A Framework of Paracellular Transport viaNanoparticles-Induced Endothelial Leakiness

Nanomaterial-induced endothelial leakiness (NanoEL) is an interfacial phenomenon denoting the paracellular transport of nanoparticles that is pertinent to nanotoxicology, nanomedicine and biomedical engineering. While the NanoEL phenomenon is complementary to the enhanced permeability and retention effect in terms of their common applicability to delineating the permeability and behavior of nanoparticles in tumoral environments, these two effects significantly differ in scope, origin, and manifestation. In the current study, the descriptors are fully examined of the NanoEL phenomenon elicited by generic citrate-coated gold nanoparticles (AuNPs) of changing size and concentration, from microscopic gap formation and actin reorganization down to molecular signaling pathways and nanoscale interactions of AuNPs with VE-cadherin and its intra/extracellular cofactors. Employing synergistic in silico methodologies, for the first time the molecular and statistical mechanics of cadherin pair disruption, especially in response to AuNPs of the smallest size and highest concentration are revealed. This study marks a major advancement toward establishing a comprehensive NanoEL framework for complementing the understanding of the transcytotic pathway and for guiding the design and application of future nanomedicines harnessing the myriad functions of the mammalian vasculature

Structure-Property Relationship of Amyloidogenic Prion Nanofibrils

The structure and its property for the prion nanofibrils, which exhibit self-assembled steric zipper, amyloid fibrils, are described in this chapter. There is the belief of origin for the infectiousness of the prion can be its molecular structure. It is due to the amyloid toxicity, which is related to its beta sheet rich molecular structure and self-aggregated long fibrils. There is evidence that the difference between PrPc and PrPsc is transitioned beta sheet from alpha helix to self-assemble and then to the amyloidogenic fibrils. Therefore, the scope of this chapter is the amyloidogenic structural characteristics of prion fibrils and its relationship to the property. The molecular structural characteristics can be changed by properties such as affinity, toxicity, infectivity, and so on, so this is a key factor to understand the origin of prion disease and develop the therapeutic strategy. One of the main properties of amyloid fibrils that we want to describe here is mechanical property such as dynamic property and material property for prion nanofibrils. This chapter can shed light on understanding the infectious characteristics of prion and the relationship of its molecular structures

Effects of End-Terminal Capping on Transthyretin (105–115) Amyloid Protofibrils Using Steered Molecular Dynamics

Numerous degenerative diseases are associated with amyloidosis, which can be caused by amyloid proteins. These amyloid proteins are generated from misfolded and denatured amyloid monomers under physiological conditions. Changes in protonation state, pH, ionic strength, and temperature, in addition to mutations, are related to the promotion of amyloidosis. Specifically, an understanding of the mechanical characteristics of amyloid protofibrils is important, since amyloid growth proceeds by a mechanism involving cycles of fragmentation and elongation. However, there remains a lack of knowledge of amyloid structural conformations and their mechanical characteristics, particularly considering end-terminal capping effects. In the present study, we investigated the mechanical characteristics of transthyretin amyloid protein (TTR), which have been implicated in cardiovascular disease, and specifically considered the contribution of end-terminal capping effects. Using steered molecular dynamics (SMD) simulations, we report different structural behaviors between uncapped and capped TTR amyloid protofibrils. We show that end-terminal capping strengthens the structural stability and improves the mechanical properties of amyloid protofibrils. This study provides useful information concerning the structural and mechanical characteristics of TTR amyloid protofibrils, with a particular emphasis on end-terminal capping effects

Internal Interaction Changes Within The Mutation Of Slc26A4 Stas Domain

Pendrin (SLC26A4) is a protein associated with the auditory system. Pendred syndrome (PDS) and DFNB4 are typical auditory disorders caused by mutations in the SLC26A4 STAS domain. We generated an SLC26A4 STAS domain model and six mutated STAS domain models related to PDS, DFNB4, and PDS/DFNB4 by homology modeling. Molecular dynamics simulation was performed to find the equilibration conformation and fluctuation information. Using fluctuation information, we calculated betweenness centrality and edge betweenness to reveal communication between secondary structures of STAS domain. The edge betweenness results showed that mutated models generate communication signals that are less clear than WT models

Emission Characteristics of PM (PMtotal, PM10, PM2.5), NOx, CO and VOCs Emitted from LNG-fired Gas Turbine and Small Domestic Boiler

Abstract In recent years, natural gas is increasingly being used in the heating and power generation sectors as a clean fuel with an aim to reduce air pollution. In this study, a standard test method was used to measure air pollutants and identify emission characteristics for gas turbines and small domestic boilers, which use LNG as fuel. For gas turbines, the air pollutants were measured at 14 sites, whereas for small domestic boilers, six of them were installed in a laboratory to run tests due to limitations in on-site measuring and testing. However, the small domestic boilers were all new machines and were operated for long consecutive hours for testing, meaning that the results could vary from that of on-site boilers. The results show that gas turbines and small domestic boilers not only emit PM2.5, but also particulate matters larger than PM2.5. According to the measurements, the average concentration level of PMtotal, PM10, and PM2.5 generated from gas turbines are 51.8, 38.5, and 28.1 µg/m3 (@O2 15%), respectively. Those generated from small domestic boilers were 31.3, 26.2, and 20.0 µg/m3 (@O2 4%), respectively. The NOx concentration levels complied with the emission limits. Especially where a NOx control device was in place, both the NOx and CO concentration levels were relatively low. However, the NOx and CO concentration levels were generated from small domestic boilers were relatively high, since the emission limits were not applied. VOCs were measured at 10 facilities where 28 samples were collected. The compounds that were identified were Aromatics, Oxygenated VOCs, Alkanes, in that order, which were consistent across the samples. Aromatics consisted mostly of toluene, o,m,p-xylenes, benzene, and ethylbenzene. Among oxygenated VOCs, ethyl acetate, vinyl acetate, and isopropyl alcohol, etc. were identified. In other words, gas turbines generated a wider range and higher concentration levels of VOCs compared to small domestic boilers. The emission factors of gas turbines and small domestic boilers were derived from the measurements, and then compared with the standard emission factors of other countries (NAER, U.S. EPA AP-42, EMEP/EEA). PM emission factors calculated in this study were lower than that of existing emission factors and the calculated NOx emission factors (uncontrolled) for the small boilers were also lower. The CO emission factor for gas turbines was lower than that of existing emission factors, but higher for the small domestic boilers. Emission factors of benzene, toluene, and xylenes, which are hazardous air pollutants, were lower than those of U.S. EPA AP-42

Role of Sequence and Structural Polymorphism on the Mechanical Properties of Amyloid Fibrils

<div><p>Amyloid fibrils playing a critical role in disease expression, have recently been found to exhibit the excellent mechanical properties such as elastic modulus in the order of 10 GPa, which is comparable to that of other mechanical proteins such as microtubule, actin filament, and spider silk. These remarkable mechanical properties of amyloid fibrils are correlated with their functional role in disease expression. This suggests the importance in understanding how these excellent mechanical properties are originated through self-assembly process that may depend on the amino acid sequence. However, the sequence-structure-property relationship of amyloid fibrils has not been fully understood yet. In this work, we characterize the mechanical properties of human islet amyloid polypeptide (hIAPP) fibrils with respect to their molecular structures as well as their amino acid sequence by using all-atom explicit water molecular dynamics (MD) simulation. The simulation result suggests that the remarkable bending rigidity of amyloid fibrils can be achieved through a specific self-aggregation pattern such as antiparallel stacking of β strands (peptide chain). Moreover, we have shown that a single point mutation of hIAPP chain constituting a hIAPP fibril significantly affects the thermodynamic stability of hIAPP fibril formed by parallel stacking of peptide chain, and that a single point mutation results in a significant change in the bending rigidity of hIAPP fibrils formed by antiparallel stacking of β strands. This clearly elucidates the role of amino acid sequence on not only the equilibrium conformations of amyloid fibrils but also their mechanical properties. Our study sheds light on sequence-structure-property relationships of amyloid fibrils, which suggests that the mechanical properties of amyloid fibrils are encoded in their sequence-dependent molecular architecture.</p></div

Mechanical properties of mutated hIAPP fibrils:

<p><b>(a)</b> soft bending rigidity, <b>(b)</b> stiff bending rigidity, <b>(c)</b> torsional shear modulus, and <b>(d)</b> axial elastic modulus. (<b>e</b>) Intermolecular interactions between β sheet layers for wild type hIAPP fibril and mutated fibril of class 5. The hydrogen bond networks colored in red, and the side chain is shown with colored in yellow (hydrogen), red (oxygen), blue (nitrogen) and cyan (carbon).</p

MM-PBSA free energy calculations.

<p>MM-PBSA free energy calculations.</p

Effect of a single point mutation on the equilibrium dynamics of polymorphic hIAPP fibrils.

<p>(<b>a</b>) Conformations of mutated hIAPP fibrils at time of 60 ns obtained from explicit water MD simulation. (<b>b</b>) Root-mean-square distance (RMSD) for mutated fibrils with respect to time. (<b>c</b>) Dihedral angles of mutated hIAPP fibrils as a function of time. (<b>d</b>) Order parameters for mutated fibrils with respect to their polymorphism. (<b>e</b>) Bending angles for mutated fibrils as a function of time.</p