Influence of the β‐Sheet Content on the Mechanical Properties of Aggregates during Amyloid Fibrillization

Amyloid fibrils associated with neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, consist of insoluble aggregates of α‐synuclein and Aβ‐42 proteins with a high β‐sheet content. The aggregation of both proteins occurs by misfolding of the monomers and proceeds through the formation of intermediate oligomeric and protofibrillar species to give the final fibrillar cross‐β‐sheet structure. The morphological and mechanical properties of oligomers, protofibrils, and fibrils formed during the fibrillization process were investigated by thioflavin T fluorescence and circular dichroism in combination with AFM peak force quantitative nanomechanical technique. The results reveal an increase in the Young’s modulus during the transformation from oligomers to mature fibrils, thus inferring that the difference in their mechanical properties is due to an internal structural change from a random coil to a structure with increased β‐sheet content.     

Site-Specific Hyperphosphorylation Inhibits,Rather than Promotes,Tau Fibrillization,Seeding Capacity,and Its Microtubule Binding

The consistent observation of phosphorylated tau in the pathology of Alzheimer's disease has contributed to the emergence of a model where hyperphosphorylation triggers both tau disassociation from microtubules and its subsequent aggregation. Herein, we applied a total chemical synthetic approach to site-specifically phosphorylate the microtubule binding repeat domain of tau (K18) at single (pS356) or multiple (pS356/pS262 and pS356/pS262/pS258) residues. We show that hyperphosphorylation of K18 inhibits 1) its aggregation in vitro, 2) its seeding activity in cells, 3) its binding to microtubules, and 4) its ability to promote microtubule polymerization. The inhibition increased with increasing the number of phosphorylated sites, with phosphorylation at S262 having the strongest effect. Our results argue against the hyperphosphorylation hypothesis and underscore the importance of revisiting the role of site-specific hyperphosphorylation in regulating tau functions in health and disease.     

On Legendre polynomial approximation with the VIM or HAM for numerical treatment of nonlinear fractional differential equations

The variational iteration method and the homotopy analysis method, as alternative methods, have been widely used to handle linear and nonlinear models. The main property of the methods is their flexibility and ability to solve nonlinear equations accurately and conveniently. This paper deals with the numerical solutions of nonlinear fractional differential equations, where the fractional derivatives are considered in Caputo sense. The main aim is to introduce efficient algorithms of variational iteration and homotopy analysis methods that can be simply used to deal with nonlinear fractional differential equations. In these algorithms, Legendre polynomials are effectively implemented to achieve better approximation for the nonhomogeneous and nonlinear terms that leads to facilitate the computational work. The proposed algorithms are capable of reducing the size of calculations, improving the accuracy and easily overcome the difficulty arising in calculating complicated integrals. Numerical examples are examined to show the efficiency of the algorithms.     

Kinetic and theoretical studies on the protonation of [Ni(2-SC6H4N){PhP(CH2CH2PPh2)2}]+: nitrogen versus sulfur as the protonation site

The complexes [Ni(4-Spy)(triphos)]BPh(4) and [Ni(2-Spy)(triphos)]BPh(4) {triphos = PhP(CH(2)CH(2)PPh(2))(2), 4-Spy = 4-pyridinethiolate, 2-Spy = 2-pyridinethiolate} have been prepared and characterized both spectroscopically and using X-ray crystallography. In both complexes the triphos is a tridentate ligand. However, [Ni(4-Spy)(triphos)](+) comprises a 4-coordinate, square-planar nickel with the 4-Spy ligand bound to the nickel through the sulfur while [Ni(2-Spy)(triphos)](+) contains a 5-coordinate, trigonal-bipyramidal nickel with a bidentate 2-Spy ligand bound to the nickel through both sulfur and nitrogen. The kinetics of the reactions of [Ni(4-Spy)(triphos)](+) and [Ni(2-Spy)(triphos)](+) with lutH(+) (lut = 2,6-dimethylpyridine) in MeCN have been studied using stopped-flow spectrophotometry, and the two complexes show very different reactivities. The reaction of [Ni(4-Spy)(triphos)](+) with lutH(+) is complete within the deadtime of the stopped-flow apparatus (2 ms) and corresponds to protonation of the nitrogen. However, upon mixing [Ni(2-Spy)(triphos)](+) and lutH(+) a reaction is observed (on the seconds time scale) to produce an equilibrium mixture. The mechanistic interpretation of the rate law has been aided by the application of MSINDO semiempirical and ADF calculations. The kinetics and calculations are consistent with the reaction between [Ni(2-Spy)(triphos)](+) and lutH(+) involving initial protonation of the sulfur followed by dissociation of the nitrogen and subsequent transfer of the proton from sulfur to nitrogen. The factors affecting the position of protonation and the coupling of the coordination state of the 2-pyridinethiolate ligand to the site of protonation are discussed.     

Metal-Chelating Nanopolymers for Antibody Purification from Human Plasma

The purification of immunoglobulin G (IgG) from human plasma was performed by using a novel metal-chelated adsorbent with nano size. The non-porous nanoparticles were produced by surfactant free emulsion polymerization of ethylene glycol dimethacrylate (EDMA) and 2-methacryloylamidohistidine (MAH). Then, Cu(II) ions were chelated on the nanoparticles. The nano-poly(EDMA-MAH) nanoparticles were characterized by Fourier transform infrared, scanning electron microscope, atomic force microscope and elemental analysis. The non-porous nanoparticles were spherical form and have 100?C250?nm size distribution. The maximum IgG adsorption capacity of the Cu(II) chelated nanoparticles was found to be 463?mg/g polymer at pH 7.0 in HEPES buffer. Desorption of IgG was performed by 1.0?M NaCl and desorption rate was found to be 97?%. IgG was obtained from human plasma with purity of 94?% (up to 578?mg/g polymer). The non-porous nanoparticles allowed one-step purification of IgG from human plasma.     

Improvement of the bit error rate of a non-coherent OCDMA system for FTTH network applications

In this paper, an optical code division multiple access (OCDMA) system was analysed to improve the bit error rate (BER) performance at 10 Gbps. The improvements to this system were based on a modified double weight code and a NAND subtraction technique and aimed to support the large number of active users in the fibre-to-the-home network. The system performance was investigated through extensive theoretical and numerical simulation analyses. The theoretical and simulation results revealed that the new detection technique exhibits improved BER performance compared to conventional techniques, such as complimentary subtraction techniques. The system performance was characterised by the signal-to-noise ratio, the bit error rate (BER), and various transmit powers ( $P_{sr} - 10$  dBm). The results show that the proposed system, which is based on a new detection technique, can achieve the optimal BER with a high number of users and maintains the error floor transmission rate $(\le 10^{-9})$ .     

In vivo lipid diffusion coefficient measurements in rat bone marrow

The diffusion coefficient of lipids, D_l, within bone marrow, fat deposits and metabolically active intracellular lipids in vivo will depend on several factors including the precise chemical composition of the lipid distribution (chain lengths, degree of unsaturation, etc.) as well as the temperature. As such, D_l may ultimately prove of value in assessing abnormal fatty acid distributions linked to diseases such as cystic fibrosis, diabetes and coronary heart disease. A sensitive temperature dependence of D_l may also prove of value for MR-guided thermal therapies for bone tumors or disease within other fatty tissues like the breast. Measuring diffusion coefficients of high molecular weight lipids in vivo is, however, technically difficult for a number of reasons. For instance, due to the much lower diffusion coefficients compared to water, much higher b factors than those used for central nervous system applications are needed. In addition, the pulse sequence design must incorporate, as much as possible, immunity to motion, susceptibility and chemical shift effects present whenever body imaging is performed. In this work, high b-factor line scan diffusion imaging sequences were designed, implemented and tested for D_l measurement using a 4.7-T horizontal bore animal scanner. The gradient set available allowed for b factors as high as 0.03 μs/nm² (30,000 s/mm²) at echo times as short as 42 ms. The methods were used to measure lipid diffusion coefficients within the marrow of rat paws in vivo, yielding lipid diffusion coefficients approximately two orders of magnitude smaller than typical tissue water diffusion coefficients. Phantom experiments that demonstrate the sensitivity of lipid diffusion coefficients to chain length and temperature were also performed.     

Single Posttranslational Modifications in the Central Repeat Domains of Tau4 Impact its Aggregation and Tubulin Binding

A variety of methods have been employed to study the impact of posttranslational modifications on Tau protein function. Here, a semisynthesis strategy is described that enables selective modification within the central repeat domain of Tau4 (residues 291‐321), comprising a major interaction motive with tubulin as well as one of the key hexapeptides involved in Tau aggregation. This strategy has led to the preparation of four semisynthetic Tau variants with phosphoserine residues in different positions and one with a so far largely ignored carboxymethyllysine modification that results from a non‐enzymatic posttranslational modification (nPTM). The latter modification inhibits tubulin polymerization but exhibits an aggregation behavior very similar to unmodified Tau. In contrast, phosphorylated Tau variants exhibit similar binding to tubulin as unmodified Tau4 but show lower tendencies to aggregate.     

Degradation of dissolved diazinon pesticide in water using the high frequency of ultrasound wave

This article aims to apply the ultrasound technique in the field of clean technology to protect environment. The principle of sonochemistry is conducted here to degrade pesticides in simulated industrial wastewater resulted from a factory manufacturing pesticides namely diazinon. Diazinon pesticide selected in this study for degradation under high frequency ultrasound wave. Three different initial concentrations of diazinon (800, 1200, and 1800 ppm), at different solution volumes were investigated in to degrade dissolved diazinon in water. Ultrasound device with 1.7 MHz, and 0.044 cm diameter, was used to study the degradation process.

It is found that as the concentration of diazinon increased, the degradation is also increasing, and when the solution volume increases, the ability to degraded pesticides decreases. The experimental results showed an optimum condition achieved for degradation of diazinon at 1200 ppm as initial concentration and 50 ml solution volume. Kinetic modeling applied for the obtained results showed that the degradation of diazinon by high ultrasound frequency wave followed a pseudo-first-order model with apparent rate constant of around of 0.01 s⁻¹.     

Isolation,Identification and Pharmacological Effects of Mandragora autumnalis Fruit Flavonoids Fraction

Since ancient times, Mandragora autumnalis has been used as a traditional medicinal plant for the treatment of numerous ailments. In light of this, the current study was designed to isolate and identify the chemical constituents of the flavonoids fraction from M. autumnalis ripe fruit (FFM), and evaluate its DPPH scavenging, anti-lipase, cytotoxicity, antimicrobial and antidiabetic effects. An ethyl acetate extract of M. autumnalis was subjected to a sequence of silica gel column chromatography using different eluents with various polarities. The chemical structures of the isolated compounds were identified using different spectral techniques, including ¹H NMR and ¹³C NMR. FFM’s anti-diabetic activity was assessed using a glucose transporter-4 (GLUT4) translocation assay, as well as an inhibition against α-amylase and α-glucosidase using standard biochemical assays. The FFM anti-lipase effect against porcine pancreatic lipase was also evaluated. Moreover, FFM free radical scavenging activity using the DPPH test and antimicrobial properties against eight microbial strains using the micro-dilution method were also assessed. Four flavonoid aglycones were separated from FFM and their chemical structures were identified. The structures of the isolated compounds were established as kaempferol 1, luteolin 2, myricetin 3 and (+)-taxifolin 4, based on NMR spectroscopic analyses. The cytotoxicity test results showed high cell viability (at least 90%) for up to 1 mg/mL concentration of FFM, which is considered to be safe. A dose-dependent increase in GLUT4 translocation was significantly shown (p < 0.05) when the muscle cells were treated with FFM up to 0.5 mg/mL. Moreover, FFM revealed potent α-amylase, α-glucosidase, DPPH scavenging and porcine pancreatic lipase inhibitory activities compared with the positive controls, with IC₅₀ values of 72.44 ± 0.89, 39.81 ± 0.74, 5.37 ± 0.41 and 39.81 ± 1.23 µg/mL, respectively. In addition, FFM inhibited the growth of all of the tested bacterial and fungal strains and showed the greatest antibacterial activity against the K. pneumoniae strain with a MIC value of 0.135 µg/mL. The four flavonoid molecules that constitute the FFM have been shown to have medicinal promise. Further in vivo testing and formulation design are needed to corroborate these findings, which are integral to the pharmaceutical and food supplement industries.