than the WT-substrate.     

Application of the Exp-function method to the (2+1)-dimensional Boiti–Leon–Pempinelli equation using symbolic computation

This paper deals with the so-called Exp-function method for studying a particular nonlinear partial differential equation (PDE): the (2+1)-dimensional Boiti–Leon–Pempinelli equation. The method is constructive and can be carried out in a computer with the aid of a computer algebra system. The obtained generalized solitary wave solutions contain more arbitrary parameters compared with the earlier works, and thus, they are wider. This means that our method is effective and powerful for constructing exact and explicit analytic solutions to nonlinear PDEs.     

Analysis of phenological change patterns using 1982–2000 Advanced Very High Resolution Radiometer (AVHRR) data

Using the National Oceanic & Atmospheric Administration (NOAA) National Aeronautics & Space Administration (NASA) Pathfinder Land dataset (PAL data) from 1982–2000, vegetation phenology (onset, peak and offset) was defined and analysed with climate data. In areas of precipitation-dependent phenology such as Central Africa, it was found that Normalized Difference Vegetation Index (NDVI) is affected approximately 20–40 days after the occurrence of precipitation, depending on land cover types. In areas of temperature-dependent phenology such as Siberia, the relationship of phenology and latitude/elevation was investigated. Using temporal NDVI data of 1982–2000, changes in seasonal NDVI pattern were classified into 11 classes and mapped in the Northern Hemisphere. From this analysis, increasing trends of the annual sum of NDVI were found in Siberia, NE Europe and the northern part of North America where good correspondence with the increasing trend of air temperature was recognized. In contrast, some areas such as the east of the Aral Sea showed a decreasing trend of the annual sum of NDVI. It was found that, in the Northern Hemisphere, the area with increasing trend of the annual sum of NDVI is approximately 12 times larger than the area with the decreasing trend. Also, it was found that areas of increasing/decreasing trend of the annual sum of NDVI correspond roughly to areas with increasing/decreasing trend of air temperature from 1982 to 1995.     

Quantum Surface of Section Method: Decomposition of the Resolvent (E - Ĥ)-1

The paper presents the exact surface of section reduction of quantum mechanics. The main theoretical result is a decomposition of the energy-dependent propagator (E) = (E - )-1 in terms of the propagators which (also or exclusively) act in Hilbert space of complex-valued functions over the configurational surface of section, which has one dimension less than the original configuration space. These energy-dependent quantum propagators from and/or onto the configurational surface of section can be explicitly constructed as the solutions of the first order nonlinear Riccati-like initial value problems.     

Conformational changes of Aβ (1–42) monomers in different solvents

Amyloid proteins are known to be the main cause of numerous degenerative and neurodegenerative diseases. In general, amyloids are misfolded from monomers and they tend to have β-strand formations. These misfolded monomers are then transformed into oligomers, fibrils, and plaques. It is important to understand the forming mechanism of amyloids in order to prevent degenerative diseases to occur. Aβ protein is a highly noticeable protein which causes Alzheimer’s disease. It is reported that solvents affect the forming mechanism of Aβ amyloids. In this research, Aβ_1–42 was analyzed using an all-atom MD simulation with the consideration of effects induced by two disparate solvents: water and DMSO. As a result, two different conformation changes of Aβ_1–42 were exhibited in each solvent. It was found that salt-bridge of Asp23 and Lys28 in Aβ_1–42 was the key for amyloid folding based on the various analysis including hydrogen bond, electrostatic interaction energy and salt-bridge distance. Since this salt-bridge region plays a crucial role in initiating the misfolding of Aβ_1–42, this research may shed a light for studies related in amyloid folding and misfolding.     

Remote sensing of the terrestrial environment using middle infrared radiation (3.0–5.0 µm)

The middle infrared (MIR) spectral region, between 3.0 and 5.0?µm in the electromagnetic spectrum, features a myriad of atmospheric windows. The favourable atmospheric penetration of electromagnetic radiation at MIR wavelengths has been readily noted. To exploit this atmospheric window, there have been several remote sensing instruments acquiring radiation from the terrestrial environment. However, these data remain under-utilized for terrestrial environmental studies. The principal reason for this is the hybrid nature of this spectral region, as it comprises a combination of both reflected and emitted radiation during daytime measurement. Despite this, there are many attributes of the MIR spectral region that should encourage its use. Studies focusing on a wide range of terrestrial environment characteristics using MIR radiation have advocated that these data be used. Moreover, there has been a progressive maturation of the methods for processing the radiation acquired by instruments in the MIR spectral region, allowing the informed use of the unique information provided by this part of the spectrum. In particular, these methods have allowed the retrieval of MIR reflectance from the full MIR radiation acquired by a sensor and this information has been demonstrated to be particularly useful for the study of the terrestrial environment and its change. It would appear that the full potential of MIR radiation is unrealized. This paper is a review that aims to motivate and advise of future research using MIR radiation, and in particular MIR reflectance. The paper outlines the physical principles determining MIR radiation interactions with the terrestrial environment; reviews current status of processing methods of MIR radiation to retrieve MIR reflectance; and how the retrieved data have been used. In conclusion, future research priorities are suggested.     

Study of the Radio Frequency (RF) performance of a Wafer-Level Package (WLP) with Through Silicon Vias (TSVs) for the integration of RF-MEMS and micromachined waveguides in the context of 5G and Internet of Things (IoT) applications: Part 1—validation of the 3D modelling approach

Microsystem Technologies - Packaging of Radio Frequency MicroElectroMechanical-Systems (RF-MEMS) and other passive components is a delicate issue, especially in the riverbed of upcoming application...     

Multivariate Analysis of Biomechanical Profiles for the Coracobrachialis and Biceps Brachii (Caput Breve) Muscles in Humans∗

A multivariate analysis of various biomechanical parameters for the muscles coracobrachialis and biceps brachii (caput breve) was conducted for two groups of human subjects while they practiced a skill acquisition task conducted over a period of time and at different subject-to-target distances. Practice at different distances had no effect on either muscle. Comparisons of pre- and post-test data indicated that the biomechanical parameters were altered as a function of practice or increased time spent at the task. A specific statistical comparison of these two morphologically similar muscles indicated significant differences in their response profiles. Lastly, practice had a differential effect on the activity of the two muscles.     

Log-Linear Convergence and Divergence of the Scale-Invariant (1+1)-ES in Noisy Environments

Noise is present in many real-world continuous optimization problems. Stochastic search algorithms such as Evolution Strategies (ESs) have been proposed as effective search methods in such contexts. In this paper, we provide a mathematical analysis of the convergence of a (1+1)-ES on unimodal spherical objective functions in the presence of noise. We prove for a multiplicative noise model that for a positive expected value of the noisy objective function, convergence or divergence happens depending on the infimum of the support of the noise. Moreover, we investigate convergence rates and show that log-linear convergence is preserved in presence of noise. This result is a strong theoretical foundation of the robustness of ESs with respect to noise.