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Oligomers and fibrils of the amyloid-β (Aβ) peptide are implicated in the pathology of Alzheimer's disease. Here, we monitor the growth of individual Aβ40 fibrils by time-resolved in situ atomic force microscopy and thereby directly measure fibril growth rates. The measured growth rates in a population of fibrils that includes both single protofilaments and bundles of filaments are independent of the fibril thickness, indicating that cooperation between adjacent protofilaments does not affect incorporation of monomers. The opposite ends of individual fibrils grow at similar rates. In contrast to the "stop-and-go" kinetics that has previously been observed for amyloid-forming peptides, growth and dissolution of the Aβ40 fibrils are relatively steady for peptide concentration of 0-10 μM. The fibrils readily dissolve in quiescent peptide-free solutions at a rate that is consistent with the microscopic reversibility of growth and dissolution. Importantly, the bimolecular rate coefficient for the association of a monomer to the fibril end is significantly smaller than the diffusion limit, implying that the transition state for incorporation of a monomer into a fibril is associated with a relatively high free energy. more...

Ubiquitous processes in nature and the industry exploit crystallization from multicomponent environments1–5; however, laboratory efforts have focused on the crystallization of pure solutes6,7 and the effects of single growth modifiers8,9. Here we examine the molecular mechanisms employed by pairs of inhibitors in blocking the crystallization of haematin, which is a model organic compound with relevance to the physiology of malaria parasites10,11. We use a combination of scanning probe microscopy and molecular modelling to demonstrate that inhibitor pairs, whose constituents adopt distinct mechanisms of haematin growth inhibition, kink blocking and step pinning12,13, exhibit both synergistic and antagonistic cooperativity depending on the inhibitor combination and applied concentrations. Synergism between two crystal growth modifiers is expected, but the antagonistic cooperativity of haematin inhibitors is not reflected in current crystal growth models. We demonstrate that kink blockers reduce the line tension of step edges, which facilitates both the nucleation of crystal layers and step propagation through the gates created by step pinners. The molecular viewpoint on cooperativity between crystallization modifiers provides guidance on the pairing of modifiers in the synthesis of crystalline materials. The proposed mechanisms indicate strategies to understand and control crystallization in both natural and engineered systems, which occurs in complex multicomponent media1–3,8,9. In a broader context, our results highlight the complexity of crystal–modifier interactions mediated by the structure and dynamics of the crystal interface., SCOPUS: ar.j, info:eu-repo/semantics/published more...

This study describes the formation of functional organic monolayers on thin, nanoporous silicon nitride membranes. We demonstrate that the vapor-phase carbene insertion into the surface C-H bonds can be used to form sub-5 nm molecular coatings on nanoporous materials, which can be further modified with monolayers of polyethylene glycol (PEG) molecules. We investigate composition, thickness, and stability of the functionalized monolayers and the changes in the membrane permeability and pore size distribution. We show that, due to the low coating thickness (~7 nm), the functionalized membrane retains 80% of the original gas permeance and 40% of the original hydraulic permeability. We also show that the carbene/PEG functionalization is hydrolytically stable for up to 48 h of exposure to water and that it can suppress nonspecific adsorption of the proteins BSA and IgG. Our results suggest that the vapor-phase carbenylation can be used as a complementary technology to the traditional self-assembly and polymer brush chemistries in chemical functionalization of nanoporous materials, which are limited in their ability to serve as stable coatings that do not occlude nanomembrane pores. more...

Malaria is a pervasive disease that affects millions of lives each year in equatorial regions of the world. During the erythrocytic phase of the parasite life cycle, Plasmodium falciparum invades red blood cells, where it catabolizes hemoglobin and sequesters the released toxic heme as innocuous hemozoin crystals. Artemisinin (ART)-class drugs are activated in vivo by newly released heme, which creates a carbon-centered radical that markedly reduces parasite density. Radical damage to parasite lipids and proteins is perceived to be ARTs’ dominant mechanism of action. By contrast, quinoline-class antimalarials inhibit the formation of hemozoin and in this way suppress heme detoxification. Here, we combine malaria parasite assays and scanning probe microscopy of growing β-hematin crystals to elucidate an unexpected mechanism employed by two widely administered antimalarials, ART, and artesunate to subdue the erythrocytic phase of the parasite life cycle. We demonstrate that heme–drug adducts, produced after the radical activation of ARTs and largely believed to be benign bystanders, potently kills P. falciparum at low exogenous concentrations. We show that these adducts inhibit β-hematin crystallization and heme detoxification, a pathway which complements the deleterious effect of radicals generated via parent drug activation. Our findings reveal an irreversible mechanism of heme–ART adduct inhibition of heme crystallization, unique among antimalarials and common crystal growth inhibitors, that opens new avenues for evaluating drug dosing regimens and understanding growing resistance of P. falciparum to ART. more...

Ubiquitous processes in nature and the industry exploit crystallization from multicomponent environments

This study describes the formation of functional organic monolayers on hard and soft interfaces via a vapor-phase carbene insertion into Si–H and C–H bonds. We demonstrate that functional diazirine molecules can be used to form monomolecular coatings on silicon, silicon nitride, and urethane–acrylate polymers under mild vacuum conditions and exposure to UV light. We investigate the molecular coverage and the long-term stability of the resulting monolayers in air, isopropanol, and water. Our results suggest that vapor-phase carbenylation can be used as a complementary technology to the traditional self-assembly, permitting functionalization of various passivated substrates with stable and functional molecular coatings under mild and scalable conditions. more...

For achieving the compensation method which is used for balancing the three-phase unbalanced load by TCR, unbalance factor, phase angle difference of positive and negative sequence component of three-phase voltage should be detected. Accuracy and rapidity of detection is the key factors which affects three-phase unbalance compensation effect. This paper proposes a calculating method of unbalance factor, phase angle difference of positive and negative sequence component of three-phase voltage in the condition of supply voltage unbalance. The method can use dq transformation to achieve the relative parameters by delay sampling voltage to construct PLL signal. Simulation results show that the method can detect the parameters rapidly and accurately. more...

Due to ip-iq current detection method based on instantaneous reactive power theory will produce detecting error when voltage is unbalance, This paper proposed a method which uses the phase angle of positive sequence fundamental voltage to correct the error, Simulation results show that the active and reactive component of positive sequence fundamental current and the active and reactive component of negative sequence fundamental current can be obtained rapidly and accurately. more...

A novel PWM technique for single-switch three-phase AC-DC buck converter is proposed to reject input voltage fluctuation, obtain high quality output voltage and realize open-loop operation mode. By controlling the duty cycle of the switch which tracks the change of input voltage, the energy supplied by ac mains and the energy consumed in load can keep invariable in every switching cycle. So the output dc voltage maintains at a constant value and random-harmonic voltage contained in input stage is eliminated. Based on the principle of energy conservation, the system operation is analyzed and the control strategy is introduced in detail both in discontinuous conduction mode (DCM) and continuous conduction mode (CCM). Experimental results are provided to show its validity and feasibility. more...